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DIGOXIN

Evaluaciones de DRUGDEX

OVERVIEW
1) Class a) This drug is a member of the following class(es): Antiarrhythmic Cardiac Glycoside Cardiovascular Agent Digitalis Glycoside Inotropic Agent 2) Dosing Information a) Adult 1) Atrial fibrillation a) loading dose, 0.25 mg IV/ORALLY every 2 hours up to 1.5 mg MAX; maintenance dose, 0.125 to 0.375 mg IV/ORALLY daily (guideline dosing) [60] b) (tablet) for rapid digitalization, give total loading dose of 10 to 15 mcg/kg ORALLY; administer one-half of total loading dose initially, followed by onefourth of the total loading dose every 4 to 8 hours twice; for daily maintenance doses or for gradual digitalization, give 3.4 to 5.1 mcg/kg ORALLY once daily; titrate every 2 weeks (manufacturer dosing) [2] 2) Heart failure a) (IV) for rapid digitalization, give loading dose of 0.4 to 0.6 mg IV; additional doses of 0.1 to 0.3 mg IV may be given cautiously at 6- to 8-hour intervals if necessary to achieve response (a 70-kg person typically requires 0.6 to 1 mg) [1] b) (tablet) for rapid digitalization, give total loading dose of 10 to 15 mcg/kg ORALLY; administer one-half of total loading dose initially, followed by onefourth of the total loading dose every 4 to 8 hours twice; for initial daily maintenance doses or for gradual digitalization, give 3.4 to 5.1 mcg/kg ORALLY once daily; titrate every 2 weeks [2] c) (oral solution) maintenance dose, 3 mcg/kg ORALLY daily, adjust as necessary [3]

b) Pediatric 1) Heart failure a) (IV) for rapid digitalization, (premature infant) 15 to 25 mcg/kg; (full-term) 20 to 30 mcg/kg; (1 to 24 months) 30 to 50 mcg/kg; (2 to 5 years) 25 to 35 mcg/kg; (5 to 10 years) 15 to 30 mcg/kg; (over 10 years) 8 to 12 mcg/kg; for daily maintenance doses or for gradual digitalization, give 20% to 30% of digitalizing dose for premature infants or 25% to 35% of digitalizing dose for all other pediatric patients; give in divided doses for age under 10 years [4] b) (oral solution) loading dose, first dose: give half the total loading dose; subsequent doses: as clinically indicated, give additional fractions of the total loading dose at 4- to 8-hour intervals; TOTAL ORAL loading dose: (premature) 20 to 30 mcg/kg; (full term) 25 to 35 mcg/kg; (1 to 24 months) 35 to 60 mcg/kg; (2 to 5 years) 30 to 45 mcg/kg; (5 to 10 years) 20 to 35 mcg/kg; (over 10 years) 10 to 15 mcg/kg [5] c) (oral solution) maintenance dose, ORALLY (premature) 2.3 to 3.9 mcg/kg twice daily; (full term) 3.8 to 5.6 mcg/kg twice daily; (1 to 24 months) 5.6 to 9.4 mcg/kg twice daily; (2 to 5 years) 4.7 to 6.6 mcg/kg twice daily; (5 to 10 years) 2.8 to 5.6 mcg/kg twice daily; (over 10 years) 3 to 4.5 mcg/kg once daily [5] d) (tablet) 5 to 10 years: for rapid digitalization, give total loading dose of 20 to 45 mcg/kg ORALLY; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 4 to 8 hours twice; for initial daily maintenance doses or for gradual digitalization, give 3.2 to 6.4 mcg/kg ORALLY twice daily [2] e) (tablet) older than 10 years: for rapid digitalization, give total loading dose of 10 to 15 mcg/kg ORALLY; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 4 to 8 hours twice; for initial daily maintenance doses or for gradual digitalization, give 3.4 to 5.1 mcg/kg ORALLY once daily; titrate every 2 weeks [2] 3) Contraindications a) hypersensitivity to digoxin or other digitalis preparations [2] [5] [4] b) ventricular fibrillation [2] [5]

[4] 4) Serious Adverse Effects a) Cardiac dysrhythmia b) Thrombocytopenia 5) Clinical Applications a) FDA Approved Indications 1) Atrial fibrillation 2) Heart failure

DOSING INFORMATION
Drug Properties
A) Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index) B) Synonyms Digoxin C) Physicochemical Properties 1) Molecular Weight a) 780.95 [363] [5] [844] 2) pH a) 6.8 to 7.2 (injection: buffered with 0.17% dibasic sodium phosphate and 0.08% anhydrous citric acid) [844] 3) Solubility a) Practically insoluble in water and in ether; slightly soluble in diluted alcohol (50%) and in chloroform; freely soluble in pyridine [363] [5] [844] . 4) Melting point, above 230 degrees C [363] [844]

Storage and Stability


A) Preparation 1) Intramuscular route a) Intramuscular administration (IM) is not the preferred route; however, if digoxin is administered IM, inject deep into the muscle and follow with massage [1] [4] . b) It is recommended that no more than 500 micrograms (mcg) (2 mL) should be injected into a single site for adults and no more than 200 mcg (2 mL) should be injected into a single site for pediatrics [1] [4] . 2) Intravenous route a) May be administered undiluted or diluted with a 4-fold or greater volume of Sterile Water for Injection (SWFI), 0.9% Sodium Chloride for Injection, or 5% Dextrose for Injection (D5W). Using less than a 4-fold volume of diluent could lead to precipitation of digoxin [1] [4] . b) It is recommended to use digoxin immediately after diluting [4] . c) Do not flush syringe with the parenteral solution after its contents are expelled into an indwelling vascular catheter [1] [4] . d) Slow infusion is preferred over bolus administration. The recommendation is to infuse over at least 5 minutes or longer [1] [4] . 3) Oral route a) Take maintenance doses after morning meals (and after evening meals if giving in divided doses) [111] B) Injection route 1) Solution

a) Store at controlled room temperature, 25 degrees C (77 degrees F); excursions permitted from 15 to 30 degrees C (59 to 86 degrees F). Protect from light [844] . C) Oral route 1) Solution/Tablet a) Store at controlled room temperature, 25 degrees C (77 degrees F); excursions permitted from 15 to 30 degrees C (59 to 86 degrees F). Protect from light [5] . Protect tablets from moisture [363] .

Adult Dosage
Normal Dosage Intramuscular route Atrial fibrillation a) Intramuscular (IM) injection of digoxin can cause severe pain at the injection site, therefore, intravenous administration is preferred. If IM injection is required, administer deep into the muscle followed by massage. Administer no more than 500 microgram (2 mL) into a single injection site [1] . Heart failure a) Intramuscular (IM) injection of digoxin can cause severe pain at the injection site; therefore, intravenous administration is preferred. If IM injection is required, administer deep into the muscle followed by massage. Administer no more than 500 micrograms (2 mL) into a single injection site [1] . Intravenous route Atrial fibrillation a) The American College of Cardiology/American Heart Association/European Society of Cardiology guidelines recommended digoxin loading dose for the management of atrial fibrillation was 0.25 mg intravenously every 2 hours up to 1.5 mg. The recommended daily maintenance dose was 0.125 to 0.375 mg intravenously or orally [65]

. b) Peak digoxin body stores larger than the 8 to 12 mcg/kg (eg, heart failure, normal sinus rhythm) have been used for control of ventricular rate in patients with atrial fibrillation. Doses of digoxin used for the treatment of chronic atrial fibrillation should be titrated to the minimum dose that provides the desired ventricular rate control without causing untoward side effects [1] . c) The maintenance dose should be based on the percentage of peak body stores lost each day through elimination. Daily excretion rates can be calculated from creatinine clearance (CrCl) using the following formula [42] [1] . Maintenance dose = loading dose (ie, peak body stores) x % daily loss/100, where: % daily loss = 14 + creatinine clearance (CrCl) in milliliters/minute (mL/min)/5

Usual daily maintenance dose requirements in micrograms of digoxin injection for estimated peak body stores of 10 microgram/kg [1] : Daily maintenance doses rounded to the nearest 25microgram (mcg) increment Cor CrCl (mL/min/70 kg)** Lean Body Weight (kg (lb)) and Daily Dose (mcg) 50 kg (110 lb) 0 10 20 30 40 50 75 75 100 100 100 125 60 kg (132 lb) 75 100 100 125 125 150 70 kg (154 lb) 100 100 125 150 150 175 80 kg (176 lb) 100 125 150 150 175 200 90 kg (198 lb) 125 150 150 175 200 225 100 kg (220 lb) 150 150 175 200 225 250 22 19 16 14 13 12 Days to Reach SS*

60 70 80 90 100

125 150 150 150 175

150 175 175 200 200

175 200 200 225 250

200 225 250 250 275

225 250 275 300 300

250 275 300 325 350

11 10 9 8 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; Cor CrCl = corrected creatinine clearance; mcg = micrograms; * = if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For adults, if only serum creatinine concentrations (Scr) are available, a corrected CrCl, corrected to 70 kg body weight may be estimated in men as (140 - Age)/Scr. For women, multiply this result by 0.85. Do not use this equation for estimating CrCl in pediatric patients. d) Oral Solution 1) General Dosing Information a) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions and concomitant medications [3] . 2) Maintenance Dosing a) The recommended initial digoxin daily oral dose is 3 micrograms/kg/day. The dose will tend to produce steady-state post-absorptive level of 1 to 2 nanograms/mL in uncompleted patients. although the range around these levels is wide [3] . Heart failure a) General Dosing Information 1) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions and concomitant medications [1] .

2) Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orally [1] . b) Serum Digoxin Concentrations 1) Serum digoxin concentrations ranging from 0.8 to 2 nanograms/milliliter (ng/mL) have corresponded with about two-thirds of adult patients who were considered adequately digitalized without signs of toxicity. Isolated serum concentration measurements are not recommended for determining dosage adjustments. Sampling should be done just before the next scheduled dose or 6 to 8 hours after the last dose, regardless of route of administration. If the patients clinical response does not correspond to the serum digoxin concentration, reevaluate testing procedure, time of sampling, concomitant medications and conditions, or exercise, which can cause acute decreases in serum digoxin concentration due to binding of digoxin to skeletal muscle [1] . c) Rapid Digitalization, Loading Dose Regimen 1) In adult patients with congestive heart failure and normal sinus rhythm, rapid digitalization may be achieved with a loading dose based on projected peak digoxin body stores of 8 to 12 micrograms/kg [1] . 2) The loading dose should be administered in divided doses with approximately one-half of the planned total loading dose given as the first dose. The remaining divided doses of the planned total dose may be administered at 6- to 8-hour intervals, after careful assessment of clinical response before each subsequent dose [1] . a) A single initial intravenous (IV) dose of 400 to 600 microgram (mcg) of digoxin injection usually produces a detectable effect in 5 to 30 minutes that becomes maximal in 1 to 4 hours. Additional doses of 100 to 300 mcg may be given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate effect is noted. The usual dose of digoxin injection is 600 to 1000 mcg for a 70-kg patient required to achieve 8- to 12-mcg/kg peak body stores

[1] . d) Maintenance Dosing 1) In controlled, clinical trials in patients with heart failure, maintenance doses of digoxin ranged from 125 to 500 micrograms (mcg) once daily based on patient age, ideal/lean body weight and renal function. Treatment was generally titrated at 250 mcg once daily for patients under age 70 years and with good renal function. Doses may be increased every 2 weeks based on clinical response [43] . 2) The maintenance dose should be based on the percentage of peak body stores lost each day through elimination. Daily excretion rates can be calculated from creatinine clearance (CrCl) using the following formula [1] [42] . Maintenance dose = loading dose (ie, peak body stores) x % daily loss/100, where: % daily loss = 14 + creatinine clearance (CrCl) in milliliters/minute (mL/min)/5

Usual daily maintenance dose requirements in micrograms (mcg) of digoxin injection for estimated peak body stores of 10 mcg/kg [1] : Daily maintenance doses rounded to the nearest 25microgram (mcg) increment Cor CrCl (mL/min/70 kg)** Lean Body Weight (kg (lb)) and Daily Dose (mcg) 50 kg (110 lb) 0 10 20 30 75 75 100 100 60 kg (132 lb) 75 100 100 125 70 kg (154 lb) 100 100 125 150 80 kg (176 lb) 100 125 150 150 90 kg (198 lb) 125 150 150 175 100 kg (220 lb) 150 150 175 200 22 19 16 14 Days to Reach SS*

40 50 60 70 80 90 100

100 125 125 150 150 150 175

125 150 150 175 175 200 200

150 175 175 200 200 225 250

175 200 200 225 250 250 275

200 225 225 250 275 300 300

225 250 250 275 300 325 350

13 12 11 10 9 8 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; Cor CrCl = corrected creatinine clearance; mcg = micrograms; * = steady state if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For adults, if only serum creatinine concentrations (Scr) are available, a corrected CrCl, corrected to 70 kg body weight may be estimated in men as (140 - Age)/Scr. For women, multiply this result by 0.85. Do not use this equation for estimating CrCl in pediatric patients. 3) If a change of the calculated loading dose is clinically warranted, calculate the maintenance dose based on the actual amount of digoxin administered [1] Conversion To Oral Formulation a) Lanoxicap(R) digoxin capsules have been discontinued by the manufacturer. b) After rapid digitalization with digoxin injection, when converting to oral digoxin formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages with conversion to tablets, capsules, or solution for maintenance therapy [2] [1]

TABLETS* (60% to 80% Bioavailability) Equivalent Doses Tablets Solution Capsule Injection 50 mcg 62.5 mcg 62.5 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg 250 mcg 250 mcg 200 mcg 200 mcg

500 mcg 500 mcg 400 mcg 400 mcg SOLUTION* (70% to 85% Bioavailability) Equivalent Doses Solution Tablet Capsule Injection 50 mcg 62.5 mcg 62.5 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg 250 mcg 250 mcg 200 mcg 200 mcg 500 mcg 500 mcg 400 mcg 400 mcg CAPSULE* (90% to 100% Bioavailability) Equivalent Doses Capsule 50 mcg Tablet Solution Injection 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg 200 mcg 250 mcg 250 mcg 200 mcg 400 mcg 500 mcg 500 mcg 400 mcg INJECTION* (100% Bioavailability) Equivalent Doses Injection Tablet 50 mcg Solution Capsule 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg 200 mcg 250 mcg 250 mcg 200 mcg 400 mcg 500 mcg 500 mcg 400 mcg * Lanoxin(R) brand digoxin

Oral route Atrial fibrillation a) Oral Capsules 1) Important Note a) Lanoxicap(R) digoxin capsules have been discontinued by the manufacturer. b) Due to more complete absorption of digoxin from capsules, the recommended oral doses of digoxin capsules are approximately 80% of those for tablets and solution [43] .

c) Divided daily dosing is presently recommended for patients requiring a daily dose of 300 micrograms or greater, for patients with a previous history of digitalis toxicity, for patients considered likely to become toxic, and patients in whom compliance is not a problem [43] . 2) Serum Digoxin Concentrations a) Serum digoxin concentrations ranging from 0.8 to 2 nanograms/mL have corresponded with about two-thirds of adult patients who were considered adequately digitalized without signs of toxicity. Isolated serum concentration measurements are not recommended for determining dosage adjustments. Sampling should be done just before the next scheduled dose or 6 to 8 hours after the last dose, regardless of route of administration. If the patients clinical response does not correspond to the serum digoxin concentration, reevaluate testing procedure, time of sampling, concomitant medications and conditions, or exercise, which can cause acute decreases in serum digoxin concentration due to binding of digoxin to skeletal muscle [43] . 3) Peak digoxin body stores larger than the 8 to 12 micrograms/kg (eg, heart failure, normal sinus rhythm) have been used for control of ventricular rate in patients with atrial fibrillation. Doses of digoxin capsules used for the treatment of chronic atrial fibrillation should be titrated to the minimum dose that provides the desired ventricular rate control without causing untoward side effects [43] . 4) The maintenance dose should be based on the percentage of peak body stores lost each day through elimination. Daily excretion rates can be calculated from creatinine clearance (CrCl) using the following formula [42] [1] . Maintenance dose = loading dose (ie, peak body stores) x % daily loss/100, where: % daily loss = 14 + creatinine clearance (CrCl) in milliliters/minute (mL/min)/5

Usual daily maintenance dose requirements in micrograms (mcg) of digoxin capsules for estimated peak body stores of 10 mcg/kg [43] . Cor CrCl (mL/min/70 kg)** Lean Body Weight (kg (lb)) and Daily Dose (mcg) 50 kg (110 lb) 0 10 20 30 40 50 60 70 80 90 100 50 60 kg (132 lb) 70 kg (154 lb) 80 100 90 kg kg kg (198 (176 (220 lb) lb) lb) 100 150 150 150 150 150 150 200 200 200 200 250 200 250 250 250 150 150 200 200 250 250 300* 300* 22 19 16 14 13 12 11 10 9 8 7 Days to Reach SS***

100 100

100 100 100 100 100 150 100 150 150 100 150 150 150 150 200 150 150 200 150 200 200 150 200 200 150 200 250 200 200 250

250 300* 300* 250 300* 350* 300 300* 350*

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; mcg = micrograms; Cor CrCl = creatinine clearance; *** = steady state if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For adults, if only serum creatinine concentrations (Scr) are available, a corrected CrCl, corrected to 70 kg body weight may be estimated in men as (140 - Age)/Scr. For women, multiply this result by 0.85. Do not use this equation for estimating CrCl in pediatric patients. * = Divided daily dosing is presently recommended for patients requiring a daily dose of 300 micrograms or greater, for patients with a previous history of digitalis toxicity, for patients considered likely to become toxic and for patients in whom compliance is not a problem. b) Oral Tablets

1) The American College of Cardiology/American Heart Association/European Society of Cardiology guidelines recommended digoxin loading dose for the management of atrial fibrillation was 0.25 mg intravenously every 2 hours up to 1.5 mg. The recommended daily maintenance dose was 0.125 to 0.375 mg intravenously or orally [60] . 2) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions, and concomitant medications [2] . a) Serum Digoxin Concentrations 1) Serum digoxin levels of less than 0.5 nanograms/mL (ng/mL) have been associated with decreased efficacy, while levels greater than 2 ng/mL have been associated with increased toxicity without additional clinical benefit. Isolated serum concentration measurements are not recommended for determining dosage adjustments. Sampling should be done just before the next scheduled dose or at least 6 hours after the last dose [2] . b) Rapid Digitalization, Loading Dose Regimen 1) For rapid digitalization, give a total loading dose of 10 to 15 mcg/kg orally, with one-half of the total loading dose administered initially, followed by one-fourth of the total loading dose every 4 to 8 hours twice [2] . c) Initial Maintenance Dosage or Gradual Digitalization 1) For initial daily maintenance dosage, or for gradual digitalization, give 3.4 to 5.1 mcg/kg orally once daily. Titrate every 2 weeks based on clinical response, serum drug levels, and toxicity [2] . 2) Alternatively, the maintenance dose may be based on the percentage of peak body stores lost each day through elimination. Daily excretion rates can be calculated from creatinine clearance (CrCl) using the following formula [2] [42]

. Maintenance dose = loading dose (ie, peak body stores) x % daily loss/100; where % daily loss = 14 + creatinine clearance (CrCl in mL/min)/5

3) Recommended daily maintenance dosing (in mcg to be given once daily) based on lean body weight and renal function is provided in the following table [2] : Usual daily maintenance dose requirements in micrograms (mcg) Cor CrCl (mL/min/7 0 kg)** Lean Body Weight (kg (lb)) and Daily Dose (mcg) 40 kg (88 lb) 10 20 30 40 50 60 70 80 90 100 50 kg (110 lb) 60 kg (132 lb) 125 125 70 kg (154 lb) 80 kg (176 lb) 90 kg (198 lb) 100 kg (220 lb) 19 16 14 13 12 11 10 9 8 7 Days to Reac h SS*

62.5 125 125 125 125 125 125 125 125

187. 187. 187. 250 5 5 5 187. 187. 250 5 5 250 250 312. 5

187. 187. 250 5 5 250 250

187. 187. 250 5 5 187. 187. 250 5 5 187. 250 5 250 250

312. 312. 5 5 312. 312. 5 5

312. 312. 375 5 5 312. 375 5 375 437. 5

187. 187. 250 5 5 187. 187. 250 5 5 187. 250 5 187. 250 5 250

312. 312. 375 5 5 312. 375 5

437. 437. 5 5 437. 500 5

312. 312. 375 5 5

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; Cor CrCl = corrected creatinine clearance; mcg = micrograms; * = steady state if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For adults, if only serum creatinine concentrations (Scr) are available, a corrected CrCl, corrected to 70 kg body weight may be estimated in men as (140 - Age)/Scr. For women, multiply this result by 0.85. Do not use this equation for estimating CrCl in pediatric patients.

Heart failure a) Oral Tablets 1) General Dosing Information a) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions, and concomitant medications [2] . 2) Serum Digoxin Concentrations a) Serum digoxin levels of less than 0.5 nanograms/mL (ng/mL) have been associated with decreased efficacy, while levels greater than 2 ng/mL have been associated with increased toxicity without additional clinical benefit. Isolated serum concentration measurements are not recommended for determining dosage adjustments. Sampling should be done just before the next scheduled dose or at least 6 hours after the last dose [2] . 3) Rapid Digitalization, Loading Dose Regimen a) For rapid digitalization, give a total loading dose of 10 to 15 mcg/kg orally, with one-half of the total loading dose administered initially, followed by one-fourth of the total loading dose every 4 to 8 hours twice [2] . 4) Initial Maintenance Dosage or Gradual Digitalization a) For initial daily maintenance dosage, or for gradual digitalization, give 3.4 to 5.1 mcg/kg orally once daily.

Titrate every 2 weeks based on clinical response, serum drug levels, and toxicity [2] . b) Alternatively, the maintenance dose may be based on the percentage of peak body stores lost each day through elimination. Daily excretion rates can be calculated from creatinine clearance (CrCl) using the following formula [2] [42] . Maintenance dose = loading dose (ie, peak body stores) x % daily loss/100; where % daily loss = 14 + creatinine clearance (CrCl in mL/min)/5

c) The recommended daily maintenance dosing (in mcg, to be given once daily) based on lean body weight and renal function is provided in the following table [2] :

Usual daily maintenance dose requirements in micrograms (mcg) Cor CrCl (mL/min/70 kg)**

Lean Body Weight (kg (lb)) and Daily Dose (mc 50 kg 40 kg (110 (88 lb) lb) 60 kg (132 lb) 125 125 187.5 187.5 187.5 250 250 250 250 312.5 70 kg (154 lb) 187.5 187.5 187.5 250 250 250 250 312.5 312.5 312.5 80 kg (176 lb) 187.5 187.5 250 250 250 312.5 312.5 312.5 375 375 90 kg (198 lb) 187.5 250 250 312.5 312.5 312.5 375 375 437.5 437.5

1 (2

10 20 30 40 50 60 70 80 90 100

62.5 125 125 125 125 125 187.5 187.5 187.5 187.5

125 125 125 187.5 187.5 187.5 187.5 187.5 250 250

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; corrected creatinine clearance; mcg = micrograms; * = steady st

dose administered; ** = corrected creatinine clearance (CrCl) is C 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For serum creatinine concentrations (Scr) are available, a corrected C to 70 kg body weight may be estimated in men as (140 - Age)/Scr multiply this result by 0.85. Do not use this equation for estimatin pediatric patients.

b) Oral Capsules 1) Important Note a) Lanoxicap(R) digoxin capsules have been discontinued by the manufacturer. b) Due to more complete absorption of digoxin from capsules, the recommended oral doses of capsules are approximately 80% of those for tablets and solution [43] . c) Divided daily dosing is presently recommended for patients requiring a daily dose of 300 micrograms (mcg) or greater, for patients with a previous history of digitalis toxicity, for patients considered likely to become toxic, and for patients in whom compliance is not a problem [43] . 2) General Dosing Information a) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions and concomitant medications [43] . 1) Serum Digoxin Concentrations a) Serum digoxin concentrations ranging from 0.8 to 2 nanograms/mL (ng/mL) have corresponded with about two-thirds of adult patients who were considered adequately digitalized without signs of toxicity. Isolated serum concentration measurements are not recommended for determining dosage adjustments. Sampling should be done just before the next scheduled dose or 6 to 8 hours after the last dose, regardless of route of administration. If the patients clinical response does not correspond to the serum digoxin concentration, reevaluate testing procedure, time of sampling, concomitant medications and conditions, or exercise,

which can cause acute decreases in serum digoxin concentration due to binding of digoxin to skeletal muscle [43] . 3) Rapid Digitalization, Loading Dose Regimen a) In adult patients with congestive heart failure and normal sinus rhythm, rapid digitalization may be achieved with a loading dose based on projected peak digoxin body stores of 8 to 12 micrograms per kilogram (mcg/kg) [43] . b) The loading dose should be administered in divided doses with approximately one-half of the planned total loading dose given as the first dose. The remaining divided doses of the planned total dose may be administered at 6- to 8-hour (hr) intervals, after careful assessment of clinical response before each subsequent dose [43] . 1) A single initial dose of 400 to 600 micrograms (mcg) of digoxin capsules usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2 to 6 hours (hr). Additional doses of 100 to 300 mcg may be given cautiously at 6- to 8-hr intervals until clinical evidence of an adequate effect is noted. The usual dose of digoxin capsules is 600 to 1000 mcg for a 70-kg patient required to achieve 8 to 12 mcg/kg peak body stores [43] . 4) Maintenance Dosing a) Divided daily dosing is presently recommended for patients requiring a daily dose of 300 micrograms or greater, for patients with a previous history of digitalis toxicity, for patients considered likely to become toxic and for patients in whom compliance is not a problem [43] . b) The maintenance dose should be based on the percentage of peak body stores lost each day through elimination. Daily excretion rates can be calculated from creatinine clearance (CrCl) using the following formula [1] [42] .

Maintenance dose = loading dose (ie, peak body stores) x % daily loss/100, where: % daily loss = 14 + creatinine clearance (CrCl) in milliliters/minute (mL/min)/5

Usual daily maintenance dose requirements in micrograms (mcg) of digoxin capsules for estimated peak body stores of 10 mcg/kg [43] . Cor CrCl (mL/min/70 kg)** Lean Body Weight (kg (lb)) and Daily Dose (mcg) 50 kg (110 lb) 0 10 20 30 40 50 60 70 80 90 100 50 60 kg (132 lb) 70 kg (154 lb) 80 100 90 kg kg kg (198 (176 (220 lb) lb) lb) 100 150 150 150 150 150 150 200 200 200 200 250 200 250 250 250 150 150 200 200 250 250 300* 300* 22 19 16 14 13 12 11 10 9 8 7 Days to Reach SS***

100 100

100 100 100 100 100 150 100 150 150 100 150 150 150 150 200 150 150 200 150 200 200 150 200 200 150 200 250 200 200 250

250 300* 300* 250 300* 350* 300 300* 350*

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; mcg = micrograms; Cor CrCl = creatinine clearance; *** = steady state if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For adults, if only serum creatinine concentrations (Scr) are available, a corrected CrCl, corrected to 70 kg body weight may be estimated in men as (140 - Age)/Scr. For women, multiply this result by 0.85. Do not use this equation for estimating CrCl in pediatric patients. * = Divided daily dosing is presently recommended for patients requiring a daily dose of 300 micrograms or greater,

for patients with a previous history of digitalis toxicity, for patients considered likely to become toxic and for patients in whom compliance is not a problem. c) If a change of the calculated loading dose is clinically warranted, calculate the maintenance dose based on the actual amount of digoxin administered [43] . c) Oral Solution 1) General Dosing Information a) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions and concomitant medications [3] . 2) Maintenance Dosing a) The recommended initial digoxin daily oral dose is 3 micrograms/kg/day. The dose will tend to produce steady-state post-absorptive level of 1 to 2 nanograms/mL in uncompleted patients. although the range around these levels is wide [3] . Ideal Body Weight Calculations 1) Most clinicians use ideal body weight instead of lean body weight in estimating the loading dose of digoxin since the calculation is easier. Digoxin is similarly distributed into ideal body weight in obese patients and normal subjects; there is no apparent distribution of digoxin into excess body weight over ideal body weight [86] . 2) Ideal body weight may be estimated using the following formulas [87] : (females) ideal body weight = 48.67 kilograms + 1.65 kilograms per inch over 5 feet

(males) ideal body weight = 51.65 kilograms + 1.85 kilograms per inch over 5 feet

3) In adults, if only serum creatinine levels (Scr) are available, a corrected creatinine clearance (CrCl) (corrected to 70 kg body weight) may be estimated [1] . Males: creatinine clearance (CrCl) = (140 - Age)/serum creatinine (Scr)

Females: creatinine clearance (CrCl) = ((140 - Age)/serum creatinine (Scr)) x 0.85

4) In obese subjects, digoxin loading and maintenance should be calculated on the basis of ideal body weight [86] . 5) The maintenance dose should be based on the percentage of peak body stores lost each day through elimination. Daily excretion rates can be calculated from creatinine clearance (CrCl) using the following formula [42] [1] . Maintenance dose = loading dose (ie, peak body stores) x % daily loss/100, where: % daily loss = 14 + creatinine clearance (CrCl) in milliliters/minute (mL/min/5)

Conversion To Oral Dosage Forms 1) Lanoxicap(R) digoxin capsules have been discontinued by the manufacturer. 2) Typically intravenous digoxin is used to achieve rapid digitalization with conversion to an oral dosage form for maintenance therapy. However, when switching a patient from intravenous to oral digoxin, allowances must be made for differences in bioavailability [2] [1] : TABLETS* (60% to 80% Bioavailability)

Equivalent Doses Tablets Solution Capsule Injection 50 mcg 62.5 mcg 62.5 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg 250 mcg 250 mcg 200 mcg 200 mcg 500 mcg 500 mcg 400 mcg 400 mcg SOLUTION* (70% to 85% Bioavailability) Equivalent Doses Solution Tablet Capsule Injection 50 mcg 62.5 mcg 62.5 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg 250 mcg 250 mcg 200 mcg 200 mcg 500 mcg 500 mcg 400 mcg 400 mcg CAPSULE* (90% to 100% Bioavailability) Equivalent Doses Capsule 50 mcg Tablet Solution Injection 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg 200 mcg 250 mcg 250 mcg 200 mcg 400 mcg 500 mcg 500 mcg 400 mcg INJECTION* (100% Bioavailability) Equivalent Doses Injection Tablet 50 mcg Solution Capsule 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg 200 mcg 250 mcg 250 mcg 200 mcg 400 mcg 500 mcg 500 mcg 400 mcg * Lanoxin(R) brand digoxin

Conversion To Digitoxin 1) Digitoxin has the same pharmacologic actions as digoxin, however, its pharmacokinetic profile does differ. Patients can be converted from digitoxin (half-life, 7 days) to digoxin (half-life, 48 hours) or vice versa. To change drug therapy from maintenance doses of digoxin 0.25 mg daily to digitoxin (assuming a therapeutic digoxin serum concentration

initially, normal renal function and a loading dose of 0.8 mg of digitoxin), the digoxin is stopped abruptly and followed 24 hours later with digitoxin 0.4 mg. This same dose is repeated the next day. On the third day, digitoxin 0.2 mg is administered with subsequent daily doses of 0.1 mg of digitoxin for maintenance therapy. Patients should be monitored for further dosage adjustments. To convert from maintenance digitoxin to digoxin, the digitoxin is stopped for 3 days with the anticipated maintenance dose of digoxin being started on day 4 [88] . Withdrawal Schedule 1) One study reported that in most patients in sinus rhythm with compensated congestive heart failure and ischemic heart disease, digoxin can be withdrawn safely when diuretic and vasodilator treatment is maximized. Only 2 of 24 patients in the study demonstrated an increase in heart failure when digoxin was discontinued [89] . Another study indicated that 108 of 134 patients (81%) did not require digoxin maintenance therapy [90] . Dosage in Renal Failure A) Renal Failure 1) Doses of digoxin should be adjusted in patients with renal impairment because of their higher risk for digoxin toxicity [2] [43] [1] . 2) The dosage of digoxin must be reduced in renal insufficiency (Marcus, 1966). The most reliable indicator of digoxin excretion is creatinine clearance [68] . 3) The volume of distribution (Vd) of digoxin can decrease by as much as 50% in patients with renal failure [93] [94] . However, it is not clear whether or not dosage should be reduced corresponding to the reduced Vd, as tissue uptake (including myocardial uptake) of digoxin is reduced in renal failure [95] . The pharmacologic and clinical effects of this reduced uptake are not clear, but increased digitalis tolerance has been reported in uremic patients [96]

. Some investigators prefer digitoxin over digoxin in renal failure patients, since digitoxin pharmacokinetics are not as affected by impaired renal function [97] [98] [94] [99] . 4) Patients with normal renal function will excrete 35% to 40% of digoxin body stores daily, in contrast to 14% daily elimination of total body stores in anephric patients [42] [94] . B) Loading Dose, Renal Failure 1) Loading doses of 0.5 to 1.25 mg or 0.4 to 0.75 mg/45 kg body weight) can be given to patients with normal or impaired renal function [94] . Since even a small degree of renal failure will decrease the volume of distribution (Vd) of digoxin, adjustments in loading dose should be made. The Vd may be roughly estimated using a linear equation [100] Vd = 4.5 +(0.028 x CrCl) (creatinine clearance) The loading dose may then be estimated with the formula, Dose = Cp (desired serum level) x Vd 2) One study compared 2 groups of renal patients receiving digoxin loading doses of 0.625 mg and 1.25 mg given over 48 hours. Maintenance doses of 0.125 mg were given to both groups. Initial plasma levels reflected the difference in loading doses; however, after 120 hours of maintenance therapy, plasma levels of the 2 groups were comparable [101] . Large loading doses (1.25 mg) may account for arrhythmias seen in early therapy. For patients with creatinine clearance less than 20 mL/min, a loading dose of 0.625 mg and maintenance with 0.125 mg is recommended. C) Maintenance Dose, Renal Failure 1) Recommended daily maintenance dosing (in mcg, to be given once daily) based on lean body weight and renal function is provided in the following table [2] :

Cor CrCl (mL/min/7 0 kg)**

Lean Body Weight (kg (lb)) and Daily Dose (mcg) 40 kg (88 lb) 50 kg (110 lb) 60 kg (132 lb) 125 125 70 kg (154 lb) 80 kg (176 lb) 90 kg (198 lb) 100 kg (220 lb)

Days to Reac h SS*

10 20 30 40 50 60 70 80 90 100

62.5 125 125 125 125 125 125 125 125

187. 187. 187. 250 5 5 5 187. 187. 250 5 5 250 250 312. 5

19 16 14 13 12 11 10 9 8 7

187. 187. 250 5 5 250 250

187. 187. 250 5 5 187. 187. 250 5 5 187. 250 5 250 250

312. 312. 5 5 312. 312. 5 5

312. 312. 375 5 5 312. 375 5 375 437. 5

187. 187. 250 5 5 187. 187. 250 5 5 187. 250 5 187. 250 5 250

312. 312. 375 5 5 312. 375 5

437. 437. 5 5 437. 500 5

312. 312. 375 5 5

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; Cor CrCl = corrected creatinine clearance; mcg = micrograms; * = steady state if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For adults, if only serum creatinine concentrations (Scr) are available, a corrected CrCl, corrected to 70 kg body weight may be estimated in men as (140 - Age)/Scr. For women, multiply this result by 0.85. Do not use this equation for estimating CrCl in pediatric patients.

2) In patients with renal impairment, a dose of 125 micrograms (mcg) (0.125 mg) once daily and at a dose of 62.5 mcg (0.0625 mg) in

patients with marked renal impairment are recommended. Doses may be increased every 2 weeks according to clinical response. [1] . 3) Maintenance doses should replace daily digoxin loss as based upon daily excretion rates [42] . Daily excretion rates can be calculated from creatinine clearance (CrCl) or serum creatinine levels [42] [102] : Maintenance dose = Peak body stores (ie, loading dose) x % daily loss/100 Where: % daily loss = 14 + CrCl milliliters/minute (mL/min)/5 If only serum creatinine levels are available, creatinine clearance (corrected to 70 kg body weight) may be estimated Males: creatinine clearance (CrCl) = (140-age)/serum creatinine (Scr) Females: creatinine clearance (CrCl) = ((140-age)/serum creatinine (Scr)) x 0.85 a) If patients are switched from intravenous to oral dosing, the bioavailability of the dosage forms must be considered [1] . 4) Digitalization may be achieved gradually with administration of a maintenance dose. This dose is based on lean body weight and creatinine clearance. Steady-state levels should be reached within 1 to 3 weeks depending on renal function [1] . 5) One of two methods of dosage adjustment in patients with renal failure have been recommended [103] : a) The dosing interval may be increased as follows: every 24 hours in patients with mild renal failure (glomerular filtration rate (GFR) greater than 50 mL/minute), every 36 hours in moderate renal failure (GFR 10 to 50 mL/minute), and every 48 hours in severe renal failure (GFR less than 10 mL/minute). b) The dose may be reduced as follows: glomerular filtration rate (GFR) 10 to 50 mL/minute, 25% to 75% of the usual dose; GFR less

than 10 mL/minute, 10% to 25% of the usual dose given at the normal dosage interval. 6) A review of the pharmacokinetics of digoxin and other cardiac glycosides in patients with renal insufficiency has been provided [104] . Dosage in Hepatic Insufficiency A) No specific dosage adjustment is necessary in patients with hepatic insufficiency [105] . However, severe impairment of digoxin elimination was reported in 2 patients with combined hepatic and renal disease; the effects of nonrenal excretion mechanisms in reducing elimination were apparent. The presence of hepatic disease superimposed on renal insufficiency may alter the predicted elimination kinetics that are based upon renal function alone [106] . Dosage in Geriatric Patients A) Because the geriatric population is more inclined to have impaired renal function, dosing should be based on renal function [2] [1] [43] . B) Elderly patients appear to have compromised digoxin tolerance and excretion, thus requiring downward dosing adjustment . This appears to be related to reduction in lean body mass and reduction in renal clearance [107] . C) Digitalizing doses should be calculated based on lean body mass and maintenance doses should be calculated using actual creatinine clearance [108] . Dosage Adjustment During Dialysis A) A patient on dialysis is expected to be receiving a digoxin dose based on severe renal failure (ie, glomerular filtration rate less than 10 mL/minute). Since cardiac glycosides are highly tissue bound, additional doses following dialysis do not appear to be necessary [103] [109] [110] . B) Potassium removal with resultant hypokalemia which predisposes to digitalis toxicity is a significant consideration in the patient on dialysis who is receiving digoxin. Many centers use a modest (2 to 3 mEq/L) concentration of potassium in the dialysate for such patients, and report less difficulty in dialyzing digitalized patients.

Dosage in Other Disease States A) Obesity or Edema (Oral Tablets) 1) Dose reductions are necessary when lean weight is an abnormally small fraction of total body mass because of obesity or edema [2] .

Pediatric Dosage
Normal Dosage Intramuscular route Atrial fibrillation a) Intramuscular (IM) injection of digoxin can cause severe pain at the injection site, therefore, intravenous administration is the preferred route. If IM injection is required, administer deep into the muscle followed by massage. Administer no more than 200 microgram (2 mL) into a single injection site [4] . See Drug Consult reference: TREATMENT OF PEDIATRIC SUPRAVENTRICULAR TACHYCARDIAS Heart failure a) Intramuscular (IM) injection of digoxin can cause severe pain at the injection site; therefore, intravenous administration is the preferred route. If IM injection is required, administer deep into the muscle followed by massage. Administer no more than 200 micrograms (2 mL) into a single injection site [4] . Intravenous route Atrial fibrillation a) Peak digoxin body stores larger than the 8 to 12 mcg/kg (heart failure, normal sinus rhythm) have been used for control of ventricular rate in patients with atrial fibrillation. Doses of digoxin tablets used for the treatment of chronic atrial fibrillation should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects [4] . Usual maintenance doses of digoxin injection in pediatrics and children with normal renal function based on lean body weight [4]

Age Premature Infant Full-Term Infant 1 to 24 months 2 to 5 years 5 to 10 years Over 10 years

IV Digitalizing Dose (mcg/kg) 15 to 25 20 to 30 30 to 50 25 to 35 15 to 30 8 to 12

Daily IV Maintenance Dose (mcg/kg)* 20% to 30% of IV digitalizing dose

25% to 35% of IV digitalizing dose**

KEY: mcg = microgram; kg = kilogram; * = intravenous digitalizing doses are 80% of oral digitalizing doses; ** = projected or actual digitalizing dose providing clinical response; IV = intravenous. b) Divided daily dosing is recommended for children under 10 years of age [4] . c) Intravenous (IV) digitalizing doses are 80% of oral digitalizing dose [4] . See Drug Consult reference: TREATMENT OF PEDIATRIC SUPRAVENTRICULAR TACHYCARDIAS Heart failure a) General Dosing Information 1) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions and concomitant medications [4] . 2) Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orally [4] . b) Rapid Digitalization, Loading Dose Regimen

1) In infants and children, rapid digitalization may be achieved with administration of a loading dose based on projected peak digoxin body stores. Peak digoxin body stores of 8 to 12 microgram/kg should provide digitalis effect with minimum risk of toxicity in most patients assuming normal renal function [4] . 2) The loading dose should be administered in divided doses with approximately one-half of the planned total loading dose given as the first dose. The remaining divided doses of the planned total dose may be administered at 6- to 8-hour intervals, after careful assessment of clinical response before each subsequent dose [4] . 3) After rapid digitalization is achieved, conversion to oral formulation can be used for maintenance treatment. Anticipate bioavailability changes upon conversion to oral formulations [4] : Age Premature Infant Full-Term Infant 1 to 24 months 2 to 5 years 5 to 10 years Over 10 years IV Digitalizing Dose (mcg/kg) 15 to 25 20 to 30 30 to 50 25 to 35 15 to 30 8 to 12 Daily IV Maintenance Dose (mcg/kg)* 20% to 30% of IV digitalizing dose

25% to 35% of IV digitalizing dose**

KEY: mcg = microgram; kg = kilogram; * = intravenous digitalizing doses are 80% of oral digitalizing doses; ** = projected or actual digitalizing dose providing clinical response; IV = intravenous.

4) Maximum total intravenous (IV) digitalizing dose in pediatric patients (17 years and younger) should not exceed 1 mg (Anon, 1993).

c) Gradual Digitalization 1) Gradual digitalization may be accomplished starting with an appropriate maintenance dose. Anticipate significant variations in dosages among patients and proceed based on clinical assessment [4] . d) Maintenance Dosing 1) Usual maintenance doses of digoxin injection in infants and children with normal renal function, based on lean body weight [4] : Age Premature Infant Full-Term Infant 1 to 24 months 2 to 5 years 5 to 10 years Over 10 years IV Digitalizing Dose (mcg/kg) 15 to 25 20 to 30 30 to 50 25 to 35 15 to 30 8 to 12 Daily IV Maintenance Dose (mcg/kg)* 20% to 30% of IV digitalizing dose

25% to 35% of IV digitalizing dose**

KEY: mcg = microgram; kg = kilogram; * = intravenous digitalizing doses are 80% of oral digitalizing doses; ** = projected or actual digitalizing dose providing clinical response; IV = intravenous.

2) Divided daily dosing is recommended for children under 10 years of age [4] . 3) Intravenous (IV) digitalizing doses are 80% of oral digitalizing dose [4] . 4) If a change of the calculated loading dose is clinically warranted, calculate the maintenance dose based on the actual amount of digoxin administered [4]

. Oral route Atrial fibrillation a) Oral Solution 1) General Dosing Information a) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions and concomitant medications [6] . 2) Rapid Digitalization, Loading Dose Regimen a) Loading dose (rapid digitalization) is generally used only in urgent situations (eg, treating arrhythmias or acute congestive heart failure). The total digitalizing dose is usually given over 16 to 24 hours as 3 divided doses every 6 to 8 hours [44] [6] . Age Premature infant Loading Dose 20 mcg/kg

Full-term up to 30 mcg/kg 2 mo 2 mo to 2 yr 2 yr to 10 yr 40 to 50 mcg/kg 30 to 40 mcg/kg

Greater than 10 0.75 to 1.5 mg total loading yr dose (adult dose) KEY: mcg/kg = micrograms/kilograms; mg = milligrams; mo = months; yr = years

b) Oral doses should be 25% greater than IV doses [44] . 3) Gradual Digitalization a) A slower digitalization can be accomplished by initiating an appropriate maintenance dose [44] .

