Treatment Guidelines, 2008

1 Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines.
The drugs of choice for treatment of some fungal

infections are listed in the tables that begin on the next
page. Some of the indications and dosages recom-
mended here have not been approved by the FDA.
Other guidelines are available from the Infectious
Diseases Society of America (www.idsociety.org).
AZOLES
Azole antifungals inhibit synthesis of ergosterol, an
essential component of the fungal cell membrane.
FLUCONAZOLE Fluconazole is active against
most Candida species other than C. krusei, which is
intrinsically resistant, and many strains of C. glabrata,
which are increasingly resistant. Fluconazole has good
activity against Coccidioides, Histoplasma and
Cryptococcus spp., but high doses are needed. The
drug has no clinically significant activity against most
molds, including Aspergillus spp., Fusarium spp. and
Zygomycetes.
Adverse Effects Fluconazole is generally well tol-
erated. Headache, gastrointestinal distress and rash
can occur. Stevens-Johnson syndrome, anaphylaxis
and hepatic toxicity have been reported. Fluconazole
is teratogenic in animals (pregnancy category C).
Drug Interactions Fluconazole is a moderate
inhibitor of CYP3A4 and may increase serum concen-
trations of drugs metabolized by 3A4, such as
cyclosporine (Sandimmune, and others), tacrolimus
(Prograf), carbamazepine (Tegretol, and others), and
lovastatin (Mevacor, and others).
1
Fluconazole is a
strong inhibitor of CYP2C9 and can increase serum
concentrations of phenytoin (Dilantin, and others),
zidovudine (Retrovir), warfarin (Coumadin, and oth-
ers) and other drugs metabolized by 2C9. Concomitant
administration of rifampin (Rifadin, and others) can
lower serum concentrations of fluconazole.
ITRACONAZOLE Itraconazole has a broader
spectrum of activity than fluconazole. It is active
against a wide variety of fungi including Cryptococcus
neoformans, Aspergillus spp., Blastomyces dermati-
tidis, Coccidioides immitis, Histoplasma capsulatum,
Paracoccidioides brasiliensis, Scedosporium
apiospermum (the asexual form of Pseudallescheria
boydii), Sporothrix spp., and dermatophytes. It also has
good activity against most Candida spp. Itraconazole
has no clinically meaningful activity against Fusarium
spp. or Zygomycetes.
Itraconazole is available orally in both capsules and solu-
tion. The IVformulation will no longer be available after
February 2008. Absorption after oral dosing is variable;
the solution is more bioavailable than the capsules and is
generally preferred. The capsules should be taken with
food, while the solution is absorbed best without food.
The absorption of itraconazole capsules is reduced by
drugs that decrease gastric acidity, such as antacids,
H
2
-receptor blockers or proton pump inhibitors.
Antifungal Drugs
Tables
1. Azoles Page 1
2. Treatment of Candida Infections Page 2
3. Echinocandins Page 4
4. Treatment of Onychomycosis and Tinea Pedis Page 5
5. Amphotericin B Formulations Page 5
6. Treatment of Other Fungal Infections Page 6-7
Treatment Guidelines
from The Medical Letter
Published by The Medical Letter, Inc. 1000 Main Street, New Rochelle, NY 10801 A Nonprofit Publication
Volume 6 (Issue 65) January 2008
www.medicalletter.org
Table 1. Azoles
Drug Usual Dosage Cost
1
Parenteral
Fluconazole 100-800 mg 1x/d
Diflucan (Pfizer) $357.62
Voriconazole 4 mg/kg bid
Vfend (Pfizer) 364.89
Oral
Fluconazole 100-800 mg 1x/d
generic 57.20
Diflucan (Pfizer) 71.15
Itraconazole 200 mg 1x/d-bid
Sporanox (Janssen) 43.76
Posaconazole 100 mg 1x/d-200 mg qid
Noxafil (Schering) 145.80
Voriconazole 200-300 mg bid
Vfend (Pfizer) 116.97
2
1. For one day's treatment of a 70-kg patient at the highest usual dosage,
according to AWP listings in Red Book 2007 and Update December
2007. Cost may vary among institutions based on formulary contracts.
2. Cost of three 200 mg tablets.
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Forwarding, copying or any other distribution of this material is strictly prohibited.
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Antifungal Drugs
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 65) January 2008 2
Table 2. Treatment of Candida Infections
Infection Drug Dosage/Duration
1,2
Alternatives
CANDIDIASIS
Vaginal
3
Topical therapy Butoconazole, clotrimazole, 1x/d x 1-7d
(intravaginal creams, miconazole, tioconazole,
ointments, tablets, or terconazole
ovules or suppositories)
Systemic therapy Fluconazole 150 mg PO once
4
Itraconazole
5
200 mg PO bid x 1d
x 1d Ketoconazole
5
200 mg PO bid x 5d
Recurrent
6
Fluconazole 150 mg PO 1x/wk
Urinary
7
Fluconazole 200 mg IV or PO Amphotericin B
8
0.3-0.5 mg/kg/d IV
9
x
1x/d x 7-14d 1-7d
Flucytosine 25 mg/kg PO qid x 5-7d
10
Oropharyngeal Fluconazole 200-400 mg IV or PO Other Azoles:
or Esophageal
11,12,13
once, then 100- Voriconazole
16
200 mg PO bid x
200 mg 1x/d x 1-3 wks
14
1-3 wks
14,15
Itraconazole
17
200 mg PO 1x/d x
1-3 wks
14
Posaconazole 100 mg bid x 1d then
100 mg 1x/d x 1-3 wks
14,18
or An echinocandin Amphotericin B 0.3-0.5 mg/kg/d IV x
Caspofungin 50 mg IV 1x/d 1-3 wks
9,14
x 1-3 wks
14
Micafungin 150 mg IV 1x/d x 1-3 wks
14
Anidulafungin 100 mg IV once, then
50 mg 1x/d x 1-3 wks
14
Candidemia
12
Fluconazole
19
400-800 mg 1x/d IV, Voriconazole 6 mg/kg IV q12h x 1d
then PO
20,21
then 4 mg/kg IV bid then 200-300 mg
PO bid
21
or An echinocandin
Caspofungin
22
70 mg IV x 1d, then 50 mg
IV 1x/d
21
Anidulafungin 200 mg IV once, then 100 mg
1x/d
21
Micafungin
5
100 mg IV 1x/d
21
or Amphotericin B 0.5-1 mg/kg/d IV
9,21
1. Usual adult dosage. Some patients may need dosage adjustment for renal or hepatic dysfunction or when used with interacting drugs.
2. The optimal duration of treatment with antifungal drugs is often unclear. Depending on the disease and its severity, they may be continued for
weeks or months or, particularly in immunocompromised patients, indefinitely.
3. Non-albicans species, such as C. glabrata and C. krusei, respond to boric acid 600 mg intravaginally daily x 14d or to topical flucytosine cream
(JD Sobel et al, Am J Obstet Gynecol 2003; 189:1297).
4. May be repeated in 72 hours if patient remains symptomatic.
5. Not FDA-approved for this indication.
6. JD Sobel et al, N Engl J Med 2004; 351:876.
7. Asymptomatic candiduria usually does not require treatment. Patients who are symptomatic, neutropenic, have renal allografts or are undergoing
urologic manipulation, and infants with low birth weight, should be treated (PG Pappas et al, Clin Infect Dis 2004; 38:161).
8. Bladder irrigation with amphotericin B has been used to treat candidal cystitis, but does not treat disease beyond the bladder, and is generally not
recommended.
9. Dosage of amphotericin B deoxycholate given once daily. For safety reasons, lipid-based formulations may be preferred. Usual doses of lipid-
based formulations for treatment of invasive fungal infection are: amphotericin B lipid complex (Abelcet) 5 mg/kg/d; liposomal amphotericin B
(AmBisome) 3-5 mg/kg/d; amphotericin B cholesteryl sulfate (Amphotec) 3-6 mg/kg/d.
10. Dosage must be decreased in patients with diminished renal function.
11. For uncomplicated oropharyngeal thrush, clotrimazole troches (10 mg) 5x/d or nystatin suspension 500,000 units (5 mL) qid can also be used.
Azole-resistant oropharyngeal or esophageal candidiasis usually responds to amphotericin B or an echinocandin.
12. Candida albicans is generally highly susceptible to fluconazole. C. krusei infections are resistant to fluconazole. C. glabrata infections are often
resistant to low doses, but may be susceptible to high doses of fluconazole. C. lusitaniae may be resistant to amphotericin B.
13. HIV-infected patients with frequent or severe recurrences of oral or esophageal candidiasis may require prophylaxis. For patients with organisms that
are still susceptible, the regimen of choice is fluconazole 100-200 mg PO once daily.
14. Duration of treatment for esophageal candidiasis is 14 to 21 days after clinical improvement.
15. Use higher end of range for esophageal candidiasis.
16. R Ally et al, Clin Infect Dis 2001; 33:1447.
17. For patients with oropharyngeal disease, itraconazole oral solution 200 mg (20 mL) given once daily without food is more effective than itracona-
zole capsules.
18. For refractory oropharyngeal candidiasis, use 400 mg once/d or bid.
19. Non-neutropenic patients only.
20. In general, a loading dose of twice the daily dose is recommended on the first day of therapy.
21. For 2 weeks after afebrile and blood cultures negative.
22. In a large controlled trial, caspofungin was at least as effective as amphotericin B for treatment of invasive candidiasis or candidemia (J Mora-
Duarte et al, N Engl J Med 2002; 347:2020).
Antifungal Drugs
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 65) January 2008
3
Adverse Effects The most common adverse effects
of itraconazole are dose-related nausea and abdominal
discomfort. Rash, including Stevens-Johnson syn-
drome, and serious hepatic toxicity can occur. The
drug can cause hypokalemia, edema and hypertension.
Congestive heart failure has been reported, and the
drug should not be used in patients with ventricular
dysfunction. Itraconazole is teratogenic in rats (preg-
nancy category C).
Drug Interactions Itraconazole is a strong inhibitor
of CYP3A4 and may increase serum concentrations of
cyclosporine, tacrolimus and other drugs metabolized
by this enzyme.
1
It is contraindicated for use with cis-
apride (Propulsid), dofetilide (Tikosyn), ergot alka-
loids, levomethadyl (Orlaam), lovastatin (Mevacor,
and others), oral midazolam (Versed, and others),
pimozide (Orap), quinidine, simvastatin (Zocor, and
others), and triazolam (Halcion, and others).
Itraconazole is also a substrate of CYP3A4; its metab-
olism may be affected by both inducers of the enzyme,
such as rifampin, phenytoin or carbamazepine, and by
other inhibitors. When some protease inhibitors, such
as ritonavir (Norvir) or indinavir (Crixivan), are taken
with itraconazole, serum concentrations of both drugs
may increase. Itraconazole can increase serum con-
centrations of digoxin (Lanoxin, and others). A
decreased contraceptive effect has been reported in
patients taking oral contraceptives with itraconazole.
VORICONAZOLE Voriconazole has a spectrum
of activity similar to that of itraconazole but appears to
be more active against Aspergillus spp. and some
species of Candida, including C. glabrata and C. kru-
sei. Unlike itraconazole, voriconazole is active against
Fusarium. It is not active against zygomycetes, such
as Mucor and Rhizomucor spp.; infection with these
organisms has developed during treatment with the
drug. In a randomized trial of initial treatment of inva-
sive aspergillosis, voriconazole was shown to improve
survival more than amphotericin B and was associated
with fewer severe adverse effects.
2
Serum concentra-
tions of voriconazole vary from patient to patient and
may need monitoring.
3,4
Adverse Effects Transient visual disturbances,
including blurred vision, photophobia and altered per-
ception of color or image, can occur with voricona-
zole. Rash (including Stevens-Johnson syndrome)
photosensitivity, increased transaminase levels, confu-
sion and hallucinations have also occurred. In patients
with creatinine clearance <50 mL/min, the oral drug is
preferred because the solubilizing agent in the IV for-
mulation (sulfobutyl ether -cyclodextrin) can accu-
mulate. Patients with mild to moderate hepatic cirrho-
sis should receive a normal loading dose of voricona-
zole, but half the maintenance dose. Voriconazole is
teratogenic in animals (pregnancy category D).
Drug Interactions Voriconazole is metabolized in the
liver by, and is an inhibitor of, CYP2C19, 2C9 and 3A4.
CYP2C19 is genetically variable (about 3% to 5% of
Caucasians and African-Americans and about 15% of
Asians do not express it) and patients deficient in this
enzyme may be exposed to higher concentrations of the
drug. Voriconazole is contraindicated in patients taking
rifampin, rifabutin (Mycobutin), ergot alkaloids, long-
acting barbiturates, carbamazepine, pimozide, quini-
dine, cisapride or sirolimus (Rapamune). Clinical mon-
itoring or dose adjustment may be required in patients
taking warfarin, sulfonylureas, statins, benzodi-
azepines, vinca alkaloids, nevirapine (Viramune) and
HIV protease inhibitors other than indinavir.
Omeprazole (Prilosec, and others), efavirenz (Sustiva),
cyclosporine and tacrolimus require dose reductions
when given with voriconazole. Patients taking pheny-
toin require increased doses of voriconazole and more
frequent monitoring for phenytoin toxicity.
POSACONAZOLE Posaconazole, one of the
newer triazole antifungals,
5
has an antifungal spectrum
similar to that of itraconazole, but unlike other azoles it
has in vitro activity against Zygomycetes such as
Mucor. Before approval of posaconazole, amphotericin
B formulations were the only products available for
treatment of Zygomycete infections. Posaconazole is
only available as an oral suspension and must be taken
with high-fat meals for adequate absorption.
Monitoring of serum concentrations may be helpful.
Clinical Use A randomized, open-label clinical trial
found that adults who were neutropenic due to acute
myelogenous leukemia or myelodysplastic syndrome
had fewer invasive mycoses and lower mortality when
receiving posaconazole prophylaxis compared to those
receiving fluconazole or itraconazole.
6
A double-blind
randomized trial in adults with graft-versus-host disease
following allogeneic hematopoietic stem cell transplan-
tation (HSCT) found posaconazole similar to flucona-
zole in preventing invasive mycoses and superior in
preventing invasive aspergillosis.
7
Oropharyngeal and
esophageal candidiasis refractory to treatment with flu-
conazole or itraconazole have responded to posacona-
zole.
8
Posaconazole has also been used in therapy of
other refractory mycoses, including aspergillosis, coc-
cidioidomycosis and zygomycosis.
9-11
Adverse Effects Posaconazole has a safety profile
comparable to that of fluconazole; dry mouth, rash,
headache, diarrhea, fatigue, nausea, vomiting, QT
Antifungal Drugs
prolongation, and abnormal liver function have been
reported, but infrequently led to drug discontinua-
tion. Arrhythmias, toxic epidermal necrolysis,
angioedema and anaphylaxis have been rare.
Posaconazole causes skeletal malformations in rats
(pregnancy category C).
Drug Interactions Posaconazole inhibits CYP3A4;
doses of coadministered drugs that are metabolized by
this isozyme, such as cyclosporine or tacrolimus,
should be reduced.
1
KETOCONAZOLE Ketoconazole is now seldom
used. The other azoles have fewer adverse effects and
are generally preferred.
Adverse Effects Anorexia, nausea and vomiting are
common with higher doses (>400 mg/day) of keto-
conazole; taking the drug with food or at bedtime may
improve tolerance. Pruritus, rash and dizziness may
occur. Ketoconazole can decrease plasma testosterone
concentrations and cause gynecomastia, decreased
libido and loss of potency in men and menstrual irreg-
ularities in women. High doses may inhibit adrenal
steroidogenesis and decrease plasma cortisol concen-
trations. Hepatic toxicity, including fatal hepatic
necrosis, can occur. Ketoconazole is teratogenic in
animals (pregnancy category C).
Drug Interactions Ketoconazole is a strong
inhibitor of CYP3A4. Drug interactions with keto-
conazole are similar to those with itraconazole.
ECHINOCANDINS
Echinocandins inhibit synthesis of (1, 3)-D-glucan,
an essential component of the fungal cell wall. Their
potential for adverse effects in humans is low due to
the absence in mammalian cells of enzymes involved
in glucan synthesis. Caspofungin, anidulafungin and
micafungin all have activity against most Candida
species, including those resistant to azoles. Their
activity against molds appears confined to Aspergillus.
All three echinocandins are given intravenously once
daily, do not require dose adjustment for renal failure
and appear to be similar in efficacy and safety.
12
CASPOFUNGIN Caspofungin is FDA-approved
for treatment of esophageal candidiasis, candidemia,
intra-abdominal abscesses, peritonitis, and pleural
space infections due to Candida. It is also approved for
empiric treatment of presumed fungal infections in
febrile, neutropenic patients and for treatment of inva-
sive aspergillosis in patients who are refractory to or
intolerant of other therapies. Data on its use for pri-
mary treatment of aspergillosis are lacking.
Adverse Effects Although generally well tolerated,
caspofungin occasionally causes rash, fever and mild
hepatic toxicity. Anaphylaxis has occurred. Dosage
should be reduced in patients with moderate hepatic
dysfunction. Caspofungin is embryotoxic in animals
(pregnancy category C).
Drug Interactions Rifampin, carbamazepine, dex-
amethasone, efavirenz, nevirapine and phenytoin may
increase clearance of caspofungin. An increase in
caspofungin dosage to 70 mg should be considered
when it is co-administered with these drugs.
Caspofungin can decrease serum concentrations of
tacrolimus. Liver function tests should be monitored
in patients taking cyclosporine with caspofungin.
MICAFUNGIN Micafungin is FDA-approved for
treatment of esophageal candidiasis and prevention of
invasive candidiasis in autologous or allogeneic stem cell
transplant recipients. In one trial in patients with can-
didemia and deeply invasive candidiasis, micafungin was
noninferior to liposomal amphotericin B (success rate of
89.6% vs. 89.5%).
13
Adverse Effects Micafungin is well tolerated.
Possible histamine-like effects, as with other
echinocandins, have included rash, pruritus and facial
swelling. Anaphylaxis has been rare. Fever, hepatic
function abnormalities, headache, nausea, vomiting
and diarrhea have been reported, but rarely limit ther-
apy. Micafungin is teratogenic in animals (pregnancy
category C).
ANIDULAFUNGIN Anidulafungin
14
is
approved by the FDA for treatment of esophageal
candidiasis and candidemia. It was as effective as
fluconazole for invasive candidiasis in a randomized,
double-blind trial.
15
Adverse Effects Anidulafungin has a low incidence
of adverse effects similar to those of caspofungin and
micafungin. Its safety in pregnancy has not been
established (pregnancy category C).
Table 3. Echinocandins
Drug Dosage Cost
1
Caspofungin 50 mg IV once/d
Cancidas (Merck) $395.36
Anidulafungin 100 mg IV once/d
Eraxis (Pfizer) 216.00
Micafungin 100 mg IV once/d
Mycamine (Astellas) 224.40
1. For one day's treatment according to AWP listings in Red Book 2007 and
Update December 2007. Cost may vary among institutions based on for-
mulary contracts.
Antifungal Drugs
5
Table 4. Treatment of Onychomycosis and Tinea Pedis
1,2
Alternatives
ONYCHOMYCOSIS
3, 4
Terbinafine 250 mg PO once/d x 12 wks
5
or Itraconazole 200 mg PO once/d x 3 mos
5
Fluconazole
6
150-300 mg
or 200 mg PO bid 1 wk/mo PO once wkly x
x 3 mos
5
6-12 mos
5
TINEA PEDIS
7
Terbinafine cream
8
twice daily application x 1-2 wks Fluconazole
6
150 mg PO
once/wk x 1-4 wks
or Topical azoles (i.e. clotrimazole, once or twice daily application
miconazole, econazole) x 4 wks
3. Nail specimens should be obtained prior to any drug therapy to confirm the diagnosis of onychomycosis.
4. Topical treatment with ciclopirox 8% nail laquer (Penlac) is indicated for treatment of mild-to-moderate onychomycosis caused by T. rubium that
does not involve the lunula. Ciclopirox is less effective than systemic therapy, but has no systemic side effects or drug interactions.
5. Duration for toenail infection. Duration of treatment for fingernail infection: 6 weeks with terbinafine, 2 months with itraconazole and 3-6 months with
fluconazole.
7. Topical treatment of athletes foot is adequate for mild cases. Relapse is common and requires prolonged treatment (>4 wks).
8. Other topical non-azoles, including butenafine and naftifine may also be used, but the duration of treatment should then be increased to 2-4 weeks.
AMPHOTERICIN B
Amphotericin B binds to ergosterol in the fungal cell
membrane, leading to loss of membrane integrity and
leakage of cell contents. Conventional amphotericin B
and the newer lipid-based formulations have the same
spectrum of activity and are active against most path-
ogenic fungi and some protozoa. They are not active
against most strains of Aspergillus terreus,
Scedosporium apiospermum (the asexual form of
Pseudallescheria boydii), Trichosporon and Candida
lusitaniae. Amphotericin B is the preferred treatment
for deep fungal infections during pregnancy.
Conventional Amphotericin B Amphotericin B
deoxycholate, the non-lipid formulation of ampho-
tericin, is the least expensive but also the most toxic,
particularly to the kidney. The development of better
tolerated lipid-based formulations has led to a
decrease in its use. Intravenous infusion of ampho-
tericin B deoxycholate frequently causes fever and
chills, and sometimes headache, nausea, vomiting,
hypotension and tachypnea, usually beginning 1 to 3
hours after starting the infusion and lasting about 1
hour. The intensity of these infusion-related acute
reactions tends to decrease after the first few doses.
Pretreatment with acetaminophen (Tylenol, and oth-
ers) or a nonsteroidal anti-inflammatory drug
(NSAID) such as ibuprofen, diphenhydramine
(Benadryl, and others) 25 mg IV and/or hydrocorti-
sone 25 mg IV can decrease the severity of the reac-
tion. Treatment with meperidine (Demerol, and oth-
ers) 25-50 mg IV can shorten the duration of rigors.
Nephrotoxicity is the major dose-limiting toxicity of
amphotericin B deoxycholate; sodium loading with
normal saline may prevent or ameliorate it and is gen-
erally recommended for patients who can tolerate a
fluid load. The nephrotoxicity of amphotericin B may
add to the nephrotoxicity of other drugs including
cyclosporine, tacrolimus and aminoglycoside antibi-
otics such as gentamicin (Garamycin, and others).
Hypokalemia and hypomagnesemia are common and
are usually due to a mild renal tubular acidosis.
Weight loss, malaise, anemia, thrombocytopenia and
mild leukopenia can occur. Cardiac toxicity and
myopathy have been reported.
Table 5. Amphotericin B Formulations
Daily
Drug Dosage Cost
1
Amphotericin B
deoxycholate 1-1.5 mg/kg IV
generic (Abbott) $34.92
Amphotericin B lipid complex
(ABLC)
Abelcet (Enzon) 5 mg/kg IV 960.00
Liposomal amphotericin B
(L-AmB)
AmBisome (Astellas) 3-6 mg/kg IV 1318.80
Amphotericin B colloidal
dispersion (ABCD)
Amphotec (Three Rivers) 3-4 mg/kg IV 480.00
1. For one day's treatment of a 70-kg patient at the highest usual
dosage, according to AWP listings in Red Book 2007. Cost may vary
among institutions based on formulary contracts.
Antifungal Drugs
Table 6. Treatment of Other Fungal Infections
1,2
Alternatives
ASPERGILLOSIS
Voriconazole
3
6 mg/kg IV q12h x 1d,
then 4 mg/kg IV bid
or 200-300 mg PO bid
>10 wks
or Amphotericin B 1-1.5 mg/kg/d IV
4
Posaconazole 200 mg PO tid-qid
Itraconazole 200 mg PO tid x 3d
followed by 200 mg PO bid
Caspofungin
5
70 mg IV x 1d, then
50 mg IV 1x/d
BLASTOMYCOSIS
6
Itraconazole 200 mg PO bid x 6-12 mos Fluconazole 400-800 mg PO 1x/d
7,8
or Amphotericin B 0.5-1.0 mg/kg/d IV
4
COCCIDIOIDOMYCOSIS
9
Itraconazole
8
200 mg PO bid x >1 yr
or Fluconazole
8
400-800 mg PO 1x/d x >1 yr
7
or Amphotericin B 0.5-1.5 mg/kg/d IV
4
x >1 yr
CRYPTOCOCCOSIS
Amphotericin B 0.5-1 mg/kg/d IV
4
x 2 wks
+
Flucytosine 25 mg/kg PO qid
10
followed by Fluconazole 400 mg PO 1x/d x 10 wks
7
Itraconazole
8
200 mg PO bid
Chronic suppression
11
Fluconazole 200 mg PO 1x/d Itraconazole
8
200 mg PO bid
Amphotericin B 0.5-1 mg/kg IV wkly
4
FUSARIOSIS
Amphotericin B 1-1.5 mg/kg/d IV
4
or Voriconazole 6 mg/kg IV q12h x 1d,
then 4 mg/kg q12h
or 200 mg PO bid
3. In one large controlled trial, voriconazole was more effective than amphotericin B for treatment of invasive aspergillosis (R Herbrecht et al, N Engl
J Med 2002; 347:408).
4. Dosage of amphotericin B deoxycholate given once daily. For safety reasons, lipid-based formulations may be preferred. Usual doses of lipid-
based formulations for treatment of invasive fungal infection are: amphotericin B lipid complex (Abelcet) 5 mg/kg/d; liposomal amphotericin B
(AmBisome) 3-5 mg/kg/d; amphotericin B cholesteryl sulfate (Amphotec) 3-6 mg/kg/d. For treatment of zygomycosis, the dosage of AmBisome is 5
mg/kg/d. For treatment of cryptococcal meningitis in HIV patients, the dosage of AmBisome is 4-6 mg/kg/d.
5. Micafungin and anidulafungin are also active against Aspergillus.
6. Patients with severe illness or CNS involvement should receive amphotericin B.
7. In general, a loading dose of twice the daily dose is recommended on the first day of therapy.
(Table continues on the next page)
OTHER DRUGS
FLUCYTOSINE(Ancobon) Potentially lethal, dose-
related bone marrow toxicity and rapid development of
resistance with monotherapy have limited use of flucy-
tosine mainly to combination use with amphotericin B
for treatment of cryptococcal meningitis. Keeping
serum concentrations below 100 mcg/mL (some clini-
cians recommend staying below 50 mcg/mL) decreases
toxicity, but delays in obtaining assay results often limit
their utility. Flucytosine is only available for oral use.
TERBINAFINE (Lamisil) Terbinafine is a synthet-
ic allylamine approved by the FDA for treatment of
onychomycosis of the toenail or fingernail due to der-
matophytes. It probably acts by inhibiting squalene
epoxidase and blocking ergosterol synthesis.
Lipid Formulations The 3 lipid formulations of
amphotericin B marketed in the US appear to be as
effective as amphotericin B deoxycholate. Compared
to conventional amphotericin B, acute infusion-related
reactions are more severe with Amphotec, less severe
with Abelcet, and least severe with AmBisome.
Nephrotoxicity is less common with lipid-based prod-
ucts than with amphotericin B deoxycholate and,
when it occurs, less severe. Liver toxicity, which is
generally not associated with amphotericin B deoxy-
cholate, has been reported with the lipid formulations.
Cost comparisons of amphotericin B formulations
should take into account the fact that conventional
amphotericin B deoxycholate may cause renal failure,
which can increase the length of hospital stays, health-
care costs and mortality rates.
16
Antifungal Drugs
7
Table 6. Treatment of Other Fungal Infections (continued)
1,2
Alternatives
HISTOPLASMOSIS
Amphotericin B
12
0.5-1.0 mg/kg/d IV
4
x 2 wks
or Itraconazole 200 mg tid x 3d then Fluconazole
8
400-800 mg PO 1x/d
7,13
200 mg PO bid x
6 wks->12 mos
Chronic suppression
11
Itraconazole
8
200 mg PO 1x/d or bid Amphotericin
8
B 0.5-1 mg/kg IV wkly
4
PARACOCCIDIOIDOMYCOSIS
6
Itraconazole
8
100-200 mg PO 1x/d Ketoconazole 200-400 mg PO 1x/d
x 6-12 mos
or Amphotericin B
14
0.4-0.5 mg/kg/d IV
4
SCEDOSPORIOSIS (asexual form of Pseudallescheriasis)
Voriconazole 6 mg/kg IV q12h x 1d, then Itraconazole
8
200 mg PO tid x 3d, then 200 mg
4 mg/kg IV bid, or 200 mg PO bid
PO bid x 12 wks Posaconazole
8
200 mg PO qid
SPOROTRICHOSIS
Cutaneous Itraconazole
8
200 mg PO 1x/d x 3-6 mos Terbinafine
8
500 mg PO bid
Saturated solution of potassium iodide 1-5 mL
PO tid
Fluconazole
7,8
400-800 mg 1x/d
Extracutaneous
6
Amphotericin B 0.7-1 mg/kg/d IV
4
x 6-12 wks
or Itraconazole
8
200 mg PO bid x 12 mos
ZYGOMYCOSIS
Amphotericin B 1-1.5 mg/kg/d IV
4
Posaconazole
8,15
200 mg PO qid
x 6-10 wks
9. Itraconazole is the drug of choice for non-meningeal coccidioidomycosis. Fluconazole is preferred for coccidioidal meningitis. Patients with meningitis
who do not respond may require intrathecal amphotericin B. One patient with meningitis was successfully treated with voriconazole (KJ Cortez et
al, Clin Infect Dis 2003; 36:1619).
10. Dosage must be decreased in patients with diminished renal function. When given with amphotericin B, some Medical Letter consultants recom-
mend beginning flucytosine at 75 mg/kg/day divided q6h, until the degree of amphotericin nephrotoxicity becomes clear or flucytosine blood levels
can be detemined.
11. Suppressive for patients with HIV infection.
12. For severe disease, before switching to itraconazole. Amphotericin B should be continued for 4-6 weeks in patients with CNS involvement. In one
study, liposomal amphotericin B (AmBisome) was associated with greater improvement in survival compared to amphotericin B deoxycholate (PC
Johnson et al, Ann Intern Med 2002; 137:105).
13. For use only in patients who cannot tolerate itraconazole or amphotericin B.
14. Initial treatment of severely ill patients. To be followed by itraconazole.
15. Posaconazole has been used after mucormycosis was clinically improved and oral alimentation was sufficient to enhance absorption (AM Tobon
et al, Clin Infect Dis 2003; 36:1488).
The most common adverse effects of oral terbinafine
have been headache, gastrointestinal symptoms
including diarrhea, dyspepsia and abdominal pain,
and occasionally a taste disturbance that may persist
for weeks after the drug is stopped. Rash, pruritus and
urticaria, usually mild and transient, have occurred.
Toxic epidermal necrolysis and erythema multiforme
have been reported. Increased aminotransferase lev-
els and serious hepatic injury have occurred. Liver
function should be assessed before initiation and peri-
odically during treatment with terbinafine.
Anaphylaxis, pancytopenia and severe neutropenia
have also been reported.
Drug Interactions Terbinafine is an inhibitor of
CYP2D6 and may increase the effect or toxicity of
drugs metabolized by this enzyme, including tri-
cyclic antidepressants. Cimetidine (Tagamet, and
others) may reduce the clearance of terbinafine.
Enzyme inducers such as rifampin may increase
terbinafine clearance.
COMBINATION THERAPY
Use of combination therapy for treatment of immuno-
suppressed patients with invasive aspergillosis (IA),
which has a high morbidity and mortality despite cur-
rent treatments, is controversial. In vitro studies and
animal data suggest a potential benefit of combining
an echinocandin with either an azole or amphotericin
B, but clinical studies are lacking.
NEUTROPENIA
PROPHYLAXIS High-risk neutropenic patients,
such as those undergoing allogeneic and certain autol-
ogous stem cell transplants, and those with hemato-
logic malignancy who are expected to have prolonged
profound neutropenia, may require prophylactic treat-
ment with antifungal drugs. Fluconazole 400 mg PO
or IV once daily has been used, but because of the
high risk of invasive aspergillosis in these patients,
many clinicians now use voriconazole or posacona-
Antifungal Drugs
Coming Soon in Treatment Guidelines:
Drugs for Lipids February 2008
Drugs for Migraine March 2008
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EDITOR: Mark Abramowicz, M.D.
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zole instead. Itraconazole solution, 200 mg once

daily, is an alternative but may not be well tolerated.
Micafungin has also been effective in this population.
In a prospective randomized trial for prevention of
invasive fungal infections in neutropenic patients
with acute myelogenous leukemia or myelodysplastic
syndrome undergoing chemotherapy, posaconazole
was superior to fluconazole or itraconazole and
improved survival.
6
FEVER AND NEUTROPENIA For neutropenic
patients with fever that persists despite treatment with
antibacterial drugs, empiric addition of an antifungal
drug is common practice. Caspofungin and voricona-
zole appear to be as effective as liposomal ampho-
tericin B. Fluconazole and itraconazole have also
been used for this indication.
1. CYP3A and drug interactions. Med Lett Drugs Ther 2005; 47:54.
2. R Herbrecht et al. Voriconazole versus amphotericin B for primary
therapy of invasive aspergillosis. N Engl J Med 2002; 347:408.
3. J Smith et al. Voriconazole therapeutic drug monitoring. Antimicrob
Agents Chemother 2006; 50:1570.
4. S Trifilio et al. Monitoring plasma voriconazole levels may be nec-
essary to avoid subtherapeutic levels in hematopoietic stem cell
transplant recipients. Cancer 2007; 109:1532.
5. Posaconazole (Noxafil) for invasive fungal infections. Med Lett
Drugs Ther 2006; 48:93.
6. OA Cornely et al. Posaconazole vs. fluconazole or itraconazole pro-
phylaxis in patients with neutropenia. N Engl J Med 2007; 356:348.
7. AJ Ullmann et al. Posaconazole or fluconazole for prophylaxis in
severe graft-versus-host disease. N Engl J Med 2007; 356:335.
8. DJ Skiest et al. Posaconazole for the treatment of azole-refractory
oropharyngeal and esophageal candidiasis in subjects with HIV
infection. Clin Infect Dis 2007; 44:607.
9. TJ Walsh et al. Treatment of invasive aspergillosis with posacona-
zole in patients who are refractory to or intolerant of conventional
therapy: an externally controlled trial.Clin Infect Dis 2007; 44:2.
10. DA Stevens et al. Posaconazole therapy for chronic refractory coc-
cidioidomycosis. Chest 2007; 132:952.
11. JAVan Burik et al. Posaconazole is effective as salvage therapy in
zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis
2006; 42:e61.
12. C Wagner et al. The echinocandins: comparison of their pharmaco-
kinetics, pharmacodynamics and clinical applications. Pharmacology
2006; 78:161.
13. ER Kuse et al. Micafungin versus liposomal amphotericin B for can-
didaemia and invasive candidosis: a phase III randomised double-
blind trial. Lancet 2007; 369:1519.
14. Anidulafungin (Eraxis) for Candida infections. Med Lett Drugs Ther
2006; 48:43.
15. AC Reboli et al. Anidulafungin versus fluconazole for invasive can-
didiasis. N Engl J Med 2007; 356:2472.
16. AJ Ullmann et al. Prospective study of amphotericin B formulations
in immunocompromised patients in 4 European countries. Clin
Infect Dis 2006; 43:e29.
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1. Which one of the following is an advantage of the lipid formulations
of amphotericin B over conventional amphotericin B deoxycholate?
a. less expensive
b. decreased nephrotoxicity
c. decreased hepatotoxicity
d. no infusion-related reactions
Pgs. 5-6
2. Which one of the following is the most appropriate regimen for
maintenance therapy in a patient with recurrent vaginal candidiasis?
a. fluconazole 150 mg PO once weekly
b. itraconazole 200 mg PO bid
c. ketoconazole 200 mg PO bid
d. none of the above
Pg. 2
Issue 65 Questions
Continues on next page >>
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3. Which one of the following is true regarding itraconazole?
a. It is a weak inhibitor of CYP3A4 and has few drug
interactions.
b. It is available only as an IV formulation.
c. Absorption is reduced by concomitant use of drugs that
decrease gastric acidity.
d. Nausea is uncommon.
Pgs. 1 & 3
4. Posaconazoles spectrum of activity differs from the other azoles in
that it has activity against which of the following?
a. zygomycetes
b. aspergillus
c. candida
Pg. 3
5. A controlled trial comparing voriconazole to amphotericin B for
treatment of aspergillosis found which one of the following:
a. Voriconazole improved survival, but had more severe
adverse effects.
b. Amphotericin B improved survival and had fewer severe
adverse effects.
c. Voriconazole improved survival and had fewer severe
adverse effects.
d. Amphotericin B improved survival, but had more severe
adverse effects.
Pg. 3
6. Mr. X. is an otherwise healthy 70-year-old male with asymptomatic
candiduria. Which one of the following is appropriate treatment for
this patient?
a. Mr. X should be treated with fluconazole 200 mg IV once
daily for 7 days.
b. The patient is asymptomatic and does not require treatment
at this time.
c. He should be started on flucytosine and amphotericin B.
d. None of the above.
Pg. 2
7. A limitation of posaconazole use is:
a. It is only available in an oral suspension which must be
taken with meals for adequate absorption.
b. It is only available as an IV formulation and has significant
infusion-related reactions.
c. Renal dose adjustments are required.
d. None of the above.
Pg. 3
8. An advantage of the echinocandins is:
a. a low potential for adverse effects because mammalian cells
lack the enzymes involved in glucan synthesis
b. they have activity against most species of Candida including
those resistant to azoles
c. they do not require renal dose adjustment
d. all of the above
Pg. 4
9. Mr. Y. is a 50-year-old male with confirmed toenail onychomycosis.
He is started on terbinafine 250 mg daily. Which one of the
following is true?
a. Liver function tests should be done before starting and
periodically during treatment.
b. The patient may experience GI adverse events.
c. He should be treated for 12 weeks.
d. All of the above.
Pgs. 5-7
10. Mr. Q. is a 30-year-old HIV-positive patient with severe recurrent
esophageal candidiasis. Which one of the following is an option for
prophylaxis?
a. fluconazole 100-200 mg PO once daily
b. clotrimazole troches (10 mg) five times daily
c. nystatin suspension 500,000 units four times daily
Pg. 2
11. Which one of the following is true about ketoconazole?
a. Ketoconazole is now seldom used as the other azoles have
fewer adverse effects and are generally preferred.
b. Anorexia, nausea and vomiting are common with higher
doses (>400 mg/day).
c. Ketoconazole is a strong inhibitor of CYP3A4.
d. All of the above.
Pg. 4
12. Which one of the following is generally preferred for treatment of
deep fungal infections during pregnancy?
a. amphotericin B
b. voriconazole
c. itraconazole
d. caspofungin
Pg. 5
ACPE UPN: 379-000-08-065-H01-P
Drugs for Lipids
Tables
1. Statins Page 10
2. Non-Statins Page 11
3. Adverse Effects Page 14
4. Statin Combination Products Page 15
Volume 6 (Issue 66) February 2008
Drugs that lower low-density lipoprotein cholesterol
(LDL-C) concentrations can prevent formation, slow
progression and cause regression of atherosclerotic
lesions. They should not be used as a substitute for
lifestyle changes; a combination of diet, exercise and
lipid-lowering drugs is optimal for prevention of coro-
nary disease. Lipid-regulating drugs must be taken
indefinitely; when they are stopped, plasma lipopro-
tein levels return to pretreatment levels in 2-3 weeks.
MEASURES OF RISK High concentrations of
low-density lipoproteins are associated with an
increased risk of atherosclerotic disease. The size, den-
sity and number of LDL particles also may affect risk.
Smaller, denser forms, often associated with a larger
number of particles and high triglycerides, may be
more atherogenic.
High triglycerides carried in very low-density lipopro-
teins (VLDL) and intermediate-density (IDL) lipopro-
teins are also associated with an increased risk of
coronary heart disease.
Since each of the atherogenic lipoprotein particles
(LDL, VLDL and IDL) contains a single molecule of
apolipoprotein B (apo B), the concentration of apo B
may be a better indicator of risk than LDL-C. Another
alternative indicator is non-HDLcholesterol, the sum
of cholesterol in both LDL-C and triglyceride-rich
lipoproteins.
Low plasma concentrations of high-density lipopro-
tein cholesterol (HDL-C) or of apolipoprotein A-I
(apo A-I), the major protein component of HDL, are
also a major risk factor for coronary heart disease, even
when LDL-C is normal. Low HDL-C concentrations
are commonly associated with high triglyceride levels
and increased numbers of small dense LDL particles.
Trials of lipid-regulating drugs have shown an associ-
ation between higher concentrations of HDL-C and a
lower incidence of clinical coronary events. Drug treat-
ment to raise low HDL-C is often considered in high-
risk patients with normal triglyceride concentrations,
but the clinical benefit of doing so has not been proven.
When triglycerides are high, lowering them will often
raise low HDL-C concentrations. In short-term stud-
ies, intravenous infusions of synthetic HDL have been
reported to reduce coronary lesions.
1,2
For therapeutic purposes, the majority of lipoprotein
abnormalities can be divided into 2 groups: those with
high LDL-C and those with combined dyslipidemia
(low HDL-C, high triglycerides, high non-HDL-C and
normal LDL-C levels).
STATINS HMG-CoA reductase inhibitors
(statins) inhibit the enzyme that catalyzes the rate-
limiting step in cholesterol synthesis. The subsequent
reduction in hepatic cholesterol leads to increased LDL
receptor activity and increased clearance of LDL-C
from the blood. Statins are more effective than other
drugs in lowering LDL-C, and they also lower triglyc-
erides. Most statins increase HDL-C only modestly.
Statins also have other effects: they improve endothe-
lial function, decrease platelet aggregation, and reduce
inflammation. Statins decrease serum concentrations
of C-reactive protein (CRP), a marker for circulating
inflammatory cytokines.
Clinical Studies Primary Prevention When
taken by patients with risk factors (such as high LDL-
C, low HDL-C, hypertension or diabetes) but no previ-
ous coronary disease, pravastatin, lovastatin and
atorvastatin have been shown to reduce the risk of sub-
sequent cardiovascular events. A10-year post-trial fol-
low-up of primary prevention with pravastatin
(WOSCOPS) showed continuing reduction in coro-
nary events with patients who received pravastatin
compared to those who received placebo.
3
Drugs for Lipids
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 66) February 2008
Secondary Prevention Controlled trials in patients
with coronary heart disease indicate that recommended
doses of lovastatin, simvastatin, pravastatin and ator-
vastatin can lower the incidence of cardiac events and
stroke and decrease mortality from all causes, even in
patients with normal LDL-C levels.
4
Statin therapy ini-
tiated around the time of elective percutaneous coro-
nary intervention, compared to placebo or usual care,
significantly reduced the incidence of myocardial
infarction by 43% (from 5.2% to 3%) in a meta-analy-
sis of 6 trials.
5
High- vs. Low-Dose Statins Among nearly 10,000
patients with stable coronary disease treated with 80
or 10 mg of atorvastatin daily for 5 years (TNT), the
higher dose reduced LDL-C to 77 mg/dL (2.0
mmol/L), compared to 101 mg/dL (2.6 mmol/L) with
the lower dose, and reduced major cardiovascular
events by 22% (relative) and 2.2% (absolute) com-
pared to the lower dose. Total mortality was similar in
the 2 groups.
6
A second trial (IDEAL) included close
to 9000 patients treated after myocardial infarction
10
with 80 mg atorvastatin or 20-40 mg simvastatin for 5
years. Mean LDL-C was 81 mg/dL (2.1 mmol/L) and
104 mg/dL (2.7 mmol/L) during atorvastatin and sim-
vastatin treatment, respectively. Major coronary
events (the primary endpoint) were insignificantly
(p=0.07) reduced by atorvastatin 80 mg compared to
the 2 simvastatin doses. Rates of all-cause, cardiovas-
cular and non-cardiovascular deaths were similar in
the 2 groups.
7
Started within 5 days after onset of acute coronary
syndrome, simvastatin 40 mg/d for the first month fol-
lowed by 80 mg/d thereafter, compared to placebo for
the first 4 months followed by simvastatin 20 mg/d
(Ato Z), failed to show a statistically significant bene-
fit in reducing the primary composite endpoint of car-
diovascular death, myocardial infarction, readmission
for acute coronary syndrome, and stroke.
8
Started
within 10 days of hospitalization for acute coronary
syndrome, atorvastatin 80 mg compared to pravastatin
40 mg for 18-36 months (PROVE IT-TIMI 22) signifi-
cantly reduced a composite of death, major cardiac
FDA-Approved Usual Decreases in
Drug Formulation Daily Dosage
1
LDL Cholesterol Cost
2
Atorvastatin Lipitor (Pfizer) 10, 20, 40, 80 mg tabs Initial: 10 mg once 35%40% $81.99
Maximum: 80 mg once 50%60% 112.99
Fluvastatin Lescol (Novartis) 20, 40 mg capsules Initial: 20 mg once 20%25% 83.51
Maximum: 40 mg bid 30%35% 167.02
extended release Lescol XL 80 mg tablet 80 mg once 35%38% 105.49
Lovastatin 10, 20, 40 mg tab Initial: 20 mg once 25%30% 22.99
generic Maximum: 80 mg once
3
35%40% 71.98
Mevacor (Merck) 20, 40 mg tabs Initial: 20 mg once 25%30% 74.99
Maximum: 80 mg once
3
35%40% 245.98
extended release 20, 40, 60 mg tabs Initial: 20 mg once 20%25% 119.99
Altoprev (Andrx) Maximum: 60 mg once 40%45% 135.35
Pravastatin generic 10, 20, 40, 80 mg tabs Initial: 40 mg once
4
30%35% 20.99
Maximum: 80 mg once 35%40% 133.00
Pravachol (Bristol-Myers 10, 20, 40, 80 mg tabs Initial: 40 mg once
4
30%35% 131.99
Squibb) Maximum: 80 mg once 35%40% 179.12
Rosuvastatin Crestor 5, 10, 20, 40 mg tabs Initial: 10 mg once
5
45%50% 107.60
(AstraZeneca) Maximum: 40 mg once 50%60% 105.48
Simvastatin generic 5, 10, 20, 40, 80 mg Initial: 20 mg once 35%40% 27.99
tabs Maximum: 80 mg once 45%50% 32.99
Zocor (Merck) 5, 10, 20, 40, 80 mg Initial: 20 mg once 35%40% 139.99
tabs Maximum: 80 mg once 45%50% 146.99
1. For initial treatment of patients with only modest elevations of LDL or a history of poor tolerance for these drugs some Medical Letter consultants
use lower doses. Statins are generally most effective when taken in the evening.
2. Cost for 30 days treatment based on prices at drugstore.com, accessed January 16, 2008. Generic prices may vary widely; for example the cost of
30 days treatment with 20 mg per day of generic simvastatin is $5.82 at Costco.com and $126.60 based on the most recent data (November 30,
2007) from retail pharmacies nationwide available from Wolters Kluwer Health.
3. Or 40 mg bid.
4. 10 mg initially for patients with renal or hepatic dysfunction.
5. Asian patients should probably start with 5 mg.
Table 1. Statins
Drugs for Lipids
events and stroke by 16% (relative) and 3.9%
(absolute).
9
Acombined analysis of Ato Z and PROVE
IT-TIMI 22 found that intensive statin treatment led to
significant reductions in both cardiovascular and all-
cause mortality, while non-cardiovascular mortality
was unaffected.
10
A meta-analysis of statin trials in more than 90,000
patients showed a significant 21% relative reduction in
stroke, and the greater the reduction in LDL-C, the
greater the reduction in the incidence of stroke.
11
In
4731 patients with a recent stroke or TIAand no coro-
nary disease (SPARCL), atorvastatin 80 mg compared
to placebo significantly decreased the number of recur-
rent strokes (265 vs. 311). The number of patients with
ischemic stroke decreased by 56 cases while the num-
ber with hemorrhagic stroke increased by 22, both sta-
tistically significant.
12
LDL-C Targets Ameta-analysis of 58 placebo-con-
trolled trials (including some using non-statin drugs)
showed that ischemic heart disease events were
reduced by 20%, 31% and 51% when mean reductions
of LDL-C were 20 mg/dL(0.5 mmol/L), 40 mg/dL(1.0
mmol/L) and 62 mg/dL (1.6 mmol/L), respectively;
strokes were reduced 10% and 17% when LDL-C was
lowered by 40 mg/dL (1.0 mmol/L) and 70 mg/dL (1.8
mmol/L), respectively.
13
Two years of treatment with
40 mg of rosuvastatin (ASTEROID) reduced LDL-C
by 53% to 61 mg/dL (1.6 mmol/L), increased HDL-C
by 15% and led to significant regression of coronary
atherosclerosis.
14
11
Table 2. Non-Statins
Drug Formulation Usual Daily Dosage Cost
1
Bile Acid Sequestrants
Colesevelam Welchol (Daiichi Sankyo) 625 mg tabs 3.75 g once $195.97
or 1.9 g bid
Colestipol Colestid tablets (Pfizer) 1 g tabs 10 g once 225.12
Colestid packets 5 g/packet or 5 g bid 141.88
Cholestyramine generic (packets) 4 g/packet 8 g once 122.99
Questran (Par) or 4 g bid 210.22
generic light (packets) 88.99
Questran Light 212.48
generic (granules) 4 g/dose 52.87
Questran 146.07
Cholesterol Absorption Inhibitor
Ezetimibe Zetia (Merck/Schering-Plough) 10 mg tabs 10 mg once 92.99
Fibrates
Gemfibrozil generic 600 mg tabs 600 mg bid 15.99
Lopid (Pfizer) 135.43
Fenofibrate
2
Tricor (Abbott) 48, 145 mg tabs 145 mg once 118.52

micronized
Antara (Oscient) 43, 130 mg caps 130 mg once 111.99
Lofibra (Gate) 67, 134, 200 mg caps 200 mg once 81.02
Niacin
Niacin immediate-release OTC 500 mg tabs 1000 mg tid 15.99
extended-release Niaspan (Abbott) 500, 750, 1000 ER tabs 1000 mg once
3
120.62
sustained-release Slo-Niacin (Upsher-Smith) 250, 500, 750 SR tabs 1000 mg bid 28.23
Fish Oil Capsules
Lovaza (Reliant) caps
4
4 caps once or 2 caps bid
5
161.98
USP-verified fish oil capsules
6
caps
7
4 caps tid 8.99
8
1. Cost for 30 days treatment with the lowest usual dosage, based on prices at drugstore.com.
2. Generic fenofibrate products are also available. Micronized fenofibrate should be taken with food.
3. Taken with a low-fat snack at bedtime.
4. Each 1 gram capsule contains 465 mg EPA, 375 mg DHA (total 900 mg polyunsaturated fatty acids [PUFAs]).
5. FDA-approved dose for treating hypertriglyceridemia (>500 mg/dL).
6. USP-verified fish oil products are manufactured by Berkley & Jensen, Equaline, Kirkland, Nature Made and NutriPlus.
7. Each 1 g capsule contains 300 mg PUFAs (180 mg EPA and 120 mg DHA); Nature Made Capsules are 1.2 g containing 360 mg PUFAs (216 mg
EPA and 144 mg DHA). Three capsules are approximately equal to 1 Lovaza capsule.
8. Cost of one bottle containing 400 Kirkland fish oil capsules at Costco.com accessed January 16, 2008.
Drugs for Lipids
For high-risk patients, the National Cholesterol
Education Program recommends that LDL-C be low-
ered to less than 100 mg/dL(2.6 mmol/L) or at least 30-
40%, but considers a value <70 mg/dL (1.8 mmol/L) a
reasonable goal for patients at very high risk. A meta-
analysis of 4 large trials of patients with either stable or
acute coronary disease showed that high-dose statin
therapy, compared to standard dosage, lowered LDL-C
levels further and significantly reduced cardiovascular
events.
15
Adverse Effects Statins are generally well tolerated.
Some patients who cannot tolerate one statin may tol-
erate another. Mild gastrointestinal disturbances,
headache or rash may occur. Myopathy including
myalgia and muscle weakness, with or without
increased serum creatine kinase (CK), is common.
Rarely, rhabdomyolysis and myoglobinemia leading to
renal failure can occur. Whether the risk and severity of
myopathy are uniformly dose-related with all statins is
unclear.
