Propofol: Pediatric drug information http://www.uptodate.com/contents/propofol-pediatric-drug-information...

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Propofol: Pediatric drug information

Copyright 1978-2016 Lexicomp, Inc. All rights reserved.

(For additional information see "Propofol: Drug information" and see "Propofol: Patient drug information")

For abbreviations and symbols that may be used in Lexicomp (show table)

Brand Names: US Diprivan; Fresenius Propoven

Brand Names: Canada Diprivan; PMS-Propofol; Propofol Injection; Propofol-II Injection
Therapeutic Category General Anesthetic
Dosing: Neonatal Consult local regulations and individual institutional policies and procedures; should only be used by experienced
personnel who are not actively engaged in the procedure.

Endotracheal intubation, nonemergent: Very limited data available; optimal dose not established: IV: 1 to 2.5 mg/kg usually administered over
60 seconds has been used; consider lower doses for PNA ≤1 day (1 mg/kg) or if concurrent analgesia including fentanyl, remifentanil (eg,
propofol: 1 to 2 mg/kg) (AAP [Kumar 2010]; Ghanta 2007; Papoff 2008; Penida 2011; Simons 2013; Welzing 2010). The largest reported
experience is from a prospective observational study in which 62 intubation procedures were performed in 44 patients (GA: 24 to 40 weeks;
PNA at treatment: Median: 5 days; range: 1 to 40 days; weight at treatment: Median: 1.18 kg; range: 0.64 to 4.38 kg;) which used a 2
mg/kg propofol dose without analgesia; hypotension occurred in 39% of patients and was treated with additional intravascular fluids; two
patients required the use of dobutamine to treat their hypotension (Simons 2013). Note: Significantly decreased mean arterial pressures
(MAP <25 mm Hg) were reported in a small trial of premature neonates (n=13, GA: 29 to 32 weeks) receiving propofol (1 mg/kg) with
atropine at PNA <8 hours. The 1 mg/kg dose decreased the mean MAP from 38 mm Hg to 24 mm Hg; investigators ended the trial early as
a result. Previous experience by these investigators had similar findings, with MAPs sometimes refractory to fluid therapy, when a dose of
2.5 mg/kg was used (Welzing 2010).

Dosing: Usual
(For additional information see "Propofol: Drug information")

Consult local regulations and individual institutional policies and procedures; should only be used by experienced personnel who are not actively
engaged in the procedure or surgery; if used in a nonintubated and/or nonmechanically ventilated patient, qualified personnel and appropriate
equipment for rapid institution of respiratory and/or cardiovascular support must be immediately available.

Note: Dosage must be individualized based on total body weight and titrated to the desired clinical effect; wait at least 3 to 5 minutes between
dosage adjustments to clinically assess drug effects; smaller doses are required when used with opioids; the following are general dosing
guidelines (see "Abbreviations, Acronyms, and Symbols" section in front section for explanation of ASA-PS classes).

Pediatric:

Anesthesia, general: Note: Increase dose in patients with chronic alcoholism (Fassoulaki 1993); decrease dose with acutely intoxicated
(alcoholic) patients.

Induction of general anesthesia: Children and Adolescents (healthy) 3 to 16 years, ASA-PS 1 or 2: IV: 2.5 to 3.5 mg/kg over 20 to 30
seconds; use a lower dose for ASA-PS 3 or 4

Maintenance of general anesthesia: Infants, Children, and Adolescents (healthy) ≥2 months to ≤16 years, ASA-PS 1 or 2: IV infusion:
General range: 125 to 300 mcg/kg/minute (7.5 to 18 mg/kg/hour); Initial dose immediately following induction: 200 to 300 mcg/kg
/minute; then decrease dose after 30 minutes if clinical signs of light anesthesia are absent; usual infusion rate after initial 30
minutes: 125 to 150 mcg/kg/minute (7.5 to 9 mg/kg/hour); infants and children ≤5 years may require higher infusion rates
compared to older children.

Procedural sedation: Limited data available: Infants, Children, and Adolescents: IV:

Repeated bolus method: Usual initial dose: 1 mg/kg; reported range for initial dose: 1 to 2 mg/kg; follow initial dose with 0.5 mg/kg
every 3 to 5 minutes as needed until adequate level of sedation achieved (ACEP [Godwin 2014]; Bedirli 2012; Cho 2010; Ince
2013; Krauss 2006).