4) Maintenance Dosing a) Daily maintenance doses are given twice daily in children 10 years of age and younger and once daily in children older than 10 years [44] [6] . Age Daily Maintenance Dose

Premature infant 5 mcg/kg Full-term up to 2 8 to 10 mcg/kg mo 2 mo to 2 yr 2 yr to 10 yr Greater than 10 yr 10 to 12 mcg/kg 8 to 10 mcg/kg 0.125 to 0.5 mg/kg (adult dose)

KEY: mcg/kg = micrograms/kilograms; mg = milligrams; mo = months; yr = years

b) Maintenance doses are approximately 25% of digitalizing doses [44] . See Drug Consult reference: TREATMENT OF PEDIATRIC SUPRAVENTRICULAR TACHYCARDIAS Heart failure a) Oral Solution 1) General Dosing Information a) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions and concomitant medications [5] . 2) Loading Dose Regimen a) The recommended pediatric loading dose of digoxin oral solution is to give HALF of the total loading dose as a first dose. Subsequent doses, as clinically indicated, give

additional fractions of the total loading dose at 4 to 8 hour intervals [5] : Age premature full-term 1 to 24 months 2 to 5 years over 10 years Total oral loading dose 20 to 30 mcg/kg 25 to 35 mcg/kg 35 to 60 mcg/kg 30 to 45 mcg/kg

5 to 10 years 20 to 35 mcg/kg 10 to 15 mcg/kg

b) Oral doses should be 25% greater than IV doses [44] . 3) Gradual Digitalization a) A slower digitalization can be accomplished by initiating an appropriate maintenance dose [5] [44] . Steady state will be reached after approximately 5 days in patients with normal renal function [5] . 4) Maintenance Dosing a) Digoxin serum levels less than 0.5 nanograms/mL has been associated with diminished efficacy. Levels above 2 nanograms/mL are associated with increased toxicity without increased benefit. Sampling of digoxin levels should be done just prior to the next scheduled dose [5] . b) The recommended maintenance dose or digoxin oral solution in pediatric patients [5] : Age Maintenance Dose, Oral

premature full-term 1 to 24 months 2 to 5 years 5 to 10 years over 10 years

2.3 to 3.9 mcg/kg twice daily 3.8 to 5.6 mcg/kg twice daily 5.6 to 9.4 mcg/kg twice daily 4.7 to 6.6 mcg/kg twice daily 2.8 to 5.6 mcg/kg twice daily 3 to 4.5 mcg/kg once daily

c) Divided doses are recommended in patients less than 10 years of age [5] . d) Maintenance doses are approximately 25% of digitalizing doses [44] . b) Oral Tablets 1) General Dosing Information a) Recommended doses of digoxin will vary based on patient age, ideal/lean body weight, renal function, clinical response, concomitant conditions, and concomitant medications [2] . b) Divided daily dosing is recommended for children under 10 years of age [2] . 2) Rapid Digitalization, Loading Dose Regimen a) For rapid digitalization in children 5 to 10 years of age, give a total loading dose of 20 to 45 mcg/kg orally, with one-half of the total loading dose administered initially, followed by one-fourth of the total loading dose every 4 to 8 hours twice [2] . b) For rapid digitalization in children older than 10 years, give a total loading dose of 10 to 15 mcg/kg orally, with one-half of the total loading dose administered initially,

followed by one-fourth of the total loading dose every 4 to 8 hours twice [2] . 3) Initial Maintenance Dosage or Gradual Digitalization a) For initial daily maintenance doses or for gradual digitalization in children 5 to 10 years, give 3.2 to 6.4 mcg/kg orally twice daily [2] . b) For initial daily maintenance doses or for gradual digitalization in children older than 10 years, give 3.4 to 5.1 mcg/kg orally once daily; titrate every 2 weeks based on clinical response, serum drug concentrations, and toxicity [2] . c) Recommended daily maintenance dosing (in mcg, to be given twice daily) for pediatric patients 5 to 10 years based on lean body weight and renal function is provided in the following table [2] : Cor CrCl (mL/min/70 kg)** Days to Lean Body Weight (kg (lb)) and Reach Daily Dose (mcg) SS* 20 kg 30 kg 50 kg 60 kg 40 kg (44 (66 (110 (132 (88 lb) lb) lb) lb) lb) 10 20 30 40 50 60 70 80 90 100 62.5 62.5 62.5 62.5 125 62.5 62.5 125 62.5 62.5 125 62.5 125 62.5 125 62.5 125 62.5 125 62.5 125 62.5 125 125 125 125 125 125 125 125 187.5 19 16 14 13 12 11 10 9 8 7

187.5 187.5 187.5 187.5 187.5 250

187.5 187.5 250 187.5 187.5 250 187.5 250 187.5 250 250 312.5

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; Cor CrCl = corrected creatinine clearance; mcg = micrograms; * = steady state if no loading dose

administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For pediatrics, the modified Schwartz equation corrected to 1.73 m(2) body surface area may be used.

d) Recommended daily maintenance dosing (in mcg, to be given once daily) for pediatric patients older than 10 years based on lean body weight and renal function is provided in the following table [2] : Cor CrCl (mL/min/7 0 kg)** Days to Reac h SS*

Lean Body Weight (kg (lb)) and Daily Dose (mcg) 40 kg (88 lb) 50 kg (110 lb) 60 kg (132 lb) 125 125 70 kg (154 lb) 80 kg (176 lb) 90 kg (198 lb) 100 kg (220 lb)

10 20 30 40 50 60 70 80 90 100

62.5 125 125 125 125 125 125 125 125

187. 187. 187. 250 5 5 5 187. 187. 250 5 5 250 250 312. 5

19 16 14 13 12 11 10 9 8 7

187. 187. 250 5 5 250 250

187. 187. 250 5 5 187. 187. 250 5 5 187. 250 5 250 250

312. 312. 5 5 312. 312. 5 5

312. 312. 375 5 5 312. 375 5 375 437. 5

187. 187. 250 5 5 187. 187. 250 5 5 187. 250 5 187. 250 5 250

312. 312. 375 5 5 312. 375 5

437. 437. 5 5 437. 500 5

312. 312. 375 5 5

KEY: kg = kilograms; lb = pounds; mL = milliliters; min =

minute; Cor CrCl = corrected creatinine clearance; mcg = micrograms; * = steady state if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For pediatrics, the modified Schwartz equation corrected to 1.73 m(2) body surface area may be used.

Atrial flutter See Drug Consult reference: TREATMENT OF PEDIATRIC SUPRAVENTRICULAR TACHYCARDIAS Ectopic atrial tachycardia See Drug Consult reference: TREATMENT OF PEDIATRIC SUPRAVENTRICULAR TACHYCARDIAS His Bundle (junctional ectopic) tachycardia See Drug Consult reference: TREATMENT OF PEDIATRIC SUPRAVENTRICULAR TACHYCARDIAS Re-entrant atrial tachycardia See Drug Consult reference: TREATMENT OF PEDIATRIC SUPRAVENTRICULAR TACHYCARDIAS Wolff-Parkinson-White syndrome See Drug Consult reference: TREATMENT OF PEDIATRIC SUPRAVENTRICULAR TACHYCARDIAS General Dosing Information 1) Injection contains propylene glycol 40% and alcohol 10% [4] . 2) Digoxin injection can be administered undiluted or diluted with a 4fold or greater volume. It is important if diluting the digoxin to use the appropriate volume to avoid precipitation and to use the diluted solution immediately [4] . 3) Unless oral dosing is precluded, intravenous dosing provides little clinical benefit since full onset of action from this route will not be apparent for up to 6 hours. Intramuscular injections may be given but are seldom justified and are extremely painful. Digitalization with

loading dose regimens are usually only necessary in the management of arrhythmias or acute congestive failure. Non-acute conditions are best managed using the gradual digitalization/maintenance dose approach. Serum levels should be monitored weekly until stabilized, with samples drawn immediately prior to a dose, but at least 6 to 8 hours after the previous dose. Therapeutic range is 0.8 to 2 nanogram per milliliter, but with great individual variation possible for the expression of both clinical benefit or toxicity [4] [91] . Conversion To Oral Dosage Forms 1) Lanoxicap(R) digoxin capsules have been discontinued by the manufacturer. 2) Typically intravenous digoxin is used to achieve rapid digitalization with conversion to an oral dosage form for maintenance therapy. However, when switching a patient from intravenous to oral digoxin, allowances must be made for differences in bioavailability [2] [1] : TABLETS* (60% to 80% Bioavailability) Equivalent Doses Tablets Solution Capsule Injection 50 mcg 62.5 mcg 62.5 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg 250 mcg 250 mcg 200 mcg 200 mcg 500 mcg 500 mcg 400 mcg 400 mcg SOLUTION* (70% to 85% Bioavailability) Equivalent Doses Solution Tablet Capsule Injection 50 mcg 62.5 mcg 62.5 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg 250 mcg 250 mcg 200 mcg 200 mcg 500 mcg 500 mcg 400 mcg 400 mcg CAPSULE* (90% to 100% Bioavailability) Equivalent Doses Capsule 50 mcg Tablet Solution Injection 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg 200 mcg 250 mcg 250 mcg 200 mcg 400 mcg 500 mcg 500 mcg 400 mcg INJECTION* (100% Bioavailability) Equivalent Doses Injection Tablet 50 mcg Solution Capsule 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg 200 mcg 250 mcg 250 mcg 200 mcg 400 mcg 500 mcg 500 mcg 400 mcg * Lanoxin(R) brand digoxin

Drug Resistance 1) One study reported that the observed resistance to digoxin in infants and in children is not related to bacterial inactivation by gut flora. Excretion of large amounts of cardioinactive digoxin metabolites was not observed in patients younger than 9 years of age. Therefore, the capacity to inactivate digoxin in vivo develops gradually. In this study, children were colonized with intestinal bacteria that were capable of metabolizing the drug as early as the second week of life, with the adult frequency of colonization being achieved by 2 years of age and the adult pattern of metabolism being achieved at adolescence. Other mechanisms appear to be responsible for the increased digoxin dosage requirements in infants and children [92] . Dosage in Renal Failure A) Renal Failure 1) Because renal clearance is decreased in the newborn and pronounced in premature infants, dosage adjustments are recommended [4] [3] . 2) The dosage of digoxin must be reduced in renal insufficiency (Marcus, 1966). The most reliable indicator of digoxin excretion is creatinine clearance [68] . 3) The volume of distribution (Vd) of digoxin can decrease by as much as 50% in patients with renal failure [93]

[94] . However, it is not clear whether or not dosage should be reduced corresponding to the reduced Vd, as tissue uptake (including myocardial uptake) of digoxin is reduced in renal failure [95] . The pharmacologic and clinical effects of this reduced uptake are not clear, but increased digitalis tolerance has been reported in uremic patients [96] . Some investigators prefer digitoxin over digoxin in renal failure patients, since digitoxin pharmacokinetics are not as affected by impaired renal function [97] [98] [94] [99] . 4) Patients with normal renal function will excrete 35% to 40% of digoxin body stores daily, in contrast to 14% daily elimination of total body stores in anephric patients [42] [94] . B) Maintenance Dose, Renal Failure 1) Recommended daily maintenance dosing (in mcg, to be given twice daily) for pediatric patients 5 to 10 years based on lean body weight and renal function is provided in the following table [2] : Cor CrCl (mL/min/70 kg)** Days to Lean Body Weight (kg (lb)) and Reach Daily Dose (mcg) SS* 20 kg 30 kg 50 kg 60 kg 40 kg (44 (66 (110 (132 (88 lb) lb) lb) lb) lb) 10 20 30 40 50 60 70 80 62.5 62.5 62.5 62.5 125 62.5 62.5 125 62.5 62.5 125 62.5 125 62.5 125 62.5 125 62.5 125 125 125 125 125 125 125 125 187.5 19 16 14 13 12 11 10 9

187.5 187.5 187.5 187.5 187.5 250

187.5 187.5 250 187.5 187.5 250

90 100

62.5 125 62.5 125

187.5 250 187.5 250

250 312.5

8 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; Cor CrCl = corrected creatinine clearance; mcg = micrograms; * = steady state if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For pediatrics, the modified Schwartz equation corrected to 1.73 m(2) body surface area may be used.

2) Recommended daily maintenance dosing (in mcg to be given once daily) for children older than 10 years based on lean body weight and renal function is provided in the following table [2] : Cor CrCl (mL/min/7 0 kg)** Days to Reac h SS*

Lean Body Weight (kg (lb)) and Daily Dose (mcg) 40 kg (88 lb) 50 kg (110 lb) 60 kg (132 lb) 125 125 70 kg (154 lb) 80 kg (176 lb) 90 kg (198 lb) 100 kg (220 lb)

10 20 30 40 50 60 70 80 90

62.5 125 125 125 125 125 125 125 125

187. 187. 187. 250 5 5 5 187. 187. 250 5 5 250 250 312. 5

19 16 14 13 12 11 10 9 8

187. 187. 250 5 5 250 250

187. 187. 250 5 5 187. 187. 250 5 5 187. 250 5 250 250

312. 312. 5 5 312. 312. 5 5

312. 312. 375 5 5 312. 375 5 375 437. 5

187. 187. 250 5 5 187. 187. 250 5 5 187. 250 250

312. 312. 375 5 5 312. 375

437. 437.

5 100 187. 250 5

5 312. 312. 375 5 5

5 7

437. 500 5

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minute; Cor CrCl = corrected creatinine clearance; mcg = micrograms; * = steady state if no loading dose administered; ** = corrected creatinine clearance (CrCl) is CrCl corrected to 70 kilogram (kg) body weight or 1.73 m(2) body surface area. For pediatrics, the modified Schwartz equation corrected to 1.73 m(2) body surface area may be used.

3) Maintenance doses should replace daily digoxin loss as based upon daily excretion rates [42] . Daily excretion rates can be calculated from creatinine clearance (CrCl) or serum creatinine levels [42] [102] : Maintenance dose = Peak body stores (ie, Loading dose) x % daily loss/100 Where: % daily loss = 14 + creatinine clearance (CrCl) milliliters/minute (mL/min)/5 a) If patients are switched from intravenous to oral dosing, the bioavailability of the dosage forms must be considered [1] . 4) Digitalization may be achieved gradually with administration of a maintenance dose. This dose is based on lean body weight and creatinine clearance. Steady-state levels should be reached within 1 to 3 weeks depending on renal function [1] . 5) One of two methods of dosage adjustment in patients with renal failure have been recommended [103] : a) The dosing interval may be increased as follows: every 24 hours in patients with mild renal failure (glomerular filtration rate (GFR) greater than 50 mL/minute), every 36 hours in moderate renal failure (GFR 10 to 50 mL/minute), and every 48 hours in severe renal failure (GFR less than 10 mL/minute).

b) The dose may be reduced as follows: glomerular filtration rate (GFR) 10 to 50 mL/minute, 25% to 75% of the usual dose; GFR less than 10 mL/minute, 10% to 25% of the usual dose given at the normal dosage interval. Dosage in Hepatic Insufficiency A) No specific dosage adjustment is necessary in patients with hepatic insufficiency [105] . However, severe impairment of digoxin elimination was reported in 2 patients with combined hepatic and renal disease; the effects of nonrenal excretion mechanisms in reducing elimination were apparent. The presence of hepatic disease superimposed on renal insufficiency may alter the predicted elimination kinetics that are based upon renal function alone [106] . Dosage Adjustment During Dialysis A) No specific dosage adjustment necessary during dialysis [109] [103] since cardiac glycosides are highly tissue bound [110] . B) Potassium removal with resultant hypokalemia which predisposes to digitalis toxicity is a significant consideration in the patient on dialysis who is receiving digoxin. Many centers use a modest (2 to 3 mEq/L) concentration of potassium in the dialysate for such patients, and report less difficulty in dialyzing digitalized patients. Dosage in Other Disease States A) Obesity or Edema (Oral Tablets) 1) Dose reductions are necessary when lean weight is an abnormally small fraction of total body mass because of obesity or edema [2] .

PHARMACOKINETICS
Onset and Duration
A) Onset 1) Initial Response a) ORAL, tablet, capsule, or elixir: 30 minutes to 2 hours [776] [777] . b) INTRAVENOUS: 5 to 30 minutes [778]

[777] . c) INTRAMUSCULAR: 30 minutes to 2 hours [778] . 2) Peak Response a) ORAL, tablet, capsule, or elixir: within 2 to 6 hours [776] [777] . b) INTRAVENOUS: 1.5 to 4 hours [778] [779] . c) INTRAMUSCULAR: 2 to 6 hours [778] .

Drug Concentration Levels


A) Therapeutic Drug Concentration 1) The therapeutic serum levels range from 0.8 to 2 ng/mL [776] [780] . a) A post hoc analysis based on data from the Digitalis Investigation Group (DIG) trial suggested that serum digoxin concentrations (SDC) in the range of 0.5 to 0.8 ng/mL may be associated with reduced all-cause mortality and hospitalization compared with SDCs of 0.9 ng/mL and above for men with heart failure (left ventricular ejection fraction below 46%). Data were stratified according to 3 digoxin serum levels: 0.5 to 0.8 ng/mL (n=572), 0.9 to 1.1 ng/mL (n=322); or 1.2 ng/mL and above (n=277). Subjects were followed for mean 37 months. Rates of all cause mortality were 29.9%, 38.8%, and 48.0% for the groups according to serum levels, 0.5 to 0.8, 0.9 to 1.1, and 1.2 ng/mL and over, respectively (p=0.006 for trend). The patients with the highest digoxin concentrations (1.2 ng/mL and above) had 11.8% and 11.5% more all-cause deaths and cardiovascular deaths, respectively, than the placebo group [781] . b) Drug levels should be drawn during the post-absorptive, post-distributive phase of drug elimination, ie, during the 8 to 24 hour interval following the previous dose [782] . c) Plasma levels are significantly lower and urinary excretion levels are significantly higher in patients that are hyperthyroid

[783] . d) There are no controlled clinical trials which have established a therapeutic digoxin serum level for the management of neonatal supraventricular tachycardia. e) Studies in pregnant women [784] [785] and in adults with renal impairment [786] who were not receiving digoxin have demonstrated false positive digoxin values on most assays. f) The serum of neonates not receiving digoxin contains a digoxin-like immunoreactive substance (DLIS) which confounds measurement of therapeutic serum levels in neonates who receive digoxin. Studies also demonstrate lot-to-lot variability with immunoassay kits and day-to-day variation in DLIS levels appear to preclude serum measurement prior to administration of digoxin to obtain a base-line level. It has been speculated that DLIS may be coming from the fetal adrenal cortex since involution of the fetal adrenal cortex appears to coincide with peak levels of DLIS and there is some similarity between the structure of digoxin and adrenal corticosteroids [787] [788] [789] [790] [791] . g) According to 1 study, there is no correlation between hair and blood digoxin concentrations. However, determination of digoxin in hair is a rapid and inexpensive method to screen for the presence or absence of digoxin [792] .

ADME
Absorption A) Bioavailability 1) ORAL, tablets: 60% to 80% [776] . a) Absorption from tablets is reported to be 60% to 80%, as compared to 70% to 85% with the pediatric elixir and by the intramuscular route. Although some gastric absorption is reported, the major site of absorption is the small intestine [793] [794]

. Impaired absorption has been reported due to mucosal abnormalities, gastrointestinal irradiation, alteration in gastrointestinal motility and neomycin [795] . b) Tablets and elixir are approximately 80% as bioavailable as the capsule (90% to 100%) and IV (100%) formulations [776] . Bioavailability problems have been documented with oral administration of products from various manufacturers [777] [779] . Bioavailability is not dependent on dose [796] . 2) INTRAMUSCULAR: incomplete and erratic absorption [797] . B) Effects of Food 1) Reduces absorption [776] . a) Administration with meals reduces the rate of absorption, but the total amount absorbed is usually unchanged. However, oral administration with meals high in bran fiber may reduce the extent of absorption [776] . Distribution A) Distribution Sites 1) Protein Binding a) 20% to 25% [776] . 2) OTHER DISTRIBUTION SITES a) TISSUES, good [800] 1) Highest levels occur in heart muscle, kidneys, and liver [801] . Digoxin also distributes to red blood cells [800] .

B) Distribution Kinetics 1) Volume of Distribution a) large 4 to 7 L/kg [776] [802] [803] . 1) Vd is proportional to lean body mass, with muscular individuals having a larger Vd than obese individuals based on body weight [776] [803] . 2) Vd is increased in hyperthyroid patients but is reduced in the presence of hypothyroidism and impaired renal function [804] [805] . Vd can decrease by as much as 50% in patients with renal failure [806] . A significantly smaller Vd at steady state in severe renal failure (creatinine clearance less than 10 mL/min) was confirmed using fluorescence polarization immunoassay [807] . 3) In the ELDERLY, the volume of distribution may be reduced, which could increase serum concentrations [802] . Metabolism A) Metabolism Sites and Kinetics 1) LIVER, 16% [776] . a) There does not appear to be any significant difference between digoxin capsules and tablets with respect to the drug's metabolism in the elderly [808] . b) The metabolism of digoxin is not dependent upon the cytochrome P450 system. Digoxin is not known to induce or inhibit the cytochrome P-450 system [776] . B) Metabolites 1) Digoxigenin bisdigitoxoside, (active)

[809] . 2) Digoxigenin monodigitoxoside, (active) [809] . Excretion A) Kidney 1) Renal Excretion (%) a) 57% to 80% [809] [810] [811] . 2) Excretion of unchanged drug is by glomerular filtration without significant reabsorption by the renal tubule. Single IV dose studies report 57% to 80% of the administered dose is excreted in urine within 6 to 12 hours [809] [810] [811] . Approximately 30% to 35% of total body stores of digoxin are excreted unchanged in the urine daily [806] . 3) Although digoxin renal clearance correlates with creatinine clearance and somewhat with increasing urinary output, diuresis does not appear to significantly increase digoxin excretion [793] . 4) Urinary excretion was similar whether administered by rapid IV bolus over 3 to 5 minutes, or the same dose by constant IV infusion over 1 hour [812] . 5) Urinary excretion of digoxin increases and fecal excretion decreases in elderly subjects with hypochlorhydria (HC). In 1 study involving 10 elderly subjects, urinary excretion of digoxin increased from 37% of the dose in normochlorhydric (NC) subjects to 46% in HC subjects, whereas fecal excretion decreased from 29% in NC subjects to 14% in HC subjects. The altered route of excretion in subjects with HC may be the result of decreased hydrolysis of digoxin by stomach acid and increased intestinal metabolism [813] . B) Other 1) OTHER EXCRETION

a) BILE, 6% to 8% [820] [821] . 1) Biliary excretion with enterohepatic recycling is reported to be approximately 6% to 8% [820] [821] . However, another study indicates that enterohepatic cycling may be greater with 30% of an IV dose reaching the GI tract in 24 hours [822] . Approximately 14% to 28% is eliminated by non-renal routes [809] [823] . b) FECES, 3% to 5% [806] [793] . 1) Only 3% to 5% of total body stores are excreted in the stool daily [806] [793] . Approximately 14% to 28% is eliminated by non-renal routes [809] [823] . 2) Fecal excretion of digoxin decreases and urinary excretion increases in elderly subjects with hypochlorhydria (HC). In 1 study involving 10 elderly subjects, urinary excretion of digoxin increased from 37% of the dose in normochlorhydric (NC) subjects to 46% in HC subjects, whereas fecal excretion decreased from 29% in NC subjects to 14% in HC subjects. The altered route of excretion in subjects with HC may be the result of decreased hydrolysis of digoxin by stomach acid and increased intestinal metabolism [813] . Elimination Half-life A) Parent Compound 1) ELIMINATION HALF-LIFE a) 1.3 to 2.2 days [810] [824] [825] . 1) Average half-life is 1.5 to 1.8 days in normal patients

[810] [824] [825] . 2) Half-life is unaffected by thyroid function [804] . Extracorporeal Elimination A) Hemodialysis 1) Dialyzable: No [814] [815] a) Very little digoxin is removed from the body in renal failure patients during dialysis. Mean clearances of 10 to 26 mL/min have been reported [814] [815] . b) A major concern of dialysis in digitalized patients is the possible shift of potassium levels. To avoid cardiac arrhythmias it is recommended that the dialysate potassium be 3 mEq/L [816] . B) Peritoneal 1) Dialyzable: No [799] [798] a) Digoxin is not removed by hemodialysis [799] [798] . b) Small amounts of digoxin are removed by peritoneal dialysis [806] . This is true with either intermittent peritoneal dialysis or continuous ambulatory peritoneal dialysis [817] . c) A major concern of dialysis in digitalized patients is the possible shift of potassium levels. To avoid cardiac arrhythmias it is recommended that the dialysate potassium be 3 mEq/L [816] . C) Hemoperfusion

1) Dialyzable: Yes [818] a) In the first case report of direct hemoperfusion, a beta-2microglobulin absorption column connected to the arterial end of a hemodialysis unit reduced serum digoxin levels from 6.0 to 2.31 nanograms per milliliter over 4 hours. A second session 3 days later further reduced serum digoxin levels from 3.59 to 1.70 ng/mL. With hemodialysis alone prior to the use of the B-2-MG column, a 4-hour session reduced serum digoxin from 6.38 to 5.30 ng/mL [818] . D) Hemofiltration 1) Dialyzable: Yes [819]

CAUTIONS
Adverse Reactions
Cardiovascular Effects Cardiac dysrhythmia 1) Summary a) Many types of arrhythmia can be seen with digitalis toxicity. The most common arrhythmias seen with digitalis toxicity are unifocal or multifocal ventricular premature complexes and nonparoxysmal atrioventricular (AV) junctional tachycardia. Bigeminal and trigeminal rhythms are also characteristic of digoxin toxicity. Digitalis-induced arrhythmias should be treated by discontinuing digoxin therapy, determining potassium levels, and administering potassium chloride and antiarrhythmics as necessary. In children and infants, arrhythmias are a more reliable indication of toxicity [112] . 2) In 2 parallel, double-blind, placebo-controlled withdrawal trials of patients stable on digoxin and also taking diuretics with or without ACE inhibitors, palpitations, ventricular extrasystole, tachycardia, and cardiac arrest were reported in less than 2% of patients taking digoxin (n=123) compared with 3% of patients taking placebo [112] . 3) High doses of digoxin may cause first-degree, seconddegree, or third-degree heart block (including asystole); ventricular tachycardia; ventricular fibrillation; atrioventricular

(AV) dissociation; accelerated junctional (nodal) rhythm; atrial tachycardia with block; and/or unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy). Excessive slowing of the pulse is a potential clinical sign of digoxin toxicity [112] . 4) Therapeutic doses of digoxin may cause heart block in patients with preexisting sinoatrial or atrioventricular (AV) conduction disorders; heart block can be avoided by adjusting the dose of digoxin. Additionally, digitalis-induced AV block may proceed to complete heart block [112] . 5) In children and infants, gastrointestinal (nausea, vomiting, diarrhea) and CNS symptoms are rare as initial signs of toxicity, but arrhythmias are a more reliable indication of toxicity. Although any type of arrhythmia is possible, the most commonly reported are conduction disturbances or supraventricular tachyarrhythmias such as atrial tachycardia with or without block and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may also be seen, particularly in infants, even in the absence of first-degree heart block. Any alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin until further evaluation proves otherwise [112] . 6) Exercise-induced ventricular tachycardia and a wide QRS complex were reported in a patient 2 weeks after therapy with digoxin (0.25 mg/day) had been instituted [116] . 7) Cardiac arrhythmias with acute exposure may be more pronounced than with chronic exposure. However, patients on digoxin therapy in the absence of toxicity were no more sensitive than controls to induced cardiac arrhythmias by electrical cardioversion [117] . Electrocardiogram abnormal 1) Summary a) ECG changes associated with digoxin use appear to affect atrioventricular conduction primarily. ECG changes are manifested as T-wave depression or inversion, ST-segment depression or elevation, and prolonged PR interval. Toxicity may mimic almost any arrhythmia [118] [119]

; however, PR prolongation and ST-segment depression should not by themselves be considered digoxin toxicity [112] . A prospective, randomized, placebo-controlled study also reported results that indicated IV administration of digoxin produces marked changes on ECG in patients with recent-onset atrial fibrillation [120] . 2) Results of a prospective, randomized, placebo-controlled study indicate that IV administration of digoxin produces marked changes on ECG in patients with recent-onset atrial fibrillation (maximum 7 days duration). In this study, patients (n=167; mean age 66.7 years, range 21 to 89 years) received either IV placebo or digoxin (mean total dose 0.012 mg/kg; 0.92 mg). Compared with placebo, digoxin caused a significant prolongation of the RR intervals (p less than 0.0001), a marginal increase in QRS width, and a significant decrease in ST-segment, T-wave amplitude, and QTc interval (p=0.009, p=0.002, and p=0.01, respectively). Digoxin produced these changes within 2 hours after the first dose and were more pronounced after 16 hours. There was no statistically significant correlation between digoxin serum concentration and changes in ECG or heart rate [120] . 3) Digitalis causes characteristic ECG changes within 2 to 4 hours after a large dose. Changes first appear in the T wave and ST segment, which may occur alone or together. The T wave becomes diminished in amplitude, isoelectric, or inverted. The ST segment usually becomes depressed when the QRS complex is upward, or may be elevated when the QRS deflection is downward. The PR interval becomes prolonged (rarely greater than 0.25 second unless underlying conduction disease exists) sometime after the T wave and ST segment ECG changes occur. Digitalis accelerates ventricular repolarization causing the QT interval to shorten. In addition to these changes, digitalis may simulate almost every possible ECG tracing associated with heart disease, with the exception of QRS widening [118] . 4) Toxic doses of digitalis may mimic almost any arrhythmia. Digitalis toxicity may include the following manifestations on the ECG : SA (sinoatrial) block, sinus arrest, AV (atrioventricular) block, atrial tachycardia with block, atrial fibrillation with highgrade AV block, nonparoxysmal AV junctional tachycardia, complex ventricular premature beats, and ventricular tachycardia [118] [119]

. Dermatologic Effects Rash 1) In 2 parallel, double-blind, placebo-controlled, withdrawal trials, patients on stable doses of digoxin and concomitant diuretics with or without ACE inhibitors were randomized to digoxin (n=123) or placebo (n=125). Rash was reported by 2 patients treated with digoxin compared with 1 patient treated with placebo. Maculopapular rash has rarely been observed [112] . 2) Although rare, cases of erythematous, raised, pruritic rash, maculopapular rash, and Stevens-Johnson syndrome have been reported in patients receiving digitalis compounds [146] [147] . Endocrine/Metabolic Effects Breast cancer 1) In a population-based, prospective case-control study of postmenopausal Danish women (age 55 years and older), digoxin treatment was associated with a higher breast tumor incidence rate. Registries identified 5565 cases of incident invasive breast carcinoma diagnosed in postmenopausal women and 55,650 matched population controls. During the study period, there were 324 breast cancer cases (5.6%) and 2546 controls (4.6%) identified with a history of digoxin use as the sole cardiac glycoside. There was a higher incidence of breast cancer among digoxin users compared with nonusers in both unadjusted and adjusted analyses (adjusted odds ratio (OR), 1.3; 95% confidence interval (CI), 1.14 to 1.48). The breast cancer OR was higher as duration of digoxin exposure increased (adjusted OR, 1.39; 95% CI, 1.1 to 1.74 for 7 to 18 years of digoxin use). An association between digoxin and incident breast cancer was still observed when the digoxinexposed women were compared with an alternative reference group of unexposed women with cardiovascular medical histories (adjusted OR, 1.42; 95% CI, 1.14 to 1.77). The results were robust with adjustment for age, confounding by indication, medical detection bias, and concurrent drug therapy with anticoagulants, NSAIDs, aspirin, and hormone replacement therapy [126] . Gynecomastia 1) Unilateral and bilateral gynecomastia have been reported occasionally after chronic therapy [112] . These effects are usually reversible on drug discontinuation. Androstenedione, the immediate precursor of most naturally

occurring estrogens, has the same cyclopentanoperhydrophenanthrene (steroid) chemical nucleus as digitalis glycosides. While the addition of different chemical side chains significantly alters the effects of various substances with this nucleus, these structural similarities may be sufficient to provide an explanation for the occurrence of certain digitalisassociated effects which appear estrogenic in nature [102] [133] [134] [135] [136] [137] [138] . Hypokalemia 1) Incidence: 9% [127] [128] [129] [130] [131] 2) Hypokalemia and/or hypomagnesemia predisposes patients and facilitates the development of digitalis toxicity. Hypomagnesemia has been reported in 19% of patients receiving digitalis while only 9% have been shown to be hypokalemic, suggesting that hypomagnesemia may more often contribute to the development of digitalis toxicity than hypokalemia. Serum electrolyte levels, particularly potassium and magnesium levels, should be routinely monitored in patients receiving digitalis glycosides [127] [128] [129] [130] [131] . Hypomagnesemia 1) Incidence: 19% [127] [128] [129] [130] [131] 2) Hypokalemia and/or hypomagnesemia predisposes patients and facilitates the development of digitalis toxicity. Hypomagnesemia has been reported in 19% of patients receiving digitalis while only 9% have been shown to be

hypokalemic, suggesting that hypomagnesemia may more often contribute to the development of digitalis toxicity than hypokalemia. Serum electrolyte levels, particularly potassium and magnesium levels, should be routinely monitored in patients receiving digitalis glycosides [127] [128] [129] [130] [131] . 3) Metabolic alkalosis, a measure of abnormal potassium ratios inside and outside the cell, was additive with digoxin for inducing cardiac arrhythmias [132] . Gastrointestinal Effects Diarrhea 1) In 2 parallel, double-blind, placebo-controlled, withdrawal trials, patients on stable doses of digoxin and concomitant diuretics with or without ACE inhibitors were randomized to digoxin (n=123) or placebo (n=125). Diarrhea was reported by 4 patients treated with digoxin compared with 1 patient treated with placebo. Although digoxin may cause anorexia, nausea, vomiting, and diarrhea, digoxin has rarely been associated with abdominal pain, intestinal ischemia, or hemorrhagic necrosis of the intestines [112] . Dysphagia 1) A case report described an 89-year-old female who was treated with 0.125 mg daily of digoxin for several years. She was inadvertently switched to 0.25 mg daily. Approximately 1 month later, she noted dysphagia initially for solids, then for liquids. Hospital admission noted an 18 kg weight loss. ECG showed first-degree heart block. Digoxin was stopped and serum level the following day was 4 nanograms/mL. Upper gastrointestinal tract series and fluoroscopy 3 days after admission were normal. Two months later, the patient gained 9 kg and had a normal ECG [139] . Mesenteric vascular insufficiency 1) In a case report, a 44-year-old male with heart failure developed angiographically proven mesenteric vasospasm associated with digitoxin toxicity. The vasospasm and mesenteric ischemia were reversed with infusion of sodium nitroprusside (up to 150 mcg/min). Similar reports have not occurred with digoxin [140]

. Nausea 1) In 2 parallel, double-blind, placebo-controlled, withdrawal trials, patients on stable doses of digoxin and concomitant diuretics with or without ACE inhibitors were randomized to digoxin (n=123) or placebo (n=125). Nausea was reported by 4 patients treated with digoxin compared with 2 patients treated with placebo. Although digoxin may cause anorexia, nausea, vomiting, and diarrhea, digoxin has rarely been associated with abdominal pain, intestinal ischemia, or hemorrhagic necrosis of the intestines [112] . Hematologic Effects Thrombocytopenia 1) Incidence: rare [112] 2) Thrombocytopenia has been observed rarely [112] . 3) Thrombocytopenia in association with digitalis therapy appears to be related specifically to the precise type of glycoside taken. Thus, a patient who develops thrombocytopenia with digitoxin may not necessarily develop the side effects when administered digoxin. This lack of crosssensitivity has been documented clinically [113] . However, despite the lack of any type of cross-reactivity, the mechanism of the thrombocytopenia appears to be immunological. Digitoxin acts as a hapten and has been found to concentrate in the gamma-globulin fashion of immune serum and attaches loosely to the platelet surface in the presence of the patient's serum. Thrombocytopenia then results from increased platelet destruction [114] . Both digitoxin and digoxin have been implicated in cases of thrombocytopenia. 4) A case of a 60-year-old male who developed thrombocytopenia on 2 occasions while being treated with digoxin has been reported. Each time it was reversed by withdrawal of digoxin [115] . Immunologic Effects Immune hypersensitivity reaction 1) Occasional allergic reactions have been reported with digoxin therapy; there should be a history of previous exposure [150] .

Musculoskeletal Effects Disorder of musculoskeletal system 1) IM injection of digoxin may result in a 15- to 17-fold increase in serum CPK levels after a single IM injection [148] [149] . Neurologic Effects Dizziness 1) In 2 parallel, double-blind, placebo-controlled, withdrawal trials, patients on stable doses of digoxin and concomitant diuretics with or without ACE inhibitors were randomized to digoxin (n=123) or placebo (n=125). Dizziness was reported by 6 patients treated with digoxin compared with 5 patients treated with placebo [112] . Encephalopathy 1) Encephalopathy has been reported in 2 patients taking oral digoxin (0.25 mg daily) without other features of digoxin toxicity. In both cases, the patients had no gastrointestinal or cardiac side effects consistent with digoxin toxicity. In one case, the patient had extreme drowsiness and the second case had EEG changes consistent with metabolic or drug-induced encephalopathy. Once digoxin was discontinued or the dose decreased, symptoms resolved [121] . Headache 1) In 2 parallel, double-blind, placebo-controlled, withdrawal trials, patients on stable doses of digoxin and concomitant diuretics with or without ACE inhibitors were randomized to digoxin (n=123) or placebo (n=125). Headache was reported by 4 patients treated with digoxin and with placebo [112] . Seizure 1) Summary a) Seizure activity has on rare occasions been associated with digoxin toxicity. The elderly or patients with cerebral arteriosclerosis may be more prone to developing digoxininduced seizures [122] [123] [124] . 2) A 64-year-old woman who developed epileptiform seizures and EEG abnormalities in association with digoxin toxicity has been reported. Digoxin poisoning was confirmed by

measurements of plasma digoxin concentration. EEG abnormalities and seizures persisted while the plasma digoxin concentration remained in the toxic range of greater than 5 mcg/L and resolved only when the plasma concentration returned to the therapeutic range. The inhibition of Na+/K+ adenosine triphosphatase activity by digoxin may have caused interference with the function of electrically excitable tissue [122] . 3) Faintness and blackouts in a 73-year-old male who presented with digoxin toxicity have been reported. Digoxin intoxication was detected by electrocardiograph changes; plasma digoxin concentrations were not determined. Abnormal EEG patterns were noted during intoxication and returned to normal after IV administration of phenytoin [124] . Trigeminal neuralgia 1) A case of trigeminal neuralgia following the administration of digoxin 0.25 mg orally and 0.375 mg orally on alternate days for 1 month has been reported. Serum digoxin levels measured 3.28 nanograms(ng)/mL. The patient had an irregular pulse and atrial fibrillation. Digoxin was discontinued. On day 5 the patient's facial pain ceased and serum digoxin levels measured 1.45 ng/mL. Rechallenge with digoxin, because the patient's congestive heart failure worsened, produced mild facial attacks a second time [125] . Ophthalmic Effects Reduced color discrimination 1) Color discrimination was impaired in 17 of 28 subjects with therapeutic digoxin plasma concentrations (less than 2 nanograms/mL). Each of 5 subjects with toxic plasma levels had disturbed color vision. Conversely, none of the subjects receiving digitoxin had impairment in color vision and only 7 of 13 experienced impairments at toxic levels. The authors postulated that digoxin is distributed in higher amounts to the retina due to lower plasma protein binding than digitoxin [145] . Visual disturbance 1) The cardiac glycosides may cause blurred vision, halos around bright objects, disturbed color vision (yellow vision) [112] , and visual acuity associated with ocular muscle palsies, alteration of pupillary size, retrobulbar neuritis, or central scotomas. These effects are particularly prominent, with a reported incidence as high as 95% in patients who are digitalis

toxic. These effects are rarely permanent and usually subside with reversal of digitalis toxicity [141] [142] [143] . Visual disturbances (ie, shimmering lights, blurred vision, decreased visual acuity and visual fields) have been reported with therapeutic blood levels of digoxin [144] . Psychiatric Effects Dream anxiety disorder 1) A case report described nightmares in a patient on digoxin. Digoxin levels were in the toxic range and the nightmares stopped upon withdrawal of the drug [151] . Psychiatric sign or symptom 1) Apathy, confusion, and mental disturbances (eg, anxiety, depression, delirium, and hallucination) have been reported in patients receiving digoxin [112] . Irritability is a nonspecific symptom that may precede objective signs of toxicity [150] . Psychotic disorder 1) Psychosis has been reported in patients receiving digoxin. In one study that reported psychosis in patients, the serum digoxin levels in these patients were in the toxic range. Withdrawal of the drug was consistent with remission of the psychosis. Psychiatric patients may be more susceptible to this effect. The overall occurrence is rare [152] . There are also reports of visual and auditory hallucinations and digitalis delirium [143] . 2) Visual hallucinations as the initial sign of digitalis intoxication in an 84-year-old female following prolonged digoxin therapy has been reported. She remained nontoxic for approximately 3 years while receiving high doses of digoxin (0.65 mg) and toxicity might have been precipitated by Dyazide(R) administration which was prescribed 2 days prior to the hallucinations [153] . Reproductive Effects Breast cancer

1) In a population-based, prospective case-control study of postmenopausal Danish women (age 55 years and older), digoxin treatment was associated with a higher breast tumor incidence rate. Registries identified 5565 cases of incident invasive breast carcinoma diagnosed in postmenopausal women and 55,650 matched population controls. During the study period, there were 324 breast cancer cases (5.6%) and 2546 controls (4.6%) identified with a history of digoxin use as the sole cardiac glycoside. There was a higher incidence of breast cancer among digoxin users compared with nonusers in both unadjusted and adjusted analyses (adjusted odds ratio (OR), 1.3; 95% confidence interval (CI), 1.14 to 1.48). The breast cancer OR was higher as duration of digoxin exposure increased (adjusted OR, 1.39; 95% CI, 1.1 to 1.74 for 7 to 18 years of digoxin use). An association between digoxin and incident breast cancer was still observed when the digoxinexposed women were compared with an alternative reference group of unexposed women with cardiovascular medical histories (adjusted OR, 1.42; 95% CI, 1.14 to 1.77). The results were robust with adjustment for age, confounding by indication, medical detection bias, and concurrent drug therapy with anticoagulants, NSAIDs, aspirin, and hormone replacement therapy [126] . Sexual dysfunction See Drug Consult reference: DRUG-INDUCED SEXUAL DYSFUNCTION Uterine cancer 1) In a population-based study of postmenopausal Danish women aged 20 years and older, current use of digoxin was associated with a higher incidence of uterine cancer compared with nonusers. Registries identified 104,648 women with digoxin exposure with 249,652 person years (PY) of follow up for current exposure and 143,186 PY of follow up for prior exposure. During the study, uterine cancer, ovarian cancer, and cervical cancer were diagnosed in 8124, 7124, and 5001 women, respectively. Age-adjusted analysis revealed a higher incidence of uterine cancer in women with current digoxin use (n=350) compared with nonexposed women (risk ratio (RR), 1.48; 95% CI, 1.32 to 1.65). The incidence of uterine cancer increased significantly in women with a digoxin treatment duration of 36 months or longer compared with those using digoxin for 13 to 35 months (incidence rate ratio, 37 vs 71; p=0.0008); among all women using digoxin for at least 36 months (n=123), the overall RR for uterine cancer was 1.57 (1.31 to 1.89). The overall RR was not increased for ovarian or cervical cancers among digoxin users compared with nonusers. The incidence of uterus, ovarian, and cervical cancers were also

not increased in other angina drug users compared with nonusers. For former digoxin users (starting 6 months after last digoxin prescription) there was a nonsignificant increase in uterine cancer (RR, 1.20; 95% CI, 0.99 to 1.45), while ovarian and cervical cancer incidence rates did not increase [154] Other Death 1) In an observational, retrospective, cohort study, digoxin therapy in hemodialysis patients was associated with an increased risk of mortality, especially in patients with low baseline serum potassium levels. Adjusted analysis revealed incident hemodialysis patients treated with digoxin (n=4549) had a 28% increased risk of mortality (hazard ratio (HR), 1.28; 95% confidence interval (CI), 1.25 to 1.31) compared with nonusers (n=116,315). While digoxin dose was not significantly associated with mortality (p=0.11), every 1-nanogram/mL increase in baseline serum digoxin level resulted in a 19% increased risk of death (HR, 1.19; 95% CI, 1.05 to 1.35; p less than 0.006); and this risk was significantly more prominent in patients with predialysis serum potassium levels less than or equal to 4.6 mEq/L (p less than 0.01). There was no relationship among digoxin serum level and mortality risk in patients with predialysis serum potassium levels greater than 4.6 mEq/L [155] . 2) Variables considered risk factors that increase the likelihood of developing digoxin toxicity include a serum digoxin level above 2 nanograms/mL, hypokalemia, hypomagnesemia, hypercalcemia, hypoxia, ischemic heart disease, hypothyroidism, advanced age, small body mass, female gender, and declining renal function. Hyperthyroidism, childhood, and atrial fibrillation have been associated with a reduced risk of developing digoxin intoxication. Digoxin serum level is one of the most powerful independent factors related to predicting digoxin toxicity. However, there is some overlap between toxic and nontoxic concentrations [156] [157] . 3) Digoxin serum levels must be interpreted in the overall clinical context. The various clinical manifestations of digoxin toxicity may have different thresholds. Signs of automaticity may occur at a lower serum digoxin level than gastrointestinal symptoms. In addition, the various clinical manifestations of digoxin toxicity are associated with a different risk of intoxication. Electrocardiographic signs of automaticity are more strongly associated with digoxin toxicity than gastrointestinal symptoms, atrioventricular (AV) block, or bradycardia. Therefore, patients

with signs of automaticity are more likely to be intoxicated than patients with gastrointestinal symptoms, AV block, or bradycardia [156] [157] .

