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`EDITORIAL STAFF
`
`Warren S. Joseph, DPM
`Editor
`
`Glenn B. Gastwirth, DPM
`Executive Editor
`
`Annette Theuring, MA
`Managing Editor
`
`David James Rose
`Assistant Editor
`
`EDITORIAL ADVISORY BOARD
`
`Alan S. Banks, DPM
`Michael S. Downey, DPM
`Charles W. Gibley, Jr, PhD
`
`Adam S. Landsman, DPM, PhD
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`
`William H. Sanner, DPM
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`
`David G. Armstrong, DPM
`James R. Black, DPM
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`Jeffrey C. Christensen, DPM
`Robert A. Christman, DPM
`Stephen V. Corey, DPM
`Mary E. Crawford, DPM
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`Gary L. Dockery, DPM
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`Gerald A. Gorecki, DPM
`
`CONTRIBUTING EDITORS
`
`Howard Hillstrom, PhD
`Keith B. Kashuk, DPM
`Kevin A. Kirby, DPM
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`Thomas McPoil, PhD, PT, ATC
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`JOURNAL INFORMATION
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`Clinical Pathology
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`The Journal of the American Podiatric Medical Association
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`
`Possible Drug Interactions in Oral
`Treatment of Onychomycosis
`
`H. IRVING KATZ, MD*
`
`A variety of medications may interact with oral antifungal agents used to
`treat onychomycosis. This article summarizes some possible conse-
`quences of concurrent administration of various therapeutic agents with
`the oral antifungals fluconazole, griseofulvin,
`itraconazole, ketocona—
`zole, and terbinafine.
`
`Oral antifungal medications used to treat onychomy-
`cosis are generally safe, with very low rates of seri-
`ous adverse events. However, when an oral antifun-
`gal medication is given concurrently with another
`therapeutic agent, an adverse drug interaction may
`occur. Some possible consequences of concurrent
`use of various therapeutic agents with oral antifungal
`agents prescribed for the treatment of onychomycosis
`are summarized in this article. The oral antifungals
`discussed are fluconazole (Diflucan®),i griseofulvin
`(Fulvicin®, GrifulVin®, Gris—PEG®), itraconazole
`(Sporanox®), ketoconazole (Nizoral®), and terbina-
`fine (Lamisil®).
`The pharmacologic mechanisms underlying drug
`interactions are pharmacokinetic and/or pharmaco-
`dynarnic.” Pharmacokinetic drug interactions affect
`the concentration, or the patient’s blood levels, of a
`medication. The factors that determine the blood level
`
`of a drug at any given time include its absorption, dis-
`tribution, metabolism, and elimination. Pharmacody—
`namic drug interactions affect a patient through com-
`petition for similar receptors or physiologic systems,
`resulting in either additive, synergistic, or antagonistic
`activity. For example, because many of the oral anti-
`fungals are metabolized by the liver and excreted
`renally, concurrent medications that may impair he-
`patic or renal function should be monitored closely.
`The major types of drug interactions involving the
`oral antifungal agents used to treat onychomycosis
`are the result of pharmacokinetic factors that either
`limit gastrointestinal absorption or affect drug metab-
`*Clinical Professor of Dermatology, Department of
`Dermatology, University of Minnesota, Minneapolis; private
`practice, Associated Skin Care Specialists, 7205 University
`Ave NE, Fridley, MN 55432.
`"As of this writing, fluconazole has not yet been approved
`by the US Food and Drug Administration for the treatment
`of onychomycosis.
`
`olism through their effect on the cytochrome P-450
`catabolic enzymes.” For example, griseofulvin, itra-
`conazole, and ketoconazole are best given with a
`meal because their respective gastrointestinal absorp-
`tions are increased by the presence of food.7'9 Further-
`more, the absorptions of itraconazole and ketocona—
`zole increase in an acidic gastric pH.
`The cytochrome P-450 enzymes catalyze the intra-
`molecular biotransformation of substrate drugs into
`more easily handled compounds that can be further
`processed for clearance and removal.1» 2» 1° Griseoful—
`vin is a cytochrome P-450 enzyme inducer. Therefore,
`the metabolic clearance of certain concurrent sub-
`
`strate drugs may be accelerated by the presence of
`griseofulvin, leading to possible therapeutic failure.
`The imidazole antifungal agents represented by flu-
`conazole, itraconazole, and ketoconazole are, to vari-
`ous degrees, human cytochrome P-450 3A inhibitors;
`fluconazole is also a cytochrome P-450 2C9 inhibitor.
`Therefore, depending on the pharmacokinetic factors
`of the particular imidazole as well as its blood concen-
`tration, the metabolism of cytochrome P-450 3A sub-
`strate drugs may be impaired, resulting in potentially
`toxic concentrations of the drugs. In addition, the irni—
`dazoles are themselves cytochrome P—450 3A sub-
`strates and may suffer metabolic acceleration by
`inducers, resulting in decreased imidazole levels and
`possible loss of antifungal effectiveness.
