Treatment Guidelines,2008

8/10/2019 Treatment Guidelines,2008

1/114

1Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines.

The drugs of choice for treatment of some fungalinfections 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 InfectiousDiseases Society of America (www.idsociety.org) .

AZOLES

Azole antifungals inhibit synthesis of ergosterol, anessential component of the fungal cell membrane.

FLUCONAZOLE Fluconazole is active againstmost Candida species other than C. krusei , which isintrinsically resistant, and many strains of C. glabrata ,which are increasingly resistant. Fluconazole has goodactivity against Coccidioides , Histoplasma andCryptococcus spp., but high doses are needed. Thedrug has no clinically significant activity against mostmolds, including Aspergillus spp., Fusarium spp. andZygomycetes.

Adverse Effects Fluconazole is generally well tol-erated. Headache, gastrointestinal distress and rashcan occur. Stevens-Johnson syndrome, anaphylaxisand hepatic toxicity have been reported. Fluconazoleis teratogenic in animals (pregnancy category C).

Drug Interactions Fluconazole is a moderateinhibitor of CYP3A4 and may increase serum concen-trations of drugs metabolized by 3A4, such ascyclosporine ( Sandimmune , and others), tacrolimus(Prograf) , carbamazepine ( Tegretol , and others), andlovastatin ( Mevacor , and others). 1 Fluconazole is astrong inhibitor of CYP2C9 and can increase serumconcentrations of phenytoin ( Dilantin , and others),zidovudine (Retrovir) , warfarin ( Coumadin , and oth-ers) and other drugs metabolized by 2C9. Concomitantadministration of rifampin ( Rifadin , and others) canlower serum concentrations of fluconazole.

ITRACONAZOLE Itraconazole has a broader spectrum of activity than fluconazole. It is activeagainst a wide variety of fungi including Cryptococcusneoformans , Aspergillus spp., Blastomyces dermati-tidis , Coccidioides immitis , Histoplasma capsulatum ,

Paracoccidioides brasiliensis , Scedosporiumapiospermum (the asexual form of Pseudallescheriaboydii) , Sporothrix spp., and dermatophytes. It also hasgood activity against most Candida spp. Itraconazolehas no clinically meaningful activity against Fusariumspp. or Zygomycetes.

Itraconazole is available orally in both capsules and solu-tion. The IV formulation will no longer be available after February 2008. Absorption after oral dosing is variable;the solution is more bioavailable than the capsules and isgenerally preferred. The capsules should be taken withfood, while the solution is absorbed best without food.

The absorption of itraconazole capsules is reduced bydrugs that decrease gastric acidity, such as antacids,H2-receptor blockers or proton pump inhibitors.

Antifungal Drugs

Tables1. Azoles Page 12. Treatment of Candida Infections Page 23. Echinocandins Page 44. Treatment of Onychomycosis and Tinea Pedis Page 55. Amphotericin B Formulations Page 56. Treatment of Other Fungal Infections Page 6-7

Treatment Guidelinesfrom The Medical Letter

Published by The Medical Letter, Inc. 1000 Main Street, New Rochelle, NY 10801 A Nonprofit Publication

Volume 6 (Issue 65) January 2008www.medicalletter.org

Table 1. Azoles

Drug Usual Dosage Cost 1

ParenteralFluconazole 100-800 mg 1x/d

Diflucan (Pfizer) $357.62Voriconazole 4 mg/kg bid

Vfend (Pfizer) 364.89OralFluconazole 100-800 mg 1x/d

generic 57.20Diflucan (Pfizer) 71.15Itraconazole 200 mg 1x/d-bid

Sporanox (Janssen) 43.76Posaconazole 100 mg 1x/d-200 mg qid

Noxafil (Schering) 145.80Voriconazole 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 December2007. Cost may vary among institutions based on formulary contracts.

2. Cost of three 200 mg tablets.

The Medical Letter publications are protected by US and international copyright laws.Forwarding, copying or any other distribution of this material is strictly prohibited.

For further information call: 800-211-2769
http://www.idsociety.org/http://www.idsociety.org/http://www.idsociety.org/http://www.idsociety.org/


2/114

Antifungal Drugs

Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 65) January 20082

Table 2. Treatment of Candida Infections

Infection Drug Dosage/Duration 1,2 Alternatives

CANDIDIASISVaginal 3

Topical therapy Butoconazole, clotrimazole, 1x/d x 1-7d

(intravaginal creams, miconazole, tioconazole,ointments, tablets, or terconazoleovules or suppositories)

Systemic therapy Fluconazole 150 mg PO once 4 Itraconazole 5 200 mg PO bid x 1dx 1d Ketoconazole 5 200 mg PO bid x 5d

Recurrent 6 Fluconazole 150 mg PO 1x/wkUrinary 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 1-7dFlucytosine 25 mg/kg PO qid x 5-7d 10

Oropharyngeal Fluconazole 200-400 mg IVor 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 141-3 wks 14,15 Itraconazole 17 200 mg PO 1x/d x

1-3 wks 14Posaconazole 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 xCaspofungin 50 mg IV 1x/d 1-3 wks 9,14x 1-3 wks 14

Micafungin 150 mg IV 1x/d x 1-3 wks 14Anidulafungin 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 1dthen PO 20,21 then 4 mg/kg IV bid then 200-300 mg