16
In one study (A to Z), among 2265 patients
receiving 80 mg of simvastatin, 9 (0.4%) developed
myopathy and 3 of these (0.13%) had rhabdomyolysis
compared to 1 patient (0.04%) with myopathy among
2232 patients receiving 20 mg of simvastatin or
placebo.
8
A similar dose-relationship has not been
reported with atorvastatin in clinical trials. CK values
should be measured at baseline and subsequently if the
patient develops myalgia; if levels exceed 3-5 times the
upper limit of normal (ULN), some Medical Letter con-
sultants would lower the dose or discontinue the drug.
Others would wait until CK levels reach 5-10 times
ULN.
An increase in plasma aminotransferase activities to
more than 3 times ULN occurs in 1-2% of patients tak-
ing higher doses of statins, but symptomatic hepatitis
has been rare. Patients who develop biochemical hepa-
titis with one statin may be able to tolerate another or
lower doses of the same one. Current recommendations
for hepatic monitoring vary. One approach would be
baseline evaluation of liver function and transaminase
measurements after 3 months and annually thereafter,
or more frequently if indicated.
An observational study has suggested a rare association
of statin use with polyneuropathy.
17
Other reports
have described memory loss, sleep disturbances, impo-
tence, gynecomastia, a lupus-like syndrome and acute,
usually mild, pancreatitis, but with all of these, cause
and effect are not clear.
Ameta-analysis of 26 large randomized controlled tri-
als, using predominantly low to intermediate statin
doses, showed no effect on cancer incidence or
death.
18
Long-term follow-up studies of simvastatin
12
(4S)
19
and pravastatin (WOSCOPS)
3
have found no
excess incidence of cancer.
Drug Interactions Statin-induced myopathy is often
caused by drug interactions. Simvastatin and lovastatin
undergo extensive first-pass metabolism by CYP3A4
in the liver, and their plasma concentrations can be
increased dramatically by concurrent use of strong
CYP3A4 inhibitors such as itraconazole (Sporanox),
ketoconazole (Nizoral, and others), clarithromycin
(Biaxin), nefazodone, and many HIV protease
inhibitors. Grapefruit juice inhibits intestinal CYP3A4
and in large amounts (1 quart or more) may also
increase plasma levels of simvastatin and lovastatin.
Atorvastatin undergoes less first-pass metabolism by
CYP3A4 and most 3A4 inhibitors produce only small
increases in its plasma concentration, but rhabdomyol-
ysis has occurred. Fluvastatin is mainly metabolized by
CYP2C9, and few interactions have been reported.
Pravastatin and rosuvastatin are not metabolized by the
cytochrome system and are least affected by other
drugs.
Cyclosporine (Sandimmune, and others) taken concur-
rently increases serum concentrations of all statins and
the risk of rhabdomyolysis; the mechanism is not clear.
Gemfibrozil inhibits metabolism of statins by inhibit-
ing statin glucuronidation and increases the risk of
rhabdomyolysis when used in combination. A few
patients taking a statin have developed myalgia when
ezetimibe was added.
20, 21
Choice of a Statin Lovastatin, pravastatin and sim-
vastatin are available generically. Statins differ in
potency, and the maximum FDA-approved dose does
not always reflect these differences accurately.
Rosuvastatin may be more effective than other statins
in lowering LDL-C, and the incidence of rhabdomyol-
ysis with rosuvastatin to date has been similar to that
with other statins, but its safety record is not as long
and no trial demonstrating a clinical benefit on cardio-
vascular disease has been completed. Higher serum
concentrations of rosuvastatin have been reported in
some Asian patients; an initial dose of 5 mg once daily
is recommended.
FIBRIC ACID DERIVATIVES Fibrates activate
the nuclear transcription factor peroxisome proliferator
activated receptor-alpha (PPAR-alpha), which regulates
genes that control lipid and glucose metabolism,
inflammation, and endothelial function.
22
Gemfibrozil
(Lopid, and others), fenofibrate (Tricor, and others) and
bezafibrate (Bezalip available in Canada, not in the
US) lower triglycerides, usually 25-50%, and increase
HDL-C, usually 10-35%. They may lower LDL-C, but
13
Drugs for Lipids
when they decrease elevated triglycerides, LDL-C may
increase. Patients for whom fibrates are particularly
indicated include those with hypertriglyceridemia
severe enough to be at risk for pancreatitis and those
who have hypertriglyceridemia with low HDL-C, espe-
cially when associated with diabetes, insulin resistance
and the metabolic syndrome.
Gemfibrozil A13-year post-trial follow-up of the 5-
year Helsinki Heart Study showed that patients treated
with gemfibrozil had a significant 23% reduction in
coronary mortality.
23
Fenofibrate Taken once daily, fenofibrate may be
more effective than gemfibrozil in lowering plasma
LDL-C and triglycerides. Alarge 5-year combined pri-
mary and secondary prevention trial in patients with
type 2 diabetes (the FIELD study) found that fenofi-
brate 200 mg once daily produced a nonsignificant 11%
reduction in coronary events, which was the primary
endpoint. Non-fatal myocardial infarctions and total
cardiovascular disease events were significantly
reduced, but all-cause mortality was not. Relatively
high statin use in the placebo group may have limited
the positive effects of fenofibrate.
24
Bezafibrate In a large placebo-controlled trial in
patients with stable angina or a previous myocardial
infarction who had average plasma lipid concentra-
tions, the incidence of myocardial infarction or sudden
cardiac death after 6 years was 13.6% with bezafibrate
versus 15% with placebo; this difference was not sta-
tistically significant, but a post-hoc analysis suggested
that patients with high triglyceride levels at baseline
achieved a significant 40% reduction in major cardiac
events.
25
Adverse Effects Fibrates are generally well tolerated.
Gastrointestinal problems are the most common com-
plaint, mainly with gemfibrozil. Cholelithiasis, hepati-
tis and, especially with gemfibrozil, myositis can occur.
Drug Interactions Fibrates may potentiate the effect
of oral anticoagulants and oral hypoglycemic agents.
Gemfibrozil inhibits metabolism of most statins and
increases the risk of rhabdomyolysis. Fenofibrate does
not inhibit statin metabolism and is much less likely to
increase the risk.
NIACIN (NICOTINIC ACID) Niacin modifies all
plasma lipoproteins and lipids favorably and has been
shown to lower the incidence of non-fatal myocardial
infarction and overall mortality rates. It increases
HDL-C 15-35% and decreases triglycerides 20-35%. It
decreases total plasma and LDL-C 5-25%, changing
small, dense LDL particles to large, buoyant forms.
26
Addition of niacin to statin treatment caused regression
of carotid atherosclerosis
27
and, when combined with
the bile acid sequestrant colestipol plus gemfibrozil,
caused regression of coronary lesions and reduced car-
diovascular events.
28
Niacin is available in an immediate-release, quickly
absorbed formulation, an extended-release preparation
(Niaspan) absorbed over 8 hours, and a sustained-release
formulation absorbed over 12-24 hours. A combination
of extended-release niacin and immediate-release lova-
statin has been marketed (Advicor).
Adverse Effects Niacin can cause skin flushing and
pruritus, gastrointestinal distress, blurred vision,
fatigue, glucose intolerance, hyperuricemia, hepatic
toxicity, exacerbation of peptic ulcer and, rarely, dry
eyes or hyperpigmentation. Some adverse effects, par-
ticularly flushing, are more common with the immedi-
ate-release formulation. Sustained-release preparations
have been hepatotoxic in doses of > 2 grams per day.
Less flushing and little hepatic toxicity have been
reported with the extended-release preparation in daily
doses up to 2 grams. The cutaneous reactions can be
diminished by starting with a low dose, taking niacin
after meals, and by taking aspirin (325 mg) or ibupro-
fen (200 mg) first.
CHOLESTEROL ABSORPTION INHIBITOR
Ezetimibe (Zetia in US; Ezetrol in Canada) inhibits
intestinal absorption of both dietary and biliary choles-
terol by blocking its transport at the brush border of the
small intestine.
29
The recommended dose of 10 mg/day
reduces LDL-C by about 18%. A fixed-dose combina-
tion of ezetimibe and simvastatin is available
(Vytorin)
30
; it lowers LDL-C by 20-65%, depending on
the simvastatin dose. An unpublished 2-year study
(ENHANCE) in 720 patients with heterozygous famil-
ial hypercholesterolemia (mean baseline LDL-C 318
mg/dL) comparing ezetimibe 10 mg plus simvastatin
80 mg with simvastatin 80 mg alone found no signifi-
cant difference in the primary endpoint of change in
intima-media thickness of the carotid artery. LDL-C
decreased significantly more with ezetimibe (58% vs.
41%). No trial has yet demonstrated a reduction of car-
diovascular outcomes with ezetimibe alone or in com-
bination with a statin.
Adverse Effects Ezetimibe has generally been well
tolerated. Severe diarrhea has been reported. Myalgia,
rhabdomyolysis, severe hepatitis, toxicity, pancreatitis
and thrombocytopenia have also been reported.
31, 32
According to the package insert, patients with moder-
ate to severe hepatic insufficiency may have increased
serum concentrations of the drug and should not
take it.
Drugs for Lipids
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 66) February 2008 14
Drug Interactions Ezetimibe may increase the anti-
coagulant effect of warfarin. Bile acid sequestrants
interfere with absorption of ezetimibe and if used con-
currently, should be taken at least several hours apart.
Cyclosporine increases plasma levels of ezetimibe; the
clinical significance is unknown. Afew patients taking
a statin have developed myalgia when ezetimibe was
added.
20, 21
BILE ACID SEQUESTRANTS The resins
cholestyramine (Questran, and others) and colestipol
(Colestid) and the hydrophilic polymer colesevelam
hydrochloride (Welchol)
33
are not absorbed from the
gastrointestinal tract. Bile acid sequestrants bind bile
acids in the intestinal lumen, increasing clearance of
cholesterol from the blood to replace the lost bile acids.
These drugs can lower LDL-C by up to 20% and
increase HDL-C, but may raise plasma triglyceride
concentrations in patients with hypertriglyceridemia.
Cholestyramine has been shown to reduce the number
of cardiovascular events, but no clinical outcome data
are available for colestipol or colesevelam.
Adverse Effects The resins can decrease plasma
folate levels, and supplementation should be consid-
ered in younger women and children. The adverse
effects of colestipol and cholestyramine are similar;
constipation occurs frequently and may be accompa-
nied by heartburn, nausea, eructation and bloating.
These symptoms may diminish over time. Increased
dietary fiber or a fiber supplement (Metamucil, and
others) may relieve constipation and bloating. Giving
the drugs in moderate doses (8-10 g/d or less) just
before meals improves tolerance, but decreases effec-
tiveness.
Colesevelam is much better tolerated than cholestyra-
mine or colestipol, with fewer gastrointestinal symp-
toms, and it does not decrease the absorption of other
drugs taken concurrently.
Drug Interactions A number of drugs, including
statins, should be taken either 1-2 hours before or 4-6
hours after colestipol and cholestyramine.
34
FISH OIL Long-chain, highly unsaturated
omega-3 fatty acids, present in cold-water fish and
commercially available in capsules, can decrease
triglyceride concentrations 20-50% by reducing
hepatic triglyceride production and increasing
triglyceride clearance.
35
With long-term intake, they
may increase HDL-C. Omega-3 fatty acids may
increase total LDL-C as they lower triglyceride lev-
els. Alarge, randomized 5-year trial of statin-treated,
hypercholesterolemic Japanese patients showed a sig-
nificant 19% reduction in major coronary events
when 1.8 g eicosapentanoic acid was added to statin
therapy.
36
Lovaza The first FDA-approved omega-3 product,
Lovaza (formerly Omacor), marketed in 1-g capsules,
is approved for treatment of hypertriglyceridemia. In
the recommended dosage of 4 g per day, it lowers
triglycerides by 20-50%. Lovaza may represent an
attractive alternative to fibrates for combination use
with a statin because it does not increase the risk of
rhabdomyolysis.
COMBINATIONS In high-risk patients with treat-
ment goals of LDL-C concentrations below 100 mg/dL
(2.6 mmol/L), statin monotherapy is often not suffi-
cient; addition of another LDL-C lowering drug such as
colesevelam, niacin or ezetimibe may be necessary.
When combinations are used, substantial LDL-C reduc-
tions can be obtained with relatively low drug doses
and therefore a lower potential for adverse effects.
Statins may be used in combination with fenofibrate,
niacin or omega-3 fatty acids to achieve, besides LDL-
C reductions, lowering of triglycerides and increases in
HDL-C. Although concurrent use of ezetimibe and a
fibrate may normalize plasma lipids in patients with
combined dyslipidemia, this combination might dis-
pose to gallbladder disease because both drugs
increase biliary cholesterol excretion. In severe hyper-
triglyceridemia not adequately controlled by diet,
fibrates and niacin may be used together, possibly in
combination with omega-3 fatty acids. Since treatment
of hypertriglyceridemia with a fibrate may increase
LDL-C, it sometimes becomes necessary to add a
statin to what was initially fibrate monotherapy.
STATINS
GI disturbances, headache, rash, fatigue, myalgia and muscle
weakness leading to rhabdomyolysis, elevated hepatic enzymes,
hepatic dysfunction
Rare: Polyneuropathy, memory loss, sleep disturbances,
impotence, gynecomastia, lupus-like syndrome, pancreatitis
FIBRIC ACID DERIVATIVES
GI disturbances, cholelithiasis, hepatitis, myositis
NIACIN
Skin flushing, pruritus, GI disturbances, blurred vision, fatigue,
glucose intolerance, hyperuricemia, hepatic toxicity, exacerba-
tion of peptic ulcers, (adverse effects, especially flushing, are
more frequent with IR products)
Rare: Dry eyes, hyperpigmentation
EZETIMIBE
Abdominal pain, diarrhea, arthralgia, myalgia, rhabdomyolysis,
hepatitis, pancreatitis, thrombocytopenia
BILE ACID SEQUESTRANTS
Constipation, heartburn, nausea, eructation, bloating (adverse
effects are more common with colestipol and cholestyramine
and may diminish over time)
Table 3. Adverse Effects of Cholesterol-Lowering
Drugs
Drugs for Lipids
PREGNANCY Statins are contraindicated in preg-
nancy; congenital anomalies have been reported with
lovastatin in some animal species and in a few human
infants. Gemfibrozil and fenofibrate are teratogenic in
animals. The safety of niacin in lipid-lowering doses is
unknown. Cholestyramine and colestipol might inter-
fere with absorption of important nutrients.
Colesevelam appears to be safe in animal reproductive
studies. Ezetimibe has caused skeletal defects in some
animal studies.
CONCLUSION HMG-CoA reductase inhibitors
(statins) are the lipid-regulating drugs of first choice for
treatment of most patients with or at risk for coronary
and other atherosclerotic vascular disease. They can
decrease the incidence of major coronary events and
death in such patients. Patients at very high risk, such
as those with acute coronary syndrome, have been
shown to benefit from high doses of statins that achieve
> 50% lowering of LDL-C. High-risk patients, such as
those with diabetes, may benefit from taking a statin
even if they have normal LDL-C levels.
When choosing a statin, a major consideration should
be the magnitude of LDL-C reduction required. If mod-
erate lowering is needed, lovastatin, simvastatin or a
low dose of atorvastatin (10 mg) would be a reasonable
choice. Intense LDL-C reduction can be obtained by
using atorvastatin or rosuvastatin, but clinical outcomes
data are lacking for rosuvastatin. In patients with acute
coronary syndromes, atorvastatin is preferred.
Additional LDL-C reductions can be achieved by com-
bining statins with other LDL-C lowering drugs, such
as colesevelam, niacin or ezetimibe, but clinical out-
come studies of such combinations are lacking.
Colesevelam is tolerated much better than the resin bile
acid sequestrants and does not interfere with intestinal
absorption of other drugs. Immediate-release niacin
costs much less than the extended-release preparation,
but is less well tolerated and less convenient; over-the-
counter brands of immediate-release niacin, which are
by far the cheapest, may not be reliable in their purity
and potency.
For patients with combined dyslipidemia, combinations
of a statin with fenofibrate, niacin or fish oil are rec-
ommended. When both HDL-C and LDL-C are low in
patients at risk for coronary disease, a fibrate alone,
niacin alone, or a combination of niacin with a statin
would be a reasonable choice. Of the two fibrate prepa-
rations available in the US, the clinical benefit is best
documented for gemfibrozil, which costs less.
Fenofibrate is less likely than gemfibrozil to interact
with statins.
1. SE Nissen et al. Effect of recombinant ApoA-I Milano on coronary
atherosclerosis in patients with acute coronary syndromes: a random-
ized controlled trial. JAMA 2003; 290:2292.
2. JC Tardif et al. Effects of reconstituted high-density lipoprotein infu-
sions on coronary atherosclerosis: a randomized controlled trial.
JAMA 2007; 297:1675.
3. I Ford et al. Long-term follow-up of the West of Scotland Coronary
Prevention Study. N Engl J Med 2007; 357:1477.
4. R Collins et al. Effects of cholesterol-lowering with simvastatin on
stroke and other major vascular events in 20536 people with cere-
brovascular disease or other high-risk conditions. Heart Protection
Study Collaborative Group. Lancet 2004; 363:757
5. GR Mood et al. Meta-analysis of the role of statin therapy in reduc-
ing myocardial infarction following elective percutaneous coronary
intervention. Am J Cardiol 2007; 100:919.
6. JC LaRosa et al [TNT]. Intensive lipid lowering with atorvastatin in
patients with stable coronary disease. N Engl J Med 2005; 352:1425.
7. TR Pedersen et al [IDEAL]. High-dose atorvastatin vs usual-dose
simvastatin for secondary prevention after myocardial infarction: the
IDEAL study: a randomized controlled trial. JAMA 2005; 294:2437.
8. JA de Lemos et al [A to Z Trial]. Early intensive vs a delayed conser-
vative simvastatin strategy in patients with acute coronary syn-
dromes: phase Z of the A to Z trial. JAMA 2004; 292:1307.
9. CP Cannon et al [PROVE IT-TIMI 22]. Intensive versus moderate
lipid lowering with statins after acute coronary syndromes. N Engl J
Med 2004; 350:1495.
10. SA Murphy et al. Effect of intensive lipid-lowering therapy on mor-
tality after acute coronary syndrome (a patient-level analysis of the
Aggrastat to Zocor and Pravastatin or Atorvastatin Evaluation and
Infection Therapy-Thrombolysis in Myocardial Infarction 22 trials).
Am J Cardiol 2007; 100:1047.
11. P Amarenco et al. Statin in stroke prevention and carotid atheroscle-
rosis: systemic review and meta-analysis. Stroke 2004; 35:2902.
12. The Stroke Prevention by Aggressive Reduction in Cholesterol
Levels [SPARCL] Investigators. High-dose atorvastatin after stroke
or transient ischemic attack. N Engl J Med 2006; 355:549.
13. MR Law et al. Quantifying effect of statins on low density lipopro-
tein cholesterol, ischaemic heart disease, and stroke: systematic
review and meta-analysis. BMJ 2003; 326:1423.
14. SE Nissen et al. [ASTEROID]. Effect of very high-intensity statin
therapy on regression of coronary atherosclerosis: the ASTEROID
trial. JAMA 2006; 295:1556.
15. CP Cannon et al. Meta-analysis of cardiovascular outcomes trials
comparing intensive versus moderate statin therapy. J Am Coll
Cardiol 2006; 48:438.
16. MH Davidson and JG Robinson. Safety of aggressive lipid manage-
ment. J Am Coll Cardiol 2007; 49:1753.
17. D Gaist et al. Statins and risk of polyneuropathy: a case-control
study. Neurology 2002; 58:1333.
18. KM Dale et al. Statins and cancer risk: a meta-analysis. JAMA 2006;
295:74.
15
Drug Size Cost
1
Niacin ER/lovastatin
Advicor (Abbott)
2
500/20 mg $100.34
750/20 mg 104.26
1000/20 mg 116.53
1000/40 mg 113.29
Ezetimibe/simvastatin
Vytorin (Merck/Schering)
3
10/10 mg 103.99
10/20 mg 100.99
10/40 mg 100.99
10/80 mg 100.99
1. Cost of 30 tablets based on prices from drugstore.com, accessed January
16, 2008.
2. Usual daily dosage is 1-2 tablets. Maximum daily dosage is 2000/40 mg.
Taken with a low-fat snack at bedtime.
3. Usual daily dosage is 1 tablet in the evening. Maximum daily ezetimibe
dosage is 10 mg.
Table 4. Statin Combination Products
Drugs for Lipids
19. TE Strandberg et al. Mortality and incidence of cancer during 10-
year follow-up of the Scandinavian Simvastatin Survival Study (4S).
Lancet 2004; 364:771.
20. R Fux et al. Ezetimibe and statin-associated myopathy. Ann Intern
Med 2004; 140:671.
21. C Simard and P Porier. Ezetimibe-associated myopathy in monother-
apy and in combination with a 3-hydroxy-3-methylglutaryl coen-
zyme A reductase inhibitor. Can J Cardiol 2006; 22:141.
22. B Staels and JC Fruchart. Therapeutic roles of peroxisome prolifera-
tor-activated receptor agonists. Diabetes 2005; 54:2460.
23. L Tenkanen et al. Gemfibrozil in the treatment of dyslipidemia. Arch
Intern Med 2006; 166:743.
24. A Keech et al. Effects of long-term fenofibrate therapy on cardiovas-
cular events in 9795 people with type 2 diabetes mellitus (The
FIELD study): randomized controlled trial. Lancet 2005; 366:1849.
25. BIP Study Group. Secondary prevention by raising HDL cholesterol
and reducing triglycerides in patients with coronary artery disease:
the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;
102:21.
26. JT Kuvin et al. Effects of extended-release niacin on lipoprotein par-
ticle size, distribution, and inflammatory markers in patients with
coronary artery disease. Am J Cardiol 2006; 98:743.
27. AJ Taylor et al. The effect of 24 months of combination statin and
extended-release niacin on carotid intima-media thickness:
ARBITER 3. Curr Med Res Opin 2006; 22:2243.
28. EJ Whitney et al. A randomized trial of a strategy for increasing
high-density lipoprotein cholesterol levels: effects on progression of
coronary heart disease and clinical events. Ann Intern Med 2005;
142:95.
29. Three new drugs for hyperlipidemia. Med Lett Drugs Ther 2003;
45:17.
30. Vytorin: A combination of ezetimibe and simvastatin. Med Lett
Drugs Ther 2004; 46:73.
31. MF Stolk et al. Severe hepatic side effects of ezetimibe. Clin
Gastroenterol Hepatol 2006, 4:908
32. J Havranek et al. Monotherapy with ezetimibe causing myopathy.
Am J Med 2006; 119:285.
33. Colesevelam (Welchol) for hypercholesterolemia. Med Lett Drugs
Ther 2000; 42:102.
34. The Medical Letter Adverse Drug Interactions Program.
35. Fish oil supplements. Med Lett Drugs Ther 2006; 48:59.
36. M Yokoyama et al. Effects of eicosapentaenoic acid on major coro-
nary events in hypercholesterolaemic patients (JELIS): a randomized
open-label, blinded end point analysis. Lancet 2007; 369:1090.
16
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Founded in 1959 by
Now available: Drugs for Parasitic Infections
To purchase a handbook or a downloadable copy go
to: medicalletter.org/parasitic
MISSION:
management.
1. When lipid-regulating drugs are stopped, plasma lipoprotein levels
return to normal:
a. in a few days
b. in 2-3 weeks
c. in 1-2 years
d. never
Page: 9
2. In FDA-approved doses, rosuvastatin is at least as effective as
atorvastatin in lowering LDL-C, but:
a. It has a higher incidence of rhabdomyolysis.
b. In maximum doses it is more expensive.
c. No trial demonstrating a clinical benefit on cardiovascular
disease has been completed.
d. No study has demonstrated that it causes regression of
coronary atherosclerosis.
Page 10-13
Issue 66 Questions
Introducing
24 Category 1 AMA PRA Credits per year in the format thats right for you:
3. The 2 statins not metabolized by the cytochrome system and least
affected by other drugs are:
a. lovastatin and simvastatin
b. atorvastatin and simvastatin
c. rosuvastatin and pravastatin
d. fluvastatin and atorvastatin
Page: 12
4. Symptomatic hepatitis with statins:
a. has not occurred
b. has been rare
c. has been common
d. is frequently fatal
Page: 12
5. The principal effects on serum lipids of fibrates such as
gemfibrozil are that they:
a. lower triglycerides and increase HDL-C
b. lower triglycerides and LDL-C
c. lower LDL-C and HDL-C
d. shift the size distribution of LDL-C to smaller, denser
particles
Page: 13
6. Clinical studies have yet to document favorable cardiovascular
outcomes for:
a. rosuvastatin and ezetimibe
b. atorvastatin, pravastatin and lovastatin
c. gemfibrozil
d. niacin and fish oil when added to statin therapy
Page: 13,14
7. The FDA has approved an omega-3 fish oil product for treatment
of:
a. high LDL-C
b. high triglycerides
c. low HDL-C
Page: 14
8. In lowering LDL-C, the best benefit/cost ratio would come from
using:
a. atorvastatin
b. rosuvastatin
c. generic simvastatin
d. fluvastatin
Page: 10
9. Patients with diabetes:
a. should not take statins
b. are at high risk for statin myopathy
c. should take a statin if their HDL-C is high
d. may benefit from taking a statin even if they have no lipid
abnormalities
Page: 15
10. Patients with acute coronary syndromes have been shown to
benefit from:
a. high doses of statins that achieve 50% or greater lowering
of LDL-C
b. niacin
c. a statin and an omega-3 fatty acid product
d. ezetimibe
Page: 15
11. Combining a statin with another LDL-C lowering drug has been
shown to:
a. decrease the risk of rhabdomyolysis
b. improve clinical outcomes
c. achieve additional LDL-C reductions
d. all of the above
Page: 15
12. When both HDL-C and LDL-C are low in patients at risk for
coronary disease, reasonable treatment choices would be:
a. gemfibrozil
b. niacin alone
c. niacin plus a statin
d. any of the above
Page: 15
ACPE UPN: 379-000-08-066-H01-P
Drugs for Migraine
Tables
1. Triptans: Onset of Action Page 17
2. Some Drugs for Treatment of Migraine Page 18
3. Some Drugs for Prevention of Migraine Page 20
Volume 6 (Issue 67) March 2008
Some drugs for treatment of migraine attacks are listed
in table 2 on page 18. Drugs for prevention of migraine
are listed in table 3 on page 20. Treatment of migraine
in the emergency room, which may involve use of
intravenous drugs, is not included here.
ANALGESICS
Treatment with a nonopioid analgesic may be suffi-
cient for mild or moderate episodes of migraine with-
out nausea, disability or a need for bed rest. Aspirin
and acetaminophen alone have been shown to be
effective for treatment of migraine; they are also mar-
keted in combinations such as Fiorinal (aspirin, caf-
feine and butalbital) and Fioricet or Esgic
(acetaminophen, caffeine and butalbital). Butalbital
has not been shown to be effective for treatment of
migraine in controlled trials and is associated with tol-
erance, dependence and analgesic rebound. Midrin,
which contains acetaminophen, isometheptene (a sym-
pathomimetic amine) and dichloralphenazone (a chlo-
ral hydrate compound) is also used for mild to
moderate migraine. A combination of acetaminophen,
aspirin and caffeine (Excedrin Migraine, and others) is
available over the counter (OTC).
Ibuprofen 200 mg (Advil, Motrin, Advil Migraine,
Motrin Migraine Pain, and others) is FDA-approved
for OTC treatment of migraine.
1
Other nonsteroidal
anti-inflammatory drugs (NSAIDs) such as naproxen
sodium(Anaprox, and others) also have been effective
in relieving migraine pain. In one study, the combina-
tion of acetaminophen 500 mg, aspirin 500 mg and caf-
feine 130 mg was more effective than ibuprofen 400
mg for treatment of an acute migraine attack and had a
faster onset of action.
2
Oral opioid combinations and injected opioids are
effective for relief of pain, but they produce the usual
opioid adverse effects (such as constipation), and fre-
quent use can lead to drug dependence.
3
In one study,
a single 2-tablet dose containing tramadol 75 mg com-
bined with acetaminophen 650 mg (Ultracet, and oth-
ers) was more effective than placebo in patients with
moderate-to-severe acute migraine pain.
4
Decreased gastric motility during an acute migraine
attack may interfere with absorption of oral analgesics.
Metoclopramide (Reglan, and others) taken promptly
after the onset of symptoms can enhance absorption by
increasing gastric motility and may prevent the nausea
associated with many migraine attacks.
SEROTONIN (5-HT
1B/1D
) RECEPTOR
AGONISTS (TRIPTANS)
Sumatriptan was the first triptan marketed in the US.
A selective serotonin-receptor agonist with a short
duration of action, it is highly effective for treatment of
acute migraine. Sumatriptan is available for subcuta-
neous self-injection, as a nasal spray, and for oral
administration. The injection and nasal spray formula-
tions have a more rapid onset of action than oral
tablets. A subcutaneous injection of sumatriptan pro-
duces relief within 2 hours in 70% to 80% of patients
Onset Elimination
of action half-life
Almotriptan (Axert) 30-60 min 3-4 hrs
Eletriptan (Relpax) 30-60 min 3-4 hrs
Frovatriptan (Frova) ~2 hrs ~25 hrs
Naratriptan (Amerge) 1-3 hrs ~6 hrs
Rizatriptan (Maxalt) 30-60 min 2-3 hrs
Sumatriptan (Imitrex) ~2 hrs
tablets 30-60 min
nasal spray 10-15 min
SC injection ~10 min
Zolmitriptan (Zomig) 2-3 hrs
tablets 30-60 min
nasal spray 10-15 min
Table 1. Triptans: Onset of Action
Drugs for Migraine
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 67) March 2008 18
with moderate to severe migraine. Sumatriptan nasal
spray has produced relief in about 60% of patients after
2 hours. Oral sumatriptan has been effective in about
50% to 60% of patients with acute migraine after 2
hours and in about 70% after 4 hours.
5
Sumatriptan nasal spray was effective and well toler-
ated in children 8-17 years old.
6
The reformulated
rapid-release sumatriptan tablets may produce pain
relief sooner than the older formulation; direct com-
parisons with other triptans are lacking.
7
In 2 random-
ized, double-blind studies, a fixed-dose combination
tablet containing sumatriptan 85 mg and naproxen 500
mg, under review by the FDA, achieved better pain
relief than either agent as monotherapy in patients with
a moderate or severe migraine.
8
Four other triptans (almotriptan, eletriptan, rizatriptan
and zolmitriptan) are similar in efficacy to sumatrip-
tan.
9
Zolmitriptan, like sumatriptan, is available as a
nasal spray as well as orally; compared to sumatrip-
tan, fewer patients complain about its taste.
10
Naratriptan and especially frovatriptan each have a
longer half-life and appear to have a slower onset of
action and lower initial response rate than other trip-
tans.
Use of a triptan early in an attack, when pain is still
mild to moderate in intensity, has been shown to
improve outcomes compared to later use.
11
In patients
with moderate or severe migraine, the rate of recur-
rence within 24 hours after treatment with a triptan is
generally 20% to 40%; it is slightly lower with nara-
Drug Formulations Usual dosage Cost
1
Serotonin (5-HT
1B/1D
) Receptor Agonists ("Triptans")
Almotriptan Axert (Ortho-McNeil) 6.25, 12.5 mg tabs 12.5 mg PO; can be repeated $21.15
once after 2 hrs (max 2 doses/d)
Eletriptan Relpax (Pfizer) 20, 40 mg tabs 20 or 40 mg PO; can be 19.95
repeated after 2 hrs (max 80 mg/d)
Frovatriptan Frova (Endo) 2.5 mg tabs 2.5 mg PO; can be 21.92
repeated after 2 hrs (max 7.5 mg/d)
Naratriptan Amerge (GlaxoSmithKline) 1, 2.5 mg tabs 2.5 mg PO; can be 24.47
repeated once after 4 hrs (max 5 mg/d)
Rizatriptan Maxalt, Maxalt-MLT 5, 10 mg tabs; 5, 10 mg 5 or 10 mg PO; can be repeated 21.06
(Merck) orally disintegrating tabs after 2 hrs (max 30 mg/d)
2
Sumatriptan Imitrex 25, 50, 100 mg tabs 50 or 100 mg PO; can be 22.88
(GlaxoSmithKline) repeated after 2 hrs
(max 200 mg/d)
5, 20 mg nasal spray 5, 10 or 20 mg intranasally; 34.71
can be repeated once after
2 hrs (max 40 mg/d)
4, 6 mg/0.5 mL cartridges; 6 mg SC; can be repeated once 81.62
6 mg/0.5 mL vials after 1 hr (max 12 mg/d)
Zolmitriptan Zomig, Zomig ZMT 2.5, 5 mg tabs; 2.5, 5 mg 2.5 or 5 mg PO; can be repeated 20.07
(AstraZeneca) orally disintegrating tabs after 2 hrs (max 10 mg/d)
5 mg/100 mcL nasal 5 mg intranasally; can be 29.25
spray repeated once after 2 hrs
Ergot Alkaloids
Dihydroergotamine mesylate 1 mg/mL ampules 1 mg IM or SC; can be
generic repeated at 1 hr intervals 33.99
D.H.E. 45 (Valeant) (max 3 mg/24 hrs, 6 mg/wk) 81.93
Migranal Nasal Spray (Valeant) 4 mg/mL nasal spray 1 spray (0.5 mg) into each nostril, 44.27
repeated 15 min later (2 mg/dose;
max 3 mg/24 hrs)
Ergotamine tartrate Ergomar 2 mg sublingual tabs 2 mg sublingually; can be repeated 8.66
(Rosedale) q30min PRN (max 6 mg/24 hrs,
10 mg/wk)
Ergotamine/caffeine
Cafergot (Novartis) 1 mg/100 mg tabs 2 tabs PO, then 1 q30min x 4 PRN 1.50
(max 6 tabs/attack)
2 mg/100 mg rectal 1 rectal suppository; can be repeated 8.03
suppositories once 1 hr later
1. Average cost of one dose at the lowest usual dosage, according to the most recent data (December 31, 2007) from retail pharmacies nationwide
available from Wolters Kluwer Health. Prices of generic drugs may vary widely.
2. Patients also taking propranolol should only use a 5-mg dose (max 15 mg/24 hrs).
Table 2. Some Drugs for Treatment of Migraine
Drugs for Migraine
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 67) March 2008
19
triptan and frovatriptan. Recurrences usually respond
to a second dose of the triptan.
Adverse Effects A burning sensation at the injection
site is common with subcutaneous sumatriptan.
Tingling, flushing, dizziness, drowsiness, fatigue, and a
feeling of heaviness, tightness or pressure in the chest
may occur with all triptans, but most commonly with
injectable sumatriptan. CNS symptoms such as somno-
lence and asthenia following triptan therapy may be
partly related to the resolution of a migraine attack.
12
Angina, myocardial infarction, cardiac arrhythmia,
stroke and death have occurred rarely with these drugs.
They are contraindicated in patients with coronary, cere-
brovascular or other arterial disease, or uncontrolled
hypertension.
Drug Interactions Atriptan should not be used within
24 hours after another triptan or an ergotamine-contain-
ing drug because vasoconstriction could be additive.
Rizatriptan, sumatriptan and zolmitriptan are con-
traindicated in patients taking an MAO inhibitor or
within two weeks of stopping one. Propranolol increases
serum concentrations of eletriptan, rizatriptan and
zolmitriptan.
13
Inhibitors of CYP3A4, including vera-
pamil, increase serum concentrations and may increase
the toxicity of eletriptan; it should not be used within 72
hours of a strong CYP3A4 inhibitor such as clar-
ithromycin (Biaxin, and others).
14
Taking a triptan with
an SSRI, or an SNRI such as venlafaxine (Effexor), can
cause potentially life-threatening serotonin syndrome.
15
ERGOTALKALOIDS
Ergotamine tartrate, a non-specific serotonin agonist
and a vasoconstrictor, has been used for many years for
treatment of moderate to severe migraine headache. It is
available alone in sublingual tablets and combined with
caffeine in oral tablets and suppositories. Comparative
studies have shown that oral ergotamine plus caffeine is
less effective than a triptan for treatment of acute
migraine.
16
Dihydroergotamine mesylate, which can be injected
subcutaneously, intramuscularly or intravenously, or
sprayed intranasally, is also effective in treating
migraine attacks. It is a weaker arterial vasoconstrictor
than ergotamine. Dihydroergotamine nasal spray
relieves migraine after 2 hours in about 50% of patients
with a 15% incidence of headache recurrence within 24
hours. According to Medical Letter consultants, it can be
effective in some patients who do not respond to trip-
tans.
Adverse Effects Nausea and vomiting are fairly com-
mon with ergotamine, but can be prevented by pretreat-
ment with or concurrent use of an antiemetic such as
prochlorperazine (Compazine, and others). Serious
adverse effects, such as vascular (including coronary)
occlusion and gangrene, are rare and usually associated
with overdosage (more than 6 mg in 24 hours or 10 mg
per week). Liver disease or fever can accelerate devel-
opment of severe vasoconstriction. In one retrospective
case-control study in >17,000 patients, overuse of ergo-
tamine (>90 daily doses/yr), particularly in patients tak-
ing cardiovascular drugs, increased the risk of ischemic
events, while overuse of a triptan did not.
17
Long-term
use of ergotamine has been associated with retroperi-
toneal, pleural and pericardial fibrosis and fibrotic
thickening of cardiac valves. Dihydroergotamine
causes fewer adverse effects than ergotamine; it can
cause diarrhea.
Drug Interactions The effects of ergot alkaloids
may be potentiated by triptans, beta-blockers,
dopamine, nicotine or CYP3A4 inhibitors. Ergot alka-
loids and triptans should not be taken within 24 hours
of each other. Use of ergot alkaloids is contraindicated
with strong CYP3A4 inhibitors such as clarithromycin
or itraconazole (Sporanox, and others).
14
MEDICATION-OVERUSE HEADACHE
Overuse (two or more days a week for >3 months) of
analgesics, ergot alkaloids (except dihydroergotamine)
or triptans can cause medication-overuse headache, a
dull or migraine-like headache that is present at least
15 days per month.
18
Preventive measures include
restricting use of these drugs (per attack, per week and
per month) and initiating prophylactic treatment when
necessary.
19
PREVENTION
Patients with frequent or severe disabling migraine
headaches and those who cannot take vasoconstrictors
or are refractory to acute treatment should receive pro-
phylactic treatment. Menstrual or other predictable
migraine attacks may sometimes be prevented by a
brief course of an NSAID, ergot alkaloid or triptan,
particularly naratriptan or frovatriptan taken for sev-
eral days before and during the first few days of men-
struation.
20,21
For continuous prophylaxis, beta-blockers are com-
monly used. Propranolol and timolol are the only beta-
blockers approved by the FDA for this indication, but
metoprolol, nadolol (Corgard, and others) and atenolol
(Tenormin, and others) also have been effective in pre-
venting migraine.
22
All beta-blockers can cause
fatigue, exercise intolerance, depression and orthosta-
tic hypotension, and should not be used in patients with
Drugs for Migraine
decompensated heart failure. All are relatively con-
traindicated in patients with asthma.
The antiepileptic drugs valproate and topiramate
have been effective in decreasing migraine frequency;
about 50% of patients achieve a >50% reduction in
headache frequency with these drugs.
23-25
Other
antiepileptic drugs such as gabapentin (Neurontin, and
others) have also been tried for this indication with
varying degrees of success.
24,26
In randomized,
placebo-controlled studies, topiramate and valproate
have shown similar efficacy to propranolol for
migraine prevention.
27
Topiramate has also reduced the
number of migraines per month in patients with
chronic migraine (>15 headaches/month), with and
without medication overuse.
28,29
Adverse effects of valproate include nausea, fatigue,
tremor, weight gain and hair loss. Acute hepatic failure,
pancreatitis and hyperammonemia (in patients with
urea cycle disorders) occur rarely. Rare complications
include polycystic ovary syndrome, hyperinsulinemia,
lipid abnormalities, hirsutism and menstrual distur-
bances. Topiramate, which is a carbonic anhydrase
inhibitor, commonly causes paresthesias; other adverse
effects include fatigue, language and cognitive impair-
ment, taste perversion and weight loss.
30
Topiramate
can rarely cause angle-closure glaucoma, oligohydro-
sis, nephrolithiasis and symptomatic metabolic acido-
sis. An analysis of data from clinical trials found that
patients taking antiepileptic drugs, including valproate
and topiramate, were more likely to report suicidal
ideation or behavior than those taking a placebo
(0.43% vs. 0.22%).
31
Tricyclic antidepressants can prevent migraine in
some patients and may be given concurrently with
other prophylactic agents, but often cause sedation, dry
mouth and weight gain. Amitriptyline has been shown
to be effective.
32
Nortriptyline (Aventyl, and others) is
Table 3. Some Drugs for Prevention of Migraine
Drug Formulations Usual dosage Cost
1
Beta-Blockers
Metoprolol generic
2
25, 50, 100 mg tabs 50-100 mg bid $29.40
Lopressor (Novartis)
2
50, 100 mg tabs 78.60
Extended-release generic
2
25, 50, 100, 200 mg tabs 100-200 mg once/d 34.50
Toprol-XL (AstraZeneca)
2
42.30
Propranolol generic 10, 20, 40, 60, 80 mg tabs 160-240 mg/d divided 33.60
Inderal (Wyeth) bid, tid or qid 84.60
Extended-release generic 60, 80, 120, 160 mg caps 160-240 mg once/d 64.20
Inderal LA (Wyeth) 81.60
Timolol generic 5, 10, 20 mg tabs 10-15 mg bid or 28.80
20 mg once/d
Antiepileptic Drugs
Valproate
3
125, 250, 500 mg tabs;
Depakote (Abbott) 125 mg sprinkle caps 250-500 mg bid 100.80
Depakote ER 250, 500 mg tabs 500-1000 mg once/d 82.20
Topiramate Topamax (Ortho-McNeil) 25, 50, 100, 200 mg tabs; 50 mg bid 255.00
15, 25 mg caps
Tricyclic Antidepressants
Amitriptyline
2
generic 10, 25, 50, 75, 100, 150 mg tabs 30-150 mg once/d 13.50
Calcium-Channel Blocker
Verapamil
2
generic 40, 80, 120 mg tabs 80 mg tid or qid 27.90
Calan (Pfizer) 82.80
Extended-release generic 120, 180, 240 mg tabs; 240 mg once/d 32.70
120, 180, 240 mg caps 76.20
Calan SR 120, 180, 240 mg caplets
Angiotensin-Converting Enzyme (ACE) Inhibitor
Lisinopril
2
generic 5, 10, 20 mg tabs 5-40 mg once/d 24.90
Prinivil (Merck) 30.30
Zestril (AstraZeneca) 2.5, 5, 10, 20, 30, 40 mg tabs 39.30
Angiotensin Receptor Blocker (ARB)
Candesartan
2
4, 8, 16, 32 mg tabs 8-32 mg once/d
Atacand (AstraZeneca) 55.80
1. Average cost for 30 days treatment with the lowest usual dosage, according to the most recent data (December 31, 2007) from retail pharmacies
nationwide, available from Wolters Kluwer Health. Prices of generic drugs may vary widely.
2. Not approved by the FDA for this indication.
3. Marketed as divalproex sodium (Depakote) and valproic acid (Depakene, and others). Only divalproex sodium is FDA-approved for prevention of
migraine.
Drugs for Migraine
21
also frequently used for this purpose and has fewer
anticholinergic adverse effects.
Calcium-channel blockers are also used for preven-
tion of migraine, but the evidence for their effective-
ness is weak. Verapamil was somewhat more effective
than placebo in some small studies.
22
Calcium-chan-
nel blockers should not be used with beta-blockers
because of the potential for heart block.
In small double-blind studies, the angiotensin-con-
verting enzyme (ACE) inhibitor lisinopril and the
angiotensin receptor blocker (ARB) candesartan
cilexetil have reduced migraine frequency.
33,34
Nonsteroidal anti-inflammatory drugs (NSAIDs),
particularly naproxen sodium and flurbiprofen
(Ansaid, and others), have been used for short-term
prevention of migraine, as in menstrual migraine, as
well as for aborting acute attacks.
The dietary supplements petasites (butterbur) 100-
150 mg per day, riboflavin 400 mg per day, magnesium
citrate 600 mg per day, coenzyme Q10 300 mg per day,
and feverfew 18.75 mg per day, have been reported to
be effective in small randomized placebo-controlled
trials.
35-39
Pericranial injections of botulinum toxin type A
(Botox) have been tried for prophylactic treatment of
episodic migraine, but they are ineffective;
40-42
their
use in chronic migraine is under investigation.
PREGNANCY
All ergot alkaloids are contraindicated in pregnancy.
NSAIDs should not be used in the 3rd trimester
because they can cause premature closure of the ductus
arteriosus. The triptans are classified as category C
(risk cannot be ruled out) for use in pregnancy, but
sumatriptan, which has been used the longest, does not
appear to be associated with an increased risk of birth
defects.
43,44
Preventive therapy is generally not recom-
mended in pregnancy.
DRUGS OF CHOICE
A nonopioid analgesic may be effective for treatment
of mild to moderate migraine. A triptan is the drug of
choice for treatment of moderate to severe migraine
headache. Oral ergot preparations cost less than the trip-
tans, but are not as effective and are associated with
more adverse events. Short-acting oral triptans are sim-
ilar in their efficacy and speed of onset; naratriptan and
especially frovatriptan have a slower onset and longer
duration. The nasal spray forms of sumatriptan and
zolmitriptan have a faster onset of action than all the oral
triptans and probably deserve wider use. Sumatriptan
SC is expensive, but it is the fastest acting and most
effective triptan formulation. Some patients may
respond to one triptan and not to another.
For prevention of migraine attacks, the antiepileptics
valproate and topiramate are increasingly being used,
but there is no evidence that they are more effective
than beta-blockers, which cost much less.
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migraine treatment: systematic review and meta-analysis. Ann
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31. Information for Healthcare Professionals: Suicidalilty and
antiepileptic drugs. FDAAlert. January 31, 2008. Available at:
www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm.
32. DK Ziegler et al. Propranolol and amitriptyline in prophylaxis of
migraine. Pharmacokinetic and therapeutic effects. Arch Neurol
1993; 50:825.
33. H Schrader et al. Prophylactic treatment of migraine with
angiotensin converting enzyme inhibitor (lisinopril): randomised,
placebo controlled, crossover study. BMJ 2001; 322:19.
34. E Tronvik et al. Prophylactic treatment of migraine with an
angiotensin II receptor blocker: a randomized controlled trial.
JAMA 2003; 289:65.
35. RB Lipton et al. Petasites hybridus root (butterbur) is an effective
preventive treatment for migraine. Neurology 2004; 63:2240.
36. J Schoenen et al. Effectiveness of high-dose riboflavin in migraine
prophylaxis. a randomized controlled trial. Neurology 1998: 50:466.
37. A Peikert et al. Prophylaxis of migraine with oral magnesium:
results from a prospective, multi-center, placebo-controlled and dou-
ble-blind randomized study. Cephalalgia 1996; 16:257.
38. PS Sandor et al. Efficacy of coenzyme Q10 in migraine prophylaxis:
a randomized controlled trial. Neurology 2005; 64:713.
39. HC Diener et al. Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-
extract (MIG-99) in migraine preventiona randomized, double-
blind, multicentre, placebo-controlled study. Cephalalgia 2005;
25:1031.
40. S Evers and J Olesen. Botulinum toxin in headache treatment: the
end of the road? Cephalalgia 2006; 26:769.
41. SK Aurora et al. Botulinum toxin type A prophylactic treatment of
episodic migraine: a randomized, double-blind, placebo-controlled
exploratory study. Headache 2007; 47:486.
42. AH Elkind et al. A series of three sequential, randomized, controlled
studies of repeated treatments with botulinum toxin type A for
migraine prophylaxis. J Pain 2006; 7:688.
43. JP Gladstone et al. Migraine in special populations. Treatment
strategies for children and adolescents, pregnant women, and the
elderly. Postgrad Med 2004; 115:39.
44. ML Hilaire et al. Treatment of migraine headaches with sumatriptan
in pregnancy. Ann Pharmacother 2004; 38:1726.
Diet, Drugs and Surgery for Weight Loss April
2008
Anticoagulants and Antiplatelet Drugs May 2008
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CONTRIBUTING EDITOR: Eric J. Epstein, M.D. Albert Einstein College of Medicine
ADVISORY BOARD:
EDITORIAL FELLOWS:
Western Ontario
FULFILLMENT AND SYSTEMS MANAGER: Cristine Romatowski
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
MISSION:
management.
1. Metoclopramide taken at the onset of migraine symptoms can:
a. increase gastric motility
b. enhance absorption of oral analgesics
c. decrease nausea
d. all of the above
Page: 17
2. The fastest-acting triptan formulations (excluding injections) are:
a. sublingual tablets
b. swallowed tablets
c. nasal sprays
d. rectal suppositories
Page: 17
Issue 67 Questions
Introducing
3. The highest response rate within 2 hours has been with:
a. sumatriptan tablets
b. sumatriptan nasal spray
c. sumatriptan subcutaneous injection
d. naratriptan
Page: 17/18
4. Naratriptan and frovatriptan, compared to sumatriptan, have:
a. a faster onset of action
b. a higher initial response rate
c. a shorter half-life
d. a lower rate of recurrences
Page: 18/19
5. Triptans can cause adverse reactions if they are taken
concurrently with:
a. ergotamine tartrate
b. an MAO inhibitor
c. an SSRI
d. all of the above
Page: 19
6. Overuse of ergots or triptans can cause:
a. leukopenia
b. Lupus
c. hair loss
d. headache
Page: 19
7. Topiramate is effective for migraine prophylaxis, but it can
often cause:
a. hyperglycemia
b. cognitive impairment
c. bronchospasm
d. compulsive gambling
Page: 20
8. For the first-line treatment of mild migraine, it would be
reasonable to use:
a. a nonopioid analgesic
b. an opioid analgesic
c. ergotamine tartrate
d. botulinum toxin
Page: 21
9. For continuous prophylaxis of migraine, the drug of choice
for most patients would be:
a. a triptan
b. a beta-blocker
c. a tricyclic antidepressant
d. an ACE inhibitor
Page: 21
10. The drug of choice for treatment of moderate to severe
migraine is:
a. naproxen sodium
b. a beta-blocker
c. a triptan
d. dihydroergotamine
Page: 21
11. Which one of the following statements about triptans is true?
a. Patients who do not respond to one may respond
to another
b. Patients who do not respond to one are unlikely to
respond to another
c. they all have about the same duration of action
d. they all can be given parenterally
Page: 21
12. For prevention of migraine attacks, the antiepileptics valproate
and topiramate appear to be:
a. less effective than beta-blockers
b. about as effective as beta-blockers
c. more effective than beta-blockers
d. ineffective
Page: 21
ACPE UPN: 379-000-08-067-H01-P
Diet, Drugs and Surgery for Weight Loss
Tables
1. Common Diets Page 23
2. Some Drugs for Treatment of Obesity Page 26
Volume 6 (Issue 68) April 2008
Definitions of overweight and obesity are now based
on the body mass index (BMI). The BMI is calculated
by dividing the weight in kilograms by the square of
the height in meters (kg/m
2
). Adults with a BMI of
>25 are considered overweight; those with a BMI of
>30 are considered obese.
DIETS
For any diet to be effective, caloric expenditure must
exceed caloric intake. One pound of fat is equivalent to
3500 Kcalories; adults can lose 1-2 lbs per week by
consuming 500-1000 fewer Kcalories per day.
TYPES OF DIETS Table 1 lists 5 popular diets.
Manipulation of the proportions of protein, fat and car-
bohydrate in the diet is an old approach to making one
type of diet more attractive than another. Most diet
plans also include a component of lifestyle and behav-
ior modification.
months. In both trials, adherence was poor and attrition
was high.
1,2
In a 1-year trial, 160 overweight or obese patients
(BMI range 27-42) with at least one risk factor for car-
diovascular disease were randomized to the Zone,
Atkins, Ornish or Weight Watchers diet. All diets suf-
fered from diminished adherence over time, with drop-
out rates of 35-50%. In completers, the diets were
successful at inducing weight loss of 2.1-3.3 kg; there
was no significant difference between them in the
amount of weight lost.