`Table 1 lists various medications whose concur-
`
`rent use with oral antifungal drugs may lead to ad-
`verse interactions. The reader should refer to the
`
`manufacturer’s specific product literature for addi-
`tional data or the most current prescribing recom-
`mendations. The irnidazole antifungals have greater
`potential for clinically significant drug interactions
`than the other oral antifrmgal agents. Therefore, it is
`prudent to use caution with this class of drugs.
`
`Volume 87 - Number 12 - December 1997
`
`571
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`
`
`Table 1. Drugs Listed by Generic Name, with Brand Name ExampIe(s), That May Interact with Oral Antlfungal Agents
`
`Oral Antifungal(s)
`
`Consequences of Interaction and Suggestions for Management
`
`Disulfiram-like reactions may occur. Avoid.9~ “
`
`Prolonged sedation may occur. Avoid.‘=v 13
`
`Antilungal antagonism reported. Monitor antifungal therapeutic effects.“
`Decreased itraconazole or ketoconazole absorption may occur. Avoid or w *
`least 2 hours between dosing.‘-9
`Impaired aspirin absorption may occur.”
`Serious cardiac arrhythmias (torsades de pointes) may occur. Avoid.5-9- 13
`
`Increased caffeine levels occur with intravenous caffeine administration.
`Limit caffeine intake.”
`
`Decreased imidazole levels may occur. Monitor antifungal efficacy.“
`Hypoglycemia may occur. Avoid or monitor blood glucose |eve|s.3-9- 13
`
`Decreased imidazole absorption may occur.” *3
`
`Increased terbinafine levels may occur.“
`
`Serious cardiac arrhythmias (torsades de pointes) may occur. Avoid.“-9-13
`
`Discrepant results with corticotropin-stimulated cortisol testing may occur
`Avoid.‘3- 17
`
`Increased cyclosporine blood levels may occur. Monitor cyclosporine
`levels.3- 9- ‘3
`
`Decreased cyclosporine levels may occur. Monitor cyclosporine levels.“
`
`Prolonged sedation may occur. Monitor.“
`Decreased itraconazole or ketoconazole absorption may occur. Avoid or
`at least 2 hours between dosing and give with a cola beverage.”
`Increased digoxin levels may occur. Monitor digoxin levels.”-9
`
`Peripheral edema may occur.‘
`Hypoglycemia may occur. Avoid or monitor blood glucose |eve|s.°~9r‘3
`
`Hypoglycemia may occur. Avoid or monitor blood glucose levels.“-9-‘3
`
`Increased fluconazole blood levels may occur.”
`
`Increased indinavir levels may occur. Monitor.“
`
`Decreased imidazole levels may occur. Avoid.“
`
`Increased loratadine levels may occur, but there is no evidence of cardiac.‘
`arrhythmias.9- *9
`Rhabdomyolysis may occur. Avoid.B- “-20
`
`
`
`Concurrent
`
`Therapeutic Agent
`
`Alcohol
`
`Alprazolam (Xanax®)
`
`Amphotericin B (Fungizone®)
`Antacids (Maaloxf-1’)
`
`Aspirin
`Astemizole (Hismana|®)
`
`Caffeine
`
`Carbamazepine (Tegretol®)
`Chlorpropamide
`
`Cimetidine (Tagamet®)
`
`Cimetidine (Tagamet®)
`Cisapride (Propu|sid®)
`
`Corticotropin
`
`Cyclosporine
`(Neoral®, Sandimmune®)
`
`Cyclosporine
`(Neoral®, Sandimmune®)
`Diazepam (Valium®)
`Didanosine (Videx®)
`
`Digoxin (Lanoxin®)
`
`Felodipine (P|endi|®)
`Glipizide (G|ucotro|®)
`
`Glyburide
`(DiaBeta®, Micronase°)
`
`Hydrochlorothiazide
`(HydroD|URIL®)
`indinavir (Crixivan®)
`
`lsoniazid
`(Nydrazid°, FIifamate@)
`Loratadine (C|aritin®)
`
`Lovastatin (Mevacor®)
`
`Griseofulvin,
`ketoconazole
`
`itraconazole,"
`ketoconazole
`Ketoconazole
`
`itraconazole,
`ketoconazole
`Griseofulvin
`
`Fluconazolefib
`itraconazole,“
`ketoconazole
`Terbinafine
`
`itraconazole‘
`
`Fluconazole,=
`itraconazole,‘
`ketoconazole
`
`Fluconazole,
`itraconazole,
`ketoconazole
`Terbinafine
`
`Fluconazole,=: D
`itraconazole,‘
`ketoconazole
`
`Fluconazolefi
`ketoconazole
`
`F|uconazole,=r°
`itraconazole,"
`ketoconazole
`Terbinatine
`
`itraconazole‘
`
`itraconazole,
`ketoconazole
`
`itraconazole,“
`ketoconazole
`itraconazole‘
`
`Fluconazolefi
`itraconazole,“
`ketoconazole
`
`Fluconazole,=
`itraconazole,“
`ketoconazole
`Fluconazolel
`
`itraconazole,‘
`ketoconazole
`
`Itraconazole,=
`ketoconazole
`Ketoconazole
`
`FIuconazo|e,=~ '7
`itraconazole}
`ketoconazole
`
`572
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`Table 1—Contimwd
`
`
`Concurrent
`
`Oral Antifungal(s)
`
`Consequences of Interaction and Suggestions for Management
`
`Therapeutic Agent
`
`ltraconazolefi
`ketoconazole
`
`Methylprednisolone
`
`Increased methylprednisolone levels may occur.9.
