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ORAL ANTIFUNGAL DRUG INTERACTIONS
Current Therapy
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Bruce H. Thiers, MD,Consulting Editor
ORAL ANTIFUNGAL DRUG INTERACTIONS H. Irving Katz, MD, and Aditya K. Gupta, MD
Drug interactions can cause iatrogenic disease. Dermatologists may be lulled into a false sense of security with the medication they prescribe because, by and large, their patients are in good health. If concurrent medications are taken, however, the potential exists for a drug interaction to occur. Renewed interest in the topic of drug interactions has been generated by the recent approval of two oral antifungal agents, itraconazole (Sporanox) and terbinafine (Lamisil),for the treatment of onychomycosis. These two agents, along with other oral antifungal medications such as griseofulvin (Fulvicin, Grisactin) and ketoconazole (Nizoral), can be involved in drug interactions (Table 1). The consequences of these drug interactions vary in clinical significance, extent, and effect. Some interactions are theoretical whereas others may lead to severe iatrogenic adverse experiences including lethal consequences. The purpose of this review of oral antifungal agents is to alert the medical practitioner to potential drug interactions that may occur when oral antifungal agents are prescribed for onychomycosis. The pharmacologic basis and clinical significance of these interactions of the oral antifungal medications are reviewed. The pharmacologic mechanisms underlying the most significant oral antifungals interactions are illustrative of
those that may be involved for many other medications. Dermatologists and their patients should be aware of the potential pitfalls that may occur when an oral antifungal is prescribed with concurrent medications. WHAT ARE DRUG INTERACTIONS?
Drug interactions are alterations in an expected pharmacologic response of a drug or drugs when two or more agents (such as a food, chemical, or drug[s]) are administered concurrently. The altered response may be of little significance or may result in a clinically significant adverse experience. Drug interactions are a common problem that may not necessarily get the attention that they deserve.3,13, 23, 36, 72,87 Many patients take one or more medications daily. As medical practitioners who focus on the skin, we may be particularly vulnerable to a knowledge gap in this rapidly expanding branch of pharmacologic science. Drug interactions are classified as being either pharmacokinetic or pharmacodynamic. Pharrnacokinetic interactions involve either the absorption, distribution, biotransformation, or elimination of therapeutic agents that ultimately affect the plasma drug concentration. Pharmacodynamic drug interactions are
From the Department of Dermatology, University of Minnesota, Minneapolis, Minnesota (HIK); and the Division of Dermatology, Department of Medicine, Sunnybrook Health Science Center and the University of Toronto, Toronto, Ontario, Canada (AKG)
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KATZ & GUPTA
Table 1. ORAL ANTIFUNGALS THAT MAY BE USED TO TREAT ONYCHOMYCOSIS Griseofulvin lmidazole antifungals ltraconazole Fluconazole Ketoconazole Terbinafine
not dependent on drug concentration per se but involve competition for similar receptors or a physiologic system that may have either synergistic or antagonist effects. As discussed in the following section, alterations in the pharmacokinetics involving gastrointestinal absorption and biotransformation are relevant for the drug interactions involving oral antifungal agents used to treat onychomycosis. ORAL ANTIFUNGAL GASTROINTESTINAL ABSORPTION Medications that are taken by mouth must first be absorbed from the gastrointestinal tract. Most drugs are weak acids or bases, and in their non-ionized form are lipophilic, which facilitates their absorption. Substances that bind to lipophilic agents such as foods, polyvalent cations, resins, or activated charcoal may interfere with the absorption of medications from the gastrointestinal tract. Some oral antifungal agents are best absorbed with meals and are dependent on the gastric pH. For example, alteration of gastric pH by an antacid or an H2blocker may influence the bioavailability of medications such as itraconazole or ketoconazole, which require an acid milieu for optimal absorption. Impaired gastrointestinal absorption may result in decreased drug plasma levels and possibly a reduction in antifungal therapeutic efficacy. ORAL ANTIFUNGAL DRUG DISTRIBUTION Once a drug is absorbed, it is distributed via the circulatory system to tissue sites either in a free unbound form or, more commonly, bound to a plasma protein such as albumin. Generally, it is only the free form of the drug that has pharmacologic activity. Although some of the oral antifungal agents are highly protein bound, protein displacement interac-