3
Another randomized 1-year trial compared the
Atkins, Zone, Ornish and LEARN diets in overweight
or obese pre-menopausal women (mean age 41; mean
BMI 32) and managed to keep retention rates high,
ranging from 76-88%. The range of weight loss at one
year was 2-5% of baseline weight. The only signifi-
cant difference was between the Atkins diet (4.7 kg)
and the Zone diet (1.6 kg). There was no significant
difference in weight loss between the Zone, Ornish
and LEARN programs (The A to Z Weight Loss
Study).
4
MAINTENANCE Short-term results tend to be
encouraging with almost all diets, but maintenance of
weight loss is often disheartening. Patients on a diet
generally lose 5% of body weight over the first 6
months, but by 12-24 months weight has usually
returned to baseline. The long-term ineffectiveness of
weight-reduction diets may be due to compensatory
changes in energy expenditure that oppose the main-
tenance of a lower body weight, as well as a complex
set of genetic and environmental interactions.
5
Aper-
sistent energy deficit is critical for active weight loss;
increased physical activity and self-monitoring of
weight are critical in the successful maintenance of
weight loss.
6
SIDE EFFECTS Carbohydrate restriction leads to
ketosis; there is no evidence that ketosis suppresses
Type Description
Weight Watchers Moderate energy deficit
www.weightwatchers.com Portion control
LEARN Moderate energy deficit
(Lifestyle, Exercise, Attitude, Intensive lifestyle
Relationships, Nutrition) modification
www.thelifestylecompany.com
Ornish Vegetarian-based
www.ornish.com Fat restricted
(<10% of total calories)
Zone Low carbohydrate
www.zonediet.com Carbs/Protein/Fat 40/30/30
Atkins Very low carbohydrate
www.atkins.com Minimal fat restriction
Table 1. Common Diets
COMPARATIVE TRIALS Two trials of low-car-
bohydrate vs. conventional diets showed significantly
greater weight loss with the low-carbohydrate diet in
the first 6 months, but no significant difference at 12
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 68) April 2008
appetite, but it does often lead to diuresis, producing a
particularly rapid weight loss in the first 7-14 days. At
least for the first 6-12 months, a high-fat, low-carbo-
hydrate diet, appears to have no adverse effects on
risk factors for atherosclerosis, such as serum lipids,
blood pressure, serum glucose or serum insulin. In
multiple studies, a low-carbohydrate diet improved
cardiometabolic risk factors, such as HDL-cholesterol
and triglyceride concentrations, more than a low-fat
diet did.
2,7
The mechanism is unclear.
LIFESTYLE CHANGES
One of the greatest risks of obesity, type 2 diabetes,
can be reduced by lifestyle modification programs
that focus on weight loss, increased physical activity
and changes in energy intake.
8,9
One study in more than 3000 patients (mean age 50;
mean BMI 34) with fasting and post-load serum glucose
elevations found that lifestyle changes over an average
of 2.8 years appeared more effective than metformin
(Glucophage, and others) in preventing diabetes
(Diabetes Prevention Program Research Group).
9
Every kilogram of weight loss produced a 16% reduction
in diabetes risk. The participants who did not meet the
weight loss goal but did achieve the physical activity
goal still had a 44% lower-than-predicted incidence of
diabetes.
10
A randomized trial in more than 5000 overweight or
obese patients with type 2 diabetes found that inten-
sive lifestyle intervention focusing on caloric restric-
tion and increased physical activity was more
successful than traditional diabetes support and edu-
cation in achieving and maintaining significant
weight loss. At 1 year, lifestyle patients lost 8.6% of
initial body weight compared to a 0.7% loss in the
traditional group (The LOOK AHEAD Trial).
11
DRUGS
A number of drugs such as antipsychotics, antidepres-
sants and antidiabetic agents cause weight gain, and
stopping them or substituting another drug, if possible,
can help with weight control. Only a few drugs have
been approved by the FDAfor treatment of obesity, and
all have major drawbacks.
FDA-APPROVED DRUGS All of the drugs
approved for weight reduction by the FDA may be
effective in the short term when used in conjunction
with diet and exercise, but when the drug is stopped,
the weight is often regained.
Sympathomimetic amines The oldest weight-loss
drugs are sympathomimetic amines such as metham-
24
phetamine (Desoxyn), phentermine (Adipex-P, and
others) and diethylpropion. All of these drugs are con-
trolled substances. Phentermine was widely used with
fenfluramine until the combination (phen-fen) was
found to be associated with heart valve abnormali-
ties.
12
Fenfluramine alone and dexfenfluramine,
13
a
related drug, were also associated with heart valve
abnormalities and primary pulmonary hypertension,
and were removed from the market.
Drugs in this class are approved only for short-term
(up to 12 weeks) use in weight management, but are
often used for longer periods. Short-term use of phen-
termine or diethylpropion was associated with a mean
weight loss of about 3 kg more than with placebo.
14
With continued use, tolerance develops, they become
ineffective, and the risk of dependence and abuse
increases. Data on adverse events in weight-loss trials
that used sympathomimetic amines are limited, but
include increases in heart rate and blood pressure, dry
mouth, nervousness, insomnia and constipation.
Sibutramine (Meridia) Sibutramine
15
is a norepi-
nephrine, serotonin and, to a lesser extent, dopamine
reuptake inhibitor. It has been used for weight loss for
up to 2 years in conjunction with a low-calorie diet.
Two different meta-analyses of sibutramine use in
adults found a mean weight loss of 4 kg after one
year.
14,16
A randomized controlled trial found that the
addition of sibutramine to a lifestyle modification pro-
gram increased weight loss by 5.4 kg.
17
Dose-related increases in blood pressure and heart
rate can occur, in addition to dry mouth, headache,
insomnia and constipation. Sibutramine is not recom-
mended for patients with poorly controlled hyperten-
sion, tachycardia or underlying cardiovascular
disease. It should not be used concurrently with other
serotonergic drugs such as selective serotonin reup-
take inhibitors (SSRIs).
Orlistat (Xenical; Alli) Now available OTC,
18
orlis-
tat is a lipase inhibitor that decreases absorption of fat
from the gastrointestinal tract. It is modestly effective
in increasing weight loss as an adjunct to diet. Patients
taking it for 2 years have lost about 2.5-3 kg more than
those taking a placebo.
14,16
Adverse effects including
flatulence with discharge, oily spotting and fecal
urgency occur predominantly after high-fat dietary
indiscretions and are associated with a high incidence
of drug discontinuation. Fat-soluble vitamin supple-
ments should be taken 2 hours before or 1 hour after
taking orlistat.
19
DRUGS FOR DEPRESSION (OFFLABEL) Some
reports have suggested that patients who take fluoxetine
(Prozac, and others), setraline (Zoloft, and others), parox-
etine (Paxil, and others) or another SSRI for depression
tend to lose weight. (Serotonin is believed to play a role
in regulation of satiety.) Clinical trials have confirmed
that these drugs can enhance weight loss in the first 6-12
months of a calorie-restricted diet.
16
Long-term use of
SSRIs, however, seems to cause weight gain, with some
patients becoming heavier than they were at baseline.
Other adverse effects include nervousness, insomnia and
sexual dysfunction.
Bupropion (Wellbutrin SR) Anon-SSRI antidepres-
sant also used for treatment of tobacco dependence,
20
bupropion SR 300-400 mg/day has been modestly
effective in promoting weight loss. In a 24-week, dou-
ble-blind trial, 215 patients (mean BMI 36) took 300 or
400 mg of the drug in addition to a low-calorie diet.
Among the 147 actively treated patients who com-
pleted all 24 weeks of the trial, weight loss was 7.2%
and 10.1%, compared to 5% with placebo.
21
Bupropion
is generally well tolerated. It has been reported to
increase the risk of seizures, but the slow-release for-
mulation is less likely to have this effect. Insomnia and
anxiety can occur.
DRUGS FOR EPILEPSY (OFF LABEL)
Zonisamide (Zonegran, and others) An antiepilep-
tic drug that caused weight loss as an adverse effect,
zonisamide was tried for weight reduction as an adjunct
to calorie restriction. In a 16-week, double-blind, ran-
domized trial, 30 patients with a mean BMI of 36 who
took gradually increasing doses of the drug (maximum
600 mg per day, as in epilepsy) lost an average of 5.9
kg, compared to 0.9 kg lost by 30 patients on placebo.
22
Zonisamide has caused dizziness, cognitive problems
such as confusion, difficulty concentrating and speech
abnormalities, increases in serum creatinine concentra-
tions, and fatal Stevens-Johnson Syndrome.
23
Topiramate (Topamax) Topiramate is another
antiepileptic drug that caused weight loss in patients
with epilepsy. A randomized, double-blind trial in
385 patients (mean BMI 37) also on a reduced-calo-
rie diet found that 64-384 mg per day of topiramate
for 6 months led, in the 248 patients who completed
the trial, to a 4.8-6.3% weight loss, compared to a
loss of 2.6% with placebo.
24
In a 60-week study, 854
obese participants who took topiramate in doses of
96, 192 and 256 mg daily achieved weight loss of
7.0%, 9.1% and 9.7% respectively, compared to a
1.7% weight loss with placebo.
25
In a 16-week
placebo-controlled study of 111 obese patients with
type 2 diabetes, controlled-release topiramate
titrated to 175 mg per day, alone or in combination
with metformin, produced significant weight loss
(6.0 vs. 2.5 kg), but with high rates of neurological
and psychiatric adverse events including paresthesias,
somnolence, and difficulties in memory, concentra-
tion and attention.
26
DRUGS FOR DIABETES (OFF-LABEL)
Metformin (Glucophage, and others) A biguanide
marketed for oral treatment of type 2 diabetes, met-
formin has caused modest weight loss in some patients.
In patients with early blood glucose abnormalities, met-
formin plus diet was associated with an average 2.1-kg
weight loss compared to a loss of 0.1 kg with placebo
plus diet over an average of 2.8 years.
9
Metformin (250
mg tid, a formulation not available in the US) was also
used in combination with lifestyle intervention in a pop-
ulation of patients with recently diagnosed schizophre-
nia who were on single-drug antipsychotic therapy and
had gained >10% of their pre-drug weight. While
patients on placebo had gained an additional 3.1 kg at
week 12, patients taking metformin had lost 3.2 kg
(4.9% of their baseline weight), and patients on both
metformin and lifestyle intervention had lost 4.7 kg
(7.3% of their baseline weight).
27
Metformin occasion-
ally has unpleasant gastrointestinal effects, including
metallic taste, nausea, diarrhea and abdominal pain.
28
Exenatide (Byetta), a synthetic peptide that stimulates
glucose-dependent insulin secretion, is FDA-approved
as an adjunct to oral agents in the treatment of type 2
diabetes.
29
Given twice daily by subcutaneous injec-
tion, it causes a dose-dependent reduction in weight in
patients with type 2 diabetes also taking metformin or a
sulfonylurea; 30-week trials found weight loss of 1.6 to
2.8 kg.
30,31
The most common adverse effects are nau-
sea, which tends to decrease over time, and hypo-
glycemia, which occurs predominantly in conjunction
with a sulfonylurea.
32
Because it slows gastric empty-
ing, exenatide can decrease the rate and extent of
absorption of other drugs.
Pramlintide (Symlin), an amylin analog given by sub-
cutaneous injection before meals at the same time as
insulin, has been associated with weight loss.
33,34
(Patients with diabetes on insulin otherwise tend to gain
weight as glycemic control improves.) In a 1-year ran-
domized study of 656 patients with type 2 diabetes,
patients taking pramlintide 120 mcg twice daily in
addition to insulin lost 1.4 kg compared to a gain of 0.7
kg with placebo.
34
In a 16-week randomized study of
204 non-insulin-using obese patients (mean BMI 38),
among whom only 20% had type 2 diabetes, taking
pramlintide 240 mcg tid was associated with a 3.7%
placebo-corrected weight loss.
35
Adverse effects
include nausea, irritation at the injection site and mild
hypoglycemia. Since pramlintide slows gastric empty-
ing, it may decrease the rate and extent of absorption of
orally administered drugs.
25
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 68) April 2008 26
dures are Roux-en-Ygastric bypass and adjustable gas-
tric banding. When performed laparoscopically they
are associated with lower complication and morbidity
rates than open procedures. Vertical banded gastro-
plasty has generally been replaced by adjustable gastric
banding.
In a 10-year prospective, non-randomized trial, maxi-
mal weight loss for any type of surgery was seen at 1-2
years: 32% with gastric bypass and 20% with gastric
banding. After 10 years, weight loss was stabilized at
25% and 14% respectively. Mortality (adjusted for sex,
age and risk factors) was 29% lower in the patients who
had surgery.
40
Obesity-related co-morbidities such as
obstructive sleep apnea and diabetes often resolve after
bariatric surgery even before patients achieve signifi-
cant weight loss.
41
ROUX-EN-Y GASTRIC BYPASS A mixed
restrictive and malabsorptive procedure, Roux-en-Y
gastric bypass creates a proximal 20-30 mL pouch of
stomach and anastomoses it to a limb of jejunum,
EXPERIMENTAL DRUGS Rimonabant
Stimulation of cannabanoid type 1 (CB1) receptors has
been associated in animal models with increased food
intake and peripheral fat accumulation; antagonism of
this receptor has been shown to blunt these responses.
36
In a randomized, controlled trial in more than 3000 obese
or high-risk overweight patients, 20 mg of rimonabant
(Acomplia in Europe Sanofi-Aventis), a selective CB1
antagonist, was shown to induce clinically significant
weight loss (4.7 kg more than placebo at one year) and
improve dyslipidemia (RIO-North America).
37
However, a meta-analysis of 4 randomized controlled tri-
als of rimonabant found a significant increase in adverse
psychiatric events, including depressive mood disorders
and anxiety.
38
Rimonabant is approved in some
European countries, but not in the US or Canada.
39
SURGERY
Surgical treatment for obesity is generally limited to
patients with a BMI >40 or a BMI >35 with an obesity
related co-morbidity. The two most common proce-
Drug Formulations Dosage Cost
2
SYMPATHOMIMETIC AMINES
3,4
Benzphetamine generic 50 mg tabs 25-50 mg once/d
5
$12.44
6
Didrex (Pfizer) 50 mg tabs to 50 mg tid 15.33
6
Diethylpropion
generic 25 mg tabs 25 mg tid
7
8.66
extended-release generic 75 mg ER tabs 75 mg once
8
9.00
Methamphetamine
Desoxyn (Ovation) 5 mg tabs 2.5-5 mg bid-tid
9
64.44
10
Phendimetrazine
generic 35 mg tabs 35 mg bid-tid 4.18
Bontril PDM (Valeant) to 70 mg tid
7
12.88
extended-release generic 105 mg ER caps 105 mg once
11
6.78
Bontril Slow-release (Valeant) 14.30
12
Phentermine
generic 15, 30, 37.5 mg tabs, caps 5-37.5 mg once
8
8.44
Adipex-P (Gate) 37.5 mg tabs, caps 37.5 mg once
8
19.16
OTHERS
Orlistat Xenical (Roche) 120 mg caps 120 mg tid
14
86.25
Alli
13
60 mg caps 60 mg tid
14
18.33
Sibutramine
4
Meridia (Abbott) 5, 10, 15 mg caps 10-15 mg once
15
39.20
1. Weight loss drugs including OTC medications are not recommended for use during pregnancy.
2. Cost of 10 days treatment with lowest recommended dosage according to prices at drugstore.com.
3. Approved only for short-term use (a few weeks).
4. Do not take within 2 weeks of starting or stopping a monoamine oxidase (MAO) inhibitor.
5. Usually taken mid-morning to mid-afternoon.
6. Cost of 50 mg once/day.
7. One hour before meals.
8. Usually taken mid-morning.
9. Taken 30 minutes before meals.
10. Cost of 5 mg bid.
11. Taken 30-60 minutes before breakfast.
12. Cost based on AWP listing in Price Alert February 15, 2008.
13. Available OTC.
14. Taken with fatty meals or up to 1 hour later; omit dose if meal is skipped; approved for up to 2 years use. Diet should contain less than 30% fat.
15. Taken with or without food; 5 mg recommended for patients who cannot tolerate 10 mg; approved for 2 years use.
Table 2. Some Drugs for Treatment of Obesity
1
bypassing most of the stomach, all of the duodenum
and the first 15-20 cm of the jejunum. Undigested
nutrients meet digestive enzymes in the common chan-
nel where the two separated limbs join.
Efficacy The mean loss of excess weight (the differ-
ence between actual weight and ideal weight) with this
procedure has been 65-75%.
41
Resolution or improve-
ment rates for diabetes have been about 90%, for
hypertension 90%, and for hyperlipidemia about 95%.
A large retrospective cohort study suggested a 40%
reduction in all-cause mortality, including deaths from
diabetes, cardiovascular disease and cancer, in patients
who had undergone gastric bypass surgery compared to
a severely obese control population, but the incidence
of death related to accidents or suicide was higher in
the surgical group.
42
Adverse effects Perioperative mortality is about
0.5%. Iron, calcium, vitamin D and vitamin B
12
defi-
ciency can occur because of malabsorption. Dumping
syndrome (nausea, bloating, colic, diarrhea) can
occur because of rapid emptying from the gastric
pouch into the jejunum. Pulmonary embolism has
been reported. Some patients who had a gastric
bypass developed clinically significant hyperinsu-
linemic hypoglycemia; the pathophysiology is
unclear.
43
ADJUSTABLE GASTRIC BANDING Use of a
laparascopically adjustable gastric band placed around
the proximal portion of the stomach and injected with
variable amounts of saline has now largely replaced
fixed gastric banding. If patients continue to feel hun-
gry or are not losing weight at an expected rate, they
can receive an outpatient injection of saline to help
increase restriction and promote satiety.
Efficacy Data on gastric banding are confounded by
studies that have combined non-adjustable with
adjustable gastric bands. Excess weight loss is about
50-65% with resolution or improvement rates of about
80% for diabetes, about 70% for hypertension and
about 60% for hyperlipidemia.
41
In a 2-year trial of
60 patients with BMI 30-40 and a recent diagnosis of
type 2 diabetes, those who underwent laparascopic
adjustable gastric banding had a remission rate for
diabetes of 73% compared to 13% in a medical treat-
ment arm.
44
Patients with BMI 30-35 would not meet
current NIH guidelines for weight reduction surgery.
45
Adverse Effects Adjustable gastric banding is a
restrictive procedure with no associated malabsorption;
it has a perioperative mortality of 0.1%, the lowest rate
among all commonly employed bariatric procedures.
Slippage, band erosion, excess vomiting and port site
27
and tubing problems are the most common adverse
effects; these may require an operative revision for cor-
rection.
CONCLUSION
Losing even a small amount of weight and increasing
physical activity can prevent some of the complications
of obesity, particularly type 2 diabetes. Diet and exer-
cise are the preferred methods for losing weight but are
associated with high long-term failure rates. Drugs may
help some patients, but all currently available drugs for
weight reduction have drawbacks. Gastric surgery can
produce marked weight loss in the severely obese, but
long-term data on safety are limited.
1. GD Foster et al. A randomized trial of a low-carbohydrate diet for
obesity. N Engl J Med 2003; 348:2082.
2. L Stern et al. The effects of low-carbohydrate versus conventional
weight loss diets in severely obese adults: one-year follow-up of a
randomized trial. Ann Intern Med 2004; 140:778.
3. ML Dansinger et al. Comparison of the Atkins, Ornish, Weight
Watchers, and Zone diets for weight loss and heart disease risk
reduction: a randomized trial. JAMA 2005; 293:43.
4. CD Gardner et al. Comparison of the Atkins, Zone, Ornish, and
LEARN diets for change in weight and related risk factors among
overweight premenopausal women: the A to Z Weight Loss Study: a
randomized trial. JAMA 2007; 297:969.
5. RL Leibel et al. Changes in energy expenditure resulting from altered
body weight. N Engl J Med 1995; 332:621.
6. RR Wing and S Phelan. Long-term weight loss maintenance. Am J
Clin Nutr 2005; 82:222S
7. WS Yancy et al. A low-carbohydrate, ketogenic diet versus a low-fat
diet to treat obesity and hyperlipidemia: a randomized, controlled
trial. Ann Intern Med 2004; 140:769.
8. J Tuomilehto et al [Finnish Diabetes Prevention Study Group].
Prevention of type 2 diabetes mellitus by changes in lifestyle among
subjects with impaired glucose tolerance. N Engl J Med 2001;
344:1343.
9. WC Knowler et al [Diabetes Prevention Program Research Group].
Reduction in the incidence of type 2 diabetes with lifestyle interven-
tion or metformin. N Engl J Med 2002; 346:393.
10. RF Hamman et al. Effect of weight loss with lifestyle intervention on
risk of diabetes. Diabetes Care 2006; 29:2102.
11. X Pi-Sunyer et al [The Look AHEAD Research Group]. Reduction in
weight and cardiovascular disease risk factors in individuals with
type 2 diabetes: one-year results of the LOOK AHEAD trial.
Diabetes Care 2007; 30:1374.
12. H Jick. Heart valve disorders and appetite-suppressant drugs. JAMA
2000; 283:1738.
13. Dexfenfluramine for obesity. Med Lett Drugs Ther 1996; 38:64.
14. Z Li et al. Meta-analysis: pharmacologic treatment of obesity. Ann
Intern Med 2005; 142: 532-546.
15. Sibutramine for obesity. Med Lett Drugs Ther 1998; 40:32
16. D Rucker et al. Long term pharmacotherapy for obesity and over-
weight: updated meta-analysis. BMJ 2007; 335:1194.
17. TAWadden et al. Randomized trial of lifestyle modification and
pharmacotherapy for obesity. N Engl J Med 2005; 353:2111.
18. Orlistat OTC for weight loss. Med Lett Drugs Ther 2007; 49:49.
19. Orlistat for obesity. Med Lett Drugs Ther 1999; 41:55.
20. Drugs for tobacco dependence. Treat Guidel Med Lett 2003; 1:65.
21. JWAnderson et al. Bupropion SR enhances weight loss: a 48-week
double-blind, placebo- controlled trial. Obes Res 2002; 10:633.
22. KM Gadde et al. Zonisamide for weight loss in obese adults: a ran-
domized controlled trial. JAMA 2003; 289:1820.
23. Zonisamide (Zonegran) for epilepsy. Med Lett Drugs Ther 2000;
42:94.
24. GA Bray et al. A 6-month randomized, placebo-controlled, dose-
ranging trial of topiramate for weight loss in obesity. Obes Res 2003;
11:722.
25. J Wilding et al. A randomized double-blind placebo-controlled study
of the long-term efficacy and safety of topiramate in the treatment of
obese subjects. Intl J Obes Related Metab Disord 2004; 28:1399.
26. J Rosenstock et al. A randomized, double-blind, placebo-controlled,
multicenter study to assess the efficacy and safety of topiramate con-
trolled release in the treatment of obese type 2 diabetic patients.
27. RR Wu et al. Lifestyle intervention and metformin for treatment of
antipsychotic-induced weight gain: a randomized trial. JAMA 2008;
299:185.
28. Drugs for diabetes. Treat Guidel Med Lett 2005; 36:57.
29. Exenatide (Byetta) for type 2 diabetes. Med Lett Drugs Ther 2005;
47:45.
30. JB Buse et al. Effects of exenatide (Exendin-4) on glycemic control
over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.
31. RA DeFronzo et al. Effects of exenatide (Exendin-4) on glycemic
control and weight over 30 weeks in metformin-treated patients with
type 2 diabetes. Diabetes Care 2005; 28:1092.
32. In Brief: exenatide (Byetta) for weight loss. Med Lett Drugs Ther
2006; 48:21.
33. Pramlintide (Symlin) for diabetes. Med Lett Drugs Ther 2005; 47:43.
34. P Hollander et al. Pramlintide as an adjunct to insulin therapy
improves long-term glycemic and weight control in patients with
type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care
2003; 26:784.
35. LAronne et al. Progressive reduction in body weight after treatment
with the amylin analog pramlintide in obese subjects: a phase 2, ran-
domized, placebo-controlled dose-escalation study. J Clin Endocrinol
Metab. 2007; 92:2977.
36. V Di Marzo, I Matias. Endocannabinoid control of food intake and
energy balance. Nat Neurosci 2005; 8:585.
37. FX Pi-Sunyer et al. Effect of rimonabant, a cannabinoid-1receptor
blocker, on weight and cardiometabolic risk factors in overweight or
obese patients: RIO-North America: a randomized controlled trial.
JAMA 2006; 295:761.
38. R Christensen et al. Efficacy and safety of the weight-loss drug
rimonabant: a meta-analysis of randomized trials. Lancet. 2007;
370:1706.
39. Food and Drug Administration, Endocrinologic and Metabolic Drugs
Advisory Committee. Briefing information (NDA 21-888): Zimulti
(rimonabant). Available at http://www.fda.gov/ohrms/dockets/
ac/07/briefing/2007-4306b1-00-index.htm. Accessed March 12,
2008.
40. L Sjostrom et al. Effects of bariatric surgery on mortality in Swedish
obese subjects. N Eng J Med 2007; 357:741.
41. H Buchwald et al. Bariatric surgery: a systematic review and meta-
analysis. JAMA 2004; 292:1724.
42. TD Adams et al. Long-term mortality after gastric bypass surgery. N
Engl J Med 2007; 357:753.
43. GJ Service et al. Hyperinsulinemic hypoglycemia with nesidioblasto-
sis after gastric-bypass surgery. N Engl J Med 2005; 353:249.
44. JB Dixon et al. Adjustable gastric banding and conventional therapy
for type 2 diabetes: a randomized controlled trial. JAMA 2008;
299:316.
45. NIH conference. Gastrointestinal surgery for severe obesity.
Consensus Development Conference Panel. Ann Intern Med 1991;
115:956.
28
Anticoagulants and Antiplatelet Drugs May 2008
Tobacco Dependence June 2008
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1. The body mass index (BMI) is defined by which one of the
following ratios?
a. lbs/inch
b. lbs/m
2
c. kg/m
d. kg/m
2
Page: 23
2. Patients on a diet alone often lose weight in the first 6 months,
but weight usually returns to baseline by:
a. 12 months
b. 12-24 months
c. 18 months
d. 18-36 months
Page 23
Issue 68 Questions
Introducing
3. Drugs that cause weight gain include all except which one of the
following:
a. antipsychotics
b. insulin
c. topiramate
d. SSRIs
Page: 24,25
4. Mean weight loss with sibutramine plus diet after one year was:
a. 4 kg
b. 6 kg
c. 8 kg
d. 10 kg
Page: 24
5. Use of sympathomimetic amines for weight loss is FDA-approved
for up to:
a. 8 weeks
b. 12 weeks
c. 26 weeks
d. 52 weeks
Page: 24
6. Bupropion has been modestly effective in promoting weight loss,
but it may increase the risk of:
a. seizures
b. diabetes
c. depression
d. soiling
Page: 25
7. Metformin has also been modestly effective as an adjunct to diet
in promoting weight loss. Its main toxicity is:
a. CNS depression
b. unpleasant GI effects
c. headache
d. seizures
Page: 25
8. The main adverse effects of zonisamide are related to:
a. glucose control
b. depression
c. cognition
d. GI effects
Page: 25
9. Surgery for obesity is generally limited to patients with a BMI over:
a. 25
b. 30
c. 35
d. 40
Page: 26
10. After bariatric surgery, obesity-related co-morbidities such
as diabetes:
a. generally do not resolve
b. resolve as the patient loses weight
c. often resolve before patients achieve significant weight loss
d. often become worse
Page: 26
11. The mean loss of excess weight with the Roux-en Y gastric
bypass has been:
a. 35-45%
b. 45-55%
c. 55-65%
d. 65-75%
Page: 27
12. Adjustable gastric banding is adjusted:
a. by the patient
b. laparoscopically
c. surgically
Page: 27
ACPE UPN: 379-000-08-068-H01-P
Antiplatelet and Anticoagulant Drugs
Tables
1. Antiplatelet and Anticoagulant Drugs Page 30
2. Drugs for PCI Page 32
3. Drugs for Treatment of VTE Page 33
4. Drugs for Prevention of VTE Page 34
5. Antiplatelet and Anticoagulant Drugs Page 35
of Choice
Volume 6 (Issue 69) May 2008
Arterial and venous thrombosis are major causes of
morbidity and mortality. Arterial thrombi consist of
platelet aggregates held together by small amounts of
fibrin. Antiplatelet drugs are the drugs of choice for
prevention and treatment of arterial thrombosis, but
anticoagulants are also effective, and their effects can
add to those of antiplatelet drugs. Venous thrombi are
composed mainly of fibrin and trapped red blood cells,
with relatively few platelets. Anticoagulants are the
agents of choice for prevention and treatment of
venous thromboembolism and for prevention of car-
dioembolic events in patients with atrial fibrillation.
ANTIPLATELET DRUGS
ASPIRIN Aspirin acetylates cyclooxygenase-1,
blocking thromboxane synthesis and inhibiting platelet
activation and aggregation for 5-7 days. Its use slightly
increases the risk of major bleeding. In addition, like
other nonsteroidal anti-inflammatory drugs, aspirin
can cause asthma and other hypersensitivity symptoms
in aspirin-intolerant patients.
DIPYRIDAMOLE A pyrimidopyrimidine deriva-
tive, dipyridamole inhibits platelet uptake of adenosine
and blocks adenosine diphosphate (ADP)-induced
platelet aggregation. Although the antiplatelet effect of
dipyridamole, which was first marketed as a vasodila-
tor (Persantine), has been known for decades, the drug
was not widely used for this indication until it was
marketed in an extended-release formulation in combi-
nation with aspirin (Aggrenox).
1
Dipyridamole causes
severe headache and diarrhea, which tend to disappear
with continued use. It should be used with caution in
patients with severe or recent coronary artery disease.
THIENOPYRIDINES The thienopyridines clopi-
dogrel (Plavix) and ticlopidine (Ticlid, and others) irre-
versibly inhibit P2Y12, a major ADP receptor on the
platelet surface. Some patients do not respond to these
agents and their delayed onset of action (they are pro-
drugs that must be metabolized before becoming
active) can be problematic in patients who require a
rapid antithrombotic effect.
2
Like aspirin, they are irre-
versible platelet inhibitors, increasing the risk of bleed-
ing for 5-7 days after drug cessation. Ticlopidine is
used less commonly because it can cause skin reac-
tions and thrombotic thrombocytopenic purpura; it has
largely been supplanted by clopidogrel.
GLYCOPROTEIN IIb/IIIa (GPIIb/IIIa) RECEP-
TOR ANTAGONISTS The GPIIb/IIIa receptor
antagonists, which are administered intravenously, pre-
vent platelet aggregation by competing with fibrino-
gen and von Willebrand factor for occupancy of
platelet receptors. Abciximab (ReoPro) is the Fab frag-
ment of a chimeric monoclonal antibody to the
GPIIb/IIIa receptor that binds to both activated and
non-activated platelets. While the plasma half-life of
abciximab is only 30 minutes, a strong platelet affinity
results in measurable platelet inhibition after 24-48
hours, with low levels still detectable after 15 days.
Eptifibatide (Integrilin) and tirofiban (Aggrastat) bind
to the GPIIb/IIIa receptor of activated platelets.
Bleeding at arterial access sites is the most common
complication of these drugs. GPIIb/IIIa inhibitors, par-
ticularly abciximab, can also cause profound acute
thrombocytopenia.
ANTICOAGULANTS
HEPARIN Heparins act by combining with plasma
antithrombin III to form a complex that is more active
in neutralizing thrombin and factor Xa. Unfractionated
heparin (UFH) has numerous disadvantages compared
to low-molecular-weight heparin (LMWH). UFH is
more likely to cause heparin-induced thrombocytope-
nia.
3,4
It also has a more variable anticoagulant
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 69) May 2008 30
Drug Some Available Formulations Usual Dosage Cost
1
Antiplatelet Drugs
Aspirin generic 81 mg chew tab; 81, 162, 325, 81-325 mg PO daily $1.20
500, 650, 975 mg tab;
800 mg ER tab
Dipyridamole 25, 50, 75 mg tabs 75-100 mg PO qid 121.20
Persantine (Boehringer Ingelheim) 182.40
Dipyridamole/aspirin
Aggrenox (Boehringer Ingelheim) 200/25 mg caps 1 cap PO bid (morning and 157.20
evening)
Clopidogrel
Plavix (Sanofi Aventis) 75, 300 mg tabs 300-600 mg PO loading dose; 149.70
75 mg PO daily
Ticlopidine generic 250 mg tabs 250 mg PO bid 94.20
Ticlid (Roche) 153.00
GPIIB/IIIA Inhibitors
Abciximab Reopro (Centocor/Lilly) 10 mg/5 mL vial
1
0.25 mg/kg IV bolus, then 693.16
10 mcg/min IV x 12-24 hrs
Eptifibatide Integrilin
2
(Schering- 20 mg/10 mL
1
; 75, 180 mcg/kg IV bolus 1-2x, 107.21
Plough) 200 mg/100 mL vials (10 min apart), then
2 mcg/kg/min IV x 18-24 hrs
Tirofiban Aggrastat (Medicure) 12.5 mg/50 mL vial; 0.4 mcg/kg/min IV x 30 min, then 253.62
5 mg/100 mL,
1
12.5 mg/250 mL 0.1 mcg/kg/min IV
premixed container
Anticoagulants, Parenteral
Unfractionated Heparin generic 1000,
1
5000, 10,000, 20,000 60-100 units/kg IV bolus, then 1.10
units/mL injection; 1000 12-18 units/kg/hr IV; or
(500 mL), 2000 (1000 mL), 5000 units SC q8-12h
10,000 (100 mL), 12,500 (250 mL)
20,000 (500 mL), 25,000 (250,
500 mL), units IV
Low-Molecular-Weight Heparin
2
Enoxaparin Lovenox 30 mg/0.3 mL, 40 mg/0.4 mL,
1
1 mg/kg bid or 1.5 mg/kg SC daily; 32.50
(Sanofi-Aventis) 100 mg/1 mL, 120 mg/0.8 mL, 30 mg bid or 40 mg SC daily
150 mg/1 mL syringe; 300 mg/3 mL vial
Dalteparin Fragmin (Pfizer) syringe: 2500, 5000 IU/0.2 mL
1
; 5000-10,000 IU SC daily or 32.55
7500/0.3 mL; 10,000 IU/0.4 mL; q12h
10,000 IU/1 mL
vial: 95,000 IU/3.8 mL, 95,000 IU/9.5 mL
Tinzaparin Innohep (Pharmion) 40,000 IU/2 mL vial
1
175 IU/kg SC daily 173.66
Direct Thrombin Inhibitors
Argatroban Argatroban
3
250 mg/2.5 mL vial 2-40 mcg/kg/min IV
4
1,197.01
(GlaxoSmithKline)
Lepirudin Refludan
3
(Bayer) 50 mg vial 0.2-0.4 mg/kg IV bolus, then 191.04
0.1-0.15 mg/kg/hr IV
Bivalirudin Angiomax 250 mg/vial 0.1-0.75 + 0.3 mg/kg IV bolus, 571.40
(The Medicines Co.) then 0.2-1.75 mg/kg/h IV
Others
Fondaparinux Arixtra
2
2.5 mg/0.5 mL,
1
5 mg/0.4 mL, 2.5-10 mg SC daily 50.41
(GlaxoSmithKline) 7.5 mg/0.6 mL, 10 mg/0.8 mL syringe
Anticoagulants, Oral
Warfarin generic 1, 2, 2.5, 3, 4, 5, 6, 7.5, 10 mg tabs; 2-5 mg PO daily 15.90
Coumadin (Bristol Myers Squibb) 5 mg/2.5 mL vial (Coumadin only) 28.50
1. For oral drugs, cost is for a 30-day supply at the lowest usual dosage. For parenteral drugs, cost is for one unit of the underlined formulation. Cost is based on
the most recent data (February 29, 2008) from retail pharmacies nationwide available from Wolters Kluwer Health, or based on AWP listings in Drug Topics
Red Book 2007 and April 2008 Update.
2. Dosing adjustments may be necessary for renal insufficiency.
3. For patients with heparin-induced thrombocytopenia.
4. Patients undergoing PCI receive a loading dose of 350 mcg/kg by IV injection over 3-5 minutes.
Table 1. Antiplatelet and Anticoagulant Drugs
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 69) May 2008
response that requires monitoring. But UFH has advan-
tages over LMWH that have kept it from becoming
obsolete: its anticoagulant effect can be rapidly neu-
tralized by protamine; it is not cleared by the kidneys
and therefore may be safer in patients with renal insuf-
ficiency; and it directly inhibits the contact activation
pathway (important in the genesis of thrombi in stents,
filters and catheter tips), possibly preventing coagula-
tion initiated by contact activation more than LMWH
or fondaparinux.
4
LMWH LMWHs, produced by cleaving UFH into
shorter chains, inhibit factor Xa more than they inhibit
thrombin. Their excretion is primarily renal, with an
elimination half-life of 3-4 hours. Compared to UFH,
LMWHs have longer half-lives that permit fewer doses
per day, and their greater bioavailability leads to a more
predictable anticoagulant response. Meta-analyses of
clinical trials comparing them with UFH indicate that
generally they are at least as effective and safe.
Three LMWHs, enoxaparin (Lovenox), dalteparin
(Fragmin) and tinzaparin (Innohep), have been
approved by the FDA; they generally appear to be
similar, but in clinical trials in patients with unstable
angina/non-ST segment elevation myocardial infarc-
tion (UA/NSTEMI), enoxaparin has been associated
with better outcomes, mainly because of a lower inci-
dence of non-fatal myocardial infarction (MI).
5
Enoxaparin has been at least as safe as UFH in
patients undergoing elective percutaneous coronary
intervention (PCI).
6
FONDAPARINUX Fondaparinux (Arixtra), a
synthetic analog of the pentasaccharide binding
sequence of heparin, inhibits factor Xa without neu-
tralizing thrombin. Factor Xa inhibitors have no activ-
ity against thrombin that is already formed.
Fondaparinux appears to be as effective and at least as
safe as UFH or LMWH for prophylaxis and treatment
of venous thromboembolism (VTE).
7-9
It may also be
used as an alternative to UFH or LMWH in
UA/NSTEMI.
5
The drug has a long half-life and
requires injection only once daily. One limitation of
fondaparinux is that it accumulates in patients with
renal insufficiency, which can be problematic in the
elderly, and is contraindicated in patients with a CrCl
<30 mL/min.
DIRECT THROMBIN INHIBITORS Unlike
heparins and fondaparinux, direct thrombin inhibitors
inhibit clot-bound as well as circulating thrombin.
Bivalirudin (Angiomax), which is given IV and has a
short half-life, can be used instead of heparin in
patients undergoing coronary angioplasty.
10
Whether
it is safer or more effective than UFH, LMWH or fon-
daparinux is unclear. The other two approved par-
enteral thrombin inhibitors, lepirudin (Refludan) and
argatroban (Argatroban), are indicated for use in
patients with heparin-induced thrombocytopenia.
11
ORALANTICOAGULANTS For long-term anti-
coagulation, oral agents are preferred over parenteral
drugs. Vitamin K antagonists such as warfarin
(Coumadin, and others), which require monitoring,
have long been the only oral anticoagulants available.
The orally active, direct thrombin inhibitor ximelaga-
tran, which never received FDA approval and was
withdrawn by the manufacturer because of hepatotox-
icity, did not require monitoring, and was at least as
effective as warfarin.
12,13
Ongoing clinical trials with
other orally active direct thrombin inhibitors will
determine whether hepatotoxicity is a class effect.
Pharmacogenetic tests that have recently become
available may make warfarin dosing more precise in
the future.
CLINICALUSE
The antiplatelet and anticoagulant drugs of choice for
various indications are discussed below and summa-
rized in Tables 2 to 5.
PREVENTION Aspirin prophlyaxis reduces the
incidence of MI and/or death by 15-20% in patients
with UA/NSTEMI, acute MI or cerebrovascular dis-
ease, and in those undergoing angioplasty or a coro-
nary artery bypass graft (CABG). Aspirin can also
prevent MIs in asymptomatic men and ischemic
stroke in asymptomatic women, but the risk-benefit
ratio is less favorable because of the small increased
risk of hemorrhagic stroke.
14
A randomized controlled trial in 2739 patients who
had a transient ischemic attack (TIA) or minor stroke
in the previous 6 months found that a combination of
extended-release dipyridamole (200 mg bid) and
low-dose aspirin (30-325 mg per day) was more
effective than aspirin alone in preventing a composite
of vascular death, stroke, MI or major bleeding (173
vs. 216 events). However, many more patients dis-
continued the combination (470 vs. 184), mainly
because of headache.
15
The CAPRIE study in patients with recent MI,
ischemic stroke or peripheral vascular disease found a
significantly lower annual incidence of vascular events
with clopidogrel than with aspirin (5.32% vs. 5.83%).
Occurrence of severe bleeding was similar (1.38% of
patients taking clopidogrel and 1.55% of those taking
aspirin).
16
In the MATCH trial, taking clopidogrel and
aspirin together offered no advantage over clopidogrel
31
alone in prevention of vascular events in patients with
recent ischemic stroke or transient ischemic stroke
(TIA) and substantially increased the risk of serious
bleeding.
17
The CHARISMA study compared addition of clopi-
dogrel to aspirin with aspirin alone in patients with
cardiovascular (CV) risk factors (e.g., diabetes, hyper-
tension) or established coronary, cerebrovascular or
peripheral arterial disease. MI, stroke or CV death
occurred in 6.8% of patients treated with both drugs
and 7.3% of those who took aspirin alone, which was
not statistically significant. There was no difference
in the rate of severe bleeding; moderate bleeding
occurred in 2.1% of patients taking clopidogrel with
aspirin and 1.3% of those taking aspirin alone, which
was statistically significant. A subgroup analysis
found that patients with only risk factors (primary pre-
vention) had a higher risk of death from CV causes
with both drugs than with aspirin alone, and those
with established CV disease (secondary prevention)
had a lower risk.
18
UA/NSTEMI The American College of
Cardiology and American Heart Association have
updated recommendations for the management of
patients with UA/NSTEMI, some of whom go on to
PCI.
5
They recommend that patients with
UA/NSTEMI be treated with aspirin, clopidogrel and
an anticoagulant, usually UFH or enoxaparin.
The CURE trial in patients with UA or NSTEMI
found that those treated with clopidogrel in addition to
aspirin had significantly lower rates of CV death, MI
or stroke (9.3% vs. 11.4%) but a significantly higher
risk of major bleeding (3.7% vs. 2.7%) than those
treated with aspirin alone.
19
In patients who went on
to PCI, clopidogrel in addition to aspirin significantly
lowered the risk of CV death, MI or urgent revascu-
larization within 30 days after PCI compared to
aspirin alone (4.5% vs. 6.4%), with no significant dif-
ference in major bleeding.
20
One year after PCI, the
incidence of death, MI or stroke was still significantly
lower (8.5% vs. 11.5%) in patients who received both
drugs than in those who received aspirin alone.
21
Use
Initiation Duration of
Drug Dose Relative to PCI Therapy
Unfractionated Heparin 60-100 units/kg IV bolus, titrate Immediately prior to PCI No additional heparin
to ACT 250-300 sec
1
(50-70 post-PCI
units/kg IV if GP IIb/IIIa used,
titrate to ACT 200-250 sec)
Enoxaparin 1 mg/kg SC, with an additional 2-12 hours prior to PCI No additional enoxaparin
0.3 mg/kg IV if 8-12 hrs post-PCI
since last dose
2
Bivalirudin 0.75 mg/kg IV bolus, then Immediately prior to PCI Until end of PCI
1.75 mg/kg/h IV
2
Aspirin 162-325 mg PO >30 minutes prior to PCI Lifelong
Clopidogrel 300-600 mg PO load, then 6-15 hours prior to PCI >12 months for drug-
75 mg PO daily eluting stents
1-3 months for bare
metal stents
Abciximab 0.25 mg/kg IV bolus, then 10-60 min prior to PCI 12 hours
0.125 mcg/kg/min IV
(max 10 mcg/min)
3
Eptifibatide 180 mcg/kg IV bolus x2, Immediately prior to PCI 12-24 hours
10 min apart, then
2 mcg/kg/min IV
2
Tirofiban 0.4 mcg/kg/min IV for 30 min, Prior to PCI (for ACS) 12-24 hours post-PCI
then 0.1 mcg/kg/min IV
2
ACT = Activated coagulation time; ACS = acute coronary syndrome
1. With Hemotec device and 300-350 sec with the Hemochron device.
2. Dosing adjustments may be necessary for renal insufficiency.
3. For patients with unstable angina and planned PCI: 0.25 mg/kg bolus IV followed by 18-24 hrs IV infusion of 10 mcg/min, concluding 1 hr after PCI.
Table 2. Drugs for Percutaneous Coronary Intervention (PCI)
of clopidogrel in addition to aspirin for at least 12
months appears to be especially important in patients
implanted with drug-eluting stents.
22
The SYNERGYtrial in high-risk patients with non-ST
segment elevation acute coronary syndrome undergo-
ing angioplasty and often PCI or CABG found that
enoxaparin was as effective as UFH but was associated
with more bleeding.
23
In another trial in patients with
UA/NSTEMI, fondaparinux was as effective as enoxa-
parin in preventing recurrent thrombosis, major
ischemic events and death, and 50% less likely to cause
major bleeding.
24
High-risk patients often receive a GPIIb/IIIa inhibitor
as well; in one study at one year after UA/NSTEMI,
there was no significant difference in outcome between
patients receiving routine upstream GPIIb/IIIa
inhibitors and those who received them only if and
when they underwent PCI.
25
ACUTE MI (STEMI) In patients treated with fib-
rinolysis within 12 hours after an acute ST-elevation
myocardial infarction (STEMI), the primary endpoint
of an occluded infarct-associated artery on angiogra-
phy, recurrent MI or death before angioplasty occurred
in 15.0% of patients treated with clopidogrel and
aspirin and 21.7% of those treated with aspirin alone.
26
In patients presenting within 24 hours of an acute MI,
death, reinfarction or stroke occurred in 9.2% of
patients treated with clopidogrel in addition to aspirin
and 10.1% of those treated with aspirin alone for up to
28 days, also a significant difference.
27
In both of these
studies, serious bleeding did not occur significantly
more with addition of clopidogrel.
In 20,506 patients with STEMI, enoxaparin was supe-
rior to UFH as an adjunct to fibrinolytic therapy, but
with an increase in major bleeding episodes.
28
In a prespecified subgroup analysis of the OASIS-6
trial, fondaparinux in patients with STEMI not receiv-
ing reperfusion treatment reduced the risk of death or
re-infarction without an increase in severe bleeding
compared to UFH or placebo.
29
However, in patients
who underwent PCI, fondaparinux was ineffective and
was associated with more catheter thrombosis.
30,31
PCI Patients who undergo elective PCI should
receive aspirin, clopidogrel and short-term UFH or
LMWH; they may also benefit from a GPIIb/IIIa
inhibitor.
In one randomized trial in patients with UA/NSTEMI
undergoing PCI, bivalirudin alone was as effective as
heparin plus a GPIIb/IIIa inhibitor in preventing
ischemic events (in patients pretreated with clopido-
grel), with a lower incidence of serious bleeding.
32
33
Astudy in 2,399 patients undergoing elective PCI with
stent placement found that patients who received abcix-
imab had a 30-day primary endpoint (death, MI or
urgent revascularization) rate of 5.3% versus 10.8%
with placebo.
33
Among 300 patients undergoing urgent
PCI with stent placement for acute MI, abciximab
reduced the incidence of the same endpoint from 14.6%
(with placebo) to 6.0%.
34
However, a trial in 2,159 low-
to-intermediate risk patients pre-treated with clopido-
grel before elective PCI found no difference between
abciximab and placebo in the endpoint.
35
A randomized, double-blind study in 2,064 patients
undergoing elective PCI with stent placement compared
eptifibatide with placebo; both groups were pretreated
with aspirin plus a thienopyridine. Eptifibatide reduced
the 48-hour primary endpoint (death, MI, or urgent
revascularization) from 10.5% with placebo to 6.6% and
the 30-day secondary endpoint from 10.5% to 6.8%.
36
A
randomized, double-blind trial of abciximab versus
tirofiban in PCI found a significantly higher incidence
of death, non-fatal MI or urgent revascularization with
tirofiban (7.6% vs. 6.0%) after 30 days, but after 6
months the outcome was similar with either drug.
37,38
TREATMENTOFVTE Anticoagulant treatment of
patients with deep vein thrombosis (DVT) or pulmonary
embolism (PE) can prevent new or recurrent PE and
death.
39
For initial treatment of DVT, LMWH is gener-
ally preferred to UFH. Whether LMWH is superior to
UFH in terms of recurrence rates or the incidence of
major bleeding remains to be determined.
40,41
In one
study, however, weight-based, fixed-dose subcutaneous
UFH that did not require PTT monitoring was as effec-
tive and safe as LMWH.
42
Fondaparinux is a reasonable
alternative for initial treatment of VTE; in a randomized
trial it was as effective and safe as enoxaparin.
43
Drug Dosage
Unfractionated Heparin Initial: 80 units/kg IV bolus
then 18 units/kg/hr
Enoxaparin
1
1.0 mg/kg SC bid or
1.5 mg/kg once daily
Dalteparin
1
100 IU/kg SC bid or
200 IU/kg once daily
Tinzaparin
1
175 IU/kg SC once daily
Warfarin 2-5 mg PO
2
Fondaparinux
1
5-10 mg SC
3
daily
1. Dosing adjustments may be necessary in renal insufficiency.
2. Monitored daily until results in therapeutic range (INR 2-3) for
>24 hours.
3. 5 mg daily if <50 kg, 10 mg daily if >100 kg
Table 3. Drugs for Treatment of VTE
For chronic anticoagulant treatment, which can pre-
vent recurrent VTE and death, it is not clear whether
an oral vitamin K antagonist such as warfarin is supe-
rior to subcutaneous injections of LMWH, but war-
farin is usually preferred because of the convenience
of oral dosing. In patients with cancer, long-term ther-
apy with an LMWH once daily subcutaneously has
been shown to be superior to warfarin in preventing
recurrent VTE without increasing the risk of bleed-
ing.
44
The optimal duration of anticoagulant therapy
for patients with VTE is unclear
45
; the risk of recur-
rent VTE is greatest in the first 6 months.
PREVENTION OF VTE Hospitalized Medical
Patients Many studies have shown that prophylac-
tic anticoagulation of hospitalized medical patients
confined to bed or with other risk factors prevents
symptomatic DVT and PE, but they have not shown
that it decreases all-cause mortality.
46
LMWH has
been more effective than UFH in preventing DVT but
not PE, and both have increased the risk of bleeding.
47
General Surgery Moderate-to-high risk patients
undergoing general surgery have a lower incidence of
DVT and PE if they are given anticoagulation prophy-
laxis. Preoperative subcutaneous low-dose UFH (5000
units tid) or LMWH, combined with use of compression
stockings or intermittent pneumatic compression
devices, can be used. Postoperative fondaparinux can
also be used for this indication.
48
LMWH is preferred in
trauma.
Major Orthopedic Surgery Patients undergoing
total hip replacement, total knee arthroplasty and hip
fracture surgery have an increased risk of VTE and
(especially with hip fracture surgery) PE. Many stud-
ies have shown that prophylactic anticoagulation
markedly decreases the incidence of these events.
48
For all of these indications, enoxaparin has been
more effective than UFH or warfarin, and fonda-
parinux has been more effective than enoxaparin,
with little or no increase in the risk of clinically rele-
vant bleeding.
49-51
ATRIAL FIBRILLATION (AF) Anticoagulation
can reduce the risk of thromboembolic stroke in
patients with AF by 60% or more and has been shown
to be more effective for this indication than antiplatelet
therapy.
52
With an annual rate of major bleeding of
about 2% and an absolute increase in the rate of
intracranial hemorrhage of about 0.2%, the benefits of
warfarin far surpass the risks. Warfarin is more effec-
tive than aspirin and more effective than aspirin plus
clopidogrel in preventing stroke in patients with parox-
ysmal or sustained atrial fibrillation.
53,54
The main
drawback of warfarin is the need for close monitoring
to keep the international normalized ratio (INR)
between 2 and 3.
ISCHEMIC STROKE Antiplatelet drugs can
reduce the incidence of ischemic stroke in patients
who have had a TIA or previous ischemic stroke, but
not as dramatically as anticoagulants decrease the
incidence of thromboembolic stroke in patients with
atrial fibrillation. The relative risk reduction in most
studies is between 15% and 20%.