Drug Interactions
Drug-Drug Combinations Acarbose 1) Interaction Effect: decreased digoxin efficacy 2) Summary: Coadministration of acarbose and digoxin was reported to have no effect on digoxin blood levels in healthy volunteers [283] [284] . However, in one case report, a 69-year old woman who was taking digoxin experienced subtherapeutic levels of digoxin when acarbose was added to her regimen. After discontinuation of acarbose, plasma digoxin concentration returned to its previous therapeutic level [285] . Additionally, a randomized, crossover study design found that the area under the concentration-time curve (AUC) and the mean maximum concentration (Cmax) of digoxin were significantly decreased in the presence of acarbose [286] . Another case report describes two separate patients stabilized on digoxin who experienced symptomatic subtherapeutic levels after acarbose had been added to their treatment regimen [287] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Patients receiving digoxin and acarbose therapy should be instructed to take their medications consistently at the same time interval daily to avoid any fluctuations in their digoxin levels. Additionally, digoxin levels should be appropriately monitored following the initiation of acarbose. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) A 69-year old woman with hypertension, unstable angina, congestive heart failure, and insulin-dependent diabetes was treated with several drugs including digoxin. The patient received digoxin 0.25 mg daily in addition to commonly recommended dosages of several other drugs. After the addition

of acarbose to the patient's regimen, digoxin levels were measured to be subtherapeutic, at 0.48 ng/mL. After noncompliance was investigated and then ruled out as the causative factor, the digoxin dose was increased by 0.125 mg two times a week in addition to the daily dose of 0.25 mg. The next measured digoxin level was again subtherapeutic at 0.64 ng/mL. After discontinuation of acarbose for ten days, and resumption of digoxin therapy at 0.25 mg daily, measured levels of digoxin were 1.90 ng/mL (normal range: 0.8 to 2.1 ng/mL). After ruling out interactions with the patient's other medications, the authors speculated that the subtherapeutic levels of digoxin could be due to an interaction with acarbose through an unknown mechanism [280] . b) Seven healthy male volunteers participated in a randomized, crossover study to determine the effect of acarbose on the pharmacokinetic parameters of digoxin. In phase 1, participants received a single oral dose of digoxin 0.5 mg. Phase 2 consisted of administering a 0.5 mg dose of digoxin 30 minutes after acarbose 200 mg. During phase 3, subjects were given acarbose 100 mg three times daily for three days, and on the fourth day they received a digoxin 0.5 mg dose after the acarbose dose. During phase 2, the maximum concentration (Cmax) of digoxin decreased approximately 30% (1.99 ng/mL vs. 1.43 ng/mL) while the bioavailability was reduced by 40%. Even though the dose of acarbose in phase 3 was half of the dose in phase 2, the Cmax of digoxin was less (1.22 ng/mL) than in phase 2. The area under the concentration-time curve (AUC) from 0 to 48 hours was also reduced in phases 2 and 3 from 22.3 ng/hr/mL to 13.6 ng/hr/mL and 12.8 ng/hr/mL, respectively. These findings suggest that acarbose inhibits the absorption of digoxin from the gastrointestinal tract [281] . c) Two patients experienced subtherapeutic digoxin levels when acarbose was added to their drug regimen. Patient 1, a 50-yearold male, was stabilized on digoxin when acarbose 50 mg three times daily was initiated. Three months later, he presented to the emergency room with rapid atrial fibrillation. His digoxin level at that time was 0.23 ng/mL. Acarbose was discontinued for seven days, and his digoxin dose remained at 0.25 mg daily. The digoxin level increased back to a therapeutic level (1.6 ng/mL). To test the hypothesis that acarbose was the offending agent, acarbose was reinstated, and the patient's digoxin level decreased to 0.76 ng/mL. The second patient, a 72-year-old female, was started on acarbose 100 mg twice daily. Her digoxin plasma levels were subtherapeutic on two different occasions, ranging from 0.56 ng/mL to 0.72 ng/mL. Following

the discontinuation of digoxin, her plasma level increased to 1.9 ng/mL [282] . Acebutolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for

palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption

of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Acetazolamide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [440] . If digoxin and acetazolamide are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: If concurrent therapy is required, monitor the patient's electrolytes carefully, particularly potassium, and assess the need for electrolyte (ie, potassium)

replacement therapy. 7) Probable Mechanism: diuretic-induced hypokalemia creates proarrhythmic state Activated Charcoal 1) Interaction Effect: decreased digoxin exposure 2) Summary: Six healthy volunteers participating in a randomized crossover-design study demonstrated the effects of activated charcoal on the absorption and peak serum concentrations of digoxin. Each subject ingested water or activated charcoal 50 g suspended in water within five minutes after taking digoxin 0.5 mg. Area under the concentration-time curve (AUC) of digoxin decreased from 37.4 mcg/h/L to 2.8 mcg/h/L, and excretion of digoxin in the urine revealed a 98% reduction in the total absorption of digoxin. When activated charcoal was administered one hour after digoxin, the inhibition of digoxin absorption was 40% [185] . In a cross-over study involving six healthy volunteers, activated charcoal 8 g administered immediately after digoxin 0.25 mg resulted in a 96% decrease in the digoxin absorption. Maximum concentration (Cmax) decreased from 1.1 mcg/L to 0.02 mcg/L, and the area under the concentration-time curve (AUC) of digoxin fell from 14.3 mcg/L/h to 0.2 mcg/L/h [186] . This drug interaction may make activated charcoal useful in cases of digoxin overdose, but should be kept in mind when using activated charcoal in therapy concurrently with digoxin. 3) Severity: moderate 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Since activated charcoal binds digoxin in the gastrointestinal tract, administer digoxin two hours before or four to six hours after activated charcoal. If this is not possible, separate administration times as much as possible. During concurrent therapy, monitor digoxin serum levels closely and observe the patient for changes in response to digoxin. 7) Probable Mechanism: reduced digoxin absorption Albuterol 1) Interaction Effect: a decrease in serum digoxin levels 2) Summary: Following single dose intravenous and oral administration of albuterol to healthy subjects receiving digoxin for 10 days, there was a mean decrease of 16% and 22% in serum digoxin levels, respectively. In patients with obstructive airway disease receiving chronic concomitant therapy, the clinical significance of this interaction is unclear. Evaluation of serum digoxin levels is recommended [195] [196] [197]

. 3) Severity: minor 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant use of albuterol and digoxin may cause a decrease in serum digoxin levels; therefore, evaluation of levels is recommended [195] [196] [197] . 7) Probable Mechanism: unknown Aloe 1) Interaction Effect: hypokalemia resulting in digoxin toxicity 2) Summary: Aloe acts as a stimulant laxative. Aloe is noted in the German Commission E Monograph to be associated with a loss of potassium [193] . As with other plant anthranoid laxative sources, loss of potassium can occur secondary to excessive or prolonged use, termed "laxative abuse" [193] [194] . Potassium loss is partly due to direct loss in the feces and partly as secondary renal effect associated with sodium loss [194] . Patients taking aloe for more than 1-2 weeks may experience hypokalemia (signs and symptoms include lethargy, muscle cramps, headaches, paresthesias, tetany, peripheral edema, polyuria, breathlessness, and hypertension). Patients taking digoxin are predisposed to signs and symptoms of digoxin toxicity, including anorexia, nausea, vomiting, diarrhea, weakness, visual disturbances, and ventricular tachycardia). Concomitant use should be avoided. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Patients who are taking digoxin should be advised to avoid concomitant use with aloe. If digoxin toxicity occurs, potassium should be monitored and supplemented if necessary while discontinuing aloe. 7) Probable Mechanism: laxative effect of aloe 8) Literature Reports a) Laxative abuse using plants such as aloe that contain anthraquinone glycosides can lead to depletion of 25-50% of potassium due to water and electrolyte losses [190] .

b) Diuretic and digoxin maintenance therapy in 12 congestive heart failure patients who were studied for hypokalemia and cardiac arrhythmias resulted in digoxin toxicity in 6 patients with normal serum digoxin levels. The daily dose of digoxin was 0.30 +/- 0.06 milligrams (mg) orally, and the mean serum concentration was 1.52 +/- 0.17 nanomoles/milliliter (nmol/mL). The mean serum potassium level was 3.41 +/- 0.09 millimoles/liter (mmol/L) for the 12 subjects [191] . c) Of 79 men with arrhythmias associated with digoxin intoxication, 24 were hypokalemic and 55 were normokalemic. In the hypokalemic group, mean serum potassium was 3 milliequivalents/liter (mEq/L) and mean serum digoxin level was 1.1 ng/mL compared to 4.7 mEq/L potassium and 3.7 ng/mL digoxin in the normokalemic group [192] . Alprazolam 1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Concomitant administration of alprazolam or diazepam and digoxin has been reported to increase digoxin concentrations (5% to greater than 100%) [584] . Increased monitoring of digoxin levels are suggested when either adding or deleting alprazolam or diazepam therapy in patients stabilized on digoxin therapy [585] [586] [587] . 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor for signs of digoxin intoxication (eg, nausea, vomiting, diarrhea, persistent headache, confusion, fainting, visual disturbances). If symptoms are present, obtain a digoxin level and reduce dose accordingly. 7) Probable Mechanism: reduced renal clearance of digoxin 8) Literature Reports a) Concomitant administration of alprazolam 1.5 mg per day and digoxin resulted in no change in digoxin clearance or other pharmacokinetic variables for digoxin. In addition, creatinine clearance was not significantly affected during concomitant administration [582] . Therapeutic alprazolam doses should have no effect on digoxin serum concentrations. However, more studies are

needed to evaluate the effect of higher alprazolam doses in seriously ill patients. b) A 72-year-old nursing home female patient with atherosclerotic coronary vascular disease complicated by an anterior infarction and reversible congestive heart failure had a drug regimen which included oral isosorbide, furosemide, potassium chloride, and oral digoxin (0.25 mg every morning except Sunday). Serum digoxin concentrations ranged from 1.6 to 1.8 ng/mL. The patient complained of insomnia, restlessness, and anxiety, and was started on alprazolam 1 mg at bedtime. During the second week of therapy, the patient had a number of non-specific complaints and was referred to the hospital. On admission, the serum digoxin concentration was 4.3 ng/mL. The patient's serum creatinine on admission was unchanged from previous visits. Both digoxin and alprazolam were discontinued. On her third hospital day, she developed ventricular tachycardia which required lidocaine administration. Oral digoxin was restarted at 0.125 mg per day. Follow-up steady-state digoxin concentration was 1.5 ng/mL [583] . Alprenolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart

rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased

by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535]

. Aluminum Carbonate, Basic 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time

and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Aluminum Hydroxide 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports

a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Aluminum Phosphate 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet

[368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the

peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Amiloride 1) Interaction Effect: decreased digoxin effectiveness 2) Summary: Although concurrent administration of amiloride increased renal clearance and reduced nonrenal clearance of digoxin, there was minimal net effect on digoxin plasma levels [744] . The most significant effect was a reduction in the positive inotropic effect of digoxin. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Monitor patients for reduced therapeutic effect of digoxin. 7) Probable Mechanism: unknown 8) Literature Reports a) Concomitant amiloride and digoxin therapy produced a slight increase in serum digoxin levels in 6 healthy individuals administered amiloride 10 mg daily for 8 days. The interaction was felt to result from altered digoxin elimination, increased renal tubular secretion of digoxin, and reduced extrarenal digoxin clearance. Patients experienced a reduction in the inotropic effect of digoxin [743] . The significance of this interaction, especially in congestive heart failure patients, is unknown. Until further data are available, patients receiving concurrent digoxin and amiloride therapy should be monitored for altered digoxin response. Aminosalicylic Acid 1) Interaction Effect: reduced digoxin serum concentrations 2) Summary: In two of ten patients, digoxin levels were reduced by 40% eight hours after the last dose of aminosalicylic acid 2 grams four times daily [288]

. Aminosalicylic acid may decrease the absorption of digoxin. Aminosalicylic acid is believed to inhibit the function of intestinal absorbing cells. Thus, separation of the doses of these agents would not prevent the interaction. Patients receiving both agents should be monitored for reduced digoxin response. 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Monitor patients receiving both aminosalicylic acid and digoxin for reduced digoxin response. 7) Probable Mechanism: inhibition of digoxin intestinal absorption Amiodarone 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day [249] . Cases of asystole and torsades de pointes occurring related to concomitant digoxin and amiodarone therapy have been reported [250] [251] . If amiodarone and digoxin are taken concomitantly, reduce the digoxin dose by approximately 50% and monitor serum digoxin levels closely [249] [252] . 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: When amiodarone is administered to patients taking digoxin, consider discontinuing digoxin, or reduce the digoxin dose by approximately 50%. If digoxin is continued, closely monitor serum digoxin levels and clinical evidence of digoxin toxicity. 7) Probable Mechanism: inhibition of p-glycoprotein by amiodarone, and reduction of digoxin clearance 8) Literature Reports a) Digoxin serum concentrations were increased significantly following the addition of amiodarone to oral and intravenous digoxin in patients receiving long term digoxin therapy. In patients taking oral digoxin, digoxin levels increased from 0.97 to 1.98 nanograms/milliliter (ng/mL) in 28 patients. Gastrointestinal toxicity occurred in nine patients, central nervous system toxicity in five patients, and cardiovascular reactions in four patients. Increases in digoxin serum levels were produced one to three weeks after amiodarone

administration. Kinetic studies in six patients receiving digoxin 1 milligram (mg) intravenously prior to and during amiodarone administration resulted in increased serum digoxin levels at 30 minutes (from 8.6 to 10 ng/mL); digoxin half-life was prolonged by 31%. The total body clearance and nonrenal clearance of digoxin was reduced significantly. Renal clearance of digoxin decreased by 22% [243] . b) Oral amiodarone increased the bioavailability of digoxin in healthy subjects. Subjects received a single oral dose of digoxin 0.5 mg prior to and at the end of a 7-day treatment course with amiodarone (200 mg orally three times daily). In four of six subjects, significant increases in serum digoxin levels and AUC were observed while renal clearance was unaltered. Recovery of digoxin in the urine was increased. The authors suggested that amiodarone increases the bioavailability of digoxin by a mechanism independent of changes in was suspected [244] . c) Oral amiodarone administered concomitantly with oral digoxin (0.5 milligrams as a single dose) significantly increased digoxin serum concentrations and area-under-the-curve. With intravenous digoxin, changes were marginal and not statistically significant. The bioavailability of digoxin was 33% greater with amiodarone as determined from the mean values of oral and intravenous AUC. These data suggest that the most relevant aspect of the amiodarone-digoxin interaction is the enhancement of oral digoxin bioavailability. The authors suggested that amiodarone may inhibit p-glycoprotein in the gastrointestinal tract [245] . d) Serious cardiac arrhythmias have been reported, in 2 case studies, in patients treated with amiodarone and digoxin, possibly because of a pharmacodynamic interaction. In one case a 8-second episode of asystole was observed in a 52-yearold man with severe angina and congestive heart failure treated with amiodarone and digoxin [246] . In the other case, concurrent use of amiodarone and digoxin was associated with torsades de pointes in a 74-year-old female [247] . e) In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On administration of oral amiodarone, the need for digitalis therapy

should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well [248] . Amphotericin B 1) Interaction Effect: hypokalemia and digitalis toxicity (nausea, vomiting, visual disturbances, cardiac arrhythmias) 2) Summary: Hypokalemia following systemic amphotericin B therapy may facilitate digitalis toxicity. Potassium level monitoring along with cardiac function monitoring is indicated in patients receiving the combination. Potassium chloride supplementation may be necessary [354] [355] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Carefully monitor serum potassium concentrations in patients receiving concurrent amphotericin B with digitalis glycosides. It may become necessary to give potassium chloride to these patients. 7) Probable Mechanism: decreased serum potassium Amphotericin B Cholesteryl Sulfate Complex 1) Interaction Effect: hypokalemia and digitalis toxicity (nausea, vomiting, visual disturbances, cardiac arrhythmias) 2) Summary: Concomitant digitalis glycosides and amphotericin B therapy may result in an increased risk of digitalis toxicity due to amphotericin B-induced potassium depletion [508] . A similar effect may occur with amphotericin B cholesteryl sulfate complex. Caution is warranted if these agents are to be given concomitantly. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Carefully monitor serum potassium concentrations in patients receiving concurrent amphotericin B cholesteryl sulfate complex with digitalis glycosides. It may become necessary to give potassium chloride to these patients. 7) Probable Mechanism: decreased serum potassium Amphotericin B Lipid Complex 1) Interaction Effect: hypokalemia and digitalis toxicity (nausea, vomiting, visual disturbances, cardiac arrhythmias) 2) Summary: Concomitant digitalis glycosides and amphotericin B therapy may result in an increased risk of digitalis toxicity due to amphotericin B-induced potassium depletion

[446] . A similar effect may occur with amphotericin B lipid complex. Caution is warranted if these agents are to be given concomitantly. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Carefully monitor serum potassium concentrations in patients receiving concurrent amphotericin B with digitalis glycosides. It may become necessary to give potassium chloride to these patients. 7) Probable Mechanism: decreased serum potassium Amphotericin B Liposome 1) Interaction Effect: hypokalemia and digitalis toxicity (nausea, vomiting, visual disturbances, cardiac arrhythmias) 2) Summary: Concomitant digitalis glycosides and amphotericin B therapy may result in an increased risk of digitalis toxicity due to amphotericin B-induced potassium depletion [505] . A similar effect may occur with liposomal amphotericin B. Caution is warranted if these agents are to be given concomitantly. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Carefully monitor serum potassium concentrations in patients receiving concurrent liposomal amphotericin B with digitalis glycosides. It may become necessary to give potassium chloride to these patients. 7) Probable Mechanism: decreased serum potassium Arbutamine 1) Interaction Effect: unreliable arbutamine test results 2) Summary: Because digoxin may affect heart rate, arbutamine should not be administered to a patient receiving digoxin, since arbutamine test results may be unreliable [504] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Arbutamine should not be administered to a patient receiving digoxin therapy. 7) Probable Mechanism: alteration of heart rate by digoxin Atazanavir 1) Interaction Effect: an increased risk of prolonged PR interval 2) Summary: Prolonged PR interval of the ECG has been observed following atazanavir use. Although studies between atazanavir and digoxin have not been conducted, an additive effect on the PR interval cannot be excluded. Caution is warranted with the concurrent use of atazanavir and digoxin

[242] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Due to the potential for additive PR interval prolongation, caution is warranted with the concurrent use of atazanavir and digoxin [242] . Monitor for ECG abnormalities, especially PR interval prolongation. 7) Probable Mechanism: additive PR interval prolongation Atenolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports

a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] .

f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Atorvastatin 1) Interaction Effect: increased plasma concentrations of digoxin 2) Summary: Plasma levels of digoxin increased approximately 20% when coadministered with atorvastatin in multiple doses. Patients should be monitored appropriately [358] [359]

. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Carefully monitor digoxin levels and cardiac effects. Adjustment of digoxin dose may be required. 7) Probable Mechanism: unknown 8) Literature Reports a) Coadministration of atorvastatin 80mg and digoxin 0.25mg resulted in a 20% increase in digoxin peak plasma concentration in 12 healthy volunteers. The study also reported no change in digoxin concentration when administered with atorvastatin 10mg [357] . Azithromycin 1) Interaction Effect: digoxin toxicity (vomiting, cardiac arrhythmias) 2) Summary: One of the proposed mechanisms for the interaction between azithromycin and digoxin appears to be the susceptibility of gut microbes to macrolide antibacterials. Antibacterial administration may reduce colonies of the gut microbe Eubacterium lentum, which normally metabolizes digoxin to several pharmacodynamically less active metabolites. Administration of antimicrobials may reduce the number of colonies of E. lentum, in turn decreasing the presystemic metabolism of digoxin, increasing systemic absorption and increasing the serum digoxin concentration. Interference with renal and intestinal P-glycoprotein activity may also contribute to the altered disposition of digoxin [647] . A 15-year, population-based, nested case-control study revealed a strong association between digoxin toxicity and recent treatment with macrolides (clarithromycin, erythromycin and azithromycin); however, clarithromycin imparted the highest risk [371] . Until further data are developed regarding drug interactions when azithromycin and digoxin are used concomitantly, careful monitoring of patients is advised [648] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Medications altering digoxin bioavailability or clearance may predispose the patient to toxicity because of the relatively narrow therapeutic range for digoxin. Careful clinical monitoring of all infants and children receiving digoxin when additional medications are prescribed, particularly

macrolide and azilide antibacterials, is recommended. 7) Probable Mechanism: decreased inactivation of digoxin by bacterial metabolism in the lower intestine, thereby increasing digoxin bioavailability 8) Literature Reports a) A 15-year, population-based, nested case-control study revealed a strong association between digoxin toxicity and recent treatment with macrolides (clarithromycin, erythromycin and azithromycin), with clarithromycin imparting the highest risk. Patients who received at least 1 prescription a macrolide antibiotic during digoxin treatment and who were hospitalized for digoxin toxicity within 14 days of starting the antibiotic (n=1659; median age, 80 years (yr), interquartile range (IQR), 75 to 85 yr; 34% male) were matched with controls (n=6439; median age 80 yr; IQR, 75 to 85 yr). Analysis revealed a strong correlation between digoxin toxicity and recent treatment with clarithromycin (adjusted odds ratio (OR), 14.83; 95% CI, 7.89 to 27.86), as well as erythromycin (adjusted OR, 3.69; 95% CI, 1.72 to 7.9) and azithromycin (adjusted OR, 3.71; 95% CI, 1.1 to 12.52) compared with no antibiotic treatment. The risk of digoxin toxicity was 4 times greater following treatment with clarithromycin compared with erythromycin (OR, 4.02; 95% CI, 1.49 to 10.81) and azithromycin (OR, 4; 95% CI, 1.06 to 15.73). No difference in risk of digoxin toxicity was observed between erythromycin and azithromycin (OR, 0.99; 95% CI, 0.24 to 4.18). Based on the proposed mechanism for the macrolide-digoxin interaction (inhibition of p-glycoprotein-mediated digoxin transport), as expected, there was no correlation with cefuroxime (no effect on p-glycoprotein) use and hospitalization for digoxin toxicity (adjusted OR, 0.85; 95% CI, 0.21 to 3.41) [371] . b) A case report describes a 31-month-old who developed symptoms of digoxin toxicity after initiation of treatment with azithromycin. After several days of concomitant therapy with digoxin and azithromycin the boy developed progressive worsening of his congestive heart failure, including atrioventricular block, and signs of digoxin toxicity. On the third day of azithromycin therapy his serum digoxin level was 2.37 mcg/L. Digoxin was discontinued after the fourth day of therapy and 26 hours after administration of the last dose of digoxin his serum digoxin levels decreased to 1.81 mcg/L and his atrioventricular block resolved spontaneously [646] . Azosemide 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Concomitant loop diuretic and digitalis therapy can

result in digitalis toxicity secondary to hypokalemia and possibly hypomagnesemia [205] [206] [207] [208] [209] [210] [211] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Frequent monitoring of potassium and possibly magnesium with appropriate replacement is recommended; educate patients about the importance of maintaining adequate intake of dietary potassium and/or potassium supplements. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides Bemetizide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21%

[432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Bendroflumethiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and

hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Benzthiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis

should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Bepridil 1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Concomitant administration of calcium channel blockers (nifedipine, diltiazem, nicardipine, verapamil) and digitalis glycosides (digoxin) occasionally results in up to 50% increases in serum digoxin concentrations [658]

. The magnitude of increase appears to be dependent on the dose of calcium channel blocker being used [659] [660] [661] . Although generally of minimal clinical significance [662] [663] , patients with higher pre-existing serum digoxin concentrations are at greater risk for digitalis toxicity [660] [661] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor patient for signs or symptoms of digitalis glycoside toxicity (nausea, vomiting, cardiac rhythm disturbance) and laboratory evidence of unacceptable increases in serum digoxin concentrations. Adjust dose as required. 7) Probable Mechanism: inhibition of renal and/or extrarenal digoxin clearance 8) Literature Reports a) In a double blind, placebo controlled study of 48 healthy subjects, the concurrent use of bepridil 100 mg three times daily with digoxin 0.125 mg three times daily increased digoxin concentration by a mean of 34% over a 1-week period [656] . It was not known if the serum digoxin concentrations at that time had reached final steady-state levels. Coadministration of both drugs resulted in additive chronotropic effects and the increased digoxin effects diminished the negative ionotropic effect of bepridil. Administration of bepridil with digoxin resulted in minimal change of digoxin's positive ionotropic activity. Patients receiving digoxin and bepridil should be monitored carefully, however, reduction in digoxin dosages may not be necessary. b) The in vitro addition of digoxin and bepridil to human serum did not result in altered bepridil protein binding [657] . Betaxolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528]

. Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530]

. c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of

carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Bevantolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and beta-

blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of

talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump

[535] . Bisoprolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic

pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since

it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Boceprevir 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: Coadministration of digoxin and boceprevir may lead to increased digoxin plasma concentrations. Digoxin therapy should be initiated at the lowest dose. Digoxin serum concentrations should be monitored closely and the digoxin dose titrated accordingly [666] . 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of digoxin and boceprevir may lead to increased digoxin plasma concentrations. When coadministered with boceprevir, initiate digoxin treatment at the lowest dose. Monitor serum digoxin concentrations and titrate the digoxin dose accordingly [666]

. 7) Probable Mechanism: unknown Bucindolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic

pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since

it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Bumetanide 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Potassium and magnesium losses are common complications of loop diuretics which predispose patients receiving digoxin to toxicity [555] [556] [557] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: If concurrent therapy is required, the physician may consider monitoring the patient's electrolytes (ie, potassium, magnesium) carefully and assess the need for electrolyte replacement therapy.

7) Probable Mechanism: increased potassium and magnesium loss Buthiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and

without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Calcium 1) Interaction Effect: a serious risk of arrhythmia and cardiovascular collapse 2) Summary: Calcium, particularly if administered rapidly by the intravenous (IV) route, may produce serious arrhythmias in digitalized patients [43] . The similar actions of digitalis glycosides and calcium are documented, and deaths have occurred during simultaneous administration [225] [220] [226] . Therefore, IV injection of calcium compounds should be used cautiously in patients receiving digoxin or digitalis-like preparations and only if clearly indicated [221] [222] . If concurrent use of IV calcium compounds is warranted in the digitalized patient, slow IV administration with close patient monitoring is recommended. Due to the risk of developing hypercalcemia and subsequent cardiac arrhythmias, concurrent administration of oral calcium acetate is not recommended in patients receiving digitalis [223] . 3) Severity: major 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Calcium, especially if given by rapid, intravenous (IV) injection in patients receiving digoxin may produce serious arrhythmias [43] , and cases have been reported following bolus IV calcium administrations [219] [220] . Use of IV calcium compounds in digitalized patients is recommended only if it is clearly indicated [221] [222]

. Use caution if concurrent use of IV calcium is warranted, administer slowly over several hours, and monitor patients closely. Due to the risk of developing hypercalcemia and subsequent cardiac arrhythmias, coadministration of oral calcium acetate is not recommended in patients receiving digitalis [223] . 7) Probable Mechanism: additive or synergistic cardiac effects 8) Literature Reports a) The relationship between calcium and digitalis is documented in animal studies, though controversy does exist over whether it is synergistic, additive or if a relationship exists at all [224] . Methods of evaluation have also been quite diverse. Two case reports have described serious interactions with intravenous (IV) calcium use in digitalized patients. The first case was a 32 yearold white female with no mention of heart disease who underwent a cholecystectomy. She was given a total of 15 ml of Digalen(R) over six days for tachycardia, low blood pressure and extrasystoles. The tachycardia remained persistent and 10 mL calcium gluconate was given intravenously. Two minutes later the patient suffered cardiac and respiratory arrest and died. The second patient was a 55 year-old white male with admitting diagnosis of multiple myeloma or hyperparathyroidism. Thyroid surgery was performed and 8.5 ml Digalen(R) was given over 20 hours (no stated reason). Two days later a fine tremor developed, 10 mL of calcium chloride was given intravenously and a few minutes later the patient died of cardiovascular collapse [225] [220] . b) A retrospective study of 112 cases with possible digitalis toxicity evaluated 40 cases based on defined criteria of digitalis toxicity. Two cases of toxicity were thought to be due to the administration of calcium gluconate intravenously. Both patients were digitalized, one on lanatoside C, the other on digoxin, and both were hypocalcemic. One patient died 10 minutes after receiving the calcium, the other received calcium for three days (rate not specified) and developed apparent digitalis toxicity, but did not expire [219] . Canagliflozin 1) Interaction Effect: increased digoxin exposure 2) Summary: Coadministration of canagliflozin with digoxin increased digoxin AUC and Cmax by 20% and 36%,

respectively. Use caution and monitor digoxin levels in patients coadministered canagliflozin and digoxin [237] . Consider advising the patient to report signs or symptoms of digoxin toxicity. 3) Severity: major 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Coadministration of canagliflozin and digoxin may increase digoxin exposure. Use caution if concomitant use is required and monitor digoxin levels [237] . Consider advising the patient to report signs or symptoms of digoxin toxicity. 7) Probable Mechanism: unknown 8) Literature Reports a) Coadministration of canagliflozin 300 mg/day for 7 days with digoxin 0.5 mg for 1 day followed by 0.25 mg/day for 6 days increased the digoxin AUC (24 hours) by 20% (geometric mean ratio, 1.2; 90% CI, 1.12 to 1.28) and Cmax by 36% (geometric mean ratio, 1.36; 90% CI, 1.21 to 1.53) [237] . Canrenoate 1) Interaction Effect: increased cardiac contractility 2) Summary: The interaction between digoxin and canrenoate potassium enhances the cardiac contractility in digitalized patients [591] [592] and reverses the hyporeninemic effect of digoxin [593] . Canrenoate displaces digoxin from the receptor sites where digoxin exerts its therapeutic effect (Na-K-ATPase); a possible interference with RIA digoxin assay interference may also occur [594] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Monitor cardiac function closely in patients receiving digoxin and canrenoate concurrently. 7) Probable Mechanism: displacement of digoxin from Na-KATPase of tissues 8) Literature Reports a) In 12 patients (five men and seven women, mean age 69 years) on chronic treatment with digoxin (mean plasma level 1.8

nmol/L), the infusion of canrenoate potassium 600 mg improved left ventricular contractility [588] . Infusion of canrenoate potassium 600 mg and digoxin 15 mcg/kg in eight healthy men (mean age 21 years) increased inotropic effect (p equal to 0.025) [589] . Also, the contemporary infusion of canrenoate potassium 200 mg with digoxin 0.5 mg in six mildly hypertensive men (mean age 39 years) completely reversed the reduction of plasma renin activity caused by digoxin (p less than 0.025), displacing digoxin from the Na-K-ATPase on the juxtaglomerular and macula densa cells [590] . Captopril 1) Interaction Effect: an increase in digoxin plasma concentrations 2) Summary: Coadministration of captopril increased the digoxin plasma concentration by 58% and the AUC by 39%. Digoxin serum levels should be measured before initiating captopril, and the dose of digoxin should be reduced by approximately 30% to 50%. Monitoring of digoxin levels and toxicity is recommended during concomitant therapy [5] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant administration of captopril and digoxin may increase digoxin plasma concentrations. Digoxin serum levels should be measured before initiating captopril, and the dose of digoxin should be reduced by approximately 30% to 50%. Monitoring of digoxin levels and toxicity is recommended during concomitant therapy [5] . 7) Probable Mechanism: captopril inhibition of P-glycoprotein Carbimazole 1) Interaction Effect: decreased digoxin efficacy 2) Summary: Concurrent use of digoxin and carbimazole may result in decreased peak serum levels of digoxin. Coadministered carbimazole did not affect digoxin mean time to reach peak levels (Tmax) and area under the concentration-time curve (AUC). In addition, carbimazole appears to reduce the blood pressure-lowering effects of digoxin [739] . 3) Severity: moderate 4) Onset: rapid

5) Substantiation: theoretical 6) Clinical Management: Monitor digoxin levels when carbimazole is concomitantly administered. 7) Probable Mechanism: unknown 8) Literature Reports a) When ten healthy male subjects received digoxin (0.375 mg maintenance dose) and carbimazole as a 60 mg single oral dose in a double-blind, randomized, crossover design study, peak serum levels (Cmax) of digoxin were significantly reduced (1.72 vs. 1.33 mcg/L) in nine out of ten subjects. The mean time to reach peak levels (Tmax) and area under the concentrationtime curve (AUC) were unchanged. These results indicate that carbimazole reduces the rate, but not the extent, of digoxin absorption. In one subject, serum digoxin levels increased significantly (Cmax from 1.08 to 2.38 mcg/L and AUC from 12.75 to 23.85 mcg/L/hr). Concurrent administration of digoxin and carbimazole also reduced the diastolic blood pressure for six hours; however, systolic blood pressure was unchanged. The administration of digoxin alone lowered the diastolic and systolic blood pressures for 12 hours and 3 hours, respectively. Further studies are needed to determine the individual variability in persons on concurrent digoxin and carbimazole therapy. This study does not closely resemble a clinical situation, since carbimazole would be administered chronically instead of as a single dose [738] . Carob 1) Interaction Effect: increased digoxin toxicity 2) Summary: Carob seed flour increased serum digoxin concentrations in 6 healthy subjects [499] . Theoretically, carob ingestion in food may increase the risk of digoxin toxicity. 3) Severity: moderate 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: If patients taking digoxin ingest large amounts of carob, monitor closely for signs and symptoms of digoxin toxicity and consider measuring serum digoxin. 7) Probable Mechanism: unknown 8) Literature Reports a) Carob seed flour increased serum digoxin levels in 6 healthy subjects. Subjects were given 0.8 milligram of betaacetyldigoxin orally with a formula diet and 5 grams of carob seed flour. Digoxin levels were significantly increased (p less than 0.05) and increased more rapidly than in controls [498]

. Carteolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per

minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of

digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Carvedilol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538]

. If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2

nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9

mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Cascara Sagrada 1) Interaction Effect: hypokalemia secondary to cascara sagrada bark intake, which may increase the risk of digoxin toxicity 2) Summary: Cascara sagrada bark is noted in the German Commission E Monographs to be associated with potassium loss [403] . As with other plant anthranoid laxative sources, loss of potassium can occur secondary to excessive or prolonged use, termed "laxative abuse" [403] [190] . Potassium loss is partly due to direct loss in the feces and partly as secondary renal effect associated with sodium loss [190] . Patients taking cascara sagrada bark for more than 1-2 weeks may experience hypokalemia (signs and symptoms include lethargy, muscle cramps, headaches, paresthesias, tetany, peripheral edema, polyuria, breathlessness, and hypertension). Hypokalemia may increase the risk of digoxin toxicity (signs and symptoms include anorexia, nausea, vomiting, diarrhea, weakness, visual disturbances, ventricular tachycardia). Concomitant use of cascara sagrada and digoxin should be avoided. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Patients who are taking digoxin should be advised to avoid concomitant use with cascara sagrada bark. If digoxin toxicity occurs, potassium should be monitored and supplemented if necessary while discontinuing cascara sagrada bark. 7) Probable Mechanism: hypokalemia caused by cascara sagrada 8) Literature Reports a) Laxative abuse using plants such as cascara sagrada bark that contain anthraquinone glycosides can lead to depletion of 25-50% of body potassium due to water and electrolyte losses

[190] . b) Diuretic and digoxin maintenance therapy in 12 congestive heart failure patients studied for hypokalemia and cardiac arrhythmias resulted in digoxin toxicity in 6 patients with normal serum digoxin levels. The daily digoxin dose was 0.30 +/- 0.06 milligrams (mg) orally, and the mean serum concentration was 1.52 +/- 0.17 nanomoles/milliliter (nmol/mL). The mean serum potassium level was 3.41 +/- 0.09 millimoles/liter (mmol/L) for the 12 subjects [401] . c) Of 79 men with arrhythmias associated with digoxin intoxication, 24 were hypokalemic and 55 were normokalemic. In the hypokalemic group, mean serum potassium was 3 milliequivalents/liter (mEq/L) and mean serum digoxin level was 1.1 nanograms/milliliter (ng/mL) compared to 4.7 mEq/L potassium and 3.7 ng/mL digoxin in the normokalemic group [402] . Celiprolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If

these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral

digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] .