tions are not clinically significant for any of the oral antifungal agents per se. ORAL ANTIFUNGAL BIOTRANSFORMATION (METABOLISM) Biotransformation is the metabolic conversion process that changes a lipophilic parent drug into a water-soluble metabolite(s) that is more readily eliminated. Biotransformation may begin in the gut wall, but the majority of such metabolism usually occurs in the liver. The orderly breakdown of drugs occurs during phase I and phase I1 biotransformation enzymatic processes. Phase I biotransformation involves oxidative, reduction, and hydrolysis reactions revealing or forming a functional group within a parent drug that alters its intramolecular makeup as is demonstrated in the example of a phase I biotransformation: Cytochrome P450 catalyzed reaction (intramolecular dealkylation, hydroxylation, and oxidation) CYP enzyme Parent substrate drug- SH + H' + O2 -+ Metabolized drug - OH + HzO Phase I reactions are catalyzed by the cytochrome P450 family of heme-containing enzymes.21,36, s ~s3* Cytochrome P450 enzyme biological functions are the biotransformation of endogenous agents such as corticosteroids and the biotransformation of exogenous agents such as drugs and other chemicals. There are more than 30 individual cytochrome P450 enzymes (singular isoforms) with distinctive chemical specificity. One or more cytochrome P450 enzyme pathways may be involved in biotransformation of a specific drug. Therefore, cytochrome P450 enzymes may exert a rate-limiting effect on a drug metabolism, especially if only one isoenzyme is required for such biotransformation. The prefix CYP connotes all cytochrome P450 enzymes that are subclassified into families, subfamilies, and isoforms according to their amino acid makeup and molecular specifi~ity.8~ Families have at least 40% identical amino acid sequencing and are designated by an Arabic number (ie, CYP1, CYP2, and CYP3 are the most important for drug biotransformation). Subfamilies have at least 55% amino acid identity and are denoted by a capital letter following the first Arabic number (ie,
ORAL ANTIFUNGAL DRUG INTERACTIONS
CYPlA, CYP2D, and CYP3A). Individual isoforms are noted by an Arabic number after the capital letter (ie, CYPlA2, CYP2D6, and CYP3A4). The quantity, quality, and efficiency of CYP may be influenced by the genetic makeup of the individual, disease states, exogenous chemicals, and drugs. Many of the more clinically significant and potentially serious drug interactions of the oral antifungal agents involve alteration of CYP3A4 isoenzymes. A person with a sufficient quantity and activity of a particular CYP isoform, such as CYP3A4, allows the metabolism of substrate drugs such as terfenadine, astemizole, or cisapride to proceed in a normal fashion and is considered a ”normal metabolizer.” Examples of parent substrate drugs that are dependent on optimal activity of CYP3A are illustrated in Table 2. If excess CYP3A is present, then a person is termed a ”fast metabolizer.” On the other hand, if a person has an insufficient activity of CYP3A (owing to a quantitative decrease or inhibition of activity), then a person can be classified as a ”slow metabolizer.” A normal metabolizer may be transformed into a fast metabolizer by inducing the formation of more CYP (enzyme induction). A normal or fast metabolizer may be transformed into a slow metabolizer by the destruction, competitive utilization, or repression of CYP activity (enzyme inhibition). Some drugs, such as phenobarbital, phenytoin, and rifampin, may produce enzyme in-
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duction. CYP3A subfamily enzyme inducers (Table 2) increase the quantity or the efficiency of the CYP, resulting in increased biotransformation. An enzyme inducer may decrease the blood levels of a substrate drug, reducing its activity, and lead to therapeutic failure. The clinically relevant consequences of enzyme inducers may take weeks to become apparent because of synthetic processes involved in producing more CYP. Inhibitors of CYP3A subfamily are found in Table 2 and include drugs such as cimetidine, itraconazole, ketoconazole, and erythromycin. Enzyme inhibitors can produce decreased drug metabolism within a day or two. The reasons for CYP inhibition include stereochemical interference, competition among drugs for the enzyme, or the actual destruction of the enzyme. The result of CYP inhibition may be increased blood levels of a substrate drug, decreased levels of its metabolite, and resultant drug toxicity. Drug toxicity is especially relevant when the concomitant medication has a narrow therapeutic window or is dependent on almost complete first-pass metabolism following absorption from the gastrointestinal tract (Table 3). An example of such a clinically significant drug interaction is the combination of ketoconazole and terfenadine. Ketoconazole is a known potent inhibitor of CYP3A4. Terfenadine is normally almost completely biotransformed during its first pass through the liver by CYP3A4, with generally undetectable levels of the parent
Table 2. EXAMPLES OF CYP3A SUBFAMILY INDUCERS, INHIBITORS, OR SUBSTRATES CYPBA Inducers
CYP3A Inhibitors
CYP3A Substrates
Carbamazepine Cortisol Dexamethasone (Decadron) Griseofulvin Phenobarbital Phenylbutazone Phenytoin Prednisone Rifabutin (Mycobutin) Rifampicin Rifampin
Cimetidine Clarithromycin Diltiazem (Cardizem) Erythromycin (E-Mycin, Ilosone) Fluconazole (large doses) Fluoxetine (Prozac) Fluvoxamine (Luvox) Gestodene Interferon-gamma (Actimmune) ltraconazole Ketoconazole Miconazole Nefazodone (Serzone) Nifedipine Omeprazole (Prilosec) Propoxyphene (Darvon, Datvocet N) Ritonavir Sertraline (Zoloft) Troleandomycin (Tao) Verapamil (Calan, Verelan)