PO bid 21or An echinocandin

Caspofungin 22 70 mg IV x 1d, then 50 mgIV 1x/d21

Anidulafungin 200 mg IV once, then 100 mg1x/d 21

Micafungin 5 100 mg IV 1x/d 21or 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 treate d (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 c andidiasis.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) .
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14634557&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14634557&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14634557&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14634557&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14634557&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14634557&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14634557&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=15329425&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14699449&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14699449&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14699449&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=11577374&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=11577374&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=11577374&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12490683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12490683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12490683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12490683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12490683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=11577374&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14699449&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=15329425&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=14634557&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


3/114

Antifungal Drugs

Treatment Guidelines from The Medical Letter Vol. 6 ( Issue 65) January 2008 3

Adverse Effects The most common adverse effectsof itraconazole are dose-related nausea and abdominaldiscomfort. Rash, including Stevens-Johnson syn-drome, and serious hepatic toxicity can occur. Thedrug can cause hypokalemia, edema and hypertension.Congestive heart failure has been reported, and thedrug 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 , andothers), 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 byother inhibitors. When some protease inhibitors, suchas ritonavir (Norvir) or indinavir (Crixivan), are takenwith itraconazole, serum concentrations of both drugsmay increase. Itraconazole can increase serum con-centrations of digoxin ( Lanoxin , and others). Adecreased contraceptive effect has been reported in

patients taking oral contraceptives with itraconazole.

VORICONAZOLE Voriconazole has a spectrumof activity similar to that of itraconazole but appears to

be more active against Aspergillus spp. and somespecies of Candida, including C. glabrata and C. kru-

sei . Unlike itraconazole, voriconazole is active against Fusarium . It is not active against zygomycetes, suchas Mucor and Rhizomucor spp.; infection with theseorganisms has developed during treatment with thedrug. In a randomized trial of initial treatment of inva-sive aspergillosis, voriconazole was shown to improvesurvival more than amphotericin B and was associatedwith fewer severe adverse effects. 2 Serum concentra-tions of voriconazole vary from patient to patient andmay 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 patientswith creatinine clearance


4/114

Antifungal Drugs


prolongation, and abnormal liver function have beenreported, 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 bythis isozyme, such as cyclosporine or tacrolimus,should be reduced. 1

KETOCONAZOLE Ketoconazole is now seldomused. The other azoles have fewer adverse effects andare generally preferred.

Adverse Effects Anorexia, nausea and vomiting arecommon with higher doses (>400 mg/day) of keto-conazole; taking the drug with food or at bedtime may

improve tolerance. Pruritus, rash and dizziness mayoccur. Ketoconazole can decrease plasma testosteroneconcentrations and cause gynecomastia, decreasedlibido and loss of potency in men and menstrual irreg-ularities in women. High doses may inhibit adrenalsteroidogenesis and decrease plasma cortisol concen-trations. Hepatic toxicity, including fatal hepaticnecrosis, can occur. Ketoconazole is teratogenic inanimals (pregnancy category C).

Drug Interactions Ketoconazole is a stronginhibitor 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 tothe absence in mammalian cells of enzymes involvedin glucan synthesis. Caspofungin , anidulafungin andmicafungin all have activity against most Candidaspecies, including those resistant to azoles. Their activity against molds appears confined to Aspergillus .All three echinocandins are given intravenously oncedaily, do not require dose adjustment for renal failureand appear to be similar in efficacy and safety. 12

CASPOFUNGIN Caspofungin is FDA-approvedfor treatment of esophageal candidiasis, candidemia,intra-abdominal abscesses, peritonitis, and pleuralspace infections due to Candida . It is also approved for empiric treatment of presumed fungal infections infebrile, 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 mildhepatic toxicity. Anaphylaxis has occurred. Dosageshould be reduced in patients with moderate hepaticdysfunction. Caspofungin is embryotoxic in animals(pregnancy category C).

Drug Interactions Rifampin, carbamazepine, dex-amethasone, efavirenz, nevirapine and phenytoin mayincrease clearance of caspofungin. An increase incaspofungin dosage to 70 mg should be consideredwhen it is co-administered with these drugs.Caspofungin can decrease serum concentrations of tacrolimus. Liver function tests should be monitoredin 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 wasnoninferior 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 facialswelling. Anaphylaxis has been rare. Fever, hepaticfunction abnormalities, headache, nausea, vomitingand diarrhea have been reported, but rarely limit ther-apy. Micafungin is teratogenic in animals (pregnancycategory C).

ANIDULAFUNGIN Anidulafungin 14 isapproved by the FDA for treatment of esophagealcandidiasis and candidemia. It was as effective asfluconazole for invasive candidiasis in a randomized,double-blind trial. 15

Adverse Effects Anidulafungin has a low incidenceof adverse effects similar to those of caspofungin andmicafungin. Its safety in pregnancy has not beenestablished (pregnancy category C).

Table 3. Echinocandins

Drug Dosage Cost 1

Caspofungin 50 mg IV once/dCancidas (Merck) $395.36

Anidulafungin 100 mg IV once/d

Eraxis (Pfizer) 216.00Micafungin 100 mg IV once/dMycamine (Astellas) 224.40

1. For one day's treatment according to AWP listings in Red Book 2007 andUpdate December 2007.Cost may vary among institutions based on for-mulary contracts.