Chan Su 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: Chan-su (toad venom toxin), a bufadienolide, is cardioactive with properties similar to digitalis [623] [624] [625] . Ingestion or dermal absorption of toad venom (from Bufo species) has caused typical digitalis-like poisoning, with dysrhythmias, heart block, hypotension, and vomiting [626] [627] [628] [623] [629] [630] . 3) Severity: major 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of digoxin and ChanSu is not recommended. If Chan-Su is taken with digoxin, monitor for signs and symptoms of digoxin toxicity (e.g., nausea, vomiting, diarrhea, headache, weakness, drowsiness, visual disturbance, dysrhythmias, heart block, hypotension). 7) Probable Mechanism: additive digitalis glycoside effect 8) Literature Reports a) Six previously healthy males between the ages of 17 and 40 presented with vomiting, bradycardia, and hypotension; several were hyperkalemic and 1 suffered a seizure. All exhibited positive serum digoxin concentrations. The substance they had ingested was an aphrodisiac called "love stone" or "rock hard", which was found to be identical to Chan-Su, a Chinese medication derived from toad venom. Four of the patients died of cardiac dysrhythmias. Two recovered after administration of digoxin immune Fab (Digibind(R)) [619] . b) A 65-year-old woman developed nausea, vomiting, diarrhea, general malaise, and abdominal pain 5 hours after consuming 50 tablets of kyushin, a traditional Chinese medicine containing Chan-Su (suicide attempt). Upon hospital admission her heart rate was 60 beats/minute, blood pressure was 140/70 mmHg. The electrocardiogram (EKG) showed a second degree Wenckebach AV block and a flat T-wave which normalized the next day. The serum digoxin-like immunoreactive substance (DLIS) was 2.35 ng/mL 24 hours after ingestion (using the Digoxin II kit by Abbott Laboratories, Inc.). Serum electrolytes

were normal. With supportive treatment, this gradually declined over 5 days and the patient was released on the eighth day [620] . c) A 34-year-old female developed nausea, vomiting, and general malaise two hours after consuming approximately 50 pills of kyushin, a traditional Chinese medicine containing ChanSu, during an attempted suicide. On admission to the hospital, her heart rate was 64 beats/minute, blood pressure was 110/70 mmHg. Serum DLIS 10 hours after consuming the drug was 1.84 ng/mL. This diminished to 0.67 ng/mL by the next day with supportive treatment and symptoms also subsided. Serum electrolytes were normal. All EKGs during hospitalization were normal [620] . d) The bufadienolides in toad venom (Chan-su) are presumed to be the cardioactive components of Chan-Su which has proven its ability to inhibit sodium, potassium, and ATPase activity [621] [622] . Chlorothiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports

a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Chlorthalidone 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a

rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Cholestyramine 1) Interaction Effect: decreased digoxin levels 2) Summary: Cholestyramine can bind digoxin in the gastrointestinal tract and alter its enterohepatic recycling, thereby lowering the plasma level and half-life of digoxin [616] [617] [618] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable

6) Clinical Management: Since cholestyramine binds digoxin in the gastrointestinal tract, administer digoxin two hours before or four to six hours after cholestyramine. If this is not possible, separate administration times as much as possible. During concurrent therapy, monitor digoxin serum levels closely and observe the patient for changes in response to digoxin. Digoxin dosage adjustments may be necessary when starting or stopping cholestyramine. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) Concomitant digoxin and cholestyramine therapy has resulted in impaired absorption of digoxin [613] [614] . In a cross-over study involving six healthy volunteers, cholestyramine 8 g administered immediately after digoxin 0.25 mg resulted in a decrease in the digoxin absorption by 30% to 40%. Maximum concentration (Cmax) decreased from 1.1 mcg/L to 0.7 mcg/L, and the area under the concentration-time curve (AUC) of digoxin decreased from 14.3 mcg/L/h to 8.6 mcg/L/h [615] . Cimetidine 1) Interaction Effect: altered digoxin concentration 2) Summary: Conflicting reports have been published on the potential interaction between digoxin and cimetidine. Altered digoxin plasma concentrations following oral, but not intravenous, digoxin administered with cimetidine have been reported. Both an increase in the area under the plasma concentration-time curve and a decrease in mean serum concentrations of digoxin have been noted. Differences in dosage amount, bioavailability of tablets used, measurement of plasma concentration, and disease states may account for the discrepancies. Clinically, this alteration is not considered significant [676] [677] [678] [679] . 3) Severity: minor 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Digoxin dosage adjustment should be based on ECG monitoring and digoxin serum concentrations. If possible, switch to another anti-ulcer medication (eg, sucralfate) and separate the dose from digoxin by at least two hours. 7) Probable Mechanism: increased digoxin AUC, increased

renal clearance of digoxin 8) Literature Reports a) Concomitant administration of single intravenous digoxin doses in patients receiving oral cimetidine was reported to result in no significant influence on the disposition of digoxin in peptic ulcer patients [672] . Additionally, [673] found that the individual steady state pharmacokinetics of oral digoxin were not altered following the administration of cimetidine 300 mg every 6 hours for 7 days in 4 patients. b) The addition of cimetidine 600 milligrams/day to 1200 milligrams/day to 11 hospitalized patients with congestive heart failure and 3 patients with atrial fibrillation taking digoxin (0.125 milligram/day to 0.25 milligram/day) significantly (p less than 0.05) reduced the mean serum digoxin levels from 2 +/- 1 mcg/L to 1.5 +/- 0.7 mcg/L [674] . The authors believed cimetidine reduced the absorption of digoxin, however an improvement in cardiac function could have resulted in an increase in renal blood flow thereby increasing the clearance of digoxin. c) A trial was conducted in which the area under the plasma concentration versus time curve of a single oral dose of digoxin 0.5 milligram increased by a mean of 23% following a single oral dose (400 milligrams) of cimetidine. The same investigators also administered digoxin 0.25 milligram/day and 0.5 milligram/day for 16 and 12 days, respectively, and observed that the addition of cimetidine (1.6 grams/day) increased the trough plasma digoxin levels from 0.36 +/- 0.05 mcg/L to 0.48 +/-0.04 mcg/L and from 1.23 +/-+0.34 mcg/L to 1.42 +/- 0.26 mcg/L, respectively. It is difficult to interpret the results from this study since digoxin did not achieve steady state plasma levels before the addition of cimetidine. From the above data it is difficult to assess the possibility of a clinically significant drug interaction between digoxin and cimetidine and further trials are required to evaluate this interaction [675] . Cisapride 1) Interaction Effect: decreased digoxin effectiveness 2) Summary: When administered concurrently with digoxin (0.25 mg twice daily), cisapride (10 mg three times daily) resulted in decreased gastrointestinal absorption of digoxin. This decrease was not considered significant [240] . the addition of cisapride produces reduced digoxin absorption by accelerating bowel transit

[241] . 3) Severity: minor 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: This interaction appears to be minimal and is not expected to significantly alter the clinical efficacy of digoxin therapy. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) Concurrent use of cisapride and digoxin results in low serum digoxin concentrations. The authors describe a case report of a 90-year-old patients admitted with a fractured clavicle. Her medication regimen included oral digoxin, ranitidine, furosemide, perindopril, topical and sublingual nitroglycerin. The patient had therapeutic digoxin levels (0.9 mcg/mL). Cisapride was added to her medication regimen for ongoing reflux symptoms. Ten days after initiation of cisapride therapy her digoxin level dropped to 0.7 mcg/L. One month later her serum digoxin level was measured at 0.6 mcg/L. Seven weeks later cisapride was increased to 5 mg three times daily. Three months later she presented with severe biventricular failure. Serum digoxin levels were 0.4 mcg/L. When dosing of digoxin was separated from the dosing of cisapride by 4 hours, the signs and symptoms of cardiac failure and gastroesophageal reflux were controlled. The authors speculate that the addition of cisapride produced reduced digoxin absorption by accelerating bowel transit [238] . b) When administered concurrently with digoxin (0.25 mg twice daily), cisapride (10 mg three times daily) resulted in decreased gastrointestinal absorption of digoxin. Digoxin area under the plasma concentration curve was reduced by 12% following administration of cisapride. This decrease was not considered significant. No change in therapy is suggested [239] . Clarithromycin 1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Several case reports describe patients with previous stable digoxin levels who developed digoxin toxicity induced by the administration of clarithromycin [605] [606] [607] [608] [609] [610]

[611] . Approximately 10% of the population treated with digoxin convert the drug in the gut to inactive metabolites known as digoxin reduction products (DRPs). Eubacterium lentum, an anaerobic gram-positive rod, is a common gut flora that is primarily responsible for digoxin inactivation. Clarithromycin is the most active of the macrolide antibiotics against Eubacterium species. Therefore, the administration of clarithromycin reduces Eubacterium lentum, causing increased digoxin absorption and increased digoxin serum levels. The risk of this interaction may be reduced if digoxin is given as Lanoxicaps(R) [612] [605] . A 15-year, population-based, nested case-control study revealed a strong association between digoxin toxicity and recent treatment with macrolides (clarithromycin, erythromycin and azithromycin), with clarithromycin imparting the highest risk [371] . 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: If possible, antibiotics known to inhibit the conversion of digoxin to inactive metabolites (clarithromycin, erythromycin, tetracycline) should be avoided in patients on digoxin therapy. Another alternative would be to administer digoxin parenterally, since this interaction is not expected to occur when the gut is bypassed. In addition, the risk of this interaction may be reduced if digoxin is given as Lanoxicaps(R). In cases where clarithromycin therapy must be given with oral digoxin, a temporary digoxin dose reduction should be considered. Close monitoring of digoxin serum levels is recommended [371] . 7) Probable Mechanism: decreased inactivation of digoxin by bacterial metabolism in the lower intestine, thereby increasing digoxin bioavailability 8) Literature Reports a) A 15-year, population-based, nested case-control study revealed a strong association between digoxin toxicity and recent treatment with macrolides (clarithromycin, erythromycin and azithromycin), with clarithromycin imparting the highest risk. Patients who received at least 1 prescription a macrolide antibiotic during digoxin treatment and who were hospitalized for digoxin toxicity within 14 days of starting the antibiotic (n=1659; median age, 80 years (yr), interquartile range (IQR), 75 to 85 yr; 34% male) were matched with controls (n=6439; median age 80 yr; IQR, 75 to 85 yr). Analysis revealed a strong correlation

between digoxin toxicity and recent treatment with clarithromycin (adjusted odds ratio (OR), 14.83; 95% CI, 7.89 to 27.86), as well as erythromycin (adjusted OR, 3.69; 95% CI, 1.72 to 7.9) and azithromycin (adjusted OR, 3.71; 95% CI, 1.1 to 12.52) compared with no antibiotic treatment. The risk of digoxin toxicity was 4 times greater following treatment with clarithromycin compared with erythromycin (OR, 4.02; 95% CI, 1.49 to 10.81) and azithromycin (OR, 4; 95% CI, 1.06 to 15.73). No difference in risk of digoxin toxicity was observed between erythromycin and azithromycin (OR, 0.99; 95% CI, 0.24 to 4.18). Based on the proposed mechanism for the macrolide-digoxin interaction (inhibition of p-glycoprotein-mediated digoxin transport), as expected, there was no correlation with cefuroxime (no effect on p-glycoprotein) use and hospitalization for digoxin toxicity (adjusted OR, 0.85; 95% CI, 0.21 to 3.41) [371] . b) Two elderly patients developed digoxin toxicity after clarithromycin was prescribed for a respiratory infection. The first patient, an 86-year-old female, was taking digoxin 0.25 mg daily for congestive heart failure and had a digoxin level of 1.5 ng/mL two months prior to admission. Five days before presenting to the emergency department, she was prescribed clarithromycin 500 mg twice daily for bronchitis. She experienced radiating chest pain and nausea, and was found to have a digoxin level of 3.84 ng/mL. Creatinine values were within the normal range. Clarithromycin was discontinued, and digoxin was held for four days before being resumed at a dose of 0.125 mg daily. Eleven days after discharge, the digoxin level was 1.8 ng/mL. The second patient, an 89-year old male, was seen in the emergency department for a 4-day history of nausea, vomiting, decreased appetite, and a productive cough. Drug therapy included digoxin 0.25 mg daily for the past five years, with a serum digoxin level of 1.3 ng/mL three weeks prior to admission. Nine days prior to admission, he had been prescribed clarithromycin 500 mg twice daily for an upper respiratory infection. After six days of therapy, he began to experience severe nausea, and discontinued the clarithromycin upon advise of his physician. Three days later, on admission to the emergency department, his digoxin level was 3.47 ng/mL. Digoxin was discontinued, and his digoxin level decreased to 1.36 ng/mL after five days [601] . c) A 70-year-old female receiving digoxin 0.25 mg daily for idiopathic cardiomyopathy was prescribed clarithromycin 500 mg twice daily for bronchitis. Following four days of concomitant therapy, the patient was hospitalized due to nausea, vomiting, weakness, and altered vision. Upon admission, her digoxin serum level was measured at 4.8 ng/mL and increased to 5.4

ng/mL during the first day of hospitalization. Digoxin and clarithromycin were discontinued, and her digoxin level decreased to 1.7 ng/mL within two days, along with a resolution of her symptoms [602] . d) A 72-year-old female stabilized on digoxin 0.25 mg daily and warfarin 22.5 mg weekly was prescribed clarithromycin 500 mg three times daily for two weeks for helicobacter pylori eradication. Twelve days later, she presented to the emergency room with complaints of weakness, dizziness, diarrhea, and blurred vision. Her serum digoxin concentration was measured at 4.6 ng/mL, while her international normalized ratio (INR) was 7.3. Both digoxin and warfarin were held, and she was admitted to the hospital. Eleven days later she was discharged on digoxin 0.125 mg daily and warfarin 2.5 mg daily. On follow-up her digoxin levels and INR were within the therapeutic range [603] . e) The affects of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 milligrams (mg)) were studied in nine healthy male volunteers. Subjects were randomly assigned to the following treatments: 1) digoxin only 2) digoxin plus erythromycin 3) digoxin plus clarithromycin. Subjects took erythromycin or clarithromycin on the day before digoxin dosing and during the following 4 days. Erythromycin 200 mg was given 4 times a day and clarithromycin 200 mg was given twice daily. Neither erythromycin or clarithromycin caused significant changes in AUC, clearance, volume of distribution and half-life of digoxin. There was a significant increase in urinary digoxin excretion when erythromycin and clarithromycin were coadministered (digoxin alone: 98.4 mL/min; digoxin with erythromycin: 137.3 mL/min; digoxin and clarithromycin: 133.6 mL/min). Digoxin is a substrate of p-glycoprotein while erythromycin and clarithromycin inhibit p-glycoprotein-mediated transport. Clarithromycin and erythromycin do not have a significant effect on serum digoxin disposition when digoxin is administered intravenously. This report does not support the hypothesis that the increase in digoxin concentrations by macrolides is due to reduced renal excretion of digoxin [604] . Clopamide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439]

. If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] .

Cobicistat 1) Interaction Effect: increased digoxin exposure 2) Summary: Concurrent use of cobicistat, a P-glycoprotein transport inhibitor, [360] , and digoxin, a P-glycoprotein substrate [2] , may lead to increased digoxin concentrations. In a pharmacokinetic study (n=22), digoxin AUC and Cmax increased 8% and 40%, respectively, when coadministered with cobicistat. If concomitant use is necessary, additional measurements of serum digoxin concentrations and monitoring for signs and symptoms of digoxin toxicity are recommended during initiation, dose adjustment, or discontinuation of the agent that interacts with digoxin [2] . 3) Severity: major 4) Onset: unspecified 5) Substantiation: established 6) Clinical Management: Concomitant use of cobicistat and digoxin may lead to digoxin toxicity [360] . If coadministration is necessary, additional measurements of serum digoxin concentrations and monitoring for signs and symptoms of digoxin toxicity are recommended during initiation, dose adjustment, or discontinuation of the agent that interacts with digoxin [2] . 7) Probable Mechanism: inhibition of p-glycoprotein-mediated digoxin transport by cobicistat 8) Literature Reports a) In a pharmacokinetic study conducted in 22 healthy volunteers, a single dose of digoxin 0.5 mg was administered in the presence of cobicistat 150 mg once daily. The mean ratios of digoxin Cmax and AUC (with/without cobicistat) were 1.41 (90% CI, 1.29 to 1.55) and 1.08 (90% CI, 1 to 1.17), respectively, indicating an approximate 40% increase in digoxin Cmax and 8% increase in digoxin AUC [360] . Colchicine 1) Interaction Effect: an increased risk of rhabdomyolysis 2) Summary: Concomitant use of colchicine and digoxin may result in rhabdomyolysis. If concomitant use of these two drugs is necessary, the patient should be monitored for signs and symptoms of rhabdomyolysis (dark-colored urine and/or muscle pain, tenderness, or weakness)

[741] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Coadministration of colchicine and digoxin may result in rhabdomyolysis. If concomitant use of these two drugs is necessary, monitor patients for signs and symptoms of rhabdomyolysis (dark-colored urine and/or muscle pain, tenderness, or weakness) [741] . 7) Probable Mechanism: unknown Colestipol 1) Interaction Effect: decreased digoxin effectiveness 2) Summary: Colestipol may decrease digitalis glycoside absorption and increase clearance by interrupting the enterohepatic cycle [642] [643] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Since colestipol binds digoxin in the gastrointestinal tract, administer digoxin one hour before or four hours after colestipol. If this is not possible, separate administration times as much as possible. During concurrent therapy, monitor digoxin serum levels closely and observe the patient for changes in response to digoxin. Digoxin dosage adjustments may be necessary when starting or stopping colestipol. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) There is conflicting information concerning the effect of concomitant digoxin and colestipol therapy. Colestipol may bind digitalis glycosides in the gastrointestinal tract, thereby impairing their initial absorption and enterohepatic circulation. The half-life of elimination of digoxin was 55 hours versus the predicted halflife of 85 hours when colestipol was administered to a patient with digoxin intoxication [638] . A reduction in plasma digitoxin levels was seen when colestipol was administered to four patients with digitoxin intoxication [639] . b) Decreased plasma levels of digitoxin were not seen in 11 patients administered colestipol

[640] . Colestipol 10 g did not reduce the absorption of digoxin 0.25 mg in six healthy volunteers [641] . Conivaptan 1) Interaction Effect: increased digoxin plasma concentrations and increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: The P-glycoprotein substrate digoxin (dose of 0.5 mg) administered with oral conivaptan hydrochloride (40 mg twice a day) resulted in the decreased clearance of digoxin by 30%. The corresponding digoxin Cmax increased by 79%, and the AUC increased by 43%. Monitor digoxin concentrations [352] when conivaptan is added to, changed during, or discontinued from concomitant treatment with digoxin. Also, monitor patients for signs and symptoms of digoxin toxicity. Adjust digoxin dose accordingly. 3) Severity: major 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Monitor digoxin concentrations when conivaptan is added to, changed during, or discontinued from concomitant treatment with digoxin. Also, monitor patients for signs and symptoms of digoxin toxicity. Adjust digoxin dose accordingly. 7) Probable Mechanism: inhibition of CYP3A-mediated metabolism of digoxin Cyclopenthiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet.

7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Cyclophosphamide 1) Interaction Effect: decreased digoxin effectiveness 2) Summary: High dose cyclophosphamide chemotherapy may decrease digoxin tablet absorption by 20 to 45%. Digoxin capsules (Lanoxicap(R)) absorption has not been shown to be decreased significantly [356] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Substitute digoxin in liquid form (liquid or capsules containing liquid digoxin) for digoxin tablets, or substitute digitoxin, which is not affected by this interaction, for

digoxin. 7) Probable Mechanism: decreased gastrointestinal absorption Cyclosporine 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Concomitant administration of cyclosporine and digoxin has been reported to result in a decreased volume of distribution of digoxin (by 50 to 70%), increased half-life (by 30 to 40%), and increased digoxin levels [540] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Closely monitor serum digoxin levels within three to five days of initiating or discontinuing cyclosporine. 7) Probable Mechanism: kinetic alteration 8) Literature Reports a) Combined therapy with digoxin and cyclosporine reportedly resulted in digoxin toxicity in 2 patients with severe heart disease [539] . Both patients were receiving digoxin 0.375 mg daily, and developed gastrointestinal symptoms and arrhythmias following initiation of cyclosporine therapy. Significant increases in digoxin serum levels were observed in both patients. A subsequent study involving 2 other patients demonstrated significant decreases in the volume of distribution, as well as decreases in plasma clearance, of digoxin following cyclosporine administration; the digoxin half-life increased significantly. Cyclothiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination

potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Dalfopristin 1) Interaction Effect: increased digoxin levels and digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: The coadministration of digoxin and quinupristin/dalfopristin may result in increased serum digoxin levels [509] . Eubacterium lentum bacteria converts a portion of digoxin to inactive digoxin reduction products in the gut. Quinupristin/dalfopristin has been shown in vitro to have activity against Eubacterium lentum, which could result in less digoxin

being metabolized and more digoxin absorbed. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Monitor digoxin serum concentrations when quinupristin/dalfopristin is added to or withdrawn from therapy. Also, observe patients for a change in response to digoxin. 7) Probable Mechanism: decreased digoxin metabolism by GI bacteria Darunavir 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: Digoxin AUC and Cmax increased when coadministered with darunavir/ritonavir. If these agents are coadministered, digoxin treatment should be initiated at the lowest dose. Digoxin serum concentrations should be monitored closely and the digoxin dose titrated accordingly [654] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant use of digoxin and darunavir/ritonavir may result in greater digoxin plasma concentrations. When coadministered with darunavir/ritonavir, initiate digoxin treatment at the lowest dose. Monitor serum digoxin concentrations and titrate the digoxin dose accordingly [654] . 7) Probable Mechanism: unknown 8) Literature Reports a) Concurrent administration of digoxin and darunavir/ritonavir led to increases in digoxin AUC (least-square mean ratio 1.36, 90% confidence interval (CI), 0.81 to 2.27) and Cmax (leastsquare mean ratio 1.15, 90% CI, 0.89 to 1.48). Oral darunavir 600 mg/ritonavir 100 mg twice daily were coadministered with oral digoxin 0.4 mg in 8 subjects [654] . Demeclocycline 1) Interaction Effect: increased digoxin levels and digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Coadministration of tetracyclines, such as demeclocycline, and digoxin can result in increased digoxin levels [569] . In approximately 10 to 15% of patients, digoxin is converted to inactive metabolites by colonic bacteria within the gut. Inactivation of these enteric flora by antibiotics results in a

significant increase in absorption of the parent compound digoxin [568] . If digoxin and demeclocycline are administered concurrently, patients should be monitored for digoxin toxicity. A dosage adjustment for digoxin may be required. The risk of this interaction may be reduced if digoxin is given with Lanoxicaps(R) [111] . 3) Severity: major 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: If digoxin and demeclocycline are administered concurrently, monitor for digoxin toxicity. A dosage adjustment for digoxin may be required. Alternatively, the risk of this interaction may be reduced if digoxin is given as Lanoxicaps(R). 7) Probable Mechanism: inhibition of bacterial inactivation of digoxin resulting in increased digoxin bioavailability and digoxin toxicity 8) Literature Reports a) Approximately 10% of patients receiving digoxin convert 40% or more of the drug to cardio-inactive metabolites [111] . This inactivation may be attributed to gastrointestinal bacteria. Antibiotic therapy introduced to these patients has caused a marked decrease in digoxin reduction products and a marked rise in digoxin absorption and serum levels. It is concluded that changes in the enteric flora by antibiotics may alter the state of digitalization. Although data for the interaction between digoxin and doxycycline is unavailable, elevated serum digoxin concentrations by as much as 43 to 116% were observed after a 5-day course of tetracycline in 3 volunteers who produced large amounts of digoxin reduction products [568] . Dexlansoprazole 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Dexlansoprazole produces extensive and longlasting inhibition of gastric acid secretion. For some drugs, including digoxin, absorption from the gastrointestinal tract is enhanced at higher pH. When dexlansoprazole is coadministered with digoxin, reduced acidity may increase digoxin absorption, thus increasing its bioavailability [400] . Therefore, monitoring digoxin levels should be considered when concomitant dexlansoprazole and digoxin therapy is

required. A downward dosage adjustment of digoxin may also be necessary. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of dexlansoprazole and digoxin may interfere with the absorption of digoxin [400] . Therefore, consider monitoring digoxin levels in patients requiring concomitant dexlansoprazole and digoxin therapy. A downward dosage adjustment of digoxin may be necessary. 7) Probable Mechanism: increased absorption of digoxin Diazepam 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Concomitant administration of alprazolam or diazepam and digoxin has been reported to increase digoxin concentrations (5 to 100%). Increased monitoring of digoxin levels are suggested when either adding or deleting alprazolam or diazepam therapy to patients stabilized on digoxin therapy [510] [511] [512] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Monitor for signs of digoxin intoxication (eg, nausea, vomiting, diarrhea, persistent headache, confusion, fainting, visual disturbances). If symptoms are present, obtain a digoxin level and reduce dose accordingly. 7) Probable Mechanism: unknown Diclofenac 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Increased digoxin serum concentrations have been reported during concurrent therapy with digoxin and diclofenac. Patients on concomitant treatment should be closely followed for digoxin toxicity [320] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: If diclofenac must be administered to a digitalized patient, monitor the patient for signs of digoxin toxicity, including nausea, vomiting, and arrhythmias. If digoxin toxicity is suspected, a digoxin serum concentration should be determined. 7) Probable Mechanism: unknown

Dihydroxyaluminum Aminoacetate 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide

or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Dihydroxyaluminum Sodium Carbonate 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports

a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Dilevalol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia

[527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the

discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight

children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Diltiazem 1) Interaction Effect: increased serum digoxin concentrations and toxicity (nausea, vomiting, arrhythmias) 2) Summary: Concomitant administration of calcium channel blockers (nifedipine, diltiazem, nicardipine, verapamil) and digitalis glycosides (digoxin) occasionally results in up to 50% increases in serum digoxin concentrations [521] . The magnitude of increase appears to be dependent on the dose of calcium channel blocker being used [522] [523] [524] . Although generally of minimal clinical significance [525] [526] , patients with higher pre-existing serum digoxin concentrations are at greater risk for digitalis toxicity [523] [524] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor digoxin levels when initiating,

adjusting, and discontinuing diltiazem therapy to avoid possible over- or under-digitalization. Monitor patient for signs or symptoms of digitalis glycoside toxicity (nausea, vomiting, cardiac rhythm disturbance) and laboratory evidence of unacceptable increases in serum digoxin concentrations. Adjust dose as required. 7) Probable Mechanism: inhibition of renal and/or extrarenal digoxin clearance 8) Literature Reports a) A reduction in digoxin renal clearance was observed with the concurrent use of diltiazem. Eight volunteers received oral digoxin 0.25 milligram daily alone for 13 days; and then, on day 14, diltiazem 30 mg four times daily was added and therapy continued for 15 more days. Trough blood samples were obtained throughout the study for digoxin concentration determination. Following the digoxin dose on days 13 and 28, urine was collected for 24 hours. The coadministration of diltiazem resulted in a significant elevation of the mean steadystate digoxin trough concentration from 0.32 to 0.48 ng/mL. Seven subjects displayed elevated digoxin concentrations, one demonstrating a 0.3 milligram/mL increase. Elevations became evident within one week of concurrent therapy. Mean renal clearances significantly decreased from 223 to 153 mL/min. No change in creatinine clearance was observed among the subjects between the two phases. The authors attributed the interaction to decreased tubular secretion since digoxin renal clearance decreased but creatinine clearance remained constant. However, the determination of only trough concentrations does not allow for full determination of total body clearance and V(d), which would permit a better analysis [516] . b) The effect of diltiazem on digoxin steady-state concentrations was studied in 11 patients with congestive heart failure. All patients were receiving a chronic stable oral dose of digoxin (nine were receiving 0.25 mg and two were receiving 0.125 mg) for at least 14 days. Prior to initiating diltiazem therapy (60 mg three times daily), blood samples were obtained immediately prior to and 3, 6, and 24 hours after a dose of digoxin. Similar blood levels were drawn after three days of concurrent diltiazem therapy. Additionally, digoxin trough samples were obtained following the first and seventh doses of digoxin during combined therapy. A significant increase (36%) in digoxin concentration was observed during the third day of concurrent therapy. Trough concentrations increased significantly from 1.1 ng/mL with digoxin alone to 1.5 ng/mL on the seventh day of combined therapy. None of the patients demonstrated digoxin toxicity. The authors concluded that an interaction exists between diltiazem

and digoxin, but is of minor clinical importance unless digoxin concentrations are initially at the upper limit of normal [517] . c) Not all investigators have observed an elevation in digoxin concentrations with the addition of diltiazem. Nine patients with organic heart disease (five with congestive heart failure (CHF); four with atrial fibrillation) who were receiving chronic oral digoxin 0.25 mg daily were studied. Prior to diltiazem therapy, a 24-hour urine collection and a mid-interval blood sample were obtained. Patients then received diltiazem 30 mg four times daily for 4 to 11 days (mean 7 days), which was eventually increased to 60 mg four times daily for an additional 5 to 20 days (mean 11 days). Blood and urine were collected for digoxin analysis at each diltiazem dose. No significant change in mean, midpoint digoxin concentrations or digoxin renal clearance were observed during either diltiazem phase. Only one patient demonstrated a clinically significant rise in digoxin concentration. The authors concluded that no interaction exists between digoxin and diltiazem [518] . d) A lack of change in digoxin trough concentrations following the concurrent administration of several different doses of diltiazem was reported. Eight subjects received digoxin 0.25 mg for one week at which time a trough blood sample was obtained. Diltiazem 30 mg four times daily was then coadministered for seven days before a second trough blood sample was obtained. This procedure was repeated for diltiazem 60 mg four times daily and 90 mg four times daily. No significant difference from baseline (0.85 ng/mL) in any of the digoxin trough concentration with the addition of diltiazem was noted (0.86, 0.84, and 0.90 ng/mL, respectively) [519] . e) It was of the opinion of the authors that diltiazem did not elevate digoxin concentrations. The results of another study might explain the conflicting results observed among the trials described above. Twelve patients with congestive heart failure who were receiving a stable oral dose of beta-acetyldigoxin (0.1 to 0.3 mg daily) for several weeks were entered into a trial. Trough blood samples for digoxin determination were obtained prior to the initiation of diltiazem (60 mg three times daily) and during diltiazem therapy. Urine was collected for a 24-hour period prior to and on several occasions during diltiazem therapy in nine patients. Mean digoxin concentrations did not increase with the coadministration of diltiazem overall. However, when looking at individual data, 8 of 12 patients displayed significant increases ranging from 24% to 70% (mean 46%) in digoxin plasma concentrations with the coadministration of

diltiazem. In these individuals, total body clearance was reduced 28% (oral absorption was assumed to be 80%), but renal clearance remained unchanged, suggesting the interaction in these individuals occurred through nonrenal mechanisms. Mean total body clearance and renal clearance for the total study group was not reported. It should be noted that the calculation of total body clearance and renal clearance of digoxin was not optimal in this trial since only single trough samples were used [520] . Diphenoxylate 1) Interaction Effect: increased serum digoxin levels 2) Summary: Diphenoxylate is known to inhibit gastrointestinal motility. When used concurrently with a slow-dissolving digoxin preparation, increased absorption and serum digoxin levels may result [409] . This interaction can be avoided by using digoxin formulations that dissolve rapidly according to USP standards [410] [411] . 3) Severity: major 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Monitor digoxin serum levels when diphenoxylate and a slow-dissolving digoxin preparation are used concurrently. Adjust the digoxin dose if necessary. This interaction can be avoided by using digoxin formulations that dissolve rapidly according to USP standards. 7) Probable Mechanism: increased absorption due to decreased gastrointestinal motility Dirithromycin 1) Interaction Effect: increased digoxin serum concentrations and potentially digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: When digoxin has been coadministered with a related macrolide antibiotic, erythromycin, elevated serum digoxin concentrations have been reported [407] . Concomitant use of digoxin with dirithromycin could be expected to produce similar results. Further studies are needed to determine the pharmacokinetic and clinical effects of dirithromycin-digoxin cotherapy. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Monitor patients for signs and symptoms of digoxin toxicity if coadministration of digoxin and dirithromycin is necessary. Doses of digoxin may need to be

adjusted when dirithromycin is added to or withdrawn from therapy. 7) Probable Mechanism: unknown Disopyramide 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: In studies evaluating the interaction between digoxin (0.125 to 0.25 mg daily) and disopyramide (300 mg to 600 mg daily), the average increase in digoxin concentration ranged between 0.2 to 0.3 mcg/mL. Left ventricular dysfunction has been reported with concomitant therapy in patients with congestive heart failure (without changes in digoxin levels) [490] [491] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: The digoxin dose may need to be adjusted. Monitor for clinical signs of digoxin toxicity. 7) Probable Mechanism: unknown 8) Literature Reports a) Disopyramide significantly decreased the volume of distribution (from 672 L to 407 L) at steady-state and the elimination half-life (40 hours to 22 hours) of digoxin without affecting clearance or serum concentrations. Nine subjects were administered oral digoxin 0.375 mg daily and disopyramide 300 mg and 600 mg daily, followed by an intravenous bolus dose of digoxin (0.8 mg). Five of the nine subjects experienced pharmacokinetic changes in their digoxin parameters. The clinical significance of this interaction is unclear [489] . Dofetilide 1) Interaction Effect: an increased risk of cardiotoxicity (torsade de pointes) 2) Summary: The concomitant administration of digoxin and dofetilide may result in an increased risk of torsade de pointes [5] [184] . It is not clear whether this is due to a drug interaction or to the presence of severe structural heart disease in digoxin patients. No increased mortality was observed in patients taking concomitant digoxin and dofetilide [184] . If concomitant therapy is required, patients should be monitored for ventricular tachycardia. 3) Severity: major 4) Onset: unspecified

5) Substantiation: probable 6) Clinical Management: The concomitant administration of digoxin and dofetilide may result in an increased risk of torsade de pointes [5] [184] . If concomitant therapy is required, patients should be monitored for ventricular tachycardia. 7) Probable Mechanism: unknown Dopamine 1) Interaction Effect: an increased risk of cardiotoxicity (arrhythmias) 2) Summary: The concomitant administration of digoxin and dopamine may result in an increased risk of cardiac arrhythmias [5] . If concomitant therapy is required, patients should be monitored for cardiac toxicity. 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: The concomitant administration of digoxin and dopamine may result in an increased risk of cardiac arrhythmias [5] . If concomitant therapy is required, patients should be monitored for cardiac toxicity. 7) Probable Mechanism: unknown Doxycycline 1) Interaction Effect: increased digoxin levels and digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Coadministration of tetracyclines, such as doxycycline, and digoxin can result in increased digoxin levels [569] . In approximately 10 to 15% of patients, digoxin is converted to inactive metabolites by colonic bacteria within the gut. Inactivation of these enteric flora by antibiotics results in a significant increase in absorption of the parent compound digoxin [568] . If digoxin and doxycycline are administered concurrently, patients should be monitored for digoxin toxicity. A dosage adjustment for digoxin may be required. The risk of this interaction may be reduced if digoxin is given with Lanoxicaps(R) [111] . 3) Severity: major 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: If digoxin and doxycycline are

administered concurrently, monitor for digoxin toxicity. A dosage adjustment for digoxin may be required. Alternatively, the risk of this interaction may be reduced if digoxin is given as Lanoxicaps(R). 7) Probable Mechanism: inhibition of bacterial inactivation of digoxin resulting in increased digoxin bioavailability and digoxin toxicity 8) Literature Reports a) Approximately 10% of patients receiving digoxin convert 40% or more of the drug to cardio-inactive metabolites [111] . This inactivation may be attributed to gastrointestinal bacteria. Antibiotic therapy introduced to these patients has caused a marked decrease in digoxin reduction products and a marked rise in digoxin absorption and serum levels. It is concluded that changes in the enteric flora by antibiotics may alter the state of digitalization. Although data for the interaction between digoxin and doxycycline is unavailable, elevated serum digoxin concentrations by as much as 43 to 116% were observed after a 5-day course of tetracycline in 3 volunteers who produced large amounts of digoxin reduction products [568] . Dronedarone 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: Dronedarone inhibits P-gP transporter and digoxin is a P-gP substrate. Coadministration of digoxin and dronedarone may increase digoxin AUC by 150% [2] and increase the risk of arrhythmic or sudden death. Digoxin can potentiate dronedarone electrophysiologic effects, such as decreased AV-node conduction. Consider the need for concomitant therapy. If these two agents are coadministered, consider reducing the digoxin dose by 30% to 50%, closely monitor serum digoxin levels, and observe for digoxin toxicity [2] [236] . 3) Severity: major 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Coadministration of digoxin and dronedarone may result in an increase in digoxin exposure and increase the risk of arrhythmia or sudden death. Consider the need for concomitant therapy. If these agents are coadministered, consider reducing the digoxin dose by approximately 30% to 50%, closely monitor serum digoxin levels, and observe for digoxin toxicity [2]

[236] . 7) Probable Mechanism: inhibition of p-glycoprotein transporter of digoxin by dronedarone Epinephrine 1) Interaction Effect: an increased risk of cardiotoxicity (arrhythmias) 2) Summary: The concomitant administration of digoxin and epinephrine may result in an increased risk of cardiac arrhythmias [5] [189] . If concomitant therapy is required, patients should be monitored for cardiac toxicity. 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: The concomitant administration of digoxin and epinephrine may result in an increased risk of cardiac arrhythmias [5] [189] . If concomitant therapy is required, patients should be monitored for cardiac toxicity. 7) Probable Mechanism: unknown Epoprostenol 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: Concomitant use of digoxin and epoprostenol may result in elevated digoxin plasma concentrations due to a decrease in the oral clearance of digoxin. Increased digoxin exposure following epoprostenol initiation may be clinically significant in patients who are susceptible to digoxin toxicity [681] . Monitoring the patient for increased digoxin side effects and toxicity may be warranted. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Concomitant use of digoxin and epoprostenol has resulted in increased digoxin plasma concentrations, which may be clinically significant in patients predisposed to digoxin toxicity [681] . When used concomitantly, monitor patients closely for signs/symptoms of digoxin toxicity, including nausea, vomiting, and arrhythmias. 7) Probable Mechanism: reduced oral clearance of digoxin 8) Literature Reports

a) In a pharmacokinetics substudy, the digoxin oral clearance value decreased in patients (n=30) who were receiving digoxin for congestive heart failure when epoprostenol treatment was initiated. On day two of concomitant epoprostenol therapy, the apparent oral clearance value for digoxin was reduced by 15%; however, by day 87 of concomitant therapy, it had returned to baseline [681] . Erythromycin 1) Interaction Effect: increased digoxin levels and digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: The coadministration of digoxin and erythromycin may result in increased serum digoxin levels by increasing absorption in patients who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication may result. The risk of this interaction is reduced if digoxin is given as Lanoxicaps(R) [374] [375] [376] [377] . In approximately 10% of patients, bacteria in the GI tract convert a substantial amount of digoxin to inactive digoxin reduction products. Erythromycin alters the gut flora and, in these patients, less digoxin is metabolized, more digoxin is absorbed and serum levels rise [378] [379] . Enhanced gastric emptying induced by erythromycin may also be a factor [380] [381] . This effect occurs for weeks or months after erythromycin is discontinued. There is a significant increase in digoxin renal clearance after coadministration of erythromycin and clarithromycin [382] . A 15-year, population-based, nested case-control study revealed a strong association between digoxin toxicity and recent treatment with macrolides (clarithromycin, erythromycin and azithromycin), with clarithromycin imparting the highest risk [371] . 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Monitor digoxin serum concentrations when erythromycin is added to or withdrawn from therapy. Coadministration may increase digoxin absorption in patients

who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication may result. The risk of this interaction may be reduced if digoxin is given as Lanoxicaps(R). Also, observe patients for a change in response to digoxin. 7) Probable Mechanism: decreased inactivation of digoxin by bacterial metabolism in the lower intestine, thereby increasing digoxin bioavailability 8) Literature Reports a) A 15-year, population-based, nested case-control study revealed a strong association between digoxin toxicity and recent treatment with macrolides (clarithromycin, erythromycin and azithromycin), with clarithromycin imparting the highest risk. Patients who received at least 1 prescription a macrolide antibiotic during digoxin treatment and who were hospitalized for digoxin toxicity within 14 days of starting the antibiotic (n=1659; median age, 80 years (yr), interquartile range (IQR), 75 to 85 yr; 34% male) were matched with controls (n=6439; median age 80 yr; IQR, 75 to 85 yr). Analysis revealed a strong correlation between digoxin toxicity and recent treatment with clarithromycin (adjusted odds ratio (OR), 14.83; 95% CI, 7.89 to 27.86), as well as erythromycin (adjusted OR, 3.69; 95% CI, 1.72 to 7.9) and azithromycin (adjusted OR, 3.71; 95% CI, 1.1 to 12.52) compared with no antibiotic treatment. The risk of digoxin toxicity was 4 times greater following treatment with clarithromycin compared with erythromycin (OR, 4.02; 95% CI, 1.49 to 10.81) and azithromycin (OR, 4; 95% CI, 1.06 to 15.73). No difference in risk of digoxin toxicity was observed between erythromycin and azithromycin (OR, 0.99; 95% CI, 0.24 to 4.18). Based on the proposed mechanism for the macrolide-digoxin interaction (inhibition of p-glycoprotein-mediated digoxin transport), as expected, there was no correlation with cefuroxime (no effect on p-glycoprotein) use and hospitalization for digoxin toxicity (adjusted OR, 0.85; 95% CI, 0.21 to 3.41) [371] . b) Digoxin toxicity, presumably induced by erythromycin, was described in an 86-year-old woman [372] . The patient had been receiving oral digoxin 0.25 mg daily and was given erythromycin 250 mg orally 4 times a day for 10 days for the treatment of pharyngitis and otitis media. The digoxin serum levels increased from a trough of 1.9 nmol/L to 5.1 nmol/L six days after initiation of erythromycin therapy. The only sign of toxicity was persistent lethargy. Digoxin was discontinued, resulting in improvement over a period of 1 week. Six weeks later, digoxin 0.125 mg/day was reinstituted, resulting in steady-state trough serum levels of 1.2 to 1.4 nmol/L over the ensuing year. The mechanism of the interaction was presumed to be inhibition of Eubacterium lentum by erythromycin, which

caused interference in the bacterial conversion of digoxin into inactive digoxin-reduction products. c) The affects of erythromycin and clarithromycin on pharmacokinetics of intravenously administered digoxin (0.5 milligrams (mg)) were studied in nine healthy male volunteers. Subjects were randomly assigned to the following treatments: 1) digoxin only 2) digoxin plus erythromycin 3) digoxin plus clarithromycin. Subjects took erythromycin or clarithromycin on the day before digoxin dosing and during the following 4 days. Erythromycin 200 mg was given 4 times a day and clarithromycin 200 mg was given twice daily. Neither erythromycin or clarithromycin caused significant changes in AUC, clearance, volume of distribution and half-life of digoxin. There was a significant increase in urinary digoxin excretion when erythromycin and clarithromycin were coadministered (digoxin alone: 98.4 mL/min; digoxin with erythromycin: 137.3 mL/min; digoxin and clarithromycin: 133.6 mL/min). Digoxin is a substrate of p-glycoprotein while erythromycin and clarithromycin inhibit p-glycoprotein-mediated transport. Clarithromycin and erythromycin do not have a significant effect on serum digoxin disposition when digoxin is administered intravenously. This report does not support the hypothesis that the increase in digoxin concentrations by macrolides is due to reduced renal excretion of digoxin [373] . Esmolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528]

. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone

[532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial

ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Esomeprazole 1) Interaction Effect: decreased digoxin plasma concentrations 2) Summary: Esomeprazole produces extensive and longlasting inhibition of gastric acid secretion. For some drugs, including digoxin, absorption from the gastrointestinal tract is enhanced by the presence of gastric acid. When esomeprazole is coadministered with digoxin, reduced acidity may compromise digoxin absorption, thus decreasing its bioavailability [576] [577] . Therefore, monitoring the patient for digoxin efficacy should be considered if esomeprazole is being used concurrently with digoxin. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of digoxin and esomeprazole may interfere with the absorption of digoxin [576] [577] . Therefore, consider monitoring the patient for digoxin efficacy if esomeprazole is being used concurrently with digoxin. 7) Probable Mechanism: decreased digoxin absorption Ethacrynic Acid 1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Concomitant ethacrynic acid and digoxin therapy has been reported to result in hypokalemia and digitalis toxicity [443] [444] [445] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Patients receiving a digitalis preparation and ethacrynic acid should be closely monitored for hypokalemia. 7) Probable Mechanism: diuretic-induced hypokalemia Etodolac 1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Etodolac, like other nonsteroidal antiinflammatory

agents, may cause changes in the elimination of digoxin through effects on renal prostaglandins. Patients who receive digoxin and etodolac should be observed for the development of digoxin toxicity [682] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Monitor for signs of digoxin intoxication (e.g., nausea, vomiting, diarrhea, persistent headache, confusion, fainting, visual disturbances). If symptoms are present, obtain a digoxin level and reduce dose accordingly. 7) Probable Mechanism: reduced renal clearance of digoxin Etravirine 1) Interaction Effect: increased exposure and plasma concentrations of digoxin 2) Summary: The mean AUC and Cmax of digoxin increased by approximately 19% and 18%, respectively, when coadministered with etravirine. For patients initiating a combination of etravirine and digoxin, the lowest dose of digoxin should be used. For patients on a stable digoxin regimen and initiating etravirine, no dose adjustment of either etravirine or digoxin is needed. Monitoring of digoxin serum concentrations is recommended [644] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: established 6) Clinical Management: Patients concurrently treated with digoxin and etravirine may be at an increased risk for digoxin toxicity. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. Patients who are initiating a combination of etravirine and digoxin should be started on the lowest dose of digoxin. For patients who are on a stable digoxin regimen and initiating etravirine, no dose adjustment of either digoxin or etravirine is needed [644] . 7) Probable Mechanism: unknown 8) Literature Reports a) In a pharmacokinetic drug interaction study in 16 subjects receiving etravirine, coadministration of a single-dose of digoxin 0.5 mg increased the mean digoxin AUC ratio by 1.19 (90% confidence interval (CI), 0.96 to 1.49) and mean digoxin Cmax ratio by 1.18 (90% CI, 0.9 to 1.56) [644]

. Exenatide 1) Interaction Effect: a decrease in digoxin plasma concentrations 2) Summary: Exenatide decreases digoxin plasma concentrations by slowing gastric emptying. Coadministration of exenatide decreased the digoxin Cmax by 17% and delayed the Tmax by approximately 2.5 hours; however, the digoxin AUC was unchanged [182] . Digoxin serum levels should be measured before initiating exenatide, and the dose of digoxin should be increased by approximately 20% to 40% as necessary. Monitoring of digoxin levels and clinical efficacy is recommended during concomitant therapy [5] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant administration of digoxin and exenatide may decrease digoxin plasma concentrations. The patient should wait at least 1 hour after taking digoxin before using exenatide [182] . Digoxin serum levels should be measured before initiating exenatide, and the dose of digoxin should be increased by approximately 20% to 40% as necessary. Monitoring of digoxin levels and clinical efficacy is recommended during concomitant therapy [5] . 7) Probable Mechanism: slowed gastric emptying by exenatide 8) Literature Reports a) The administration of multiple doses of exenatide 10 mcg twice daily 30 minutes before oral digoxin 0.25 mg once daily decreased the digoxin Cmax by 17% and delayed the Tmax by approximately 2.5 hours; however, the digoxin AUC was unchanged [182] . Ezogabine 1) Interaction Effect: increased digoxin serum concentrations 2) Summary: The N-acetyl metabolite of ezogabine (NAMR) may increase digoxin serum concentrations due to concentration-dependent inhibition of P-glycoprotein-mediated transport and inhibition of the renal clearance of digoxin. If concomitant use of digoxin with ezogabine is required, monitoring of digoxin serum levels is recommended

[683] . 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Monitor digoxin serum concentrations when digoxin is coadministered with ezogabine. Patients concurrently treated with digoxin and ezogabine may be at an increased risk for digoxin toxicity [683] . 7) Probable Mechanism: concentration-dependent inhibition of P-glycoproteinmediated transport and inhibition of the renal clearance of digoxin by the N-acetyl metabolite of ezogabine Felodipine 1) Interaction Effect: transient increases in the digoxin serum concentration 2) Summary: Concomitant felodipine and digoxin administration produces only transient increases in plasma digoxin concentrations which are not sustained with continued administration [290] . Twelve patients with left ventricular failure who were on stable, long-term digoxin treatment received felodipine 2.5 mg or 5 mg twice daily for seven days, followed by seven days of washout and a further week of felodipine 10 mg twice daily. Following the first doses of felodipine 2.5 mg, 5 mg, and 10 mg, mean maximum plasma concentrations of digoxin were significantly increased by 35% to 39%. The area under the digoxin concentration-time curve for 24 hours was not different from pretreatment values and no change in 24-hour urinary excretion of digoxin was observed. This interaction may be of clinical relevance only in patients whose plasma digoxin concentration is in the upper portion of the therapeutic range or in patients with pre-existing renal insufficiency. Impaired renal clearance may be the explanation for the increased peak plasma levels of digoxin seen in this study. 3) Severity: minor 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Monitor the patient for signs of digoxin toxicity (nausea, vomiting, arrhythmias) when felodipine therapy is initiated. This especially applies to a patient who is already in the upper therapeutic digoxin concentration range or who is renally impaired. 7) Probable Mechanism: unknown Fingolimod 1) Interaction Effect: severe bradycardia or heart block 2) Summary: Both digoxin and fingolimod may decrease heart rate and atrioventricular conduction