Alprazolam Astemizole Cisapride Digoxin Erythromycin Felodipine (Plendil) Ketoconazole Loratadine Lovastatin Miconazole Midazolam Nifedipine Pimozide (Orap) Prednisone Quinidine Rifampin Simvastatin Tacrolimus Terfenadine Triazolam Warfarin
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Table 3. SELECTED EXAMPLES OF DRUGS THAT HAVE A NARROW THERAPEUTIC WINDOW -~
Medication
Potential Consequences if Therapeutic Window Is Exceeded
Alprazolam Astemizole Carbamazepine Cisapride Cyclosporine Digoxin Glipizide Glyburide Lovastatin Midazolarn Phenytoin Tacrolimus Terfenadine Tolbutamide Triazolam Warfarin
Prolonged sedation, CNS depression Cardiotoxicity, QT-interval prolongation, ventricular arrhythmias CNS toxicity Cardiotoxicity, QT-interval prolongation, ventricular arrhythmias Nephrotoxicity, hypertension Cardiotoxicity, gastrointestinal distress Hypoglycemia Hypoglycemia Myopathy, rhabdomyolysis Prolonged sedation, CNS depression CNS toxicity, cardiotoxicity Nephrotoxicity, hypertension Cardiotoxicity, QT-interval prolongation, ventricular arrhythmias Hypoglycemia Prolonged sedation, CNS depression Increased prothrombin time, hemorrhage
drug in the circ~lation.~~, 84 Nonmetabolized terfenadine can exert a quinidine-like effect on the heart, with resultant prolongation of the QT interval, ventricular arrhythmias, torsades de pointes, and even death.41Therefore, the concurrent use of ketoconazole and terfenadine is contraindicated because lifethreatening cardiac arrhythmias may result from elevated blood levels of the nonmetabolized parent drug owing to impaired first84 pass metab~lisrn.~~, Phase I1 metabolism involves the conjugation or linkage of functional groups to the original parent compound or to one resulting from phase I biotransformation with glucuronic acid, sulfate, or other compounds. This yields highly polar water-soluble conjugates that are readily eliminated.
ment of dermatophyte infections of the skin, hair, and nails.39The gastrointestinal absorption of griseofulvin is variable. Optimal absorption is achieved if griseofulvin is given after ingestion of a fatty meal. Griseofulvin is a known enzyme inducer. Griseofulvin may rarely be associated with hepatotoxic, nephrotoxic, and hematotoxic adverse experiences. In addition, griseofulvin may cause phototoxicity. Hence, persons taking griseofulvin should avoid excessive exposure to ultraviolet light and other potential phototoxic agents such as methoxsalen, sulfonamides, and quinolone and tetracycline antibiotics. Examples of the potential griseofulvin drug interactions are shown in Table 4. lmidazole Oral Antifungal Agents
ORAL ANTIFUNGAL ELIMINATION
Oral antifungal elimination can occur via the gut or the kidney. Alterations in drug clearance owing to the aging process, disease, iatrogenic adverse experiences, or drug interactions may lead to modifications in the blood levels of a drug. Impaired renal function may require closer drug monitoring. SPECIFIC ORAL ANTIFUNGAL DRUG INTERACTIONS Griseofulvin
Griseofulvin is a narrow spectrum oral antifungal agent that is approved for the treat-
Imidazoles are synthetic antifungal agents that include ketoconazole, which is an azole, along with fluconazole and itraconazole, which are triazole derivatives. The imidazoles are broad-spectrum oral antifungal agents. The imidazoles interfere with the CYP fungal Ianosterol-14-demethylase activity, thereby impeding ergosterol synthesis and proper membrane formation. Oral administration of imidazoles (except for fluconazole) is dependent on the presence of acid pH for optimal gastrointestinal absorption to occur. The imidazoles are CYP3A4 substrates and may act as competitive inhibitors of this isoenzyme (see Table 2). Fluconazole may inhibit CYP3A4, but it does so to a lesser degree than either itraconazole or ketoconazole unless it is given at high doses.30Hence the imidazole
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Table 4. POTENTIAL GRISEOFULVIN DRUG INTERACTIONS
Drug Alcohol Aspirin Cyclosporine (Sandirnrnune, Neoiral) Oral contraceptives Phenobarbital Vanillylrnandelic acid testing Warfarin (Cournadin)
Possible Consequences of Concurrent Griseofulvin Administration
Avoid alcohol if possible because disulfirarn-like reactions with tachycardia, diaphoresis, and flushing may OCCUP Monitor because decreased aspirin absorption and decreased salicylate efficacy may occurB6 Monitor because decreased cyclosporine blood levels may occur1i, 39 Monitor because increased biotransforrnation may result in decreased efficacy of oral contraceptives, interrnenstrual bleeding, or unintended pregnancy3*. Monitor because decreased griseofulvin absorption may lead to decreased griseofulvin efficacy’. False-positivespectrometric vanillylrnandelic acid assay Monitor because decreased anticoagulant effects may occur; monitor anticoagulant effectsz6.39,63
antifungals in certain situations may potentially impair the biotransformation and lead to decreased clearance and increased plasma levels of many other CYP3A4 substrate drugs. In addition, the imidazoles may potentially have their respective biotransformations accelerated by certain CYP3A4 inducers.30, 84 Adverse experiences with the oral imidazoles are uncommon and include gastrointestinal distress, malaise, cutaneous eruptions, reversible elevated liver function tests, and the rare occurrence of edema and reversible idiosyncratic hepatitis. Examples of potential drug interactions for the imidazole oral antifungal agents are shown in Table 5. Terbinafine