5/114

Antifungal Drugs


Table 4. Treatment of Onychomycosis and Tinea Pedis


ONYCHOMYCOSIS 3, 4Terbinafine 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 xx 3 mos 5 6-12 mos 5

TINEA PEDIS 7Terbinafine cream 8 twice daily application x 1-2 wks Fluconazole 6 150 mg PO

once/wk x 1-4 wksor Topical azoles (i.e. clotrimazole, once or twice daily application

miconazole, econazole) x 4 wks


weeks or months or, particularly in immunocompromised patients, indefinitely.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.6. Not FDA-approved for this indication.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 cellmembrane, leading to loss of membrane integrity andleakage of cell contents. Conventional amphotericin Band the newer lipid-based formulations have the samespectrum of activity and are active against most path-ogenic fungi and some protozoa. They are not activeagainst most strains of Aspergillus terreus ,Scedosporium apiospermum (the asexual form of

Pseudallescheria boydii), Trichosporon and Candida

lusitaniae . Amphotericin B is the preferred treatmentfor deep fungal infections during pregnancy.

Conventional Amphotericin B Amphotericin Bdeoxycholate, 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 adecrease in its use. Intravenous infusion of ampho-tericin B deoxycholate frequently causes fever andchills, and sometimes headache, nausea, vomiting,hypotension and tachypnea, usually beginning 1 to 3hours after starting the infusion and lasting about 1hour. The intensity of these infusion-related acutereactions 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 withnormal saline may prevent or ameliorate it and is gen-erally recommended for patients who can tolerate afluid load. The nephrotoxicity of amphotericin B mayadd to the nephrotoxicity of other drugs includingcyclosporine, tacrolimus and aminoglycoside antibi-otics such as gentamicin ( Garamycin , and others).Hypokalemia and hypomagnesemia are common andare usually due to a mild renal tubular acidosis.Weight loss, malaise, anemia, thrombocytopenia and

mild leukopenia can occur. Cardiac toxicity andmyopathy have been reported.

Table 5. Amphotericin B FormulationsDaily

Drug Dosage Cost 1

Amphotericin Bdeoxycholate 1-1.5 mg/kg IVgeneric (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 colloidaldispersion (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 usualdosage, according to AWP listings in Red Book 2007. Cost may varyamong institutions based on formulary contracts.


6/114

Antifungal Drugs


Table 6. Treatment of Other Fungal Infections


ASPERGILLOSISVoriconazole 3 6 mg/kg IV q12h x 1d,

then 4 mg/kg IV bid

or 200-300 mg PO bid>10 wksor Amphotericin B 1-1.5 mg/kg/d IV 4 Posaconazole 200 mg PO tid-qid

Itraconazole 200 mg PO tid x 3dfollowed by 200 mg PO bid

Caspofungin 5 70 mg IV x 1d, then50 mg IV 1x/d

BLASTOMYCOSIS 6

Itraconazole 200 mg PO bid x 6-12 mos Fluconazole 400-800 mg PO 1x/d 7,8or Amphotericin B 0.5-1.0 mg/kg/d IV 4

COCCIDIOIDOMYCOSIS 9

Itraconazole 8 200 mg PO bid x >1 yror Fluconazole 8 400-800 mg PO 1x/d x >1 yr 7or 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 bidChronic suppression 11 Fluconazole 200 mg PO 1x/d Itraconazole 8 200 mg PO bid

Amphotericin B 0.5-1 mg/kg IV wkly 4

FUSARIOSISAmphotericin B 1-1.5 mg/kg/d IV 4

or Voriconazole 6 mg/kg IV q12h x 1d,then 4 mg/kg q12hor 200 mg PO bid


weeks or months or, particularly in immunocompromised patients, indefinitely.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 5mg/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.8. Not FDA-approved for this indication. (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 Bfor treatment of cryptococcal meningitis. Keeping

serum concentrations below 100 mcg/mL (some clini-cians recommend staying below 50 mcg/mL) decreasestoxicity, but delays in obtaining assay results often limittheir 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 squaleneepoxidase and blocking ergosterol synthesis.

Lipid Formulations The 3 lipid formulations of amphotericin B marketed in the US appear to be aseffective as amphotericin B deoxycholate. Comparedto conventional amphotericin B, acute infusion-relatedreactions are more severe with Amphotec , less severewith 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 isgenerally not associated with amphotericin B deoxy-cholate, has been reported with the lipid formulations.

Cost comparisons of amphotericin B formulationsshould take into account the fact that conventionalamphotericin B deoxycholate may cause renal failure,which can increase the length of hospital stays, health-care costs and mortality rates. 16
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12167683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12167683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12167683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12167683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12167683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


7/114

Antifungal Drugs


Table 6. Treatment of Other Fungal Infections (continued)


HISTOPLASMOSISAmphotericin 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 x6 wks->12 mosChronic suppression 11 Itraconazole 8 200 mg PO 1x/d or bid Amphotericin 8 B 0.5-1 mg/kg IV wkly 4

PARACOCCIDIOIDOMYCOSIS 6Itraconazole 8 100-200 mg PO 1x/d Ketoconazole 200-400 mg PO 1x/d

x 6-12 mosor 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 bidPO bid x 12 wks Posaconazole 8 200 mg PO qid

SPOROTRICHOSISCutaneous Itraconazole 8 200 mg PO 1x/d x 3-6 mos Terbinafine 8 500 mg PO bid