IV bolus followed by continuous infusion: Initial bolus: 1 to 2 mg/kg; continuous infusion: Reported initial rate and titration are variable
(Machata 2010; Srinivasan 2012; Vespasianol 2007). In a large report of a pediatric sedation program in >4,000 patients (age
range: 1 month to 21 years), after an initial bolus of at least 2 mg/kg, an infusion was started at an initial rate of 9 mg/kg/hour (150
mcg/kg/minute) and titrated as required; supplemental doses of 1 to 2 mg/kg were used as needed; however, hypotension
occurred in up to 42.5% of patients undergoing MRI and 23.2% of patients undergoing other procedures (Vespasianol 2007). In a
smaller trial of 138 young pediatric patients (age range: 3 months to 6 years), after a 1 mg/kg bolus, an infusion was initiated at an
initial rate of 5 mg/kg/hour (83 mcg/kg/minute) and then titrated upward in 1 mg/kg/hour increments (to a maximum of 8
mg/kg/hour) with additional boluses of 0.5 mg/kg given as needed to achieve adequate sedation level (Machata 2010).

Propofol with concurrent ketamine; emergency department procedures: IV: 0.5 to 0.75 mg/kg (ACEP [Godwin 2014])

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Note: When utilized by an organized service with trained and credentialed personnel, propofol use for procedural sedation outside of
the operating room was shown to have low risk for serious adverse outcomes (Cravero 2009; Kamat 2015).

Status epilepticus; refractory: Limited data available: Children and Adolescents: Note: Several experts have expressed concern when
using propofol for this indication in infants and children due to the risk for propofol-related infusion syndrome, particularly when
administered in conjunction with a ketogenic diet or when given at high doses for prolonged periods of time (Baumeister 2004; Iyer
2009). Neurocritical Care Society guidelines for status epilepticus state that use of propofol in young children is contraindicated (NCS
[Brophy 2010]):

Initial propofol infusion: IV: Loading dose 1 to 2 mg/kg, then initiate continuous IV infusion at 1.2 mg/kg/hour (20 mcg/kg/minute);
titrate to desired effect (eg, burst suppression on EEG); usual range: 1.8 to 12 mg/kg/hour (30 to 200 mcg/kg/minute) (NCS
[Brophy 2012]). Note: Use caution when administering high doses (>4 mg/kg/hour [>65 mcg/kg/minute]) for extended periods of
time (>48 hours); monitor closely for adverse effects (eg, PRIS) (NCS [Brophy 2012]).

Breakthrough seizure while on propofol infusion: IV: Increase infusion rate by 0.3 to 0.6 mg/kg/hour (5 to 10 mcg/kg/minute) every 5
minutes with or without an additional 1 mg/kg bolus (NCS [Brophy 2012])

Adult:

General anesthesia: Note: Increase dose in patients with chronic alcoholism (Fassoulaki 1993); decrease dose with acutely intoxicated
(alcoholic) patients.

Induction of general anesthesia:

Healthy adults, ASA-PS 1 or 2, <55 years: IV: 2 to 2.5 mg/kg (~40 mg every 10 seconds until onset of induction)

Debilitated, ASA-PS 3 or 4: IV: 1 to 1.5 mg/kg (~20 mg every 10 seconds until onset of induction)

Maintenance of general anesthesia:

Healthy adults, ASA-PS 1 or 2, <55 years:

IV infusion: Initial: 100 to 200 mcg/kg/minute (or 6 to 12 mg/kg/hour) for 10 to 15 minutes; usual maintenance infusion rate:
50 to 100 mcg/kg/minute (or 3 to 6 mg/kg/hour) to optimize recovery time

IV intermittent bolus: 25 to 50 mg increments as needed

Debilitated, ASA-PS 3 or 4: IV Infusion: 50 to 100 mcg/kg/minute (or 3 to 6 mg/kg/hour)

Monitored anesthesia care sedation:

Healthy adults, ASA-PS 1 or 2, <55 years: Slow IV infusion: 100 to 150 mcg/kg/minute (or 6 to 9 mg/kg/hour) for 3 to 5 minutes or
slow injection: 0.5 mg/kg over 3 to 5 minutes followed by IV infusion of 25 to 75 mcg/kg/minute (or 1.5 to 4.5 mg/kg/hour) or
incremental bolus doses: 10 mg or 20 mg