Terbinafine hydrochloride is a synthetic allylamine antifungal Terbinafine inhibits the fungal enzyme squalene epoxidase that results in the accumulation of squalene and reduced ergosterol synthesis. Squalene epoxidase is not a cytochrome P450 enzyme. Following oral administration, more than 70% of terbinafine is absorbed, with greater than 99% bound to plasma proteins, and ultimately undergoes extensive hepatic metabolism prior to renal elimination. Terbinafine may be a CYP substrate because its clearance may be altered by cimetidine (CYP inhibitor) and rifampin (CYP inducer). Terbinafine is not metabolized by CYP3A4, however. Renal or hepatic impairment, or impairment of both may decrease terbinafine clearance by 50% compared with normal volunteers. Terbinafine use is not recommended in persons with impaired renal or hepatic
function.49 In vitro tests have not demonstrated inhibition of the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vivo studies in normal volunteers have not revealed any alteration of the clearance of antipyrine, digoxin, terfenadine, or warfarin. There are no formal prospective systematic drug interaction studies conducted for the oral contraceptives, hypoglycemics, theophylline, phenytoin, thiazide diuretics, beta-blockers, or calcium channel blockers as of this review.” A recent terbinafine postmarketing surveillance study of 25,884 patients done in the United Kingdom, The Netherlands, Germany, and Austria, however, did not reveal any clinically apparent drug interactions with oral contraceptives, oral tolbutamide, terfenadine, astemizole, or r a n i t i d i ~ ~More e . ~ ~ than 40% of these subjects were taking one or more concurrent medications. No new drug interactions associated with terbinafine were identified. Adverse experiences with terbinafine are uncommon and include gastrointestinal distress, malaise, cutaneous eruptions, reversible elevated liver function test results, taste aberration, and rarely the occurrence of reversible ocular disturbances, severe neutropenia, and idiosyncratic hepatitis. Examples of potential terbinafine drug interactions are shown in Table 6. DISCUSSION
In order to avoid untoward drug interactions, both the medical professional and the patient must be active participants. All parties should be vigilant and informed. It is important for the medical professional to know
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Table 5. EXAMPLES OF POTENTIAL DRUG INTERACTIONS FOR THE IMIDAZOLE ORAL ANTIFUNGAL AGENTS Possible Consequences of Concurrent lmidazole Antifungal Agent Administration' Individual Drug or Drug Class
Fluconazole
ltraconazole
Alcohol Amphotericin B
Astemizole (Hismanal)
Benzodiazepines such as alprazolam (Xanax), chlordiazepoxide (Librium), diazepam (Valium), midazolam (Versed), triazolam (Halcion)
Calcium channel blockers (dihydropyridine class calcium) such as felodipine (Plendil), nifedipine (Adalat, Procardia) Carbamazepine (Tegretol) Cimetidine (Tagamet)
Cisapride (Propulsid)
Clarithromycin(Biaxin) Corticosteroidssuch as methylprednisolone, prednisolone, prednisone (deltasone) Corticotropin
Cyclosporine
Combination not recommended because increased risk of ventricular arrhythmias (torsades de pointes) may theoretically occur, especially with high doses of fluconazole-'. Avoid if possible or monitor closely because increased sedation may theoretically occur with those benzodiazepines that undergo CYP3A4dependent biotransformation, especially with high doses of fluconazole", 35
Case report of decreased amphotericin B efficacy for aspergillosis if itraconazole is given initially78 Contraindicated because ventricular arrhythmias (torsade de pointes) may theoretically occuP4
May be contraindicated (ie, oral midazolamw and triazolamw) or monitor closely because increased sedation may occur with those benzodiazepines that undergo CYP3A4dependent biotransformation17,27. 90
Ketoconazole
Alcohol may cause a disulfiram-like reaction', 6o Therapeutic antifungal antagonism reported but the clinical significance is not known" Contraindicated because ventricular arrhythmias (torsades de pointes) may occur60
May be contraindicated (ie, oral midazolamaoand triazolam60)or monitor closely because increased sedation may occur with those benzodiazepines that undergo CYP3A4dependent 27 ,90 biotran~formation~~,
Monitor because edema reported with dihydropyridine class calcium channel blocker types of agents". 74. w,85 Monitor because decreased fluconazole blood levels may occurffi.88 Decreased fluconazole blood levels may occur with oral but not with intravenous administration= Avoid if possible or monitor closely because serious cardiac arrhythmias (torsades de pointes) may theoretically occur, especially with high doses of fluconazole=~ 7' Monitor because increased clarithromycin blood levels may occurlo
Monitor because decreased itraconazole blood levels may ~ccurl5.65. BB Decreased itraconazole absorption can OCCUP
Monitor because decreased ketoconazole blood levels may O C C U ~ ~ ~ ~ ~ * Decreased ketoconazole absorption can occuP
Contraindicated because serious cardiac arrhythmias (torsades de pointes) have occurred32,71.