Saturated solution of potassium iodide 1-5 mLPO tid

Fluconazole 7,8 400-800 mg 1x/dExtracutaneous 6 Amphotericin B 0.7-1 mg/kg/d IV 4 x 6-12 wks

or Itraconazole 8 200 mg PO bid x 12 mosZYGOMYCOSIS

Amphotericin B 1-1.5 mg/kg/d IV 4 Posaconazole 8,15 200 mg PO qidx 6-10 wks

9. Itraconazole is the drug of choice for non-meningeal coccidioidomycosis. Fluconazole is preferred for coccidioidal meningitis. Patients with meningitiswho do not respond may require intrathecal amphotericin B. One patient with meningitis was successfully treated with voriconazole (KJ Cortez etal, 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 levelscan 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 (PCJohnson 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 terbinafinehave been headache, gastrointestinal symptomsincluding diarrhea, dyspepsia and abdominal pain,and occasionally a taste disturbance that may persistfor weeks after the drug is stopped. Rash, pruritus andurticaria, usually mild and transient, have occurred.Toxic epidermal necrolysis and erythema multiformehave 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 neutropeniahave 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 , andothers) may reduce the clearance of terbinafine.Enzyme inducers such as rifampin may increaseterbinafine 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 andanimal data suggest a potential benefit of combiningan echinocandin with either an azole or amphotericinB, 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 POor IV once daily has been used, but because of thehigh risk of invasive aspergillosis in these patients,many clinicians now use voriconazole or posacona-
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12802765&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12802765&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12802765&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12802765&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12118965&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12118965&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12118965&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12118965&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12118965&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12118965&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12118965&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12766845&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12766845&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12766845&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12766845&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12766845&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12118965&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12802765&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


8/114


Antifungal Drugs

Coming Soon in Treatment Guidelines :Drugs for Lipids February 2008Drugs for Migraine March 2008

Copyright and Disclaimer: The Medical Letter is an independent nonprofit organ-ization that provides healthcare professionals with unbiased drug prescribing rec-ommendations. The editorial process used for its publications relies on a review ofpublished and unpublished literature, with an emphasis on controlled clinical trials,and on the opinions of its consultants.The Medical Lette r is supported solely by sub-scription fees and accepts no advertising, grants or donations.

No part of the material may be reproduced or transmitted by any process in whole orin part without prior permission in writing.The editors do not warrant that all the mate-rial in this publication is accurate and complete in every respect. The editors shall notbe held responsible for any damage resulting from any error, inaccuracy or omission.

EDITOR: Mark Abramowicz , M.D.DEPUTY EDITOR: Gianna Zuccotti , M.D., M.P.H., Weill Medical College

of Cornell UniversityEDITOR, DRUG INFORMATION: Jean-Marie Pflomm , Pharm.D.ASSISTANT EDITOR, DRUG INFORMATION: Susan Morey , Pharm.D.CONTRIBUTING EDITOR: Eric J. Epstein , M.D., Albert Einstein College of Medicine

CONTRIBUTING EDITOR, DRUG INTERACTIONS: Philip D. Hansten , Pharm.D.,University of WashingtonADVISORY BOARD:Jules Hirsch , M.D., Rockefeller UniversityDavid N. Juurlink, BPhm, M.D., PhD, Sunnybrook Health Sciences CentreRichard B. Kim , M.D., University of Western OntarioGerald L. Mandell , M.D., University of Virginia School of MedicineHans Meinertz , M.D., University Hospital, CopenhagenDan M. Roden , M.D., Vanderbilt University School of MedicineF. Estelle R. Simons , M.D., University of ManitobaNeal H. Steigbigel , M.D., New York University School of MedicineEDITORIAL FELLOWS:Vanessa K. Dalton , M.D., M.P.H., University of Michigan Medical SchoolLauren K. Schwartz , M.D., Mount Sinai School of MedicineDRUG INTERACTIONS FELLOW: Emily Ung , BScPhm, Childrens Hospital of

Western OntarioSENIOR ASSOCIATE EDITORS: Donna Goodstein, Amy FaucardASSOCIATE EDITOR: Cynthia Macapagal CoveyEDITORIAL ASSISTANT: Liz DonohuePRODUCTION COORDINATOR: Cheryl BrownMANAGING EDITOR: Susie WongVP FINANCE & OPERATIONS:Yosef Wissner-Levy

Founded in 1959 byArthur Kallet and Harold Aaron, M.D.

Subscription ServicesMailing Address:The Medical Letter, Inc.1000 Main StreetNew Rochelle, NY 10801-7537

Customer Service:Call: 800-211-2769 or 914-235-0500Fax: 914-632-1733Web Site: www.medicalletter.orgE-mail: [email protected]

Permissions:To reproduce any portion of this issue,please e-mail your request to:[email protected]

Subscriptions (US):1 year - $98; 2 years - $167;3 years - $235. $49/yr. for students,interns, residents and fellows in theUS and Canada.CME: $44 for 26 credits.

E-mail site license inquiries to:[email protected] or call800-211-2769 x315.Special fees for bulk subscriptions.Special classroom rates are avail-able. Back issues are $12 each.Major credit cards accepted.

Copyright 2008. ISSN 1541-2792

Treatment Guidelinesfrom The Medical Letter

zole instead. Itraconazole solution, 200 mg oncedaily, 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 patientswith acute myelogenous leukemia or myelodysplastic

syndrome undergoing chemotherapy, posaconazolewas superior to fluconazole or itraconazole andimproved survival. 6

FEVER AND NEUTROPENIA For neutropenic patients with fever that persists despite treatment withantibacterial drugs, empiric addition of an antifungaldrug 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 celltransplant recipients. Cancer 2007; 109:1532.

5. Posaconazole (Noxafil) for invasive fungal infections. Med LettDrugs Ther 2006; 48:93.

6. OA Cornely et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356:348.

7. AJ Ullmann et al. Posaconazole or fluconazole for prophylaxis insevere graft-versus-host disease. N Engl J Med 2007; 356:335.