[362] [363] . Due to the risk of severe bradycardia and heart block with the concomitant use of digoxin and fingolimod, evaluate the possibility of switching from digoxin to a drug that does not lower heart rate or slow atrioventricular conduction prior to fingolimod initiation. If treatment with digoxin is necessary, continuous overnight ECG monitoring after the first fingolimod dose is recommended [362] . 3) Severity: major 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Due to the risk of severe bradycardia and heart block with the concomitant use of digoxin and fingolimod, evaluate the possibility of switching from digoxin to a drug that does not lower the heart rate or slow atrioventricular conduction prior to fingolimod initiation. If treatment with digoxin is necessary, continuous overnight ECG monitoring after the first fingolimod dose is recommended [362] . 7) Probable Mechanism: additive heart-rate-lowering effects Flecainide 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Concomitant administration of digoxin (0.25 mg daily) and flecainide (200 mg daily) has been reported to increase peak digoxin concentrations by 13 to 100%, increase the AUC by 25 to 40%, and reduce the digoxin renal clearance (10 to 20%). In patients with borderline high digoxin levels or those sensitive to digoxin, the concurrent use of flecainide may increase digoxin toxicity [453] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Decreasing the digoxin dose may be necessary. Monitor ECG and serum digoxin levels. 7) Probable Mechanism: unknown 8) Literature Reports a) Concomitant oral flecainide (200 mg twice daily) and maintenance oral digoxin therapy (0.25 mg daily) have been reported to result in increases in serum digoxin concentrations [451] . These increases are not considered to be a clinical problem in most patients. The increases are less than those observed with

digoxin-quinidine. However, patients with digoxin levels in the upper range of therapeutic could exhibit digoxin toxicity. In addition, prolongation of the PR interval on the EKG was observed in six of 15 subjects receiving combined therapy, suggesting that EKG monitoring might be indicated in patients with impaired AV conduction receiving the combination [451] . b) The average increase in pre-dose digoxin levels during combined therapy was 24% in healthy subjects. EKG changes were minimal, except for slight prolongation of the PR interval in some subjects. It is felt that the increases in digoxin serum levels during concurrent flecainide therapy are not clinically relevant for most patients. However, in patients with digoxin plasma levels in the upper end of the therapeutic range, monitoring should be considered to prevent digoxin toxicity [452] . Fluoxetine 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: One case report describes a 93-year-old female stabilized on digoxin who experienced toxic levels of digoxin after fluoxetine had been added to her regimen for depression. Rechallenge with fluoxetine again caused her digoxin levels to increase dramatically. While the mechanism of this interaction is not clear, it could be related to displacement of digoxin from binding sites or reduced clearance of digoxin [514] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Patients receiving fluoxetine and digoxin therapy concomitantly should be monitored for increasing levels of digoxin, along with signs and symptoms of digoxin toxicity, including anorexia. 7) Probable Mechanism: unknown 8) Literature Reports a) Digoxin 0.125 mg daily was being administered to a 93-yearold female for congestive heart failure and paroxysmal atrial fibrillation. Digoxin levels ranged from 1.0 to 1.4 nmol/L during the two months preceding the initiation of fluoxetine 10 mg daily. Within one week, the patient complained of anorexia. Her digoxin level measured 4.2 nmol/L, while renal function and potassium levels remained unchanged. Both digoxin and fluoxetine were discontinued, and her digoxin level returned to normal in five days with resolution of the anorexia. During the next three weeks her digoxin serum levels ranged from 0.9

nmol/L to 1.4 nmol/L. Because the symptoms of depression persisted, fluoxetine was again initiated at 10 mg daily and the digoxin serum level was closely monitored. After two days of fluoxetine therapy, the digoxin level increased to 2.0 nmol/L, and after four days it was 2.8 nmol/L. Renal function remained unchanged, as did serum electrolytes. The patient again experienced anorexia, and treatment with fluoxetine was discontinued [513] . Frangula 1) Interaction Effect: hypokalemia leading to digoxin toxicity 2) Summary: Buckthorn bark or berry acts as a stimulant laxative. Buckthorn is noted in the German Commission E Monograph to be associated with a loss of potassium [230] . As with other plant anthranoid laxative sources, loss of potassium can occur secondary to excessive or prolonged use, termed "laxative abuse" [230] [231] . Potassium loss is partly due to direct loss in the feces and partly as secondary renal effect associated with sodium loss [231] . Patients taking buckthorn bark or berry for more than 1 to 2 weeks may experience hypokalemia (signs and symptoms include lethargy, muscle cramps, headaches, paresthesias, tetany, peripheral edema, polyuria, breathlessness, and hypertension). Patients also taking digoxin are predisposed to signs and symptoms of digoxin toxicity, including anorexia, nausea, vomiting, diarrhea, weakness, visual disturbances, and ventricular tachycardia). Concomitant use should be avoided. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Patients who are taking digoxin should be advised to avoid concomitant use with buckthorn bark or berry. If digoxin toxicity occurs, potassium should be monitored and supplemented if necessary while discontinuing buckthorn bark or berry. 7) Probable Mechanism: laxative effect of buckthorn bark or berry 8) Literature Reports a) Laxative abuse using plants such as buckthorn bark or berry that contain anthraquinone glycosides can lead to depletion of 25-50% of potassium due to water and electrolyte losses [227] .

b) Diuretic and digoxin maintenance therapy in 12 congestive heart failure patients who were studied for hypokalemia and cardiac arrhythmias resulted in digoxin toxicity in 6 patients with normal serum digoxin levels. The daily dose of digoxin was 0.30 +/- 0.06 milligrams (mg) orally, and the mean serum concentration was 1.52 +/- 0.17 nanomoles/milliliter (nmol/mL). The mean serum potassium level was 3.41 +/- 0.09 millimoles/liter (mmol/L) for the 12 subjects [228] . c) Of 79 men with arrhythmias associated with digoxin intoxication, 24 were hypokalemic and 55 were normokalemic. In the hypokalemic group, mean serum potassium was 3 milliequivalents/liter (mEq/L) and mean serum digoxin level was 1.1 ng/mL compared to 4.7 mEq/L potassium and 3.7 ng/mL digoxin in the normokalemic group [229] . Furosemide 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Concomitant furosemide and digitalis therapy can result in digitalis toxicity secondary to hypokalemia and possibly hypomagnesemia [292] [293] [294] [295] [296] [297] [298] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Frequent monitoring of potassium and possibly magnesium with appropriate replacement is recommended; educate patients about the importance of maintaining adequate intake of dietary potassium and/or potassium supplements. 7) Probable Mechanism: potassium and magnesium loss 8) Literature Reports a) Animal studies have demonstrated that furosemide does not interact with digoxin to result in increased digoxin serum concentrations and enhancement of therapeutic effects [291] . Gatifloxacin

1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Only modest increases in maximum concentration (Cmax) and area under the concentration-time curve (AUC) of digoxin were seen (12% and 19%, respectively) in eight of 11 healthy volunteers receiving oral gatifloxacin 400 mg once daily and oral digoxin 0.25 mg once daily for seven days. However, in three of the 11 subjects, the digoxin Cmax increased by 18%, 29%, and 58% while the digoxin AUC increased by 66%, 104%, and 79%, and digoxin clearance decreased by 40%, 51%, and 45%. Digoxin did not alter the pharmacokinetics of gatifloxacin [668] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Dose adjustments of digoxin are not warranted when initiating gatifloxacin therapy. However, the patient should be monitored for signs of digoxin toxicity, including nausea, vomiting, and arrhythmias. If digoxin toxicity is suspected, a digoxin serum concentration should be determined and the dose of digoxin should be adjusted accordingly. 7) Probable Mechanism: unknown Glycopyrrolate 1) Interaction Effect: increased plasma concentrations of digoxin 2) Summary: Glycopyrrolate reduces gastrointestinal transit time. Concomitant use of glycopyrrolate and digoxin tablets may result in increased plasma concentrations of digoxin. Monitor increased digoxin effects if glycopyrrolate is coadministered with digoxin. Consider using other oral digoxin dosage form such as liquid or capsule [289] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of glycopyrrolate and digoxin tablets may result in increased plasma concentrations of digoxin. Monitor increased digoxin effects if glycopyrrolate is coadministered with digoxin. Consider using other oral digoxin dosage form such as liquid or capsule [289] . 7) Probable Mechanism: altered release of digoxin slow dissolution oral tablets due to reduced gastrointestinal transit time by glycopyrrolate Gossypol 1) Interaction Effect: reduced digoxin efficacy and/or increased digoxin toxicity 2) Summary: Gossypol delayed the onset of digoxin-induced

toxicity by reducing the sensitivity of heart muscle to digoxin in vitro. Heart failure caused by gossypol may be resistant to treatment with positive inotropic drugs that act by increasing intracellular calcium [563] . Gossypol may theoretically increase digoxin toxicity due to potassium depletion [564] [565] [566] [567] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: The clinical significance of this interaction is not known. The gossypol dose used in vitro which caused cardiac effects was 10 times higher than the usual peak plasma level achieved in humans following a usual oral dose of 20 milligrams gossypol. Cardiac effects may occur following chronic use of gossypol, presuming that gossypol accumulates in the body with long-term administration. Concomitant use should be avoided if possible. 7) Probable Mechanism: Reduction of calcium release from the sarcoplasmic reticulum may explain the initial temporary positive inotropic effect of gossypol and calcium exhaustion from these areas may explain its negative inotropic effect as well as reduced effectiveness of positive inotropic interventions 8) Literature Reports a) Gossypol in concentrations of 20 to 30 micromolar delayed the onset of digoxin-induced toxicity in atrial muscle from guinea-pig heart muscle in vitro. Positive inotropic responses followed by arrhythmias and after-contractions occurred when digoxin in doses of 1.6 and 5 micromolar was added to atrial muscle preparations. Pretreatment with gossypol delayed these effects in a dose-dependent manner (p less than 0.05 compared to control). Gossypol doses of 10 and 20 micromolar did not significantly delay toxicity following incubation with digoxin at concentrations of 1.6 and 5 micromolar, respectively [558] . b) Two patients taking gossypol for metastatic adrenal cancer developed hypokalemia two to three weeks after gossypol discontinuation. Serum potassium levels were 2.3 millimoles/liter (mmol/L) and 2.6 mmol/L (normal range: 3.5-4.0 mmol/L) [559] . c) Potassium loss was not deterred by co-administration of triamterene or supplementation with potassium in a randomized

trial with 120 male volunteers. Volunteers were divided into four groups that received gossypol alone, gossypol plus potassium salt 1.5 grams daily, gossypol plus triamterene 50 milligrams (mg) daily, or no treatment. Gossypol treatment began with a 60 day loading phase of gossypol 20 mg daily, followed by gossypol 50 mg weekly for 10 months. At the end of the 60-day loading phase, potassium levels declined in gossypol -treated groups, but not the control group (p less than 0.05). At the end of the maintenance phase, average serum potassium was 3.98 +/- 0.08 milliequivalents/liter (mEq/L) in the gossypol group, 4.11 +/- 0.14 mEq/L in the gossypol /potassium supplementation group, 3.77 +/- 1.08 mEq/L in the gossypol /triamterene-treated group, and 3.92 +/- 0.05 mEq/L in the control group. All gossypol treatment groups had potassium levels significantly lower at the end of the maintenance phase versus admission (p less than 0.05). No patient had a decline in potassium below 3 mEq/L. One case of hypokalemic paralysis (serum potassium 2 mEq/L) occurred one month after the end of treatment with gossypol and triamterene. gossypol may cause renal impairment and potassium supplementation or blocking agents, such as triamterene, may not affect the return of potassium levels to normal even after gossypol treatment is stopped [560] . d) Gossypol reduced serum potassium levels in a double-blind, randomized, controlled study of 152 male volunteers to evaluate the efficacy of gossypol as a male contraceptive. Gossypol 20 milligrams (mg)/day was taken by 75 subjects initially, followed by a maintenance phase of 50 mg/week, and continued for at least 14.5 months. One patient experienced a decrease in serum potassium level from 4.8 milliequivalents/liter (mEq/L) on admission to 3.7 mEq/L at the end of the loading phase (2.5 months), which further declined to 2.6 mEq/L, after which treatment was stopped. Another patient whose potassium was 3.5 mEq/L at admission declined to 2.4 mEq/L at 9 months, after which treatment was stopped. In the entire treatment group, potassium levels were 4.3 +/- 0.03 mEq/L at admission and 3.8 +/- 0.04 mEq/L after 14.5 months of gossypol use (p less than 0.05) [561] . e) Over a 5-year period, 148 men took gossypol as a contraceptive. Seven men (5%) developed hypokalemic paralysis with associated serum potassium levels of 2 to 2.73 milliequivalents/liter (mEq/L). Dietary potassium intake was low in these men and may have increased their risk of this adverse effect. Renal potassium excretion studies concluded that the majority of gossypol-related cases of hypokalemia involved renal potassium loss [562]

. Hydrochlorothiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and

without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Hydroflumethiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436]

. Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Hydroxychloroquine 1) Interaction Effect: increased serum digoxin concentrations 2) Summary: Concurrent digoxin and hydroxychloroquine therapy has been reported to result in increased serum digoxin concentrations. In two elderly patients on chronic digoxin therapy (0.25 mg daily) who were started on hydroxychloroquine (250 mg twice daily) for rheumatoid arthritis, the serum digoxin concentrations increased to 2.5 ng/mL and 2.3 ng/mL. One month following the discontinuation of hydroxychloroquine, the serum digoxin concentrations were 0.7 ng/mL and 0.6 ng/mL, respectively. In these two cases neither patient showed signs of digoxin toxicity [667] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Avoid concurrent use of digoxin and hydroxychloroquine. If these two agents must be used together, monitor the patient carefully for signs of digoxin toxicity. Also follow serum digoxin concentrations more frequently during hydroxychloroquine therapy and for at least one month after the discontinuation of hydroxychloroquine therapy. 7) Probable Mechanism: unknown Indapamide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be

considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Indecainide 1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias)

2) Summary: Concomitant indecainide and digoxin therapy produced an increase in digoxin levels in 3 patients [709] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: When initiating or discontinuing indecainide therapy in patients on digoxin, plasma digoxin levels should be monitored closely; adjust or hold the digoxin dose as needed. 7) Probable Mechanism: altered digoxin clearance 8) Literature Reports a) Concomitant digoxin and indecainide therapy may result in increased digoxin plasma levels [708] . During a randomized, double-blind parallel study with placebo control, indecainide was compared with quinidine; five indecainide-treated patients were also receiving digoxin. Digoxin plasma concentrations were determined in 4 patients before and after indecainide therapy. In 3 patients, the mean increase of digoxin was 201% (range, 47% to 300%). It was also noted that once indecainide was discontinued, the digoxin concentrations decreased significantly. Indomethacin 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Concurrent use of digoxin and indomethacin resulted in increased digoxin levels [426] and a significant decrease in urine output in premature and fullterm infants [427] [428] [429] . The average increase in digoxin concentrations was about 1 ng/mL, with a digoxin half-life increase of 1.5 to 2-fold. One study of digoxin and indomethacin in adults found increased serum digoxin, although the range of increase varied widely [430] , and a pharmacokinetic study in adults found no effect [431] . 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: When changing indomethacin therapy, monitor adults for serum digoxin levels and signs of toxicity such as nausea, vomiting, or changes in mental status. When using

this combination in premature infants, monitor serum digoxin levels and ECGs frequently to detect digoxin toxicity early. 7) Probable Mechanism: decreased renal clearance of digoxin 8) Literature Reports a) The renal depressant effects of indomethacin contributed to increased digoxin serum levels in an 1800 gram male infant being treated for congestive heart failure caused by persistent patent ductus arteriosus [422] . b) A case study reported toxic levels of digoxin when indomethacin was added in a full-term neonate. In this case, serum digoxin rose to 8.2 ng/mL (10.5 nmol/L) with a pronounced reduction in urine output. Clinical signs of toxicity were not apparent [423] . c) Concomitant therapy with oral indomethacin and digoxin was reported to result in significant elevations in serum digoxin concentrations, to potentially toxic levels, in preterm infants (from 2.2 to 3.2 ng/mL). This effect was correlated with a decrease in urine output. The half-life of digoxin increased significantly (to 97 hours) following indomethacin as compared with age-matched controls (half-life 43 hours) [424] . The authors suggest that digoxin dosages be reduced by 50% when indomethacin is added to digoxin therapy in preterm infants. d) A study reported an increase in serum digoxin (from 0.73 +/0.34 to 1.02 +/- 0.43 nmol/L) in 10 patients who were receiving chronic digoxin therapy when indomethacin 50 mg three times daily was added to their regimen. Eight patients who received concomitant ibuprofen 600 mg three times daily did not experience an alteration in steady-state serum digoxin concentration [425] . Itraconazole 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Several case reports demonstrate that concurrent use of itraconazole and digoxin can lead to elevation of digoxin serum levels resulting in toxicity [416] . Proposed mechanisms for these changes include inhibition of metabolism of digoxin and inhibition of renal elimination of digoxin [417] [418]

[419] [420] [421] . Monitor for signs of digoxin toxicity and measure serum levels when digoxin and itraconazole are used concurrently. 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: When itraconazole and digoxin are given concurrently, the digoxin dose may need to be reduced; serum digoxin levels should be monitored when any changes to intraconazole therapy are made. 7) Probable Mechanism: inhibition of digoxin metabolism and clearance 8) Literature Reports a) A study reported the case of a 78-year-old man who had been stabilized on digoxin 0.25 mg daily for two years (serum digoxin level was 1.4 mcg/L); other medications included furosemide and warfarin. Thirteen days after oral itraconazole 400 mg daily was added to his regimen, he experienced blurred vision, nausea, and vomiting. Five days later the itraconazole was discontinued, but the symptoms continued and worsened. Eight days later the patient was admitted with sinus bradycardia and a temporary pacemaker was inserted. His serum digoxin level was 5.6 mcg/L; digoxin was discontinued and the serum level decreased over the next several days [412] . b) A 67-year-old COPD patient was treated with itraconazole 200 mg daily for an Aspergillus fumigatus respiratory infection [413] . His drug regimen included inhaled bronchodilators and steroids, verapamil 240 mg, and digoxin 250 mcg daily (serum level, 2.1 nmol/L). Nine days after initiation of itraconazole, the patient complained of lethargy and nausea; his digoxin serum concentration was measured at 5.4 nmol/L. Digoxin was discontinued and the serum concentration dropped to 2.7 nmol/L after four days; after another four days, the serum level was 1.2 nmol/L. Digoxin was restarted at 62.5 mcg daily with regular monitoring scheduled. c) The effect of itraconazole on the pharmacokinetics of digoxin was studied in ten healthy volunteers. Subjects were randomized to receive itraconazole 200 mg once daily for five days or placebo. On day 3 each subject received a single oral dose of digoxin 0.5 mg. The average area under the plasma concentration curve was significantly increased by approximately 50% and the renal excretion of digoxin was significantly decreased by 20% during administration of itraconazole. Although the peak plasma concentration and half-

life of digoxin were increased the change was not statistically significant. It was proposed that itraconazole inhibited the pglycopeptide mediated renal excretion of digoxin [414] . d) Two cases of digoxin toxicity associated with itraconazole were reported. A 60-year-old renal transplant patient on tacrolimus experienced digoxin toxicity after receiving itraconazole and digoxin concomitantly. The patient had symptoms of shortness of breath, edema, decreased urine output, and nephrotoxicity. Electrocardiography showed atrial fibrillation with a ventricular rate of 90 to 105 beats per minute (BPM). Serum creatinine was 4.7 mg/dL and hemodialysis was initiated. Tacrolimus trough level was 8 ng/mL on 2 mg twice daily. Seven days after discharge the patient was readmitted in atrial fibrillation with a ventricular rate of 30 BPM. Serum digoxin levels were 3.9 ng/mL, tacrolimus blood level was 16.7 ng/mL, Scr was 7.9 mg/dL, and K+ was 5.3 mEq/dL. Ventricular rate increased to 61 BPM 7 hours after digoxin, atenolol, and diltiazem were discontinued. Serum digoxin levels decreased from 3.9 ng/mL to 2 ng/mL over the next 5 days. A 49-year-old Asian male with end-stage renal disease developed digoxin toxicity after receiving itraconazole therapy. The patient presented with fever, cough with hemoptysis, shortness of breath, and malaise for 4 days. Bronchoscopy cultures revealed Aspergillus niger and the patient was treated with amphotericin B lipid complex (ABLC) for 1.5 months. Itraconazole was initiated after the course of ABLC was completed. The patient developed headache, chills, fever, and chest pain several days after itraconazole was initiated. One week later he developed vomiting and blurred vision and presented to the emergency room with sinus bradycardia, SCr 2.7 ng/mL, and serum digoxin level 3.9 ng/mL. Digoxin was discontinued and symptoms subsequently resolved. The author suggests appropriate monitoring with concomitant use of itraconazole and digoxin [415] . Ivacaftor 1) Interaction Effect: increased digoxin exposure 2) Summary: Coadministration of digoxin, a P-glycoprotein substrate [5] , and ivacaftor, a P-glycoprotein inhibitor, may cause increased digoxin exposure [664] . Monitor digoxin serum concentrations and adjust the dose if necessary. Additionally, monitor for side effects and signs and symptoms of digoxin toxicity [5]

. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Use caution if digoxin and ivacaftor are coadministered as this may result in increased digoxin exposure [664] . Monitor digoxin serum concentrations and adjust the dose if necessary. Additionally, monitor for side effects and signs and symptoms of digoxin toxicity [5] . 7) Probable Mechanism: inhibition of P-glycoprotein-mediated digoxin absorption and metabolism Kaolin 1) Interaction Effect: decreased digoxin effectiveness 2) Summary: Commonly used anti-diarrheal products containing kaolin have been demonstrated to reduce the absorption of digoxin tablets by 20% to 62%. Less of a reduction in bioavailability occurs with the digoxin tablets [386] [387] [388] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: If both drugs are required, give kaolin at least two to three hours after digoxin therapy. 7) Probable Mechanism: altered absorption of digoxin Ketoconazole 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: Rare cases of elevated digoxin plasma concentrations have been reported with concomitant use of digoxin and ketoconazole. It is unclear whether this increase in digoxin plasma levels was due to the combination use of these drugs. Therefore, if these agents are coadministered, digoxin serum concentrations should be monitored [383] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of digoxin and ketoconazole may result in elevated digoxin concentrations. Monitor digoxin levels closely if these drugs are coadministered [383] . 7) Probable Mechanism: unknown Khella

1) Interaction Effect: reduced effectiveness of digoxin 2) Summary: Visnadin has been identified as one of several active components of khella. This lactone has been shown to antagonize toxic effects of digitoxin in animals [337] . While this can be used for therapeutic advantage in cases of toxicity, it is reasonable to assume that visnadin will also affect the cardiac glycosides when used in the normal dosage range. The exact mechanism of antagonistic action of visnadin on cardiac glycosides is not yet known but may be related to competitive antagonism [337] . Visnadin increases coronary perfusion and cardiac contractile force while only slightly increasing oxygen consumption by increasing myocardial glucose reserve [338] . Visnadin, khellin, visnagan, samadin, and dihydrosamidin (all components of khella, Ammi visnaga) are potent coronary vasodilators [339] [338] [340] . Visnadin and samidin are potent cAMP-phosphodiesterase inhibitors [340] . Caution is advised if khella and digoxin are used concomitantly. Frequent monitoring of blood digoxin levels and symptomatology is recommended. 3) Severity: moderate 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Animal data suggest that khella may counter digoxin adverse effects. While this may be used to advantage to counter digoxin toxicity, it is unknown how patients stabilized on digoxin will be affected. Patients should be closely monitored to determine if the desired pharmacologic effect of digoxin is achieved. Monitoring of blood digoxin levels is advised. 7) Probable Mechanism: increased coronary perfusion and cardiac contractile force, coronary vasodilation, cAMPphosphodiesterase inhibition 8) Literature Reports a) Digitoxin was administered to 10 mice by subcutaneous (SC) injection with escalating oral visnadin (khella) doses (0 to 450 milligrams/kilogram (mg/kg)). The LD50 of digitoxin was 14.4 +/0.48 mg/kg with no visnadin administered versus 24.4 +/- 0.78 mg/kg when coadministered with 300 mg/kg of visnadin. Digitoxin 2.5 mg/kg/day was administered SC for two days followed by 3.5 mg/kg/day until death occurred. One group of

mice received digitoxin only, while the second group of 10 mice received the same digitoxin dose plus 400 mg/kg of visnadin. The control group survived for an average of 9.3 days versus the visnadin-treated group whose survival averaged 12.8 days. The mean lethal doses were 25 mg/kg and 35 mg/kg for control and visnadin-treated groups, respectively. When digitoxin 2.5 mg/kg/day was given SC alone and with 200 mg/kg oral visnadin, electrocardiograms showed that the addition of visnadin strongly reduced the digitoxin-induced bradycardia [336] . Kyushin 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: One of the ingredients of kyushin is toad venom toxin. Toad venom toxin, a bufadienolide, is cardioactive with properties similar to digitalis [345] [346] [347] . Ingestion or dermal absorption of toad venom (from Bufo species) has caused typical digitalis-like poisoning, with dysrhythmias, heart block, hypotension, and vomiting [348] [349] [350] [345] [351] . 3) Severity: major 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Concomitant use of digoxin and kyushin is not recommended. If kyushin is taken with digoxin, monitor for signs and symptoms of digoxin toxicity (e.g., nausea, vomiting, diarrhea, headache, weakness, drowsiness, visual disturbance, dysrhythmias, heart block, hypotension). 7) Probable Mechanism: additive digitalis glycoside effect 8) Literature Reports a) Six previously healthy males between the ages of 17 and 40 presented with vomiting, bradycardia, and hypotension; several were hyperkalemic and 1 suffered a seizure. All exhibited positive serum digoxin concentrations. The substance they had ingested was an aphrodisiac called "love stone" or "rock hard", which was found to be identical to Chan Su, a Chinese medication made from toad venom. Four of the patients died of cardiac dysrhythmias. Two recovered after administration of digoxin immune Fab (Digibind(R)); one received 10 vials and the other, 10 vials followed by an additional 10 vials [341]

. b) A 65-year-old woman developed nausea, vomiting, diarrhea, general malaise, and abdominal pain 5 hours after consuming 50 tablets of kyushin, a traditional Chinese medicine. Upon hospital admission her heart rate was 60 beats/minute, blood pressure was 140/70 mmHg. The electrocardiogram (EKG) showed a second degree Wenckebach AV block and a flat Twave which normalized the next day. The serum digoxin-like immunoreactive substance (DLIS) was 2.35 ng/mL 24 hours after ingestion (using the Digoxin II kit by Abbott Laboratories, Inc.). Serum electrolytes were normal. With supportive treatment, this gradually declined over 5 days and the patient was released on the eighth day [342] . c) A 34-year-old female developed nausea, vomiting, and general malaise two hours after consuming approximately 50 pills of kyushin during an attempted suicide. On admission to the hospital, her heart rate was 64 beats/minute, blood pressure was 110/70 mmHg. Serum DLIS 10 hours after consuming the drug was 1.84 ng/mL. This diminished to 0.67 ng/mL by the next day with supportive treatment and symptoms also subsided. Serum electrolytes were normal. All EKGs during hospitalization were normal [342] . d) The bufadienolides in toad venom are presumed to be the cardioactive components of kyushin which has proven its ability to inhibit sodium, potassium, and ATPase activity [343] [344] . Labetalol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity

[538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] .

d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of

carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Lansoprazole 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Lansoprazole produces extensive and long-lasting inhibition of gastric acid secretion. For some drugs, including digoxin, absorption from the GI tract is enhanced at higher pH. When digoxin is coadministered with lansoprazole, reduced acidity may increase digoxin absorption, thus increasing its bioavailability [665] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Monitor digoxin levels in patients requiring concomitant digoxin and lansoprazole therapy. A downward dosage adjustment of digoxin may be necessary. 7) Probable Mechanism: increased digoxin absorption Lapatinib 1) Interaction Effect: increased exposure of digoxin 2) Summary: Concurrent administration of lapatinib, a pglycoprotein (p-gp) inhibitor, with digoxin, a p-gp substrate, led to a 2.8-fold increase in digoxin AUC. When using the 2 concomitantly, monitor digoxin concentration prior to and during therapy with lapatinib. Reduce the digoxin dose by one-half, if the serum digoxin concentration is greater than 1.2 ng/mL [707] . 3) Severity: major 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Coadministration of lapatinib, a pglycoprotein (p-gp) inhibitor, with digoxin, a p-glycoprotein substrate, may result in significant exposure to digoxin. When using the 2 concomitantly, monitor digoxin concentration prior to and during therapy with lapatinib. Reduce the digoxin dose by

one-half, if the serum digoxin concentration is greater than 1.2 ng/mL [707] . 7) Probable Mechanism: inhibition of P-glycoprotein by lapatinib Lenalidomide 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: Coadministration of digoxin and lenalidomide resulted in a 14% increase in digoxin Cmax; however, digoxin AUC was not significantly affected. If these two agents are coadministered, monitor digoxin plasma levels periodically, based on clinical judgement and standard clinical practices [706] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Coadministration of digoxin and lenalidomide resulted in a 14% increase in digoxin maximum concentration. If these agents are coadministered, monitor digoxin plasma levels periodically, based on clinical judgement and standard clinical practices [706] . 7) Probable Mechanism: unknown Levalbuterol 1) Interaction Effect: decreased digoxin serum concentrations 2) Summary: Concomitant administration of digoxin and levalbuterol may decrease digoxin plasma concentrations. In healthy subjects who received digoxin for 10 days, the average digoxin plasma concentrations were reduced by 16% and 22% after coadministration of single-dose IV or oral racemic albuterol, respectively. The clinical significance of these findings for patients receiving chronic levalbuterol therapy for COPD and chronic digoxin therapy is unknown [408] . If coadministration is required, measure serum digoxin levels prior to initiating levalbuterol [2] and carefully during coadministration [408] and increase the digoxin dose if necessary. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: The concomitant use of digoxin and levalbuterol may decrease digoxin plasma concentrations and should be undertaken with caution [408]

. If coadministration is required, measure serum digoxin levels prior to initiating levalbuterol [2] and carefully during coadministration [408] and increase the digoxin dose if necessary. 7) Probable Mechanism: unknown Levothyroxine 1) Interaction Effect: decreased digitalis glycoside effectiveness 2) Summary: When a hypothyroid patient becomes euthyroid or a patient has hyperthyroidism, serum digitalis glycoside levels may be reduced. Therefore, concomitant use of levothyroxine and a digitalis glycoside may decrease the therapeutic efficacy of the digitalis glycoside and an increase in the digitalis glycoside dose may be needed [188] [680] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of levothyroxine and a digitalis glycoside may result in decreased efficacy of the digitalis glycoside. As a result, an increase in the digitalis glycoside dose may be necessary [188] [680] . 7) Probable Mechanism: unknown Licorice 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: Symptoms of congestive heart failure and hypokalemia occurred in a patient taking licorice, furosemide, and digoxin [160] . Licorice alone has been reported to be the likely cause of hypokalemia, hypertension, and torsades de pointes [161] [162] [163] [164] [165] [166] . Hypokalemic paralysis has also resulted from licorice use [167] [168] [169] [170] . The glycyrrhetinic acid component of licorice is metabolized to 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which inhibits 11-

beta-hydroxysteroid dehydrogenase and reduces cortisol breakdown, resulting in a hypermineralocorticoid effect [171] [172] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Avoid concurrent use of licorice and digoxin. 7) Probable Mechanism: licorice-induced hypokalemia may increase the risk of digoxin toxicity 8) Literature Reports a) An 84-year-old male developed hypokalemia and symptoms of congestive heart failure after 7 days of concurrent use of a licorice-containing Chinese herbal laxative with digoxin and furosemide. The patient complained of fatigue, appetite loss, and lower extremity edema. Pulse rate was 30 beats per minute, potassium was 2.9 milliequivalents/Liter (mEq/L), and digoxin level 2.9 nanograms/milliliter (ng/mL). Chest radiograph revealed an enlarged cardiac silhouette and lung congestion. Partial arterial oxygen pressure and saturation was low, carbon dioxide pressure was high. Plasma renin activity was 0.3 ng/mL/hour (normal 0.3 to 2.9 ng/mL/hour) and aldosterone was 3.8 nanograms/deciliter (ng/dL) (normal 3.6 to 24 ng/dL). Digoxin and the herbal laxative were stopped; after 18 days, the patient's pulse increased to 60 beats per minute and symptoms of congestive heart failure were relieved. Potassium increased to 4.3 mEq/L, renin activity was 1 ng/mL/hour, aldosterone was 12 ng/dL, and digoxin level was 0.6 ng/mL [159] . Lily of the Valley 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: A case of death of a dog likely resulting from lily of the valley ingestion has been reported [331] . Both lily of the valley and digitalis, the source of digoxin, are known to contain cardiac glycosides known as cardenolides [332] [333] [334] . Lily of the valley contains convallatoxin as its principal cardiac glycoside [335] . 3) Severity: major 4) Onset: rapid 5) Substantiation: theoretical

6) Clinical Management: Given the chemical similarity between lily of the valley and digoxin, concomitant therapy with digitalis glycosides is contraindicated (Blumenthal et al, 1998). With signs and symptoms of digoxin toxicity (e.g., nausea, vomiting, abnormal vision, cardiac arrhythmias, unexplained hyperkalemia) in the absence of increased digoxin dosage, the clinician should explore the possibility of an elevation of digoxin level secondary to lily of the valley intake. A digoxin level may confirm the diagnosis, but may not quantify the severity. Treatment with digoxin-specific Fab (dsFab) antibody fragments has been successful in toxic ingestion of other cardiac glycoside-containing plants, but the efficacy of dsFab is unknown in cases of lily of the valley ingestion. 7) Probable Mechanism: additive cardiac glycoside activity 8) Literature Reports a) A one year-old female dog experienced a sudden onset of seizures and died from apparent lily of the valley ingestion in Lincoln, Nebraska. The dog was unattended for approximately 2 hours, then developed seizures and collapsed. The dog died before emergency treatment could be started. Necroscopic examination revealed severe hepatic congestion, and congestion of the mesenteric lymph nodes, ileocecal lymph nodes, thymus, and serosa of the stomach. Leaf fragments identified as lily of the valley (Convallaria majalis) were found in the small intestine, along with crabgrass and Siberian elm leaves [330] . Lomitapide 1) Interaction Effect: increased absorption of P-glycoprotein substrates 2) Summary: Concomitant use of lomitapide (a P-glycoprotein (P-gp) inhibitor) with a P-gp substrate may result in increased absorption of the P-gp substrate. Consider reducing the dose of the P-gp substrate if lomitapide is administered concurrently [181] . 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concurrent administration of lomitapide (a P-glycoprotein (P-gp) inhibitor) and a P-gp substrate may increase the absorption of the P-gp substrate. Consider reducing the dose of P-gp substrate if lomitapide is used concurrently [181] . 7) Probable Mechanism: inhibition of P-glycoprotein-mediated efflux transport by lomitapide

Lornoxicam 1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: A slight but statistically significant decrease in the clearance of digoxin (from 171 to 147 mL/minute) was reported when it was given in combination with lornoxicam in a multipledose study involving healthy subjects. Peak serum concentrations of lornoxicam were also increased during combined administration, and its half-life was prolonged [364] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: This interaction will probably not be clinically significant in most patients. However, closer monitoring of digoxin serum levels and for signs of toxicity may be prudent during initiation of combined therapy with lornoxicam, particularly in patients with renal impairment. 7) Probable Mechanism: decreased digoxin clearance Lurasidone 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: Lurasidone increases digoxin concentrations by inhibiting P-glycoprotein (P-gp). Relative to digoxin administration alone, coadministration of a single dose of digoxin 0.25 mg with lurasidone 120 mg/day at steady state resulted in an increase in digoxin Cmax and AUC by approximately 9% and 13%, respectively. However, digoxin dose adjustments are not required when digoxin and lurasidone are given concomitantly [578] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant administration of digoxin and lurasidone may increase digoxin plasma concentrations. However, no digoxin dose adjustments are required with concomitant use [578] . 7) Probable Mechanism: inhibition of P-glycoprotein by lurasidone Magaldrate 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368]

. No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2

nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Magnesium Carbonate 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60

mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Magnesium Hydroxide 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate

4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium

trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Magnesium Oxide 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366]

. c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Magnesium Trisilicate 1) Interaction Effect: decreased digoxin levels 2) Summary: Simultaneous administration of digoxin and antacids that contain aluminum hydroxide, magnesium hydroxide, and magnesium trisilicate significantly decreased digoxin absorption when digoxin was administered as a tablet [368] . No alteration in digoxin absorption was observed following coadministration with calcium carbonate containing antacids. The mechanism responsible for altered digoxin absorption by antacids has not been identified [369] [370] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin serum levels should be monitored if a patient is receiving digoxin and antacids concurrently. The possible sequelae of a drug interaction may be avoided by separating the dosing interval of digoxin and antacids by approximately two hours. The use of digoxin capsules may reduce the interaction but more studies are

required to substantiate this possibility. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In vivo absorption of digoxin is not affected by magnesium trisilicate. It was suggested that digoxin may be "desorbed" from the antacid in the gastrointestinal tract [365] . b) A randomized, single-dose, 6-way, crossover study with 12 fasting volunteers was conducted. Digoxin (capsules or tablets) 0.4 milligrams was administered with 60 mL of water, 60 mL of aluminum and magnesium hydroxide containing antacid, or 60 mL of kaolin-pectin. When compared with the control, the administration of both digoxin capsules or tablets with the antacid or the kaolin-pectin formulation reduced the peak plasma levels of digoxin, but did not significantly alter the time to peak. Interestingly, neither the antacid or kaolin-pectin affected the plasma versus time concentration curve (AUC) of digoxin capsules or tablets [366] . c) Digoxin and antacid concomitant administration has been reported to result in impaired digoxin absorption. Ten normal adult volunteers without cardiac, renal, gastrointestinal abnormalities, received 0.75 milligram Digoxin at a control time and also 60 mL of aluminum hydroxide, magnesium hydroxide or magnesium trisilicate containing antacids or kaolin-pectin at varying times. Urinary and serum digoxin samples were obtained at various times throughout a 5-day period. Bioavailability was based on an 8-hour serum digoxin concentration curve and 6 day cumulative urinary excretion of digoxin. Kaolin-pectin and magnesium trisilicate reduced the peak serum digoxin level 50% (from approximately 2.2 nanograms/mL to 1.1 nanograms/mL). Serum digoxin levels with magnesium hydroxide and aluminum hydroxide were also lower than control and were about the same as the kaolin-pectin and magnesium trisilicate doses. Mean plasma versus time concentration curve for digoxin (total absorption) for the control doses was 559 mg/min/mL, whereas it was 414 for aluminum hydroxide, 418 for magnesium hydroxide, 349 for magnesium trisilicate and 329 for kaolin-pectin. Only the magnesium trisilicate and kaolin-pectin area under the curve was significantly different from the control. The 6-day urinary excretions for the 3 antacids and kaolin-pectin were significantly different when compared to control [367] . Mepindolol

1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6

nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis

[534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Metformin 1) Interaction Effect: an increase in metformin plasma concentrations 2) Summary: Caution is warranted if metformin is to be coadministered with cationic drugs. Elevated serum levels of metformin were found when cimetidine, a cationic agent eliminated by renal tubular secretion, was given concomitantly with metformin [748] [749] . Because digoxin is also a cationic drug, it is possible that combined administration of digoxin with metformin could result in an increase in peak metformin plasma and whole blood concentrations and plasma and whole blood metformin area under the concentration-time curve (AUC). 3) Severity: moderate 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Careful patient monitoring and dose adjustment of metformin and/or digoxin is recommended in patients who are taking cationic medications that are excreted

via the proximal renal tubular secretory system. 7) Probable Mechanism: reduced metformin clearance 8) Literature Reports a) The cationic drug cimetidine was coadministered with metformin in single and multiple-dose studies in healthy volunteers. Effects on metformin included a 60% increase in peak plasma and whole blood concentrations and a 40% increase in area under the concentration-time curve (AUC). Metformin half-life was not affected. Cimetidine pharmacokinetics were unaltered. The postulated mechanism of this interaction is competition between metformin and cimetidine for renal tubular secretion. Cationic drugs that are eliminated by renal tubular secretion, such as digoxin, theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems [746] [747] . Methimazole 1) Interaction Effect: altered metabolism of the digitalis glycoside 2) Summary: Hyperthyroidism may increase the systemic clearance of digitalis glycosides. Once the patient becomes euthyroid, a dose reduction of the digitalis glycoside may be necessary [722] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of methimazole and a digitalis glycoside may alter the metabolism of the digitalis glycoside when the status of the patient changes from hyperthyroid to euthyroid. Therefore, a dose reduction of the digitalis glycoside may be required. 7) Probable Mechanism: change from thyroid to euthyroid state may alter digitalis glycoside clearance Methyclothiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed

5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Metipranolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia

[527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the

discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight

children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Metoclopramide 1) Interaction Effect: decreased digoxin levels 2) Summary: Metoclopramide may interfere with intestinal absorption of digoxin, resulting in unexpectedly low serum concentrations [651] . Absorption from digoxin capsules (Lanoxicaps(R)) or elixirs does not appear to be altered by metoclopramide [652] [653] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Metoclopramide appears to interfere with intestinal digoxin absorption, resulting in lowered serum concentrations. 7) Probable Mechanism: decreased gastrointestinal absorption 8) Literature Reports a) Serum digoxin levels with or without metoclopramide were analyzed in 11 elderly women on maintenance digoxin therapy. Metoclopramide 10 mg three times daily was orally administered for 10 days resulting in a decrease in serum digoxin concentrations from initial levels of 0.72 ng/mL to 0.46 ng/mL.