Contraindicatedbecause serious cardiac arrhythmias (torsades de pointes) may OccUP, Bo. "
Monitor because decreased corticosteroid effect may OCC"r7.29.n. m. 88.82 Inconsistent effects with adrenocorticotropic hormonestimulated cortisol response testing may OCCUP Monitor because increased cyclosporine blood levels may occurp~TI
Monitor because blunted increase in plasma cortisol level may occuP Monitor because increased cyclosporine blood levels may
Monitor because increased cyclosporine blood levels may oCcur6O Monitor because increased digoxin blood levels may
Digoxin (Lanoxin)
Monitor because increased digoxin blood levels may
Fexofenadine(Allegra)
Increasedfexofenadine blood levels may occur but no cardiotoxicity reportedz Monitor therapeutic efficacy Monitor therapeutic efficacy because increased gastric pH because increased can decrease itmwnazole blood gastric pH can decrease levels and lead to itraconazole ketoconazoleblood therapeutic failuresl8.lg, 53,56, ea levels and lead to ketoconazoletherapeutic failures7.18.1 9 . 4 S 51.53 Bo.BB.69 Table continued on opposite page
OCCUP
Gastric pH alkalinizers such as antacids (Maalox), H2 blockers, lansoprazole (Prevacid), sucralfate (Carafate), didanosine (Videx)
Fluconazoleabsorption is not affected by gastric pH alteration per se". 53 (see cimetidine for additional information)
ORAL ANTIFUNGAL DRUG INTERACTIONS
541
Table 5. EXAMPLES OF POTENTIAL DRUG INTERACTIONS FOR THE IMIDAZOLE ORAL ANTIFUNGAL AGENTS (Continued). Possible Consequences of Concurrent lmidazole Antifungal Agent Administration' lndlvidual Drug or Drug Class
Fluconazole
Monitor because theoretically increased blood levels of both agents may occuP4,52 Contraindicated because increased lovastatin blood levels may occur59and also rhabdomyolysis reporteds2,
HIV protease inhibitors such as indinavir (Crixivan), ritonavir (Norvir) HMG CoA reductase inhibitors such as lovastatin (Mevacor), simvastatin (Zocor) Hydrochlorothiazide (HydroDIURIL)
ltraconazole
Monitor because decreased itraconazole blood levels may occur12.84
lsoniazid (Nydrazid, Rifamate) Loratadine (Claritin)
Oral hypoglycemics such as chlorpropamide, glipizide (Glucotrol), glyburide (DiaBeta, Micronase) tolbutamide Phenytoin (Dilantin)
Monitor because increased anticoagulant effect and m,44 bleeding may occurs,25. Avoid or monitor glucose levels closely because clinically significant increased hypoglycemia may OCCUP, 38, Monitor because increased phenytoin blood levels", 72 or decreased fluconazole levelss5may occur
Quinidine (Quinidex) Rifampin (Rifadin, Rifarnate)
Monitor because decreased fluconazole levels may occurs. 22.30.50
Monitor because increased anticoagulant effect and bleeding may occuP,ffi, e4, Monitor glucose levels because increased hypoglycemia may theoretically occur" Monitor because altered phenytoin blood levels or decreased itraconazole blood levels may occurw Monitor because tinnitus and decreased hearing may occure4 Monitor therapeutic efficacy because decreased itraconazole blood levels and therapeutic failure may OCCUP
Tacrolimus (Prograf)
Nephrotoxicity reporteds.43
Terfenadine (Seldane)
Avoid if possible or monitor closely because increased risk of ventricular arrhythmias (torsades de pointes) may theoretically occur, especially with high doses of fluconazolef'.30, .s, Monitor because increased theophylline blood levels 36,47, ss may OCCUP.