8. DJ Skiest et al. Posaconazole for the treatment of azole-refractoryoropharyngeal and esophageal candidiasis in subjects with HIVinfection. 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 conventionaltherapy: 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. JA Van Burik et al. Posaconazole is effective as salvage therapy inzygomycosis: a retrospective summary of 91 cases. Clin Infect Dis2006; 42:e61.

12. C Wagner et al. The echinocandins: comparison of their pharmaco-kinetics, pharmacodynamics and clinical applications. Pharmacology2006; 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. ClinInfect Dis 2006; 43:e29.

The 2007 Annual Index is available at:www.medicalletter.org/downloads/tgindex2007.pdf
http://medicalletter.org/restricted/articles/w1212b.pdfhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12167683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12167683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16569888&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16569888&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17351937&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17351937&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17351937&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://medicalletter.org/restricted/articles/w1248a.pdfhttp://medicalletter.org/restricted/articles/w1248a.pdfhttp://medicalletter.org/restricted/articles/w1248a.pdfhttp://medicalletter.org/restricted/articles/w1248a.pdfhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17251531&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17251531&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17251530&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17243069&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17243069&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17243069&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17243069&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17143808&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17143808&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17143808&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17573510&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17573510&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16511748&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16511748&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16511748&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17047411&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17047411&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17047411&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17482982&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17482982&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17482982&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://medicalletter.org/restricted/articles/w1235b.pdfhttp://medicalletter.org/restricted/articles/w1235b.pdfhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17568028&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17568028&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16838223&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16838223&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16838223&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16838223&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17568028&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://medicalletter.org/restricted/articles/w1235b.pdfhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17482982&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17047411&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16511748&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17573510&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17143808&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17243069&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17251530&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17251531&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://medicalletter.org/restricted/articles/w1248a.pdfhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17351937&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=16569888&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=12167683&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://medicalletter.org/restricted/articles/w1212b.pdf


9/114


Online Series - Answer 12 questions per issue online. Earn up to 2 credits/exam. Take up to 6 short exams per six-month series and earn up to a total of12 credits. The Online Series is included with a paid subscription to Treatment Guidelines .Quick Online Credit Exam - Access content for any available issue, answer 12 questions online, and earn up to 2 credits for $12.00 (available to both sub-scribers and non-subscribers).

ACCREDITATION INFORMATION:ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Medical Letter designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s) . Physicians should only claim credit com-mensurate with the extent of their participation in this activity. This CME activity was planned and produced in accordance with the ACCME Essentials.

AAFP: The Medical Letter (2008) 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 credits. Credits may beclaimed for one year from the date of this exam.

ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This issueis acceptable for 2.0 hours of Continuing Education Credit (0.2 CEU).

AANP and AAPA: The American Academy of Nurse Practitioners (AANP) and the American Academy of Physician Assistants (AAPA) accept AMACategory 1 Credit for the Physicians Recognition Award from organizations accredited by the ACCME.

AOA: This activity, being ACCME (AMA) approved, is acceptable for Category 2-B credit by the American Osteopathic Association .

MISSION:The mission of The Medical Letter's Continuing Medical Education Program is to suppor t the professional development of health care professionals includ-ing physicians, nurse practitioners, pharmacists and physician assistants by providing independent, unbiased drug information and prescribing recom-mendations that are free of industry influence. The program content includes current information and unbiased reviews of FDA-approved and off-label usesof drugs, their mechanisms of action, clinical tri als, dosage and administration, adverse effects and drug interactions. The Medical Letter delivers educa-tional content in the form of self-study material.

The expected outcome of the CME Program is that knowledge and consideration of the information contained in The Medical Letter and Treatment Guidelines can affect health care practice and ultimately result in improved patient care and outcomes.

The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities. The Medical Letter aimsto be a leader in support ing the professional development of health care professionals by providing continuing medical education that is unbiased and freeof industry influence.

LEARNING OBJECTIVES:Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities.

Activity participants will be able to select and prescribe, or confirm the appropriateness of the prescribed usage of the drugs and other therapeutic modal-ities discussed in Treatment Guidelines with specific attention to pathophysiology, dosage and administration, drug metabolism and interactions, and patientmanagement.

Activity participants will make independent and informed therapeutic choices in their practice.

1. Which one of the following is an advantage of the lipid formulationsof amphotericin B over conventional amphotericin B deoxycholate?

a. less expensiveb. decreased nephrotoxicityc. decreased hepatotoxicityd. no infusion-related reactions

Pgs. 5-6

2. Which one of the following is the most appropriate regimen formaintenance therapy in a patient with recurrent vaginal candidiasis?

a. fluconazole 150 mg PO once weeklyb. itraconazole 200 mg PO bidc. ketoconazole 200 mg PO bidd. none of the above

Pg. 2

Issue 65 Questions

Continues on next page >>

DO NOT FAX OR MAIL THIS EXAMTo take this exam, go to:

www.medicalletter.org/tgcme

Treatment Guidelines : Online Continuing Medical EducationUp to 24 credits included with your subscription

www.medicalletter.org/tgcme

Introducing

For over 25 years, The Medical Letter has offered health care professionals continuing medical education (CME) with The Medical Letter on Drugs and Therapeutics . We are now offering CME for Treatment Guidelines from The Medical Letter in an online format only, called the Online Series. Each OnlineSeries is comprised of 6 monthly exams and eligible for up to 12 credits. For those who just need a few credits, we also offer the Quick Online Credit Exam(earn up to 2 credits/12 questions). For more information, please visit us at www.medicalletter.org/tgcme.