55
Aspirin is gener-
ally used; no optimal dose has been established, but
most experts use between 50 and 325 mg per day. The
combination of aspirin 25 mg with 200 mg extended-
release dipyridamole (Aggrenox) taken twice daily
has been more effective in some studies in preventing
recurrent stroke than aspirin alone, without increasing
the risk of serious bleeding. Concurrent use of aspirin
and clopidogrel has not been shown to prevent stroke
more effectively than clopidogrel or aspirin alone,
and in one study it doubled the incidence of life-
threatening hemorrhage.
17
Clopidogrel alone can be
used as initial therapy in patients with aspirin allergy.
PERIPHERAL ARTERIAL DISEASE
Antiplatelet therapy has been shown to prevent MI
and stroke in patients with peripheral arterial dis-
ease.
56
Addition of an oral anticoagulant to an
antiplatelet drug in such patients did not, in one
study, significantly decrease the incidence of stroke,
MI or cardiovascular death, and it markedly
increased the incidence of life-threatening bleed-
ing.
57
Whether addition of a second antiplatelet drug
would lower the incidence of ischemic events with-
out increasing the risk of serious bleeding remains to
be determined.
DRUGS OF CHOICE
For some indications, the anticoagulant and
antiplatelet drugs of choice are clearly established.
For others, the choice varies with clinical circum-
stances or is not clear. Nevertheless, the table that fol-
lows may be helpful.
Drug Dosage
Unfractionated heparin 5000 units SC q8-12h
Fondaparinux
1
2.5 mg SC once daily
Enoxaparin
1
30 mg bid SC or
40 mg once daily SC
Dalteparin
1
2500 IU-5000 IU
SC once daily
Tinzaparin
1
175 IU/kg SC
1. Dosage adjustment may be required in renal insufficiency.
Table 4. Drugs for Prevention of VTE
1. Aggrenox. Med Lett Drugs Ther 2000; 42:11.
2. DJ Fitzgerald and A. Maree. Aspirin and clopidogrel resistance.
Hematology Am Soc Hematol Educ Program 2007; 2007:114.
3. GM Arepally and TL Ortel. Clinical practice. Heparin-induced throm-
bocytopenia. N Engl J Med 2006; 355:809.
4. J Hirsh et al. Beyond unfractionated heparin and warfarin: current and
future advances. Circulation 2007; 116:552.
5. JL Anderson et al. ACC/AHA 2007 guidelines for the management of
patients with unstable angina/non-ST-elevation myocardial infarction: a
report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. J Am Coll Cardiol
2007; 50:e1.
6. G Montalescot et al. Enoxaparin versus unfractionated heparin in elec-
tive percutaneous coronary intervention. N Engl J Med 2006; 355:1006.
7. AG Turpie et al. Superiority of fondaparinux over enoxaparin in pre-
venting venous thromboembolism in major orthopedic surgery using
different efficacy end points. Chest 2004; 126:501.
8. G Agnelli et al. Randomized clinical trial of postoperative fondaparinux
versus perioperative dalteparin for prevention of venous thromboem-
bolism in high-risk abdominal surgery. Br J Surg 2005; 92:1212.
9. HR Buller et al. Subcutaneous fondaparinux versus intravenous unfrac-
tionated heparin in the initial treatment of pulmonary embolism. N Engl
J Med 2003; 349:1695.
10. Bivalirudin (Angiomax) for angioplasty. Med Lett Drugs Ther 2001;
43:37.
11. Argatroban for treatment of heparin-induced thrombocytopenia. Med
Lett Drugs Ther 2001; 43:11
12. JI Weitz. Emerging anticoagulants for the treatment of venous throm-
boembolism. Thromb Haemost 2006; 96:274.
35
13. PF Boudes. The challenges of new drugs benefits and risks analysis:
lessons from the ximelagatran FDA Cardiovascular Advisory
Committee. Contemp Clin Trials 2006; 27:432.
14. Aspirin for primary prevention of cardiovascular disease (Revisited).
Med Lett Drug Ther 2006; 48:53.
15. ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone
after cerebral ischaemia of arterial origin (ESPRIT): randomised con-
trolled trial. Lancet 2006; 367:1665.
16. CAPRIE Steering Committee. A randomised, blinded, trial of clopido-
grel versus aspirin in patients at risk of ischaemic events (CAPRIE).
CAPRIE Steering Committee. Lancet 1996; 348:1329.
17. HC Diener et al. Aspirin and clopidogrel compared with clopidogrel
alone after recent ischaemic stroke or transient ischaemic attack in
high-risk patients (MATCH): randomized, double-blind, placebo-con-
18. DL Bhatt et al. Clopidogrel and aspirin versus aspirin alone for the pre-
vention of atherothrombotic events. N Engl J Med 2006; 354:1706.
19. S Yusuf et al. Effects of clopidogrel in addition to aspirin in patients
with acute coronary syndromes without ST-segment elevation. N Engl J
Med 2001; 345:494.
20. SR Mehta et al. Effects of pretreatment with clopidogrel and aspirin fol-
lowed by long-term therapy in patients undergoing percutaneous coro-
nary intervention: the PCI-CURE study. Lancet 2001; 358:527.
21. SR Steinhubl et al. Early and sustained dual oral antiplatelet therapy
following percutaneous coronary intervention: a randomized controlled
trial. JAMA2002; 288:2411.
22. EL Eisenstein et al. Clopidogrel use and long-term clinical outcomes
after drug-eluting stent implantation. JAMA2007; 297:159.
23. JJ Ferguson. Enoxaparin vs. unfractionated heparin in high-risk patients
with non-ST segment elevation acute coronary syndromes managed
with an intended early invasive strategy: primary results of the SYN-
ERGYrandomized trial. JAMA2004; 292:45.
24. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes
Investigators; S Yusuf et al. Comparison of fondaparinux and enoxa-
parin in acute coronary syndromes. N Engl J Med 2006; 354:1461.
25. GW Stone et al. Antithrombotic strategies in patients with acute coro-
nary syndromes undergoing early invasive management: one-year
results from the ACUITYtrial. JAMA2007; 298:2497.
26. MS Sabatine et al. Effect of clopidogrel pretreatment before percuta-
neous coronary intervention in patients with ST-elevation myocardial
infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA
2005; 294:1224.
27. ZM Chen et al. Addition of clopidogrel to aspirin in 45,852 patients
with acute myocardial infarction: randomised placebo-controlled trial.
Lancet 2005; 366:1607.
28. EM Antman et al. Enoxaparin versus unfractionated heparin with fibri-
nolysis for ST-elevation myocardial infarction. N Engl J Med 2006;
354:1477.
29. J Oldgren et al. Effects of fondaparinux in patients with ST-segment
elevation acute myocardial infarction not receiving reperfusion treat-
ment. Eur Heart J 2008; 29:315.
30. The Oasis-6 Trial Group. Effects of fondaparinux on mortality and rein-
farction in patients with acute ST-segment elevation myocardial infarc-
tion: the OASIS-6 randomized trial. JAMA2006; 295:1519.
31. RM Califf. Fondaparinux in ST-segment elevation myocardial infarc-
tion: the drug, the strategy, the environment or all of the above? JAMA
2006; 295:1579.
32. GWStone et al. Bivalirudin in patients with acute coronary syndromes
undergoing percutaneous coronary intervention: a subgroup analysis
from the Acute Catheterization and Urgent Intervention Triage strategy
(ACUITY) trial. Lancet 2007; 369:907.
33. EPISTENT Investigators. Randomised placebo-controlled and balloon-
angioplasty-controlled trial to assess safety of coronary stenting with
use of platelet glycoprotein-llb/llla blockade. Evaluation of Platelet
IIb/IIIa Inhibitor for Stenting. Lancet 1998; 352:87.
34. G Montalescot et al. Platelet glycoprotein IIb/IIIa inhibition with coro-
nary stenting for acute myocardial infarction. N Engl J Med 2001;
344:1895.
Indication Drugs
Primary Prevention
Risk Factors Aspirin
No Risk Factors None
1
Secondary Prevention
Recent MI Aspirin
2
Ischemic Stroke Aspirin + dipyridamole
UA/NSTEMI Aspirin + clopidogrel
+ UFH, enoxaparin,
fondaparinux or bivalirudin
Acute MI (STEMI) Aspirin plus clopidogrel
plus UFH, enoxaparin
or fondaparinux
3
PCI Aspirin plus clopidogrel
plus UFH, enoxaparin or
bivalirudin + GPIIb/IIIa
VTE Treatment LMWH, UFH or fondaparinux
plus warfarin
VTE Prevention
Hospitalized Medical Patients LMWH or UFH
General Surgery Low-dose UFH, LMWH or
fondaparinux
Hip Fracture Surgery Fondaparinux
Atrial Fibrillation Warfarin
Peripheral Arterial Disease Aspirin
1. Some clinicians offer aspirin to women >65 and men >45 years.
2. Or, if intolerant to aspirin, clopidogrel.
3. Fondaparinux should not be used in patients undergoing PCI.
Table 5. Antiplatelet and Anticoagulant Drugs
of Choice
35. A Kastrati et al. A clinical trial of abciximab in elective percutaneous
coronary intervention after pretreatment with clopidogrel. N Engl J
Med 2004; 350:232
36. ESPRIT. Novel dosing regimen of eptifibatide in planned coronary
stent implantation (ESPRIT): a randomized, placebo-controlled trial.
Lancet 2000; 356:2037.
37. EJ Topol et al. Comparison of two platelet glycoprotein IIb/IIIa
inhibitors, tirofiban and abciximab, for the prevention of ischemic
events with percutaneous coronary revascularization. N Engl J Med
2001; 344:1888.
38. DJ Moliterno et al. Outcomes at 6 months for the direct comparison of
tirofiban and abciximab during percutaneous coronary revasculariza-
tion with stent placement: the TARGET follow-up study. Lancet 2002;
360:355.
39. H Tran et al. Anticoagulant treatment of deep vein thrombosis and pul-
monary embolism. Clin Geriatr Med 2006; 22:113.
40. JB Segal et al. Management of venous thromboembolism: a systematic
review for a practice guideline. Ann Intern Med 2007; 146:211.
41. HR Bller, et al. Antithrombotic therapy for venous thromboembolic
disease. The Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004; 126 (3Suppl):401S.
42. C Kearon et al. Comparision of fixed-dose weight-adjusted unfraction-
ated heparin and low-molecular-weight heparin for acute treatment of
venous thromboembolism. JAMA2006; 296:935.
43. HR Bller et al. Fondaparinux or enoxaparin for the initial treatment of
symptomatic deep venous thrombosis: a randomized trial. Ann Intern
Med 2004; 140:867.
44. AY Lee et al. Low-molecular-weight heparin versus a coumarin for the
prevention of recurrent venous thromboembolism in patients with can-
cer. N Engl J Med 2003; 349:146.
45. BAHutton and MH Prins. Duration of treatment with vitamin K antag-
onists in symptomatic venous thromboembolism. Cochrane Database
Syst Rev 2006; (1):CD001367.
46. F Dentali et al. Meta-analysis: anticoagulant prophylaxis to prevent
symptomatic venous thromboembolism in hospitalized medical
patients. Ann Intern Med 2007; 146:278.
47. LWein et al. Pharmacological venous thromboembolism prophylaxis in
hospitalized medical patients: a meta-analysis of randomized controlled
trials. Arch Intern Med 2007; 167:1476.
48. WH Geerts et al. Prevention of venous thromboembolism: the Seventh
ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest 2004; 126(3 suppl):338S.
49. AG Turpie et al. Postoperative fondaparinux versus postoperative
enoxaparin for prevention of venous thromboembolism after elective
hip-replacement surgery: a randomised double-blind trial. Lancet 2002;
359:1721.
50. KA Bauer et al. Fondaparinux compared with enoxaparin for the pre-
vention of venous thromboembolism after elective major knee surgery.
N Engl J Med 2001; 345:1305.
51. BI Eriksson et al. Fondaparinux compared with enoxaparin for the pre-
vention of venous thromboembolism after hip-fracture surgery. N Engl
J Med 2001; 345:1298.
52. DAGarcia and EM Hylek. Antithrombotic therapy in atrial fibrillation.
Clin Geriatr Med 2006; 22:155.
53. RG Hart et al. Meta-analysis: antithrombotic therapy to prevent stroke
in patients who have nonvalvular atrial fibrillation. Ann Intern Med
2007; 146:857.
54. ACTIVE Writing Group of the ACTIVE investigators. Clopidogrel plus
aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibril-
lation Clopidogrel Trial with Irbesartan for prevention of Vascular Events
(ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903.
55. LC Ocava et al. Antithrombotic and thrombolytic therapy for ischemic
stroke. Clin Geriatr Med 2006; 22:135.
56. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of
randomised trials of antiplatelet therapy for prevention of death, myocar-
dial infarction, and stroke in high risk patients. BMJ 2002; 324:71.
57. Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral anti-
coagulant and antiplatelet therapy and peripheral arterial disease. N
Engl J Med 2007; 357:217.
36
Drugs for Epilepsy June 2008
ADVISORY BOARD:
EDITORIAL FELLOWS:
Western Ontario
Founded in 1959 by
Mailing Address:
1000 Main Street
Customer Service:
Call: 800-211-2769 or 914-235-0500
Fax: 914-632-1733
Permissions:
Subscriptions (US):
1 year - $98; 2 years - $167;
US and Canada.
800-211-2769 x315.
MISSION:
management.
1. Aspirin inhibits platelet activation and aggregation for:
a. 4-6 hours
b. 1-2 days
c. 5-7 days
d. 10-30 days
Page: 29
2. Clopidogrel is used more than ticlopidine because it is:
a. more effective
b. less toxic
c. less expensive
Page: 29
Issue 69 Questions
Introducing
3. Disadvantages of unfractionated heparin (UFH) compared to low
molecular weight heparins (LMWH) include:
a. a more variable anticoagulant response
b. higher cost
c. more renal toxicity
d. all of the above
Page: 29, 31
4. Advantages of UFH over LMWH include:
a. rapidly neutralizable anticoagulant effect
b. not cleared by kidneys
c. may be more effective in preventing thrombi
caused by catheters
d. all of the above
Page: 31
5. Unlike heparins and fondaparinux, direct thrombin
inhibitors such as bivalirudin:
a. can cause thrombocytopenia
b. can be given orally
c. have a long half-life
d. inhibit clot-bound as well as circulating thrombin
Page: 31
6. In patients with coronary artery disease, aspirin prophylaxis
reduces the incidence of myocardial infarction and/or death by
a. <5%
b. 15-20%
c. 50%
d. >50%
Page: 31
7. Current guidelines recommend treating patients with
UA/NSTEMI with:
a. aspirin
b. aspirin plus an anticoagulant
c. aspirin plus clopidogrel
d. aspirin plus clopidogrel plus an anticoagulant
Page: 32
8. Patients who undergo an elective PCI are usually treated with:
a. aspirin plus an anticoagulant
b. aspirin plus clopidogrel
c. aspirin plus clopidogrel plus an anticoagulant
Page: 33
9. Some high-risk patients undergoing PCI may benefit
from addition of:
a. a GPIIb/IIIa inhibitor
b. fondaparinux
c. dipyridamole
Page: 33
10. VTE could be treated with:
a. fixed-dose weight-based subcutaneous UFH
b. enoxaparin
c. fondaparinux
d. any of the above
Page: 33,34
11. Prophylactic anticoagulation of hospitalized medical
patients confined to bed:
a. has been shown to prevent DVT and PE
b. has not been shown to prevent DVT and PE
c. does not increase the risk of bleeding
Page: 34
12. To reduce the risk of thromboembolic stroke in patients
with atrial fibrillation:
a. aspirin is as effective as anticoagulation
b. aspirin plus clopidogrel is as effective as anticoagulation
c. warfarin is more effective than aspirin alone or with
clopidogrel
d. neither antiplatelet therapy nor anticoagulation
is indicated
Page: 34
ACPE UPN: 379-000-08-069-H01-P
Drugs for Epilepsy
Tables
1. Cost of Some Antiepileptic Drugs Page 38
2. Treatment of Seizures Page 40
3. Some Interactions Between Page 42
Antiepileptic Drugs
Volume 6 (Issue 70) June 2008
Treatment of epilepsy should begin with a single drug,
increasing the dosage gradually until seizures are con-
trolled or adverse effects become unacceptable. If
seizures continue and further dosage increases appear
inadvisable because of adverse effects, most Medical
Letter consultants generally prescribe at least one and
sometimes a second alternative drug as monotherapy
before considering use of two drugs at the same time.
Most antiepileptic drugs initially approved by the FDA
only as adjunctive therapy for partial seizures may also
be effective for other types of seizures and as monother-
apy.
1,2
Studies suggest that when used for the appropri-
ate seizure type, antiepileptic drugs are roughly
equivalent in efficacy.
1-4
The choice of a drug is usually
based on factors such as ease of use, adverse effects and
cost.
The treatment of status epilepticus is not included here.
Most of the interactions between antiepileptics and
other drugs are also not included here; they can be
found in The Medical Letters Adverse Drug
Interactions Program.
CARBAMAZEPINE Carbamazepine (Tegretol,
and others) is available only for oral use. It is particu-
larly effective for treatment of partial and secondarily
generalized tonic-clonic seizures, but may make
absence or myoclonic seizures worse. Carbamazepine
induces its own metabolism; serum concentrations
often fall after a few weeks of treatment. Therapeutic
failure associated with poor bioavailability has been
reported with carbamazepine tablets, both generic and
Tegretol, particularly when they are stored in humid
conditions, which cause concretion of the tablets.
Carbamazepine is also FDA-approved for bipolar dis-
order under the trade name Equetro.
5
Adverse Effects Carbamazepine can cause drowsi-
ness, blurred vision, diplopia, headache, dizziness,
ataxia, nausea and vomiting. Cognitive effects can
interfere with learning. CNS adverse effects may
decrease with use of an extended-release formulation.
6
Mild leukopenia and hyponatremia are fairly common.
With high doses of the drug, thrombocytopenia can
occur, but is usually reversible if the drug is discontin-
ued. Aplastic anemia, agranulocytosis, cardiac toxic-
ity, aseptic meningitis, intractable diarrhea, and
hepatitis are rare. Circulating concentrations of thyroid
hormones may be depressed even though TSH remains
normal. Abnormal color perception can occur rarely.
Carbamazepine can cause rash, particularly with high
starting doses or rapid dose escalation. Severe reac-
tions, such as Stevens-Johnson syndrome (SJS), are
rare. The FDA recently recommended that Asian
patients, who have a ten-fold higher incidence of car-
bamazepine-induced SJS compared to other ethnic
groups, be tested for susceptibility to SJS before start-
ing the drug. The basis for this recommendation was
the finding of an association in a Chinese population
between the human leukocyte antigen (HLA)-B*1502
allele and carbamazepine-induced SJS.
7
This allele
occurs almost exclusively in Asians (but Caucasians
without HLA-B*1502 can also develop SJS with car-
bamazepine).
8,9
The test for the allele should be avail-
able in most clinical chemistry labs.
CLONAZEPAM Clonazepam (Klonopin, and oth-
ers) is a benzodiazepine used to treat myoclonic, atonic
and absence seizures resistant to treatment with other
antiepileptic drugs. It is generally less effective for
absence seizures than ethosuximide or valproate, and
development of tolerance to its effects is common.
Adverse effects of clonazepam include drowsiness,
ataxia and behavior disorders. Withdrawal symptoms
can occur after abrupt discontinuation.
Drugs for Epilepsy
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 70) June 2008 38
Usual adult
Drug Oral formulations daily dosage Cost
1
Carbamazepine generic 200 mg tabs; 100 mg chewable 800-1600 mg $ 31.20
Tegretol (Novartis) tabs; 100 mg/5 mL susp 105.60
Tegretol XR (Novartis) 100, 200, 400 mg ER tabs 107.40
Carbatrol (Shire US) 100, 200, 300 mg ER caps 169.20
Clonazepam generic 0.5, 1, 2 mg tabs 1.5-8 mg 26.99
2
Klonopin (Roche Labs) 79.50
generic 0.125, 0.25, 0.5, 1, 2 mg 76.80
Klonopin Wafers disintegrating tabs 97.80
Ethosuximide generic 250 mg caps; 250 mg/5 mL syrup 750-1250 mg 104.40
Zarontin (Pfizer) 126.00
Felbamate Felbatol (MedPointe) 400, 600 mg tabs; 2400-3600 mg 306.00
600 mg/5 mL susp
Gabapentin generic 100, 300, 400 mg caps; 100, 1800-3600 mg 92.99
2
300, 400, 600, 800 mg tabs
Neurontin (Pfizer) 100, 300, 400, 800 mg caps; 306.90
600, 800 mg tabs;
250 mg/5 mL solution
Lamotrigine generic 5, 25 mg chewable tabs 100-500 mg 349.20
Lamictal (GlaxoSmithKline) 25, 100, 150, 200 mg tabs; 150.60
2, 5, 25 mg chewable tabs
Levetiracetam Keppra (UCB Pharma) 250, 500, 750, 1000 mg tabs; 1000-3000 mg 201.00
100 mg/mL solution
Oxcarbazepine generic 150, 300, 600 mg tabs 1200-2400 mg 260.40
Trileptal (Novartis) 150, 300, 600 mg tabs; 337.80
300 mg/5 mL susp
Phenobarbital generic 15, 30, 60, 100 mg tabs; 90-150 mg 2.06
3
20 mg/5 mL elixir
Phenytoin generic 100 mg caps; 100, 200, 300 mg 300-400 mg 31.99
2
ER caps; 125 mg/5 mL susp
Dilantin Kapseals, 30, 100 mg ER caps; 36.00
Dilantin-125, 125 mg/5 mL susp;
Dilantin Infatabs (Pfizer) 50 mg chewable tabs
Pregabalin Lyrica (Pfizer) 25, 50, 75, 100, 150, 200, 225, 150-600 mg 133.20
300 mg caps
Primidone generic 50, 250 mg tabs 750-1250 mg 72.90
Mysoline (Valeant) 385.20
Tiagabine Gabitril (Abbott) 2, 4, 12, 16 mg tabs 32-56 mg 381.60
Topiramate Topamax, 25, 50, 100, 200 mg tabs; 200-400 mg 372.60
Topamax Sprinkle (Ortho-McNeil 15, 25 mg caps
Neurologics)
Valproate
Valproic acid generic 250 mg caps; 250 mg/5 mL syrup 1000-3000 mg 35.96
2
Depakene (Abbott) 314.40
Divalproex sodium Depakote; 125, 250, 500 mg delayed- 1000-3000 mg 199.80
Depakote Sprinkle (Abbott) release tabs; 125 mg caps
Depakote ER (Abbott) 250, 500 mg ER tabs 1250-3500 mg 212.10
Zonisamide generic 25, 50, 100 mg caps 55.50
Zonegran (Eisai Pharma) 25, 50, 100 mg caps 100-400 mg 85.80
1. Cost for 30 days treatment with the lowest usual dosage, according to the most recent data (March 31, 2008) from retail pharmacies nationwide
available from Wolters Kluwer Health. Generic prices may vary widely. For example, 60 200-mg tablets of generic carbamazepine cost $4.00 at
Target and Wal-Mart.
2. Price at drugstore.com. Accessed May 5, 2008.
3. Price according to AWP listings in Price Alert, April 15, 2008.
Table 1. Cost of Some Antiepileptic Drugs
Drugs for Epilepsy
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 70) June 2008
ETHOSUXIMIDE Ethosuximide (Zarontin, and
others) is recommended for treatment of uncomplicated
absence seizures and is usually well tolerated. Its elim-
ination half-life is about 60 hours in adults, but only
about 30 hours in children.
Adverse effects may include nausea, vomiting,
lethargy, hiccups, headache and behavorial changes.
Psychotic behavior can occur. Hematologic abnormali-
ties, erythema multiforme, Stevens-Johnson syndrome
and systemic lupus erythematosus (SLE) have been
reported.
GABAPENTIN Gabapentin (Neurontin, and oth-
ers) is used for adjunctive therapy in adults and chil-
dren age >3 years old with partial and secondarily
generalized seizures and is also effective, but not
FDA-approved, as monotherapy for these same types
of seizures. Like carbamazepine, gabapentin can
exacerbate myoclonic seizures. Gabapentin is also
FDA-approved for treatment of post-herpetic neural-
gia and is used off-label for treatment of other types of
neuropathic pain and anxiety disorders and for
migraine prophylaxis.
Adverse Effects Adverse effects of gabapentin
include somnolence, dizziness, ataxia, fatigue, nystag-
mus, blurred vision and confusion. Gabapentin can
cause edema, weight gain and movement disorders;
there have been reports of behavioral changes in chil-
dren, especially in those with underlying behavioral or
developmental problems. Unlike some other antiepilep-
tic drugs, gabapentin does not induce or inhibit hepatic
microsomal enzymes, so it does not affect the metabo-
lism of other drugs taken concurrently.
LAMOTRIGINE Lamotrigine (Lamictal, and
others) is FDA-approved for adjunctive therapy in
adults and children >2 years old with partial seizures
or with generalized seizures of Lennox-Gastaut syn-
drome, and as monotherapy in adults with partial
seizures as a substitute for carbamazepine, phenytoin,
phenobarbital, primidone or valproate. It is also
approved for adjunctive treatment of primary general-
ized tonic-clonic seizures in patients >2 years old.
10,11
Some reports, however, suggest it can make
myoclonus worse, particularly in severe myoclonic
epilepsy of infancy. In patients with newly diagnosed
partial or generalized seizures, lamotrigine alone gen-
erally has been as effective as carbamazepine or
phenytoin, and better tolerated. In one study in eld-
erly patients (mean age 72) with newly diagnosed
epilepsy, lamotrigine (as well as gabapentin) was bet-
ter tolerated than carbamazepine and similar in
seizure control.
12
Lamotrigine can improve depres-
sion in some patients with epilepsy. It is also FDA-
approved for maintenance treatment of bipolar disor-
der.
Adverse Effects The most common adverse effects
of lamotrigine have been dizziness, ataxia, somno-
lence, headache, diplopia, nausea, vomiting, rash,
insomnia and incoordination. Acute hepatitis has been
reported. Life-threatening rashes including Stevens-
Johnson syndrome have occurred rarely, usually dur-
ing the first 2 months of use.
13
The risk may be
increased by high starting doses, rapid increases in
dosage or co-administration with valproate, which
increases lamotrigine levels more than 2-fold. The
manufacturer recommends discontinuing lamotrigine
at the first sign of rash. Lamotrigine causes fewer
adverse cognitive effects than carbamazepine or topi-
ramate.
14
Concurrent use of oral contraceptive agents
can decrease lamotrigine concentrations, which then
transiently increase if the contraceptive includes a
week of inactive tablets.
LEVETIRACETAM Levetiracetam (Keppra) is
FDA-approved as adjunctive therapy for adults and
children >4 years old with partial seizures, adults and
children >6 years old with primary generalized tonic-
clonic seizures, and adults and adolescents >12 years
old with myoclonic seizures.
15,16
It may also be effec-
tive in children with seizures of Lennox-Gastaut syn-
drome, and in absence seizures.
17,18
In a randomized,
double-blind study comparing levetiracetam monother-
apy with controlled-release carbamazepine in patients
with newly diagnosed epilepsy, seizure-free rates at 6
months were similar in both groups.
19
Levetiracetam is
available in both oral and IV formulations.
Adverse Effects Common adverse effects of leve-
tiracetam are dizziness, somnolence, weakness and irri-
tability. Behavioral changes, hallucinations and
psychosis have occurred,
20
and are more common in
patients with underlying psychiatric diagnoses. No life-
threatening adverse effects have been reported. Mild
decreases in hematocrit and white blood cell count,
which do not require discontinuation of the drug, occur
rarely. Levetiracetam is not an inhibitor or substrate of
CYP450 enzymes, and is expected to have few drug-
drug interactions. It also appears to have a low inci-
dence of cognitive effects.
21
OXCARBAZEPINE Oxcarbazepine (Trileptal,
and others) is chemically similar to carbamazepine but
causes less induction of hepatic enzymes. It is approved
by the FDA for treatment of partial seizures as
monotherapy or adjunctive therapy in adults and chil-
dren >4 years old, and as adjunctive therapy in children
2 to <4 years old. Like carbamazepine, oxcarbazepine
is also effective in secondarily generalized seizures, but
39
Antifungal Drugs
40
Drugs for Epilepsy
Total daily adult dosage* Total daily pediatric dosage* Usual dosing
Drugs Starting Maintenance Starting Maintenance interval
Primary Generalized Tonic-Clonic
Drugs of Choice:
Valproate
1,2
500-1000 mg 1000-3500 mg 10-15 mg/kg 15-60 mg/kg once/bid/tid
3
or Lamotrigine
5
12.5-50 mg
6
100-700 mg
6
0.15-0.6 mg/kg
7
1-15 mg/kg
7
bid
or Levetiracetam
8
500-1000 mg 1000-3000 mg 10-20 mg/kg 40-60 mg/kg bid
Some Alternatives:
Carbamazepine
1
200-400 mg 800-1800 mg 10-20 mg/kg 10-30 mg/kg bid/tid
Topiramate 25-50 mg 200-400 mg 1-3 mg/kg 5-9 mg/kg bid
Zonisamide
8
100 mg 100-600 mg 1-2 mg/kg
9
6-8 mg/kg
9
once/bid
Oxcarbazepine
8
Phenytoin
1
300-400 mg 300-400 mg
4
5 mg/kg 4-8 mg/kg once/bid
Partial, Including Secondarily Generalized
Drugs of Choice:
Carbamazepine
1
200-400 mg 800-1800 mg 10-20 mg/kg 10-30 mg/kg bid/tid
or Lamotrigine 12.5-50 mg
6
100-700 mg
6
0.15-0.6 mg/kg
7
1-15 mg/kg
7
bid
or Oxcarbazepine 300-600 mg 900-2400 mg 8-10 mg/kg 6-51 mg/kg bid
or Levetiracetam
10
Some Alternatives:
Topiramate 25-50 mg 200-400 mg 1-3 mg/kg 5-9 mg/kg bid
Valproate
1
3
Gabapentin
10
900-1200 mg 1800-6400 mg 10-15 mg/kg 25-40 mg/kg
11
tid
Zonisamide
10
100 mg 100-600 mg 1-2 mg/kg
9
6-8 mg/kg
9
once/bid
Phenytoin
1
300-400 mg 300-400 mg
4
5 mg/kg 4-8 mg/kg once/bid
Pregabalin
10
150 mg 150-600 mg bid/tid
Absence
Drugs of Choice:
Ethosuximide 500 mg 750-1500 mg 10-15 mg/kg 20-40 mg/kg bid
or Valproate
1
3
Alternatives:
Lamotrigine
8
12.5-50 mg
6
100-700 mg
6
0.15-0.6 mg/kg
7
1-15 mg/kg
7
bid
Clonazepam 1.5 mg 1.5-8 mg 0.01-0.03 mg/kg 0.05-0.2 mg/kg bid/tid
Zonisamide
8
100 mg 100-600 mg 1-2 mg/kg
9
6-8 mg/kg
9
once/bid
Levetiracetam
8
Atypical Absence, Myoclonic, Atonic
Drugs of Choice:
Valproate
1,2
3
or Lamotrigine
5
12.5-50 mg
6
100-700 mg
6
0.15-0.6 mg/kg
7
1-15 mg/kg
7
bid
or Levetiracetam
12
Alternatives:
Topiramate
13
Zonisamide
8
100 mg 100-600 mg 1-2 mg/kg
9
6-8 mg/kg
9
once/bid
Clonazepam 1.5 mg 1.5-8 mg 0.01-0.03 mg/kg 0.05-0.2 mg/kg bid/tid
Felbamate
13
600-800 mg 2400-4800 mg 15 mg/kg 15-60 mg/kg tid/qid
* Dosage may need to be adjusted for renal or hepatic impairment, or concomitant use of other drugs.
1. Measurement of serum concentrations may be useful to guide therapy. Usual therapeutic serum concentrations are: carbamazepine 6-12
mcg/mL, phenobarbital 15-35 mcg/mL, phenytoin 10-20 mcg/mL, valproate 50-120 mcg/mL. Some patients achieve complete seizure control
at lower concentrations, and occasional patients need higher concentrations.
2. Not FDA-approved unless absence is involved.
3. Once daily for the extended-release formulation (Depakote ER).
4. Adjustments in maintenance dosage above 300 mg/day for adults should usually be made in 25- or 30-mg increments because metabolism
becomes saturated.
5. FDA-approved for adjunctive therapy in adults and children >2 years old with partial seizures, with Lennox-Gastaut syndrome or with primary
generalized seizures, and as monotherapy in adults with partial seizures as a substitute for carbamazepine, phenytoin, phenobarbital or val-
proate.
6 . Starting dosage is 25 mg every other day and maintenance dosage is 100 to 400 mg daily when given with valproate.
7. Starting dosage is 0.15 mg/kg daily and maintenance dosage is 1 to 5 mg/kg daily when given with valproate.
9. Not FDA-approved for pediatric use.
10. Only FDA-approved for adjunctive therapy.
11. For children more than 5 years old, 25 to 35 mg/kg/day. For children 3-4 years old, 40 mg/kg/day.
12. FDA-approved as adjunctive therapy for patients 12 years and older with myoclonic seizures.
13. FDA-approved as adjunctive therapy for patients with Lennox-Gastaut syndrome.
Table 2. Treatment of Seizures
may worsen myoclonic and absence seizures.
Oxcarbazepine has been as effective as phenytoin, car-
bamazepine or valproate in treatment of partial
seizures, and is better tolerated.
1
Most of its clinical
effect is due to the 10-monohydroxy metabolite
(MHD), which has a half-life of 8-10 hours, and is
reduced in concentration in the presence of hepatic
enzyme-inducing drugs such as phenobarbital, pheny-
toin or carbamazepine. Oxcarbazepine is used off-label
for treatment of bipolar disorder.
Adverse Effects Common adverse effects of oxcar-
bazepine are somnolence, dizziness, diplopia, ataxia,
nausea and vomiting. Stevens-Johnson syndrome and
toxic epidermal necrolysis have occurred, and multi-
organ hypersensitivity reactions have been reported.
Cross-reactivity with carbamazepine hypersensitivity
occurs in 20-30% of patients. Hyponatremia is more
common with oxcarbazepine than with carba-
mazepine. Unlike carbamazepine, oxcarbazepine
does not cause induction of its own metabolism.
PHENYTOIN Phenytoin (Dilantin, and others) is
as effective as carbamazepine for treatment of partial
and secondarily generalized tonic-clonic seizures.
Different formulations of phenytoin may not be bio-
equivalent, especially at higher doses. Fosphenytoin
(Cerebyx, and others) is a water-soluble prodrug of
phenytoin available for IV and IM use. Phenytoin is
no longer considered a drug of first choice due to its
complicated pharmacokinetics, inferior adverse effect
profile, and frequent drug-drug interactions.
Adverse Effects Nystagmus may occur with thera-
peutic serum concentrations of phenytoin and is usu-
ally present at higher concentrations. Drowsiness,
ataxia and diplopia are more likely to occur at total
serum concentrations higher than 20 mcg/mL, but can
also occur at lower levels, particularly in patients with
low serum albumin levels and in the elderly. Cerebellar
atrophy has been reported even after acute intoxica-
tion. Gingival hyperplasia, coarsening of facial fea-
tures and hirsutism can be troublesome. A
morbilliform or scarlatiniform rash may occur, usually
in the first four weeks of treatment, sometimes with
hepatitis, fever and lymphadenopathy; rarely it pro-
gresses to exfoliative dermatitis or Stevens-Johnson
syndrome. Patients who develop hypersensitivity reac-
tions to phenytoin are often susceptible to similar reac-
tions with carbamazepine and phenobarbital.
Phenytoin may interfere with cognitive function
related to learning.
Less common adverse effects include megaloblastic
anemia, a lupus-like syndrome, hepatic granulomas,
hepatitis leading rarely to fatal hepatic necrosis,
peripheral neuropathy, and nephritis. Serum folic acid,
thyroxine and vitamin K concentrations may decrease
with long-term therapy. Fosphenytoin is less likely to
cause soft tissue injury than older IVformulations, but
at rapid infusion rates it can cause transient paresthe-
sias and pruritus.
PREGABALIN Pregabalin (Lyrica) is FDA-
approved for adjunctive treatment of partial seizures in
adults.
22
Its structural similarity to gabapentin suggests
it will not be useful in the treatment of absence or
myoclonic seizures. Pregabalin is also FDA-approved
for treatment of neuropathic pain and fibromyalgia;
23
it
is approved in Europe for treatment of generalized
anxiety disorder.
Adverse Effects Among the more common adverse
effects of pregabalin in clinical trials were somnolence,
dizziness, ataxia, weight gain, dry mouth, blurred
vision, peripheral edema and confusion. Newly devel-
oped myoclonus has been reported in patients with
epilepsy taking pregabalin.
24
As with gabapentin, it has
no significant drug-drug interactions. Pregabalin is a
schedule V controlled substance because it caused
euphoria in some clinical trials.
TOPIRAMATE Topiramate (Topamax) is
approved for partial and primary generalized tonic-
clonic seizures as monotherapy for patients >10 years
old and as adjunctive therapy in adults and children >2
years old. It is also approved for Lennox-Gastaut syn-
drome as adjunctive therapy for children >2 years old
and is effective in atonic seizures in children.
Topiramate is also FDA-approved for migraine pro-
phylaxis.
25
Adverse Effects The most frequent adverse effects
of topiramate are drowsiness, dizziness, headache and
ataxia. Nervousness, confusion, paresthesias, weight
loss and diplopia can occur. Psychomotor slowing,
word-finding difficulty, impaired concentration, and
interference with memory are common, particularly
with rapid dose escalation and higher maintenance
doses, and may require dosage reduction or stopping
the drug.
26
Acute myopia associated with secondary
angle closure glaucoma, which is infrequent but
severe, typically occurs within one month of starting
treatment. Liver failure, oligohidrosis, hyperthermia
and heat stroke have been reported. Renal stones have
occurred due to metabolic acidosis caused by inhibi-
tion of carbonic anhydrase.
VALPROATE Valproate, which is marketed as
valproic acid (Depakene, and others) and divalproex
sodium (Depakote), is approved by the FDA for
monotherapy and adjunctive treatment of complex
Antifungal Drugs
41
Drugs for Epilepsy
Interacting Drugs Effects (Probable Mechanism) Management
Carbamazepine, with:
Clonazepam Decreased clonazepam effect Monitor clinical status
(increased metabolism)
Lamotrigine Carbamazepine toxicity Monitor clinical status; serum carbamazepine
(mechanism not established) measurements alone may not predict toxicity
Decreased lamotrigine effect Lamotrigine dosage may need to be adjusted;
(increased metabolism; glucuronidation) monitor lamotrigine concentration and clinical status
Levetiracetam Possible increased risk of carbamazepine Monitor for clinical evidence of carbamazepine
toxicity (mechanism not established) toxicity
Oxcarbazepine Possible decreased oxcarbazepine effect Monitor oxcarbazepine concentrations and clinical
(increased metabolism) status
Phenytoin Decreased carbamazepine effect Monitor carbamazepine and phenytoin concentra-
(increased metabolism) tions
Altered phenytoin effect
(mechanism not established)
Tiagabine Decreased tiagabine effect Monitor clinical status
Topiramate Possible decreased topiramate effect Monitor topiramate concentrations and clinical
(increased metabolism) status; may need higher doses of topiramate
Valproate Decreased valproate effect and possible Monitor valproate concentrations and clinical status
increased toxicity (increased metabolism
and formation of toxic metabolite)
Carbamazepine toxicity Monitor carbamazepine and carbamazepine epoxide
(decreased metabolism of carbamazepine concentrations
epoxide and displacement from binding)
Zonisamide Decreased zonisamide effect Monitor zonisamide concentrations and clinical
(increased metabolism by CYP3A4) status; zonisamide dosage may need to be
adjusted
Phenytoin, with:
Carbamazepine Decreased carbamazepine effect Monitor carbamazepine and phenytoin concentra-
(increased metabolism) tions
Altered phenytoin effect
Clonazepam Decreased clonazepam effect Monitor clonazepam effect or concentrations
Variable effects on phenytoin concentrations Monitor phenytoin concentrations
Lamotrigine Decreased lamotrigine serum concentrations Monitor lamotrigine serum concentrations and
(increased metabolism; induction of clinical status; lamotrigine dosage may need
glucuronidation by phenytoin) to be adjusted
Oxcarbazepine Possible decreased oxcarbazepine effect Monitor clinical status and serum concentration
Possible phenytoin toxicity with oxcarbazepine Monitor phenytoin concentrations especially when
doses of 1200 mg/day or higher oxcarbazepine dosage is 1200 mg/day or higher
(decreased metabolism)
Tiagabine Decreased tiagabine effect Monitor clinical status
Topiramate Possible decreased topiramate effect Monitor topiramate concentrations and clinical
(increased metabolism) status; may need to increase topiramate dose
Possible phenytoin toxicity Monitor phenytoin concentrations and clinical
(decreased metabolism by CYP2C19) status
Valproate Possible phenytoin toxicity Monitor phenytoin concentrations and clinical
(displacement from binding) status (unbound concentrations may be more
helpful than total)
Possible decreased valproate effect and Monitor clinical status and valproate serum
increased toxicity (increased metabolism concentrations
Zonisamide Decreased zonisamide effect Monitor zonisamide concentrations and clinical
(increased metabolism by CYP3A4) status; zonisamide dosage may need to be
adjusted
Table 3. Some Interactions Between Antiepileptic Drugs*
Drugs for Epilepsy
Drugs for Epilepsy
partial seizures and absence seizures and as adjunc-
tive therapy for multiple seizure types that involve
absence. The drug is also available in an IV formula-
tion (Depacon). Because it is effective and usually
well tolerated, valproate is widely used for myoclonic,
atonic and primary generalized tonic-clonic seizures.
4
It is highly effective in treating photosensitive
epilepsy and juvenile myoclonic epilepsy. In one con-
trolled trial, valproate was less effective than carba-
mazepine in controlling complex partial seizures, but
equally effective in controlling secondarily general-
ized seizures.
27
Aonce-daily extended-release formu-
lation (Depakote ER) is as effective as Depakote. It is
not bioequivalent to older formulations, so when
switching from valproate capsules or delayed-release
tablets to Depakote ER, the daily dosage should be
increased by 8-20%. Valproate is also FDA-approved
for migraine prophylaxis and bipolar disorder.
Adverse Effects Drowsiness due to valproate is usu-
ally mild and transient, and adverse cognitive effects
are generally minimal. Nausea and vomiting can be
reduced by using the enteric-coated formulation
(Depakote), by taking the drug with food, and by slow
titration to an optimal dose. Weight gain is common in
patients taking valproate, and has been associated with
polycystic ovary syndrome, hyperinsulinemia, lipid
abnormalities, hirsutism and menstrual disturbances in
women, and with increased serum androgen concentra-
43
tions in men. Dose-related tremor, transient hair thin-
ning and loss, decreased platelet function, and throm-
bocytopenia can also occur.
Serious adverse effects of the drug are uncommon, but
fatal liver failure has occurred, particularly in children
less than two years old taking valproate in combina-
tion with other antiepileptic drugs and in patients with
developmental delay and metabolic disorders; liver
failure has also been reported in older children and
adults taking valproate alone. Valproate can interfere
with conversion of ammonia to urea. It can cause
lethargy associated with increased blood ammonia
concentrations and fatal hyperammonemic encephalo-
pathy has occurred in patients with genetic defects in
urea metabolism; the drug is contraindicated in these
patients. Life-threatening pancreatitis, interstitial
nephritis, reversible parkinsonism and edema requir-
ing diuretics for control have occurred rarely.
Valproate has fewer drug interactions than carba-
mazepine or phenytoin.
ZONISAMIDE Zonisamide (Zonegran, and others)
is approved for adjunctive treatment of partial seizures
in adults with epilepsy. Despite the limited indication
approved by the FDA, it appears to have a broad spec-
trum of activity (infantile spasms; myoclonic, general-
ized and atypical absence seizures), and there is
Interacting Drugs Effects (Probable Mechanism) Management
Valproate, with:
Carbamazepine Decreased valproate effect and Monitor valproate concentrations and clinical
possible increased toxicity status
(increased metabolism and formation
of toxic metabolite)
Carbamazepine toxicity Monitor carbamazepine and carbamazepine
(decreased metabolism of carbamazepine epoxide concentrations
epoxide and displacement from binding)
Clonazepam Clonazepam may precipitate absence status Monitor clinical status
Ethosuximide Possible ethosuximide toxicity Monitor ethosuximide concentration
(decreased metabolism)
Possible decreased valproate effect Monitor valproate concentration
Lamotrigine Possible lamotrigine toxicity Decrease lamotrigine dose; monitor lamotrigine
(decreased metabolism; glucuronidation) concentrations and clinical status
Oxcarbazepine Possible decreased oxcabazepine Monitor oxcarbazepine concentrations and
concentration (increased metabolism) clinical status
Phenytoin Phenytoin toxicity (displacement from binding Monitor phenytoin concentrations and clinical
and decreased metabolism) status (unbound concentrations may be more
helpful than total)
Possible decreased valproate effect and Monitor clinical status and valproate serum
increased toxicity (increased metabolism concentrations
Topiramate Possible increased hepatotoxic effect of Monitor clinical status
valproate (mechanism not established)
*See The Medical Letters Adverse Drug Interactions Program, which also includes references, for additional interactions between antiepileptic
drugs.
Table 3. Some Interactions Between Antiepileptic Drugs* (contd)
(n=16,029). The overall incidence was extremely low,
and its clinical significance is questionable.
32
BONE DENSITY Evidence suggests that prolonged
use of antiepileptic drugs, particularly those that result
in enzyme induction (phenytoin, carbamazepine, phe-
nobarbital, primidone), may increase the risk of osteo-
porosis.
33,34
Valproate, which does not induce hepatic
enzymes, has also been associated with decreases in
bone mineral density.
35
ANTIEPILEPTIC DRUGS AND PREGNANCY
Most pregnant patients exposed to antiepileptic drugs
deliver normal infants,
36
but fetal exposure to older
anticonvulsants has been associated with congenital
anomalies, including oral cleft and cardiac, urinary
tract and neural tube defects. Valproate and phenobar-
bital may have the highest risk of major malforma-
tions.
37
Children exposed to valproate in utero have
been reported to have lower IQs.
38
Available data, mainly from pregnancy registries, sug-
gest that carbamazepine, lamotrigine, and phenytoin
have lower rates of major malformations than do val-
proate and phenobarbital. Clinical data regarding the
teratogenicity of other newer antiepileptic drugs is less
clear.
39
In animals, tiagabine, levetiracetam, zon-
isamide, oxcarbazepine and pregabalin were terato-
genic only at high doses, while gabapentin and
topiramate were teratogenic at treatment doses.
Topiramate has been associated with hypospadias in
male infants. In pregnancy registries, the overall risk of
major malformations with lamotrigine, which is not ter-
atogenic in animals, has been no higher than that in the
general population.
40
However, the FDA has issued a
warning about a possible increased risk of cleft lip or
cleft palate in babies exposed to lamotrigine during the
first trimester of pregnancy; the oral cleft prevalence
rate was 8.9/1000 pregnant women on lamotrigine
monotherapy compared with an expected rate of 0.5-
2.16/1000 in the general population.
41
Valproate and
phenobarbital should be avoided if possible in women
who are planning to become pregnant.
All agents should be used in monotherapy at the lowest
dose possible; the risk to offspring is generally consid-
ered to be less than the risk of seizures during preg-
nancy. The metabolism of antiepileptic drugs is induced
during pregnancy, particularly lamotrigine; levels of
lamotrigine should be followed closely.
39
Prophylactic use of folic acid is recommended for all
women of childbearing age because it has decreased the
incidence of neural tube defects, but it may not be pro-
tective in women who take antiepileptic drugs during
pregnancy.
42
Use of phenytoin, phenobarbital, primi-
Drugs for Epilepsy
considerable experience worldwide with its use in chil-
dren, as monotherapy, and for other seizure types.
28,29
Adverse Effects Adverse effects are usually tran-
sient and self-limited and include somnolence, dizzi-
ness, confusion, anorexia, nausea, diarrhea, weight
loss, agitation, irritability and rash. Fatal Stevens-
Johnson syndrome and toxic epidermal necrolysis
have been reported. Oligohidrosis, hyperthermia and
heat stroke have occurred in children. Psychosis,
aplastic anemia and agranulocytosis have also been
reported. Slow titration and dosing with meals may
decrease the incidence of adverse effects. Zonisamide
is a mild carbonic anhydrase inhibitor and has
increased the incidence of symptomatic renal stones.
It does not inhibit the metabolism of drugs metabo-
lized by CYP450 isozymes. Drugs that induce or
inhibit CYP3A4 could alter serum concentrations of
zonisamide.
RARELY USED DRUGS Felbamate (Felbatol)
is approved for partial and secondarily generalized
seizures, and for seizures associated with the Lennox-
Gastaut syndrome in patients who have failed other
drugs. There is an appreciable risk of aplastic anemia
and hepatic failure, estimated at about 1:3000-5000
patients. Phenobarbital and primidone (Mysoline,
and others) are effective for partial and secondarily
generalized tonic clonic seizures. They have a higher
incidence of sedation compared to other drugs,
although phenobarbital is still commonly used in chil-
dren and for status epilepticus. Tiagabine (Gabitril) is
approved only for adjunctive treatment of partial
seizures, and is associated with gastrointestinal and
central nervous system adverse effects. Off-label use
(for bipolar disorder, anxiety and neuropathic pain)
has been associated with new-onset seizures.
30
RECTAL DIAZEPAM Rectal administration of
diazepam gel (Diastat AcuDial) is approved for inter-
mittent use in the treatment of increased seizure activ-
ity in patients taking other antiepileptic drugs. When
given per rectum, diazepam is rapidly and completely
absorbed. Diastat AcuDial is supplied as a prefilled
syringe with either 10 mg (which can be used to deliver
5, 7.5 or 10 mg) or 20 mg (which can be used to deliver
10, 12.5, 15, 17.5 or 20 mg) for single-dose adminis-
tration by the caregiver. At-home use of rectal
diazepam in children may help terminate seizure activ-
ity and reduce emergency room visits.
31
SUICIDALITY The FDA released a report in early
2008 that suggested an increased risk of suicidal behav-
ior and ideation in patients taking most antiepileptic
drugs: 0.43% of patients on antiepileptic drugs
(n=27,863) compared to 0.22% of those on placebo
44
Drugs for Epilepsy
done and carbamazepine can cause hemorrhage in the
newborn infant due to vitamin K deficiency, and vita-
min K supplementation is recommended for the mother
in the final month of pregnancy and for the newborn,
although some data suggest that supplementation of the
mother may not be necessary.
43
GENERIC SUBSTITUTION OF BRAND-NAME
DRUGS Generic versions of many antiepileptic
drugs are now available. In general, generic drugs offer
a lower-cost alternative containing the same active com-
pound and are roughly bioequivalent. With many
antiepileptic drugs, unlike drugs used to treat other con-
ditions, there is a relatively narrow therapeutic window
between the effective dose and toxicity. In addition, the
effects of an unrecognized fall in serum concentrations
a seizure in an otherwise controlled individual can be
devastating. The American Academy of Neurology has
issued a position statement recommending that generic
substitution in epilepsy be undertaken with caution, with
the knowledge of both the prescribing physician and the
patient.
44
If possible, prescription refills should come
from the same manufacturer.
1. JA French et al. Efficacy and tolerability of the new
antiepileptic drugs I: treatment of new onset epilepsy: report
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Subcommittee and Quality Standards Subcommittee of the
American Academy of Neurology and the American Epilepsy
Society. Neurology 2004; 62:1252.
2. JA French et al. Efficacy and tolerability of the new
antiepileptic drugs II: treatment of refractory epilepsy:
report of the Therapeutics and Technology Assessment
Subcommittee and Quality Standards Subcommittee of the
American Academy of Neurology and the American
Epilepsy Society. Neurology 2004; 62:1261.
3. AG Marson et al. The SANAD study of effectiveness of car-
bamazepine, gabapentin, lamotrigine, oxcarbazepine, or
topiramate for treatment of partial epilelpsy: an unblinded
randomised controlled trial. Lancet 2007; 369:1000.