Theophylline (Primatene, Theo-Dur)
".
88
Monitor because increased tacrolimus blood levels may occure4 Contraindicated because ventricular arrhythmias may occur w,84
Monitor for hypoglycemia because ketoconazole may increase glucose toleranceE' Monitor because decreased ketoconazole blood levels may occurw Monitor because increased loratadine blood levels but no evidence of cardiac arrhythmiasm. Monitor because increased anticoagulant effect and w,85 bleeding may OCCUP Antidiabetics monitor because increased hypoglycemia may theoretically occur Monitor because altered phenytoin blood levels or decreased ketoconazole blood levels may occurQ
Avoid or monitor therapeutic efficacy because increased ketoconazole cl, decreased ketoconazole blood levels, and ketoconazole therapeutic failure may occurw,BB Monitor because incieased tacrolimus blood levels may occurw,7o Contraindicated because ventricular arrhythmias may occurw,so
Monitor because aggravation of vincristine-induced neutrotoxicity may occurf4
Vincristine (Oncovin) Zidovudine (Retrovir)
Monitor because theoretically increased blood levels of 62 both agents may occurZ4~
Monitor because increased fluconazole blood levels may occurm
Insulin
Oral anticoagulants such as warfarin (Coumadin)
Ketoconazole
Monitor because increased zidovudine blood levels may O C C U P , 78
'Note that in some instances a specific drug interaction or interactions are cited for only either one or two of the imidazole(s). It may, however, be medically prudent to observe for a similar interaction with the other imidazole class of drugs.
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Table 6. EXAMPLES OF POTENTIAL TERBINAFINE DRUG INTERACTIONS Possible Consequences of Concurrent Terbinafine Administration
Drug ~
Caffeine Cimetidine Cyclosporine Niacinlnicotinic acid (Nicobid) Rifampin Terfenadine
____
Increased caffeine blood levels may occur with intravenously administered caffeine49 Increased terbinafine blood levels may occuri6.54 Monitor because small decreases in cyclosporine blood levels may occurs~ 49, 54 One case report of hepatotoxicity possibly due to combination of niacinlnicotinic acid and terbinafine4 Monitor clinical efficacy because 100% increased terbinafine clearance and decreased terbinafine blood levels may occur49 Small increase in terbinafine blood levels may occuPg
the relevant pharmacologic information for the drugs in their therapeutic armamentarium. Drug interaction information is a dynamic and expanding universe of revisions. Much of this information is readily available from the manufacturer’s package insert, the Physicians’ Desk Reference, literature references, and commercially available drug interaction sources. In addition, pharmacists are a valuable resource for information on this topic. The prescriber should refer to the most current information, which may or may not be included in this article. Overall, the newer oral antifungal agents appear to be safe when used in the management of onychomycosis and other dermatomycoses. It is important to take a thorough medical history to rule out a hepatic, renal, or other condition (ie, allergy) that may affect a likely therapeutic interventi~n.~~, Relevant medication history including concomitant, concurrent, or prospective drug usage, including over-the-counter and prescription medications, should also be obtained. The potential consequences of drug interactions with the oral antifungal agents must be borne in mind.