Choose CME from Treatment Guidelines f rom The Medical Letter and earn up to24 Category 1 Credits per year in the format thats right for you:


10/114


Treatment Guidelines: Online Continuing Medial Education(www.medicalletter.org/tgcme)

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 inthat it has activity against which of the following?

a. zygomycetesb. aspergillusc. candidad. none of the above

Pg. 3

5. A controlled trial comparing voriconazole to amphotericin B fortreatment of aspergillosis found which one of the following:

a. Voriconazole improved survival, but had more severeadverse effects.

b. Amphotericin B improved survival and had fewer severeadverse effects.

c. Voriconazole improved survival and had fewer severeadverse effects.

d. Amphotericin B improved survival, but had more severeadverse effects.

Pg. 3

6. Mr. X. is an otherwise healthy 70-year-old male with asymptomaticcandiduria. Which one of the following is appropriate treatment forthis patient?

a. Mr. X should be treated with fluconazole 200 mg IV oncedaily for 7 days.

b. The patient is asymptomatic and does not require treatmentat 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 synthesisb. they have activity against most species of Candida including

those resistant to azolesc. they do not require renal dose adjustmentd. 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 thefollowing is true?

a. Liver function tests should be done before starting andperiodically 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 recurrentesophageal candidiasis. Which one of the following is an option forprophylaxis?

a. fluconazole 100-200 mg PO once dailyb. clotrimazole troches (10 mg) five times dailyc. nystatin suspension 500,000 units four times dailyd. none of the above

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 ofdeep fungal infections during pregnancy?

a. amphotericin Bb. voriconazolec. itraconazoled. caspofungin

Pg. 5

ACPE UPN: 379-000-08-065-H01-P


11/114


12/114

Drugs for Lipids

Treatment Guidelines from The Medical Letter Vol. 6 (Issue 66) February 2008

Secondary Prevention Controlled trials in patientswith coronary heart disease indicate that recommendeddoses of lovastatin, simvastatin, pravastatin and ator-vastatin can lower the incidence of cardiac events andstroke 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 myocardialinfarction 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 80or 10 mg of atorvastatin daily for 5 years (TNT), thehigher dose reduced LDL-C to 77 mg/dL (2.0mmol/L), compared to 101 mg/dL (2.6 mmol/L) withthe lower dose, and reduced major cardiovascular events by 22% (relative) and 2.2% (absolute) com-

pared to the lower dose. Total mortality was similar inthe 2 groups. 6 A second trial (IDEAL) included closeto 9000 patients treated after myocardial infarction

10

with 80 mg atorvastatin or 20-40 mg simvastatin for 5years. Mean LDL-C was 81 mg/dL (2.1 mmol/L) and104 mg/dL (2.7 mmol/L) during atorvastatin and sim-vastatin treatment, respectively. Major coronaryevents (the primary endpoint) were insignificantly(p=0.07) reduced by atorvastatin 80 mg compared tothe 2 simvastatin doses. Rates of all-cause, cardiovas-cular and non-cardiovascular deaths were similar inthe 2 groups. 7

Started within 5 days after onset of acute coronarysyndrome , 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(A to Z), failed to show a statistically significant bene-fit in reducing the primary composite endpoint of car-diovascular death, myocardial infarction, readmissionfor acute coronary syndrome, and stroke. 8 Startedwithin 10 days of hospitalization for acute coronarysyndrome, atorvastatin 80 mg compared to pravastatin40 mg for 18-36 months (PROVE IT-TIMI 22) signifi-cantly reduced a composite of death, major cardiac

FDA-Approved Usual Decreases inDrug Formulation Daily Dosage 1 LDL Cholesterol Cost 2

Atorvastatin Lipitor (Pfizer) 10, 20, 40, 80 mg tabs Initial: 10 mg once 35%40% $81.99Maximum: 80 mg once 50%60% 112.99

Fluvastatin Lescol (Novartis) 20, 40 mg capsules Initial: 20 mg once 20%25% 83.51Maximum: 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% 22.99generic Maximum: 80 mg once 3 35%40% 71.98Mevacor (Merck) 20, 40 mg tabs Initial: 20 mg once 25%30% 74.99

Maximum: 80 mg once 3 35%40% 245.98extended release 20, 40, 60 mg tabs Initial: 20 mg once 20%25% 119.99Altoprev (Andrx) Maximum: 60 mg once 40%45% 135.35

Pravastatin generic 10, 20, 40, 80 mg tabs Initial: 40 mg once 4 30%35% 20.99Maximum: 80 mg once 35%40% 133.00

Pravachol (Bristol-Myers 10, 20, 40, 80 mg tabs Initial: 40 mg once 4 30%35% 131.99Squibb) 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% 27.99tabs Maximum: 80 mg once 45%50% 32.99

Zocor (Merck) 5, 10, 20, 40, 80 mg Initial: 20 mg once 35%40% 139.99tabs 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 consultantsuse 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 of30 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


13/114

Drugs for Lipids


events and stroke by 16% (relative) and 3.9%(absolute). 9 A combined analysis of A to Z and PROVEIT-TIMI 22 found that intensive statin treatment led tosignificant reductions in both cardiovascular and all-cause mortality, while non-cardiovascular mortalitywas unaffected. 10