Debilitated or ASA-PS 3 or 4 patients: Use 80% of healthy adult dose

ICU sedation in intubated mechanically-ventilated patients: Avoid rapid bolus injection; individualize dose and titrate to response.
Continuous IV infusion: Initial: 5 mcg/kg/minute (or 0.3 mg/kg/hour); increase by 5 to 10 mcg/kg/minute (or 0.3 to 0.6 mg/kg/hour)
every 5 to 10 minutes until desired sedation level is achieved; usual maintenance: 5 to 50 mcg/kg/minute (or 0.3 to 3 mg/kg/hour);
reduce dose after adequate sedation established and adjust to response (eg, evaluate frequently to use minimum dose for sedation).
Daily interruption with retitration or a light target level of sedation is recommended to minimize prolonged sedative effects (Barr 2013).

Debilitated or ASA-PS 3 or 4 patients: Use 80% of healthy adult dose; reduce dose after adequate sedation established and adjust to
response (eg, evaluate frequently to use minimum dose for sedation). Daily interruption with retitration or a light target level of
sedation is recommended to minimize prolonged sedative effects (Barr 2013).

Dosing adjustment in renal impairment: No dosage adjustment necessary.

Dosing adjustment in hepatic impairment: No dosage adjustment necessary.

Dosage Forms: US Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Emulsion, Intravenous:

Diprivan: 100 mg/10 mL (10 mL); 200 mg/20 mL (20 mL); 500 mg/50 mL (50 mL); 1000 mg/100 mL (100 mL) [contains edetate disodium,
egg phospholipids (egg lecithin), glycerin, soybean oil]

Generic: 1000 mg/100 mL (100 mL); 200 mg/20 mL (20 mL); 500 mg/50 mL (50 mL)

Emulsion, Intravenous [preservative free]:

Fresenius Propoven: 200 mg/20 mL (20 mL); 500 mg/50 mL (50 mL); 1000 mg/100 mL (100 mL) [contains egg phosphatides, soybean oil]

Generic: 1000 mg/100 mL (100 mL); 200 mg/20 mL (20 mL); 500 mg/50 mL (50 mL)

Generic Equivalent Available: US Yes

Administration Note: Consult local regulations and individual institutional policies and procedures.
Parenteral: IV: Strict aseptic technique must be maintained in handling. Shake emulsion well before use. May be administered undiluted or may

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be further diluted with D5W. Do not administer via filter with <5-micron pore size. Do not administer through the same IV catheter with blood or
plasma. Tubing and any unused portions of propofol vials should be discarded after 12 hours.

To reduce pain associated with injection, use larger veins of forearm or antecubital fossa; lidocaine IV (1 mL of a 1% solution) may also be
used prior to administration or lidocaine may be added to propofol immediately before administration.

Induction: Administer pediatric induction doses over 20 to 30 seconds; may be administered more rapidly in adults

Maintenance: Administer at a concentration of 2 to 10 mg/mL at prescribed rate

Compatibility Stable in D5LR, D51/4NS, D51/2NS, D5W, LR. Do not mix with other therapeutic agents prior to administration.
Y-site administration:

Compatible: Acyclovir, alfentanil, aminophylline, ampicillin, aztreonam, bumetanide, buprenorphine, butorphanol, calcium gluconate,
carboplatin, cefazolin, cefotaxime, cefotetan, cefoxitin, cefuroxime, chlorpromazine, cimetidine, cisplatin, clindamycin,
cyclophosphamide, cyclosporine, cytarabine, dexamethasone sodium phosphate, dexmedetomidine, diphenhydramine, dobutamine,
dopamine, doxycycline, droperidol, enalaprilat, ephedrine, epinephrine, esmolol, famotidine, fenoldopam, fentanyl, fluconazole,
fluorouracil, furosemide, ganciclovir, glycopyrrolate, granisetron, haloperidol, heparin, hydrocortisone sodium succinate,
hydromorphone, hydroxyzine, ifosfamide, imipenem/cilastatin, inamrinone, insulin (regular), isoproterenol, ketamine, labetalol,
magnesium sulfate, mannitol, meperidine, milrinone, nafcillin, nalbuphine, naloxone, nitroglycerin, nitroprusside, norepinephrine,
paclitaxel, palonosetron, pentobarbital, phenobarbital, piperacillin, potassium chloride, prochlorperazine edisylate, propranolol,
ranitidine, scopolamine, sodium bicarbonate, succinylcholine, sufentanil, thiopental, ticarcillin/clavulanate, tigecycline.