4. AG Marson et al. The SANAD study of effectiveness of val-
proate, lamotrigine, or topiramate for generalised and
unclassifiable epilepsy: an unblinded randomised controlled
trial. Lancet 2007; 369:1016.
5. Extended-release carbamazepine (Equetro) for bipolar dis-
order. Med Lett Drugs Ther 2005; 47:27.
6. DM Ficker et al. Improved tolerability and efficacy in
epilepsy patients with extended-release carbamazepine.
Neurology 2005; 65:593.
7. WH Chung et al. Medical genetics: a marker for Stevens-
Johnson syndrome. Nature 2004; 428:486.
8. C Lonjou et al. A marker for Stevens-Johnson syndrome:
ethnicity matters. Pharmacogenomics J 2006; 6:265.
9. A Alfirevic et al. HLA-B locus in Caucasian patients with carba-
mazepine hypersensitivity. Pharmacogenomics 2006; 7:813.
10. V Biton et al. Double-blind, placebo-controlled study of lam-
otrigine in primary generalizad tonic-clonic seizures.
Neurology 2005; 65:1737.
11. E Trevathan et al. Lamotrigine adjunctive therapy among
children and adolescents with primary generalizad tonic-
clonic seizures. Pediatrics 2006; 118:e371.
45
12. AJ Rowan et al. New onset geriatric epilepsy: a randomized
study of gabapentin, lamotrigine, and carbamazepine.
Neurology 2005; 64:1868.
13. M Mockenhaupt et al. Risk of Stevens-Johnson syndrome
and toxic epidermal necrolysis in new users of antiepilep-
tics. Neurology 2005; 64:1134.
14. D Blum et al. Cognitive effects of lamotrigine compared with
topiramate in patients with epilepsy. Neurology 2006;
67:400.
15. SF Berkovic et al. Placebo-controlled study of levetiracetam
in idiopathic generalized epilepsy. Neurology 2007;
69:1751.
16. S Noachtar et al. Levetiracetam for the treatment of idio-
pathic generalized epilepsy with myoclonic seizures.
Neurology 2008; 70:607.
17. EC De Los Reyes. Levetiracetam in the treatment of
Lennox-Gastaut syndrome. Pediatric Neurol 2004; 30:254.
18. J Cavitt and M Privitera. Levetiracetam induces a rapid and
sustained reduction of generalized spike-wave and clinical
absence. Arch Neurol 2004; 61:1604.
19. MJ Brodie et al. Comparison of levetiracetam and con-
trolled-release carbamazepine in newly diagnosed
epilepsy. Neurology 2007; 68:402.
20. JR White et al. Discontinuation of levetiracetam because of
behavioral side effects: a case-control study. Neurology
2003; 61:1218.
21. KJ Meador et al. Neuropsychological and neurophysiologic
effects of carbamazepine and levetiracetam. Neurology
2007; 69:2076.
22. Pregabalin (Lyrica) for neuropathic pain and epilepsy. Med
Lett Drugs Ther 2005; 47:75.
23. Pregabalin (Lyrica) for fibromyalgia. Med Lett Drugs Ther
2007; 49:77.
24. HJ Huppertz et al. Myoclonus in epilepsy patients with anti-
convulsive add-on therapy with pregabalin. Epilepsia 2001;
42:790.
25. Topiramate (Topamax) for prevention of migraine. Med Lett
Drugs Ther 2005; 47:9.
26. AP Aldenkamp et al. A multicenter, randomized clinical
study to evaluate the effect on cognitive function of topira-
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mazepine in patients with partial-onset seizures. Epilepsia
2000; 41:1167.
27. RH Mattson et al. A comparison of valproate with carba-
mazepine for the treatment of complex partial seizures and
secondarily generalized tonic-clonic seizures in adults. N
Engl J Med 1992; 327:765.
28. T Seki et al. Effects of zonisamide monotherapy in children
with epilepsy. Seizure 2004; 13 suppl 1:S26.
29. T Yamauchi and H Aikawa. Efficacy of zonisamide: our
experience. Seizure 2004; 13 suppl 1:S41.
30. CM Flowers et al. Seizure activity and off-label use of
tiagabine. N Engl J Med 2006; 354:773.
31. C ODell et al. Rectal diazepam gel in the home manage-
ment of seizures in children. Pediatr Neurol 2005; 33:166.
32. Information for Healthcare Professionals. Suicidality and
antiepileptic drugs. FDA Alert, January 31, 2008. Available
at www.fda.gov/cder/drug/InfoSheets/HCP/antiepileptics
HCP.htm
33. AM Pack et al. Bone mass and turnover in women with
epilepsy on antiepileptic drug monotherapy. Ann Neurol
2005; 57: 252.
34. SJ Petty et al. Effect of antiepileptic medication on bone
mineral measures. Neurology 2005; 65:1358.
Drugs for Epilepsy
Drugs for Diabetes July 2008
ADVISORY BOARD:
EDITORIAL FELLOWS:
Western Ontario
Founded in 1959 by
Mailing Address:
1000 Main Street
Customer Service:
Call: 800-211-2769 or 914-235-0500
Fax: 914-632-1733
Permissions:
Subscriptions (US):
1 year - $98; 2 years - $167;
US and Canada.
800-211-2769 x315.
35. AM Pack et al. Bone disease associated with antiepileptic

drugs. Cleveland Clinic Journal of Medicine 2004; 71 suppl
2:S42.
36. WO Tatum et al. Updates on the treatment of epilepsy in
women. Arch Intern Med 2004; 164:137.
37. DF Wyszynski et al. Increased rate of major malformations
in offspring exposed to valproate during pregnancy.
Neurology 2005: 64:961.
38. KJ Meador et al. Cognitive/behavioral teratogenetic effects
of antiepileptic drugs. Epilepsy Behav 2007; 11:292.
39. CL Harden. Pregnancy and epilepsy. Semin Neurol 2007;
27:453.
40. J Messenheimer et al. Fifteen year interim results from an
international observational study of pregnancy outcomes
following exposure to lamotrigine. American Academy of
Neurology 60th Annual Meeting. April 12-19, 2008,
Chicago, IL, Abstract S10.002. Available at
www.aan.com/go/am. Accessed May 5, 2008.
41. Information for healthcare professionals. Lamotrigine (mar-
keted as Lamictal). FDA Alert. [9/2006] Updated January
31, 2008. Available at www.fda.gov/cder/drug/
infosheets/hcp/lamotriginehcp.htm. Accessed May 5, 2008.
42. MS Yerby. Management issues for women with epilepsy:
neural tube defects and folic acid supplementation.
Neurology 2003; 61 (6 suppl 2):S23.
43. E Kaaja et al. Enzyme-inducing antiepileptic drugs in preg-
nancy and the risk of bleeding in the neonate. Neurology
2002; 58:549.
44. K Liow et al. Position statement on the coverage of anticon-
vulsant drugs for the treatment of epilepsy. Neurology
2007; 68:1249.
MISSION:
management.
1. Drawbacks of carbamazepine include:
a. may make absence or myoclonic seizures worse
b. induces it own metabolism
c. cognitive effects
d. all of the above
Page: 37
2. Clonazepam is a:
a. barbiturate
b. CNS stimulant
c. second-line drug
Page:37
Issue 70 Questions
Introducing
3. Ethosuximide is recommended for treatment of:
a. absence seizures
b. partial seizures
c. secondarily generalized seizures
d. generalized tonic-clonic seizures
Page: 39
4. Gabapentin is used for:
a. adjunctive therapy of partial seizures
b. absence seizures
c. myoclonic seizures
d. all of the above
Page: 39
5. Compared to carbamazepine in patients with newly
diagnosed seizures, lamotrigine has been:
a. less effective
b. better tolerated
c. more effective
d. less well tolerated
Page: 39
6. Levetiracetam causes:
a. few drug interactions
b. a low incidence of cognitive effects
c. no life-threatening adverse effects
d. all of the above
Page: 39
7. Compared to phenytoin, carbamazepine or valproate,
oxcarbazepine is:
a. better tolerated
b. more effective
c. less effective
d. not as well tolerated
Page: 40
8. Phenytoin is:
a. still the drug of choice for generalized seizures
b. better tolerated than most antiepileptic drugs
c. no longer considered a drug of choice
Page: 41
9. Valproate is:
a. safe in pregnancy
b. not available generically
c. effective and usually well tolerated
Page: 43
10. Which of the following is common with valproate?
a. gingival hyperplasia
b. cognitive effects
c. pancreatitis
d. weight gain
Page: 43
11. Most women exposed to antiepileptic drugs
during pregnancy deliver normal infants, but
major malformations can occur. The highest risk
appears to be with:
a. valproate and phenobarbital
b. carbamazepine and phenytoin
c. lamotrigine and carbamazepine
d. phenytoin and lamotrigine
Page: 44
12. The American Academy of Neurology has recommended
that generic antiepileptic drugs be used:
a. in preference to brand name drugs
b. not at all
c. cautiously
d. as little as possible
Page: 45
ACPE UPN: 379-000-08-070-H01-P
Drugs for Type 2 Diabetes
Tables
1. Drugs for Type 2 Diabetes Mellitus Page 48-49
2. Some Insulin Products Page 50-51
Volume 6 (Issue 71) July 2008
The development of hyperglycemia in type 2 diabetes
results from a combination of metabolic abnormali-
ties including insulin resistance, diminished insulin
secretion and excess hepatic glucose production.
Diet, exercise and weight loss are helpful in improv-
ing glucose control, but most patients ultimately
require drug therapy.
BIGUANIDES Metformin (Glucophage, and oth-
ers), the only biguanide marketed in the US, decreases
hepatic glucose output and, to a lesser extent, increas-
es peripheral glucose utilization. Metformin produces
about the same reduction in glycated hemoglobin
(HbA
1C
) concentrations as a sulfonylurea, but typical-
ly causes modest weight loss (generally 2-3 kg) rather
than weight gain, and fewer hypoglycemic events.
Metformin used to be contraindicated in all patients
with heart failure, but in one large retrospective study in
elderly patients (mean age 72) with type 2 diabetes and
heart failure, metformin-treated patients had a lower
mortality rate than those treated with a sulfonylurea
(33% versus 52%).
1
It is still contraindicated in patients
with decompensated or acute heart failure.
2
Adverse Effects Metformin used alone generally
does not cause hypoglycemia. Its favorable effect on
body weight may be due partly to gastrointestinal
adverse effects such as a metallic taste, nausea, diar-
rhea and abdominal pain, which can be minimized by
increasing the dose slowly and taking the drug with
food. Lactic acidosis is a rare but potentially fatal
complication. It can be avoided by not using met-
formin in patients with impaired renal function
(serum creatinine >1.5 mg/dL in males, >1.4 mg/dL
in females), other diseases that predispose to acidosis
(liver failure, major surgery, decompensated or acute
heart failure), alcohol abuse, or in patients >80 years
old if their renal function cannot be monitored.
Metformin should be discontinued on the day
patients undergo radiographic studies with iodinated
contrast, which can cause a temporary reduction in
renal function, and should not be restarted until 48
hours later, after evaluating renal function. It is clas-
sified as category B (no evidence of risk in humans)
for use in pregnancy.
SULFONYLUREAS Sulfonylureas interact with
ATP-sensitive potassium channels in the beta cell
membrane to increase secretion of insulin. The more
commonly used second-generation agents, which are
more potent than the first-generation drugs, are simi-
lar to each other in efficacy. As the duration of dia-
betes increases, beta-cell function declines and these
drugs become less effective. A randomized, double-
blind trial (The ADOPT Study) in 4360 drug-nave
patients with type 2 diabetes found that the incidence
of monotherapy failure after 5 years, defined as fast-
ing plasma glucose >180 mg/dL, was higher with gly-
buride (34%) than with metformin (21%) or rosiglita-
zone (15%).
3
When sulfonylurea therapy fails, a drug
with a different mechanism of action should be added.
Adverse Effects Sulfonylureas can cause hypo-
glycemia, particularly in elderly patients with
impaired renal or hepatic function. Glyburide appears
to cause a higher incidence of hypoglycemia than
glimepiride or glipizide. Sulfonylureas also cause
weight gain. Most are classified as category C (risk
cannot be ruled out) for use in pregnancy; Micronase
and micronized glyburide (Glynase Prestab, and oth-
ers) are category B (no evidence of risk in humans).
NON-SULFONYLUREA SECRETAGOGUES
Repaglinide
4
and nateglinide,
5
although structurally
different from the sulfonylureas, also bind to ATP-sen-
sitive potassium channels on beta cells and increase
insulin release. Nateglinide appears to be less effective
than repaglinide, which is about as effective as the sul-
fonylureas in lowering HbA
1C
concentrations.
6
Both
Drugs for Diabetes
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 71) July 2008 48
1
Biguanides
Metformin generic 500, 850, 1000 mg 1500 to 2550 mg PO divided
2
55.80
Glucophage (Bristol-Myers Squibb) tabs 91.80
extended-release generic 500, 750 mg tabs 1500 to 2000 mg PO once
2
60.00
Glucophage XR (Bristol-Myers Squibb) 92.40
Fortamet (Andryx) 500, 1000 mg tabs 1500 to 2500 mg PO once
2
162.00
liquid Riomet (Ranbuxy) 4, 16 oz (500 mg/5 mL) 1500 to 2550 mg PO divided
2
87.98
3
Second Generation Sulfonylureas
Glimepiride generic 1, 2, 4 mg tabs 1 to 4 mg PO once
4
10.20
Amaryl (Sanofi-Aventis) 16.20
Glipizide generic 5, 10 mg tabs 10 to 20 mg PO once or divided
5
15.90
Glucotrol (Pfizer) 32.70
extended-release generic 2.5, 5, 10 mg tabs 5 to 20 mg PO once 10.20
Glucotrol XL sustained-release tablets 17.70
Glyburide generic 1.25, 2.5, 5 mg tabs 5 to 20 mg PO once or divided
4
18.00
DiaBeta (Sanofi-aventis) 31.80
Micronase (Pfizer) 39.30
micronized tablets generic 1.5, 3, 6 mg tabs 1.5 to 12 mg PO once or divided
4
9.30
Glynase Prestab (Pfizer) 22.50
Non-Sulfonylurea Secretagogues
Nateglinide Starlix (Novartis) 60, 120 mg tabs 60 to 120 mg PO tid before meals 138.60
Repaglinide Prandin (Novo Nordisk) 0.5, 1, 2 mg tabs 1 to 4 mg PO tid before meals 143.10
Thiazolidinediones
Pioglitazone Actos (Takeda) 15, 30, 45 mg tabs 15 to 45 mg PO once 132.30
Rosiglitazone Avandia (GlaxoSmithKline) 2, 4, 8 mg tabs 4 to 8 mg PO once or divided 110.70
1. Average retail cost to the patient for 30 days' treatment with the lowest usual daily dosage based on most recent data (May 2008) from retail
pharmacies nationwide available from Wolter Kluwers Health. The cost of generic drugs may vary widely; for example, a months supply of some
generic hypoglycemics (glimepiride, glipizide, glyburide, micronized glyburide and metformin) costs $4 at Walmart, Target and some other retail stores.
2. Should be taken with meals.
3. Cost of a 16-ounce bottle according to Drugstore.com.
4. Once-daily dosing should be given with breakfast or first meal.
Table 1. Drugs for Type 2 Diabetes Mellitus
repaglinide and nateglinide are rapidly absorbed and
rapidly cleared, causing plasma levels of insulin to
peak within 30 to 60 minutes. They must be taken
before each meal; if a meal is missed, the drug should
be omitted. Repaglinide and nateglinide are much
more expensive than the sulfonylureas. Both are
approved by the FDA for combined use with met-
formin or a thiazolidinedione.
Adverse Effects Hypoglycemia and weight gain occur
as frequently with repaglinide as with sulfonylureas;
data on nateglinide are limited. Since both nateglinide
and repaglinide are at least partly metabolized by
CYP3A4, inhibitors of this enzyme such as clar-
ithromycin (Biaxin, and others) may increase their
serum concentrations, and inducers such as rifampin
(Rifadin, and others) may decrease them.
7
Nateglinide
and repaglinide have caused nonteratogenic toxicity in
pregnant animals and are classified as category C (risk
cannot be ruled out) for use during pregnancy.
THIAZOLIDINEDIONES (TZDs) Pioglitazone
and rosiglitazone, the only thiazolidinediones cur-
rently available in the US, decrease glycated hemo-
globin (HbA
1C
) concentrations by increasing the
insulin sensitivity of adipose tissue, skeletal muscle
and the liver. They can take 6 to 14 weeks to achieve
their maximum effect. Both are FDA-approved for use
as monotherapy or in combination with metformin or
a sulfonylurea; only pioglitazone is approved for use
with insulin.
Cardiovascular Effects The cardiovascular safety
of thiazolidinediones, particularly rosiglitazone, is
controversial; a meta-analysis found an increased risk
of myocardial infarction with rosiglitazone,
8
but inter-
im results from a randomized prospective study
specifically designed to evaluate cardiovascular
effects found no evidence of increased risk.
9
Both
rosiglitazone and pioglitazone increase the risk of con-
gestive heart failure.
10
Drugs for Diabetes
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 71) July 2008
49
1
Alpha-Glucosidase Inhibitors
Acarbose Precose (Bayer) 25, 50, 100 mg tabs 50 to 100 mg PO tid with meals 92.70
Miglitol Glyset (Pfizer) 25, 50, 100 mg tabs 50 to 100 mg PO tid with meals 89.10
Other
Colesevelam Welchol (Sankyo) 625 mg tabs 3.8 g once or divided bid 199.80
Exenatide Byetta (Amylin/Lilly) 1.2, 2.4 mL prefilled 10 mcg SC bid before 213.03
7
pen (250 mcg/mL) breakfast and dinner
6
Pramlintide Symlin (Amylin/Lilly) 5-mL vial (0.6 mg/mL) 60-120 mcg SC tid before
1.5, 2.7 mL prefilled main meals
8
231.60
9
pen (1000 mcg/mL)
DPP-4 Inhibitors
Sitagliptin Januvia (Merck) 25, 50, 100 mg tabs 100 mg PO once 180.60
COMBINATION PRODUCTS
Metformin/glipizide Metaglip 250/2.5, 500/2.5, 500 mg/2.5 mg PO bid
2
72.60
(Bristol-Myers Squibb) 500/5 mg tabs
Metformin/glyburide generic 250/1.25, 500/2.5, 500 mg/5 mg PO bid
2
51.60
Glucovance (Bristol-Myers Squibb) 500/5 mg tabs 80.40
Metformin/pioglitazone Actoplus Met 500/15, 850/15 mg 500 mg/15 mg PO bid
2
201.60
(Takeda) tabs
Metformin/rosiglitazone Avandamet 500/1, 500/2, 500/4, 500 mg/2 mg PO bid
2
130.80
(GlaxoSmithKline) 1000/2, 1000/4 mg tabs
Metformin/sitagliptin Janumet (Merck) 500/50, 1000/50 mg 500 mg/50 mg PO bid
2
181.80
tabs
Glimepiride/rosiglitazone
Avandaryl (GlaxoSmithKline) 1/4, 2/4, 4/4, 2/8, 4 mg/4 mg PO bid 249.00
4/8 mg tabs
Glimepiride/pioglitazone
Duetact (Takeda) 2/30, 4/30 mg tabs 4 mg/30 mg PO once 204.00
5. Doses >15 mg/day should be divided bid.
6. Starting dose is 5 mcg twice daily up to an hour before the morning and evening meals. After a month, the dose can be increased to 10 mcg twice
daily.
7. Cost of 2.4 mL pen, according to Drugstore.com.
8. Dose for patients with type 2 diabetes. Cost based on purchase of two 5-mL vials.
9. Cost of one box containing two Symlin 120 Pens (2.7mL each) according to Drugstore.com.
Table 1. Drugs for Type 2 Diabetes Mellitus (continued)
Other Adverse Effects TZDs can cause peripheral
edema; macular edema has also been reported, but
cause and effect have not been established. Weight gain
is common; over a period of 6-12 months, mean weight
gain has been 2-3 kg and can be much higher.
11
Combination therapy with insulin can lead to even
greater weight gain. TZDs have also been associated
with reduced bone mineral density and an increased
incidence of fractures.
12,13
Since an earlier TZD was
withdrawn because of hepatic toxicity, the FDArecom-
mends checking serum alanine aminotransferase (ALT)
levels before starting TZD therapy and periodically
thereafter; these drugs should not be used in patients
with ALT levels >2.5 times the upper limit of normal.
Both pioglitazone and rosiglitazone have retarded fetal
development in animals and are classified as category C
(risk cannot be ruled out) for use in pregnancy.
ALPHA-GLUCOSIDASE INHIBITORS
Acarbose and miglitol inhibit the alpha-glucosidase
enzymes that line the brush border of the small intes-
tine, interfering with hydrolysis of carbohydrates and
delaying absorption of glucose and other monosaccha-
rides. To lower postprandial glucose concentrations,
these drugs must be taken with each meal.
Adverse Effects Unabsorbed carbohydrates cause
abdominal pain, diarrhea and flatulence due to osmot-
ic effects and bacterial fermentation; slow titration can
minimize these effects. Acarbose in high doses has
been associated rarely with moderate transaminase
elevations; miglitol has not. Fatal hepatic failure has
been reported with acarbose. Given alone, neither of
these drugs causes hypoglycemia, but use with either
a sulfonylurea or insulin may increase the risk. In the
Drugs for Diabetes
event of hypoglycemia, oral treatment of patients tak-
ing these drugs must be with glucose rather than
sucrose because alpha-glucosidase inhibitors interfere
with the breakdown of sucrose. Acarbose and miglitol
are contraindicated in patients with chronic intestinal
diseases, inflammatory bowel disease, colonic ulcera-
tion, or any degree of intestinal obstruction. Both are
classified as category B (no evidence of risk in
humans) for use in pregnancy.
EXENATIDE Exenatide is approved by the FDA
for subcutaneous injection in patients with type 2 dia-
betes who have not achieved adequate control with
metformin, a sulfonylurea, a TZD or a combination of
these drugs, but not for use in combination with
insulin. Exenatide has an amino acid sequence similar
to that of the human incretin hormone glucagon-like
peptide-1 (GLP-1), and in the presence of glucose acts
to stimulate insulin secretion.
14
In addition, it lowers
serum glucagon concentrations, slows gastric empty-
ing and increases satiety. In animals, exenatide has
been shown to stimulate production of new beta cells
and prevent beta cell apoptosis.
50
In 4 short-term, randomized controlled trials compar-
ing exenatide with placebo in patients with type 2 dia-
betes inadequately controlled by a sulfonylurea, met-
formin, both or a TZD, exenatide decreased fasting and
postprandial glucose and HbA
1C
concentrations in all
studies.
15-18
In a 26-week open-label, randomized con-
trolled trial, the use of exenatide compared favorably
with insulin glargine as add-on therapy for patients
poorly controlled on oral agents (baseline HbA
1C
8.2-
8.3%); HbA
1C
reductions were similar (-1.11%), but
body weight decreased 2.3 kg with exenatide com-
pared to a 1.8-kg increase with insulin glargine.
19
Other trials have shown weight loss of 1.5 to 2.8 kg
compared to placebo.
20
Ameta-analysis of 5 trials with
1228 participants on exenatide found a mean reduction
in HbA
1C
of 1.01% compared to placebo.
21
Adverse Effects Nausea, vomiting and diarrhea have
been the most common adverse effects; to help reduce
nausea, the dose of exenatide should not be increased
from 5 to 10 mcg until after one month of treatment.
Adding the drug to a sulfonylurea may increase the risk
of mild to moderate hypoglycemia (36% vs. 3% with
Form
1
Onset Peak Duration Cost
2
Rapid-Acting 10-30 min 30-60 min 3-5 hrs
Insulin aspart
Novolog (Novo Nordisk) 10-mL vial $94.25
3-mL FlexPen
4
191.89
Insulin lispro Humalog (Lilly) 10-mL vial 89.99
3-mL cartridge 173.28
3-mL KwikPen
4
169.98
Insulin glulisine Apidra (Sanofi- 10-mL vial 90.68
aventis) 3-mL cartridge
5
174.25
Regular Insulin 30-60 min 1-2 hrs 5-8 hrs
Humulin R (Lilly) 10-mL vial
6
46.99
Novolin R (Novo Nordisk) 10-mL vial 45.99
3-mL PenFill cartridge 115.28
3-mL Innolet 85.04
Intermediate-Acting 1-2 hrs 4-8 hrs 10-20 hrs
NPH
Humulin N 10-mL vial 49.99
3-mL cartridge 134.49
Novolin N 10-mL vial 46.99
3-mL PenFill cartridge 115.28
3-mL Innolet 87.23
1. Cartridges are used with pen injectors.
2. Cost of one vial (1000 units) or 5 cartridges or syringes (total 750 units or 1500 units),according to Drugstore.com.
3. For use with NovoPen 4 or Novopen Jr.
4. Prefilled, disposable syringe.
Table 2. Some Insulin Products
Drugs for Diabetes
placebo)
15
; the dose of the sulfonylurea should be
reduced when starting exenatide. Hypoglycemic events
did not increase compared to placebo when exenatide
was combined with metformin or a TZD. Because it
slows gastric emptying, exenatide can decrease the rate
and extent of absorption of other drugs; it should not be
used in patients with gastroparesis. Acute pancreatitis
has been reported.
22
Exenatide was teratogenic in ani-
mal studies and is classified as category C (risk cannot
be ruled out) for use during pregnancy.
SITAGLIPTIN phosphate, an oral dipeptidyl-pepti-
dase-4 (DPP-4) inhibitor, has been approved for use in
the treatment of type 2 diabetes as monotherapy or in
combination with metformin, a sulfonylurea or a TZD,
but not with insulin.
23
Sitagliptin inhibits the DPP-4
enzyme responsible for inactivation and degradation of
the incretin hormones GLP-1 and glucose-dependent
insulinotropic polypeptide (GIP). These gastrointestinal
hormones potentiate insulin synthesis and release by
pancreatic beta cells and decrease glucagon production
by pancreatic alpha cells, lowering serum glucose con-
centrations. Efficacy trials of sitagliptin, alone or in
combination with metformin, a sulfonylurea or a TZD,
have shown consistent reductions in HbA
1C
concentra-
tions (0.6-0.8% more than with placebo).
24-26
Adverse Effects Early clinical trials found no effect
on weight, but more recent studies suggest modest
weight gain with the drug.
25,26
The incidence of hypo-
glycemic events increased significantly only when
sitagliptin was added to a sulfonylurea (12.2% versus
1.8% with placebo).
26
The long-term safety of DPP-4
inhibitors is unknown; many other peptides besides the
incretin hormones, including neuropeptides, cytokines
and chemokines, are cleaved by DPP-4. It is classified
as category B (no evidence of risk in humans) for use
during pregnancy.
COLESEVELAM A bile-acid sequestrant used to
lower LDL cholesterol, colesevelamhas been approved
by the FDAas an adjunct to diet and exercise in the treat-
ment of type 2 diabetes.
27
In patients taking metformin, a
sulfonylurea
28
or insulin, it has reduced HbA
1C
by about
0.5% more than placebo. The mechanism is unclear.
Adverse Effects Colesevelam can cause constipa-
tion, nausea and dyspepsia, increase serum triglyceride
concentrations, and interfere with absorption of other
oral drugs.
REGULAR AND RAPID-ACTING INSULINS
Three rapid-acting insulin analogs have become avail-
51
Form
1
Onset Peak Duration Cost
2
Long-Acting
Insulin detemir
Levemir (Novo Nordisk) 10-mL vial 1 hr relatively flat 12-20 hrs 89.21
3-mL FlexPen
4
168.12
3-mL Innolet
Insulin glargine Lantus (Sanofi- 10-mL vial 1-2 hrs no peak 22-24 hrs 92.26
aventis) 3-mL cartridge
5
179.95
3-mL SoloStar 176.99
disposable device
Pre-Mixed
Novolin 70/30 (Novo Nordisk)
(70% NPH, human insulin isophane 10-mL vial 46.26
susp. and 30% regular human 3-mL PenFill cartridge
3
125.59
insulin injection) 3-mL Innolet 87.23
Novolog Mix 70/30 (Novo Nordisk)
(70% insulin aspart protamine susp. 10 mL vial 97.31
7
and 30% insulin aspart injection) 3-mL FlexPen 176.20
Humalog Mix 75/25 (Lilly)
(75% insulin lispro protamine susp. 10-mL vial 96.89
and 25% insulin lispro injection) 3-mL Pen 164.99
3-mL KwikPen
5. For use with OptiClick device.
6. Also available in a concentrated formula with 500 units per mL. A 20 mL vial costs 248.04 according to AWP listings in RedBook Update, June 2008.
7. Price according to AWP listings in RedBook 2008.
Table 2. Some Insulin Products (continued)
Drugs for Diabetes
able that have less tendency to form the hexamer
aggregates that slow absorption of regular insulin from
the subcutaneous injection site, and therefore have a
more rapid onset and shorter duration of action. In gen-
eral, insulin lispro, insulin aspart and insulin gluli-
sine are more effective than regular insulin in control-
ling postprandial blood sugar.
29
Adverse Effects With all insulins, the greatest risk is
hypoglycemia. The risk with the rapid-acting insulin
analogs is less than with regular insulin. Insulin lispro
and aspart are classified as category B (no evidence of
risk in humans) for use in pregnancy; insulin glulisine
is category C (risk cannot be ruled out).
30
LONGER-ACTINGINSULINS An intermediate-
acting insulin such as NPH, can be used in combina-
tion with regular and rapid-acting insulins; such regi-
mens are most effective when NPH is given twice
daily. Alternatively, patients can use pre-mixed combi-
nations (see Table 2). While these formulations simpli-
fy administration of insulin, titration of dose is more
difficult and hypoglycemia may be more frequent than
with individual insulins.
Insulin glargine
31
, a recombinant DNA analog of
human insulin, forms microprecipitates in subcuta-
neous tissue, delaying its absorption and prolonging its
duration of action to a mean of 22 + 4 hours. It has a
less pronounced peak of action than NPH insulin and
does not show differing rates of absorption when
injected at various sites. Insulin detemir, a long-act-
ing basal insulin that reversibly binds with albumin, is
equivalent to NPH in lowering HbA
1C
, but causes less
nocturnal hypoglycemia.
32,33
A randomized, open-
label comparison study in 582 insulin-nave patients
found that 55% of patients randomized to insulin
detemir required two injections and a higher total daily
dose of insulin to achieve reductions equivalent to
those with insulin glargine. The rates of hypoglycemic
events were similar, but weight gain was less common
with detemir.
34
Insulin detemir may be more effective
when used twice daily; after 12 hours, its effectiveness
appears to decrease.
35
Adverse Effects All insulins, including long-acting
ones, can cause hypoglycemia and weight gain. In a
comparative trial, detemir caused more injection site
reactions than glargine (4.5% vs. 1.4%).
34
The long-
term safety of NPH insulin has been established.
Whether long-term glargine use could lead to a higher
incidence of diabetes complications, such as retinopa-
thy, or tumors associated with insulin-like growth fac-
tors, remains to be determined. Glargine and detemir
are classified as category C (risk cannot be ruled out)
for use during pregnancy.
52
ADDITION OF INSULIN When insulin is added
to oral agents, it is usually given either in the evening
or at bedtime. In general, added insulin can be started
with 10 units, or 0.2 units/kg of a pre-mixed combina-
tion at dinnertime, or NPH, detemir or glargine at bed-
time. The dose can then be increased in 1- to 4-unit
increments to achieve fasting plasma glucose concen-
trations between 70-130 mg/dL.
Biphasic (pre-mixed) insulin (30% rapid-acting insulin
aspart and 70% intermediate-acting protaminated
insulin aspart) given twice daily, prandial insulin given
before meals three times daily, and basal insulin (bed-
time or twice-daily insulin detemir) were compared in
708 patients with type 2 diabetes and suboptimal glu-
cose control (mean HbA
1C
8.5%) on maximum tolerat-
ed doses of metformin and a sulfonylurea (Treating to
Target in Type 2 Diabetes [4T]). After 1 year, biphasic
and prandial regimens achieved greater reductions in
HbA
1C
(-1.3% and -1.4%) than basal insulin (-0.8%) at
the expense of increased weight gain (+4.7 kg, +5.7 kg
and +1.9 kg for biphasic, prandial and basal).
Hypoglycemia occurred more frequently with the
biphasic and prandial regimens (6 and 12 events per
patient per year) than with basal insulin (2.3 events per
patient per year). Overall, only a minority of partici-
pants in each group achieved a HbA
1C
<6.5%.
36
PRAMLINTIDE
37
is an amylinomimetic agent avail-
able only as a subcutaneous injection. It has been
approved for use in patients with type 1 or type 2 dia-
betes on prandial insulin who have not been able to
achieve blood glucose targets. Pramlintide acts by
slowing gastric emptying, increasing satiety and sup-
pressing postprandial plasma glucagon and hepatic
glucose production. Patients with type 2 diabetes start
pramlintide at 60 mcg before major meals, and then
increase to 120 mcg as tolerated. The major effect
seems to be in reducing postprandial glucose excur-
sions and promoting weight loss; the effect on HbA
1C
is modest (about 0.3%-0.6% decrease).
38,39
In a 16-
week trial in 212 patients with type 2 diabetes on basal
insulin glargine therapy (with or without oral agents),
addition of preprandial pramlintide led to a significant
reduction in postprandial glucose excursions and a
modest decrease in HbA
1C
(0.34%) with no additional
hypoglycemia compared to placebo. Placebo-adjusted
mean weight loss was 2.3 kg.
40
Adverse Effects Nausea, vomiting, anorexia and
headache occur with pramlintide, but less so with grad-
ual titration. The drug should not be used in patients
with gastroparesis or those taking other drugs that may
alter gastrointestinal motility. Used in combination
with insulin, pramlintide has been associated with
severe hypoglycemia. The manufacturer, therefore,
Drugs for Diabetes
recommends a reduction in short-acting insulin
dosages, including pre-mixed insulins, of 50% with
initiation of pramlintide therapy and frequent (includ-
ing postprandial) glucose monitoring. Pramlintide may
delay or decrease absorption of oral drugs taken at the
same time. It has caused congenital abnormalities in
animals and is classified as category C (risk cannot be
ruled out) for use during pregnancy.
GLYCEMIC THERAPY GOALS The goal for
drug therapy of type 2 diabetes is achieving and main-
taining a near-normal HbA
1C
concentration without
inducing hypoglycemia; the target has generally been
a HbA
1C
of < 6.5 7.0%. Treating to these HbA
1C
tar-
gets has clearly been shown to prevent microvascular
complications (retinopathy and nephropathy), but has
been inconclusive regarding prevention of macrovas-
cular outcomes.
Two large trials have found no decrease in macrovascu-
lar events with intensive glucose control. Arandomized,
double-blind study (the ACCORD trial) in about 10,000
patients with type 2 diabetes at high-risk for cardiovas-
cular disease found that patients intensively treated with
anti-hyperglycemic drugs, including frequent use of
TZDs and insulin, with a HbA
1C
target of 6.0% (actual
median HbA
1C
6.4%) did not obtain a significant reduc-
tion in major cardiovascular events (the primary end-
point) over a period of 3.5 years, and showed an increase
in all-cause mortality (257 deaths vs. 203) compared to
those with a HbA
1C
target of 7.0% 7.9% (actual medi-
an HbA
1C
7.5%). The etiology of the higher mortality is
unclear.
41
Asecond study (the ADVANCE trial) in about
11,000 similar patients treated to a HbA
1C
target of 6.5%
with a sulfonylurea-based regimen also found no
decrease in macrovascular events, but there was no
increase in all-cause mortality.
42
CONCLUSION Used alone, oral hypoglycemic
drugs generally lower glycated hemoglobin (HbA
1C
) by
0.5%-1.5%. In the absence of contraindications, met-
formin (Glucophage, and others) is generally preferred
as the first-line agent. Asulfonylurea is less likely than
metformin to be effective as monotherapy and may
cause weight gain and hypoglycemia. The thiazolidine-
diones pioglitazone (Actos) and rosiglitazone (Avandia)
are effective for glycemic control, but they increase the
risk of congestive heart failure.
If the desired goal is not achieved with metformin,
addition of a sulfonylurea or pioglitazone should be
considered. Long-term safety data with DPP-4
inhibitors are lacking, but addition of sitagliptin
(Januvia) modestly reduces HbA
1C
and appears to be
well tolerated. Many oral drug combination formula-
tions are available (see table 1). Exenatide (Byetta) is
an alternative drug for combination therapy, particular-
ly for patients who may benefit from weight loss and
can tolerate injections.
About 75% of patients with type 2 diabetes will require
multidrug therapy or insulin within 9 years. Use of
insulin should not be postponed when oral therapy fails
to control plasma glucose. Some guidelines encourage
early use of insulin if the HbA
1C
remains poorly con-
trolled on maximal-dose single-drug therapy.
43
1. DT Eurich et al. Improved clinical outcomes associated with metformin
in patients with diabetes and heart failure. Diabetes Care 2005; 28:2345.
2. SE Inzucchi et al. Metformin in heart failure. Diabetes Care 2007:
30:e129.
3. SE Kahn et al. Glycemic durability of rosiglitazone, metformin, or gly-
buride monotherapy. (The ADOPT Study Group). N Engl J Med 2006;
355:2427.
4. Repaglinide for type 2 diabetes mellitus. Med Lett Drugs Ther 1998;
40:55.
5. Nateglinide for type 2 diabetes. Med Lett Drugs Ther 2001; 43:29.
6. S Bolen et al. Systematic review: comparative effectiveness and safety
of oral medications for type 2 diabetes. Ann Intern Med 2007; 147:386.
7. CYP3Aand drug interactions. Med Lett Drugs Ther 2005; 47:54.
8. SE Nissen and K Wolski. Effect of rosiglitazone on the risk of myocar-
dial infarction and death from cardiovascular causes. N Engl J Med
2007; 356:2457.
9. PD Home et al. Rosiglitazone evaluated for cardiovascular outcomes
an interim analysis. N Engl J Med 2007; 357:28.
10. RM Lago et al. Congestive heart failure and cardiovascular death in
patients with prediabetes and type 2 diabetes given thiazolidinediones:
a meta-analysis of randomized clinical trials. Lancet 2007; 370:1129.
11. Z Hussein et al. Effectiveness and side effects of thiazolidinediones for
type 2 diabetes: real-life experience from a tertiary hospital. Med J Aust
2004; 181:536.
12. S Yaturu et al. Thiazolidinedione treatment decreases bone mineral den-
sity in type 2 diabetic men. Diabetes Care 2007; 30:1574.
13. C Meier et al. Use of thiazolidinediones and fracture risk. Arch Intern
Med 2008; 168:820.
14. Exenatide (Byetta) for type 2 diabetes. Med Lett Drugs Ther 2005;
47:45.
15. JB Buse et al. Effects of exenatide (exendin-4) on glycemic control
over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.
16. RA DeFronzo et al. Effects of exenatide (exendin-4) on glycemic con-
trol and weight over 30 weeks in metformin-treated patients with type 2
diabetes. Diabetes Care 2005; 28:1092.
17. DMKendall et al. Effects of exenatide (exendin-4) on glycemic control
over 30 weeks in patients with type 2 diabetes treated with metformin
and a sulfonylurea. Diabetes Care 2005; 28:1083.
18. B Zinman et al. The effect of adding exenatide to a thiazolidinedione in
suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern
Med 2007; 146:477.
19. RJ Heine et al. Exenatide versus insulin glargine in patients with subop-
timally controlled type 2 diabetes. Ann Intern Med 2005; 143:559.
20. Diet, Drugs and Surgery for Weight Loss. Treat Guidel Med Lett 2008;
6:23.
21. RE Amori et al. Efficacy and safety of incretin therapy in type 2 dia-
betes: systematic review and meta-analysis. JAMA2007; 298:194.
22. P Cure et al. Exenatide and rare adverse effects. N Eng J Med 2008;
358:1969.
23. Sitagliptin (Januvia) for type 2 diabetes. Med Lett Drugs Ther 2006;
49:1.
53
Drugs for Diabetes
24. PAschner et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin
as monotherapy on glycemic control in patients with type 2 diabetes.
25. BJ Goldstein et al. Effect of initial combination therapy with sitagliptin,
a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control
in patients with type 2 diabetes. Diabetes Care 2007; 30:1979.
26. K Hermansen et al. Efficacy and safety of the dipeptidyl peptidase-4
inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inade-
quately controlled on glimepiride alone or on glimepiride and met-
formin. Diab Obes Metab 2007; 9:733.
27. A new indication for Colesevelam (Welchol). Med Lett Drugs Ther
2008; 50:33.
28. VA Fonseca et al. Colesevelam HCl improves glycemic control and
reduces LDL-cholesterol in patients with type-2 diabetes inadequately
controlled on sulfonylurea-based therapy. Diabetes Care May 5, 2008
(epub).
29. IB Hirsch. Insulin analogues. N Engl J Med 2005; 352:174.
30. Insulin glulisine (Apidra), a new rapid-acting insulin. Med Lett Drugs
Ther 2006; 48:33.
31. Insulin glargine (Lantus), a new long-acting insulin. Med Lett Drugs
Ther 2001; 43:65.
32. Insulin detemir (Levemir), a new long-acting insulin. Med Lett Drugs
Ther 2006; 48:54.
33. K Hermansen et al. A 26-week, randomized, parallel, treat-to-target
trial comparing insulin detemir with NPH insulin as add-on therapy to
oral glucose-lowering drugs in insulin-nave people with type 2 dia-
betes. Diabetes Care 2006; 29:1269.
34. J Rosenstock et al. Arandomized, 52-week, treat-to-target trial compar-
ing insulin detemir with insulin glargine when administered as add-on
to glucose-lowering drugs in insulin-nave people with type 2 diabetes.
Diabetologia 2008; 51:408.
35. F Porcellati et al. Comparison of pharmacokinetics and dynamics of the
long-acting insulin analogs glargine and detemir at steady state in type
1 diabetes. Diabetes Care 2007; 30:2447.
36. RR Holman et al. Addition of biphasic, prandial, or basal insulin to oral
therapy in type 2 diabetes. (Treating to Target in Type 2 Diabetes (4-T)
study group). N Engl J Med 2007; 357:1716.
37. Pramlintide (Symlin) for diabetes. Med Lett Drugs Ther 2005; 47:43.
38. RE Ratner et al. Amylin replacement with pramlintide as an adjunct to
insulin therapy improves long-term glycaemic and weight control in
type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet
Med 2004; 21:1204.
39. PAHollander et al. Pramlintide as an adjunct to insulin therapy improves
long-term glycemic and weight control in patients with type 2 diabetes; a
1-year randomized controlled trial. Diabetes Care 2003; 26:784.
40. M Riddle et al. Pramlintide improved glycemic control and reduced
weight in patients with type 2 diabetes using basal insulin. Diabetes
Care 2007; 30:2794.
41. The ACCORD Study Group. Effects of intensive glucose lowering in
type 2 diabetes. N Engl J Med 2008; 358:2545.
42. The ADVANCE Collaborative Group. Intensive blood glucose control
and vascular outcomes in patients with type 2 diabetes. N Engl J Med
2008; 358:2560.
43. DM Nathan et al. Management of hyperglycaemia in type 2 diabetes: a
consensus algorithm for the initiation and adjustment of therapy: a consen-
sus statement from the American Diabetes Association and the European
Association for the Study of Diabetes. Diabetologia 2006; 49:1711.
54
Treatment of Peptic Ulcers and Gastroesophageal
Reflux
Drugs for Tobacco Dependence
ADVISORY BOARD:
EDITORIAL FELLOWS:
ASSISTANT MANAGING EDITOR: Liz Donohue
Founded in 1959 by
Mailing Address:
1000 Main Street
Customer Service:
Call: 800-211-2769 or 914-235-0500
Fax: 914-632-1733
Permissions:
Subscriptions (US):
1 year - $98; 2 years - $167;
US and Canada.
800-211-2769 x315.
MISSION:
management.
1. Advantages of metformin over a sulfonylurea as monotherapy
include:
a. weight loss rather than weight gain
b. fewer hypoglycemic events
c. a lower failure rate in lowering fasting blood sugar to 180
mg/dL or less
d. all of the above
Pg. 47
2. Among the sulfonylureas, the highest incidence of hypoglycemia
appears to be with:
a. glyburide
b. glipizide
c. glimepiride
Pg. 47
Issue 71 Questions
Introducing
3. The thiazolidinediones rosiglitazone and pioglitazone increase the
risk of:
a. rhabdomyolysis
b. lupus
c. congestive heart failure
d. Stevens-Johnson syndrome
Pg. 48
4. Acarbose delays:
a. glucose absorption
b. development of insulin resistance
c. insulin degradation
d. beta cell apoptosis
Pg. 49
5. Exenatide is:
a. a first-line drug
b. given subcutaneously
c. approved for use with insulin
d. a cause of weight gain
Pg. 50
6. Colesevelam has been approved by the FDA for use in diabetes,
but it is mainly:
a. an antimicrobial
b. a bile acid sequestrant
c. an antithyroid drug
d. an anticonvulsant
Pg. 52
7. Compared to regular insulin, insulin lispro, insulin aspart and
insulin glulisine:
a. have a more rapid onset of action
b. have a shorter duration of action
c. are more effective in controlling postprandial blood sugar
d. all of the above
Pg. 52
8. Compared to individual insulins, pre-mixed combinations may
cause:
a. more frequent hypoglycemia
b. less frequent hypoglycemia
c. more sterile abscesses
d. fewer sterile abscesses
Pg. 52
9. When insulin is added to oral agents, it is usually given:
a. in the morning
b. at noon
c. in the afternoon
d. in the evening
Pg. 52
10. In the 4T study comparing different insulins, the largest reduction
in glycated hemoglobin and the greatest weight gain
occurred with:
a. biphasic (pre-mixed)
b. prandial (before meals)
c. basal (at bedtime or twice-daily insulin detemir)
Pg. 52
11. Used alone, oral hypoglycemic drugs generally lower HbA
1C
levels:
a. 0.3-1.0%
b. 0.5-1.5%
c. 1.0-2.0%
d. 1.0-2.5%
Pg. 53
12. In the absence of contraindications, the drug of first choice for
treatment of type 2 diabetes is generally:
a sulfonylurea
b. rosiglitazone
c. pioglitazone
d. metformin
Pg. 53
ACPE UPN: 379-000-08-071-H01-P
Treatment of Peptic Ulcers and GERD
Tables
1. Some Drugs for Peptic Ulcers/GERD Page 56
2. Multi-Drug Regimens for H. Pylori Page 57
Volume 6 (Issue 72) August 2008
Peptic ulcers caused by treatment with nonsteroidal
anti-inflammatory drugs (NSAIDs) are mainly gastric
ulcers. Most duodenal and other gastric ulcers are
caused by the gram-negative bacillus Helicobacter
pylori. Gastroesophageal reflux disease (GERD) is
caused by gastric acid reflux into the esophagus.
Drugs that suppress gastric acid production are the pri-
mary treatment for GERD and peptic ulcers.
DRUGS
PROTON PUMP INHIBITORS (PPIs)
Currently available PPIs are listed in Table 1. These
drugs bind to the activated proton pump of the parietal
cell, inhibiting secretion of hydrogen ions into the gas-
tric lumen. They are most effective when taken 30-60
minutes before the first meal of the day.
PPIs heal peptic ulcers more rapidly than histamine-2
receptor antagonists (H
2
-blockers) or any other drug.
Standard doses of PPIs inhibit more than 90% of 24-hour
acid secretion, compared to 50-80% with H
2
-blockers.
PPIs have short serum half-lives, but their duration of
action is longer, allowing for once-daily dosing.
Tolerance and Rebound Tolerance does not occur
with PPIs, possibly because increased gastric-mediat-
ed histamine release cannot overcome blockade of the
proton pump. Rebound acid hypersecretion may occur
following discontinuation of PPI therapy.
1
Adverse Effects PPIs usually cause few adverse
effects. Headache, nausea, abdominal pain, constipa-
tion, flatulence and diarrhea can occur. Gynecomastia
and hepatic failure have occurred rarely. Subacute
myopathy, arthralgias, severe rashes and acute inter-
stitial nephritis have been reported.
Long-term use of PPIs for maintenance therapy, par-
ticularly at high doses, has been associated with
increased risk of osteoporotic fractures; cause and
effect have not been established.
2,3
Decreased
absorption and subsequent deficiency of vitamin B12
has been described among chronic users of H
2
-block-
ers and/or PPIs, especially the elderly.
4,5
Acid sup-
pression may increase the risk of gastroenteritis,
Clostridium difficile-associated colitis and community-
acquired pneumonia.
6-8
Drug Interactions The PPIs omeprazole and
esomeprazole inhibit the activity of hepatic enzyme
CYP2C19, possibly decreasing the metabolism of
diazepam (Valium, and others), phenytoin (Dilantin,
and others) and other drugs.
9
All PPIs may decrease
serum concentrations of drugs that require gastric
acidity for absorption, such as itraconazole
(Sporanox) or atazanavir (Reyataz).
H
2
-RECEPTOR BLOCKERS H
2
-blockers
inhibit the action of histamine at the H
2
-receptor of
the parietal cell, decreasing both basal and food-stim-
ulated acid secretion. All four of the H
2
-blockers list-
ed in Table 1 are about equally effective for treatment
of GERD and peptic ulcers. They are not as effective
as PPIs.
Adverse Effects Severe adverse effects are uncom-
mon with H
2
-blockers, but headache, lethargy, confu-
sion, depression and hallucinations can occur. Rarely,
these agents have been associated with hepatitis,
hematologic toxicity or dystonia. With chronic use,
cimetidine may act as an anti-androgen and cause
reversible impotence and gynecomastia.
Drug Interactions Cimetidine inhibits the activity
of hepatic enzymes 1A2, 2C19 and 2D6.
10
Clinically
significant effects have occurred when cimetidine
was used with drugs that are metabolized by these
enzymes and have a narrow therapeutic-to-toxic
ratio, such as theophylline (Theo-Dur, and others),
warfarin (Coumadin, and others), phenytoin or lido-
caine (Xylocaine, and others).
9
Ranitidine, famoti-
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 72) August 2008
dine and nizatidine are less likely to interfere with
hepatic metabolism of other drugs.
Tolerance and Rebound Continuous administration
of H
2
-blockers leads to pharmacologic tolerance and
decreased effectiveness over time.
11-14
While the
mechanism is unclear, the phenomenon seems to be
more prevalent in patients without H. pylori infec-
tion.
15
Rebound acid hypersecretion may occur fol-
lowing discontinuation of H
2
-blockers.
16,17
Whether its
occurrence can be prevented by gradual tapering
rather than abrupt withdrawal of these drugs remains to
be established.
SUCRALFATE An aluminum hydroxide complex
of sucrose that may protect the ulcer from exposure to
acid, sucralfate (Carafate, and others) has been effec-
tive for acute treatment of peptic ulcers and for pre-
vention of relapse. Multiple daily doses are required,
56
and pain relief is not as effective as with a PPI or an
H
2
-blocker.
Adverse Effects Sucralfate is generally safe.
Constipation can occur.
Drug Interactions Sucralfate decreases absorption
of some drugs; it should be taken at least two hours
after ketoconazole and fluoroquinolones and at least
30 minutes after a PPI.
9
MISOPROSTOL Misoprostol (Cytotec, and oth-
ers), a prostaglandin analog, can prevent gastric and
duodenal ulcers in patients on chronic NSAID therapy.
It may be as effective as a PPI, but requires multiple
daily dosing and is not as well tolerated.