References 1. Albright PS, Bruni J: Pharmacokinetic interactions of antiepileptic drugs. Can J Neurol Sci 11:247-251,1984 2. Allegra package insert prescribing information, Kansas City, MO, Hoechst Marion Roussel, 1996 3. Andersen WK, Feingold DS: Adverse drug interactions clinically important for the dermatologist. Arch Dermatol 131:468-473, 1995 4. Anonymous: Canadian Adverse Drug Reaction Newsletter 61-3, 1996 5. Apseloff G, Hilligoss DM, Gardner MJ, et al: Induction of fluconazole metabolism by rifampin: In vivo study in humans. J Clin Pharmacol31:35%361, 1991 6. Assan R, Fredj G, Larger E, et al: FK 506/fluconazole interaction enhances FK 506 nephrotoxicity. Diabetes Metab 20:49-52, 1994 7. Baciewicz AM, Baciewicz FA Jr: Ketoconazole and
fluconazole drug interactions [see comments]. Arch Intern Med 153:1970-1976, 1993 8. Baciewicz AM, Menke JJ, Bokar JA, et al: Fluconazole-warfarin interaction [letter]. Ann Pharmacother 28:1111, 1994 9. Back DJ, Stevenson P, Tjia J F Comparative effects of two antimycotic agents, ketoconazole and terbinafine, on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro. Br J Clin Pharmacol 28166-170, 1989 10. Biaxin package insert prescribing information, North Chicago, IL, Abbott Laboratories, 1996 11. Bickers DR: Antifungal therapy: Potential interactions with other classes of drugs. J Am Acad Dermato1 31587-90, 1994 12. Blomley M, Teare EL, de Belder A, et al: Itraconazole and anti-tuberculosis drugs [letter; comment]. Lancet 336:1255, 1990 13. Bloom JA, Frank JW, Shafir MS, et a1 Potentially undesirable prescribing and drug use among the elderly. Measurable and remediable [see comments]. Can Fam Physician 39:2337-2345, 1993 14. Bohme A, Ganser A, Hoelzer D: Aggravation of vincristine-induced neurotoxicity by itraconazole in the treatment of adult ALL. Ann Hematol 71:311-312, 1995 15. Bonay M, Jonville-Bera AP, Diot P, et al: Possible interaction between phenobarbital, carbamazepine and itraconazole. Drug Safety 9:309-311, 1993 16. Breckenridge A: Clinical significance of interactions with antifungal agents [review]. Br J Dermatol 126(S~ppl39):19-22,1992 17. Brown MW, Maldonado AL, Meredith CG, et al: Effect of ketoconazole on hepatic oxidative drug metabolism. Clin Pharmacol Ther 37290-297, 1985 18. Carafate package insert prescribing information, Kansas City, MO, Hoechst Marion Roussel, 1995 19. Carver PL, Berardi RR, Knapp MJ, et al: In vivo interaction of ketoconazole and sucralfate in healthy volunteers. Antimicrob Agents Chemother 38:326329, 1994 20. Claritin package insert prescribing information, Kenilworth, NJ, Schering Corporation, 1995 21. Cohen LJ: Principles to optimize drug treatment in the depressed elderly: Practical pharmacokinetics and drug interactions. Geriatrics 5O(Suppl 1):S32-40, 1995 22. Coker RJ, Tomlinson DR, Parkin J, et al: Interaction between fluconazole and rifampicin. BMJ 301:818, 1990 23. Colley CA, Lucas LM: Polypharmacy: The cure becomes the disease. J Gen Intern Med 8:27%283, 1993 24. Crixivan package insert prescribing information, West Point, PA, Merck & Company, 1996
ORAL ANTIFUNGAL DRUG INTERACTIONS 25. Crussell-Porter LL, Rindone JP, Ford MA, et al: Lowdose fluconazole therapy potentiates the hypoprothrombinemic response of warfarin sodium [see comments]. Arch Intern Med 153:102-104, 1993 26. Cullen SI, Catalan0 PM: Griseofulvin-warfarin antagonism. JAMA 199:582-583, 1967 27. Daneshmend TK, Warnock DW: Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet 14:1334,1988 28. De Doncker P, Van de Velde V, De Coster R, et a1 No indication of decrease in plasma levels of oral contraceptives after 15 days of ihaconazole administration in premenopausal women [poster]. 55th Annual Meeting of the American Academy of Dermatology, March 21-26, 1997 29. Deltasone package insert prescribing information, Kalamazoo, MI, Pharmacia & Upjohn Company, 1995 30. Diflucan package insert prescribing information, New York, NY, Pfizer, 1996 31. Drayton J, Dickinson G, Rinaldi M G Coadministration of rifampin and itraconazole leads to undetectable levels of serum itraconazole [letter]. Clii Infect Dis 18266, 1994 32. Dunbar F Cisapride labelling change [letter]. S Afr Med J 85:287-288, 1995 33. Fett DL, Vukov LF An unusual case of severe griseofulvin-alcohol interaction. Ann Emerg Med 249597, 1994 34. Fungizone Oral Suspension package insert prescribing kformation, Priketon, Br&ol-Myers Squibb Immunology, 1996 35. Gascon MI', Dayer P: In vitro forecasting of drugs which may interfere with the biotransformation of midazolam. Eur J Clin Pharmacol41:573-578, 1991 36. Gillum JGG, Israel Ds, Polk RE: Pharmacokinetic drug interactions with antimicrobial agents [review]. Clin Pharmacokinet 25450-482, 1993 37. Glynn AM, Slaughter RL, Brass C, et a 1 Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion. Clin