Withdrawal of metoclopramide resulted in a rise to normal levels over a period of 10 days. These changes are most likely a result of changes in gastrointestinal motility secondary to metoclopramide [649] . b) Significant reductions in the peak plasma concentration of digoxin (from 1.5 to 1.1 ng/mL) in healthy volunteers was reported following concomitant administration of metoclopramide 10 mg twice daily and digoxin 0.25 mg twice daily [650] . Metoclopramide was also demonstrated to prolong the time to reach peak digoxin concentrations (from 2 to 2.7 hours), and reduced the digoxin area under the concentration-time curve (AUC) by 19%. Metolazone 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone

[434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Metoprolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable

6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0

to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in

children possibly because of a higher expression of the Pglycoprotein pump [535] . Mibefradil 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Concomitant use of mibefradil and digoxin has been reported to result in a 30% increase in digoxin serum concentrations and digoxin area under the concentration-time curve (AUC) [573] . However, the combination of mibefradil and digoxin was not associated with an additional prolongation of the PR time beyond the effect of mibefradil alone [574] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor patient for signs or symptoms of digitalis glycoside toxicity (nausea, vomiting, cardiac rhythm disturbance) and laboratory evidence of unacceptable increases in serum digoxin concentrations. Adjust dose as required. 7) Probable Mechanism: unknown 8) Literature Reports a) Mibefradil 150 mg daily increased plasma digoxin and digoxin area under the concentration-time curve (AUC) by approximately 30% in 14 healthy subjects after concurrent administration with digoxin 0.375 mg daily for one week. These effects were dose-dependent [572] . Midodrine 1) Interaction Effect: enhanced or precipitated bradycardia, AV block, or arrhythmia 2) Summary: Concurrent use of midodrine and digoxin may enhance or precipitate bradycardia, AV block, or arrhythmia [268] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Concurrent use of midodrine and digoxin should be done only with close monitoring and where the clinical benefit outweighs the potential risk. 7) Probable Mechanism: unknown Mifepristone

1) Interaction Effect: increased digoxin exposure and plasma concentrations 2) Summary: Caution is advised with the coadministration of digoxin (a p-glycoprotein substrate) [5] and mifepristone (which interferes with p-glycoprotein transfer), as this may result in increased digoxin exposure. The coadministration of digoxin with mifepristone (Korlym(TM)) resulted in an AUC mean ratio (with/without) of 1.4 for digoxin, compared with digoxin administration alone. When concurrent therapy is indicated, use of the lowest clinically useful digoxin dose and measure plasma digoxin concentration after 1 to 2 weeks of concomitant use, and at clinically appropriate intervals thereafter. Due to the long terminal half-life of mifepristone after reaching steady state, allow at least 2 weeks following cessation of mifepristone (Korlym(TM)) before increasing the dose of digoxin [158] . 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Caution is advised with concomitant use of digoxin and mifepristone (Korlym(TM)) due to the risk for increased digoxin exposure. Use the lowest dose of digoxin clinically necessary, based on therapeutic drug monitoring and/or clinical expertise. Measure plasma digoxin concentration after 1 to 2 weeks of concomitant use, and at clinically appropriate intervals thereafter. Due to the long terminal half-life of mifepristone after reaching steady state, allow at least 2 weeks following cessation of mifepristone (Korlym(TM)) before increasing the dose of digoxin [158] . 7) Probable Mechanism: interference with p-glycoproteinmediated transport of digoxin 8) Literature Reports a) In a pharmacokinetic study, the concomitant administration of mifepristone 1200 mg once daily for 10 days with digoxin 0.125 mg once daily in healthy subjects significantly increased digoxin exposure and plasma concentrations. Compared with digoxin administration alone, coadministration with mifepristone resulted in an AUC and Cmax geometric mean ratio of 1.4 and 1.64, respectively [158] . Miglitol 1) Interaction Effect: a decrease in digoxin serum concentrations 2) Summary: The concomitant administration of digoxin and

miglitol may decrease digoxin plasma concentrations. The average digoxin plasma concentration was reduced by 19% and 28%, respectively, after coadministration of oral miglitol 50 mg or 100 mg 3 times daily in healthy volunteers. However, no alteration in the digoxin plasma concentration was reported in diabetic patients who were already receiving digoxin after 14 days of concomitant therapy with miglitol 100 mg orally 3 times daily [183] . Digoxin serum levels should be measured before initiating miglitol, and the dose of digoxin should be increased by approximately 20% to 40% as necessary. Monitoring of digoxin levels and clinical efficacy is recommended during concomitant therapy [5] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: The concomitant administration of digoxin and miglitol may decrease digoxin plasma concentrations [5] [183] . Digoxin serum levels should be measured before initiating miglitol, and the dose of digoxin should be increased by approximately 20% to 40% as necessary. Monitoring of digoxin levels and clinical efficacy is recommended during concomitant therapy [5] . 7) Probable Mechanism: unknown 8) Literature Reports a) The average digoxin plasma concentration was reduced by 19% and 28%, respectively, after coadministration of oral miglitol 50 mg or 100 mg 3 times daily in healthy volunteers. However, no alteration in the digoxin plasma concentration was reported in diabetic patients who were already receiving digoxin after 14 days of concomitant therapy with miglitol 100 mg orally 3 times daily [183] . Milnacipran 1) Interaction Effect: potentiation of adverse hemodynamic effects 2) Summary: Concomitant use of digoxin and milnacipran may potentiate adverse hemodynamic effects. There was no pharmacokinetic interaction between oral digoxin 0.2 mg/day and milnacipran 200 mg/day when multiple doses were

administered to healthy subjects. However, the coadministration of intravenous digoxin 1 mg and milnacipran resulted in postural hypotension and tachycardia. Therefore, the concomitant use of intravenous digoxin and milnacipran should be avoided [655] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of digoxin and milnacipran may potentiate adverse hemodynamic effects. When intravenous digoxin 1 mg was coadministered with milnacipran, postural hypotension and tachycardia were reported. Therefore, the concomitant use of intravenous digoxin and milnacipran should be avoided [655] . 7) Probable Mechanism: unknown Minocycline 1) Interaction Effect: increased digoxin levels and digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Coadministration of tetracyclines, such as minocycline, and digoxin can result in increased digoxin levels [569] . In approximately 10 to 15% of patients, digoxin is converted to inactive metabolites by colonic bacteria within the gut. Inactivation of these enteric flora by antibiotics results in a significant increase in absorption of the parent compound digoxin [568] . If digoxin and minocycline are administered concurrently, patients should be monitored for digoxin toxicity. A dosage adjustment for digoxin may be required. The risk of this interaction may be reduced if digoxin is given with Lanoxicaps(R) [111] . 3) Severity: major 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: If digoxin and minocycline are administered concurrently, monitor for digoxin toxicity. A dosage adjustment for digoxin may be required. Alternatively, the risk of this interaction may be reduced if digoxin is given as Lanoxicaps(R). 7) Probable Mechanism: inhibition of bacterial inactivation of digoxin resulting in increased digoxin bioavailability and digoxin toxicity 8) Literature Reports

a) Approximately 10% of patients receiving digoxin convert 40% or more of the drug to cardio-inactive metabolites [111] . This inactivation may be attributed to gastrointestinal bacteria. Antibiotic therapy introduced to these patients has caused a marked decrease in digoxin reduction products and a marked rise in digoxin absorption and serum levels. It is concluded that changes in the enteric flora by antibiotics may alter the state of digitalization. Although data for the interaction between digoxin and minocycline is unavailable, elevated serum digoxin concentrations by as much as 43 to 116% were observed after a 5-day course of tetracycline in 3 volunteers who produced large amounts of digoxin reduction products [568] . Mirabegron 1) Interaction Effect: increased digoxin exposure 2) Summary: The concomitant use of digoxin and mirabegron may increase digoxin exposure. The mean Cmax and AUC of digoxin increased by 29% and 27%, respectively, when coadministered with mirabegron. For patients initiating a combination of mirabegron and digoxin, the lowest dose of digoxin should be used. Monitor serum digoxin concentrations for titration to obtain the desired clinical effect [397] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: The concomitant use of digoxin and mirabegron may increase digoxin exposure. Patients who are initiating a combination of mirabegron and digoxin should be started on the lowest dose of digoxin. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [397] . 7) Probable Mechanism: unknown 8) Literature Reports a) In a pharmacokinetic drug interaction study, mirabegron given concomitantly with a single dose of digoxin 0.25 mg increased the mean digoxin Cmax by 29% (from 1.01 to 1.3 nanograms (ng)/mL) and AUC by 27% (from 16.7 to 19.3 ng x hr/mL) [397] . Moricizine 1) Interaction Effect: an increased risk of cardiotoxicity (first degree atrioventricular block, bundle branch block) 2) Summary: The concomitant administration of digoxin and

moricizine may result in first degree atrioventricular block or bundle branch block due to prolongation of the PR and QRS intervals [5] . If concomitant therapy is required, patients should be monitored by ECG for prolongation of the PR and QRS intervals. 3) Severity: major 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concurrent administration of digoxin and moricizine may increase the risk of cardiac toxicity (atrioventricular block or bundle branch block) [5] . If concomitant therapy is required, patients should be monitored by ECG for prolongation of the PR and QRS intervals. 7) Probable Mechanism: additive cardiac effects Nadolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval

[527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was

unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Nebivolol

1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6

nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis

[534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Nefazodone 1) Interaction Effect: an increase in digoxin serum concentrations and possibly increase the risk of digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Coadministration of digoxin and nefazodone may increase digoxin plasma concentrations, resulting in an increased risk of adverse cardiac or gastrointestinal effects [711] . Depending on the patient's digoxin level prior to nefazodone therapy, the increase in digoxin concentration may necessitate a lowering of the digoxin dose [712] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Caution is warranted if digoxin and nefazodone are to be given concomitantly. Increased monitoring of the digoxin plasma concentration is indicated when nefazodone is added to or withdrawn from therapy. 7) Probable Mechanism: unknown

8) Literature Reports a) To assess the effect of nefazodone on the pharmacokinetic and pharmacodynamic parameters of digoxin, 18 healthy male volunteers participated in an open, randomized, multiple-dose, three-way crossover study. Volunteers received nefazodone 200 mg twice daily, digoxin 0.2 mg daily, or both during three 8-day treatment periods, with a 10-day washout period in between treatment periods. Steady-state area under the concentrationtime curve (AUC) and peak (Cmax) and trough (Cmin) concentrations of digoxin were increased by 15%, 29% and 27%, respectively. No significant changes were observed in vital signs, heart rate, or PR, QRS, and QT intervals. Because digoxin has a narrow therapeutic index, monitoring of levels and an adjustment of the digoxin dose may be necessary when given concurrently with nefazodone [710] . Neomycin 1) Interaction Effect: decreased digoxin levels 2) Summary: Oral neomycin has been shown to decrease the rate and extent of oral digoxin absorption by interfering with intestinal absorption of digoxin [449] [450] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Digoxin serum concentrations should be monitored when neomycin is administered on a chronic basis. Unexpectedly low serum digoxin concentrations may result. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) In a cross-over study using healthy volunteers it was noted that concurrent digoxin and neomycin decreased serum digoxin levels, area under the concentration time curve for digoxin, and cumulative urinary digoxin excretion; the time to peak digoxin concentration was increased. Even a single dose of neomycin (1 gram) inhibited digoxin absorption. The effect occurred when solutions were substituted for tablets, tablets with varying dissolution rates were used, and dosing times for the 2 drugs were separated. The mechanism of decreased absorption is not understood [448] . Nifedipine

1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Concomitant administration of calcium channel blockers (nifedipine, diltiazem, nicardipine, verapamil) and digitalis glycosides (digoxin) occasionally results in up to 50% increases in serum digoxin concentrations [732] . The magnitude of increase appears to be dependent on the dose of calcium channel blocker being used [733] [734] [735] . Although generally of minimal clinical significance [736] [737] , patients with higher pre-existing serum digoxin concentrations are at greater risk for digitalis toxicity [734] [735] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Monitor patient for signs or symptoms of digitalis glycoside toxicity (nausea, vomiting, cardiac rhythm disturbance) and laboratory evidence of unacceptable increases in serum digoxin concentrations. Adjust dose as required. 7) Probable Mechanism: inhibition of renal and/or extrarenal digoxin clearance 8) Literature Reports a) The effect of nifedipine on digoxin pharmacokinetics is controversial. Some [723] [724] have found steady-state digoxin concentrations to increase up to 50% following nifedipine, however, these results have not been confirmed by other studies [725] [726] [727] [728] . Based upon a review of the literature, it is suggested that steady-state digoxin levels may increase from 24% to 45% when nifedipine is added to therapy, but that adverse effects have not been observed in patients studied [729] . It is suggested that, with current available data, it is not possible to recommend routine alterations in digoxin dosage with nifedipine therapy. It is felt that the interaction is of minimal

significance in most patients, but that digoxin serum level monitoring is warranted. b) The effect of nifedipine 10 mg orally three times daily titrated to clinical response or tolerance on serum digoxin concentrations in 14 cardiac patients was evaluated. Patients had steady-state digoxin levels prior to entering the study and were allowed to continue concomitant medications which consisted primarily of long-acting nitrates, beta-blockers, and diuretics. The mean trough digoxin level was 0.78 ng/mL before nifedipine and 0.8 ng/mL after one week of combined drug therapy and 0.84 ng/mL after two weeks of combined drug administration. These data suggest that cardiac patients stabilized on digoxin can receive combined digoxin and nifedipine without significantly altering the serum digoxin concentration [728] . c) Nifedipine can delay gastric emptying and may potentially be of clinical concern in geriatric and diabetic patients or those who are taking digoxin, levodopa, or penicillin [730] . d) No interaction was reported between nifedipine and digoxin in patients with coronary artery disease. Digoxin 0.5 mg was administered intravenously on the fourth day of treatment with nifedipine 10 mg six times daily. Nifedipine had no significant effect on the half-life, volume of distribution, clearance or percentage of digoxin recovered in the urine [731] . Nilotinib 1) Interaction Effect: increased exposure of P-glycoprotein substrates 2) Summary: Concurrent administration of nilotinib (a Pglycoprotein (P-gp) inhibitor) and a P-gp substrate may increase the exposure of the P-gp substrate. Exercise caution if these agents are administered concomitantly [361] . 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: Concurrent administration of nilotinib (a P-glycoprotein (P-gp) inhibitor) and a P-gp substrate may increase the exposure of the P-gp substrate. Exercise caution if these agents are administered concomitantly [361] . 7) Probable Mechanism: inhibition of P-glycoprotein-mediated efflux transport by nilotinib

Nilvadipine 1) Interaction Effect: increased serum digoxin concentrations and toxicity (nausea, vomiting, arrhythmias) 2) Summary: Concomitant administration of calcium channel blockers (nifedipine, diltiazem, nicardipine, verapamil) and digitalis glycosides (digoxin) occasionally results in up to 50% increases in serum digoxin concentrations [174] . The magnitude of increase appears to be dependent on the dose of calcium channel blocker being used [175] [176] [177] . Although generally of minimal clinical significance [178] [179] , patients with higher pre-existing serum digoxin concentrations are at greater risk for digitalis toxicity [176] [177] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor patient for signs or symptoms of digitalis glycoside toxicity (nausea, vomiting, cardiac rhythm disturbance) and laboratory evidence of unacceptable increases in serum digoxin concentrations. Adjust dose as required. 7) Probable Mechanism: inhibition of renal and/or extrarenal digoxin clearance 8) Literature Reports a) Plasma digoxin levels have, in rare instances, been increased by concomitant administration of nilvadipine [173] . Nisoldipine 1) Interaction Effect: digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Concomitant administration of calcium channel blockers (nifedipine, diltiazem, nicardipine, verapamil) and digitalis glycosides (digoxin) occasionally results in up to 50% increases in serum digoxin concentrations [716] . The magnitude of increase appears to be dependent on the dose of calcium channel blocker being used [717] [718] [719] . Although generally of minimal clinical significance

[720] [721] , patients with higher pre-existing serum digoxin concentrations are at greater risk for digitalis toxicity [718] [719] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor patient for signs or symptoms of digitalis glycoside toxicity (nausea, vomiting, cardiac rhythm disturbance) and laboratory evidence of unacceptable increases in serum digoxin concentrations. Adjust dose as required. 7) Probable Mechanism: inhibition of renal and/or extrarenal digoxin clearance 8) Literature Reports a) Concomitant administration of digoxin 0.25 mg twice daily and nisoldipine 10 mg twice daily has been reported to result in significant increases in plasma concentrations of digoxin in patients with heart failure [713] [714] . The mechanism of this interaction is unclear. It does not appear to involve an effect of nisoldipine on digoxin renal clearance [714] . b) The results of a double-blind, placebo-controlled study of concurrent treatment with nisoldipine and digoxin were reported. Nine patients with heart failure were treated for at least two weeks with digoxin 0.25 mg twice daily, followed by one week of either digoxin plus placebo (D+P) or digoxin plus nisoldipine 10 mg twice daily (D+N). An increase in digoxin trough levels was seen on day 7 in D+N (0.98 +/- 0.15 vs 1.3 +/- 0.21 ng/mL; P less than 0.05) compared with D+P. Mean digoxin plasma levels for days 5, 6, and 7 were higher with D+N (1.16 +/- 1.4 vs 1.35 +/- 0.14 mg/mL; P less than 0.02) compared with D+P. Eight hours after coadministration of D+N, the pre-ejection period was shortened from 139 +/- 11 with D+P to 129 +/- 11 milliseconds (P less than 0.05), but this may have been due to the action of nisoldipine alone. No adverse effects from the increased digoxin levels were seen in the patients in this study, but some patients may experience clinical effects from this interaction [715] . Nitrendipine 1) Interaction Effect: increased serum digoxin concentrations and toxicity (nausea, vomiting, arrhythmias)

2) Summary: Concomitant administration of calcium channel blockers (nifedipine, diltiazem, nicardipine, verapamil) and digitalis glycosides (digoxin) occasionally results in up to 50% increases in serum digoxin concentrations [262] . The magnitude of increase appears to be dependent on the dose of calcium channel blocker being used [263] [264] [265] . Although generally of minimal clinical significance [266] [267] , patients with higher pre-existing serum digoxin concentrations are at greater risk for digitalis toxicity [264] [265] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor patient for signs or symptoms of digitalis glycoside toxicity (nausea, vomiting, cardiac rhythm disturbance) and laboratory evidence of unacceptable increases in serum digoxin concentrations (therapeutic range: 0.8 to 2.0 ng/mL). Adjust the digoxin dose as required. 7) Probable Mechanism: inhibition of renal and/or extrarenal digoxin clearance 8) Literature Reports a) Concomitant nitrendipine 20 mg once daily and digoxin 0.5 mg twice daily given for three days, followed by digoxin 0.25 mg twice daily given an additional four days to six healthy volunteers, reportedly resulted in no significant changes in the pharmacokinetic parameters of nitrendipine. However, coadministration did result in significant increases in the digoxin plasma concentrations, from 0.96 mcg/L to 1.98 mcg/L [259] . Two patients experienced toxic concentrations (greater than 2 mcg/L) and adverse effects, which were described as impaired sense of smell, flickering before the eyes, and inability to concentrate. b) In another study, nitrendipine did not significantly affect digoxin pharmacokinetics [260] . When oral nitrendipine 20 mg twice daily was administered to ten healthy volunteers given oral beta-acetyldigoxin 0.3 mg once daily (following a 0.6 mg loading dose), digoxin serum concentrations decreased only slightly and urinary digoxin excretion was not altered.

c) Concomitant administration of nitrendipine 20 mg daily and digoxin 0.25 mg twice daily was reported to result in significant increases in digoxin plasma levels and AUC in healthy volunteers [261] . Combined therapy with nitrendipine 10 mg once daily did not produce significant increases in AUC or plasma levels of digoxin. These data suggest that monitoring of digoxin serum levels may be prudent in patients receiving nitrendipine, especially in higher doses. Norepinephrine 1) Interaction Effect: an increased risk of cardiotoxicity (arrhythmias) 2) Summary: The concomitant administration of digoxin and norepinephrine may result in an increased risk of cardiac arrhythmias [5] . If concomitant therapy is required, patients should be monitored for cardiac toxicity. 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: The concomitant administration of digoxin and norepinephrine may result in an increased risk of cardiac arrhythmias [5] . If concomitant therapy is required, patients should be monitored for cardiac toxicity. 7) Probable Mechanism: unknown Oleander 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: Oleander is found in tropical and subtropical areas, including California to Florida in the United States, and is planted frequently along highways [694] [695] . Nerium oleander (common pink oleander) contains oleandrin as its principal cardiac glycoside as well as neriine, oleandroside, nerioside, and digitoxigenin [695] [696] . Thevetia peruviana (yellow oleander) contains cardiac glycosides thevetin A, thevetin B, and thevetoxin [697] . Cases of digoxin-like toxicity have been reported following oleander ingestion, some resulting in death [698] [699] [694] [695]

[696] [697] . Several cases of arrhythmia resulting from oleander ingestion have been reported, including fatalities [698] [699] [700] [701] [694] [695] [696] [697] . Administration of digoxin-specific Fab antibody fragments (Digibind(R)) has been successful in treating cases of oleander toxicity [702] [698] [700] [703] [694] . 3) Severity: major 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Patients who are taking digoxin should be advised to avoid oleander in order to avoid a potentially toxic interaction. The cardiac glycosides in oleander are detectable by a digoxin radioimmunoassay; however, the digoxin level obtained varies according to the assay used and cannot be used to guide dosing of digoxin-specific Fab antibody fragments. Administration of digoxin-specific Fab antibody fragments (Digibind(R)) has been successful in treating cases of oleander toxicity. 7) Probable Mechanism: additive cardiac glycoside activity 8) Literature Reports a) Treatment of acute oleander poisoning presenting with severe cardiac arrhythmia with anti-digoxin Fab (DigiTab) 1200 milligrams (mg) resulted in rapid resolution of the arrhythmia, and correction of hyperkalemia in a randomized, double-blind, placebo-controlled study of 66 patients. The dose of DigiTab was determined in a dose-finding study involving 16 patients. All 4 patients receiving 1200 mg responded, compared with 3 of 4 receiving 800 mg or 1600 mg, and 1 of 4 receiving 400 mg. Common presenting symptoms were vomiting, diarrhea, weakness, dizziness, abdominal pain, sinus bradycardia, exit block or arrest, and/or atrioventricular conduction block. Arrhythmias completely resolved within 2 hours in 15 of 34 treated patients versus 2 of 32 controls (p less than 0.001). Within 8 hours, 24 of 33 treated patients converted to sinus

rhythm with heart rates greater than 44 beats/minute versus 5 of 32 controls (p less than 0.001). Within 8 hours, mean heart rate increased from 49 beats/minute to 69 beats/minute in treated patients versus an increase from 50 beats/min to 54 beats/min in controls (p less than 0.001). Within 2 hours, serum potassium decreased from 4.9 millimoles/liter (mmol/L) to 4.1 mmol/L in treated patients and remained at 4.7 mmol/L in control patients; within 48 hours, serum potassium was 4.0 mmol/L in both groups. No patients admitted into the trial died, as most deaths occur prior to admission or soon after admission. This study was not designed to evaluate mortality [684] . b) A 66-year-old female with no previous cardiac disease or antiarrhythmic medication use developed cardiac arrhythmia following ingestion of oleander leaves. Pulse on admission was 70 beats/minute, which decreased to 20 beats/minute with asystolic periods of 4 seconds. A serum radioimmunoassay for digoxin was 0.8 nanograms/milliliter (ng/mL), potassium was 4.8 mmol/L. She was successfully treated with 5 vials (200 mg) of digoxin-specific Fab antibody fragments (Digibind(R)). Dysrhythmias resolved, and a repeat digoxin level was 0.1 ng/mL [685] . c) A 26-year-old male presented with vomiting and pulse 57 beats/minute 2 hours after ingesting 3 bowls of unprocessed oleander leaves. He had no previous cardiac disease or antiarrhythmic medication use. Bradycardia developed (30 beats/minute) with first, second, and third degree AV blocks, and asystolic periods of greater than 5 seconds. Serum digoxin level was 0.77 ng/mL, serum potassium was 5.8 mmol/L. Dysrhythmia resolved after treatment with 10 vials (400 mg) of Digibind(R). Pulse and echocardiogram were normal at discharge [685] . d) A female patient developed nausea, vomiting, diarrhea, and severe weakness following ingestion of a self-prepared tea from oleander and lime blossom. Electrocardiogram (ECG) showed third-degree atrioventricular block with shortened QRS. Serum digitalis was 4.2 nanograms/deciliter (ng/dL), potassium was 8.8 milliequivalents/liter (mEq/L). Hydration treatment reversed symptoms and electrocardiographic changes [686] . e) A 24-year-old male developed nausea, vomiting, abdominal pain, and confusion within 10 hours of ingestion of a mixture of orange juice and 6 ground leaves later identified as Nerium oleander (common pink oleander). Blood pressure was 100/80

mmHg, pulse 40 beats/minute. Initial ECG showed AV block with junctional escape rate of 40/minute and diffuse ST depression; 2 hours later an ECG showed complete AV block, sinoatrial block, and diffuse ST depression persisted. A digoxin level of 0.8 ng/mL confirmed a presumed diagnosis of oleander intoxication. Potassium rose from 5.2 mmol/L to 6.5 mmol/L despite Kayexalate(R) therapy, and a solution of glucose, insulin, and bicarbonate was administered. Blood pressure deteriorated to 70/40 mmHg, potassium increased to 6.8 mmol/L and the patient became oliguric and nonresponsive to external stimuli. Eighteen hours after admission, empiric treatment with digoxin-specific Fab antibody fragments (Digiband, The Welcome Foundation Ltd, Beckenmam, England) 480 mg was administered intravenously over 30 minutes. The patient awoke 4 minutes after treatment was started, ECG showed sinus rhythm (44/min) with prolonged PR interval and persistence of a digitalis effect on the ST segment. Within 15 minutes, potassium decreased to 5.1 mmol/L, blood pressure increased to 100/60 mmHg, pulse 68 beats/min. Within 1 hour, potassium normalized to 4.5 mmol/L. Within 12 hours, the patient was asymptomatic but ST depression remained evident for 6 days [687] . f) In one three-year study, 170 patients were admitted to a hospital in Sri Lanka with yellow oleander (Thevetia peruviana) toxicity. The most common presenting symptoms were vomiting (68%), giddiness (36%), and diarrhea (22%), 12.9% of patients remained asymptomatic. Bradycardia was noted in 50% of the patients and palpitations were noted in 3% of the patients. Seven patients died presumably from cardiac adverse effects including sinoatrial and ventricular blocks, ST depression, and ventricular excitability with a poor response to atropine [688] . g) A 37-year-old male developed dry mouth, cramping abdominal pain, nausea, vomiting, dizziness, and irregular heart beat after ingestion of "a handful" of oleander leaves in a suicide attempt. Medical history included chronic depression and suicide attempts, and occasional alprazolam use. The patient denied any other acute drug ingestion, specifically digitalis. Electrocardiogram showed bradycardia with rate of 30 to 45 beats/minute with frequent sinus pauses and junctional escape. Digoxin level was 1.5 ng/mL, serum potassium was 4.3 mEq/L. Five vials (200 mg) of Digibind(R) were administered empirically, resulting in improved heart rate and conduction. Serum potassium was 3.4 mEq/L [689] . h) A 30-year-old female developed nausea, vomiting, and a numb tongue following ingestion of a tea prepared from

oleander, which the patient believed to be eucalyptus. Paramedics reported a pulse of 30 beats/minute, blood pressure was not palpable. Lactated Ringer's solution and naloxone was administered without change, followed by atropine. Heart rate transiently increased, then returned to 30 beats/minute and blood pressure remained impalpable. Isoproterenol administration led to ventricular tachycardia, then ventricular fibrillation on arrival to the hospital. The patient was electrically defibrillated. The leaves from which the tea was made were identified as oleander. Serum potassium was 6.6 mEq/L. Regular insulin and dextrose were administered in addition to phenytoin and sodium bicarbonate. Cardiac rhythm deteriorated to asystole with no response to transthoracic pacemaker insertion. Serum digoxin level on a postmortem specimen was 6.4 ng/mL [690] . i) A 96-year-old female was found at home, weak, vomiting, and noncommunicative after a few minutes. The patient had been depressed with suicidal intent, she took only occasional aspirin, and had no digitalis preparations at home. A history of oleander leaf ingestion was given by the patient's son. Within 15 minutes, a generalized tonic-clonic seizure occurred, after which no pulse or respirations were detected. After continuous cardiopulmonary resuscitation efforts, pharmacologic intervention, and several attempts at electrical cardioversion, the patient was pronounced dead. Ventricular tachycardia, fibrillation, and asystole were shown on electrocardiogram throughout the course. Serum potassium was 8.6 mEq/L, serum digoxin was 5.8 ng/mL. Green vegetative material was found in the stomach at autopsy [691] . j) A 3-year-old female developed vomiting, abdominal pain, sweating, and pulse 40 beats/min. ECG showed complete heart block. Atropine 0.4 mg was ineffective, and cardiac arrest occurred on transport to a hospital. Resuscitation attempts with intubation, closed cardiac massage, and administration of adrenaline and bicarbonate were unsuccessful. Digoxin assays performed on a postmortem heart sample indicated presence of cardiac glycosides consistent with Thevetia (yellow oleander) poisoning [692] . k) In 10 dogs administered tincture of oleander intravenously, digoxin-specific Fab antibody fragments (dsFab) 60 milligrams/kilogram (mg/kg) administered intravenously effectively reversed fatal dysrhythmias, converting all dogs to normal sinus rhythm within eight minutes. After a mean time of 107 minutes, three dogs treated with dsFab reverted to hemodynamically stable dysrhythmias, indicating that oleander

may contain glycosides which either are less toxic, lack affinity for dsFab, or have a prolonged distribution time, causing delayed cardiac effects. All 5 dogs treated with dsFab survived. Three of the 5 dogs which did not receive dsFab did not survive. Mean total time in normal sinus rhythm was significantly greater in dogs treated with dsFab (142 +/- 35.1 minutes) versus those untreated (15 +/- 8.2 minutes) (p equals 0.007) [693] . Omeprazole 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Digoxin toxicity has been described in patients receiving omeprazole concurrently [274] [273] . Proposed mechanisms of action include the phenotypic or agerelated alterations in digoxin metabolism, or an increase in digoxin bioavailability caused by omeprazole's inhibition of gastric acid secretion [274] . Caution is advised when omeprazole and digoxin are used concurrently and additional monitoring for digoxin toxicity is recommended, particularly when initiating or discontinuing omeprazole therapy. 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin toxicity has occurred in patients receiving omeprazole concurrently [273] [274] . Monitor digoxin levels and for signs and symptoms of digoxin toxicity in patients requiring concomitant digoxin and omeprazole therapy, particularly when initiating or discontinuing omeprazole therapy. 7) Probable Mechanism: increased digoxin absorption, alterations in digoxin metabolism 8) Literature Reports a) In a randomized, 2-way crossover study, 10 patients were given digoxin 1 mg alone. They were also given omeprazole 20 mg daily for 11 days; digoxin 1 mg was given on day 8. The AUC for digoxin increased about 10% with concomitant therapy. The net effect was minimal with respect to changes in digoxin levels and would not be clinically significant for most patients [273] . b) A 65-year-old Caucasian woman experienced signs of digoxin toxicity and an elevated serum digoxin level 3 months

after starting omeprazole 20 mg concurrently for GERD. The patient had a history of hyperlipidemia, osteoarthritis, type 2 diabetes mellitus, recurrent nephrolithiasis, and paroxysmal atrial fibrillation, and had been stable on oral digoxin 0.625 mg daily for 6 years prior to the current presentation. Concomitant medications included meloxicam, lisinopril, raloxifene, atorvastatin, gemfibrozil, warfarin, oxybutynin, hydrochlorothiazide, and potassium citrate. Her serum digoxin level prior to starting the omeprazole was 1.1 ng/mL. She presented to the emergency department following an episode of emesis and had weakness, dysequilibrium, nausea, and altered vision. She reported experiencing yellow hazy vision 2 months prior, but denied any other neurologic symptoms and had no history of neurologic disease. Her ECG revealed bigeminy, a cardiac exam reported an irregular hear rate and a III/VI systolic ejection murmur, and her serum digoxin level was 3.9 ng/mL. Her renal function was normal with a creatinine clearance of 0.8 mg/dL. She was administered digoxin antidote (digoxin immune fab) and was admitted to the ICU. Digoxin was stopped and her ECG returned to baseline within 2 days with no adverse effects. Proposed mechanisms of action include the phenotypic or agerelated alterations in digoxin metabolism, or an increase in digoxin bioavailability caused by omeprazole's inhibition of gastric acid secretion [274] . Oxprenolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528]

. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone

[532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial

ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Oxytetracycline 1) Interaction Effect: increased digoxin levels and digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Coadministration of tetracyclines, such as oxytetracycline, and digoxin can result in increased digoxin levels [569] . In approximately 10 to 15% of patients, digoxin is converted to inactive metabolites by colonic bacteria within the gut. Inactivation of these enteric flora by antibiotics results in a significant increase in absorption of the parent compound digoxin [568] . If digoxin and oxytetracycline are administered concurrently, patients should be monitored for digoxin toxicity. A dosage adjustment for digoxin may be required. The risk of this interaction may be reduced if digoxin is given with Lanoxicaps(R) [111] . 3) Severity: major 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: If digoxin and oxytetracycline are administered concurrently, monitor for digoxin toxicity. A dosage adjustment for digoxin may be required. Alternatively, the risk of this interaction may be reduced if digoxin is given as Lanoxicaps(R). 7) Probable Mechanism: inhibition of bacterial inactivation of digoxin resulting in increased digoxin bioavailability and digoxin toxicity 8) Literature Reports a) Approximately 10% of patients receiving digoxin convert 40% or more of the drug to cardio-inactive metabolites [111] . This inactivation may be attributed to gastrointestinal bacteria. Antibiotic therapy introduced to these patients has caused a marked decrease in digoxin reduction products and a marked rise in digoxin absorption and serum levels. It is concluded that changes in the enteric flora by antibiotics may alter the state of digitalization. Although data for the interaction between digoxin and oxytetracycline is unavailable, elevated serum digoxin

concentrations by as much as 43 to 116% were observed after a 5-day course of tetracycline in 3 volunteers who produced large amounts of digoxin reduction products [568] . Pancuronium 1) Interaction Effect: an increased risk of cardiac arrhythmias 2) Summary: Concomitant digoxin and pancuronium therapy has been reported to result in cardiac arrhythmias. Possible mechanisms for this interaction include the vagolytic effect of pancuronium, the direct sympathomimetic and indirect sympathomimetic effects of pancuronium, and the prevention of norepinephrine reuptake by pancuronium [571] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: established 6) Clinical Management: Cardiac rhythm should be closely monitored when administering pancuronium to a digitalized patient. 7) Probable Mechanism: unknown 8) Literature Reports a) The incidence of arrhythmias in digitalized patients who received either succinylcholine or pancuronium were compared. They divided 104 patients into four groups: Groups 1 and 2 were not receiving digitalis therapy, and Groups 3 and 4 were maintained on digoxin, diuretic therapy, and potassium supplementation. Patients in Groups 1 and 3 received succinylcholine 2 mg/kg while Groups 2 and 4 were administered pancuronium 0.12 mg/kg. Results showed that the incidence of dysrhythmias was significantly higher in the Group 4 patients who were receiving digoxin and pancuronium (6 out of 18 patients) than in Group 3, who received digoxin and succinylcholine (3 out of 46 patients). Types of arrhythmias seen in Group 4 included sinus tachycardia (n=4) and atrial flutter (n=2). Due to ethical reasons, the investigators terminated the administration of pancuronium to the digitalized patients [570] . Paromomycin 1) Interaction Effect: reduced digoxin serum concentrations and efficacy 2) Summary: To date, no reports relating to coadministered paromomycin and digoxin have appeared. A controlled study found that concurrent neomycin significantly decreased digoxin absorption [671]

. Because paromomycin is a related aminoglycoside antibiotic similar to neomycin, it may be possible that oral paromomycin could also reduce digoxin bioavailability. Caution should be used when these agents are coadministered. 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Digoxin-treated patients should be carefully followed for reduced digoxin effects if paromomycin is added to therapy. The interaction may occur even if dosing of the two agents is separated. Monitoring digoxin serum concentration when paromomycin is added to and withdrawn from therapy is advisable. 7) Probable Mechanism: unknown 8) Literature Reports a) In a cross-over pharmacokinetic study using healthy volunteers, concurrent digoxin and neomycin decreased serum digoxin concentrations, area under the concentration- time curve (AUC), and cumulative urinary digoxin excretion. Digoxin time to peak was increased. Even a single dose of neomycin (1 gram) inhibited digoxin absorption. With 1 gram of neomycin, digoxin AUC was reduced by a mean 51%, with a range in AUC reduction of 30% to 82%. The effect occurred when solutions were substituted for tablets, tablets with varying dissolution rates were used, and dosing times for the two drugs were separated. The mechanism of decreased absorption is not understood [669] . b) In a few patients, neomycin reduced the destruction of digoxin by bacteria in the gut, perhaps countering the decreased digoxin absorption. However, it was suggested that this effect may occur in only 10% of patients [670] . Penbutolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers

[537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%)

[531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol

dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Penicillamine 1) Interaction Effect: decreased digoxin effectiveness 2) Summary: In a number of case reports, the concurrent use of digoxin and penicillamine resulted in a lower digoxin concentration as compared to when digoxin was given alone [579] [580] . There have been inconsistent reports regarding the effects of penicillamine on serum digoxin concentrations [581] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Monitor clinical signs of decreased digoxin effectiveness, adjust the dose as needed. 7) Probable Mechanism: unknown Pheasant's Eye 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: Theoretically, an interaction could occur with pheasant's eye, since it contains cardiac glycosides similar in structure and function to digoxin. Both pheasant's eye and digitalis, the source of digoxin, are known to contain cardiac glycosides also known as cardenolides [232] [233] [234] . Pheasant's eye contains cymarin as its principal cardiac glycoside [235] . At this time, pheasant's eye is not widely available in the United States [235] . 3) Severity: major

4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Given the chemical similarity between pheasant's eye and digoxin, therapy with digitalis glycosides is contraindicated. With signs and symptoms of digoxin toxicity (e.g., nausea, vomiting, abnormal vision, cardiac arrhythmias, unexplained hyperkalemia) in the absence of increased dosage, the clinician should explore the possibility of an elevation of digoxin level secondary to pheasant's eye intake. A digoxin level may confirm the diagnosis, but may not quantify the severity. In cases of severe toxicity, treatment with digoxin-specific Fab antibody fragments may be helpful. 7) Probable Mechanism: additive cardiac glycoside activity Pindolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown

8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05)

[533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Piretanide 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Concomitant loop diuretic and digitalis therapy can result in digitalis toxicity secondary to hypokalemia and possibly hypomagnesemia

[198] [199] [200] [201] [202] [203] [204] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Frequent monitoring of potassium and possibly magnesium with appropriate replacement is recommended; educate patients about the importance of maintaining adequate intake of dietary potassium and/or potassium supplements. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides Polythiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433]

. Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Posaconazole 1) Interaction Effect: increased digoxin plasma concentration 2) Summary: Coadministration of digoxin and posaconazole has resulted in increased digoxin plasma concentrations. Therefore, caution is advised if these agents are used concomitantly and monitoring of digoxin plasma concentrations is recommended [502] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Use caution when digoxin and posaconazole are coadministered due to the potential for increases in digoxin plasma levels. Consider monitoring digoxin plasma concentration in patients receiving these agents concomitantly [502] . 7) Probable Mechanism: unknown Propafenone 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: The concurrent use of propafenone and digoxin resulted in increased digoxin levels (30% to 100%)

[322] . In children, this interaction has been somewhat more variable [323] . 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor digoxin levels when initiating, changing dose of, or discontinuing propafenone during concomitant digoxin therapy. 7) Probable Mechanism: decreased clearance, decreased distribution of digoxin 8) Literature Reports a) Concomitant administration of oral propafenone and intravenous digoxin resulted in an increase in the area under the plasma concentration-time curve (AUC) and a decrease in the clearance of digoxin [321] . In this study, six male volunteers were administered intravenous digoxin 1 mg alone, then the same dose after pretreatment with propafenone 150 mg orally every eight hours for seven days; intravenous digoxin 1 mg was also administered after propafenone 300 mg orally every eight hours for seven days. The total body clearance of digoxin decreased in a doserelated fashion, from 2.45 mL/min/kg on digoxin alone to 2.17 mL/min/kg after pretreatment with the lower dose of propafenone for seven days, and then to 1.92 mL/min/kg after pretreatment with the higher dose of propafenone. Propafenone serum levels increased by 2.5-fold after increasing the daily dose from 150 mg every eight hours to 300 mg every eight hours. There was a trend towards a decrease in the volume of distribution (Vd) of digoxin and a decrease in non-renal clearance during combined therapy, with decreases being more significant with the higher dose of propafenone. It was suggested that the mechanism of the interaction is related to decreases in the Vd and non-renal elimination of digoxin. This trial suggests that monitoring of digoxin serum levels are indicated during concomitant propafenone therapy, especially with higher doses of propafenone. In addition, as the interaction is dose-related, digoxin serum levels should be monitored closely when doses of propafenone are increased. Propantheline 1) Interaction Effect: increased serum digoxin levels 2) Summary: Propantheline is known to inhibit gastrointestinal motility. When used concurrently with a slow-dissolving digoxin preparation, increased absorption and serum digoxin levels may result [456] [457]

[458] . This interaction can be avoided by using digoxin formulations that dissolve rapidly according to USP standards [457] [459] [460] . 3) Severity: major 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Monitor digoxin serum levels when propantheline and a slow-dissolving digoxin preparation are used concurrently. Adjust the digoxin dose if necessary. This interaction can be avoided by using digoxin formulations that dissolve rapidly according to USP standards. 7) Probable Mechanism: increased absorption due to decreased gastrointestinal motility 8) Literature Reports a) Serum digoxin levels with or without propantheline were studied in 13 elderly women on maintenance digoxin therapy. Propantheline 15 mg three times daily orally was administered for 10 days, resulting in an increase in serum digoxin concentrations from initial levels of 1.02 ng/mL to 1.33 ng/mL. A second group of volunteers, comprised of healthy medical students, was administered either digoxin 0.5 mg in tablet form or digoxin 0.5 mg in liquid form 30 minutes after administration of propantheline 30 mg. Administration of propantheline increased serum digoxin concentrations in the four subjects who received digoxin tablets but not in the four subjects who received digoxin liquid [454] . b) In a randomized, crossover study, the effect of propantheline on the absorption of various particle-size digoxin preparations was evaluated. Ten healthy volunteers each received single doses of standardized digoxin (Lanoxin(R) brand) 0.5 mg, micronized digoxin 0.5 mg, or large particle-size digoxin 0.5 mg. Each subject also received either propantheline 30 mg, metoclopramide 10 mg, or placebo with each digoxin dose, for a total of 9 treatment combinations, separated by at least two weeks. Neither standardized nor micronized digoxin preparations were affected by the coadministration of propantheline. However, absorption of the large particle-size preparation was increased by concomitant administration of propantheline compared with placebo [455] . Propranolol

1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6

nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis

[534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Quercetin 1) Interaction Effect: increased digoxin levels and risk of digoxin toxicity (sudden death, nausea, vomiting, arrhythmias) 2) Summary: Quercetin markedly increased the absorption of digoxin when given concomitantly with digoxin to pigs. In a controlled, cross-over study, Yorkshire pigs received a single oral dose of digoxin 0.02 milligrams/kilogram (mg/kg) coadministered with (n=3) or without (n=3) quercetin 50 mg/kg. Within 30 minutes after administration of digoxin, 2 quercetintreated pigs suddenly died and the 3rd quercetin-treated pig exhibited symptoms consistent with acute digoxin toxicity. The authors propose that the absorption of digoxin was significantly enhanced through the quercetin-induced inhibition of intestinal p-glycoprotein [279] . 3) Severity: major 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Concomitant use of digoxin and quercetin is not recommended. If quercetin is taken with digoxin,

monitor digoxin serum concentrations and adjust digoxin dose accordingly whenever changes occur with the dose of either drug. Monitor patients also for signs and symptoms of digoxin toxicity, if coadministration of digoxin and quercetin is necessary. 7) Probable Mechanism: inhibition of digoxin intestinal pglycoprotein metabolism 8) Literature Reports a) Quercetin markedly increased the absorption of digoxin when given concomitantly to pigs. In a controlled, cross-over study, Yorkshire pigs received a single oral dose of digoxin 0.02 milligrams/kilogram (mg/kg) co-administered with (n=3) or without (n=3) quercetin 50 mg/kg (dissolved in glycofurol 100 mg/mL; control animals received glycofurol only). Within 30 minutes after administration of digoxin, 2 quercetin-treated pigs suddenly died and the 3rd quercetin-treated pig exhibited symptoms consistent with mild yet acute digoxin toxicity. At 20 minutes after dosing, digoxin serum mean concentrations in the 3 quercetin-group pigs ranged between 5.50 and 7.45 nanograms/milliliter (ng/mL). Pigs treated solely with digoxin did not exhibit signs of toxicity, with digoxin serum mean concentrations ranging from 1.65 to 3.54 ng/mL, 20 minutes after treatment. In order to complete the pharmacokinetic assessment, four additional pigs were given oral digoxin with or without quercetin 40 mg/kg. In pigs co-treated with quercetin, the time (Tmax) to reach maximum digoxin serum concentration (Cmax) declined from a mean of 96.7 minutes (in controls) to a mean of 10 minutes, and mean Cmax was significantly increased by 413% (from 1.72 ng/mL to 8.8 ng/mL; p less than 0.01). Co-administration of quercetin also increased by 170% the area under the concentration-time curve for digoxin (p less than 0.01). The authors propose that the absorption of digoxin was significantly enhanced through the quercetin-induced inhibition of intestinal p-glycoprotein [278] . Quinethazone 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed

5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Quinidine 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: Concurrent use of quinidine and digoxin has resulted in a 0.5 nanogram (ng)/mL or greater increase in digoxin levels in about 90% of patients, with doubling of serum levels commonly seen

[483] [484] [485] [486] [487] . Quinidine appears to reduce digoxin clearance and/or volume of distribution, with implication that digitalis intoxication may result [1] [488] . When digoxin and quinidine are coadministered, monitor serum digoxin levels and reduce the digoxin dosage as needed [461] . 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: On initiation of quinidine in a patient receiving digoxin therapy, a decrease in digoxin dosage by approximately 50% or discontinuation of digoxin therapy if no longer necessary, is recommended [3] . When digoxin and quinidine are coadministered, closely monitor serum digoxin levels [461] [3] , reducing the digoxin dose as necessary [461] , and closely monitoring patients for clinical evidence of digoxin toxicity [3] . 7) Probable Mechanism: inhibition of P-glycoprotein by quinidine 8) Literature Reports a) A case report associated neurotoxicity with co-ingestion of digoxin and quinidine, although serum levels of both medications were within the therapeutic range. On examination, a 75-year-old woman exhibited lethargy, cognitive deficits, delirium, neuromotor retardation, prolonged QT interval, depressed ST segments, and tachycardia. Her digoxin serum level was 0.9 nanogram (ng)/mL and her quinidine serum concentration was 2.4 ng/mL. Withdrawal of both drugs reversed her mental deterioration [462] . b) The effect of digoxin on the pharmacokinetics of quinidine was studied in 6 healthy volunteers. Alterations were found in the pharmacokinetics of quinidine, including significantly reduced elimination and increased half-life. The AUC of

quinidine was elevated, but not significantly. Digoxin had a significantly increased AUC resulting from reduced renal and total digoxin clearance [463] . c) Serum digoxin levels were observed in 27 patients on steadystate doses of digoxin, who were not taking any other antiarrhythmic drugs before or during quinidine therapy [464] . In 25 patients, the serum digoxin level rose significantly during quinidine therapy from a mean level of 1.4 nanograms (ng)/mL to 3.2 ng/mL, in spite of a reduction in the mean dose of digoxin from 0.31 mg to 0.25 mg. Anorexia, nausea, and vomiting developed in 16 patients on combination therapy, and disappeared in 10 patients when the digoxin dose was lowered or held. Four patients with prior ventricular arrhythmias experienced a worsened arrhythmia within 5 days after quinidine was initiated. Of 13 patients without prior ventricular premature beats, 3 developed this symptom in the same time period. One of those patients manifested ventricular fibrillation, one had asystole, and there was one sudden death. Similar but lesser effects have also been reported with digitoxin [465] . d) The alteration in renal clearance appears to be related to decreased renal-tubular secretion of digoxin, since no impact on glomerular filtration rate or protein-binding has been documented [466] [467] . An average 42% decrease in biliary clearance of digoxin when simultaneously treated with quinidine was reported [468] [469] . The effect of quinidine on the elimination half-life of digoxin has produced conflicting results ranging from no significant change [470] [471] to a significant increase in elimination half-life [472] [473] . Variable results on volume of distribution have been reported, including either no effect or a slight decrease [466] [463] . While quinidine has no effect on protein binding of digoxin [471] [470]

, evidence suggests that digoxin displacement from tissue binding sites (heart and skeletal muscle tissues) occurs in the presence of quinidine [474] [475] [472] . Subsequent direct-binding tissue-displacement data have failed to support an effect on digoxin-receptor binding [467] . Others suggest that cardiotoxicity during the quinidine-digoxin interaction may be mediated in the CNS due to findings from animal studies that the interaction produces a significant rise in digoxin concentration in the subcortical white matter of the brain [476] . Quinidine has also been reported to enhance both the rate and extent of digoxin absorption during simultaneous administration [477] [478] . e) The literature is conflicting regarding the clinical significance of the increase in serum digoxin levels. Although digitalis toxicity has been reported, several studies have reported a decrease in myocardial performance in the presence of elevated serum digoxin concentration during quinidine therapy [479] [474] [477] [467] . Research suggests that the decrease in tissue binding may decrease the efficacy of digoxin despite increased levels, making dosage adjustments of digoxin unnecessary during combined treatment [476] . These observations have not been supported by others [480] and routine downward adjustments of the digoxin dose by 50% have been recommended whenever quinidine is added to the regimen [481] . f) The combination of quinidine and spironolactone is reported to significantly reduce digoxin clearance (systemic, renal, and nonrenal) and prolong digoxin elimination half-life. The combination of quinidine and spironolactone caused a greater effect on digoxin pharmacokinetics than just quinidine alone. Further reduction in digoxin dosage is advised when these 3 drugs are prescribed along with monitoring of serum digoxin levels [482] .