A meta-analysis of statin trials in more than 90,000 patients showed a significant 21% relative reduction instroke, and the greater the reduction in LDL-C, thegreater the reduction in the incidence of stroke. 11 In4731 patients with a recent stroke or TIA and no coro-nary disease (SPARCL), atorvastatin 80 mg comparedto placebo significantly decreased the number of recur-rent strokes (265 vs. 311). The number of patients withischemic stroke decreased by 56 cases while the num-

ber with hemorrhagic stroke increased by 22, both sta-tistically significant. 12

LDL-C Targets A meta-analysis of 58 placebo-con-trolled trials (including some using non-statin drugs)showed that ischemic heart disease events werereduced by 20%, 31% and 51% when mean reductionsof LDL-C were 20 mg/dL (0.5 mmol/L), 40 mg/dL (1.0mmol/L) and 62 mg/dL (1.6 mmol/L), respectively;strokes were reduced 10% and 17% when LDL-C waslowered by 40 mg/dL (1.0 mmol/L) and 70 mg/dL (1.8mmol/L), respectively. 13 Two years of treatment with40 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 coronaryatherosclerosis. 14

11

Table 2. Non-Statins

Drug Formulation Usual Daily Dosage Cost 1

Bile Acid SequestrantsColesevelam Welchol (Daiichi Sankyo) 625 mg tabs 3.75 g once $195.97

or 1.9 g bidColestipol Colestid tablets (Pfizer) 1 g tabs 10 g once 225.12

Colestid packets 5 g/packet or 5 g bid 141.88Cholestyramine generic (packets) 4 g/packet 8 g once 122.99

Questran (Par) or 4 g bid 210.22generic light (packets) 88.99Questran Light 212.48generic (granules) 4 g/dose 52.87Questran 146.07

Cholesterol Absorption InhibitorEzetimibe Zetia (Merck/Schering-Plough) 10 mg tabs 10 mg once 92.99

FibratesGemfibrozil generic 600 mg tabs 600 mg bid 15.99

Lopid (Pfizer) 135.43Fenofibrate 2

Tricor (Abbott) 48, 145 mg tabs 145 mg once 118.52micronized

Antara (Oscient) 43, 130 mg caps 130 mg once 111.99Lofibra (Gate) 67, 134, 200 mg caps 200 mg once 81.02

NiacinNiacin immediate-release OTC 500 mg tabs 1000 mg tid 15.99

extended-release Niaspan (Abbott) 500, 750, 1000 ER tabs 1000 mg once 3 120.62sustained-release Slo-Niacin (Upsher-Smith) 250, 500, 750 SR tabs 1000 mg bid 28.23

Fish Oil CapsulesLovaza (Reliant) caps 4 4 caps once or 2 caps bid 5 161.98USP-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.


14/114

Drugs for Lipids


For high-risk patients, the National CholesterolEducation 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


15/114

Treatment Guidelines from The Medical Letter Vol. 6 (Issue 66) February 2008 13

Drugs for Lipids

when they decrease elevated triglycerides, LDL-C mayincrease. Patients for whom fibrates are particularlyindicated include those with hypertriglyceridemiasevere enough to be at risk for pancreatitis and thosewho have hypertriglyceridemia with low HDL-C, espe-cially when associated with diabetes, insulin resistance

and the metabolic syndrome.

Gemfibrozil A 13-year post-trial follow-up of the 5-year Helsinki Heart Study showed that patients treatedwith gemfibrozil had a significant 23% reduction incoronary mortality. 23

Fenofibrate Taken once daily, fenofibrate may bemore effective than gemfibrozil in lowering plasmaLDL-C and triglycerides. A large 5-year combined pri-mary and secondary prevention trial in patients withtype 2 diabetes (the FIELD study) found that fenofi-

brate 200 mg once daily produced a nonsignificant 11%

reduction in coronary events, which was the primaryendpoint. Non-fatal myocardial infarctions and totalcardiovascular disease events were significantlyreduced, but all-cause mortality was not. Relativelyhigh statin use in the placebo group may have limitedthe positive effects of fenofibrate. 24

Bezafibrate In a large placebo-controlled trial in patients with stable angina or a previous myocardialinfarction who had average plasma lipid concentra-tions, the incidence of myocardial infarction or suddencardiac death after 6 years was 13.6% with bezafibrateversus 15% with placebo; this difference was not sta-tistically significant, but a post-hoc analysis suggestedthat patients with high triglyceride levels at baselineachieved a significant 40% reduction in major cardiacevents. 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 effectof oral anticoagulants and oral hypoglycemic agents.Gemfibrozil inhibits metabolism of most statins andincreases the risk of rhabdomyolysis. Fenofibrate doesnot inhibit statin metabolism and is much less likely toincrease the risk.

NIACIN (NICOTINIC ACID) Niacin modifies all plasma lipoproteins and lipids favorably and has beenshown to lower the incidence of non-fatal myocardialinfarction and overall mortality rates. It increasesHDL-C 15-35% and decreases triglycerides 20-35%. Itdecreases total plasma and LDL-C 5-25%, changingsmall, dense LDL particles to large, buoyant forms. 26

Addition of niacin to statin treatment caused regressionof carotid atherosclerosis 27 and, when combined withthe bile acid sequestrant colestipol plus gemfibrozil,caused regression of coronary lesions and reduced car-diovascular events. 28

Niacin is available in an immediate-release, quicklyabsorbed formulation, an extended-release preparation(Niaspan) absorbed over 8 hours, and a sustained-releaseformulation absorbed over 12-24 hours. A combinationof 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, hepatictoxicity, exacerbation of peptic ulcer and, rarely, dryeyes or hyperpigmentation. Some adverse effects, par-ticularly flushing, are more common with the immedi-

ate-release formulation. Sustained-release preparationshave been hepatotoxic in doses of > 2 grams per day.Less flushing and little hepatic toxicity have beenreported with the extended-release preparation in dailydoses up to 2 grams. The cutaneous reactions can bediminished by starting with a low dose, taking niacinafter meals, and by taking aspirin (325 mg) or ibupro-fen (200 mg) first.