Incompatible: Amikacin, amphotericin B, calcium chloride, diazepam, doripenem, gentamicin, levofloxacin, methotrexate,
methylprednisolone sodium succinate, minocycline, mitoxantrone, pantoprazole, phenytoin, tobramycin. Variable (consult detailed
reference): Ascorbic acid, atracurium, atropine, cefepime, ceftazidime, ceftriaxone, ciprofloxacin, cisatracurium, digoxin, doxorubicin,
lidocaine, lorazepam, metoclopramide, midazolam, morphine, pancuronium, phenylephrine, telavancin, vancomycin, vecuronium,
verapamil.

Compatibility in syringe: Compatible: Ondansetron, thiopental. Incompatible: Ceftriaxone. Variable (consult detailed reference):
Pantoprazole.

Note: Manufacturers recommend that propofol not be mixed with any other therapeutic agents prior to administration.

Storage/Stability Store between 4°C to 22°C (40°F to 72°F); refriger ation is not required. Do not freeze. If transferred to a syringe or
other container prior to administration, use within 6 hours. If used directly from vial/prefilled syringe, use within 12 hours. If diluted in 5%
dextrose stable for 8 hours at room temperature. Shake well before use. Do not use if there is evidence of separation of phases of emulsion.

Use Induction of general anesthesia (FDA approved in ages ≥3 years and adults); maintenance of general anesthesia (FDA approved in ages
≥2 months and adults); initiation and maintenance of monitored anesthesia care sedation (FDA approved in adults); sedation of intubated,
mechanically ventilated ICU patients (FDA approved in adults); combined sedation and regional anesthesia (FDA approved in adults); has also
been used for treatment of refractory status epilepticus and procedural sedation

Note: Consult local regulations and individual institutional policies and procedures.

Medication Safety Issues

Sound-alike/look-alike issues:

Diprivan may be confused with Diflucan, Ditropan

Propofol may be confused with fospropofol

Propofol may be confused with bupivacaine (liposomal) due to similar white, milky appearance.

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing
significant patient harm when used in error.

Administration issues:

Propofol may be confused with bupivacaine liposome injectable suspension (Exparel) in operating rooms and other surgical areas due to
their similar white, milky appearance especially when prepared in syringes. Bupivacaine liposome injectable suspension (Exparel) is
intended only for administration via infiltration into the surgical site (and not for systemic use). Confusion with propofol may lead to
accidental intravenous administration of Exparel instead of the intended propofol. Therefore, to avoid potential confusion ISMP
recommends that all vials be separated when stocked in common areas and all prepared syringes be labeled.

Adverse Reactions

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Cardiovascular: Arrhythmia, bradycardia, cardiac output decreased, hyper-/hypotension, tachycardia

Central nervous system: Movement

Dermatologic: Pruritus, rash

Endocrine & metabolic: Hypertriglyceridemia

Local: Injection site burning, stinging, or pain

Respiratory: Apnea, respiratory acidosis during weaning

Rare but important or life-threatening: Agitation, amblyopia, anaphylaxis, anaphylactoid reaction, anticholinergic syndrome, asystole, atrial
arrhythmia, bigeminy, cardiac arrest, chills, cough, dizziness, delirium, discoloration (green [urine, hair, or nailbeds]), extremity pain, fever,
flushing, hemorrhage, hypersalivation, hypertonia, hypomagnesemia, hypoxia, infusion site reactions (including pain, swelling, blisters and/or
tissue necrosis following accidental extravasation); laryngospasm, leukocytosis, lung function decreased, myalgia, myoclonia (rarely
including convulsions and opisthotonos), nausea, pancreatitis, paresthesia, phlebitis, postoperative unconsciousness with or without increase
in muscle tone, premature atrial contractions, premature ventricular contractions, pulmonary edema, propofol-related infusion syndrome,
rhabdomyolysis, somnolence, syncope, thrombosis, urine cloudy, vision abnormality, wheezing

Contraindications Hypersensitivity to propofol or any component of the formulation; hypersensitivity to eggs, egg products, soybeans, or
soy products; when general anesthesia or sedation is contraindicated

Note: Fresenius Propoven is also contraindicated in patients who are hypersensitive to peanuts. In July 2012, the FDA initiated temporary
importation of Fresenius Propoven 1% (propofol) injection into the U.S. market to address a propofol shortage.