Quinine 1) Interaction Effect: increased plasma concentrations of digoxin 2) Summary: Concomitant use of quinine and digoxin may result in increased plasma concentrations of digoxin. In a pharmacokinetic study of healthy subjects (n=4) taking digoxin 0.5 to 0.75 mg/day, a 33% increase in digoxin steady-state AUC and a 35% decrease in digoxin steady-state biliary clearance was observed during treatment with quinine 750 mg/day compared with digoxin monotherapy [389] . In other reports, concomitant administration of quinine and digoxin may increase digoxin levels by 25% to 40% and increase the half-life from 30 hours to approximately 40 to 50 hours [394] [395] [396] . If quinine and digoxin are coadministered, close monitoring of serum digoxin levels and digoxin dosage adjustment, as necessary, are recommended [389] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant use of quinine and digoxin may result in increased plasma concentrations of digoxin. Coadministration of quinine with digoxin requires close monitoring of serum digoxin levels, and digoxin dose adjusted as necessary [389] . 7) Probable Mechanism: reduced clearance of digoxin 8) Literature Reports a) Since quinine is the levorotory stereoisomer of quinidine, its interaction with digoxin has been studied. The results indicate that the effect of quinidine on digoxin renal clearance is nonstereospecific. Quinidine and quinine may have the same effect on digoxin by inhibiting the tubular secretion and thus decreasing renal clearance of digoxin [390] . Quinine has also been shown to decrease biliary secretory clearance of digoxin [391] . b) The effect of quinine on the pharmacokinetics of digoxin was studied in seven healthy male volunteers. Each subject received an oral loading dose of digoxin 1 mg over a 24-hour period, followed by an oral maintenance dose of 0.1875 mg twice daily.

After two weeks of digoxin therapy, quinine sulfate 250 mg once daily was initiated for a one-week period. The quinine dose was then increased to 750 mg daily for an additional week. Results showed that quinine increased the digoxin plasma concentration from 0.64 ng/mL prior to quinine therapy to 0.80 ng/mL during quinine 250 mg administration and 0.85 ng/mL during quinine 750 mg administration. The renal clearance of digoxin fell from 181 mL/min during control to 174 mL/min during quinine 250 mg treatment and 171 mL/min during quinine 750 mg treatment. Creatinine clearance was not altered during quinine and digoxin coadministration. The renal digoxin clearance was also not changed during quinine coadministration [392] . c) Six subjects (four healthy and two hospitalized) were given an intravenous dose of digoxin 1 mg over ten minutes. Four days later, quinine sulfate 200 mg every eight hours was administered for four days before and four days after a second dose of intravenous digoxin 1 mg. Quinine decreased the digoxin total body clearance by 26% (from 2.98 mL/min/kg to 2.22 mL/min/kg). The half-life of digoxin was increased from 34.2 hours to 51.8 hours, representing a 32% decrease in the digoxin elimination rate constant. The digoxin volume of distribution and renal clearance were unaltered. These results suggest that quinine alters the metabolism or biliary secretion of digoxin, thereby reducing digoxin total body clearance [393] . Quinupristin 1) Interaction Effect: increased digoxin levels and digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: The coadministration of digoxin and quinupristin/dalfopristin may result in increased serum digoxin levels [509] . Eubacterium lentum bacteria converts a portion of digoxin to inactive digoxin reduction products in the gut. Quinupristin/dalfopristin has been shown in vitro to have activity against Eubacterium lentum, which could result in less digoxin being metabolized and more digoxin absorbed. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Monitor digoxin serum concentrations when quinupristin/dalfopristin is added to or withdrawn from therapy. Also, observe patients for a change in response to digoxin. 7) Probable Mechanism: decreased digoxin metabolism by GI bacteria Rabeprazole

1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: When oral digoxin 0.25 mg was given with rabeprazole 20 mg to 16 volunteers, a 22% increase in trough digoxin levels occurred. Digoxin area under the concentrationtime curve (AUC) and maximum concentration (Cmax) also increased 19% and 29%, respectively [441] [442] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor digoxin levels in patients requiring concomitant digoxin and rabeprazole therapy. A downward dosage adjustment of digoxin may be necessary. 7) Probable Mechanism: increased digoxin absorption Ranolazine 1) Interaction Effect: an increase in digoxin steady state plasma concentrations 2) Summary: Ranolazine increases digoxin concentrations by inhibiting P-glycoprotein (P-gp). Coadministration of ranolazine 1000 mg twice a day and digoxin 0.125 mg daily increases the digoxin steady state plasma concentrations by 1.5-fold. The dose of digoxin may have to be reduced when coadministered with ranolazine [575] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant administration of digoxin and ranolazine may increase digoxin plasma concentrations. Digoxin dose adjustment may be necessary [575] . 7) Probable Mechanism: ranolazine inhibition of P-glycoprotein Rifampin 1) Interaction Effect: decreased digoxin levels 2) Summary: In a number of case reports the concomitant use of rifampin and digoxin has been shown to decrease digoxin concentrations to subtherapeutic levels [253] [254] [255] [256] [257] . This occurs especially in patients with renal dysfunction, by increasing the non-renal clearance of digoxin [258]

. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Monitor digoxin levels within three to five days of adding or deleting rifampin, and adjust digoxin doses accordingly. 7) Probable Mechanism: increased digoxin hepatic metabolism Rifapentine 1) Interaction Effect: decreased cardiac glycoside effectiveness 2) Summary: Concurrent use of rifapentine and a cardiac glycoside may result in enhanced metabolism and decreased effect of the cardiac glycoside [447] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Higher doses of cardiac glycoside may be required in patients receiving rifapentine. During and after rifapentine therapy, monitor serum cardiac glycoside concentrations and adjust dosage if needed. 7) Probable Mechanism: increased hepatic metabolism Ritonavir 1) Interaction Effect: increased digoxin plasma concentrations and increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Digoxin exposure was increased in healthy volunteers that received concomitant ritonavir [405] . In addition, a single case has been reported of digoxin toxicity attributed to the introduction of ritonavir; the patient had previously been stabilized on digoxin and antiretroviral therapy with lamivudine, indinavir and stavudine [404] . The effects of ritonavir-associated P-glycoprotein inhibition on digoxin pharmacokinetics were comparable across the Multiple Drug Resistant Gene (MDR1) genotypes of 12 healthy subjects. Ritonavir decreased the nonrenal clearance of digoxin and significantly increased the digoxin AUC by 22% [406] . 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Closely monitor digoxin serum concentrations. Patients concurrently treated with digoxin and ritonavir may be at an increased risk for digoxin toxicity and may require dose adjustments of digoxin. 7) Probable Mechanism: decreased nonrenal clearance of

digoxin due to ritonavir-mediated inhibition of p-glycoprotein in the liver 8) Literature Reports a) A case report describes a 61-year-old woman maintained on digoxin 0.25 mg/day, lamivudine 150 mg twice daily, indinavir 800 mg three times daily, and stavudine 40 mg twice daily, who presented to the emergency room with symptoms of digoxin toxicity 3 days after the addition of ritonavir 200 mg twice daily to her antiretroviral regimen. The digoxin level on admission, measured approximately 5 hours after the last dose, was 7.2 nanomoles (nmol)/L (normal 1 to 2.6). Levels measured 11, 15, and 27 hours after the last dose were 5.5, 4.5 and 2.7 nmol/L, respectively. Digoxin was permanently discontinued without incident. The original antiretroviral drugs were resumed without significant side effects. The authors suggest the interaction between digoxin and ritonavir is mediated through pglycoprotein (inhibition by ritonavir), since digoxin is a substrate for p-glycoprotein, but not CYP3A4 [404] . b) Concomitant administration of ritonavir with digoxin significantly reduced digoxin total clearance and increased digoxin bioavailability. In a randomized, double-blind, cross-over study, healthy men (n=12) received either ritonavir 300 milligrams (mg) twice daily or placebo on study days 1 through 11. Twenty minutes after an oral dose of ritonavir 300 mg was given on study day 3, each subject received a single intravenous dose of digoxin 0.5 mg, after which digoxin pharmacokinetics were assessed in a serial manner over the next 216 hours. An oral water overload (200 milliliters/hour) was imposed over the first 12 hours after dosing in order to minimize renal tubular reabsorption of digoxin. Each subject crossed over the opposing study arm after a minimum washout period of 20 days. Concurrent administration of ritonavir with digoxin significantly decreased digoxin renal and nonrenal clearance (by 35% and 48%, respectively; p less than 0.01) and increased digoxin area under the concentration-time curve (0 to infinity) by 86% (p less than 0.01). Digoxin steady-state volume of distribution increased by 77% (p less than 0.001) and terminal elimination half-life increased by 156% (p less than 0.01) [405] . c) In a 2 treatment, 2 period, single sequence, longitudinal drug interaction study lasting 32 days, 9 out of 12 healthy subjects showed decreased nonrenal clearance of a 0.4 milligram (mg) single oral dose of digoxin by 30% after 13 days of ritonavir 200 mg twice daily. After baseline blood samples were drawn, 2 x 0.2 mg capsules were given on day 1. Blood samples were taken at 1, 4, 8, 12, 24, 48, and 72 hours. Urine samples were

collected at time 0 to 24, 24 to 48 and 48 to 72 hours. The samples were analyzed for digoxin. After an 11-day washout period, subjects received 200 ritonavir twice daily, starting on study day 16, for 15 days. Adherence was assessed with the use of ritonavir trough (C12) plasma concentrations at 4 points during the 15-day course of ritonavir. On day 13 of ritonavir administration (day 29 of the study) 0.4 mg of digoxin was given again and the study procedures of day 1 were repeated. In the 72 hours after the digoxin dose, ritonavir increased the digoxin area under the curve (AUC) by 22%, (range, 21% to 67%, p = 0.03) from 26.2 nanograms x hour/milliliter (ng x hr/ml) to 31.96 ng x hr/ml. Renal clearance of digoxin was not significantly affected by the presence of ritonavir. The effects of ritonavirassociated P-glycoprotein inhibition on digoxin pharmacokinetics were comparable across the Multiple Drug Resistance Gene (MDR1) genotypes of the 12 subjects [406] . Roxithromycin 1) Interaction Effect: possible digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: Coadministration of digoxin and roxithromycin may result in increased serum digoxin levels. Roxithromycin has the potential to decrease the amount of gastrointestinal flora, resulting in decreased digoxin breakdown in 10% to 15% of patients. This interaction has been previously documented for erythromycin and digoxin [705] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Serum digoxin levels should be carefully monitored when roxithromycin is added to or withdrawn from therapy. Patients should be observed for signs and symptoms of digoxin toxicity (nausea, vomiting, arrhythmias). 7) Probable Mechanism: decreased digoxin metabolism 8) Literature Reports a) A 76-year old woman who was stabilized on digoxin 0.25 mg daily presented to the emergency room with shortness of breath, vomiting, and general malaise. She had been started on roxithromycin (150 mg twice daily) four days earlier. Upon admission, her serum electrolyte and creatinine levels were within the normal ranges and her digoxin level was 7.5 nmol/L (normal therapeutic range, 1.0-2.6 nmol/L). In addition, electrocardiogram (ECG) measurements showed marked first degree heart block with widespread S-T segment changes. After discontinuation of digoxin and roxithromycin, serum digoxin levels returned to normal several days later. Although this

patient had a complex medical history and was on numerous medications, it was postulated that the cause of her digoxin toxicity was due to an interaction between digoxin and roxithromycin. Approximately 10% to 15% of the population rely on gastrointestinal bacteria to inactivate up to 40% of a digoxin dose. When antibiotics are given in these patients, decreased numbers of bacteria in the gastrointestinal tract may result in an increased risk of digoxin toxicity [704] . Saquinavir 1) Interaction Effect: increased exposure and plasma concentrations of digoxin 2) Summary: The AUC and Cmax of digoxin increased by approximately 50% and 30%, respectively, when coadministered with saquinavir/ritonavir. If these agents are coadministered, closely monitor digoxin serum concentrations and the dose of digoxin may need to be reduced [742] . 3) Severity: major 4) Onset: unspecified 5) Substantiation: established 6) Clinical Management: Patients concurrently treated with digoxin and saquinavir/ritonavir may be at an increased risk for digoxin toxicity. Closely monitor digoxin serum concentrations and digoxin dose reductions may be necessary when coadministered with saquinavir/ritonavir [742] . 7) Probable Mechanism: unknown 8) Literature Reports a) Concurrent administration of digoxin and saquinavir/ritonavir led to significant increases in digoxin AUC and Cmax. Oral saquinavir 1000 mg/ritonavir 100 mg twice daily were administered for 16 days followed by a single-dose of digoxin 0.5 mg orally in 16 healthy volunteers. The geometric mean AUC and Cmax of digoxin increased 49% (90% confidence interval (CI), 32% to 69%) and 27% (90% CI, 5% to 54%), respectively. Serum digoxin concentrations increased more in females compared with males [742] . Sea Cucumber 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: Patients taking digoxin should not consume sea cucumber. Sea cucumbers produce holothurin, a steroid toxin with a toxic effect similar to that of digitalis. Holothurin A and other related toxic steroids may bind to indoles to produce other

toxins in the body. There is no specific monoclonal neutralizing antibody for holothurin A [740] . 3) Severity: minor 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Avoid concomitant use of sea cucumber and digoxin. If digoxin toxicity occurs due to concomitant use of sea cucumber and digoxin, digoxin immune FAb may be used, though its effectiveness against the toxin produced by sea cucumber is unknown. 7) Probable Mechanism: sea cucumber toxin holothurin produces similar cardiotoxic effects as digoxin Senna 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: Senna is noted in the German Commission E Monographs to be associated with potassium loss [277] . As with other plant anthranoid laxative sources, loss of potassium can occur secondary to excessive or prolonged use, termed "laxative abuse" [277] [190] . Potassium loss is partly due to direct loss in the feces and partly as secondary renal effect associated with sodium loss [190] . Patients taking senna bark for more than 1-2 weeks may experience hypokalemia (signs and symptoms include lethargy, muscle cramps, headaches, paresthesias, tetany, peripheral edema, polyuria, breathlessness, and hypertension). Hypokalemia may increase the risk of digoxin toxicity (signs and symptoms include anorexia, nausea, vomiting, diarrhea, weakness, visual disturbances, ventricular tachycardia). Concomitant use of senna and digoxin should be avoided. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Patients who are taking digoxin should be advised to avoid concomitant use with senna. If digoxin toxicity occurs, potassium should be monitored and supplemented if necessary while discontinuing senna. 7) Probable Mechanism: hypokalemia due to senna 8) Literature Reports a) Laxative abuse using plants such as senna pod/leaf that contain anthraquinone glycosides can lead to depletion of 2550% of the potassium due to water and electrolyte losses [190] .

b) Diuretic and digoxin maintenance therapy in 12 congestive heart failure patients studied for hypokalemia and cardiac arrhythmias resulted in digoxin toxicity in 6 patients with normal serum digoxin levels. The daily digoxin dose was 0.30 +/- 0.06 milligrams (mg) orally, and the mean serum concentration was 1.52 +/- 0.17 nanomoles/milliliter (nmol/mL). The mean serum potassium level was 3.41 +/- 0.09 millimoles/liter (mmol/L) for the 12 subjects [275] . c) Of 79 men with arrhythmias associated with digoxin intoxication, 24 were hypokalemic and 55 were normokalemic. In the hypokalemic group, mean serum potassium was 3 milliequivalents/liter (mEq/L) and mean serum digoxin level was 1.1 nanograms/milliliter (ng/mL) compared to 4.7 mEq/L potassium and 3.7 ng/mL digoxin in the normokalemic group [276] . Simvastatin 1) Interaction Effect: increased digoxin levels 2) Summary: Concomitant administration of simvastatin 40 mg once daily for 10 days with a single dose of digoxin 0.4 mg on day 10 resulted in an increase in the maximum mean digoxin level by approximately 0.3 nanograms/mL. When simvastatin therapy is initiated in a patient stabilized on digoxin, monitor the patient for increased digoxin levels [384] and adjust the digoxin dose as needed. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concurrent administration of digoxin and simvastatin may increased the plasma digoxin levels. When simvastatin therapy is initiated in a patient stabilized on digoxin, monitor the patient for increased digoxin levels [384] and adjust the digoxin dose as needed. 7) Probable Mechanism: unknown Sitagliptin 1) Interaction Effect: increased digoxin exposure and plasma concentration 2) Summary: Concomitant administration of digoxin 0.25 mg with sitagliptin 100 mg once daily for 10 days resulted in increases of 11% and 18% in plasma AUC and Cmax of digoxin, respectively. Use caution if these agents are coadministered and monitor patients appropriately. No dosage adjustment of digoxin is recommended [385] . 3) Severity: minor

4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant administration of digoxin and sitagliptin led to minor increases in digoxin plasma AUC and Cmax. Use caution if these agents are coadministered and monitor patients appropriately. No dosage adjustment of digoxin is recommended [385] . 7) Probable Mechanism: unknown 8) Literature Reports a) Concomitant administration of digoxin and sitagliptin 100 mg for 10 days led to minor increases in digoxin plasma AUC (11%) and Cmax (18%) [385] . Sotalol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527]

[528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption

caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Spironolactone 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias)

2) Summary: Three possible mechanisms of drug interaction between digoxin and spironolactone have been described in the literature. Concomitant use of digoxin and spironolactone may result in increased digoxin plasma levels due to decreased digoxin renal clearance [314] [315] [316] [317] [318] . Spironolactone may displace digoxin from tissue binding sites [317] ; further studies are needed to evaluate whether this displacement involves the receptor sites where digoxin exerts its therapeutic effect. Also, spironolactone and its metabolites can interfere with digoxin radioimmunoassay tests causing artificially high serum digoxin level results [319] . 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: During concomitant use of digoxin and spironolactone , monitor the patient's clinical response and serum digoxin levels to adjust digoxin dosage; downward dosage adjustments may be necessary. False elevation of digoxin levels may occur with some testing methods. 7) Probable Mechanism: inhibition of active tubular secretion of digoxin 8) Literature Reports a) The mechanism of renal handling of digoxin and spironolactone were evaluated [299] . Simultaneous measurements of inulin and digoxin clearances were performed in 13 digitalized patients with chronic congestive heart disease. Nine of the patients were subsequently treated with spironolactone 100 mg daily for 10 days, and the measurements of inulin and digoxin clearances were repeated. The mean concentration of plasma digoxin increased from 0.8 ng/mL to 1 ng/mL (p less than 0.01). The data suggests that spironolactone decreases tubular secretion of digoxin in the distal segment of the renal tubulus. Digoxin radioimmunoassays free of cross-reactivity with spironolactone and its metabolites were utilized in this study [300] . b) A study was performed on four patients with arteriosclerotic heart disease and four healthy volunteers [301]

. The subjects were administered 0.75 mg digoxin intravenously, producing serum levels of 0.93 to 2.4 ng/mL. The subjects then received spironolactone 100 mg twice daily for five days followed by another digoxin 0.75 mg intravenous dose. Digoxin serum levels were 1.1 to 3.55 ng/mL. During spironolactone administration plasma and renal clearance of digoxin and digoxin volume of distribution decreased significantly. The authors concluded that both the loading dose and maintenance dosage for digoxin may need to be reduced when taking spironolactone concurrently; also, further studies are needed to evaluate whether spironolactone displaces digoxin from receptor sites where digoxin exerts its therapeutic effect. Digoxin radioimmunoassays free of cross-reactivity with spironolactone and its metabolites were utilized in this study [300] . c) The effect of quinidine and spironolactone on the pharmacokinetics of digoxin were studied in six normal subjects who each received digoxin alone, digoxin with quinidine, digoxin with spironolactone, and digoxin with both quinidine and spironolactone [302] . Spironolactone and quinidine, alone and in combination, reduced digoxin systemic, renal, and nonrenal clearance and prolonged the elimination half-life of digoxin. However, this study may not be valid due to the possible inclusion of spironolactone metabolites by the digoxin radioimmunoassay utilized [303] . d) Digoxin kinetic and hemodynamic studies were evaluated in six healthy volunteers during digoxin administration alone and digoxin plus spironolactone or triamterene [304] . Spironolactone reduced renal tubular secretion of digoxin and attenuated digoxin's positive inotropic effect. Results also indicated a drug-receptor interaction between spironolactone metabolites and digoxin at the hypothesized inotropic digitalis receptor. However, this study may not be valid due to the possible inclusion of spironolactone metabolites by the digoxin radioimmunoassay utilized. e) The effect of spironolactone on digoxin pharmacokinetics in pediatric patients with ventricular septal defects were studied [305] . Twenty-three children (2 weeks to 3 1/2 years in age; 1.5 to 15 kg in weight) were concurrently administered digoxin 9.3 +/- 4.7 mcg/kg/day and spironolactone 2.4 +/- 0.9 mg/kg/day. None of the 23 children exhibited digoxin serum concentrations greater than 2.2 ng/mL or signs of toxicity. A second group of eight children (2 weeks to 3 1/2 years in age) received digoxin 7.5 mcg/kg/day as a single agent for at least 14 days;

spironolactone 2.96 +/- 0.65 mg/kg/day was then added to the regimen. None of the eight children had elevated serum digoxin levels following administration of spironolactone. f) Spironolactone used concurrently with digoxin can interfere with the radioimmunoassay commonly used for monitoring digoxin serum levels. This occurs due to the structural similarity of spironolactone and its metabolites to digoxin [306] [307] [308] [300] [305] [309] [310] . However, many clinicians [311] [312] [313] have reported negligible interference with digoxin radioimmunoassay if therapeutic doses of spironolactone are administered. Squill 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: A case of death likely due to cardiac glycoside toxicity following squill ingestion has been reported [325] . Both squill and digitalis, the source of digoxin, are known to contain cardiac glycosides known as cardenolides [326] [327] [328] . Squill contains proscillaridin A as its principal cardiac glycoside [329] . At this time, squill is not widely available in the United States. 3) Severity: major 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Concomitant use is contraindicated due to the chemical similarity between squill and digoxin. Patients with unexplained signs and symptoms of digoxin toxicity (e.g., nausea, vomiting, abnormal vision, cardiac arrhythmias, unexplained hyperkalemia) in the absence of increased dosage should be questioned about squill intake. A digoxin level may confirm the diagnosis, but may not quantify the severity. Treatment with digoxin-specific Fab (dsFab) antibody fragments has been successful in toxic ingestion of other cardiac glycoside-containing plants, but the efficacy of dsFab is unknown in cases of squill ingestion. 7) Probable Mechanism: additive cardiac glycoside activity

8) Literature Reports a) A 55 year-old female developed nausea, vomiting, and seizures following ingestion of squill for arthritis. On admission to the hospital 2 hours after ingestion, blood pressure was 110/70 mmHg, pulse was 56 beats/minute, serum potassium was 5.9 millimoles/liter (mmol/L), and a digoxin level was 1.59 nanograms/milliliter (ng/mL). Gastric lavage was performed and activated charcoal 50 grams was administered. Nine hours after ingestion, electrocardiogram showed complete atrioventricular block, and the patient had lost consciousness. Atropine was ineffective, and a temporary cardiac pacemaker was applied at 60 beats/minute. Twenty-four hours after ingestion, ventricular tachycardia occurred and serum potassium was 6.2 mmol/L. Lidocaine injections were ineffective and ventricular fibrillation occurred which was unresponsive to direct-current cardioversion and cardiopulmonary resuscitation. Death occurred 30 hours after ingestion. The patient's medical history included hypothyroidism treated with thyroxine; a TSH level one week prior to squill ingestion was 9.4 milli-international units/milliliter (mIU/mL) (normal 0.25 to 4.3 mIU/mL) and T3 was 61 nanograms/deciliter (ng/dL) (normal 86 to 187 ng/dL). Hypothyroidism may be a risk factor for digoxin toxicity [324] . St John's Wort 1) Interaction Effect: reduced digoxin efficacy 2) Summary: Ten days of concurrent therapy with digoxin at steady-state and St. John's Wort extract resulted in a 33% reduction in the digoxin trough concentration. Maximum concentration (Cmax) was also decreased by 26% [495] . St. John's Wort may induce P-glycoprotein transport of digoxin [496] . The magnitude of the effect may depend on the dosage and formulation of St. John's Wort that is used [497] . Patients should be advised to avoid the use of St. John's Wort while taking digoxin. 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Avoid concomitant use of St. John's Wort and digoxin. If patients elect to combine products despite this advice, digoxin levels should be monitored closely, noting that by day 10, trough digoxin concentrations may be decreased by 33% with further reductions possible. Upward dosage titration of digoxin should be undertaken only if the patient engages in consistent daily intake of St. John's Wort with a reputable product containing a constant amount of active ingredients of St.

John's Wort. Under these circumstances, patients should be advised that if they discontinue use of St. John's Wort, that digoxin blood levels may escalate to toxic levels. Patients should not discontinue St. John's Wort without notifying their physician. 7) Probable Mechanism: induction of P-glycoprotein drug transporter 8) Literature Reports a) Twenty-five healthy volunteers participated in a single-blind, placebo-controlled parallel study to investigate the influence of single and multiple doses of St. John's Wort extract on the steady-state pharmacokinetics of digoxin. Each study participant was given digoxin 0.25 mg twice daily for two days, followed by 0.25 mg once daily until study day 15 to attain steady-state. St. John's Wort 300 mg or placebo three times daily was started on day 6 and continued for 10 days. The St. John's Wort extract contained 92 mcg hypericin, 262 mcg pseudohypericin, and 18.37 mg hyperforin (Lichtwer Pharma, Berlin). No statistically significant differences in digoxin pharmacokinetics were observed after only one day of combination therapy with St. John's Wort and digoxin (study day 6). However, after ten days of coadministration, the digoxin area under the concentrationtime curve (AUC) had decreased from 17.2 mcg h/L to 12.9 mcg h/L (a 25% decrease, p equal to 0.0035). Maximum concentration (Cmax) had also decreased from 1.9 mcg/L to 1.4 mcg/L (a 26% decrease, p equal to 0.0095), while trough digoxin concentrations decreased from 0.58 mcg/L to 0.38 mcg/L (a 33% decrease, p equal to 0.0023). Half-life of terminal digoxin elimination did not change significantly, suggesting that the reduction in Cmax and AUC may result from an influence on absorption or distribution by St. John's Wort extract. Pharmacodynamically, no differences were observed in blood pressure, pulse, or PQ interval between the placebo and St. John's Wort groups. The authors hypothesize that the changes in digoxin pharmacokinetics are mediated by induction of Pglycoprotein [492] . b) The effect on digoxin levels was dependent on dose and formulation of St. John's Wort in a randomized, double-blinded, placebo-controlled, parallel group study of 55 volunteers. After digoxin reached steady-state, St. John's Wort was added for 14 days. St. John's Wort formulations and dosages used were as follows: St. John's Wort extract 900 milligrams (mg) (Jarsin(R)) daily; encapsulated powder 0.5 grams, 1 gram, 2 grams, or 4 grams; 2 cups of tea each with 1.6 grams St. John's Wort; or 1.2 grams encapsulated fatty oil formulation. Digoxin 24 hour area under the concentration-time curve (AUC) was reduced by 27.1% with 4 grams encapsulated powder, 24.6% with

Jarsin(R), and 17.6% with 2 grams encapsulated powder. Digoxin trough levels in these groups were reduced by 18%, 18%, and 13%, respectively. Encapsulated powder 0.5 grams and 1 gram, tea, and fatty oil formulations did not significantly alter digoxin AUC and trough levels [493] . c) St. John's Wort significantly increased P-glycoprotein expression and associated drug efflux in a randomized, singleblind, placebo-controlled trial of 22 healthy subjects (13 female, 9 male). Subjects received St. John's Wort (Good n' Natural, standardized to 0.15% hypericin) 600 milligrams (mg) (n=15) or placebo (n=7) three times daily for 16 days. P-glycoprotein expression in peripheral blood mononuclear cells increased 4.2fold with St. John's Wort after 16 days (29.5 +/- 14.3 median fluorescence intensity (MFI, a measure of P-glycoprotein expression) versus 7 +/- 1.9 MFI, p less than 0.05, 95% confidence interval (CI): 13.5, 31.6). Individual variability occurred with a range of 1.09 to 9.06 MFI after St. John's Wort. No change in P-glycoprotein expression occurred in subjects receiving placebo. P-glycoprotein expression returned to baseline 16 days after discontinuing St. John's Wort. Efflux of the known P-glycoprotein substrate rhodamine was increased with St. John's Wort (p less than 0.05); no change in efflux occurred with placebo. Ritonavir (5 micromoles), known to reverse P-glycoprotein drug efflux, was significantly less effective in reducing rhodamine efflux in subjects treated with St. John's Wort (75.4 +/- 16.4% versus 23.9 +/- 15.3%, p less than 0.01, 95% CI: 43.7, 70.1). Three subjects receiving St. John's Wort withdrew from the study, one experienced adverse effects (nausea, dry mouth), and two needed potentially interacting medications. Analyses of 2 capsules from 3 batches of St. John's Wort with high performance liquid chromatography verified the hypericin content to be 0.15%, 0.14%, and 0.15% [494] . Succinylcholine 1) Interaction Effect: an increased risk of cardiac arrhythmias 2) Summary: Concomitant digoxin and succinylcholine therapy has been reported to result in cardiac arrhythmias [597] [598] [599] [600] . This interaction is presumably due to exacerbation of digitalisinduced ventricular irritability and effects on conduction, and/or shifts of potassium from inside muscle cells to the outside of the digitalized myocardium. An effect on cholinergic receptors resulting in release of catecholamines has also been postulated.

3) Severity: major 4) Onset: rapid 5) Substantiation: theoretical 6) Clinical Management: Cardiac rhythm should be closely monitored when administering succinylcholine to a digitalized patient. 7) Probable Mechanism: exacerbation of digitalis-induced ventricular irritability and/or shifts of intracellular potassium 8) Literature Reports a) A digitalized 63-year-old female developed ventricular arrhythmias following repeated doses of succinylcholine. A total of 160 mg of succinylcholine had been administered when the patient developed ventricular fibrillation and cyanosis. After approximately 30 seconds, sinus rhythm returned. This patient had a history of myocardial infarction, and had also developed an atrial fibrillation following a calcium infusion test two days prior to the administration of succinylcholine [595] . b) The incidence of arrhythmias in digitalized patients who received either succinylcholine or pancuronium were compared. They divided 104 patients into four groups: Groups 1 and 2 were not receiving digitalis therapy, and Groups 3 and 4 were maintained on digoxin, diuretic therapy, and potassium supplementation. Patients in Groups 1 and 3 received succinylcholine 2 mg/kg while Groups 2 and 4 were administered pancuronium 0.12 mg/kg. Results showed that the incidence of dysrhythmias was significantly higher in the Group 4 patients who were receiving digoxin and pancuronium (6 out of 18 patients) than in Group 3, who received digoxin and succinylcholine (3 out of 46 patients). Additionally, there was no significant difference in the incidence of dysrhythmias following the administration of succinylcholine in digitalized or nondigitalized patients. The authors concluded that succinylcholine need not be withheld in patients on digitalis therapy, and that caution should be exercised when administering succinylcholine and pancuronium to digitalized patients [596] . Sucralfate 1) Interaction Effect: decreased digoxin effectiveness 2) Summary: Concomitant single doses of oral sucralfate and digoxin caused a 19% decrease in digoxin bioavailability. When digoxin was given two hours before sucralfate, no interaction occurred. The mechanism is not established; presumably, there was a reduction in the gastrointestinal absorption of digoxin [501] . 3) Severity: moderate

4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Concurrent administration of sucralfate and digoxin is not recommended. If concurrent use cannot be avoided, sucralfate should be taken at least two hours after digoxin. 7) Probable Mechanism: decreased digoxin absorption 8) Literature Reports a) Subtherapeutic levels of digoxin, quinidine, and warfarin occurred in a 71-year-old patient, even though the administration of sucralfate was separated by two hours from the other agents. Following hospitalization, sucralfate was administered four hours apart from the remainder of the therapeutic regimen and was subsequently discontinued; digoxin and quinidine levels returned to therapeutic levels and the prothrombin time improved. Clinicians should be aware that sucralfate may reduce the bioavailability of other drugs, even if the administration times are staggered [500] . Sulfasalazine 1) Interaction Effect: decreased digoxin levels 2) Summary: Concomitant administration of digoxin and sulfasalazine has been reported to result in reduced digoxin absorption and serum levels (decreased AUC by 24%). This combination is not contraindicated, however, serum digoxin levels should be monitored in patients receiving the combination [271] [272] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: Monitor digoxin serum levels during the initiation and after discontinuation of sulfasalazine. The dose of digoxin may need to be increased during therapy with sulfasalazine. 7) Probable Mechanism: may decrease absorption 8) Literature Reports a) Concomitant sulfasalazine and digoxin therapy has been reported to result in decreased digoxin bioavailability [269] . b) When digoxin is administered to patients concomitantly on sulfasalazine, reduced serum digoxin levels and a decrease in the cumulative urinary digoxin excretion were noted. Levels rose when sulfasalazine was discontinued. Although the mechanism is undetermined, patients who receive both courses of therapy

should have their serum digoxin levels monitored carefully. There have been no reported bioavailability problems with sulfasalazine and digitoxin [270] . Talinolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] .

b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should

decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Teduglutide 1) Interaction Effect: increased absorption of oral drugs with a narrow therapeutic index (eg, critical-dose drugs) 2) Summary: Coadministration of teduglutide with an oral medication that has a narrow therapeutic index (NTI; eg, criticaldose drugs) may significantly increase absorption of the NTI drug. A reduced dose of the oral NTI drug may be necessary when administered concomitantly with teduglutide [503] . If coadministration is necessary, monitor the patient for increased side effects of the NTI drug. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical

6) Clinical Management: Caution is advised if teduglutide is coadministered with an oral medication which has a narrow therapeutic index (NTI; eg, critical-dose drugs). Concomitant use may cause increased absorption of the NTI drug, and may require dose adjustment of the orally administered NTI drug [503] . Monitor for increased side effects if a patient is taking teduglutide concomitantly with an oral NTI drug. 7) Probable Mechanism: unknown Telaprevir 1) Interaction Effect: increased digoxin plasma concentrations 2) Summary: In drug interaction studies, the concomitant administration of digoxin and telaprevir increased the AUC of digoxin by 85%. Digoxin therapy should be initiated at the lowest dose. Digoxin serum concentrations should be monitored closely and the digoxin dose titrated accordingly [645] . 3) Severity: major 4) Onset: rapid 5) Substantiation: established 6) Clinical Management: Concomitant use of digoxin and telaprevir may lead to increased digoxin plasma concentrations. When coadministered with telaprevir, initiate digoxin treatment at the lowest dose. Monitor serum digoxin concentrations and titrate the digoxin dose accordingly [645] . 7) Probable Mechanism: unknown 8) Literature Reports a) In drug interaction studies, the concomitant administration of digoxin and telaprevir resulted in an increase in digoxin AUC and Cmax. Patients (n=20) received telaprevir 750 mg every 8 hours for 11 days and a single dose of digoxin 2 mg. Comparing digoxin plus telaprevir versus digoxin administration alone, the ratio estimate for digoxin Cmax was 1.5 (90% confidence interval (CI), 1.36 to 1.65), and for AUC was 1.85 (90% CI, 1.7 to 2) [645] . Telithromycin 1) Interaction Effect: increased digoxin plasma levels 2) Summary: The digoxin plasma peak and trough levels were increased by 73% and 21%, respectively, in healthy volunteers when coadministered with telithromycin. Trough plasma concentrations of digoxin (when equilibrium between plasma and tissue concentrations had been achieved) ranged from 0.74 to 2.17 ng/mL. There were no signs of digoxin toxicity and no significant changes in ECG parameters

[515] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Consider monitoring for digoxin side effects or serum levels during concomitant administration of digoxin and telithromycin. 7) Probable Mechanism: unknown Telmisartan 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: When digoxin and telmisartan are coadministered, a 49 to 50% increase in the digoxin peak plasma concentration and a 13 to 20% increase in the trough digoxin concentration have been observed [542] [543] . Digoxin levels should be closely monitored in patients also receiving telmisartan therapy. 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor digoxin levels when initiating, adjusting, and discontinuing therapy with telmisartan. Dose adjustments of digoxin may be necessary. 7) Probable Mechanism: unknown 8) Literature Reports a) A multiple-dose, open label, two period crossover randomized study in 12 healthy volunteers demonstrated that coadministration of telmisartan and digoxin resulted in higher serum digoxin concentrations than when digoxin is administered alone. The mean values for area under the concentration-time curve (AUC), maximum serum concentration (Cmax) and minimum serum concentration (Cmin) for digoxin were increased by 22%, 50%, and 13%, respectively for telmisartan plus digoxin administration than the corresponding values for digoxin administration alone. The clinical significance of these findings in a small group of healthy male volunteers has not been determined [541] . Teriparatide 1) Interaction Effect: increased risk of digoxin toxicity 2) Summary: The concomitant administration of digoxin and teriparatide may result in digoxin toxicity due to elevations in serum calcium from teriparatide [5] [187]

. If concomitant therapy is required, patients should be monitored for hypercalcemia and digoxin toxicity. 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: The concomitant administration of digoxin and teriparatide may result in digoxin toxicity due to elevations in serum calcium from teriparatide [5] [187] . If concomitant therapy is required, patients should be monitored for hypercalcemia and digoxin toxicity. 7) Probable Mechanism: transient elevation in serum calcium from teriparatide Tertatolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527] [528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown

8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05)

[533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Tetracycline 1) Interaction Effect: increased digoxin levels and digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: In approximately 10% of patients, digoxin is converted to inactive metabolites by colonic bacteria within the gut. In these patients the coadministration of digoxin with

tetracycline inhibits this metabolism and results in a significant increase in absorption of the parent compound digoxin [568] . If digoxin and tetracycline are administered concurrently, patients should be monitored for digoxin toxicity. A dosage adjustment for digoxin may be required. The risk of this interaction may be reduced if digoxin is given with Lanoxicaps(R) [111] . 3) Severity: major 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: If concurrent therapy is required, monitor for digoxin toxicity. A dosage adjustment for digoxin may be required. Alternatively, the risk of this interaction may be reduced if digoxin is given as Lanoxicaps(R). 7) Probable Mechanism: inhibition of bacterial inactivation of digoxin resulting in increased digoxin bioavailability and digoxin toxicity 8) Literature Reports a) Approximately 10% of patients receiving digoxin convert the drug to cardio-inactive metabolites. This inactivation may be attributed to gastrointestinal bacteria. Antibiotic therapy introduced to patients on digoxin has caused a marked decrease in digoxin reduction products and a marked rise in digoxin absorption and serum levels. It is concluded that changes in the enteric flora via antibiotics may alter the state of digitalization. Elevated serum digoxin concentrations by as much as 43 to 116% were observed after a 5-day course of tetracycline in 3 volunteers who produced large amounts of digoxin reduction products [568] . Thyroid 1) Interaction Effect: decreased digoxin efficacy 2) Summary: When a hypothyroid patient becomes euthyroid or a patient has hyperthyroidism, serum digitalis glycoside levels may be reduced [188] . The concomitant use of digoxin and thyroid may increase the dose requirements of digoxin and an increase in the digoxin dose may be needed [5] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: The use of digoxin in hypothyroid

patients treated with thyroid may increase the digoxin dose requirements, therefore an increase in the digoxin dose may be needed [5] . 7) Probable Mechanism: unknown Ticagrelor 1) Interaction Effect: increased digoxin levels 2) Summary: Due to the inhibition of the p-glycoprotein transporter by ticagrelor, concomitant use of digoxin and ticagrelor may increase the digoxin serum concentrations. Monitoring digoxin serum levels with initiation of or any change in ticagrelor therapy; no specific dosage adjustment is recommended [745] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Concomitant use of digoxin and ticagrelor may increase the digoxin serum concentrations. Monitor digoxin levels with initiation of or any change in ticagrelor therapy. No specific dosage adjustment recommended [745] . 7) Probable Mechanism: inhibition of p-glycoprotein transporter by ticagrelor Timolol 1) Interaction Effect: increased risk of bradycardia and possible digitalis glycoside toxicity 2) Summary: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia [527] [528] . Caution is warranted when this combination of medications is given. Bradycardia was more common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone [536] . Such additive interactions have also been reported with ophthalmic administration of beta-blockers [537] . Carvedilol increases serum concentrations of digoxin in children, and its dose may need to be reduced to avoid toxicity [538] . If digitalis glycosides and beta-blockers are coadministered, monitor heart rate and PR interval [527]