Adverse Effects Abdominal pain and dose-related
diarrhea are the most common adverse effects of miso-
Drug Dosage
1
Tablet / Capsule Size Cost
2
Proton-Pump Inhibitors
Esomeprazole Nexium (AstraZeneca) 20-40 mg once daily 20, 40 mg caps
3
$166.20
Lansoprazole Prevacid (TAP) 15-30 mg once daily
4
15, 30 mg tabs, ODT 167.70
Omeprazole generic 20-40 mg once daily
4
10, 20, 40 mg caps 98.70
Prilosec (AstraZeneca) 148.50
Prilosec OTC 20 mg tabs 21.30
generic 17.16
Zegerid 20, 40 mg caps
3,5
150.60
Pantoprazole Protonix (Wyeth) 20-40 mg once daily 20, 40 mg tabs 127.20
Rabeprazole Aciphex (Janssen) 20 mg once daily 20 mg tabs 167.40
H
2
-Receptor Blockers
6
Cimetidine generic 200-400 mg bid 200, 300, 400, 800 mg tabs 82.20
Tagamet (GlaxoSmithKline) 140.40
Tagamet HB (OTC) 200 mg tabs 34.80
generic 14.39
Famotidine generic 10-20 mg bid 20, 40 mg tabs 99.60
Pepcid (Merck) 112.20
Pepcid AC (OTC) 10, 20 mg tabs 21.00
generic 5.29
Pepcid Complete (OTC)
7
10-20 mg once daily 10 mg chew tabs 10.80
Nizatidine generic 75-150 mg bid 150, 300 mg caps 114.60
Axid (Lilly) 150, 300 mg caps
3
188.40
Axid AR (OTC) 75 mg 36.00
Ranitidine generic 75-150 mg bid 150, 300 mg tabs, caps
3
87.00
Zantac (GlaxoSmithKline) 150, 300 mg tabs
3
198.00
Zantac (OTC) 75, 150 mg 38.40
generic 15.22
Other Drugs
Misoprostol
8
generic 200 mcg bid-tid
8
100, 200 mcg tabs 61.20
Cytotec (Searle) 103.80
Sucralfate generic 1 g qid 1 g tabs
3
69.60
Carafate (Aventis) 160.80
OTC = Over the counter; ODT = orally disintegrating tabs.
1. The lower end of the range is generally used for initial treatment of GERD. Customary doses of antisecretory drugs may not be effective in patients with peptic
ulcers due to hypersecretory states like Zollinger-Ellison Syndrome.
2. Cost for 30 days' treatment at the lowest dosage used for treatment of peptic ulcers, according to the most recent data (May 31, 2008) from retail pharmacies
nationwide available from Wolters Kluwer Health. Generic OTC prices are from drugstore.com or cvs.com (accessed July 14, 2008).
3. Also available as an oral suspension, syrup or solution.
4. Lower dose is for GERD and duodenal ulcer; higher dose is for gastric ulcer.
5. Both strengths contain sodium bicarbonate 1.1 g; therefore, two 20-mg caps are not equivalent to a 40-mg cap.
6. Twice the dose once daily in the evening is effective.
7. Also contains calcium carbonate 800 mg and magnesium hydroxide 165 mg.
8. FDA-approved only for prevention of NSAID-associated gastric ulcers.
Table 1. Some Drugs for Peptic Ulcers/GERD
prostol. Severe nausea can also occur. Misoprostol is an
abortifacient and is contraindicated during pregnancy.
ANTACIDS Aluminum- and magnesium-contain-
ing antacids can be helpful in transiently relieving the
symptoms of peptic ulcers and GERD. Antacids have
many adverse interactions with other drugs. They may
decrease absorption of H
2
-blockers and of metronida-
zole and other antibiotics.
9
PEPTIC ULCERS
The first step in the management of peptic ulcers is the
diagnosis and treatment of H. pylori. Eradication of H.
pylori promotes healing and decreases recurrence of
both duodenal and gastric ulcers.
18
TESTING FOR H. PYLORI For diagnosis or test-
ing for eradication, the sensitivity of urea-based tests
and the stool antigen test is reduced by use of PPIs, bis-
muth or antibiotics. Patients should not take these drugs
for about 4 weeks before testing.
Urea breath tests can be used for office-based diag-
nosis of H. pylori (BreathTek UBT Meretek; PYtest
Kimberly-Clark/Ballard). The patient ingests a urea
solution or capsule labeled with a carbon isotope and
then breathes into a container; in the presence of H.
pylori, bacterial urease hydrolyzes the urea to release
labeled CO
2
, which can be detected by a mass spec-
trometer. These tests typically have >90% sensitivity
and specificity.
19
The BreathTek-UBT used with a
desktop infrared spectrometer can provide results
within a few minutes.
Stool Antigens A stool antigen enzyme immuno-
assay (Premier Platinum HpSA - Meridian Bioscience)
has a sensitivity of about 94% and specificity of about
90%.
20
It should not be used to test for eradication of
H. pylori until 6-8 weeks after therapy.
Biopsy Endoscopic biopsy of the gastric antrum per-
mits isolation by culture or identification by histology.
Culture is used mainly for antibiotic sensitivity testing
to detect resistant organisms. Urease testing of biopsy
specimens can provide a rapid diagnosis.
Serology Serologic antibody tests for H. pylori are
useful in ruling out the diagnosis.
21
They are not reli-
able (because of persisting antibodies) in document-
ing eradication.
TREATMENT OF H. PYLORI Antibacterial agents
used to treat H. pylori infection (Table 2) include amoxi-
cillin, clarithromycin, metronidazole, tetracycline and
bismuth subsalicylate. Various combinations of 2 or 3
antimicrobial drugs along with a PPI are standard. A
combination of clarithromycin, amoxicillin and a PPI is
the most common first-line regimen. In penicillin-allergic
patients, bismuth-based quadruple therapy is preferred.
21
57
Drug Daily Dose Duration
1
Cost
2
Triple Therapy
Clarithromycin (Biaxin,and others) 500 mg bid 10-14 days $106.68
+ Amoxicillin (Amoxil, and others) 1 gram bid 10-14 days 20.16
or Metronidazole (Flagyl, and others) 500 mg bid 10-14 days 18.48
+ a PPI
3
Quadruple Therapy
Bismuth subsalicylate 2 tablets (525 mg) tid or qid 14 days 8.96
4
(PeptoBismol, and others) or 30 mL tid or qid 36.96
4
+ Metronidazole 500 mg tid or qid 14 days 5.60
4
+ Tetracycline (Sumycin, and others) 500 mg tid or qid 14 days
+ a PPI
3
or H
2
-blocker
Three Combination Products
Helidac Therapy 14 blister cards, each containing eight bismuth subsalicylate 322.56
262.4-mg tabs, four metronidazole 250-mg tabs and four tetracycline
500-mg tabs
Prevpac 14 blister cards, each containing two lansoprazole 30-mg caps, 379.40
four amoxicillin 500-mg tabs and two clarithromycin 500-mg tabs
Pylera 120 capsules, each combining bismuth subcitrate potassium 140 mg, 303.60
metronidazole 125 mg and tetracycline HCl 125 mg
1. Antisecretory drugs may be needed longer to heal the ulcer.
2. Cost for 14 days' treatment using generic drugs according to the most recent data (May 31, 2008) from retail pharmacies nationwide provided by Wolters
Kluwer Health.
3. Standard oral PPI dosages are: esomeprazole 40 mg once daily, lansoprazole 30 mg bid, omeprazole 20 mg bid, pantoprazole 40 mg bid, rabeprazole 20 mg
bid.
4. Given qid.
Table 2. Common Multi-Drug Regimens for Helicobacter Pylori
In large clinical trials, antimicrobial drugs active
against H. pylori have been successful in eradicating
the organism in about 70-90% of patients. In practice,
eradication rates are lower due to patient nonadherence
and the increasing prevalence of bacterial resistance to
clarithromycin and metronidazole. If treatment failure
occurs with a regimen containing one of these drugs,
the other should be used in the re-treatment regimen.
Common second-line approaches include bismuth-
based quadruple therapy or triple therapy with amoxi-
cillin, levofloxacin (Levaquin, and others) and a PPI.
22
Sequential therapy may improve treatment efficacy. In
a meta-analysis of randomized controlled trials, treat-
ment with amoxicillin plus a PPI for 5 days, followed
by clarithromycin, tinidazole and a PPI for an addi-
tional 5 days, achieved greater eradication rates than 7-
10 days of standard triple therapy in treatment-nave
patients (93% vs. 77%). Treatment success was also
improved in patients with clarithromycin-resistant
strains of H. pylori (82% vs. 41%).
23
Adverse Effects Bismuth subsalicylate temporari-
ly turns the tongue and stool black and can cause tin-
nitus. Amoxicillin may cause diarrhea. Both metron-
idazole and tetracycline frequently cause mild gas-
trointestinal disturbances. Clarithromycin causes
fewer gastrointestinal symptoms, but commonly
causes disturbances in taste that some patients find
intolerable. Clarithromycin, metronidazole and tetra-
cycline can all interact adversely with many other
drugs.
9
Metronidazole can cause a disulfiram-type
reaction to alcohol.
SUMMARY When patients with active peptic ulcers
are infected with H. pylori, eradication of the infection
with antibacterial drugs markedly decreases the inci-
dence of recurrence. The urea breath test or stool antigen
test is the best choice for office-based diagnosis. All
patients with peptic ulcers need treatment with antise-
cretory drugs; proton pump inhibitors (PPIs) are more
effective than H
2
-receptor blockers. Omeprazole gener-
ally is as effective as any other PPI, and is available
generically and over the counter (OTC). Among H
2
-
blockers, the low price of generic cimetidine probably
does not outweigh its many adverse drug interactions.
All H
2
-blockers are available OTC.
GASTROESOPHAGEAL REFLUX
GERD is typically a benign condition, although com-
plications such as strictures and Barretts esophagus
can occur, and the risk of esophageal adenocarcinoma
is increased. Patients presenting with typical, uncom-
plicated GERD can be treated with lifestyle modifica-
tions and acid-suppressive therapy.
58
LIFESTYLE MODIFICATIONS Common
maneuvers include avoiding recumbancy for at least 3
hours after a meal and elevating the head of the bed.
Foods and drugs that decrease lower esophageal
sphincter pressure (chocolate, alcohol, peppermint,
coffee, tobacco and carbonated beverages) and/or
delay gastric emptying (fatty foods) are discouraged.
24
For obese patients, weight loss may reduce the inci-
dence of GERD symptoms.
25
ACID-SUPPRESSIVE THERAPY Medications
that suppress gastric acid production are the mainstay
of GERD therapy. Options include antacids, H
2
-block-
ers and PPIs. The choice of drug depends on symptom
severity and frequency and the presence of esophagitis.
Non-Erosive Reflux Disease Antacids and H
2
-
blockers are preferred for symptom relief in patients
with mild GERD. While these agents have similar
peak potency, antacids may act faster and H
2
-blockers
act longer (up to 10 hours).
26
PPIs are used less fre-
quently for symptom relief because their enteric coat-
ing delays their release and absorption. An immediate-
release form of omeprazole (Zegerid)
27
combines non-
enteric-coated drug with sodium bicarbonate.
In patients with more severe forms of non-erosive
reflux, continuous therapy with an H
2
-blocker or PPI is
required. PPIs are generally preferred
28
and have been
shown to maintain remission of symptoms.
29
Erosive Esophagitis A PPI is the drug of choice for
acute and chronic management of erosive esophagitis.
PPIs decrease symptoms and heal esophagitis more
effectively than other drugs. Symptom relief has
occurred in 27% of patients treated with placebo, 60%
with an H
2
-blocker, and 83% with a PPI. Healing of
mucosal defects occurred in 24% with placebo, 50%
with an H
2
-blocker, and 78% with a PPI.
26
PPI dosing
should be titrated to maintain symptom and esophagi-
tis control.
ADJUNCTIVE TREATMENTS Adjunctive agents
targeting transient lower esophageal sphincter relaxations
(TLESRs, the primary pathophysiologic mechanism
underlying reflux disease) may be used when GERD symp-
toms are refractory to maximal acid-suppressive therapy.
Baclofen is a gamma-aminobutyric acid
B
(GABA
B
)
receptor agonist that inhibits TLESRs and decreases
postprandial acid reflux in patients with GERD.
30
Baclofen is also effective at reducing symptoms among
patients refractory to PPI therapy.
31
These effects are
preserved with use of baclofen over a 4-week period.
32
Common side effects include drowsiness, dizziness,
lightheadedness, hypotension and nausea.
Treatment of Peptic Ulcer and GERD
Promotility agents such as metoclopramide and
bethanechol may be used in some patients with
GERD as an adjunct to acid-suppressive therapy. Data
supporting their use are fairly limited, and side effects
are often intolerable.
GERD IN PREGNANCY Heartburn occurs in
approximately 30-50% of pregnancies, and is largely
attributed to a progesterone-mediated decrease in
lower esophageal sphincter tone. When treating preg-
nant patients, the potential teratogenicity of common
anti-reflux medications must be considered and a step-
up approach should be employed.
33
Initial therapy
includes lifestyle modifications. Therapeutics that act
locally with minimal systemic absorption may then be
introduced, including antacids, alginates, and sucral-
fate. Antacids containing sodium bicarbonate should
be avoided due to the risks of maternal or fetal alkalo-
sis and fluid overload. If these interventions are insuf-
ficient, H
2
-blockers can be used; all are classified as
FDA category B (no evidence of risk in humans) for
use during pregnancy, but only ranitidine has trial-
proven efficacy in pregnancy.
34
Cimetidine should be
avoided in pregnancy due to its anti-androgenic effects
and concerns about fetal feminization.
Use of PPIs in pregnancy is reserved for patients with
intractable symptoms or complicated reflux disease
(esophagitis, stricture formation). Although generally
considered safe, clinical data on their use during preg-
nancy are limited. A meta-analysis evaluating first-
trimester use of PPIs (predominantly omeprazole)
found no increased risk of congenital malformations.
35
PPIs are classified as FDAcategory B, with the excep-
tion of omeprazole, which is category C (risk cannot
be ruled out).
SURGERY Antireflux surgery has not been shown
to be superior to medical therapy. Both result in simi-
lar rates of esophagitis healing, stricturing disease,
Barretts esophagus, and esophageal adenocarcino-
ma.
36,37
Laparoscopic fundoplication is the primary
surgical procedure for management of GERD. During
fundoplication, the gastric fundus is wrapped around
the gastroesophageal junction either partially or com-
pletely, creating a mechanical barrier.
At least one third of patients treated with fundoplica-
tion will still require chronic acid-suppressive therapy
for ongoing reflux symptoms.
38,39
Antireflux surgery is
associated with a 30-day mortality of 0.08-0.2%.
Immediate perioperative complications occur in 4-6%
of patients, and include wrap herniation, pneumotho-
rax, perforation and wound infection. Dysphagia is
common in the early post-operative period, but typi-
cally resolves after 2-3 months. In some patients, dys-
phagia persists and may require endoscopic dilation or
surgical revision. Postprandial bloating (gas-bloat syn-
drome), increased flatus, and diarrhea are common
post-operatively.
40-42
ENDOSCOPIC THERAPY Three modalities of
endoscopic reflux therapy have been tried: application
of radiofrequency energy to the gastroesophageal junc-
tion, suture plication of the proximal stomach, and
either injection of a biopolymer or implantation of a
bioprosthesis at the level of the lower esophageal
sphincter. Convincing data supporting use of these
techniques are lacking.
43,44
SUMMARY Medical therapy for gastroesophageal
reflux disease (GERD) is based on acid suppression.
H
2
-receptor blockers and antacid therapy should be
used for patients with mild, intermittent symptoms.
Treatment with a proton pump inhibitor (PPI) is pre-
ferred for more severe disease.
1. NG Hunfeld et al. Systematic review: rebound acid hypersecretion after
therapy with proton pump inhibitors. Aliment Pharmacol Ther 2007; 25:39.
2. YX Yang et al. Long-term proton-pump inhibitor therapy and risk of
hip fracture. JAMA2006; 296:2947.
3. P Vestergaard et al. Proton pump inhibitors, histamine H2 receptor
antagonists, and other antacid medications and the risk of fractures.
Calcif Tissue Int 2006; 79:76.
4. RJ Valuck and JM Ruscin. A case-control study on adverse effects: H2
blocker or proton pump inhibitor use and risk of vitamin B12 defi-
ciency in older adults. J Clin Epidemiol 2004; 57:422.
5. TS Dharmarajan et al. Do acid-lowering agents affect vitamin B12 sta-
tus in older adults? Am Med Dir Assoc 2008; 9:162.
6. J Leonard et al. Systematic review of the risk of enteric infection in
patients taking acid suppression. Am J Gastroenterol 2007; 102:2047.
7. RJ Laheij et al. Risk of community-acquired pneumonia and use of gas-
tric-acid suppressive drugs. JAMA2004; 292:1955.
8. RB Canani et al. Therapy with gastric acidity inhibitors increases the
risk of acute gastroenteritis and community-acquired pneumonia in
children. Pediatrics 2006; 117:e817.
10. Drug interactions. Med Lett Drugs Ther 2003; 45:46.
11. CU Nwokolo. Tolerance during 29 days of conventional dosing with
cimetidine, nizatidine, famotidine or ranitidine. Aliment Pharmacol
Ther 1990; 4 Suppl 1:29.
12. L Lachman and CWHowden. Twenty-four-hour intragastric pH: toler-
ance within 5 days of continuous ranitidine administration. Am J
Gastroenterol 2000; 95:57.
13. AK Sandvik et al. Review article: the pharmacological inhibition of
gastric acid secretion tolerance and rebound. Aliment Pharmacol Ther
1997; 11:1013.
14. K Furuta et al. Tolerance to H2 receptor antagonist correlates well with
the decline in efficacy against gastroesophageal reflux in patients with
gastroesophageal reflux disease. J Gastroenterol Hepatol 2006; 21:1581.
15. T Fujisawa et al. Helicobacter pylori infection prevents the occurrence
of the tolerance phenomenon of histamine H2 receptor antagonists.
Aliment Pharmacol Ther 2004; 20:559.
16. CU Nwokolo et al. Rebound intragastric hyperacidity after abrupt with-
drawal of histamine H2 receptor blockade. Gut 1991; 32:1455.
17. GM Fullarton et al. Rebound nocturnal hypersecretion after four weeks
treatment with an H2 receptor antagonist. Gut 1989; 30:449.
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Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 72) August 2008 60
Drugs for Acne, Rosacea and Psoriasis
Drugs for Osteoporosis
18. RJ Hopkins et al. Relationship between Helicobacter pylori eradication
and reduced duodenal and gastric ulcer recurrence: a review.
Gastroenterology 1996; 110:1244.
19. RJ Saad and WD Chey. Breath tests for gastrointestinal disease: the
real deal or just a lot of hot air? Gastroenterology 2007; 133:1763.
20. L Gatta et al. Non-invasive techniques for the diagnosis of
Helicobacter pylori infection. Clin Microb Infec 2003; 9:489.
21. WD Chey and BC Wong. American college of gastroenterology guide-
line on the management of Helicobacter pylori infection. Am J
22. RJ Saad et al. Levofloxacin-based triple therapy versus bismuth-based
quadruple therapy for persistent Helicobacter pylori infection: a meta-
analysis. Am J Gastroenterol 2006; 101:488.
23. NS Jafri et al. Meta-analysis: Sequential therapy appears superior to
standard therapy for Helicobacter pylori infection in patients nave to
treatment. Ann Intern Med 2008; 148:923.
24. A Meining and M Classen. The role of diet and lifestyle measures in
the pathogenesis and treatment of gastroesophageal reflux disease. Am
J Gastroenterol 2000; 95:2692.
25. H Hampel et al. Meta-analysis: obesity and the risk for gastroesophageal
reflux disease and its complications. Ann Intern Med 2005; 143:199.
26. KR DeVault and DO Castell. Updated guidelines for the diagnosis and
treatment of gastroesophageal reflux disease. Am J Gastroenterol
2005; 100:190.
27. Zegerid. Med Lett Drugs Ther 2005; 47:29.
28. M Khan et al. Medical treatments in the short term management of
reflux oesophagitis. Cochrane Database Syst Rev 2007 Apr 18;
(2):CD003244.
29. TLVenables et al. Maintenance treatment for gastro-oesophageal reflux
disease. A placebo-controlled evaluation of 10 milligrams omeprazole
once daily in general practice. Scand J Gastroenterol 1997; 32:627.
30. Zhang Q et al. Control of transient lower oesophageal sphincter relax-
ations and reflux by the GABA
B
agonist baclofen in patients with gas-
tro-oesophageal reflux disease. Gut 2002; 50:19.
31. Koek GH et al. Effect of the GABA
B
agonist baclofen in patients with
symptoms and duodeno-gastro-oesophageal reflux refractory to proton
pump inhibitors. Gut 2003; 52:1397.
32. Ciccaglione AF and Marzio L. Effect of acute and chronic administra-
tion of the GABA
B
agonist baclofen on 24 hour pH metry and symp-
toms in control subjects and in patients with gastro-oesophageal reflux
disease. Gut 2003; 52:464.
33. Richter JE. Review article: the management of heartburn in pregnancy.
Aliment Pharmacol Ther 2005; 22:749.
34. Larson JD et al. Double-blind placebo-controlled study of ranitidine
for gastroesophageal reflux symptoms during pregnancy. Obstet
Gynecol 1997; 90:83.
35. Nikfar S et al. Use of proton pump inhibitors during pregnancy and rates
of major malformation. Ameta-analysis. Dig Dis Sci 2002; 47:1526.
36. SJ Spechler et al. Long-term outcome of medical and surgical therapies
for gastroesophageal reflux disease: follow-up of a randomized con-
trolled trial. JAMA2001; 285:2331.
37. T Tran et al. Fundoplication and the risk of esophageal cancer in gas-
troesophageal reflux disease: a Veterans Affairs cohort study. Am J
38. N Vakil et al. Clinical effectiveness of laparoscopic fundoplication in a
US community. Am J Med 2003; 114:1.
39. A Madan and A Minocha. Despite high satisfaction, majority of gastro-
oesophageal reflux disease patients continue to use proton pump
inhibitors after antireflux surgery. Aliment Pharmacol Ther 2006; 23:601.
40. MA Carlson and CT Frantzides. Complications and results of primary
minimally invasive antireflux procedures: a review of 10,735 reported
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41. TK Rantanen et al. Fatal and life-threatening complications in antire-
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43. F Pace et al. Review article: endoscopic antireflux procedures an
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Mailing Address:
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Customer Service:
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EDITOR IN CHIEF: Mark Abramowicz, M.D.

EDITOR: Jean-Marie Pflomm, Pharm.D.
ADVISORY BOARD:
EDITORIAL FELLOW:
Founded in 1959 by
44. MP Schwartz and AJ Smout. Review article: the endoscopic treatment
of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2007;
26 (Suppl 2):1.
MISSION:
management.
1. Most duodenal ulcers are caused by:
a. stress
b. NSAIDs
c. Helicobacter pylori
d. all of the above
Pg. 55
2. PPIs are most effective when taken:
a. 30-60 minutes before the first meal of the day
b. 30-60 minutes after each meal
c. 30-60 minutes before bedtime
d. in the morning and the evening
Pg. 55
Issue 72 Questions
Introducing
3. The most effective drug for healing of peptic ulcers is:
a. an H2-receptor blocker
b. a PPI
c. an antacid
d. clarithromycin
Pg. 55
4. Pharmacologic tolerance occurs with continued use of:
a. an H2-receptor blocker
b. a PPI
c. an antacid
d. clarithromycin
Pg. 56
5. H. pylori can be diagnosed by:
a. a urea breath test
b. a stool antigen test
c. a biopsy of the gastric antrum
d. all of the above
Pg. 57
6. The most common first-line regimen for eradication of H. pylori is:
a. tetracycline, metronidazole and bismuth
b. amoxicillin, metronidazole and an H2-receptor blocker
c. clarithromycin, amoxicillin and a PPI
d. bismuth, metronidazole, tetracycline and a PPI
Pg. 57
7. Clarithromycin commonly causes:
a. tinnitus
b. disulfiram-type reaction
c. taste disturbances
d. all of the above
Pg. 58
8. Liquids that decrease lower esophageal sphincter pressure include:
a. coffee
b. wine
c. cola
d. all of the above
Pg. 58
9. For symptomatic relief of mild GERD, the fastest acting drug may be:
a. an antacid
b. an H2-receptor blocker
c. a PPI
Pg. 58
10. When lifestyle changes are unsuccessful in treating GERD
associated with pregnancy, a reasonable next step would be the
addition of:
a. sodium bicarbonate
b. antibiotics
c. ranitidine
d. omeprazole
Pg. 59
11. Anti-reflux surgery is commonly followed by:
a. dysphagia
b. bloating
c. diarrhea
d. all of the above
Pg. 59
12. Endoscopic therapy:
a. has comparable efficacy to medical therapy
b. appears to be safe
c. should be reserved for patients with intermittent symptoms
d. is not recommended for routine use
Pg. 59
ACPE UPN: 379-000-08-072-H01-P
Table
1. Some Drugs for Treating Tobacco Dependence Page 62
Volume 6 (Issue 73) September 2008
Tobacco dependence is a chronic disease that often
requires pharmacological therapy, but counseling
improves the effectiveness of any treatment for this
indication. The greater the number of office visits and
the longer the counseling time, the higher the smoking
cessation rates have been.
1
FIRST-LINE DRUGS
NICOTINE All nicotine replacement therapies
(NRTs) deliver nicotine, which acts as an agonist at the
nicotinic acetylcholine receptor, to the central nervous
system (CNS) in a lower dose and at a substantially slow-
er rate than tobacco cigarettes. All of these products
roughly double smoking cessation rates.
2
Nicotine is sub-
ject to first-pass metabolism, limiting the effectiveness of
oral pill formulations. Nicotine gum, lozenges and patch-
es are available without a prescription in the US; these
products appear to be as effective as those that require a
prescription (the oral inhaler and nasal spray).
3,4
When
using short-acting NRTs as monotherapy, the drugs
should be taken on a regular schedule to prevent nicotine
withdrawal symptoms. NRTs, particularly gum and
lozenges, may decrease weight gain associated with
smoking cessation.
Transdermal Nicotine patches deliver nicotine to
the CNS more slowly than any other NRT, taking 6-8
hours to achieve peak serum concentrations. High
doses of transdermal nicotine, up to 45 mg/16 hours,
appear to be safe, but no more effective than a stan-
dard dose (21 mg/24 hrs).
2,5
Starting treatment with a
nicotine patch before stopping smoking (the target
quit date) doubles the smoking cessation rate at 6
months.
6,7
Oral Oral nicotine is absorbed through the buccal
mucosa. Nicotine polacrilex gum, polacrilex
lozenges and oral inhalers are intermediate in CNS
delivery speed; serum nicotine concentrations reach a
peak in 20-60 minutes. The nicotine lozenge,
although available in 2- and 4-mg doses like the gum,
provides about 25% more nicotine because the
lozenge dissolves completely.
8
If nicotine from gum
or lozenges is swallowed, first-pass metabolism limits
its bioavailability.
Nasal Spray Nicotine nasal spray, by far the fastest-
acting of all nicotine formulations (but still much
slower than cigarettes), delivers a peak level to the
CNS in 5-20 minutes. Patients using the nasal spray
notice faster relief of nicotine withdrawal symptoms
than with other nicotine delivery systems. In a 1-year,
randomized, double-blind, placebo-controlled trial,
combination use of the nicotine patch for 5 months
with the nasal spray ad libitum for 1 year significant-
ly increased smoking cessation rates after 1 year, com-
pared to the nicotine patch used alone (27% vs. 11%).
Six years later the rates were 16% vs. 9%.
9
Adverse Effects Transdermal nicotine is general-
ly well tolerated, but some patients discontinue it
because of pruritus at the patch site, insomnia or vivid
dreams. Instructing the patient to remove the patch at
bedtime usually minimizes or eliminates vivid dreams
and other sleep disturbances. Patients who experience
skin irritation with one brand of nicotine patch may be
able to tolerate a different brand. The nicotine oral
inhaler may cause minor mouth and throat irritation
and cough; tolerance to the irritating effects usually
occurs within a day or two. Nicotine gum can cause
flatulence, indigestion, nausea, unpleasant taste, hic-
cups and a sore mouth, throat and jaw. Nicotine
lozenges may cause heartburn, hiccups and nausea
due to swallowed nicotine. Nicotine nasal spray
causes transient burning and stinging of the nasal
mucosa, throat irritation, flushing, coughing, sneez-
ing, lacrimation, rhinorrhea and nausea. These symp-
toms may diminish after about one week, but are a
common cause of drug discontinuation.
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 73) September 2008
Recommended doses of nicotine medications are gen-
erally safe in patients with cardiovascular disease; they
do not activate clotting, increase thrombogenesis or
cause myocardial infarction.
Drug Interactions Nicotine replacement products are
metabolized by CYP2A6, but do not inhibit or induce
CYP enzymes to any significant extent. Tobacco smoke,
not nicotine itself, induces the hepatic microsomal enzyme
CYP1A2, and may increase the metabolism and decrease
the effect of drugs that are CYP1A2 substrates.
10
These
include clozapine (Clozaril, and others), fluvoxamine
(Luvox CR, and others), olanzapine (Zyprexa, and others)
and theophylline (TheoDur, and others).
11
Doses of these
drugs may need to be lowered when patients stop smok-
ing, even though they are taking nicotine.
62
BUPROPION SR Bupropion is a dopamine-nor-
epinephrine reuptake inhibitor used mainly for treat-
ment of depression, but it also has some nicotine
receptor blocking activity.
12
The FDAhas approved a
sustained-release (SR) formulation of bupropion
(marketed as Zyban) for treatment of tobacco depend-
ence; the same drug is available generically, and as
Wellbutrin SR for treatment of depression.
Immediate-release bupropion, available both as a
generic and as Wellbutrin, has also been used to treat
tobacco dependence. Bupropion XL (Wellbutrin XL,
and others), an extended-release formulation taken
once daily in the morning, has not been studied for
use in tobacco dependence. Bupropion SR should be
started 7-14 days before the target quit date to allow
for adequate CNS steady-state levels. Typically,
Table 1. Some Drugs for Treating Tobacco Dependence
Daily
Adult FDA
Medication Forms Maintenance Approved Cost
1
First-Line
Nicotinic-Acetylcholine Receptor Agonists
Nicotine transdermal
2,3
7, 14, 21 mg/24 hr 1 patch/d
4
Yes
generic $ 76.50
NicoDerm CQ (Sanofi-aventis) 103.20
Nicotine nasal spray 0.5 mg/spray; 1 dose 8-40x/d Yes
Nicotrol NS (Pfizer) 1 dose = 2 sprays 178.00
5
Nicotine oral inhaler 10 mg cartridge 4-16 cartridges/d Yes
Nicotrol 178.08
6
Nicotine polacrilex
3
gum 2, 4 mg/piece 8-24 pieces/d Yes
generic 64.80
Nicorette (GSK) 96.00
Nicotine polacrilex lozenge
3
2, 4 mg/lozenge 8-20 lozenges/d Yes
generic 122.40
Commit
3
(GSK) 124.80
Dopaminergic-Noradrenergic Reuptake Inhibitors
Bupropion SR generic 50, 100, 150, 200 mg 150 mg 2x/d Yes 164.40
Wellbutrin SR sustained-release tabs No 210.00
Zyban (GSK) 150-mg sustained-release Yes 211.20
tabs
Nicotinic Receptor Partial Agonists
Varenicline Chantix (Pfizer) 0.5, 1 mg tabs 1 mg 2x/d Yes 129.60
Second-Line
Alpha
2
Adrenergic Agonists
Clonidine generic 0.1, 0.2, 0.3 mg tabs 0.2 or 0.3 mg No 15.60
Catapres (Boehringer 2x/d 113.40
Ingelheim)
Clonidine transdermal 0.1, 0.2, 0.3 mg/d/1 wk 1 patch/wk No
Catapres TTS patch 163.68
Noradrenergic-Serotonergic Reuptake Inhibitors
Nortriptyline generic 10, 25, 50, 75 mg caps 25 mg 3-4x/d No 61.20
1. Cost for 30 days treatment at the lowest dosage based on most recent data (June 30, 2008) from retail pharmacies nationwide available from
Wolters Kluwers Health.
2. See specific label for details regarding dose up-titration.
3. Available without prescription, over-the-counter (OTC). Do not eat or drink within 15 minutes of gum or lozenge therapy.
4. Wearing the 24-hr patch for 16 hrs yields the same dosage as a 16-hr patch, 15-mg nicotine.
5. Cost of 4 10-mL bottles; each 10-mL bottle contains 200 sprays.
6. Cost of 168 10-mg cartridges; each cartridge delivers 4 mg of nicotine.
patients start with 150 mg each morning for three
days, then increase to 150 mg bid.
Effectiveness Bupropion has been shown to be
effective for treating tobacco dependence in non-
depressed volunteers,
13
African-Americans,
14
adoles-
cents,
15
and primary care patients,
16,17
and for re-treat-
ing patients who used bupropion successfully in the
past, but relapsed after stopping it.
18
Arandomized, 9-week double-blind trial in 893 smokers
compared 300 mg of bupropion SR alone, transdermal
nicotine alone (21 mg/24 hours), or a combination of the
two. Nonsmoking rates after 4 weeks were 67% (bupro-
pion + nicotine), 60% (bupropion), 48% (nicotine) and
34% (placebo). Abstinence rates at 12 months were 36%
(combination), 30% (bupropion), 16% (nicotine) and
16% (placebo).
19
Combination therapy was not signifi-
cantly better than bupropion alone. Among 429 smokers
who quit after 7 weeks of bupropion SR, 55% were
abstinent after an additional 45 weeks on 300 mg daily
of the drug compared to 42% on placebo. After an addi-
tional year of followup, abstinence rates were similar
(41.6% vs. 40%). Weight gain was less with bupropion
(3.8 kg) than with placebo (5.6 kg).
20
Adverse Effects Few smokers have to stop bupropi-
on due to adverse effects. The most common adverse
effects in clinical trials were insomnia (35% with the
300-mg bupropion dose vs. 21% with placebo) and dry
mouth (13% vs. 5%); other reported effects included
headache, nausea, tinnitus and anxiety.
21
Wellbutrin SR
has been associated with a seizure incidence of 0.1%.
Among more than 2,000 patients who took the drug in
clinical trials for smoking cessation, there were no
seizures, but these patients were screened for seizure
risk before enrollment in the study. Patients with a his-
tory of seizure, stroke, brain tumor, brain surgery or
serious closed head injury should not take bupropion.
The risk of seizures may also be increased with bupro-
pion use in patients with anorexia-bulimia. In general,
bupropion treatment of tobacco dependence has been
well tolerated, and not associated with any major
adverse events. The FDArequires a warning about sui-
cide for bupropion similar to that required with other
antidepressants.
Drug Interactions Bupropion is extensively metab-
olized, primarily by CYP2B6 to hydroxybupropion, its
most active metabolite. Drugs that are inhibitors or
substrates of 2B6, such as cyclophosphamide, may
interact with bupropion. Potent inducers of hepatic
enzymes, such as rifampin (Rifadin, and others), car-
bamazepine (Tegretol, and others), phenytoin
(Dilantin, and others) or phenobarbital, and inhibitors
such as cimetidine (Tagamet, and others), may also
interact with bupropion. Bupropion and hydroxy-
bupropion are inhibitors of 2D6; many antidepressants,
antipsychotics, beta-blockers and type 1C antiarrhyth-
mics are substrates of 2D6 and should be used with
caution in patients taking bupropion. Use of bupropi-
on with MAO inhibitors, or within 2 weeks of stopping
an MAO inhibitor, is contraindicated.
VARENICLINE Varenicline tartrate (Chantix
Pfizer) is the second non-nicotine medication to gain
FDA approval for treating tobacco dependence.
22
A
partial agonist that binds selectively to alpha4/beta2
nicotinic acetylcholine receptors, it stimulates recep-
tor-mediated activity, relieving cravings and withdraw-
al symptoms during abstinence. Since varenicline
binds to the alpha4/beta2 receptor with greater affinity
than nicotine, it also acts as an antagonist to nicotine
delivery from active cigarette use, thus reducing the
reward of smoking.
Effectiveness Three comparative trials have found
varenicline more effective than bupropion SR. After 12
weeks of treatment, continuous abstinence rates for
placebo, bupropion SR and varenicline were, respective-
ly, 18%, 30% and 44%
23
; 18%, 30% and 44% again
24
;
and 17%, 33% and 48%.
25
A randomized, open-label
trial in more than 700 patients also found varenicline
more effective than transdermal nicotine, with continu-
ous abstinence rates of 56% vs. 43% at the end of the 12-
week trial, and 26% vs. 20% after 52 weeks.
26
A 6-month maintenance study found that among
patients who had quit smoking after 12 weeks of
varenicline, an additional 12 weeks of the drug was
more effective than placebo in preventing relapse.
Varenicline more than doubled the time to first relapse
during weeks 13-24: 198 days for varenicline vs. 87
days for placebo. Continuous abstinance rates for
weeks 13-24 were 50% with placebo and 71% with
varenicline.
27
Adverse Effects Varenicline was generally well tol-
erated in clinical trials. The most frequent adverse
events were nausea, sleep disturbances, abnormal
dreams, headache, constipation, vomiting, flatulence
and xerostomia.
24
Unlike bupropion SR and most nico-
tine drugs, varenicline does not reduce weight gain in
the short term after stopping smoking.
An FDA Warning The FDA has warned of neu-
ropsychiatric symptoms and exacerbations of pre-
existing psychiatric illness that occurred in patients
who were taking varenicline. The FDA warnings,
based on post-marketing adverse event reports, were
recently incorporated into the package insert of the
drug; serious symptoms, including agitation, changes
63
in behavior, depressed mood, suicidal ideation and sui-
cidal behavior, have occurred in patients who took
varenicline and continued to smoke as well as in those
who stopped. Smoking itself has been associated with
psychiatric disease.
28-30
Psychiatric symptoms includ-
ing suicidal ideation and completed suicide have been
associated both with smoking and with smoking cessa-
tion, and a dose-response relationship has been
described between smoking and suicide.
31
Independent of prior depression and substance abuse,
current smoking has been associated with suicidal
thoughts and attempted suicide.
32
In clinical trials
including about 2800 patients treated with varenicline,
there was no increase in treatment-emergent depres-
sion or suicide-related events.
Drug Interactions Varenicline is not metabolized in
the liver and has no clinically meaningful drug-drug
interactions. Co-administration of varenicline with
transdermal nicotine does not affect nicotine pharma-
cokinetics, but nausea, headache, vomiting, dizziness,
dyspepsia and fatigue may occur more frequently with
the two together than with transdermal nicotine alone.
Dosing Varenicline should be started at least 7 days
before the target quit date to allow for adequate
steady-state CNS levels. The recommended dosage is
0.5 mg once daily for 3 days, increasing to 0.5 mg
twice daily for days 4-7, and then increasing to the
maintenance dose of 1 mg twice daily for the remain-
der of the first 12 weeks of treatment. Patients who
have had a good treatment response during the first 12
weeks should continue varenicline for at least another
12 weeks. Dosage should be reduced in patients with
severe renal impairment.
COMBINATIONS The most commonly used com-
bination pharmacotherapy for tobacco dependence is a
nicotine drug with a rapid onset for cravings and a nico-
tine patch to provide steady nicotine levels. This com-
bination appears to be useful and may be more effective
than NRT monotherapy.
1,33
Although one study found
combining bupropion and the nicotine patch more effi-
cacious than either drug alone, other studies have not
reproduced these results.
19,34
Varenicline has not been
studied in combination with other medications.
DURATION Longer-duration pharmacotherapy
may improve smoking cessation.
1
Most patients who
want to stop smoking should receive a minimum of 3-
6 months of effective therapy. Generally, the dosage of
nicotine medications should be tapered at the end of
treatment; bupropion SR and varenicline can usually
be discontinued without a gradual reduction of dosage,
but some clinicians recommend a taper.
64
SECOND-LINE DRUGS
CLONIDINE Although not approved for this indi-
cation by the FDA, the antihypertensive drug cloni-
dine, an alpha
2
-adrenergic agonist available both as
tablets (Catapres, and others) and in a patch formula-
tion (Catapres TTS), can be used as a second-line
treatment for patients who cannot tolerate or do not
wish to use NRTs, bupropion or varenicline. Clinical
trial results have been mixed, but one meta-analysis
concluded that clonidine was effective.
35
Dosages for
tobacco dependence begin at 0.1 mg per day, increas-
ing slowly to the highest tolerated dose, which is usu-
ally about 0.3 mg per day. The main adverse effects
are dry mouth, sedation, dizziness and hypotension,
which appear to cause a higher discontinuation rate
than is found with NRTs, bupropion or varenicline.
NORTRIPTYLINE The tricyclic antidepressant
nortriptyline (Pamelor and others) has also improved
smoking cessation rates.
36,37
Adverse effects, similar to
those seen when nortriptyline is used for treatment of
depression, include sedation, dry mouth, blurred vision,
urinary retention, lightheadedness and tremor. Therapy
should start before stopping smoking to allow nortripty-
line to reach steady-state levels in the CNS. Dosing
should start at 25 mg per day and increase slowly to a
maximum of 75-100 mg per day. In one study in 158
patients, 6-month cessation rates were 23% with the
combination of nortriptyline and a nicotine patch and
10% with the patch alone, but the difference was not sta-
tistically significant.
38
OTHER POSSIBILITIES
NICOTINE VACCINE Several nicotine vaccines
are under investigation. These vaccines stimulate the
immune system to produce antibodies that bind circu-
lating nicotine and prevent it from crossing the blood-
brain barrier, thereby decreasing the pharmacologic
reward from smoking.
39
Phase II and early Phase III
clinical-trial results have shown promise for using
such vaccines in treating tobacco dependence.
39,40
RIMONABANT Rimonabant (Acomplia
Sanofi-Aventis), an antagonist of cannabinoid type 1
(CB1) receptors, decreases nicotine self-administra-
tion in rats.
41
In one randomized, double-blind, place-
bo-controlled trial in 784 tobacco-dependent study
participants, rimonabant 20 mg per day doubled the
smoking cessation rate, compared to placebo or
rimonabant 5 mg per day.
42
Rimonabant is approved
for treatment of obesity in some European countries,
but not in the US or Canada because of psychiatric
side effects.
TOPIRAMATE The anti-epileptic drug topiramate
(Topamax), which increases the activity of some
GABA receptors and attenuates the activity of some
glutamate receptors, has been effective off-label for
treatment of smoking in alcohol-dependent patients.
43
However, preliminary data for outpatient smokers
found topiramate no more effective than placebo in
lowering smoking cessation rates.
44
SSRIs AND MAO INHIBITORS Selective sero-
tonin reuptake inhibitors (SSRIs) are ineffective in
treating tobacco dependence.
34
Monoamine oxidase
(MAO) inhibitors have also been ineffective, but oral
selegiline (Eldepryl and others), an MAO B inhibitor
FDA-approved for the treatment of Parkinsons dis-
ease, may be an effective second-line drug for treat-
ment of tobacco dependence.
45
PATIENTS WITH RESPIRATORY DISEASES
Patients with chronic obstructive pulmonary disease
(COPD) who still smoke are particularly difficult to
treat. However, providing effective tobacco-depend-
ence treatment for these patients is the only way to
reverse the downward clinical course of COPD.
46
Both
bupropion SR and nortriptyline have been effective in
these patients.
47
The effectiveness of varenicline in
COPD patients is not yet known. Combination phar-
macotherapy has not been evaluated in COPD, but
should be more effective than monotherapy.
The response to inhaled corticosteroids, the foundation
of treatment for persistent asthma, is attenuated in
asthmatic patients who still smoke.
48
No tobacco-
dependence medications have been studied specifical-
ly in patients with asthma, but both first- and second-
line tobacco-dependence medications should be effec-
tive in such patients.
PREGNANCY
Counseling is the preferred treatment for pregnant
patients who smoke. Nicotine is classified by the FDA
as pregnancy category D (positive evidence of risk).
However, using nicotine replacement therapy during
pregnancy is probably safer for the fetus than smoking,
which increases the incidence of low birth weight
deliveries, and is associated with many peri- and post-
natal complications. Bupropion and varenicline are in
pregnancy category C (risk cannot be ruled out).
CONCLUSION
Tobacco dependence remains the chief preventable
cause of death in the United States, but it can be safe-
ly and effectively treated. Attempts to quit smoking are
improved by counseling. All of the nicotine replace-
ment therapies (NRTs) appear to be about equally
effective, but results may be better with the combina-
tion of a patch and a rapid-onset nicotine medication.
NRTs should be started 1-4 weeks before the target
quit date. Varenicline appears to be the most effective
single drug for treatment of tobacco dependence, but
bupropion has been available much longer and is also
well tolerated. The optimum duration of treatment is
not clear; 3-6 months is probably the minimum, and
some patients may need even longer treatment in order
to remain abstinent.
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14. JS Ahluwalia et al. Sustained-release bupropion for smoking cessation in
African Americans: Arandomized controlled trial. JAMA2002; 288:468.
15. ML Muramoto et al. Randomized, double-blind, placebo-controlled
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18. DH Gonzales et al. Bupropion SR as an aid to smoking cessation in
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19. DE Jorenby et al. Acontrolled trial of sustained-release bupropion, a nico-
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65
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 73) September 2008 66
Drugs for Osteoporosis
Mailing Address:
1000 Main Street
Customer Service:
Call: 800-211-2769 or 914-235-0500
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Permissions:
Subscriptions (US):
1 year - $98; 2 years - $167;
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24. DE Jorenby et al. Efficacy of varenicline, an alpha4beta2 nicotinic

acetylcholine receptor partial agonist, vs placebo or sustained-release
bupropion for smoking cessation: A randomized controlled trial.
JAMA2006; 296:56.
25. M Nides et al. Smoking cessation with varenicline, a selective
alpha4beta2 nicotinic receptor partial agonist: Results from a 7-week,
randomized, placebo- and bupropion-controlled trial with 1-year fol-
low-up. Arch Intern Med 2006; 166:1561.
26. HJ Aubin et al. Varenicline versus transdermal nicotine patch for
smoking cessation: results from a randomised open-label trial. Thorax
2008; 63:717.
27. S Tonstad et al. Effect of maintenance therapy with varenicline on smok-
ing cessation: Arandomized controlled trial. JAMA2006; 296:64.
28. BF Grant et al. Nicotine dependence and psychiatric disorders in the
United States: results from the national epidemiologic survey on alco-
hol and related conditions. Arch Gen Psych 2004; 61:1107.
29. RD Goodwin et al. Nicotine dependence and mental disorders among
adults in the USA: evaluating the role of the mode of administration.
Psychol Med 2008; 38:1277.
30. L Dierker and E Donny. The role of psychiatric disorders in the rela-
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35. LS Covey et al. Ameta-analysis of double-blind placebo-controlled tri-
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37. CLda Costa et al. Stopping smoking: Aprospective, randomized, double-
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39. DK Hatsukami et al. Safety and immunogenicity of a nicotine conju-
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40. EJ Wagena et al. The immunogenicity and safety of a nicotine vaccine
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Ann Pharmacother 2005; 39:684.
43. BA Johnson et al. Use of oral topiramate to promote smoking absti-
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44. RM Anthenelli et al. Preliminary evidence for gender-specific effects
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45. TP George et al. A preliminary placebo-controlled trial of selegiline
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46. NR Anthonisen et al. The effects of a smoking cessation intervention on
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142:233.
47. EJ Wagena et al. Efficacy of bupropion and nortriptyline for smoking
cessation among people at risk for or with chronic obstructive pul-
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48. SC Lazarus et al. Smoking affects response to inhaled corticosteroids
or leukotriene receptor antagonists in asthma. Amer J Respir Crit Care
Med 2007; 175:783.
.
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ADVISORY BOARD:
EDITORIAL FELLOW:
Founded in 1959 by
ADVISORY BOARD:
EDITORIAL FELLOW:
Founded in 1959 by
MISSION:
The expected outcome of the CME Program is that knowledge and consideration of the information contained in Treatment Guidelines can affect health
care practice.
The objective is to meet the need of health care professionals for unbiased, reliable and timely information on treatment of major diseases.
Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and drug classes. Participants will be able to
select and prescribe, or confirm the appropriateness of the prescribed usage of the drugs and other therapeutic modalities discussed in Treatment
Guidelines with specific attention to clinical evidence of effectiveness, adverse effects and patient management. Through this program, The Medical
Letter expects to provide the prescribing health care community with educational content that they will use to make independent and informed therapeu-
tic choices in their practice.
1. The fastest acting of nicotine replacement therapies is the:
a. patch
b. gum
c. lozenge
d. nasal spray
Pg. 61
2. To minimize or eliminate vivid dreams caused by nicotine patches,
patients should be told to:
a. remove the patch at night
b. take a short-acting benzodiazepine receptor agonist
c. seek counseling
d. use a mouthguard
Pg. 61
Issue 73 Questions
Introducing
3. In one controlled trial comparing it to transdermal nicotine, bupropion
was:
a. less effective
b. more effective
c. about equally effective
d. better tolerated
Pg. 63
4. In clinical trials, the most common adverse effect of bupropion was:
a. seizures
b. insomnia
c. dry mouth
d. suicidal thoughts
Pg. 63
5. Varenicline does which of the following:
a. reduces cravings
b. relieves withdrawal symptoms
c. antagonizes nicotine delivery from smoking
d. all of the above
Pg. 63
6. Compared to bupropion in clinical trials, varenicline was:
a. less effective
b. more effective
c. about the same
d. in various trials, all of the above
Pg. 63
7. The FDA has warned that varenicline may cause:
a. progressive multifocal leukoencephalopathy
b. Guillain-Barre syndrome
c. neuropsychiatric symptoms
d. Stevens-Johnson syndrome
Pg. 63
8. A combination of a nicotine patch and nicotine nasal spray would be:
a. more effective than either alone
b. no more effective than either alone
c. more toxic than either alone
Pg. 64
9. Clonidine can be used off-label for patients who:
a. cannot tolerate nicotine drugs
b. cannot tolerate bupropion
c. cannot tolerate varenicline
d. all of the above
Pg. 64
10. In treating tobacco dependence, SSRIs are:
a. the drugs of choice
b. contraindicated
c. modestly effective
d. ineffective
Pg. 65
11. For pregnant smokers, the treatment of choice is:
a. nicotine replacement therapy
b. bupropion
c. varenicline
d. counseling
Pg. 65
12. The most effective single medication for treatment of tobacco
dependence appears to be:
a. nicotine
b. bupropion
c. varenicline
d. clonidine
Pg. 65
ACPE UPN: 379-000-08-073-H01-P
Drugs for Postmenopausal Osteoporosis
Tables
1. Some Calcium Products Page 67
2. Calcium Content of Some Foods Page 68
3. Vitamin D Content of Some Foods Page 68
4. Some Drugs for Osteoporosis Page 70
5. Estrogen Preparations for Osteoporosis Page 71
Volume 6 (Issue 74) October 2008
Osteoporosis is characterized by low bone mass with
microarchitectural disruption and skeletal fragility
that results in an increased risk of fracture. The diag-
nosis has traditionally been established by bone den-
sitometry, which is generally reported in terms of
standard deviations (SD) from mean values in young
adults (T score). The World Health Organization
(WHO) has defined normal bone mineral density
(BMD) for women as a value within one SD of the
young adult mean. Values 2.5 SD (T score -2.5) or
more below the mean are defined as osteoporosis.
The WHO has developed a computerized model
(FRAX) that predicts the 10-year probability of hip
fracture based on clinical risk factors and BMD at the
femoral neck.
1
CALCIUM AND VITAMIN D Whether a life-
long increase in calcium intake decreases the risk of
osteoporosis is unclear. Calcium supplementation can
increase BMD in children and adolescents and reduce
bone loss in postmenopausal women and older men,
2
but 3 randomized trials found that it did not reduce
the fracture rate in older women.
3-5
Asubgroup analy-
sis of the largest of these trials, the Womens Health
Initiative (WHI) reported a reduction in fractures
among the women who were most compliant with
calcium and vitamin D supplementation.
5
A meta-
analysis in patients >60 years old indicated that a
minimum of 700 IU/d of vitamin D
3
(cholecalciferol),
with or without calcium supplementation, could pre-
vent nonvertebral fractures.
6
Another meta-analysis
reported that use of calcium alone or calcium plus
vitamin D reduced fractures of all types, especially
with calcium doses of >1200 mg/d and with vitamin
D >800 IU/d.
7
Other meta-analyses also found a
reduction in fractures when vitamin D and calcium
were taken together.
8,9
Recommendations The Institute of Medicine rec-
ommends a daily elemental calcium intake of 1000
mg for all adults 19-50 years old, including pregnant
and lactating women, and 1200 mg for everyone over
the age of 50. Calcium supplements are available in a
variety of salts with varying concentrations of ele-
mental calcium. Calcium citrate can be taken with or
without food. Calcium carbonate should be taken
with food to enhance calcium absorption.