Warnings/Precautions
Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, angioedema,
bronchospasm, and erythema; medications for the treatment of hypersensitivity reactions should be available for immediate use. Use
with caution in patients with history of hypersensitivity/anaphylactic reaction to peanuts; a low risk of crossreactivity between soy and
peanuts may exist. Use is contraindicated in patients who are hypersensitive to eggs, egg products, soybeans, or soy products.

• ECG effects: In most cases, propofol does not significantly affect the QT interval (Staikou, 2014). However, prolongation of the QT
interval, usually within normal limits, has occurred in case reports and small prospective studies and may be dose dependent (Hume-
Smith, 2008; Kim, 2008; McConachie, 1989; Saarnivaara, 1990; Saarnivaara, 1993; Sakabe, 2002). Shortening of the QT interval has
also occurred (Erdil, 2009; Tanskanen, 2002).

• Hypertriglyceridemia: Because propofol is formulated within a 10% fat emulsion, hypertriglyceridemia is an expected side effect. Patients
who develop hypertriglyceridemia (eg, >500 mg/dL) are at risk of developing pancreatitis. Serum triglyceride levels should be obtained
prior to initiation of therapy and every 3 to 7 days thereafter. Monitoring of serum triglycerides should especially be considered with
therapy >48 hours with doses exceeding 50 mcg/kg/minute (Devlin, 2005). An alternative sedative agent should be employed if
significant hypertriglyceridemia occurs. Use with caution in patients with preexisting hyperlipidemia as evidenced by increased serum
triglyceride levels or serum turbidity.

• Hypotension: The major cardiovascular effect of propofol is hypotension especially if patient is hypovolemic or if bolus dosing is used.
Hypotension may be substantial with a reduction in mean arterial pressure occasionally exceeding 30%. Use with caution in patients
who are hemodynamically unstable, hypovolemic, or have abnormally low vascular tone (eg, sepsis).

• Injection-site reaction: Transient local pain may occur during IV injection; lidocaine 1% solution may be administered prior to administration
or may be added to propofol immediately prior to administration to reduce pain associated with injection (see Administration).

• Myoclonus: Perioperative myoclonus (eg, convulsions and opisthotonos) has occurred with administration.

• Propofol-related infusion syndrome (PRIS): PRIS is a serious side effect with a high mortality rate (up to 33%) characterized by
dysrhythmia (eg, bradycardia or tachycardia), heart failure, hyperkalemia, lipemia, metabolic acidosis, and/or rhabdomyolysis or
myoglobinuria with subsequent renal failure. Risk factors include poor oxygen delivery, sepsis, serious cerebral injury, and the
administration of high doses of propofol (usually doses >83 mcg/kg/minute or >5 mg/kg/hour for >48 hours), but has also been
reported following large dose, short-term infusions during surgical anesthesia. PRIS has also been reported with lower-dose infusions
(Chukwuemeka, 2006; Merz, 2006). The onset of the syndrome is rapid, occurring within 4 days of initiation. The mechanism of the
syndrome has yet to be determined. Alternate sedative therapy should be considered for patients with escalating doses of
vasopressors or inotropes, when cardiac failure occurs during high-dose propofol infusion, when metabolic acidosis is observed, or in
whom lengthy and/or high-dose sedation is needed (Barr, 2013; Corbett, 2008).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with severe cardiac disease (ejection fraction <50%) or hypotension; may have more
profound adverse cardiovascular responses to propofol.

• Increased intracranial pressure: Use with caution in patients with increased intracranial pressure or impaired cerebral circulation;
substantial decreases in mean arterial pressure and subsequent decreases in cerebral perfusion pressure may occur; consider
continuous infusion or administer as a slow bolus.