`
`Midazolam (Versed®)
`
`Nevirapine (Viramune®)
`
`Nifedipine
`(Adalat®, Procardia®)
`Oral contraceptives
`
`Phenobarbital
`
`Phenytoin (Dilantin®)
`
`Quinidine (Quinidex®)
`Ranitidine (Zantac®)
`
`Rifabutin (Mycobutin®)
`
`Flitampin
`(Rifadin®, Rifamate®)
`
`Flitonavir (Norvir®)
`
`Simvastatin (Zocor®)
`Sucralfate (Caratate®)
`
`Tacrolimus (Prograf®)
`
`Terfenadine (Seldane®)
`
`Terfenadine (Se|dane®)
`Theophylline
`(Primatene®, Theo-Dur®)
`Tolbutamide
`
`Triazolam (Halcion®)
`
`Vincristine (Oncovin®)
`Warfarin (Coumadin®)
`
`Warfarin (Coumadin®)
`Zidovudine (Retrovir®)
`
`F|uconazole,=- 0
`itraconazolefl
`ketoconazole
`
`ltraconazoles‘
`ketoconazole
`ltraconazolea
`
`Griseofulvin
`
`Griseofulvin,
`itraconazolea
`
`Fluconazolefi
`itraconazolefi
`ketoconazole
`ltraconazole-‘i
`
`ltraconazolefi
`ketoconazole
`ltraconazolefl
`
`Fluconazole,=
`itraconazole,
`ketoconazole,
`terbinafine
`
`ltraconazolefi
`ketoconazole
`Itraconazole‘
`Itraconazole,
`ketoconazole
`
`ltraconazole,-1
`ketoconazole
`
`Fluconazolefi °
`itraconazolefi
`ketoconazole
`Terbinafine
`Fluconazolea
`
`Fluconazolefi
`itraconazolefi
`ketoconazole
`
`Fluconazolefit °
`itraconazolefl
`ketoconazole
`ltraconazo|e-
`
`FIuconazole,'
`itraconazolefi
`ketoconazole
`Griseofulvin
`Fluconazolefl
`
`Prolonged sedation may occur. Avoid.” *3
`
`Theoretically, decreased imidazole levels may occur. Monitor therapeutic
`antifungal effects.”
`Peripheral edema may occur.“
`
`Oral contraceptive—pi|l failure may occur. Avoid concurrent administration
`or use additional approved method of contraception (barrier, spermicide).7
`Decreased oral antifungal agent levels may occur. Monitor antifungal
`efficacy.8- 22
`9
`Changes in phenytoin levels“-9: 13 or decreased imidazole efficacy may occur.5
`Monitor clinical status and phenytoin levels.
`
`Tinnitus and/or hearing loss reported.”
`Decreased itraconazole or ketoconazole absorption may occur. Avoid or
`wait at least 2 hours between dosing and give with a cola beverage.“-9
`
`Decreased oral antifungal levels may occur. Avoid or monitor
`antifungal efficacy.“
`Decreased oral antifungal levels may occur. Avoid or monitor antifungal
`efficacy.3- 9- ‘3- ‘G
`
`Theoretically, increased imidazole levels may occur.”
`
`Rhabdomyolysis may occur. Avoid.“
`Decreased itraconazole or ketoconazole absorption may occur. Avoid or
`wait at least 2 hours between dosing and give with a cola beverage.“
`Increased tacrolimus levels or nephrotoxicity may occur. Monitor renal
`function and tacrolimus levels.“-M‘-25
`
`Serious cardiac arrhythmlas (torsades de pointes) may occur. Avoid.°-9-13
`
`Small increase In terbinafine levels reported.“
`
`Increased theophylline levels may occur. Monitor theophylline levels.“
`
`Hypoglycemia may occur. Avoid or monitor blood glucose |evels.5v9- 13
`
`Prolonged sedation may occur. Avoid.°-9- 13
`
`Neurotoxicity may occur.“
`Increased anticoagulation may occur. Monitor prothrombin activity.°~ 9-13
`
`Decreased anticoagulation may occur. Monitor prothrombin activlty.7
`Increased zidovudine levels may occur. Monitor zidovudine levels.“
`
`5 Applies to continuous daily dosing schedules. It is not known if the interaction will occur with intermittent dosing schedules.
`Further interaction studies are needed with imidazole intermittent dosing schedules.
`“May occur only if high doses ol tluconazole (2 400 mg/day) are used on a continuous daily dosing schedule.
`
`Volume 87 - Number 12 - December 1997
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