Absorption of calcium is incomplete, usually averag-
ing 10-12%; vitamin D is necessary for optimal
absorption. Vitamin D status can be evaluated by
measuring serum concentrations of 25-hydroxy vita-
Ca
*
D
3
*
1
Drug (mg) (IU) Tabs/d
2
Cost
3
Calcium Carbonate
4
Caltrate +D (Lederle) 600 400 2 $5.85
Os-Cal 500+D (GSK) 500 400 2 8.50
Tums EX 750 (GSK) 300 3 5.79
Viactiv (McNeil)
5
500 100 2 8.49
Calcium Citrate
4
Citracal +D (Mission) 315 200 3 9.74
Calcium Citrate 1000 250 4 10.99
(GNC)
Calcium Complex (carbonate, lactate, gluconate)
Calcet (Mission) 150 100 7 17.40
Calcium Phosphate
Posture-D (Inverness)
6
600 125 2 11.49
* Content per tablet.
1. Absorbed better than other forms.
2. Needed to provide about 1,000 mg elemental calcium daily.
3. Retail cost for a 30-day supply from drugstore.com. Accessed
September 5, 2008.
4. Available generically.
5. Available as a soft chewable preparation and in tablet form; also
contains 40 mcg vitamin K.
6. Also contains 266 mg phosphorus.
Table 1. Some Calcium Products
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 74) October 2008 68
dosing in increasing BMD and may be better tolerated.
Alendronate is the only bisphosphonate available
generically in the US.
In more than 4000 postmenopausal women 54-81 years
old with low BMD (femoral neck T score < -1.6), alen-
dronate 5 mg/d for 2 years, followed by 10 mg/d for 2
more years, increased BMD at all sites and significant-
ly lowered the incidence of new radiographic vertebral
fractures from 78 (3.8%) with placebo to 43 (2.1%)
with alendronate. Among women with a T-score of
<-2.5, the incidence of clinical fractures was reduced
from 158 (19.6%) with placebo to 107 (13.1%) with
alendronate.
13
Among 2000 postmenopausal women
with low bone mass and at least one vertebral fracture
at baseline, hip fractures occurred in 22 women (2.2%)
on placebo and in 11 (1.1%) taking alendronate.
14
In a
continuation study, 1099 postmenopausal women who
had received alendronate for 5 years were randomized
to an additional 5 years of alendronate or placebo;
patients who received the additional years of alen-
dronate had a statistically significant decrease in clini-
cally recognized vertebral fractures (2.4% vs. 5.3%) but
not in nonvertebral fractures.
15
A study in 247 postmenopausal women with osteo-
porosis treated with alendronate for up to 10 years
found that spinal BMD continued to increase through-
out the study period; the lowest rate of clinical verte-
bral fractures occurred in the women who took the
drug for the entire 10-year period.
16
Risedronate The second oral bisphosphonate
approved for prevention and treatment of osteoporosis
in postmenopausal women, risedronate (Actonel) is
available in daily, once-weekly, twice-monthly and
once-monthly formulations, which all appear to have
equivalent effects on BMD.
17-20
A 24-month trial in postmenopausal women with low
BMD (T score <-2.0) found that 5 mg daily of rise-
Serving Calcium
Food size content (mg)
Yogurt, lowfat, fruit-flavored 8 oz 345
Figs, dried 10 figs 310
Milk, skim 1 cup 306
Collards, cooked 1 cup 266
Swiss cheese 1 oz 224
Gruyere cheese 1 oz 214
Mozzarella cheese, 1 oz 207
part-skim
Cheddar cheese 1 oz 204
Calcium-fortified 6 oz 200
orange juice
Tofu, raw, firm block 163
American cheese, 1 oz 162
processed
Creamed cottage cheese 1 cup 126
Mustard greens 1 cup 104
Breakfast cereals, Ca fortified
2
cup 100
Kale, boiled 1 cup 94
Broccoli, boiled 1 cup 62
Parmesan cheese, grated 1 tbsp 55
1. US Department of Agriculture, Agricultural Research Service
Nutrient Data Laboratory (www.nal.usda.gov/fnic/foodcomp/search/)
Accessed September 10, 2008.
2. Calcium content varies, Total Whole Grain cereal (General Mills)
contains 1000 mg of calcium per serving.
Table 2. Calcium Content of Some Foods
1
min D (25-OH-D); >30 ng/mL (>75 nmol/L) may be
optimal and <20 ng/mL (<50 nmol/L) is generally
considered deficient.
10,11
In an observational nested
case-control study, levels of 25-OH-D <19 ng/mL
(47.5 nmol/L) were associated with an increased risk
of hip fracture compared to levels >28 ng/mL (71
nmol/L).
12
The National Osteoporosis Foundation rec-
ommends a daily intake of 400-800 IU of vitamin D
for adults <50 years old, and 800-1000 IU of vitamin
D daily for adults >50 years old. Some patients may
require more than the recommended daily intake of
vitamin D to achieve concentrations of >30 ng/mL.
Adverse Effects Calcium supplements are generally
well tolerated. Constipation, intestinal bloating and
excess gas can occur. A slightly higher risk of kidney
stones has been reported among women with high
baseline calcium intake.
5
BISPHOSPHONATES These nonhormonal
agents decrease bone resorption by binding to active
sites of bone remodeling and inhibiting osteoclasts.
Food, calcium supplements, antacids and other med-
ications containing divalent cations, such as iron, may
interfere with their absorption from the gastrointestinal
(GI) tract. Fracture data for oral bisphosphonates are
available only for once-daily formulations.
Alendronate Alendronate (Fosamax, and others) is
an oral bisphosphonate approved for daily or once-
weekly use for prevention and treatment of osteoporo-
sis. Weekly dosing appears to be as effective as daily
Serving Vitamin D
Food size content (IU)
Herring 3 oz 1383
Cod liver oil 1 tbsp (15 mL) 1360
Salmon, cooked 3.5 oz 360
Mackerel, cooked 3.5 oz 345
Sardines, canned 1.75 oz 250
Tuna, canned 3 oz 200
Soy Milk (fortified) 8 oz 100
Milk, skim (fortified) 8 oz 100
Egg, whole 1 20
1. US Department of Agriculture, Agricultural Research Service
Nutrient Data Laboratory (www.nal.usda.gov/fnic/foodcomp/search).
Accessed September 10, 2008. Breakfast cereals, margarine and
many other products are often fortified with vitamin D.
Table 3. Vitamin D Content of Some Foods
1
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 74) October 2008
dronate increased spine BMD by a mean of 4.1% and
femoral neck BMD by 1.3%, while the group receiving
placebo showed either no change or a decrease in
BMD at these sites.
21
An analysis of 630 postmenopausal women with very
low BMD (mean T-score -3.3) without pre-existing
vertebral fractures found that the incidence of first frac-
ture in women who took risedronate 5 mg daily for up
to 3 years was 2.6% compared to 9.4% with placebo.
22
A 3-year placebo-controlled trial in more than 9000
elderly women found that risedronate 2.5 or 5 mg/d in
patients with osteoporosis significantly decreased the
incidence of hip fractures from 3.2% to 1.9%; patients
> 80 years old at high risk for fracture who took rise-
dronate did not have a significant decrease in the inci-
dence of hip fracture (5.1% vs. 4.2%).
23
In women
with postmenopausal osteoporosis treated with rise-
dronate 5 mg daily for 7 years, increases in BMD were
maintained over the duration of the study, and the risk
of vertebral fractures after 5 years was significantly
lower with risedronate than with placebo.
24
A 3-year trial in about 1300 postmenopausal women
(average age 69) with low bone mass and at least one
vertebral fracture found 61 (11%) new vertebral
fractures with risedronate daily and 93 (16%) with
placebo, a significant difference. Nonvertebral frac-
tures also decreased significantly in the group receiv-
ing risedronate compared to placebo (33 vs. 52).
25
In
an extension of this study, women were re-evaluated
one year after discontinuing treatment. BMD
decreased and bone turnover markers returned to base-
line. The incidence of new vertebral fractures, howev-
er, remained significantly lower (6.5 vs. 11.6%) in the
former risedronate users.
26
Ibandronate Ibandronate (Boniva) is approved for
both prevention and treatment of postmenopausal
osteoporosis. The recommended oral dose is 2.5 mg
daily or 150 mg once monthly. Daily oral ibandronate
reduced the incidence of vertebral fractures in osteo-
porotic women, and appeared to reduce the incidence
of nonvertebral fractures in a small subgroup of high-
risk women with markedly reduced femoral neck
BMD.
27
Monthly oral ibandronate appears to be at
least as effective in increasing BMD and as well toler-
ated as taking the drug daily.
28
Intravenous (IV) ibandronate has also been approved
for the treatment of postmenopausal osteoporosis. In a
non-inferiority trial, 1358 postmenopausal women
with osteoporosis were randomized to ibandronate 3
mg IV every 3 months, 2 mg IV every 2 months, or 2.5
mg oral ibandronate daily. The 1-year results demon-
strated that lumbar spine BMD, the primary endpoint,
increased 4.8% with the 3 mg IVdose, 5.1% with 2 mg
and 3.8% with the oral dose.
29
No fracture data are
available for IV ibandronate.
Zoledronic Acid Zoledronic acid (Reclast) is the first
bisphosphonate approved by the FDA for once-yearly
IV treatment of osteoporosis in postmenopausal
women.
30
In the 3-year HORIZON Pivotal Fracture
Trial, new hip fractures occurred in 52 of 3875 women
(1.4%) infused annually with 5 mg of IVzoledronic acid
vs. 88 of 3861 (2.5%) infused with placebo, a statistical-
ly significant difference. Other nonvertebral fractures
and clinical vertebral fractures were also significantly
decreased in drug-treated patients.
31
In the HORIZON
Recurrent Fracture Trial, among men and women who
had had surgical repair of a hip fracture within 90 days
and were unable or unwilling to take oral bisphospho-
nates, new fractures occurred after a median of 1.9 years
follow-up in 92 (8.6%) of 1065 patients infused once a
year with zoledronic acid 5 mg and in 139 (13.9%) of
1062 placebo-treated patients. Significantly fewer
deaths from all causes occurred in patients who received
zoledronic acid (9.6% vs. 13.3%).
32
The optimal dura-
tion of yearly treatment and its long-term safety (>3
years) have not been established.
Adverse Effects Oral alendronate, risedronate or
ibandronate can cause heartburn, esophageal irritation,
esophagitis, abdominal pain, diarrhea and other adverse
GI effects. To ensure adequate absorption and avoid
esophageal injury, they must be taken after an overnight
fast, while in an upright position, along with 8 ounces
of plain (not mineral) water. After taking the drug, the
patient must take nothing by mouth except plain water
for at least 30 minutes (60 minutes with ibandronate)
and avoid lying down. GI adverse effects have occurred
even when patients followed these instructions.
Severe bone, joint and muscle pain have been report-
ed with the bisphosphonates. Ocular inflammation
has also been reported. Hypocalcemia can occur, typ-
ically in those with vitamin D deficiency. IV bispho-
sphonates have been associated with an acute phase
reaction with low-grade fevers, myalgias, and arthral-
gias within 1-3 days of the infusion most frequently
with the first infusion; NSAIDs or acetaminophen
can diminish these symptoms. Acute phase reactions
have also been reported with monthly formulations of
oral bisphosphonates. Osteonecrosis of the jaw (ONJ)
has been described with chronic use of bisphospho-
nates. The majority of cases have occurred in cancer
patients or in patients with compromised immunity
given IV bisphosphonates. Rare cases have been
reported with oral bisphosphonates prescribed for
postmenopausal osteoporosis.
33
The risk of ONJ with
69
FDA-Approved
Drug Indication Dosage
1
Cost
2
Oral Bisphosphonates
Alendronate
generic Prevention 35 mg/wk $ 105.00
3
Fosamax (Merck)
4
1033.76
generic Treatment 70 mg/wk 105.00
3
Fosamax (Merck)
4
1055.60
Fosamax Plus D 70 mg + 2800 IU D
3
/wk 1107.60
70 mg + 5600 IU D
3
/wk 1095.64
Ibandronate Boniva (Roche/GSK) Prevention, Treatment 150 mg/mo 1174.56
Risedronate Actonel (Procter & Gamble) Prevention, Treatment 35 mg/wk 1187.16
75 mg x2d/mo 1174.08
150 mg/mo 1173.84
Actonel with Calcium 35 mg once/wk + 1081.92
500 mg Ca other days
Intravenous (IV) Bisphosphonates
Ibandronate
Boniva (Roche/GSK) Treatment 3 mg IV every 3 mos 1881.80
Zoledronic acid
5

Reclast (Novartis) Treatment 5 mg IV once/yr 1212.00
Selective Estrogen Receptor Modulator
Raloxifene Evista (Lilly) Prevention, Treatment 60 mg/d 1310.35
Calcitonin Treatment
Fortical Nasal Spray (Upsher-Smith) 200 IU intranasal/d 1093.56
Miacalcin Nasal Spray (Novartis) 200 IU intranasal/d 1433.16
Parathyroid Hormone
Teriparatide Forteo (Lilly) Treatment 20 mcg SC/d 8478.30
1. Alendronate, ibandronate and risedronate are also available in smaller oral doses given daily.
2. Cost of one years treatment based on the most recent data available (August 31, 2008) from Wolters Kluwer Health.
3. The cost of generic alendronate (35 mg/wk or 70 mg/wk) for 4 weeks is $9 and for 12 weeks is $24 at Walmart, Target and some other stores.
4. Fosamax is also available in a 70 mg/75 mL liquid formulation.
5. Zoledronic acid is also available in a 4-mg formulation (Zometa) for treatment of hypercalcemia of malignancy, multiple myeloma and bone meta-
stasis from solid tumors.
Table 4. Some Drugs for Osteoporosis
IV bisphosphonates in the doses recommended for
osteoporosis is unknown.
Bisphosphonates have also been associated with atri-
al arrhythmias. In one study, the percentage of
patients who developed serious atrial fibrillation was
significantly greater with zoledronic acid than with
placebo (1.3% vs. 0.5%).
31
A subsequent trial with
zoledronic acid in a smaller number of older patients
with recent hip fracture did not find an increase in
atrial fibrillation.
37
In a case-control study, use of
alendronate was associated with an increased risk of
incident atrial fibrillation in women.
34
Long-term Bone Strength The half-life of alen-
dronate in bone can be as long as 10 years. Whether
long-term suppression of bone turnover could weaken
bone rather than strengthen it is unknown. In one
report, 9 patients with nonvertebral fractures who had
taken alendronate for 3-8 years (5 of the 9 patients
were also on estrogen or corticosteroids) showed evi-
dence on bone biopsy of severe suppression of bone
formation.
35
Case reports have also described atypical
low-energy fractures of the femoral shaft in patients
on long-term alendronate.
36
Some Medical Letter con-
sultants stop the bisphosphonate temporarily after 5
years if bone turnover markers are markedly sup-
pressed, and resume the drug if bone turnover markers
increase or BMD falls. Overall, there is no consensus
on the optimal duration of bisphosphonate treatment.
RALOXIFENE Raloxifene (Evista)
37
is a selec-
tive estrogen receptor modulator (SERM) with estro-
gen-like effects on bone and antiestrogen effects on
the uterus and breast. It is approved by the FDA for
both prevention and treatment of postmenopausal
osteoporosis. In 7705 postmenopausal women with
established osteoporosis, lumbar spine and femoral
neck BMD after 3 years were 2.1-2.7% higher with
raloxifene than with placebo. Among women taking
60 mg and 120 mg of raloxifene, 6.6% and 5.4%
respectively had new vertebral fractures, compared
71
FDA-Approved
Drug Indication Dosage Cost
1
Estrogens
2
Oral Estrogens Prevention
Estradiol, micronized generic 0.5 mg/d $ 40.00
3
Estrace (Warner Chilcott) 627.80
Gynodiol (Fielding)
Esterified estrogens Menest (Monarch) 0.3 mg/d 215.35
Estropipate generic 0.75 mg/d 40.00
3
Ogen (Pharmacia) 416.10
Ortho-est (Women First Healthcare) 324.85
Conjugated equine estrogens
Premarin (Wyeth) 0.3 mg/d 580.35
Oral Estrogen-Progestin Combinations Prevention
Estradiol/norgestimate
Prefest (Duramed) 1 mg/d x 3 days, followed by 673.20
Estradiol/norethindrone acetate
Activella (Novo Nordisk) 1 mg/0.5 mg/d 719.04
Femhrt (Warner Chilcott) 5 mg/1 mg/d 688.80
Conjugated equine estrogens/medroxyprogesterone
Premphase (Wyeth) 0.625 mg/d days 1-14, then
0.625 mg/5 mg/d days 15-28 675.36
Prempro (Wyeth) 0.3 mg/1.5 mg/d 672.00
Transdermal Estrogens Prevention
Estradiol, transdermal
generic 15.5 cm
2
patch/wk (0.05 mg/d) 424.84
Alora (Watson) 18 cm
2
patch 2x/wk (0.05 mg/d) 576.16
Climara (Berlex) 6.5 cm
2
patch/wk (0.025 mg/d) 620.88
Estraderm (Novartis) 10 cm
2
patch 2x/wk (0.05 mg/d) 678.08
Menostar (Berlex) 3.25 cm
2
patch once/wk (0.014 mg/d) 735.28
Vivelle (Novartis) 7.25 cm
2
patch 2x/wk (0.025 mg/d) 446.16
Vivelle Dot 2.5 cm
2
patch 2x/wk (0.025 mg/d) 631.28
1. Cost of one years treatment based on the most recent data available from Wolters Kluwer Health.
2. Estrogen products are available in many sizes. For a woman with an intact uterus, a progestin must be added to estrogen therapy. Oral estrogens
are usually given continuously or in a cyclic regimen. Medroxyprogesterone is available for $4 for 1 month or $10 for 3 months from Walmart, Target
and some other stores.
3. At Walmart, Target and some other stores.
Table 5. Estrogen Preparations for Osteoporosis
to 10.1% in the placebo group, a statistically signifi-
cant difference. The risk of nonvertebral fractures,
however, was about the same after 8 years in both
groups
38,39
In a trial designed to examine the effects of raloxifene
on coronary heart disease (CHD) and breast cancer,
10,101 postmenopausal women randomized to either
60 mg of raloxifene daily or placebo and followed for
a median of 5.6 years. Raloxifene significantly
reduced the risk of clinical vertebral fractures (64 vs.
97 events), but not nonvertebral fractures.
40
Other Benefits Clinical trials in postmenopausal
women with osteoporosis taking raloxifene have
shown a marked reduction in the incidence of invasive
estrogen receptor (ER) positive breast cancer, but no
decrease in ER negative invasive breast cancer or non-
invasive breast cancer.
41,42
Raloxifene has not been
shown to decrease or increase the incidence of
endometrial hyperplasia or uterine cancer.
Adverse Effects Hot flashes, leg cramps and periph-
eral edema can occur in patients taking raloxifene.
Like estrogens, raloxifene increases the risk of throm-
boembolic events; in one study the risk of pulmonary
emboli after 8 years of use was 0.62% with raloxifene
compared to 0.16% with placebo.
41
In another study in
postmenopausal women with CHD or at high risk for
CHD, raloxifene increased the risk of fatal stroke and
venous thromboembolism.
40
ESTROGEN In some women, lack of estrogen
after menopause is associated with rapid bone loss. A
number of estrogen products are available for preven-
tion of osteoporosis; none are approved for treatment.
In the Womens Health Initiative, a placebo-con-
trolled, randomized trial of daily oral conjugated
equine estrogens plus medroxyprogesterone (0.625
mg/2.5 mg; Prempro) in healthy postmenopausal
women, the number of hip fractures after an average
follow-up of 5.6 years was lower in women taking
estrogen plus a progestin (52/8506; 0.6%) than in
those taking placebo (73/8102; 0.9%). The number of
vertebral fractures was also significantly lower with
the hormones (41 vs. 60).
43
Findings were similar in
women without a uterus receiving estrogen alone.
44
Women who have an intact uterus are advised to take a
progestin in addition to estrogen to lower the risk of
endometrial cancer. However, given its adverse effect
profile, estrogen is no longer used as a first-line thera-
py for prevention of postmenopausal osteoporosis.
Adverse Effects The estrogen-plus-progestin arm of
the Womens Health Initiative was stopped premature-
ly because of an increased incidence of coronary
events (cardiac death or myocardial infarction), stroke,
pulmonary emboli and breast cancer. The estrogen-
only arm showed an increased risk of stroke, but no
statistically significant effect on cardiovascular or
breast cancer risk. Long-term use of estrogen may also
increase the risk of ovarian cancer.
45
The long-term safety of taking estrogen in lower doses
or in different formulations remains unknown.
PARATHYROID HORMONE Unlike other drugs
available for osteoporosis, which act by decreasing
bone turnover, low-dose, intermittent subcutaneous
injection of parathyroid hormone (PTH) increases
bone density by stimulating bone formation.
Teriparatide (Forteo), the 1-34 sequence of PTH, was
approved by the FDAfor treatment of osteoporosis for
up to 2 years in both men and postmenopausal women
at high risk for fractures. A prospective, placebo-con-
trolled trial in 1637 women with postmenopausal
osteoporosis and at least one vertebral fracture who
received injections of teriparatide 20 or 40 mcg once
daily for 21 months found a significant decrease in the
incidence of vertebral (4-5% vs. 14%) and nonverte-
bral fractures (3% vs. 6%) compared to placebo.
46
Another recombinant PTH (Preos in US; available as
Preotact in Europe), which has the full 1-84 sequence
and is currently being reviewed by the FDA, has also
been shown to improve BMD and decrease the risk of
vertebral fracture.
47
Adverse Effects Adverse effects of PTH have
included nausea, headache, dizziness and muscle
cramps.
48
Hypercalcemia has been reported; it can
generally be corrected by decreasing calcium or vita-
min D supplementation.
49
The FDA, based on animal
data, has included a black box warning regarding a risk
of osteosarcoma in the labeling.
CALCITONIN Salmon calcitonin, a peptide hor-
mone approved by the FDA for treatment of osteo-
porosis, decreases bone resorption by inhibiting osteo-
72
clast function. It may also have an analgesic effect. A
5-year trial in 1200 women with osteoporosis found
new vertebral fractures in 51 of 287 (18%) receiving a
200 IU dose of calcitonin nasal spray once daily and in
70 of 270 (26%) receiving a placebo, a statistically sig-
nificant difference. The incidence of fractures with a
higher dose of 400 IU (61/278; 22%) was not signifi-
cantly lower than placebo.
50
Adverse Effects Rhinitis and occasional epistaxis have
occurred with the intranasal calcitonin.
DENOSUMAB Denosumab is an investigational
human monoclonal antibody that inhibits osteoclast
formation and activation. The drug has been shown to
increase BMD and decrease bone turnover markers
when given subcutaneously once every 6 months.
51
COMBINATION THERAPY Additive effects on
BMD and biochemical markers of bone turnover have
been demonstrated with combinations of alendronate
and either estrogen or raloxifene. Whether such a com-
bination has an additive effect in reducing the risk of
fractures has not been established. There is also a the-
oretical concern that combination treatment with 2 dif-
ferent antiresorptive agents could oversuppress bone
turnover and increase the risk of fractures.
35
One study in 126 patients already taking oral alen-
dronate weekly found that adding a synthetic PTH (1-
34) daily, or cyclically for 3 months on and 3 months
off, for 15 months increased spinal BMD more than
taking alendronate alone; BMD increases were similar
whether PTH was given daily or intermittently.
52
However, in other studies, treatment with PTH and
alendronate, or alendronate prior to PTH, delayed or
decreased the effects of PTH on bone turnover and
BMD.
53-55
When given prior to PTH, other anti-resorp-
tives, such as raloxifene or risedronate, may not have
this effect.
53,56
No fracture data are available with any
of these regimens.
Declines in BMD have been reported after PTH is dis-
continued; subsequent therapy with alendronate has
been shown to maintain the densitometric gains from
PTH.
57
Subsequent treatment with raloxifene has also
been shown to help prevent bone loss following PTH
treatment.
58
The effect of this sequence of therapy on
fracture risk has not been determined, but given the
decline in BMD after cessation of PTH, most Medical
Letter consultants recommend following teriparatide
with a bisphosphonate.
CONCLUSION To decrease the risk of osteoporo-
sis, patients of both sexes and all ages should maintain
an adequate intake of calcium and vitamin D. The oral
bisphosphonates have been shown to prevent vertebral
and nonvertebral fractures in postmenopausal women
with osteoporosis, and all appear to be relatively safe.
Weekly or monthly doses of bisphosphonates have been
at least as effective as daily doses in increasing BMD
and are probably better tolerated. IV bisphosphonates
such as ibandronate or zoledronic acid are effective
alternatives. Raloxifene is effective in preventing verte-
bral fractures but has thromboembolic effects similar to
those of estrogen. Estrogen with or without a progestin
is effective in preventing fractures in postmenopausal
women, but cardiovascular and cancer risks may out-
weigh the fracture benefits. Once-daily injections of
teriparatide increase BMD and decrease the incidence
of vertebral and nonvertebral fractures in patients at
high risk for fracture.
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12. JA Cauley et al. Serum 25-hydroxyvitamin D concentrations and risk
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14. DM Black et al. Randomised trial of effect of alendronate on risk of
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15. DM Black et al. Effects of continuing or stopping alendronate after 5
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in postmenopausal women. N Engl J Med 2004; 350:1189.
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women with low bone mass: results from a multinational, double-blind,
placebo-controlled trial. BMD-MN Study Group. J Clin Endocrinol
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22. RP Heaney et al. Risedronate reduces the risk of first vertebral fracture
in osteoporotic women. Osteoporos Int 2002; 13:501.
23. MR McClung et al. Effect of risedronate on the risk of hip fracture in
elderly women. Hip Intervention Program Study Group. N Engl J Med
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24. DD Mellstrom et al. Seven years of treatment with risedronate in
women with postmenopausal osteoporosis. Calcif Tissue Int 2004;
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25. ST Harris et al. Effects of risedronate treatment on vertebral and non-
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domized controlled trial. Vertebral Efficacy With Risedronate Therapy
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26. NB Watts et al. Fracture risk remains reduced one year after discontinu-
ation of risedronate. Osteoporos Int 2008; 19:365.
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efficacy in North American and European women: new clinical find-
ings from BONE. Curr Med Res Opin 2005; 21:391.
28. PD Miller et al. Monthly oral ibandronate therapy in postmenopausal
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2005; 20:1315.
29. PD Delmas et al. Intravenous ibandronate injections in postmenopausal
women with osteoporosis: one-year results from the dosing intravenous
administration study. Arthritis Rheum 2006 Jun; 54:1838.
30. A once-yearly IV bisphosphonate for osteoporosis. Med Lett Drugs
Ther 2007; 49:89.
31. DM Black et al. Once-yearly zoledronic acid for treatment of post-
menopausal osteoporosis. N Engl J Med 2007; 356:1809.
32. KW Lyles et al. Zoledronic acid and clinical fractures and mortality
after hip fractures. N Engl J Med 2007; 357:1799.
33. SB Woo et al. Systemic review: bisphosphonates and osteonecrosis of
the jaws. Ann Intern Med 2006; 144:753.
34. SR Heckbert et al. Use of alendronate and risk of incident atrial fibrilla-
tion in women. Arch Intern Med 2008; 168:826.
35. CV Odvina et al. Severely suppressed bone turnover: a potential com-
plication of alendronate therapy. J Clin Endocrinol Metab 2005;
90:1294.
36. BA Lenart et al. Atypical fractures of the femoral diaphysis in post-
menopausal women taking alendronate. N Engl J Med 2008; 358:1304.
37. Raloxifene for postmenopausal osteoporosis. Med Lett Drugs Ther
1998; 40:29.
38. B Ettinger et al. Reduction of vertebral fracture risk in postmenopausal
women with osteoporosis treated with raloxifene: results from a 3-year
randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation
(MORE) Investigators. [MORE]. JAMA1999; 282:637.
39. ES Siris et al. Skeletal effects of raloxifene after 8 years: results from
the continuing outcomes relevant to Evista (CORE) study. [CORE]. J
Bone Miner Res 2005; 20:1514.
40. E Barrett-Connor et al. Effects of raloxifene on cardiovascular events
and breast cancer in postmenopausal women. N Engl J Med 2006;
355:125.
41. S Martino et al. Continuing outcomes relevant to Evista: breast cancer
incidence in postmenopausal osteoporotic women in a randomized trial
of raloxifene. J Natl Cancer Inst 2004; 96:1751.
42. D Grady, et al. Reduced incidence of invasive breast cancer with ralox-
ifene among women at increased coronary risk. J Natl Cancer Inst
2008; 100:854.
43. JA Cauley et al. Effects of estrogen plus progestin on risk of fracture
and bone mineral density: the Womens Health Initiative randomized
trial. JAMA2003: 290:1729.
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44. Womens Health Initiative. Effects of conjugated equine estrogen in
postmenopausal women with hysterectomy: the womens health initia-
tive randomized controlled trial. JAMA2004; 291:1701.
45. JV Lacey, Jr et al. Menopausal hormone replacement therapy and risk
of ovarian cancer. JAMA2002; 288:334.
46. RM Neer et al. Effect of parathyroid hormone (1-34) on fractures and
bone mineral density in postmenopausal women with osteoporosis. N
Engl J Med 2001; 344:1434.
47. SLGreenspan et al. Effect of recombinant human parathyroid hormone
(1-84) on vertebral fracture and bone mineral density in post-
menopausal women with osteoporosis: a randomized trial. Ann Intern
Med 2007; 146:326.
48. PJ Kakaria et al. Debilitating muscle cramps after teriparatide therapy.
Ann Intern Med 2005; 142:310.
49. E Canalis et al. Mechanisms of anabolic therapies for osteoporosis. N
Engl J Med 2007; 357:905.
50. CH Chesnut III et al. A randomized trial of nasal spray salmon calci-
tonin in postmenopausal women with established osteoporosis: the
prevent recurrence of osteoporotic fractures study. PROOF Study
Group. Am J Med 2000; 109:267.
51. HG Bone et al. Effects of denosumab on bone mineral density and
bone turnover in the postmenopausal women. J Clin Endocrinol Metab
2008; 93:2149.
52. F Cosman et al. Daily and cyclic parathyroid hormone in women
receiving alendronate. N Engl J Med 2005; 353:566.
53. B Ettinger et al. Differential effects of teriparatide on BMD after treat-
ment with raloxifene or alendronate. J Bone Miner Res 2004; 19:745.
54. JS Finkelstein et al. Effects of teriparatide, alendronate, or both on
bone turnover in osteoporotic men. J Clin Endocrinol Metab 2006;
91:2882.
55. DM Black et al. The effects of parathyroid horomone and alendronate
alone after or in combination in postmenopausal osteoporosis. N Engl J
Med 2003; 349:1207.
56. PD Miller et al. Early responsiveness of women with osteoporosis to
teraparatide following therapy with alendronate or risedronate. J Clin
Endocrinol Metab 2008; August 5 (epub).
57. DM Black et al. One year of alendronate after one year of parathyroid
hormone (1-84) for osteoporosis. N Engl J Med 2005; 353:555.
58. S Adami et al. Effect of raloxifene after recombinant teriparatide
[hPTH(1-34)] treatment in postmenopausal women with osteoporosis.
Osteoporos Int 2008; 19:87.
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CONTRIBUTING EDITORS:
Eric J. Epstein, M.D., Albert Einstein College of Medicine
ADVISORY BOARD:
EDITORIAL FELLOW: Lauren K. Schwartz, M.D., Mount Sinai School of Medicine
DRUG INTERACTIONS FELLOW: Manouchkathe Cassagnol, Pharm.D., St. Johns
University
Founded in 1959 by
Drugs for Asthma
MISSION:
care practice.
Guidelines with specific attention to clinical evidence of effectiveness, adverse effects and patient management. Through this program, The Medical Letter
expects to provide the prescribing health care community with educational content that they will use to make independent and informed therapeutic choices
in their practice.
1. Men and women over the age of 50 should have a calcium intake of:
a. 600 mg
b. 800 mg
c. 1000 mg
d. 1200 mg
Pg. 67
2. Calcium supplements can cause:
a. intestinal bloating
b. gas
c. constipation
d. all of the above
Pg. 68
Issue 74 Questions
Introducing
3. The only bisphosphonate available generically in the US is:
a. alendronate
b. ibandronate
c. risedronate
d. zoledronate
Pg. 68
4. Foods with high calcium content include:
a. milk
b. yogurt
c. dried figs
d. all of the above
Pg. 68
5. In postmenopausal women with very low BMD, risedronate 5 mg
daily for up to 3 years compared to placebo:
a. increased the incidence of vertebral fractures
b. decreased the incidence of first fractures
c. decreased spine BMD
d. did none of the above
Pg. 69
6. Bisphosphonates have been associated with development of:
a. torsades de point
b. cardiac arrest
c. atrial fibrillation
Pg. 70
7. Which of the following statements is true about the efficacy of
raloxifene?
a. It has not been shown to lower BMD.
b. It has not been shown to prevent vertebral fractures.
c. It has not been shown to prevent nonvertebral fractures.
d. None of the above
Pg. 71
8. Which of the following is true about the adverse effects of
raloxifene?
a. It has been shown to increase the incidence of breast cancer.
b. It has been shown to increase the incidence of uterine cancer.
c. It has been shown to increase the incidence of
thromboembolic events.
d. None of the above
Pg. 71
9. The estrogen-plus-progestin arm of the Womens Health Initiative
was stopped prematurely because of an increased incidence of:
a. coronary events
b. pulmonary emboli
c. breast cancer
d. all of the above
Pg. 72
10. Parathyroid hormone increases bone density by:
a. decreasing osteoclast formation
b. stimulating bone formation
c. decreasing osteoclast activation
d. all of the above
Pg. 72
11. To maintain gains in BMD achieved by treatment with
teriparatide, patients could take:
a. an antiresorptive agent such as a bisphosphanate
b. vitamin D
c. salmon calcitonin
Pg. 72
12. To decrease the risk of osteoporosis, patients of both sexes and
all ages should:
a. take small amounts of estrogen
b. take a bisphosphonate
c. limit weight-bearing exercise
d. maintain an adequate intake of calcium and vitamin D
Pg. 72
ACPE UPN: 379-000-08-074-H01-P
Tables
1. Some Topical Antibacterial Drugs Page 76
2. Some Oral Antibiotics for Acne Page 77
3. Some Retinoids Page 78
4. Some Topical Corticosteroids Pages 79-80
5. Systemic Agents for Psoriasis Page 81
Volume 6 (Issue 75) November 2008
ACNE
The pathogenesis of acne is multifactorial: follicular hyperk-
eratinization, bacteria, sebum production, androgens
and inflammation all play a role. The gram-positive micro-
aerophilic bacteria Propionibacterium acnes promote devel-
opment of acne lesions by secreting chemotactic factors
that attract leukocytes to the follicle, causing inflammation.
TOPICAL THERAPY Salicylic Acid Widely
available OTC both alone and in many combinations,
topical salicylic acid is a well-tolerated keratolytic agent.
It is often used with benzoyl peroxide.
Benzoyl Peroxide An oxidizing agent, benzoyl perox-
ide is available in a wide variety of OTC and prescription
preparations. Its effect is primarily due to its bactericidal
activity against P. acnes. Benzoyl peroxide is most useful
for treatment of mild to moderate acne. In one random-
ized controlled trial, it was as effective as oral antibiotics
in reducing the number of inflamed lesions.
1
Benzoyl
peroxide is often used in combination with topical or oral
antibiotics, or with a retinoid. Skin irritation and bleach-
ing (skin or fabric) can occur and may be intolerable for
some patients. Contact dermatitis is uncommon.
Antibiotics The topical antibiotics clindamycin and
erythromycin are commonly used to treat mild to moder-
ate acne and are equally effective. Both have antibacter-
ial and anti-inflammatory properties. Metronidazole
(Metrogel, Noritate, and others), elemental sulfur and
sulfur compounds are also used. Topical antibiotics are
generally safe and well tolerated, but bacterial resistance
can occur. Concomitant use of topical antibiotics and
benzoyl peroxide may be effecive against resistant P.
acnes.
1
Skin irritation may occur but is typically mild.
Azelaic Acid An anti-keratinizing agent with antibac-
terial and anti-inflammatory activity, azelaic acid (Azelex
for acne; Finacea for rosacea) is less irritating than ben-
zoyl peroxide; hypopigmentation can occur, particularly
in people with dark skin.
Retinoids Topical retinoids, including tretinoin (Retin-
A, and others), adapalene (Differin) and tazarotene
(Tazorac), can be used to treat both inflamed and nonin-
flamed acne lesions, alone or in combination with antibi-
otics. A formulation containing tretinoin 0.025% and
clindamycin phosphate 1.2% (Ziana gel) has been intro-
duced.
2
A fixed-dose combination of adapalene and ben-
zoyl peroxide (Epiduo) is available in Europe.
3
All topi-
cal retinoids normalize keratinization and appear to have
anti-inflammatory effects. It is not clear that any one of
these agents is more effective than the others.
4
Adverse effects typically associated with topical retinoids,
including dry skin, scaling, photoirritation, erythema,
burning and pruritus, vary with the formulation, concen-
tration and frequency of application. Tazarotene gel may
be less tolerable than adapalene.
5
Retinoids are terato-
gens; even though only small amounts are absorbed sys-
temically, tretinoin and adapalene are labeled as category
C (risk cannot be ruled out) for use in pregnancy;
tazarotene is contraindicated during pregnancy.
SYSTEMIC THERAPY Oral Antibiotics Oral
antibiotics are the second most effective treatment after
isotretinoin (Accutane, and others) for inflammatory acne.
Tetracycline, doxycycline, minocycline, erythromycin and
trimethoprim/sulfamethoxazole have all been used. They
are usually taken for months, which can lead to develop-
ment of bacterial resistance. Tetracyclines, in addition to
their antibacterial activity, have direct anti-inflammatory
effects. An extended-release formulation of minocycline
(Solodyn) has become available for once-daily treatment
of acne; whether it is as effective as immediate-release
minocycline or less likely to cause vertigo remains to be
established, and it is expensive.
6
Tetracyclines should not
be used during pregnancy. Some oral antimicrobials may
decrease the effectiveness of oral contraceptives.
7
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 75) November 2008
Isotretinoin Isotretinoin (Accutane, and others), a vita-
min A derivative, is the most effective drug available for
treatment of acne. It inhibits P. acnes colonization by
reducing sebum production and has keratinolytic and
anti-inflammatory effects. Isotretinoin can completely
clear severe nodulocystic lesions, in some cases leading
to remissions that can persist for years after treatment is
stopped. The usual dosage is 0.5 to 1 mg/kg/day given in
2 doses with food for 15-20 weeks.
Mucocutaneous adverse effects include dry skin, alope-
cia, eczema, skin fragility and photosensitivity. Myalgias,
hypertriglyceridemia, hepatitis, pancreatitis and pseudo-
tumor cerebri can occur. Isotretinoin, a potent human ter-
atogen, is regulated by iPLEDGE, a computer-based risk
management program (www.ipledgeprogram.com)
designed to prevent fetal exposure to the drug.
Oral Contraceptives Acne in women is often treated
with oral contraceptives. These drugs raise sex hormone
binding globulin and decrease free testosterone concen-
trations, which may lead to improvement in acne. Several
oral contraceptives have been approved by the FDA for
treatment of acne.
8
Spironolactone (Aldactone, and others) The anti-
androgen aldosterone receptor antagonist spironolactone
is used off-label to treat acne in women. It has been use-
ful in some patients with resistant disease.
9
Hyperkalemia can occur. It is classified as category C for
use in pregnancy.
76
CHOICE OF DRUGS Topical salicylic acid and ben-
zoyl peroxide, both available over the counter, are often
tried first for treatment of acne. For mild to moderate acne,
benzoyl peroxide is usually combined with a topical
antibiotic. A topical retinoid can be used for more severe
acne. The most effective drug available for inflammatory
acne is isotretinoin; it can clear severe recalcitrant nodular
acne, but has many potential adverse effects. Oral antibi-
otics are the second most effective treatment for acne.
ROSACEA
This common, chronic inflammatory facial eruption of
unknown cause is characterized by erythema, telangiecta-
sia and recurrent, progressive crops of acneiform papules
and pustules, usually on the central part of the face. Some
patients develop cystic nodules, granulomas and tissue
hypertrophy, sometimes leading to rhinophyma (a bul-
bous nose). Blepharitis and conjunctivitis are common.
Keratitis and corneal scarring occur rarely. Rosacea is
more prevalent in women, but rhinophyma occurs more
frequently in men.
TOPICAL THERAPY Metronidazole and azelaic
acid (Finacea for rosacea) are the standard topical antimi-
crobials used to treat the papules and pustules of rosacea;
they appear to be about equally effective, but few well-
controlled comparative trials have been published.
Benzoyl peroxide, erythromycin gel, sulfacetamide-sulfur,
benzoyl peroxide/clindamycin and 5% permethrin (to treat
Demodex mites, which have been implicated in the patho-
Drug Formulation
1
Size Cost
2
Clindamycin
Cleocin T (Pfizer) 1% gel (solution, lotion) 30 g $ 56.70
Clindamycin/benzoyl peroxide
Duac (Steifel) 1%/5% gel 45 g 154.35
Benzaclin (Dermik) 1%/5% gel 25 g 154.00
Erythromycin
generic 2% gel 30 g 21.90
2% solution 60 pads 45.00
60 mL 13.80
Erythromycin/benzoyl peroxide
generic 3%/5% gel 23.3 g 57.08
Benzamycin (Dermik) 0.8 g pouch (box of 60) 119.40
Azelaic acid Azelex (Allergan) 20% cream 30 g 96.00
Finacea
3
(Berlex) 15% gel 50 g 117.50
Metronidazole
3

generic 0.75% gel (cream, lotion) 45 g 71.15
4
Metrogel (Galderma) 0.75% gel 45 g 73.80
1% gel 79.65
Noritate (Dermik) 1% cream 60 g 125.40
1. Other available formulations are listed in parentheses.
2. Cost of the smallest size tube or bottle or cost of one box based on the most recent data (August 31, 2008) from retail pharmacies nationwide
available from Wolters Kluwer Health.
3. FDA-approved for treatment of rosacea, but not for acne.
4. Price according to RedBook October 2008 Update.
Table 1. Some Topical Antibacterial Drugs
Table 2. Some Oral Antibiotics for Acne
response.
13
Topical retinoids are used for patients who do
not respond to topical antimicrobials. Isotretinoin is gen-
erally reserved for patients with severe inflammatory
nodulocystic disease.
PSORIASIS
This common, chronic condition, characterized by ery-
thematous plaques covered by silver scales, takes many
forms ranging from diaper rash to arthritis.
14
TOPICAL THERAPY Corticosteroids Topical cor-
ticosteroids are the most widely used drugs for treatment of
psoriasis. They are listed according to potency in Table 4.
Topical corticosteroids come in a variety of vehicles,
including creams, ointments, gels, lotions, solutions, sprays,
foams, shampoos and tapes. Ointments are generally the
most effective. Foams and sprays, the newest vehicles, are
easy to apply to large areas but their alcohol base may cause
sensitive patients to complain of a burning sensation.
15
Super-high potency topical corticosteroids, such as clobe-
tasol propionate 0.05% ointment, have been shown to
induce adrenal suppression, but clinically significant adre-
nal insufficiency is rare. Local cutaneous adverse effects
such as atrophy of the dermis and epidermis, telangiec-
tasias and irreversible striae can occur when these agents
are used for prolonged periods of time, when too much is
applied, or when corticosteroid-sensitive areas such as the
face and intertrigenous regions are treated.
Calcipotriene The vitamin D
3
analog calcipotriene
16
(Dovonex, and others) is about as effective as a medium-
potency corticosteroid for treatment of plaque psoriasis.
Calcipotriene inhibits epidermal proliferation and stimu-
lates cellular differentiation. It is generally well tolerated,
but burning and itching occur in about 10% of patients.
Hypercalcemia has been reported. The drug is available in
a cream or scalp solution; the ointment was discontinued.
Tazarotene An acetylenic retinoid, tazarotene (Tazorac)
has been as effective as high-potency corticosteroids for
treatment of psoriasis, and in some patients the therapeutic
effect of 6 weeks treatment has persisted for months after
treatment was stopped. The incidence of erythema, burn-
ing, pruritus and peeling has been higher with tazarotene
gel than with other retinoids (tretinoin or adapalene).
77
genesis of rosacea) have been used. The topical retinoids
used to treat acne are also sometimes used to treat rosacea.
It may take 4-6 weeks of treatment with topical drugs for
improvement to become visible.
SYSTEMIC THERAPY Oral Antibiotics
Systemic antibiotic therapy tends to be effective for treat-
ment of papules, pustules, erythema and ocular inflam-
mation, but not for telangiectasia, rhinophyma or the
flushing that nearly always accompanies rosacea.
Effective treatment often requires a prolonged course
(months or sometimes years) of an oral antibiotic, such as
doxycycline. The antibiotic dose can often be reduced
when papules and pustules improve. Low-dose (40 mg),
once-daily doxycycline (Oracea) has been shown to be
effective and safe in the treatment of rosacea, but it is
expensive.
10
Oral metronidazole (Flagyl, and others) is
also effective for rosacea, but has some unpleasant side
effects such as metallic taste.
Isotretinoin Patients with severely inflamed rosacea, or
those whose disease has a marked nodulocystic compo-
nent, can be treated with low doses of isotretinoin (0.1-
0.5 mg/kg/day) for 6-8 months; as with acne, careful
monitoring is necessary in women of childbearing age
(see page 76). Significant reductions in erythema, papules
and telangiectasia occur after about 2 months of treat-
ment; no other pharmacologic treatment has been report-
ed to reduce telangiectasia.
LIGHT-BASED THERAPY In small clinical trials,
light and laser therapies were effective in decreasing the
severity of telangiectasias and erythema in patients with
rosacea.
11
Adverse effects included purpura and hyper-
pigmentation. In one randomized, controlled split-face
trial in 20 patients, treatment with long-pulsed dye laser
or intense pulsed light was similarly effective in reducing
telangiectasia and irregular pigmentation; subjects report-
ed less pain with laser therapy.
12
Long-term studies are
lacking; maintenance treatment with topical drugs or with
additional light-based therapy every 4-6 months would
probably be needed.
CHOICE OF DRUGS Topical antimicrobials such as
metronidazole and azelaic acid are generally tried first for
treatment of rosacea, sometimes in combination with oral
antimicrobials, which can produce a more rapid
Agent Dosage Adverse Effects Cost
Tetracycline (Sumycin, and others) 250 mg qid GI upset, vaginal candidiasis $4.00
1
Doxycycline (Vibramycin, and others) 100 mg bid Photosensitivity 4.00
1
Minocycline (Minocin, and others) 100 mg bid Vertigo 182.40
2
extended-release Solodyn 1 mg/kg once daily 565.80
2
Erythromycin (Erythrocin, and others) 250 mg qid GI upset, drug interactions 4.00
1
1. Cost of 30 days treatment with the generic drug from Walmart, Target and some other stores.
2. Cost of 30 days treatment, based on most recent data (August 31, 2008) from retail pharmacies nationwide available from Wolters Kluwer Health.
Limiting contact time to 5 minutes may improve its toler-
ability. The incidence of burning and pruritus appears to be
lower with the cream formulation, but dry skin has been
more frequent. Even though systemic absorption is mini-
mal, the drug is contraindicated in pregnancy.
Calcipotriene/Betamethasone Dipropionate This
combination (Taclonex) is FDA-approved for treating
plaque psoriasis.
17
Once-daily treatment with the com-
pound ointment appeared to be safe and well tolerated,
whether used alone or alternating every 4 weeks with cal-
cipotriene alone for up to 52 weeks.
18
A newer prepara-
tion formulated for use on the scalp (Taclonex Scalp) con-
tains the same ingredients.
PHOTOTHERAPY UVB phototherapy is used when
the disease is widespread or unresponsive to topical
agents. Photochemotherapy with oral or topical psoralens
combined with UVA radiation (PUVA) is effective in pso-
riasis, but increases the risk of skin cancer.
SYSTEMIC THERAPY Methotrexate In low
doses (7.5-25 mg per week), methotrexate is highly effec-
tive for psoriasis. It is indicated for the control of severe
psoriasis refractory to topical treatments and photothera-
py. It is also prescribed for patients with psoriatic arthri-
tis and those with disfiguring lesions.
Hepatotoxicity, which can be fatal, is the most common
serious adverse effect of methotrexate. The drug is terato-
78
genic and is contraindicated in pregnancy. After stopping
it, men should wait at least 3 months and women should
wait one ovulatory cycle before attempting to conceive.
Methotrexate can accumulate in patients with decreased
renal function. The drug is immunosuppressive and
should not be used in patients with active infections.
Methotrexate-induced pneumonitis can be fatal.
Additional adverse reactions to methotrexate include gas-
trointestinal symptoms such as anorexia, nausea, ulcera-
tive stomatitis and hematologic toxicity, including macro-
cytic anemia, leukopenia and thrombocytopenia. Giving
1-5 mg of oral folic acid daily can decrease some of these
effects. Methotrexate should not be used concurrently
with trimethoprim-sulfamethoxazole (Bactrim, Septra,
and others), another antifolate drug, to avoid possible
bone marrow suppression.
Cyclosporine Cyclosporine (Neoral, and others) has been
as effective as methotrexate in treating moderate to severe
psoriasis; relative reductions in Psoriasis Area Severity
Index (PASI) scores were 64% for methotrexate and 72%
for cyclosporine at 16 weeks.
19
The doses of cyclosporine
used for this indication (3-5 mg/kg/day) have generally
been safe. Nephrotoxicity can occur, but a short course (12
weeks) of cyclosporine may be safer than methotrexate.
Cyclosporine interacts with many other drugs.
7
Acitretin Use of acitretin (Soriatane), an oral retinoid,
in a dose of 30-50 mg/day can result in a 60-70% reduc-
Oral
Drug Formulation Size Cost
1
Topical
Adapalene Differin (Galderma) 0.1% gel,cream 45 g $152.63
0.3% gel 45 g 167.88
Tazarotene Tazorac (Allergan)
2
0.1% gel, cream 30 g 127.36
0.05% cream, gel 30 g 119.88
Tretinoin generic 0.01% gel 15 g 35.59
0.025% gel 15 g 29.93
0.025% cream 20 g 43.33
0.05% cream 20 g 50.28
0.1% cream 20 g 58.69
Atralin (Coria) 0.05% gel 45 g 158.75
Retin-A (OrthoNeutrogena) 0.01% gel 15 g 53.77
0.025% gel 15 g 54.25
0.025% cream 20 g 67.72
0.05% cream 20 g 75.94
0.1% cream 20 g 88.63
0.05% solution 28 mL 41.58
Retin-A Micro (OrthoNeutrogena) 0.04%, 0.1% gel 20 g 80.30
Ziana (Medias) 0.025% tretinoin/1.2% clindamycin gel 30 g 144.91
Isotretinoin generic 10, 20, 30, 40 mg caps 505.80
3
Accutane (Roche) 10, 20, 40 mg caps 1987.20
3
Acitretin
Soriatane (Stiefel) 10, 25 mg caps 1689.30
4
1. Cost based on AWP listings in Drug Topics Red Book 2008.
2. Also available in 0.05% cream and gel for treatment of psoriasis.
3. Cost of 30 days treatment with 1 mg/kg/day divided into 2 daily doses for a 60-kg patient.
4. Cost of 30 days treatment at 30 mg/day.
Table 3. Some Retinoids
High Potency (continued)
79
Super-High Potency
High Potency
Table 4. Some Topical Corticosteroids
Drug Vehicle Cost
1
Betamethasone dipropionate
augmented 0.05% generic oint, gel $ 75.90
Diprolene (Schering-Plough) 116.08
Clobetasol propionate 0.05%
generic cream, oint, gel 49.42
soln 53.10
Cormax (Watson) cream 81.20
Clobex (Galderma) lotion 172.61
shampoo 186.33
spray 227.97
Olux (Connetics Corp) foam 149.66
Temovate (GSK) cream, 60.31
oint, gel
Fluocinonide 0.1%
Vanos (Medicis) cream 103.24
Halobetasol propionate 0.05%
generic cream, oint 62.98
Ultravate (Westwood Squibb) 75.30
Amcinonide 0.1% generic oint 46.12
2
Betamethasone dipropionate 0.05%
augmented generic cream 72.86
Diprolene AF 116.08
(Schering-Plough)
generic oint 18.80
Desoximetasone 0.25%
Topicort (Taro) cream, oint 99.62
generic gel 70.02
Diflorasone diacetate 0.05%
generic oint 51.86
Diflorasone diacetate emollient 0.05%
Psorcon E (Dermik) cream 60.47
Fluocinonide 0.05%
generic gel, oint, 42.50
soln, 27.27
cream 21.22
Medium-High Potency
Drug Vehicle Cost
1
Halcinonide 0.1%
Halog (BMS) cream, $ 40.15
oint, soln 63.64
Mometasone 0.1%
generic oint 47.80
Elocon (Schering-Plough) oint 74.40
Triamcinolone acetonide 0.5%
generic oint 11.60
Amcinonide 0.1%
generic cream 27.46
lotion 42.18
generic cream 15.60
Betamethasone
valerate 0.1% generic oint 12.62
generic cream 70.06
Diflorasone diacetate 0.05%
generic cream 50.78
Fluocinonide emollient 0.05%
generic cream 26.82
Fluticasone propionate 0.005%
generic oint 33.33
Cutivate (PharmDerm) 41.70
generic oint 7.20
generic cream 10.28
Betamethasone valerate 0.12%
Luxiq (Connetics Corp) foam 131.38
Fluocinolone acetonide 0.025%
generic oint 10.75
Hydrocortisone valerate 0.2%
generic oint 29.62
Westcort (Ranbaxy) oint 35.06
oint = ointment (continued)
1. Cost of 2x15 g or 1x30 g for ointment, gel or cream, 50 or 60 mL for lotion, solution or spray, 118 mL for shampoo, and 50 g for foam, based on
AWP listings in Drug Topics Red Book 2008.