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• Infection risk: Propofol vials and prefilled syringes have the potential to support the growth of various microorganisms despite product
additives intended to suppress microbial growth. To limit the potential for contamination, strictly adhere to recommendations in product
labeling for handling and administering propofol.

• Pancreatitis: Use with caution in patients with preexisting pancreatitis; use of propofol may exacerbate this condition.

• Respiratory disease: Use with caution in patients with respiratory disease.

• Seizure disorder: Use with caution in patients with a history of epilepsy or seizures; seizure may occur during recovery phase.

Concurrent drug therapy issues:

• Opioids: Concomitant use may lead to increased sedative or anesthetic effects of propofol, more pronounced decreases in systolic,
diastolic, and mean arterial pressures and cardiac output; lower doses of propofol may be needed. In addition, fentanyl may cause
serious bradycardia when used with propofol in pediatric patients. Alfentanil use with propofol has precipitated seizure activity in
patients without any history of epilepsy.

Special populations:

• ASA-PS (American Society of Anesthesiologists - Physical Status) 3/4 patients: Use a lower induction dose, a slower maintenance rate of
administration, and avoid rapidly delivered boluses in ASA-PS 3/4 patients to reduce the incidence of unwanted cardiorespiratory
depressive events.

• Debilitated patients: Use a lower induction dose, a slower maintenance rate of administration, and avoid rapidly delivered boluses in
debilitated patients to reduce the incidence of unwanted cardiorespiratory depressive events.

• Elderly: Use a lower induction dose, a slower maintenance rate of administration, and avoid rapidly delivered boluses in elderly patients to
reduce the incidence of unwanted cardiorespiratory depressive events.

• Pediatric: Safety and efficacy have not been established in pediatric intensive care unit patients; concurrent use of fentanyl and propofol in
pediatric patients may result in bradycardia.

• Pregnancy: Propofol should only be used in pregnancy if clearly needed. Not recommended for use in obstetrics, including cesarean
section deliveries.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have
been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic
acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and
cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding
sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Edetate disodium: Some formulations contain edetate disodium which may lead to decreased zinc levels in patients with prolonged therapy
(>5 days) or a predisposition to zinc deficiency (eg, burns, diarrhea, or sepsis). A holiday from propofol infusion should take place after
5 days of therapy to allow for evaluation and necessary replacement of zinc.

• Sulfites: Some formulations may contain sulfites.

Other warnings/precautions:

• Abrupt discontinuation: Avoid abrupt discontinuation prior to weaning or daily wake up assessments. Abrupt discontinuation can result in
rapid awakening, anxiety, agitation, and resistance to mechanical ventilation; wean the infusion rate so the patient awakens slowly.
Discontinue opioids and paralytic agents prior to weaning. Long-term infusions can result in some tolerance; taper propofol infusions to
prevent withdrawal.

• Analgesic supplementation: Propofol lacks analgesic properties; pain management requires specific use of analgesic agents, at effective
dosages, propofol must be titrated separately from the analgesic agent.

• Experienced personnel: Use requires careful patient monitoring, should only be used by experienced personnel who are not actively
engaged in the procedure or surgery. If used in a nonintubated and/or non–mechanically ventilated patient, qualified personnel and
appropriate equipment for rapid institution of respiratory and/or cardiovascular support must be immediately available. Use to induce
moderate (conscious) sedation in patients warrants monitoring equivalent to that seen with deep anesthesia. Consult local regulations
and individual institutional policies and procedures.

Warnings: Additional Pediatric Considerations Metabolic acidosis with fatal cardiac failure has occurred in several infants and
children (4 weeks to 11 years of age) who received propofol infusions at average rates of infusion of 4.5 to 10 mg/kg/hour for 66 to 115 hours
(maximum rates of infusion: 6.2 to 11.5 mg/kg/hour) (Bray 1995; Parke 1992; Strickland 1995). Anecdotal reports of serious adverse events,
including death, have been reported in pediatric patients with upper respiratory tract infections receiving propofol for ICU sedation. Not
recommended for ICU sedation of pediatric patients; an increased number of deaths was observed in a multicenter clinical trial of pediatric ICU
patients who received propofol (9% mortality) versus patients who received other sedative agents (4% mortality); although causality was not
established, propofol is not indicated for sedation in PICU patients until further studies can document its safety in this population.