[528] . 3) Severity: moderate 4) Onset: unspecified 5) Substantiation: probable 6) Clinical Management: Both digitalis glycosides and betablockers slow atrioventricular conduction and decrease heart rate, and concurrent use can increase the risk of bradycardia. If these drugs are coadministered, monitor heart rate and PR interval [527] [528] , and use with caution. 7) Probable Mechanism: unknown 8) Literature Reports a) The effect of adding sotalol (80 to 320 mg daily) to digoxin in a placebo-controlled trial was studied. Heart rates were lower in the sotalol group and 2 of the 24 patients had to cease sotalol therapy due to excessive asymptomatic bradycardia [529] . b) A 91-year old woman with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide, ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per minutes (bpm) and irregular, her blood pressure was 160/90 mmHg, and digoxin serum concentration was 2.6 nanograms/deciliter. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm and the arrhythmia cleared completely [530] . c) A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in small increases in digoxin bioavailability, but the increases were not clinically significant. Changes in digoxin pharmacokinetics included increases in AUC (14%), Cmax (32%), renal clearance (26%), and urinary excretion (45%) [531] . d) An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum concentrations (0.8 to 2 nanograms/milliliter) in 12 healthy male subjects had no effect on esmolol pharmacokinetics. Digoxin serum levels were

increased by 9% to 19% at 4 hours post-infusion compared with digoxin therapy alone [532] . e) Coadministration of oral talinolol (100 mg) increased the AUC of talinolol from 0 to 6 hours by 18%. The AUC of digoxin from 0 to 72 hours was increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were increased by 45%. When talinolol 30 mg IV was coadministered with oral digoxin (0.5 mg), digoxin pharmacokinetics did not change significantly. The disposition of oral or IV talinolol was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be increased by 1 hour after oral administration as compared to IV administration (10.2 +/- 1.2 vs 11.2 +/- 0.9 hours; p less than 0.05) [533] . f) The digoxin-talinolol drug interaction may be dosage-form dependent and may not involve P-glycoprotein (P-gp) as the main cause for this interaction. The dosage forms of digoxin determine it oral bioavailability. Theoretically, for P-gp to exert its efflux effect, the fraction of dose absorbed should increase and the time to reach peak plasma concentrations should decrease with an increase in dose. The P-gp efflux pump does not appear to play a significant role in retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in bioavailability compared with the control study since it may have caused an increase of in vivo dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to confirm this above hypothesis [534] . g) Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex congenital heart disease were observed for any pharmacokinetic interactions before and after the addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol daily dose was titrated according to clinical response. The clearance of digoxin was calculated before and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02 mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was a mean 2-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 m(2) to 80.6 +/- 23.9 mL/min/1.73 m(2), p=0.056), and the ratio of digoxin clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24

(p=0.002). Multiple regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the initial ratio the significant factor (p=0.05), whereas dose (p=0.78) and age (p=0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is enhanced in children possibly because of a higher expression of the Pglycoprotein pump [535] . Torsemide 1) Interaction Effect: digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Concomitant loop diuretic and digitalis therapy can result in digitalis toxicity secondary to hypokalemia and possibly hypomagnesemia [212] [213] [214] [215] [216] [217] [218] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Frequent monitoring of potassium and possibly magnesium with appropriate replacement is recommended; educate patients about the importance of maintaining adequate intake of dietary potassium and/or potassium supplements. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides Tramadol 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, cardiac arrhythmias) 2) Summary: Digoxin toxicity has occurred rarely during coadministration of digoxin and tramadol [353] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Closely monitor digoxin serum concentrations and adjust doses accordingly. 7) Probable Mechanism: unknown Trazodone 1) Interaction Effect: increased digoxin serum concentrations and an increased risk of digoxin toxicity (nausea, vomiting,

arrhythmias) 2) Summary: Digoxin maximum serum concentrations were increased nearly 30% compared with baseline after nefazodone (an antidepressant structurally related to trazodone ) was given concurrently, in an open, randomized, crossover interaction study [635] . Digoxin toxicity occurred in a 68-year-old woman after trazodone was added to a stable treatment regimen that included digoxin. Her digoxin level had remained within a stable therapeutic range for many months prior to beginning trazodone therapy [636] . Increased serum digoxin serum concentrations have also been reported in patients treated concurrently with trazodone and digoxin [637] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor digoxin concentrations when trazodone is added to, changed during, or discontinued from concomitant treatment with digoxin. Also, monitor patients for signs and symptoms of digoxin toxicity. Adjust digoxin dose accordingly. 7) Probable Mechanism: unknown 8) Literature Reports a) Digoxin serum concentrations were increased nearly 30% compared with baseline after nefazodone (a phenylpiperazine antidepressant structurally related to trazodone ) was given concurrently with digoxin. In an open, randomized, triplecrossover interaction study, healthy subjects (n=18) received an 8-day oral regimen of digoxin 0.2 milligrams (mg) daily, nefazodone 200 mg twice daily, or both drugs administered concomitantly during each 8-day trial period; all subjects crossed over to an alternate study regimen after a 10-day washout period. Steady-state area under the concentration-time curve (AUC) and peak (Cmax) and trough (Cmin) serum concentrations of digoxin were increased by 15%, 29% and 27%, respectively (p less than 0.05, each parameter). No significant changes were observed in vital signs, heart rate, or PR, QRS, and QT intervals. The frequency and severity of adverse events did not differ between treatment groups [632] . b) Digoxin toxicity occurred in a 68-year-old woman after trazodone was added to a stable treatment regimen that included digoxin. Prior to beginning trazodone therapy, her

serum digoxin level had remained within therapeutic range for many months (at a dose of digoxin 125 micrograms (mcg) daily), and on admission was 0.8 nanograms/milliliter (ng/mL). She was hospitalized for severe depression; trazodone was initiated at a dose of 50 milligrams (mg) on day 1, and then escalated to 300 mg daily by day 11. On treatment day 14, the patient complained of nausea and vomiting; her digoxin level measured at 2.8 ng/mL. Trazodone 300 mg daily was continued and digoxin was withdrawn until therapeutic digoxin serum levels were restored. The patient's digoxin levels were sustained within therapeutic range after conversion to an every-other-day regimen of digoxin 125 mcg while she continued to receive trazodone 300 mg daily [633] . c) Increased serum concentrations of digoxin have been observed in patients receiving concurrent treatment with trazodone [634] . Trichlormethiazide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432]

[433] . Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Trimethoprim 1) Interaction Effect: an increased risk of digoxin toxicity 2) Summary: Digoxin levels have been reported to increase during concurrent trimethoprim therapy, especially in elderly patients. This effect may be due to decreased renal tubular secretion of digoxin. Trimethoprim administration did not affect the total body clearance of digoxin or the glomerular filtration rate in young, healthy subjects. However, the renal clearance of digoxin decreased significantly in elderly subjects, resulting in a 30% to 50% increase in digoxin concentrations [507] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: In digitalized patients who receive trimethoprim therapy for seven days or longer, monitor digoxin serum concentrations and monitor the patient for signs and symptoms of digoxin toxicity (nausea, vomiting, arrhythmias). A decrease in the digoxin dose may be necessary. 7) Probable Mechanism: decreased renal tubular secretion of digoxin

8) Literature Reports a) A study of nine elderly patients stabilized on digoxin therapy showed that the addition of trimethoprim 200 mg twice daily for two weeks significantly altered the serum concentrations of digoxin. All patients had normal serum creatinine values, and no signs of hepatic or cardiac disease existed. Immediately prior to the addition of trimethoprim, digoxin serum concentrations averaged 1.0 nmol/L. After seven days and 14 days of trimethoprim treatment, serum digoxin concentrations had risen to 1.3 nmol/L and 1.5 nmol/L, respectively. Seven days after the discontinuation of trimethoprim, digoxin levels had decreased to 0.9 nmol/L [506] . b) Six healthy young male subjects received a single intravenous infusion of digoxin 1 mg over 15 minutes, followed by four days of intermittent venous blood samples. On the fifth day, participants were started on oral trimethoprim 200 mg twice daily. Another intravenous dose of digoxin was given on day 10. Pharmacokinetic parameters for digoxin revealed that the renal clearance was reduced by 17%, from an average of 1.93 mL/min/kg to 1.61 mL/min/kg. Digoxin total body clearance, extra renal clearance, and glomerular filtration rate were not significantly affected by the administration of trimethoprim [506] . Ulipristal 1) Interaction Effect: increased serum digoxin concentrations 2) Summary: In vitro data suggests that ulipristal may inhibit the P-glycoprotein (P-gP) efflux transport system [631] . Concomitant use of ulipristal and digoxin, a P-gP substrate, may result in increased digoxin exposure [631] [5] . If concomitant use is required, measure serum digoxin concentrations before initiating concomitant therapy, consider digoxin dose reduction if necessary, and monitor for evidence of digoxin toxicity. 3) Severity: major 4) Onset: unspecified 5) Substantiation: theoretical 6) Clinical Management: The concomitant use of digoxin and ulipristal may result in increased digoxin exposure [631] [5] . If concomitant use is required, measure serum digoxin concentrations before initiating concomitant therapy, consider digoxin dose reduction if necessary, and monitor for evidence of

digoxin toxicity. 7) Probable Mechanism: inhibition of P-glycoprotein-mediated efflux of digoxin Valspodar 1) Interaction Effect: an increased risk of digoxin toxicity (nausea, vomiting, arrhythmias) 2) Summary: In healthy volunteers, the coadministration of oral digoxin and valspodar resulted in a twofold to threefold increase in digoxin systemic exposure. The mechanism of this interaction is attributed to decreased volume of distribution, decreased biliary excretion, and decreased renal tubular secretion as a result of p-glycoprotein inhibition caused by valspodar. An initial digoxin dose reduction of 50% is recommended when treatment with valspodar is started [399] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: An initial digoxin dose reduction of 50% should be considered when starting oral valspodar therapy. Digoxin concentrations should be carefully monitored, as well as patients should be observed for signs of digoxin toxicity. Further digoxin dose modifications should be based on individual response. 7) Probable Mechanism: inhibition of p-glycoprotein in the intestinal lumen 8) Literature Reports a) Twelve healthy volunteers enrolled in an open-label study to confirm and quantify the effect of valspodar on the pharmacokinetics of digoxin. Each study participant received an oral loading dose of digoxin 1 mg on day 1, followed by digoxin 0.125 mg daily on days 2 to 11. Oral valspodar was administered as a single 400 mg on day 7, followed by 200 mg twice daily from days 8 to 11. When comparing the single-dose effects of valspodar in digoxin (day 6 vs. day 7), the maximum concentration (Cmax) of digoxin was increased by 80% and the area under the concentration-time curve (AUC) increased an average of 76%. Digoxin renal clearance was reduced by 62%. By day 11, the overall accumulation of digoxin was 154% for Cmax and 211% for AUC. There was no evidence that a clinically relevant alteration in digoxin pharmacodynamics occurred; however, this study was conducted in healthy volunteers without cardiovascular compromise. An exploratory comparison of valspodar pharmacokinetics in these study participants did not reveal any notable differences [398] . Verapamil

1) Interaction Effect: increased serum digoxin concentrations and risk of digitalis toxicity 2) Summary: Concomitant administration of verapamil and digoxin may result in a 50% to 75% increase in serum digoxin concentrations, and may increase the risk of digitalis toxicity. These effects were reported to be dose-dependent [546] [549] . Consider reducing the digoxin dose when digoxin and verapamil are coadministered, particularly in patients with hepatic cirrhosis as this effect may be magnified [550] . Additionally, monitor serum digoxin concentrations and for signs or symptoms of digitalis glycoside toxicity and discontinue or withhold digoxin therapy if toxicity develops or is suspected [554] . In patients with mild ventricular dysfunction, optimum doses of digitalis and/or diuretics should be established prior to initiating verapamil. If verapamil is stopped after concurrent therapy, digoxin levels should be monitored and doses adjusted accordingly, to avoid under-digitalization [545] . 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Concurrent use of digoxin and verapamil may increase serum digoxin levels by 50% to 75% in the first week of therapy, and may result in digitalis toxicity. Consider reducing the digoxin dose when digoxin and verapamil are coadministered, particularly in patients with hepatic cirrhosis as this effect may be magnified. Monitor serum digoxin concentrations and for signs or symptoms of digitalis glycoside toxicity. Discontinue or withhold digoxin therapy if toxicity develops or is suspected [544] [545] . In patients with mild ventricular dysfunction, optimum doses of digitalis and/or diuretics should be established prior to initiating verapamil. If verapamil is stopped after concurrent therapy, digoxin levels should be monitored and doses adjusted accordingly, to avoid under-digitalization [545] . 7) Probable Mechanism: inhibition of renal and/or extrarenal digoxin clearance 8) Literature Reports a) In clinical trials in patients receiving verapamil for ventricular control and digoxin for atrial fibrillation or flutter, 15% of patients

had ventricular rates below 50 beats/minute at rest and 5% of patients experienced asymptomatic hypotension [544] . b) Serum digoxin concentrations increase gradually and linearly during the first few days of verapamil therapy, reach 90% of the peak value by 7 days, and peak values by 14 days. The interaction is dose-dependent and occurs at all levels of digitalization [546] . After 5 to 6 weeks of verapamil therapy, however, plasma digoxin concentrations decline from about 60% to 30% above pre-verapamil levels and renal clearance normalizes. Extrarenal clearance of digoxin remains affected and patients with renal failure may be more likely to experience persistent elevations in digoxin levels [547] . c) Concomitant verapamil and digoxin therapy was reported to increase serum digoxin levels from 0.96 +/- 0.08 to 1.63 +/- 0.12 nanograms/mL in 41 patients treated with verapamil 240 mg daily for a chronic atrial fibrillation [548] . d) A study evaluated the pharmacokinetics of digoxin during concomitant verapamil therapy in patients with chronic atrial fibrillation. Verapamil in doses of 240 mg daily was administered to patients receiving maintenance digoxin doses, resulting in significant increases in digoxin serum concentrations (from 0.76 to 1.31 nanograms/mL). These effects were reported to be dose-dependent. In 7 of 49 patients evaluated, signs and symptoms of digitalis toxicity were observed. Steady state serum digoxin concentrations were achieved approximately one week after administration of verapamil. Following discontinuation of the drug, elevated serum digoxin levels persisted for at least 10 hours, but when patients were retested 2 weeks later the digoxin serum concentrations had returned to baseline levels. The effect of verapamil on digoxin distribution is explained partially by reduced renal excretion of digoxin, without a reduction in glomerular filtration [549] . e) A study reported a more pronounced interaction of verapamil and digoxin in patients with cirrhosis. Concurrent therapy with a single low dose of oral verapamil 80 mg and oral digoxin 0.5 mg in cirrhotic patients was reported to result in significant increases in the AUC and peak serum levels of digoxin (32% and 98%, respectively), with an associated decrease in renal digoxin clearance by 23%. In normal subjects, much smaller

alterations in digoxin kinetics were observed during concurrent verapamil administration [550] . f) One report found the addition of oral verapamil 320 mg daily (range, 160 mg to 480 mg daily) provided increased control of ventricular response rates in digitalized patients with chronic atrial fibrillation. Heart rates at rest and during exercise were significantly reduced following the addition of verapamil. Although mean serum digoxin levels increased from 1.6 +/- 0.4 to 2.7 +/- 0.9 nanograms/mL, clinical signs of digitalis toxicity were not present [551] . g) The inotropic activity of digoxin appears to be enhanced during concomitant verapamil therapy. Evidence suggests that this effect is due to the elevated plasma digoxin concentration induced by verapamil, rather than verapamil itself [552] . Fatalities have occurred secondary to the verapamil-digoxin interaction [553] . Ventricular fibrillation and death occurred in a 73-year-old patient following the addition of oral verapamil 80 mg twice daily to digoxin therapy (0.25 mg daily). In a 77-year-old patient receiving digoxin 0.25 mg daily, asystole occurred following intravenous verapamil in aliquots of 5 mg for a total of 35 mg over a period of 130 minutes. In both patients, addition of verapamil was of no benefit in controlling rapid heart rate. In both patients, death occurred when digoxin levels reached 4 ng/mL. Vincristine 1) Interaction Effect: decreased digoxin effectiveness 2) Summary: The AUC of digoxin was reduced by 25 to 30% in six patients given prednisone, cyclophosphamide, procarbazine and vincristine (COPP therapy) or 24h post-cyclophosphamide, vincristine and prednisone (COP therapy), while taking concurrent digoxin tablets. It is not known whether individual antineoplastic agents alone will produce the same effect [180] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Closely monitor serum digoxin trough concentrations when administered concomitantly with chemotherapeutic combination therapies. Also monitor patients for response to digoxin. 7) Probable Mechanism: altered absorption Vincristine Sulfate Liposome

1) Interaction Effect: decreased digoxin effectiveness 2) Summary: The AUC of digoxin was reduced by 25 to 30% in six patients given prednisone, cyclophosphamide, procarbazine and vincristine (COPP therapy) or 24h post-cyclophosphamide, vincristine and prednisone (COP therapy), while taking concurrent digoxin tablets. It is not known whether individual antineoplastic agents alone will produce the same effect [180] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: theoretical 6) Clinical Management: Closely monitor serum digoxin trough concentrations when administered concomitantly with chemotherapeutic combination therapies. Also monitor patients for response to digoxin. 7) Probable Mechanism: altered absorption Xipamide 1) Interaction Effect: digitalis toxicity (nausea, vomiting, arrhythmias) 2) Summary: The most common cause of digitalis toxicity is concurrent use of a digitalis glycoside and a potassium-wasting diuretic [439] . If a digitalis glycoside and a thiazide diuretic are used concurrently, the patient should be monitored for ECG signs of potassium depletion, and potassium supplementation should be considered. 3) Severity: major 4) Onset: delayed 5) Substantiation: established 6) Clinical Management: Patients given diuretics with digitalis should be told to add rich sources of potassium to their diet or they should be given potassium supplements, even though their serum potassium level is normal. The use of combination potassium-sparing potassium-depleting diuretics is also a rational approach. You may want to include some extra potassium in your diet. 7) Probable Mechanism: diuretic-induced hypokalemia and hypomagnesemia enhance Na-K-ATPase inhibition by cardiac glycosides 8) Literature Reports a) The incidence of digitalis intoxication in hospitalized patients varies between 8% to 35%, with mortality attributable to toxicity ranging from 3% to 21% [432] [433]

. Twenty-four percent of 144 patients on combination therapy of digoxin plus diuretic experienced digoxin toxicity, compared to only 9% of 53 patients on digoxin alone [434] . Other authors reported that of 88 patients intoxicated with digitalis, 69% were also on diuretics (30 on chlorothiazide) [435] . One author found that 19 of 25 (75%) patients with digitalis toxicity were also on diuretics [436] . Another study concludes that diuretic therapy was thought to be a primary or contributory factor in precipitating digitalis intoxication in 40% of patients showing adverse reactions [437] . The thiazides have the potential of producing hypokalemia in a large number of patients. It has been demonstrated that 40% of patients treated for more than one week with chlorothiazide and without a potassium supplement will develop hypokalemia (serum potassium of 3.5 mEq/L or less) [438] . Because intracellular potassium may be reduced, even though the serum potassium is normal or even elevated, electrocardiographic signs of potassium depletion may be of greater value than serum potassium levels [438] . Drug-Food Combinations Food 1) Interaction Effect: decreased peak digoxin concentrations 2) Summary: When digoxin tablets, elixir, or capsules are taken with food, the absolute bioavailability of digoxin is 60 to 80%, 70 to 85%, or 90 to 100%, respectively, but the extent of absorption is unchanged. The amount of digoxin absorbed from an oral digoxin dose may be reduced when taken with meals high in bran fiber [750] . However, in most settings, this is clinically insignificant [753] [754] [755] . Some high-bran foods lower serum levels by 15% to 32% for tablets but not for capsules [759] [761] . 3) Severity: moderate 4) Onset: rapid 5) Substantiation: probable 6) Clinical Management: When oral digoxin is taken with food, the absolute bioavailability of digoxin is reduced, but the extent

of absorption is unchanged. The amount of digoxin absorbed from an oral digoxin dose may be reduced when taken with meals high in bran fiber [750] . Therefore, administering oral digoxin consistently with relationship to meals and avoiding ingesting high-fiber foods concomitantly should be considered [751] [752] . 7) Probable Mechanism: delayed digoxin absorption 8) Literature Reports a) Neither gel-forming wheat bran nor non-gel bulk-forming ispaghula cathartic significantly affected the steady state plasma concentrations of digoxin in 30 geriatric patients who received either wheat bran 7.5 g twice daily plus digoxin (n=16) or ispaghula 4 g twice daily plus digoxin (n=14) for 4 weeks. Digoxin doses were 0.13 mg in most, 0.25 mg (n=2), 0.195 mg (n=1), and 0.065 mg (n=1) taken in the morning at the same time as the first dose of wheat bran or ispaghula. The wheat bran group showed significantly reduced plasma digoxin levels of 1.04 nanomoles (nmol)/L at 2 weeks compared with 1.16 nmol/L at baseline (p less than 0.01); however, digoxin levels remained within therapeutic range. There was no such effect on digoxin levels at weeks [753] . b) Digoxin AUC and steady state concentrations, but not peak serum digoxin concentration, time-to-peak serum digoxin concentration, or cumulative urinary excretion, were significantly affected by a diet with bran compared with no bran in an open, analyst-blind, multiple-dose, steady-state, crossover study of healthy subjects (n=16). All subjects received digoxin 0.4 mg as two 0.2-mg capsules with their breakfast each morning for 10 days. Then, subjects were randomized to receive either a breakfast of bran cereal (11 g fiber) or no bran cereal for the next 10 treatment days. Mean AUC was 30.5 nanograms (ng) hr/mL and 28.4 ng hr/mL for no bran and bran, respectively. Among 11 of the 16 subjects, bran resulted in a significant reduction in AUC of 6.9% (p less than 0.5) and in mean steady state digoxin levels compared to baseline (0.89 ng/mL vs 0.84 ng/mL; p less than 0.5). It is suggested that these values do not show a clinically important interaction between bran and digoxin in the capsule formulation [754] . c) In a study of patients in a rehabilitation center receiving digoxin for organic heart disease (n=12), serum digoxin concentrations were not significantly different when subjects

were given their regular diet compared with a bransupplemented diet. Digoxin tablets were given in doses of 0.125 or 0.25 mg 15 to 30 minutes before breakfast for 10 days. Subjects ingested two bran muffins (11 g bran each), one at breakfast and the other one in the afternoon. Serum digoxin samples were taken before adding bran to the diet, after 9 to 10 days of receiving bran, and 10 days after bran had been discontinued. Serum digoxin concentrations showed a nonsignificant mean increase of 0.5% (90% confidence interval, -12% to +14%) with a bran-supplemented diet compared with a regular diet [755] . d) In healthy subjects ages 23 to 45 years, digoxin doses of 0.5 mg to 1 mg daily were given 30 minutes [756] [757] to 90 minutes [758] following a standard breakfast or following an overnight fast, followed by an additional four hours of fasting. Plasma concentrations were measured every 10 to 15 minutes for the first hour and until at least 48 hours after the last dose. Two of 3 studies [758] [757] found statistically significant elevations in the plasma concentration-time curves during the fasting state. The peak concentration when digoxin was given 90 minutes after breakfast did not differ significantly from 30-minute mean values. While the rate of absorption is reduced in the postprandial state, the extent of absorption is the same in the fasting and postprandial states. The AUC was similar for both fasting and fed [758] [756] . Delay in peak serum concentrations from postprandial administration is unlikely to be of clinical significance, since the onset of action of digoxin is slow and during chronic therapy steady state serum levels are not dependent on the rate of absorption. e) Dietary fiber added in different forms to a formula diet may cause a significant increase in serum digoxin concentrations. This was observed after ingestion of carob seed flour. With other dietary fibers (cellulose, pectin, wheat bran), mean peak concentrations were reached later as compared to the control. However, there was no significant difference in the amount of digoxin absorbed [759]

. A 20% decrease in digoxin bioavailability has been demonstrated when given with a diet supplemented with 22 g of bran daily, but digoxin absorption was not affected [760] . Intravenous Admixtures Drugs Bretylium 1) Compatible a) Bretylium 1 mg/mL with digoxin 2 mcg/mL, visually compatible for 48 hours at 25 degrees C in Dextrose 5% in water or Sodium chloride 0.9% [1219] Cefotetan 1) Compatible a) Cefotetan with digoxin, compatible and cefotetan stable for 24 hours at 22 to 25 degrees C; drug concentrations not specified [1214] Ceftaroline Fosamil 1) Compatible a) Digoxin 0.25 mg/mL (undiluted) and ceftaroline fosamil 2.22 mg/mL (diluted with either 0.9% sodium chloride, 5% dextrose, or lactated Ringer injection) were compatible for at least 4 hours at room temperature (23 degrees C) under fluorescent light during simulated Y-site administration [1221] . Cimetidine 1) Compatible a) Cimetidine 3 g/L with digoxin 2.5 mg/L, visually compatible and cimetidine chemically stable for 4 hours at 25 degrees C in Dextrose 5% in water; digoxin not tested [1206] Ciprofloxacin 1) Compatible a) Ciprofloxacin 2 mg/mL with digoxin 0.25 mg/mL, compatible at 25 degrees C under fluorescent lighting; only the stability and potency of ciprofloxacin were tested [1198]

Dobutamine 1) Incompatible a) Dobutamine (1 g/L with digoxin 4 mg/L develops slight pink color within 24 hours at 25 degrees C in Dextrose 5% in water or Sodium chloride 0.9%) [1199] b) Digoxin (4 mg/L with dobutamine 1 g/L develops slight pink color within 24 hours at 25 degrees C in Dextrose 5% in water or Sodium chloride 0.9%) [1200] Doripenem 1) Compatible a) Digoxin 0.25 mg/mL (tested undiluted) with doripenem 5 mg/mL (diluted in either 5% dextrose injection or in 0.9% sodium chloride injection) is physically compatible for 4 hours at room temperature, approximately 23 degrees C, under fluorescent light during simulated Y-site administration [1215] . Doxapram 1) Incompatible a) Digoxin (0.25 mg/1 mL with doxapram 400 mg/20 mL, 10% doxapram decomposition reported in 9 hours and 17% in 24 hours; temperature not specified) [1222] Famotidine 1) Compatible a) Famotidine (prepared as an intravenous solution according to manufacturer's instructions in Dextrose 5% in water with digoxin 250 mcg/mL, undiluted, visually compatible for 14 hours; exact famotidine concentration and test conditions not specified) [1217] b) Digoxin (250 mcg/mL, undiluted, with famotidine, prepared as an intravenous solution according to manufacturer's instructions in Dextrose 5% in water visually compatible for 14 hours; exact famotidine concentration and test conditions not specified) [1218]

Fat Emulsion 1) Compatible a) Digoxin (625 mcg/50 mL in Dextrose 5% in water or Sodium chloride 0.9% added via a Y-site to a total parenteral nutrition solution containing intravenous fat emulsion 10% visually compatible for a 4-hour study period at 25 degrees C; specific composition of total parenteral nutrition solution - 1500 mL - listed below) [1208] : Amino acids 10% Dextrose 70% Lipid emulsion 20% Sterile water for injection Calcium gluconate 10% Magnesium sulfate 50% Potassium chloride Sodium chloride Sodium phosphate Heparin sodium Multivitamins - 12 Trace minerals Fenoldopam Mesylate 1) Compatible a) Digoxin 0.25 mg/mL (undiluted) with fenoldopam mesylate 80 mcg/mL in Sodium chloride 0.9% injection, visually and physically compatible for up to 4 hours at 23 degrees C in a clear glass tube under constant fluorescent light during simulated Y-site administration [1195] . Fluconazole 1) Incompatible 750 mL 429 mL 225 mL 15 mL 20 mL 2 mL 40 mEq 60 mEq 15 mM 6000 U 10 mL 3 mL

a) Digoxin 0.25 milligrams/milliliter (mg/mL) with fluconazole 2 mg/mL, visually incompatible, gas production reported [1211] Foscarnet 1) Incompatible a) Digoxin 250 mcg/mL with foscarnet 24 mg/mL, gas production reported [1223] Heparin 1) Compatible a) Digoxin 0.25 mg/1 mL with heparin 2500 U/1 mL, physically compatible for at least 5 minutes in direct admixture in syringe [1201] b) Digoxin (250 mg/L and heparin 1000 U/L with hydrocortisone sodium succinate 100 mg/L visually compatible, macroscopically and microscopically, for a 4hour study period at 25 degrees C in the following solutions) [1213] : Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0.9% Heparin Sodium 1) Compatible a) Hydrocortisone sodium succinate (100 mg/L in combination with heparin sodium 1000 U/L with digoxin 0.25 mg/mL visually compatible, macroscopically and microscopically, for a 4-hour study period at 25 degrees C in the solutions listed below) [1192] : Dextrose 5% in water

Lactated Ringer's injection Sodium chloride 0.9% Hydrocortisone Sodium Succinate 1) Compatible a) Hydrocortisone sodium succinate (100 mg/L in combination with heparin sodium 1000 U/L with digoxin 0.25 mg/mL visually compatible, macroscopically and microscopically, for a 4-hour study period at 25 degrees C in the solutions listed below) [1192] : Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0.9% b) Digoxin (250 mg/L and heparin 1000 U/L with hydrocortisone sodium succinate 100 mg/L visually compatible, macroscopically and microscopically, for a 4hour study period at 25 degrees C in the following solutions) [1213] : Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0.9% Insulin, Regular 1) Conflicting Data a) Incompatible 1) Digoxin 0.005 mg/mL with insulin (both Humulin R(R) and Iletin(R)) 1 U/mL, both in Dextrose 5% in water, slight

haze observed after 1 hour in Viaflex IV bags at ambient laboratory temperature under constant fluorescent light [1209] b) Compatible 1) Digoxin 0.005 mg/mL in Sodium chloride 0.9% with insulin (both Humulin R(R) and Iletin(R)) 1 U/mL in Dextrose 5% in water or Sodium chloride 0.9%, no observed evidence of incompatibility over 3 hours in Viaflex IV bags at ambient laboratory temperature under fluorescent light [1210] Insulin Human Regular 1) Conflicting Data a) Incompatible 1) Digoxin 0.005 mg/mL with insulin (both Humulin R(R) and Iletin(R)) 1 U/mL, both in Dextrose 5% in water, slight haze observed after 1 hour in Viaflex IV bags at ambient laboratory temperature under constant fluorescent light [1209] b) Compatible 1) Digoxin 0.005 mg/mL in Sodium chloride 0.9% with insulin (both Humulin R(R) and Iletin(R)) 1 U/mL in Dextrose 5% in water or Sodium chloride 0.9%, no observed evidence of incompatibility over 3 hours in Viaflex IV bags at ambient laboratory temperature under fluorescent light [1210] Lidocaine 1) Compatible a) Lidocaine (2 g/L with digoxin 1 mg/L visually compatible for 24 hours at 25 degrees in the following solutions: Dextrose 5% in water, Lactated Ringer's injection, Sodium chloride 0.9%) [1212] b) Digoxin (1 mg/L with lidocaine 2 g/L visually compatible for 24 hours at 25 degrees C in the following solutions: Dextrose 5% in water, Lactated Ringer's injection, Sodium Chloride 0.9%) (Kirschenbaum, 1982) Linezolid

1) Compatible a) Digoxin 0.25 mg/mL with linezolid 2 mg/mL (both tested undiluted) is physically compatible for 4 hours at room temperature (approximately 23 degrees C) under fluorescent light during simulated Y-site administration [1197] . Meperidine 1) Compatible a) Digoxin (0.25 mg/mL with meperidine 10 mg/mL visually compatible for a 4-hour study period at 25 degrees C under fluorescent light) [1191] Meropenem 1) Compatible a) Meropenem at concentrations of 1 mg/mL and 50 mg/mL in sodium chloride 0.9% is compatible with digoxin 0.25 mg/mL given via simulated Y-site administration [1207] . Milrinone 1) Compatible a) Milrinone (100 mcg/mL with digoxin 125 mcg/mL visually compatible and chemically stable for a 4-hour study period at 22 to 23 degrees C in Dextrose 5% in water under fluorescent light; 3.5 mg/3.5 mL with digoxin 500 mcg/2 mL brought to a total volume of 10 mL with Dextrose 5% in water, visually compatible and chemically stable for a 4-hour study period at 23 degrees C under fluorescent light) [1203] b) Digoxin (125 mcg/mL with milrinone 100 mcg/mL visually compatible and chemically stable for a 4-hour study period at 23 degrees C in Dextrose 5% in water under fluorescent light; 500 mcg/2 mL with milrinone 3.5 mg/3.5 mL brought to a total volume of 10 mL with Dextrose 5% in water, visually compatible and chemically stable for a 4-hour study period at 23 degrees C under fluorescent light) [1204] Morphine

1) Compatible a) Digoxin 0.25 mg/mL with morphine 1 mg/mL, visually compatible for a 4-hour study period at 25 degrees C under fluorescent light [1205] Potassium Chloride 1) Compatible a) Dextrose 5% in sodium chloride 0.45% with potassium chloride 20 mEq/L (with digoxin 2.5 mg/L physically compatible and stable for 6 hour study period at 23 degrees C) [1193] b) Potassium chloride (40 mEq/L with digoxin 0.25 mg/mL visually compatible, macroscopically and microscopically, for a 4-hour study period at 25 degrees C in the solutions listed below) [1192] : Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0.9% c) Digoxin (250 mg/L with potassium chloride 40 mEq/L visually compatible, macroscopically and microscopically, for a 4-hour study period at 25 degrees C in the following solutions) [1194] : Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0.9% Propofol 1) Compatible

a) Propofol 1% injectable emulsion and digoxin 0.25 milligram/milliliter in a 1:1 volume mixture (simulated Ysite administration) are visually compatible in polycarbonate test tubes at 15 minutes and 1 hour at approximately 23 degrees Celsius as determined by visualization with fluorescent light and a high-intensity, mono-directional light source (Tyndall beam) [1196] . Ranitidine 1) Compatible a) Digoxin (0.25mg/100 mL with ranitidine 100 mg/100 mL stated to be compatible for 24 hours at 25 degrees C in Dextrose 5% in water; digoxin concentration not tested) [1220] b) Ranitidine (100 mg/100 mL with digoxin 0.25 mg/100 mL stated to be compatible for 24 hours at 25 degrees C in Dextrose 5% in water; digoxin concentration not tested) [1220] Tacrolimus 1) Compatible a) Digoxin 0.25 mg/mL, undiluted, with tacrolimus 1 mg/mL in 0.9% Sodium chloride injection, visually compatible for 24 hours at room temperature under fluorescent light [1216] Verapamil 1) Compatible a) Digoxin 2 mg/L with verapamil 80 mg/L, visually compatible for 48 hours in Dextrose 5% in water or Sodium chloride 0.9%; no temperature specified [1202] Vitamin B Complex/Ascorbic Acid 1) Compatible a) Vitamin B complex with C (2 mL/L with digoxin 0.25 mg/mL visually compatible, macroscopically and microscopically, for a 4-hour study period at 25 degrees C in the solutions listed below) [1192]

: Dextrose 5% in water Lactated Ringer's injection Sodium chloride 0.9% Solutions Dextrose 5% in water 1) Conflicting Data a) Incompatible 1) Dextrose 5% in water (precipitation of digoxin unless diluted with a 4-fold or greater volume of Dextrose 5% in water) [102] b) Compatible 1) Dextrose 5% in water (with digoxin 2.5 mg/L physically compatible and stable for 24 hours at 4 and 23 degrees C) [1193] ; (compatible with digoxin diluted with a 4-fold or greater volume of Dextrose 5% in water) [102] LACTATED RINGER'S INJECTION 1) Conflicting Data a) Incompatible 1) Lactated Ringer's injection (precipitation of digoxin unless diluted with a 4-fold or greater volume of Lactated Ringer's injection) [102] b) Compatible 1) Lactated Ringer's injection (with digoxin 2.5 mg/L physically compatible and stable for 6 hours study period at 23 degrees C) [1193] ; (compatible with digoxin diluted with a 4-fold or greater volume of Lactated Ringer's injection)

[102] Sodium chloride 0.9% 1) Conflicting Data a) Incompatible 1) Sodium chloride 0.9% (precipitation of digoxin unless diluted with a 4-fold or greater volume of Sodium chloride 0.9%) [102] b) Compatible 1) Sodium chloride 0.9% (with digoxin 2.5 mg/L physically compatible and stable for 24 hours at 4 and 23 degrees C) [1193] ; (compatible with digoxin diluted with a 4-fold or greater volume of Sodium chloride 0.9%) [102] STERILE WATER FOR INJECTION 1) Conflicting Data a) Incompatible 1) Sterile water for injection (precipitation of digoxin unless diluted with a 4-fold or greater volume of Sterile water for injection) [102] b) Compatible 1) Sterile water for injection (compatible with digoxin diluted with a 4-fold or greater volume of Sterile water for injection) [102] TOTAL PARENTERAL NUTRITION 1) Compatible a) Digoxin 0.25 mg/mL (undiluted solution) added to total parenteral nutrition solution compatible in simulated Ysite administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed below [1224] :

Amino acids 10% (Aminosyn(R) II) Dextrose Sterile water for injection Potassium phosphates Sodium chloride Potassium chloride Magnesium sulfate Multivitamins Trace elements Calcium gluconate

3.5% 5% 516.8 mL 3.5 mM 25 mEq 35 mEq 8 mEq 10 mL 1 mL 9.3 mEq

b) Digoxin 0.25 mg/mL (undiluted solution) added to total parenteral nutrition solution compatible in simulated Ysite administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed below [1224] : Amino acids 10% (FreAmine(R) 3.5% III) Dextrose 5% 516.75 Sterile water for injection mL Sodium chloride 37.5 mEq Potassium chloride 40 mEq Magnesium sulfate 8 mEq Multivitamins 10 mL Trace elements 1 mL Calcium gluconate 5 mEq c) Digoxin 0.25 mg/mL (undiluted solution) added to total parenteral nutrition solution compatible in simulated Ysite administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed below [1224] : Amino acids 10% (Aminosyn(R) II) Dextrose 4.25% 25%

Sterile water for injection Potassium phosphates Sodium chloride Potassium chloride Magnesium sulfate Multivitamins Trace elements Calcium gluconate

161 mL 15 mM 25 mEq 18 mEq 8 mEq 10 mL 1 mL 9.15 mEq

d) Digoxin 0.25 mg/mL (undiluted solution) added to total parenteral nutrition solution compatible in simulated Ysite administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed below [1224] : Amino acids 10% (FreAmine(R) 4.25% III) Dextrose 25% 158.6 Sterile water for injection mL 5.75 Potassium phosphates mM Sodium chloride 40 mEq Potassium chloride 25 mEq Magnesium sulfate 8 mEq Multivitamins 10 mL Trace elements 1 mL Calcium gluconate 7.5 mEq e) Digoxin 12.5 mg/L in Dextrose 5% in water or Sodium chloride 0.9% added to total parenteral nutrition solution visually compatible for 4 hours; specific composition of total parenteral nutrition solution follows) [1225]

Amino acids 10% Dextrose 70% Lipid emulsion 20%

750 mL 429 mL 225

mL Sterile water for injection Sodium phosphate Magnesium sulfate 50% Heparin sodium Sodium chloride Potassium chloride Trace minerals - 4 Multivitamins - 12 15 mL 15 mM 2 mL 6000 U 60 mEq 40 mEq 3 mL 10 mL

CLINICAL APPLICATIONS
Comparative Efficacy / Evaluation With Other Therapies
Acetyldigoxin 1) Efficacy a) In comparison with digoxin, alpha- and beta-acetyldigoxin are claimed to offer advantages with regard to more complete and rapid absorption [870] [871] . Both isomers are diacetylated to digoxin during intestinal absorption [872] [873] [874] [870] . This diacetylation process appears relatively complete for betaacetyldigoxin, with digoxin appearing as the primary plasma component [874] [872] ; for alpha-acetyldigoxin, both parent compound and digoxin have been reported in urine 12 hours after oral administration in some subjects, suggesting incomplete intestinal diacetylation of this compound [870] . Deslanoside Congestive heart failure a) Deslanoside is as effective as pentaformilgitoxin for treating congestive heart failure. Both medications, administered in

equal doses of 0.8 mg, demonstrated equivalent effects in six cardiac patients during a cross-over study [930] . Heart disease a) Deslanoside has similar efficacy to digoxin for treating various cardiac arrhythmias and congestive heart failure. For emergency digitalization, deslanoside has a slightly faster onset of action and may be advantageous than digoxin. However, digoxin is supplied in either oral or parenteral forms and is equivalent to deslanoside in all other pharmacodynamic factors [926] [927] [928] [929] ; (Doherty et al, 1977). Metildigoxin Atrial fibrillation a) SUMMARY: Oral metildigoxin has been similar in efficacy to oral digoxin in patients with atrial fibrillation; there appears to be no reason to use metildigoxin over digoxin in this setting. Two open cross-over studies have reported the similar efficacy of metildigoxin 0.2 to 0.3 milligram daily and digoxin 0.25 to 0.5 milligram daily in controlling the ventricular response in patients with atrial fibrillation [890] [891] . Similarly, another study [892] reported the comparable efficacy of metildigoxin 0.1 milligram twice daily and digoxin 0.13 milligram twice daily in slowing the ventricular rate at rest in decompensated patients with atrial fibrillation. During exercise, heart rate was slightly but significantly higher in patients receiving digoxin. The reasons for this difference were unclear, although it is of doubtful clinical significance. Congestive heart failure a) SUMMARY: Despite evidence of its more rapid and complete absorption, available data do not suggest that metildigoxin will offer any clinical advantage over digoxin in treating patients with congestive heart failure; however, adequate comparisons of onset and magnitude of inotropic responses following intravenous and oral administration of these agents in heart failure patients are lacking. In 1 double-blind study involving 86 patients with congestive heart failure, metildigoxin 0.15 milligram daily was similarly as effective as digoxin 0.3 milligram daily as maintenance therapy [893] . b) In a study involving healthy volunteers, time to maximal

response and magnitude of cardiac (inotropic) effects were similar with equivalent doses of oral metildigoxin and oral digoxin, despite the better absorption of the former. Positive inotropic responses to intravenous digoxin and intravenous metildigoxin were similar and of greater magnitude than with oral administration of these agents. Time to maximal response was similar (4 hours) regardless of the agent administered or route of administration. Thus, the higher serum levels observed with oral metildigoxin, which persisted for about 4 hours, were of no benefit in providing more rapid or superior cardiac effects in comparison to oral digoxin in this population. These data do not support the contention that oral metildigoxin could obviate the need for intravenous digoxin in acute situations [894] [895] . c) For metildigoxin to be considered further as a potential alternative to digoxin, similar types of investigations are needed in congestive heart failure patients. Any future studies should also compare the stable solution/capsule formulation of digoxin (Lanoxicaps(R)) with metildigoxin. The bioavailability of digoxin as Lanoxicaps(R) is 90% to 100% [896] . Efficacy a) Based on pharmacokinetic data, it would appear that the dose of digoxin would have to be increased by at least 1.5-fold compared to metildigoxin in order to achieve comparable serum glycoside concentrations. Clinically, a maintenance dose ratio of 1:2 for metildigoxin:digoxin has produced similar improvement in patients with heart failure (0.15 milligram metildigoxin/day versus 0.3 milligram digoxin/day) [897] [893] . b) One study [891] reported higher steady-state serum glycoside levels with lower doses of metildigoxin as compared to digoxin in patients with atrial fibrillation. Serum levels of 1.3 and 0.8 nanograms/milliliter were observed with metildigoxin 0.2 milligram daily and digoxin 0.25 milligram daily, respectively. With oral doses of 0.3 milligram metildigoxin and 0.5 milligram digoxin, corresponding levels were 1.3 and 1 nanogram/milliliter, respectively. An even greater difference in glycoside levels was reported with higher doses of each drug (1.6 nanograms/milliliter with metildigoxin 0.4 mg daily and 1 nanogram/milliliter with digoxin 0.625 milligram daily). However, in other studies, similar mean steady-state plasma glycoside

concentrations (1.4 to 1.5 nanogram/milliliter) have been reported with both metildigoxin 0.3 milligram daily and digoxin 0.5 milligram daily [890] [898] . Milrinone Congestive heart failure a) In a randomized study, oral milrinone 10 mg four times daily offered no advantage over oral digoxin 0.125 to 0.5 mg daily in the treatment of moderately severe heart failure [889] . In addition, the combination of oral milrinone and digoxin provided no advantage over digoxin alone. This report also suggested that milrinone therapy may aggravate ventricular arrhythmias in these patients. This trial suggests that no clinical benefit would be derived either from substitution of milrinone for digoxin or the addition of milrinone to digoxin treatment in patients with chronic heart failure. Last Modified: April 04, 2013 2013 Truven Health Analytics Inc.

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