2. Cost of 60 g.
tion in the area and severity of psoriasis, but about 40%
of patients relapse within 12 weeks after treatment is
stopped. Lower doses may reduce its toxicity, but are not
as effective. Synergism has been reported when acitretin
was used with UVB radiation or PUVA, or sequentially
with cyclosporine.
As with other systemic retinoids, acitretin often causes
cheilitis, hair loss, dry skin and desquamation.
Increases in aminotransferase activity occur in about
one third of patients; this usually returns to normal even
when treatment is continued, but symptomatic retinoid
hepatitis can occur, and progression to cirrhosis has
been reported. Decreased HDL cholesterol, hyper-
triglyceridemia, skeletal hyperostosis, conjunctivitis,
corneal erosions and opacities, iritis and decreased
visual acuity can occur. Acitretin is a long-lasting ter-
atogen; pregnancy and blood donation are contraindi-
cated for at least 3 years after taking it.
BIOLOGIC AGENTS T-cell inhibitors and tumor-
necrosis-factor (TNF) inhibitors are now used to treat
psoriasis. It is not clear that these expensive drugs are
more effective than the other systemic drugs used to treat
psoriasis. Only one comparative trial has been published;
it showed improved efficacy of adalimumab (Humira)
compared to methotrexate over a 16-week period.
20,21
The long-term safety of these agents, particularly the
possibility of inducing malignancy or auto-immune dis-
ease, is unclear.
T-CELL INHIBITORS Alefacept
22
(Amevive), a human
protein that inhibits T-cell activation, is indicated for
treatment of adults with moderate to severe chronic
Medium Potency
Medium-Low Potency (continued) Medium Potency (continued)
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 75) November 2008 80
Medium-Low Potency
Low Potency
Drug Vehicle Cost
1
Mometasone furoate 0.1%
generic cream 53.80
lotion 55.45
Elocon (Schering-Plough) cream 74.40
lotion 77.03
generic cream 7.20
generic lotion 38.85
generic cream 9.90
Desonide 0.05%
generic oint 30.94
Desowen (Galderma) 55.00
generic cream 9.38
Flurandrenolide 0.05%
Cordran (Aqua) lotion 132.00
Cordran SP (Aqua) cream 90.00
Fluticasone propionate 0.05%
generic cream 34.18
Cutivate (PharmaDerm) 66.93
Hydrocortisone butyrate 0.1%
generic cream 44.50
oint 22.30
soln 14.34
Locoid (Ferndale) cream, oint 97.56
Locoid Lipocream cream 102.60
Hydrocortisone valerate 0.2%
generic cream 31.00
Prednicarbate 0.1%
Dermatop (Dermik) 52.76
Drug Vehicle Cost
1
generic oint 7.10
Alclometasone dipropionate 0.05%
Aclovate (GSK) 84.30
Clocortolone 0.1%
Cloderm (Coria) cream 75.00
Desonide 0.05%
generic cream 30.94
lotion 32.83
Desonate (SkinMedica) gel 202.50
2
Desowen (Galderma) cream 51.00
lotion 118.63
Verdeso (Stiefel Labs) foam 130.68
generic cream 4.44
soln 11.00
generic cream 7.10
lotion 42.43
Hydrocortisone 0.5%
3
generic cream 3.06
Hydrocortisone 1.0%
3
lotion 6.86
4
Hydrocortisone 2.5%
lotion 52.03
Efalizumab (Raptiva)
25
is a humanized monoclonal anti-
body that inhibits T-cell activation. It is given subcuta-
neously for treatment of adults with moderate to severe
chronic plaque psoriasis. Randomized placebo-controlled
trials in patients with moderate to severe plaque psoriasis
treated with efalizumab once a week for 12 weeks found
that the primary endpoint, 75% improvement, was
achieved in 22-39% of patients treated with 1 mg/kg/wk,
and in 2-5% with placebo.
26-28
Efalizumab has been
shown to be effective in hand-and-foot psoriasis.
29
The most common adverse effects of efalizumab have
been mild constitutional symptoms (headache, chills,
fever, nausea, and myalgia) following the first one or two
injections. Immune-mediated thrombocytopenia and
hemolytic anemia have been reported rarely. As with ale-
facept, some serious acute infections and reactivation of
latent chronic infections have been reported.
plaque psoriasis who are candidates for systemic therapy
or phototherapy. In an international multicenter trial,
33% of patients given alefacept 15 mg IM once a week
for 12 weeks achieved at least a 75% PASI reduction
compared to 13% of patients receiving placebo.
23
In
another study, using two 12-week courses of IV alefacept
(7.5 mg once weekly), up to 40% of patients achieved a
75% reduction in PASI score and 71% achieved a 50%
reduction, with remissions lasting for as long as one year
without further treatment.
24
Chills, predominantly with IV administration, was the
only adverse effect that occurred at a >5% incidence
among alefacept-treated patients. The drug decreases the
number of lymphocytes, and its use has been associated
with some serious acute infections and activation of
chronic latent infections such as tuberculosis.
1. Cost of 2x15 g or 1x30 g for ointment, gel or cream, 50 or 60 mL for lotion, solution or spray, 118 mL for shampoo, and 50 g for foam, based on
AWP listings in Drug Topics Red Book 2008.
2. Cost of 60 g.
3. Available without a prescription.
4. Cost of 120 mL.
Lowest Potency (may be ineffective for some indications)
Table 4. Some Topical Corticosteroids (continued)
Table 5. Systemic Agents for Psoriasis
TNF INHIBITORS Etanercept (Enbrel), a TNF
inhibitor made from fusion of two naturally occurring
TNF-receptors, binds TNF with greater affinity than natu-
ral receptors, resulting in a reduction in inflammatory
activity. The drug is given subcutaneously. In one study,
the percentage of patients achieving 75% improvement in
PASI score was 49% at 12 weeks and 59% at 24 weeks
with 50 mg twice weekly.
30
In a single clinical trial in chil-
dren and adolescents with moderate-to-severe plaque pso-
riasis, etanercept significantly reduced disease severity, but
it is not approved for use in children with psoriasis.
31
Infliximab (Remicade), an intravenous TNF inhibitor, is
effective in the treatment of psoriasis with about 75% of
patients achieving a 75% reduction in PASI score after 3
injections over a 10-week period.
32
The drug has been
approved by the FDA for both psoriasis and psoriatic
arthritis.
Adalimumab (Humira) is a fully human monoclonal
antibody that binds TNF and is approved for psoriasis and
psoriatic arthritis. The drug is given subcutaneously every
other week. In a 52-week multicenter study of 1212
patients randomized to receive adalimumab (40 mg) or
placebo every other week, 71% (578 of 814) of adali-
mumab-treated and 7% (26 of 398) of placebo-treated
patients had achieved >75% improvement in the PASI
score by week 16.
33
Adverse Effects Serious infections, including bacterial
sepsis and reactivation of tuberculosis, have been report-
ed with all the TNF inhibitors, particularly in the first 2-7
months of treatment. These drugs should not be given to
patients with active localized or chronic infections. Skin
testing for exposure to Mycobacterium tuberculosis and a
baseline chest x-ray are now recommended before start-
ing anti-TNF therapy. Lymphoma and other malignancies
have been reported in association with these drugs, but
cause and effect have not been established. Medical
Letter consultants would generally not use them in
patients with a recent malignancy. All three agents have
been associated with development of auto-antibodies,
including anti-nuclear antibodies and anti-dsDNA anti-
bodies, and the induction of a lupus-like syndrome.
Whether long-term use of TNF inhibitors such as etaner-
cept or infliximab could increase the incidence of auto-
immune diseases is unknown. Pancytopenia and demyeli-
nating disorders such as multiple sclerosis have been report-
ed with these agents. They are categorized as class B (no
evidence of risk in humans) for use in pregnancy.
A NEW BIOLOGIC AGENT Ustekinumab, an inves-
tigational human monoclonal antibody against inter-
leukins 12 and 23, has shown therapeutic potential for pso-
riasis. In a double-blind, placebo-controlled study, 1230
patients with moderate-to-severe psoriasis were randomly
assigned to receive ustekinumab 45 mg or 90 mg at weeks
0 and 4, then every 12 weeks, or placebo. A total of 273
(66.7%) patients receiving ustekinumab 45 mg, 311
(75.7%) receiving ustekimumab 90 mg, and 15 (3.7%)
receiving placebo achieved the primary endpoint of 75%
improvement in PASI. Serious adverse events occurred in
8 patients (2.0%) in the 45 mg group, 5 (1.2%) in the 90
mg group, and 8 (2.0%) in the placebo group.
34
CHOICE OF DRUGS Mild to moderate psoriasis is
generally treated with topical corticosteroids; cal-
cipotriene or tazarotene are topical alternatives.
Phototherapy is used when the disease is widespread or
unresponsive to topical agents. Systemic drugs are usual-
ly reserved for moderate to severe disease.
1. M Ozolins et al. Comparison of five antimicrobial regimens for treat-
ment of mild to moderate inflammatory facial acne vulgaris in the com-
munity: randomised controlled trial. Lancet 2004; 364:2188.
2. J Schlessinger. Clinical safety and efficacy studies of a novel formula-
tion combining 1.2% clindamycin phosphate and 0.025% tretinoin for
the treatment of acne vulgaris. J Drugs Dermatol 2007; 6:607.
3. DM Thiboutot et al. Adapalene-benzoyl peroxide, a fixed-dose combina-
tion for the treatment of acne vulgaris: results of a multicenter, random-
ized double-blind, controlled study. J Am Acad Dermatol 2007; 57:791.
4. TJ Phillips. An update on the safety and efficacy of topical retinoids.
Cutis 2005; 75:14.
81
Agent Dosage Cost
1
Methotrexate generic 7.5-25 mg/wk 9.03
Cyclosporine generic 3-5 mg/kg/day 73.22
Neoral (Novartis) 82.71
Adalimumab
2
Humira (Abbott) 80 mg x 1, then 40 mg SC q2wk $779.84
3
Alefacept Amevive (Biogen) 15 mg IM once/wk 957.62
Efalizumab Raptiva (Genentech) 0.7 mg/kg SC x 1, then 1 mg/kg SC once/wk 444.76
Etanercept
2
Enbrel (Amgen/Wyeth) 50 mg SC twice/wk
2
x 12 wks, then once/wk 390.91
Infliximab
2
Remicade (Centocor) 5 mg/kg IV weeks 0, 2, 6 then q8 wks 2579.04
4
1. Approximate cost for 1 weeks maintenance treatment, or 1 weeks treatment at the lowest dosage for methotrexate and cyclosporine, for a 65-kg
patient, based on the most recent data (August 31, 2008) from retail pharmacies nationwide available from Wolters Kluwer Health.
2. Also approved for psoriatic arthritis.
3. Cost of 1 40-mg syringe.
4. Cost of four 100-mg single-use vials.
Table 5. Systemic Agents for Psoriasis
Biologics
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 75) November 2008 82
Mailing Address:
1000 Main Street
Customer Service:
Call: 800-211-2769 or 914-235-0500
Fax: 914-632-1733
Permissions:
Subscriptions (US):
1 year - $98; 2 years - $167;
US and Canada.
800-211-2769 x315.

ADVISORY BOARD:
EDITORIAL FELLOW:
Founded in 1959 by
5. D Thiboutot et al. Efficacy and tolerability of adapalene 0.3% gel com-
pared to tazarotene 0.1% gel in the treatment of acne vulgaris. J Drugs
Dermatol 2008; 7 (6 suppl):s3.
6. Extended-release minocycline (Solodyn) for acne. Med Lett Drugs
Ther 2006; 48:95.
8. P Rich. Hormonal contraceptives for acne management. Cutis 2008;
81 (1 suppl):13.
9. CB Turowski and WD James. The efficacy and safety of amoxicillin,
trimethoprim-sulfamethoxazole, and spironolactone for treatment-
resistant acne vulgaris. Adv Dermatol 2007; 23:155.
10. Low-dose doxycycline (Oracea) for rosacea. Med Lett Drugs Ther
2007; 49:5.
11. KJ Butterwick et al. Laser and light therapies for acne rosacea. J Drugs
Dermatol 2006; 5:35.
12. GF Jrgensen et al. Long-pulsed dye laser versus intense pulsed light
for photodamaged skin: a randomized split-face trial with blinded
response evaluation. Lasers Surg Med 2008; 40:293.
13. JQ Del Rosso. Recently approved systemic therapies for acne vulgaris
and rosacea. Cutis 2007; 80:113.
14. A Menter et al. Guidelines of care for the management of psoriasis and
psoriatic arthritis: section 1. Overview of psoriasis and guidelines of
care for the treatment of psoriasis with biologics. J Am Acad Dermatol
2008; 58:826.
15. Clobetasol propionate (Clobex) spray for psoriasis. Med Lett Drugs
Ther 2006; 48:27.
16. Calcipotriene for psoriasis. Med Lett Drugs Ther 1994; 36:70.
17. A betamethasone-calcipotriene combination for psoriasis. Med Lett
Drugs Ther 2006; 48:55.
18. K Kragballe et al. A 52-week randomized safety study of a cal-
cipotriol/betamethasone dipropionate two-compound product
(Dovobet/Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br
J Dermatol 2006; 154:1155.
19. VM Heydendael et al. Methotrexate versus cyclosporine in moderate-
to-severe chronic plaque psoriasis. N Engl J Med 2003; 349:658.
20. JH Saurat et al. Efficacy and safety results from the randomized con-
trolled comparative study of adalimumab vs. methotrexate vs. placebo
in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158:558.
21. J Schmitt et al. Efficacy and tolerability of biologic and nonbiologic
systemic treatments for moderate-to-severe psoriasis: meta-analysis of
randomized controlled trials. Br J Dermatol 2008; 159:513.
22. Alefacept (Amevive) for treatment of psoriasis. Med Lett Drugs Ther
2003; 45:31.
23. M Lebwohl et al. An international, randomized, double-blind, placebo-
controlled phase 3 trial of intramuscular alefacept in patients with
chronic plaque psoriasis. Arch Dermatol 2003; 139:719.
24. GG Krueger et al. A randomized, double-blind, placebo-controlled
phase III study evaluating efficacy and tolerability of 2 courses of ale-
facept in patients with chronic plaque psoriasis. J Am Acad Dermatol
2002; 47:821.
25. Efalizumab (Raptiva) for treatment of psoriasis. Med Lett Drugs Ther
2003; 45:97.
26. M Lebwohl et al. A novel targeted T-cell modulator, efalizumab, for
plaque psoriasis. N Engl J Med 2003; 349:2004.
27. KB Gordon et al. Efalizumab for patients with moderate to severe
plaque psoriasis: a randomized controlled trial. JAMA 2003; 290:3073.
28. CL Leonardi et al. Extended efalizumab therapy improves chronic
plaque psoriasis: results from a randomized phase III trial. J Am Acad
Dermatol 2005; 52:425.
29. M Chacko and JM Weinberg. Efalizumab. Dermatol Ther 2007; 20:265.
30. CL Leonardi et al. Etanercept as monotherapy in patients with psoria-
sis. N Engl J Med 2003; 349:2014.
31. AS Paller et al. Etanercept treatment for children and adolescents with
plaque psoriasis. N Engl J Med 2008; 358:241.
32. A Menter et al. A randomized comparison of continuous vs. intermittent
infliximab maintenance regimens over 1 year in the treatment of moder-
ate-to-severe plaque psoriasis. J Am Acad Dermatol 2006; 56:31.
Mailing Address:
1000 Main Street
Customer Service:
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Fax: 914-632-1733
Permissions:
Subscriptions (US):
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US and Canada.
800-211-2769 x315.

ASSISTANT EDITORS, DRUG INFORMATION:
Susan M. Daron, Pharm.D.
Blaine M. Houst, Pharm.D.
Corinne E. Zanone, Pharm.D.
Eric J. Epstein, M.D. Albert Einstein College of Medicine
DRUG INTERACTIONS FELLOW: Manouchkathe Cassagnol, Pharm.D.,
St. Johns University
ADVISORY BOARD:
Founded in 1959 by
33. A Menter et al. Adalimumab therapy for moderate to severe psoriasis: A
randomized, controlled phase III trial. J Am Acad Dermatol 2008; 58:106.
34. KA Papp et al. Efficacy and safety of ustekinumab, a human inter-
leukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week
results from a randomised, double-blind, placebo-controlled trial
(PHOENIX 2). Lancet 2008; 371:1675.
AAFP: Treatment Guidelines from The Medical Letter has been reviewed and is acceptable for up to 15 Prescribed credits by the American Academy of
Family Physicians. AAFP accreditation begins 01/01/08. Term of approval is for one year from this date. This exam is approved for 1.25 Prescribed cred-
its. Credits may be claimed for one year from the date of this exam.
MISSION:
care practice.
in their practice.
1. The therapeutic effect of benzoyl peroxide in acne is primarily
due to its:
a. antioxidant effect
b. anti-inflammatory effect
c. antibacterial effect
Pg. 75
2. Adverse effects of topical retinoids include:
a. dry skin
b. photoirritation
c. pruritus
d. all of the above
Pg. 75
Issue 75 Questions
Introducing
3. The most effective drug available for the treatment of acne is:
a. minocycline
b. tretinoin
c. isotretinoin
d. metronidazole
Pg. 76
4. The mechanism of action by which oral contraceptives improve
acne is thought to be:
a. decreasing free testosterone concentrations
b. increasing estrogen concentrations
c. increasing progestin concentrations
Pg. 76
5. Rosacea is more common in the first and rhinophyma in the second:
a. women and women
b. women and men
c. men and men
d. men and women
Pg. 76
6. Systemic antibiotic therapy for rosacea tends not to be effective for:
a. telangiectasia
b. rhinophyma
c. flushing
d. all of the above
Pg. 77
7. The greatest concern with use of isotretinoin in either acne or
rosacea is:
a. teratogenicity
b. nephrotoxicity
c. cardiotoxicity
d. all of the above
Pg. 76/77
8. Light-based therapy for rosacea can reduce:
a. telangiectasias
b. erythema
c. irregular pigmentation
d. all of the above
Pg. 77
9. The most widely used drugs for treatment of psoriasis are:
a. topical antibiotics
b. topical corticosteroids
c. vitamin D analogs
d. immunosuppressives
Pg. 77
10. The most common serious adverse effect of methotrexate is:
a. anaphylaxis
b. Stevens-Johnson syndrome
c. aseptic meningitis
d. hepatotoxicity
Pg. 78
11. After a woman of childbearing age takes acitretin, pregnancy is
contraindicated for:
a. 6 months
b. 1 year
c. 2 years
d. 3 years
Pg. 79
12. The most effective treatment for psoriasis is:
a. methotrexate
b. a T-cell inhibitor
c. a TNF inhibitor
d. not clear
Pg. 79
ACPE UPN: 379-000-08-075-H01-P
Drugs for Asthma
Tables
1. Drugs for Asthma Pages 86-87
Volume 6 (Issue 76) December 2008
No truly new drugs have been approved for treatment
of asthma since omalizumab (Xolair) in 2003, but
some randomized controlled trials of older drugs
have been published, and new guidelines have
become available.
1
INHALATION DEVICES
Inhalation is the preferred route of delivery for most
asthma drugs. Chlorofluorocarbons (CFCs), which
have ozone-depleting properties, are being phased out
as propellants in metered-dose inhalers; albuterol
inhalers with CFCs will not be available in the US
after December 31, 2008. Non-chlorinated hydrofluo-
roalkane (HFA) propellants, which do not deplete the
ozone layer, will replace them.
2
Metered-dose inhalers (MDIs) require coordination
of inhalation with hand-actuation of the device.
Valved holding chambers (VHCs) or spacers can help
young children or elderly patients use MDIs effec-
tively. VHCs have one-way valves that prevent the
patient from exhaling into the device, eliminating the
need for coordinated actuation and inhalation.
Spacers are open tubes placed on the mouthpiece of
an MDI. Both VHCs and spacers retain the large par-
ticles emitted from the MDI, preventing their deposi-
tion in the oropharynx and leading to a higher pro-
portion of small respirable particles being inhaled.
Dry powder inhalers (DPIs), which are breath-actu-
ated, can be used in patients who are capable of per-
forming a rapid deep inhalation.
Delivery of inhaled asthma medications through a neb-
ulizer with a face mask or mouthpiece is less dependent
on the patients coordination and cooperation, but more
time-consuming than delivery through an MDI or DPI.
3
INHALED CORTICOSTEROIDS
For mild, moderate or severe persistent asthma, inhaled
corticosteroids are the most effective long-term treat-
ment for control of symptoms in all age groups. In ran-
domized, controlled trials, they have been significantly
more effective than leukotriene modifiers, long-acting
beta-2 agonists, cromolyn or theophylline in improving
pulmonary function, preventing symptoms and exacer-
bations, reducing the need for emergency department
treatment, and decreasing deaths due to asthma. The
majority of the benefit is achieved at relatively low
doses. The optimal dose for a given patient may
increase or decrease over time, but should always be
the lowest that maintains asthma control. Doses vary
depending on the inhaled corticosteroid and the deliv-
ery device; these medications are not precisely inter-
changeable on a per mcg or per puff basis.
Adverse Effects Local adverse effects of inhaled
corticosteroids may include oral candidiasis (thrush),
dysphonia (hoarseness), and reflex cough and bron-
chospasm. Use of a VHC or a spacer and rinsing the
mouth after use may reduce the incidence of these
effects. No clinically relevant changes occur in hypo-
thalamic-pituitary-adrenal axis function with low- or
medium-dose inhaled corticosteroids, but childrens
growth should be monitored. Patients who require
high-dose inhaled corticosteroid treatment should be
monitored for osteoporosis and development of
cataracts.
SHORT-ACTING BETA-2 AGONISTS
Inhaled short-acting selective beta-2 agonists
(albuterol, levalbuterol, pirbuterol) increase airflow
within 3-5 minutes; they are the medications of first
choice for treating acute wheeze, chest tightness, cough
Drugs for Asthma
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 76) December 2008
and shortness of breath as needed, and for preventing
exercise-induced bronchospasm. Regularly scheduled
daily use is not recommended. Use of these agents for
symptom relief on more than 2 days per week suggests
inadequate control of asthma, and the need for starting
or possibly increasing the dose of an inhaled cortico-
steroid. Over-reliance of asthma patients on a short-act-
ing beta-2 agonist has been associated with an increased
risk of death.
4
Levalbuterol and racemic albuterol
(which is 50% levalbuterol, the pharmacologically
active isomer of the racemate) in recommended doses
produce comparable bronchodilation and have compar-
able adverse effects.
5,6
Adverse Effects Systemic toxicity from short-acting
beta-2 agonists is uncommon, but may occur with high
doses or use in elderly patients. Adverse effects can
include paradoxical bronchospasm, tachycardia and
other cardiovascular symptoms, skeletal muscle
tremor, headache, hypokalemia and hyperglycemia.
LONG-ACTING BETA-2 AGONISTS
Long-acting beta-2 agonists should be used in combi-
nation with an inhaled corticosteroid; they should not
be used to relieve acute asthma symptoms and are not
recommended for use as monotherapy in the treatment
of asthma. Addition of salmeterol (Serevent) or for-
moterol (Foradil) to the treatment of patients with
persistent asthma not well controlled on low-dose
inhaled corticosteroids improves lung function,
decreases symptoms, and reduces exacerbations and
rescue use of short-acting beta-2 agonists.
7,8,9
Long-
acting beta-2 agonists are best administered in a fixed-
dose combination in the same inhaler with an inhaled
corticosteroid. How the fixed-dose combinations of
fluticasone/salmeterol and budesonide/formoterol
compare with each other remains to be determined.
10
Adverse Effects Addition of a long-acting beta-2
agonist to inhaled corticosteroid therapy has been
reported in a few patients to cause down-regulation
of the beta-2 receptor with loss of the bronchoprotec-
tive effect from rescue therapy with a short-acting
beta-2 agonist.
11
In one large trial in patients with
asthma in which salmeterol or placebo was added to
usual asthma treatment, 13 of 13,176 salmeterol-
treated patients died of asthma, compared to only 3
of 13,179 placebo-treated patients
12
; therefore, a
black box warning about a higher risk of asthma-
related death was added to the package inserts of all
preparations containing a long-acting beta-2 agonist.
However, a matched case-control study found that
long-acting beta-2 agonist use during the prior 3
84
months was not associated with increased risk of
death from asthma.
13
In doses higher than recommended, long-acting beta-2
agonists can produce clinically relevant tremor, cardio-
vascular effects including tachycardia and QTc interval
prolongation, hypokalemia and hyperglycemia.
LEUKOTRIENE MODIFIERS
Leukotriene modifiers are used as an alternative to
inhaled corticosteroids for persistent asthma, but they
are less effective. They can be used as an additional
treatment for patients with mild or moderate persist-
ent asthma not well controlled on inhaled cortico-
steroids, but addition of a long-acting beta-2 agonist
(in the same inhaler) is preferred. Leukotriene modi-
fiers are not recommended for treatment of acute
asthma symptoms, and their dose-response curve is
flat. Most published efficacy data relate to mon-
telukast, and it is the only one of these drugs
approved by the FDA for use in preventing exercise-
induced asthma.
Adverse Effects Churg-Strauss vasculitis has been
reported with montelukast and zafirlukast, but in most
cases it could have been a consequence of corticos-
teroid withdrawal rather than a direct effect of the
leukotriene modifier. Montelukast is less likely than
zafirlukast or zileuton to cause drug-drug interactions
or hepatitis, and is generally considered safe for long-
term use, but the FDA has received post-marketing
reports of psychiatric symptoms including suicidality.
Zafirlukast is a moderate inhibitor of CYP2C9 that
increases the serum concentrations of concomitantly
administered medications such as warfarin
(Coumadin, and others). Zileuton is a moderate
inhibitor of CYP1A2 that inhibits the metabolism of
theophylline and many other drugs.
14
Both zafirlukast
and zileuton have been reported to cause life-threaten-
ing hepatic injury; alanine aminotransferase should be
monitored, and patients should be warned to discontin-
ue the medication immediately if abdominal pain, nau-
sea, jaundice, itching or lethargy occur.
CROMOLYN SODIUM
Cromolyn is now infrequently used for treatment of
mild persistent asthma. Although relatively ineffec-
tive compared to inhaled corticosteroids (it may take
weeks to detect any benefit), it has an excellent safe-
ty profile, except for occasional complaints of cough
and irritation. Nedocromil, which was similar to cro-
molyn, is no longer available.
Drugs for Asthma
THEOPHYLLINE
Sustained-release theophylline is now infrequently
used for persistent asthma, taken either alone or con-
currently with an inhaled corticosteroid. Monitoring of
serum theophylline concentrations and keeping them
between 5 and 15 mcg/mL is recommended. Many
other drugs used concomitantly can interact with theo-
phylline, either by increasing its metabolism and
decreasing its serum concentrations and efficacy, or by
decreasing its metabolism, leading to higher concen-
trations and toxicity.
14
Adverse effects include nausea, vomiting, nervous-
ness, headache and insomnia. At high serum concen-
trations, hypokalemia, hyperglycemia, tachycardia,
cardiac arrhythmias, tremor, neuromuscular irritability,
seizures and death can occur.
ANTICHOLINERGICS
Ipratropium bromide (Atrovent, and others), an inhaled
short-acting anticholinergic bronchodilator used to treat
chronic obstructive pulmonary disease (COPD), has
also been used as an alternative to short-acting beta-2
agonists in patients with asthma who cannot tolerate
them; it should not be used in the treatment of persist-
ent asthma and has not been approved for any use in
asthma by the FDA. Tiotropium bromide (Spiriva), an
inhaled long-acting anticholinergic agent, is also used
to treat COPD, but it has not been studied in persistent
asthma, and is not FDA-approved for use in asthma.
Adverse effects from these agents include dry mouth,
pharyngeal irritation, urinary retention, and increased
intraocular pressure; they should be used with caution
in patients with glaucoma, prostatic hypertrophy or
bladder neck obstruction.
ANTI-IgE ANTIBODY
Omalizumab (Xolair) is a recombinant humanized
monoclonal antibody that prevents IgE from binding
to mast cells and basophils, thereby preventing release
of inflammatory mediators after allergen exposure. It
is approved by the FDA for adjunctive use in patients
at least 12 years old with well-documented specific
allergies and moderate to severe persistent asthma that
is not well controlled on an inhaled corticosteroid with
or without a long-acting beta-2 agonist. Subcutaneous
injection of omalizumab every 2-4 weeks has been
reported to lead to fewer asthma exacerbations, with a
modest (inhaled) corticosteroid-sparing effect.
15,16
It
is expensive.
17
Adverse Effects Adverse effects of omalizumab
include injection site pain and bruising in up to 20% of
patients. Anaphylaxis, usually occurring within 2 hours
after injection but sometimes up to 4 days later, has been
reported in 0.2% of patients, resulting in an FDA black
box warning.
18
An asthma task force has advised keep-
ing patients under observation for 2 hours after the first
three omalizumab injections, and for 30 minutes after
subsequent injections, and educating patients about
recognition of anaphylaxis and the need for prompt
treatment with self-injected epinephrine.
19
Serum sick-
ness and Churg-Strauss vasculitis have occurred rarely
after omalizumab injection. Malignant neoplasms have
been reported in 0.5% of patients receiving omalizu-
mab, compared to 0.2% of those receiving placebo;
cause and effect have not been established.
EXERCISE-INDUCED BRONCHOSPASM
Exercise-induced bronchospasm may be the only man-
ifestation of asthma in patients with mild disease.
Short-acting inhaled beta-2 agonists used just before
exercise will prevent it in more than 80% of patients;
they have a duration of action of 2-3 hours. Long-act-
ing beta-2 agonists can prevent exercise-induced bron-
chospasm for up to 12 hours, but if they are adminis-
tered on a regular basis, the protection may wane and
not last throughout the day. Montelukast decreases
exercise-induced bronchospasm in up to 50% of
patients; its onset of action has been reported to begin
as soon as 2 hours after administration and persist for
up to 24 hours,
20
with no loss of protection over time.
In patients whose exercise-induced bronchospasm
occurs because of poorly controlled persistent asthma,
daily long-term anti-inflammatory medication should
be started or its dosage increased.
21
ASTHMA DURING PREGNANCY
Maternal asthma increases the risk of pre-eclampsia,
perinatal mortality, pre-term birth and low birth
weight. It is safer for pregnant women who have asth-
ma to be treated with asthma medications than to have
poorly controlled asthma symptoms. Albuterol is the
preferred short-acting beta-2 agonist for use in preg-
nancy because of its excellent safety profile. Inhaled
corticosteroids are the preferred long-term controller
medication. More data are available on the safety of
budesonide during pregnancy than on that of other
inhaled corticosteroids. Long-acting beta-2 agonists,
used in combination with an inhaled corticosteroid,
also appear to be safe in pregnancy. Limited data sug-
gest that montelukast appears to be safe.
22
Animal
studies have found teratogenicity with zileuton.
23
85
Drugs for Asthma
Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 76) December 2008 86
Adult Pediatric
Drug Formulation Dosage Dosage Cost
1
Inhaled Corticosteroids
Beclomethasone dipropionate
QVAR (Teva) HFA MDI (100 inh/unit) 40-320mcg bid 5-11 yrs: 71.25
40, 80 mcg/inhalation 40-80 mcg bid
Budesonide
Pulmicort Flexhaler DPI (60, 120 inh/unit) 360-720 mcg bid 6-17 yrs: 134.88
(AstraZeneca) 90, 180 mcg/inhalation 180-360 mcg bid
Pulmicort Respules Susp for nebulization 0.25-0.5 mg 1x/d or bid 1-8 yrs: 183.00
(AstraZeneca) 0.25, 0.5mg, 1mg/2mL or 1 mg 1x/d
2
0.5 -1 mg/day
single-dose ampules
Ciclesonide
Alvesco (Sepracor) HFA MDI (60, 120 inh/unit) 80-320 mcg bid > 12 yrs: 139.08
80, 160 mcg/inhalation 80-320 mcg bid
Flunisolide
AeroBid (Forest) CFC MDI (100 inh/unit) 500-1000 mcg bid 6-15 yrs: 90.51
250 mcg/inhalation 500 mcg bid
Fluticasone propionate
Flovent Diskus (GSK) DPI (60 inh/unit) 100-500 mcg bid 4-11 yrs: 187.20
50 mcg/blister 50-100 mcg bid
Flovent HFA (GSK) HFA MDI (120 inh/unit) 88-440 mcg bid 4-11 yrs: 95.82
44, 110 or 220 mcg/inhalation 88 mcg bid
Mometasone furoate
Asmanex Twisthaler DPI (30, 60, 120 inh/unit) 220-440 mcg 1x/day 4-11 yrs: 113.92
(Schering-Plough) 110 or 220 mcg/inhalation or 220 mcg bid 110 mcg 1x/d
Triamcinolone acetonide
Azmacort (Abbott) CFC MDI (240 inh/unit) 150 mcg tid-qid or 6-12 yrs: 75-150 145.20
75 mcg/inhalation 300 mcg bid mcg tid-qid or
(max 1200 mcg/day) 150-300 mcg bid
(max 900 mcg/day)
Inhaled Beta-2 Agonists, Short-Acting
Albuterol
3
generic Solution for nebulization
4
1.25-5 mg q4-8h PRN 2-4 yrs:
single-dose vials 0.63, 1.25, or 2.5mg/3mL; 0.63-2.5 mg 159.00
5
2.5 mg/0.5 mL; q4-6h PRN
multi-dose vials 100 mg/20 mL 5-11 yrs: 17.00
1.25-5 mg
q4-8h PRN
AccuNeb (Dey) Solution for nebulization
4
2-12 yrs: 0.63 or 183.00
single-dose vials 0.63 or 1.25 mg/3 mL 1.25 mg tid-qid PRN
ProAir HFA (Teva) HFA MDI (200 inh/unit) 180 mcg q4-6h PRN > 4 yrs: 33.92
Proventil HFA (Schering) 90 mcg/inhalation 180 mcg 41.34
Ventolin HFA (GSK) q4-6h PRN 36.18
Levalbuterol
6
Xopenex (Sepracor) Solution for nebulization
4
0.63-1.25 mg 6-11 yrs: 393.00
0.31, 0.63 or 1.25 mg/3 mL tid q6-8h PRN 0.31-0.63 mg
tid q6-8h PRN
Xopenex HFA HFA MDI (200 inh/unit) 90 mcg > 4 yrs: 90 mcg 52.50
(45 mcg/inh) q4-6h PRN q4-6h PRN
Pirbuterol breath-actuated 400 mcg q4-6h PRN > 12 yrs:
Maxair Autohaler (Graceway) CFC MDI (80, 400 inh/unit) 400 mcg q4-6h 57.96
200 mcg/inh PRN
CFC = Chlorofluorocarbon; DPI = Dry powder inhaler; HFA = Hydrofluoroalkane; MDI = Metered -dose inhaler
1. Cost of short-acting beta-2 agonists is for 100 adult doses at the lowest recommended dosage. Cost of oral corticosteroids is for 40 mg/d for 10
days. Cost of other drugs is based on 30 days treatment with the lowest recommended adult dosage. Prices are based on most recent data
(September 30, 2008) from retail pharmacies nationwide available from Wolters Kluwer Health.
2. FDA-approved only for use in children 12 months-8 years old.
3. CFC-containing albuterol MDIs will not be available after December 2008 and no generic equivalents for HFA-propelled albuterol MDIs are cur-
rently available.
4. Nebulized solutions may be more convenient for very young, very old and other patients unable to use pressurized aerosols, and higher drug
doses can be used. More time is required to administer the drug, however, and the device is usually not portable.
5. Cost for albuterol solution for nebulization 0.083% (75 mL at 2.5 mg/3 mL) and 0.5% (20 mL at 5 mg/mL), methylprednisolone 4 mg (21 tabs), or
prednisone 2.5, 5, 10 and 20 mg (30 tabs) is $4 at Walmart, Target and some other stores.
6. Only 100/50 is approved for children.
7. Montelukast is taken once daily in the evening, with or without food. Zafirlukast is taken 1 hour before or 2 hours after a meal. Zileuton is taken
within one hour after morning and evening meals.
Table 1. Drugs for Asthma
Drugs for Asthma
87
Adult Pediatric
Drug Formulation Dosage Dosage Cost
1
Inhaled Beta-2 Agonists, Long-Acting
Salmeterol
Serevent Diskus (GSK) DPI (60 inh/unit) 50 mcg bid > 4 yrs: 153.00
50 mcg/blister 50 mcg bid
Formoterol
Foradil Aerolizer (Novartis) DPI (60 inh/unit) 12 mcg bid > 5 yrs: 145.80
12 mcg/capsule 12 mcg bid
Inhaled Corticosteroid/Long-Acting Beta-2 Agonist Combination
Fluticasone/salmeterol
Advair Diskus (GSK) DPI (60 inh/unit) 1 inhalation bid 4-11 yrs: 172.80
100, 250, 500 mcg/ 1 inhalation
50 mcg/blister
6
(100/50 mcg) bid
Advair HFA (GSK) MDI (120 inh/unit) 2 inhalations bid > 12 yrs: 174.24
45, 115, 230 mcg 2 inhalations bid
21 mcg/inhalation
Budesonide/formoterol
Symbicort HFA (AstraZeneca) MDI (120 inh/unit) 2 inhalations bid > 12 yrs: 162.08
80, 160 mcg/4.5 mcg/inhalation 2 inhalations bid
Leukotriene Modifiers
Montelukast
7
Singulair (Merck) 10 mg tabs, 4.5 mg chew tabs, 10 mg once/day > 1 yr:
8
117.30
4 mg oral granules 4 or 5 mg once/d
8
Zafirlukast
7
Accolate (AstraZeneca) 10, 20 mg tabs 20 mg bid 5-11 yrs: 101.40
10 mg bid
Zileuton
7
- Zyflo CR (Critical) 600 mg tabs 1200 mg bid > 12 yrs: 310.80
1200 mg bid
Cromolyn Sodium
generic Solution for nebulization
3
20 mg tid-qid 1-2 inhalations 100.80
10 mg/mL tid-qid
Theophylline
generic 100, 125, 200, 300 mg ER caps; 300-600 mg/once day 10 mg/kg/d
10
18.00
100, 200, 300, 400, 450, 600 mg or divided bid
ER tabs; 80 mg/15mL oral elixir
9
Theo-24 (UCB Pharma) 100, 200, 300, 400 mg ER caps
9
300-600 mg once/day 33.00
Uniphyl (Purdue) 400, 600mg ER tabs
9
400-600 mg once/day 41.40
Anti-IgE Antibody
Omalizumab Xolair (Genentech) Powder for subcutaneous 150-300 mg q4wks > 12 yrs: 150- 559.87
12
injection or 225-375 mg q2wks
11
300 mg q4wks or
150 mg/vial 225-375 mg q2wks
11
Oral Corticosteroids
Methylprednisolone
generic 2, 4, 8, 16, 32 mg tabs 59.30
5
Medrol (Pfizer) 68.20
7.5-60 mg 0.25-2 mg/kg
Prednisolone in AM in AM
generic 5 mg tabs or or 10.40
5, 15 mg/5 mL syrup every other every other 30.80
Prelone (Teva) 15 mg/5 mL syrup day day 71.40
or or
40-60 mg 1-2 mg/kg
Orapred (Ascent Pediatrics) 15 mg/5 mL PO solution, 1x/day or (max 60 mg/day) 109.20
Orapred ODT (Sciele) 10, 15, 30 mg disintegrating divided bid x 3-10 114.50
tabs x 3-10 days
Pediapred (Celltech) 5 mg/5mL PO solution days 120.00
Prednisone
generic 1, 2.5, 5, 10, 20, 50 mg tabs; 3.00
5
5 mg/5 mL PO solution 64.00
8. Montelukast is approved for prevention of exercise-induced bronchoconstriction only in patients >15 years. Dosage for 6-14 yrs: 5 mg chewable
tab once/d; for 2-5 yrs: 4 mg chewable tab once/d or one packet of 4 mg oral granules; for 12-23 months: one packet of 4 mg oral granules.
9. Extended-release formulations may not be interchangeable. If Theo-24 is taken with food, the entire 24-hour dose is released in a 4-hour period.
10. Starting dose. Usual maximum is 16 mg/kg/day in children more than 1 year old; in infants 0.2 (age in weeks) + 5 = dose in mg/kg/d.
11. Depending on the patients body weight and total serum IgE level. See package insert.
12. Per 150-mg dose.
Table 1. Drugs for Asthma (continued)
{
Drugs for Asthma
ASTHMA IN INFANTS AND CHILDREN
For infants and children with mild intermittent asthma,
a short-acting beta-2 agonist should be used as need-
ed. One report suggested that a short course of mon-
telukast started at the first sign of an asthma episode
may be beneficial.
24
For mild, moderate or severe per-
sistent asthma, inhaled corticosteroids are the pre-
ferred long-term treatment for control of symp-
toms
25,26
; however, they do not affect the underlying
severity or progression of the disease.
27,28
Inhaled cor-
ticosteroids can be delivered through a metered-dose
inhaler (MDI) with a valved holding chamber (VHC)
and face mask or mouthpiece, or through a nebulizer
or dry powder inhaler (DPI).
Inhaled corticosteroids given in low doses even for
extended periods of time are generally safe for use in
infants and children, but linear growth should be mon-
itored. Low- to medium-dose inhaled corticosteroids
may reduce growth velocity slightly during the first
year of treatment, but usually not after that, and final
height appears not to be affected.
29
Dry powder inhalers (DPIs) are not suitable for use in
infants or young children. Fluticasone and mometa-
sone dry powder inhalers are approved for children as
young as four years of age, but children that young
may have difficulty inhaling rapidly or deeply enough
to use the device effectively. Budesonide nebulizer
suspension is approved for children as young as one
year of age. Montelukast is also approved for use in
children as young as one year.
IMMUNOTHERAPY
In selected patients with allergic asthma, specific
immunotherapy (allergy shots) may provide long-
lasting benefits in reducing asthma symptoms and the
need for medications.
30
FAILURE OF PHARMACOLOGIC TREATMENT
Lack of adherence to the prescribed medication regi-
men is the most common cause of pharmacologic fail-
ure in asthma. Co-morbid conditions that may make
asthma management more difficult include chronic
rhinitis/sinusitis,
31
gastroesophageal reflux disease
(GERD),
32
obesity,
33, 34
and depression and psychoso-
cial factors. Some patients with asthma may concur-
rently be taking aspirin or other NSAIDs that can cause
asthma symptoms. Oral or topical nonselective beta-
adrenergic blockers such as propranolol (Inderal, and
others) or timolol (Blocadren, and others) can precipi-
tate bronchospasm in patients with asthma and
decrease the bronchodilating effect of beta-2 agonists.
Patients with asthma who continue to smoke do not
respond optimally to inhaled corticosteroids
8
; they may
respond better to montelukast.
35
Asthmatics should also
avoid exposure to second-hand smoke, airborne pollu-
tants, and allergens.
36
Patients with asthma may also
benefit from meeting with trained asthma educators.
37
MANAGING EXACERBATIONS OFASTHMA
Patient education, including a written Asthma Action
Plan, should guide the initial self-management of exac-
erbations at home.
37
Such a plan involves recognition
of early signs of worsening asthma, appropriate inten-
sification of treatment by increasing the dose of
inhaled short-acting beta-2 agonists, and in some
patients, initiating a short course of an oral cortico-
steroid; patients should also communicate with their
clinician about symptoms and responsiveness to inter-
vention. Doubling the dose of inhaled corticosteroids
is not effective.
38
Oral Corticosteroids Oral systemic corticosteroids
are the most effective drugs available for exacerbations
of asthma incompletely responsive to bronchodilators.
Even when an acute exacerbation responds to bron-
chodilators, addition of a short course of an oral corti-
costeroid can decrease symptoms and may prevent a
relapse. For asthma exacerbations, daily systemic cor-
ticosteroids are generally required for only 3-10 days,
after which no tapering is needed.
39
Oral corticosteroids should only rarely be used as
long-term control medications and then only in that
small minority of patients with uncontrolled severe
persistent asthma. In this situation, an oral cortico-
steroid should be given at the lowest effective dose,
preferably on alternate mornings, in order to produce
the least toxicity.
39
Steroid resistance has been recog-
nized in some patients with asthma.
40
Potential adverse effects of long-term oral cortico-
steroids include endocrinologic effects such as adrenal
suppression, weight gain, Cushingoid stigmata and
diabetes mellitus; musculoskeletal effects such as
osteoporosis, aseptic necrosis and myopathy; ophthal-
mologic effects such as cataracts and glaucoma; der-
matologic effects such as dermal thinning, striae, acne,
hirsutism and delayed wound healing; psychologic
effects such as mood swings, depression and psy-
chosis; metabolic effects such as hypokalemia, hyper-
glyclemia, and hyperlipidemia; and cardiovascular
Drugs for Asthma
effects such as hypertension. Immune function is
potentially impaired, and re-activation of latent tuber-
culosis, herpes, varicella, and Strongyloides infections
may occur. Short-term use of oral corticosteroids may
cause increased appetite, weight gain, changes in
mood and hypertension.
In the urgent care or emergency department setting,
treatment of asthma exacerbations includes: oxygen to
relieve hypoxemia; a short-acting beta-2 agonist,
sometimes in combination with ipratropium, to relieve
airflow obstruction; and a systemic corticosteroid to
decrease airway inflammation. Ipratropium is a useful
bronchodilator for patients with acute asthma symp-
toms who do not respond adequately to or cannot tol-
erate a short-acting beta-2 agonist, or who are taking
nonselective beta-blockers. Severe asthma exacerba-
tions unresponsive to the above treatments may
respond to intravenous magnesium sulfate or inhala-
tion of heliox, a mixture of helium and oxygen; helium
decreases airway resistance.
41
SUMMARY
For monotherapy of persistent asthma, inhaled corti-
costeroids are more effective than long-acting beta-2
agonists, leukotriene modifiers, theophylline or cro-
molyn. If regular use of an inhaled corticosteroid in a
low dose does not prevent symptoms, the dose can be
increased or regular daily treatment with an inhaled
long-acting beta-2 agonist in the same inhaler can be
started. In patients with allergic asthma, immunothera-
py may provide long-lasting benefits. If severe per-
sistent allergic asthma remains uncontrolled, omal-
izumab can be added in patients >12 years. Failure of
pharmacologic treatment in asthma may occur due to
lack of adherence to prescribed medication, co-morbid
conditions, or ongoing exposure to tobacco smoke, air-
borne pollutants or allergens.
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Immunol 2007; 119:769.
31. P Demoly and PJ Bousquet. Links between allergic rhinitis and asth-
ma still reinforced. Allergy 2008; 63:251.
32. SS Rothenberg and D Bratton. The effects of laparoscopic Nissen fun-
doplication to enhance pulmonary function in the treatment of a
patient with severe asthma and gastroesophageal reflux disease. J
33. B Taylor et al. Body mass index and asthma severity in the National
Asthma Survey. Thorax 2008; 63:14.
Drugs for Asthma
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34. DM Mosen et al. The relationship between obesity and asthma sever-
ity and control in adults. J Allergy Clin Immunol 2008; 122:507.
35. SC Lazarus et al. Smoking affects response to inhaled corticosteroids
or leukotriene receptor antagonists in asthma. Am J Respir Crit Care
Med 2007; 175:783.
36. J McCreanor et al. Respiratory effects of exposure to diesel traffic in
persons with asthma. N Engl J Med 2007; 357:2348.
37. S Tapp et al. Education interventions for adults who attend the emer-
gency room for acute asthma. Cochrane Database Syst Rev 2007;
(3):CD003000.
38. TW Harrison et al. Doubling the dose of inhaled corticosteroid to
prvent asthma exacerbations: randomised controlled trial. Lancet
2004; 363:271.
39. GL Colice et al. Oral corticosteroids in poorly controlled asthma. J
40. E Goleva et al. Corticosteroid-resistant asthma is associated with clas-
sical antimicrobial activation of airway macrophages. J Allergy Clin
Immunol 2008; 122:550.
41. DL Lee et al. Beneficial effects of albuterol therapy driven by heliox
versus by oxygen in severe asthma exacerbation. Acad Emerg Med
2005; 12:820.
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care practice.
in their practice.
1. Chlorofluorocarbons (CFCs) are being phased out as propellants
in metered-dose inhalers because:
a. they are costly
b. they deplete the ozone layer of the atmosphere
c. they are hepatotoxic
d. they are nephrotoxic
Pg. 83
2. In randomized controlled trials, inhaled corticosteroids have been
more effective than:
a. leukotriene modifiers
b. long-acting beta-2 agonists
c. theophylline
d. all of the above
Pg. 83
Issue 76 Questions
Introducing
3. Regularly scheduled daily use of short-acting beta-2 agonists is:
a. not recommended
b. a useful alternative to prn use
c. sometimes a useful addition to prn use
Pg. 84
4. Addition of salmeterol or formoterol to the treatment of patients
with persistent asthma not well controlled on low-dose inhaled
corticosteroids:
a. improves lung function
b. decreases symptoms
c. reduces use of short-acting beta-2 agonists
d. all of the above
Pg. 84
5. Montelukast is less likely than zafirlukast or zileuton to:
a. be effective
b. be safe in pregnancy
c. cause hepatotoxicity
d. prevent exercise-induced asthma
Pg. 84
6. Omalizumab is:
a. indicated only for allergic asthma
b. given subcutaneously
c. expensive
d. all of the above
Pg. 85
7. A short-acting beta-2 agonist inhaled just before exercise will
prevent exercise-induced bronchospasm in what percentage of
patients?
a. 40%
b. 60%
c. 80%
d. 100%
Pg. 85
8. The short-acting beta-2 agonist preferred for use in pregnancy is:
a. albuterol
b. levalbuterol
c. pirbuterol
d. propanolol
Pg. 85
9. The most common cause of treatment failure in asthma is:
a. drug toxicity
b. lack of adherence to the prescribed medication
c. co-morbid GERD
d. co-morbid obesity
Pg. 88
10. The most effective drug available for treatment of an asthma
exacerbation that is not responding to bronchodilators is:
a. omalizumab
b. ipratropium
c. an oral corticosteroid
Pg. 88
11. Oral corticosteroids can cause:
a. hirsutism
b. hyperkalemia
c. hypoglycemia
d. all of the above
Pg. 89
12. Addition of a long-acting beta-2 agonist to an inhaled
corticosteroid:
a. is contraindicated in patients with allergic asthma
b. should be done by giving them both in the same inhaler
c. should only be done if raising the dose of the inhaled
corticosteroid proves ineffective
d. all of the above
Pg. 89
ACPE UPN: 379-000-08-076-H01-P

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