Use extreme caution when using for refractory status epilepticus because higher doses are often required to control seizures for an extended
period of time (in pediatric patients: doses >65 mcg/kg/minute (4 mg/kg/hour) for >48 hours) which may increase risk for PRIS (NCS [Brophy
2012]). Fatal cardiac failure has also been reported with concurrent ketogenic diet and propofol therapy (Baumeister 2004).

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In neonates, decreased mean arterial pressure (MAP) is frequently observed with propofol administration. Significantly decreased MAP (<25
mm Hg) were reported in a trial of premature neonates (n=13, GA: 29 to 32 weeks) receiving propofol (1 mg/kg) with atropine at PNA <8 hours.
The 1 mg/kg dose decreased the mean MAP from 38 mm Hg to 24 mm Hg; investigators ended the trial early as a result. Previous experience
by these investigators had similar findings of hypotension, sometimes refractory to fluid therapy, when a dose of 2.5 mg/kg was used (Welzing
2010). In the largest reported experience from a prospective observational study (n=44; 62 intubation procedures; GA: 24 to 40 weeks), 39% of
patients experienced hypotension after receiving propofol and were treated with additional intravascular fluid; two patients (5%) required the use
of dobutamine to treat their hypotension (Simons 2013); use extreme caution with use in neonates; monitor hemodynamic status closely.

Propofol use for procedural sedation outside of the operating room was shown to have low risk for serious adverse outcomes when utilized by
an organized service with trained and credentialed personnel. Data was collected by the Pediatric Sedation Research Consortium from 37
institutions including 49,836 encounters. There were no deaths, two cardiopulmonary resuscitations, and four aspiration events. Less serious
events included central apnea/airway obstruction (5.7%), excessive secretions (3.4%), other respiratory events (0.5% to 1.5%, eg,
desaturation, stridor, laryngospasm) and vomiting (0.5%). The pulmonary adverse effects were similar to expected values (Cravero 2009). The
same study group reported an additional 5 years of data with an additional 91,189 encounters and showed similar findings. In comparison to the
earlier time period, the incidence of airway obstruction was lower (1.6%). Risk factors for adverse reaction included: primary diagnosis of
respiratory infection, prematurity, concomitant medications, and certain procedure locations (eg, dental clinic, catheter lab) (Kamat 2015).

Acute febrile reactions: In June 2007, the FDA alerted clinicians of several reports of chills, fever, and body aches occurring in clusters of
patients after administration of propofol for sedation in gastrointestinal suites. These reports were received from several facilities and involved
multiple vials and lots. Symptoms appeared 6 to 18 hours following propofol therapy and persisted for ≤3 days. There is no evidence that any
patient had sepsis or that the vials were contaminated. The FDA has tested multiple propofol vials and lots used in these patients and presently
have found no evidence of bacterial contamination. Regardless, propofol vials and prefilled syringes have the potential to support the growth of
various microorganisms despite product additives intended to suppress microbial growth. To limit the potential for contamination, the FDA is
reminding healthcare professionals to strictly adhere to recommendations in product labeling for handling and administering propofol. Clinicians
should also be vigilant for signs and symptoms of acute febrile reactions and evaluate patients for bacteremia. The FDA is continuing to work
with the Centers for Disease Control and Prevention to investigate factors contributing to these occurrences. Additional information is available at
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm109357.htm.

Metabolism/Transport Effects Substrate of CYP1A2 (minor), CYP2A6 (minor), CYP2B6 (major), CYP2C19 (minor), CYP2C9
(minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant
drug interaction potential; Inhibits CYP1A2 (weak), CYP2C9 (weak), CYP2E1 (weak), CYP3A4 (weak)

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program)

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfentanil: May enhance the adverse/toxic effect of Propofol. Specifically the development of opisthotonus (severe hyperextension and spasticity
resulting in arching or bridging position) and/or grand mal seizures. Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at
chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood
pressure lowering therapy cannot be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic
Agents (Second Generation [Atypical]). Risk C: Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased
aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or
indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Risk D: Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other
CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches
(Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Risk D: Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

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Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine),
intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other
CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