CHOLESTEROL ABSORPTION INHIBITOR Ezetimibe ( Zetia in US; Ezetrol in Canada) inhibitsintestinal absorption of both dietary and biliary choles-terol by blocking its transport at the brush border of thesmall intestine. 29 The recommended dose of 10 mg/dayreduces 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 onthe simvastatin dose. An unpublished 2-year study(ENHANCE) in 720 patients with heterozygous famil-ial hypercholesterolemia (mean baseline LDL-C 318mg/dL) comparing ezetimibe 10 mg plus simvastatin80 mg with simvastatin 80 mg alone found no signifi-cant difference in the primary endpoint of change inintima-media thickness of the carotid artery. LDL-Cdecreased 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 welltolerated. Severe diarrhea has been reported. Myalgia,rhabdomyolysis, severe hepatitis, toxicity, pancreatitisand thrombocytopenia have also been reported. 31, 32According to the package insert, patients with moder-ate to severe hepatic insufficiency may have increasedserum concentrations of the drug and should nottake it.


16/114


17/114

Drugs for Lipids


PREGNANCY Statins are contraindicated in preg-nancy; congenital anomalies have been reported withlovastatin in some animal species and in a few human

infants. Gemfibrozil and fenofibrate are teratogenic inanimals. The safety of niacin in lipid-lowering doses isunknown. Cholestyramine and colestipol might inter-fere with absorption of important nutrients.Colesevelam appears to be safe in animal reproductivestudies. Ezetimibe has caused skeletal defects in someanimal 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 coronaryand other atherosclerotic vascular disease. They candecrease the incidence of major coronary events anddeath in such patients. Patients at very high risk, suchas those with acute coronary syndrome, have beenshown to benefit from high doses of statins that achieve> 50% lowering of LDL-C. High-risk patients, such asthose with diabetes, may benefit from taking a statineven 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 alow dose of atorvastatin (10 mg) would be a reasonablechoice. Intense LDL-C reduction can be obtained byusing atorvastatin or rosuvastatin, but clinical outcomesdata are lacking for rosuvastatin. In patients with acutecoronary syndromes, atorvastatin is preferred.

Additional LDL-C reductions can be achieved by com- bining statins with other LDL-C lowering drugs, suchas colesevelam, niacin or ezetimibe, but clinical out-come studies of such combinations are lacking.Colesevelam is tolerated much better than the resin bileacid sequestrants and does not interfere with intestinalabsorption of other drugs. Immediate-release niacincosts 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 purityand 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 statinwould be a reasonable choice. Of the two fibrate prepa-rations available in the US, the clinical benefit is bestdocumented for gemfibrozil, which costs less.Fenofibrate is less likely than gemfibrozil to interactwith statins.

1. SE Nissen et al. Effect of recombinant ApoA-I Milano on coronaryatherosclerosis 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 CoronaryPrevention Study. N Engl J Med 2007; 357:1477.

4. R Collins et al. Effects of cholesterol-lowering with simvastatin onstroke and other major vascular events in 20536 people with cere-

brovascular disease or other high-risk conditions. Heart ProtectionStudy 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 coronaryintervention. 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-dosesimvastatin for secondary prevention after myocardial infarction: theIDEAL 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 moderatelipid lowering with statins after acute coronary syndromes. N Engl JMed 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 theAggrastat to Zocor and Pravastatin or Atorvastatin Evaluation andInfection 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 CholesterolLevels [SPARCL] Investigators. High-dose atorvastatin after strokeor 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: systematicreview and meta-analysis. BMJ 2003; 326:1423.

14. SE Nissen et al. [ASTEROID]. Effect of very high-intensity statintherapy on regression of coronary atherosclerosis: the ASTEROIDtrial. JAMA 2006; 295:1556.

15. CP Cannon et al. Meta-analysis of cardiovascular outcomes trialscomparing intensive versus moderate statin therapy. J Am CollCardiol 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-controlstudy. 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/lovastatinAdvicor (Abbott) 2 500/20 mg $100.34

750/20 mg 104.261000/20 mg 116.53

1000/40 mg 113.29Ezetimibe/simvastatinVytorin (Merck/Schering) 3 10/10 mg 103.99

10/20 mg 100.9910/40 mg 100.9910/80 mg 100.99

1. Cost of 30 tablets based on prices from drugstore.com, accessed January16, 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 ezetimibedosage is 10 mg.

Table 4. Statin Combination Products
http://www.ncbi.nlm.nih.gov/pubmed/14600188?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14600188?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14600188?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17387133?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17387133?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17387133?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17928595?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17928595?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15016485?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15016485?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15016485?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15016485?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17826370?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17826370?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15755765?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15755765?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15755765?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16287954?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16287954?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16287954?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15337732?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15337732?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15337732?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15007110?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15007110?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15007110?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17884359?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17884359?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17884359?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17884359?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/17884359?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15514180?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/15514180?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16899775?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16899775?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16899775?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/12829554?ordinalpos=1&itool=EntrezSystem2.PEnt

Documents

Treatment Guidelines,2008