EPHEDrine (Systemic): Propofol may enhance the therapeutic effect of EPHEDrine (Systemic). Risk C: Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of
Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close
monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Risk D: Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to
30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also
be warranted. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk
C: Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Risk C: Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day
may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose
may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS
depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant
methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine
dose is established. Risk D: Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Midazolam: May increase the serum concentration of Propofol. Propofol may increase the serum concentration of Midazolam. Risk C: Monitor
therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management:
Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should
generally be avoided when possible. Risk D: Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Risk C: Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect
of Moderate Risk QTc-Prolonging Agents. Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood
pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion.
Risk D: Consider therapy modification

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Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with
another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose
should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that
has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and
coordination, until they have experience using the combination. Risk D: Consider therapy modification

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

RifAMPin: May enhance the hypotensive effect of Propofol. Management: Note that use of propofol in a patient who has been taking rifampin
may result in clinically significant hypotension. If possible, avoid use of this combination. Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Ropivacaine: Propofol may increase the serum concentration of Ropivacaine. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C:
Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors.
Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When
combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is
contraindicated. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any
other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other
drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of
the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of
excessive CNS depression. Risk D: Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates. Risk C: Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when
possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient
response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual
zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women.
Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions Edetate disodium, an ingredient of propofol emulsion, may lead to decreased zinc levels in patients on prolonged
therapy (>5 days) or those predisposed to deficiency (burns, diarrhea, and/or major sepsis). Management: Zinc replacement therapy may be
needed.

Pregnancy Risk Factor B (show table)

Pregnancy Implications Propofol crosses the placenta and may be associated with neonatal CNS and respiratory depression. Propofol
is not recommended by the manufacturer for obstetrics, including cesarean section deliveries.

Monitoring Parameters Cardiac monitor, blood pressure, oxygen saturation (during monitored anesthesia care sedation), arterial blood
gas (with prolonged infusions). With prolonged infusions (eg, ICU sedation), monitor for metabolic acidosis, hyperkalemia, rhabdomyolysis or
elevated CPK, hepatomegaly, and progression of cardiac and renal failure.

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ICU sedation: Adult: Assess and adjust sedation according to scoring system (Richmond Agitation-Sedation Scale [RASS] or Sedation-Agitation
Scale [SAS]) (Barr 2013); assess CNS function daily. Serum triglyceride levels should be obtained prior to initiation of therapy and every 3
to 7 days thereafter, especially if receiving for >48 hours with doses exceeding 50 mcg/kg/minute (Devlin 2005); use intravenous port
opposite propofol infusion or temporarily suspend infusion and flush port prior to blood draw.

Diprivan: Monitor zinc levels in patients predisposed to deficiency (burns, diarrhea, major sepsis) or after 5 days of treatment.

Mechanism of Action Propofol is a short-acting, lipophilic intravenous general anesthetic. The drug is unrelated to any of the currently
used barbiturate, opioid, benzodiazepine, arylcyclohexylamine, or imidazole intravenous anesthetic agents. Propofol causes global CNS
depression, presumably through agonism of GABAA receptors and perhaps reduced glutamatergic activity through NMDA receptor blockade.

Pharmacodynamics and pharmacokinetics (Adult data unless noted)

Onset of action: Anesthetic: Bolus infusion (dose dependent): 9 to 51 seconds (average 30 seconds)

Duration: 3 to 10 minutes depending on the dose, rate and duration of administration; with prolonged use (eg, 10 days ICU sedation), propofol
accumulates in tissues and redistributes into plasma when the drug is discontinued, so that the time to awakening (duration of action) is
increased; however, if dose is titrated on a daily basis, so that the minimum effective dose is utilized, time to awakening may be within 10 to
15 minutes even after prolonged use

Distribution: Large volume of distribution; highly lipophilic ; Vd:

Children 4 to 12 years: 5 to 10 L/kg

Adults: 2 to 10 L/kg; after a 10-day infusion, Vd approaches 60 L/kg; decreased in the elderly

Protein binding: 97% to 99%

Metabolism: Hepatic to water-soluble sulfate and glucuronide conjugates (~50%)

Half-life elimination: Biphasic: Initial: 40 minutes; Terminal: 4 to 7 hours (after 10-day infusion, may be up to 1 to 3 days)

Excretion: Urine (~88% as metabolites, 40% as glucuronide metabolite); feces (<2%)

Additional Information Propofol injection contains ∼0.1 g of fat/mL (1.1 kcal/mL)

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