Pharmacol Ther 39654459, 1986 38. Grant SM, Clissold SP: Fluconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses [published erratum appears in Drugs 402362, 19901. Drugs 39:877-916, 1990 39. Grisactin package insert prescribing information, Philadelphia, PA, Wyeth-Ayerst Laboratories, 1992 40. Hismanal package insert prescribing information, Titusville, NJ, Janssen Pharmaceutica, 1996 41. Honig PK, Worham DC,Zamani K, et al: The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 53:630636, 1993 42. Hughes GS, Francom SF, Spillers CR, et al: The effect of ketoconazole and transdermal estradiol on serum sex steroid hormone levels. Eur J C l i Pharmacol 38:555-560, 1990 43. Iwasaki K, Matsuda H, Nagase K, et al: Effects of twenty-three drugs on the metabolism of FK506 by human liver microsomes. Res Commun Chem Pathol Pharmacol82:209-216, 1993 44. Kefr HD: Case report: Potentiation of warfarin by fluconazole. Am J Med Sci 305:164-165, 1993 45. Kivisto KT, Neuvonen PJ, Klotz U Inhibition of terfenadine metabolism. Pharmacokinetic and pharmacodynamic consequences. Clin Pharmacokinet 271-5, 1994
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46. Knupp CA, Brater DC,Relue J, et al: Pharmacokinetics of didanosine and ketoconazole after coadministration to patients seropositive for the human immunodeficiency virus. J Clin Pharmacol33:912-917,1993 47. Konishi H, Morita K, Yamaji A: Effect of fluconazole on theophylline disposition in humans. Eur J Clin Pharmacol46309-312, 1994 48. Kovacs I, Somos P, Hamori M: Examination of the potential interaction between ketoconazole (Nizoral) and oral contraceptives with special regard to products of low hormone content (Rigevidon, anteovin). Ther Hung 2167-170, 1986 49. Lamisil Tablet package insert prescribing information, East Hanover, NJ, Sandoz Pharmaceuticals, 1996 50. Lazar JD, Wilner KD: Drug interactions with fluconazole. Rev Infect Dis 12(Suppl 3):S327-33, 1990 51. Lee BL, Safrin S Interactions and toxicities of drugs used in patients with AIDS [see comments; review]. Clin Infect Dis 14773-779, 1992 52. Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole [letter]. N Engl J Med 333:664-665, 1995 53. Lim SG,Sawyerr AM, Hudson M, et al: Short report The absorption of fluconazole and itraconazole under conditions of low intragastric acidity [published erratum appears in Aliment Pharmacol Ther 1993 Oct; 7(5):587]. Aliment Pharmacol Ther 7:317-321,1993 54. Long CC, Hill SA, Thomas RC, et al: Effect of terbinafine on the pharmacokinetics of cyclosporin in humans. J Invest Dermatol 102740-743, 1994 55. May DB, Drew RH, Yedinak KC, et a1 Effect of simultaneous didanosine administration on itraconazole absorption in healthy volunteers. Pharmacotherapy 14509-513, 1994 56. Meyboom RH, de Jonge K, Veentjer H, et al: [Potentiation of digoxin by itraconazole]. Ned Tijdschr Geneeskd 1382353-2356, 1994 57. Monahan BP, Ferguson CL, Killeavy ES, et a 1 Torsades de pointes occurring in association with terfenadine use [see comments]. JAMA 264278%2790,1990 58. Neuvonen PJ, Suhonen R Itraconazole interacts with felodipine. J Am Acad Dermatol33134-135, 1995 59. Neuvonen PJ, Jalava K Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 54-61, 1996 60. Nizoral package insert prescribing information, Titusville, NJ, Janssen Pharmaceutica, 1995 61. Nizoral (ketoconazole) section. In Krogh CM (ed): Compendium of Pharmaceutical and Specialties. Toronto, CK Productions, 1996, pp 903-997 62, Norvir package insert prescribing information, North Chicago, IL, Abbott Laboratories, 1996 63. Okino K, Weibert R T Warfarin-griseofulvin interaction. Drug Intel Clin Pharm 20291-293,1986 64. Patsalos PN, Duncan J S Antiepileptic drugs. A review of clinically significant drug interactions. Drug Safety 9:156-184, 1993 65. Perfect JR, Lindsay MH, Drew RH: Adverse drug reactions to systemic antifungals. Prevention and management. Drug Safety 7:323-363, 1992 66. Phillips KR, Wideman SD, Cochran EB, et al: Griseofulvin significantly decreases serum salicylate concentrations. Pediatr Infect Dis J 12:350-352, 1993 67. Pillans PI, Sparrow MJ: Pregnancy associated with a combined oral contraceptive and itraconazole [letter]. N Z Med J 106436,1993 68. Piscitelli SC, Goss TF, Wilton JH, et a1 Effects of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrob Agents Chemother 35:1765-1771, 1991
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69. Prevacid package insert prescribing information, Deerfield, IL, Tap Pharmaceuticals, 1995 70. Prograf package insert prescribing information, Deerfield, IL, Fujisawa USA, 1995 71. Propusid package insert prescribing information, Titusville, NJ,Janssen Pharmaceutica, 1995 72. Quinn DI, Day RO: Drug interactions of clinical importance. An updated guide. Drug Safety 12393452, 1995 73. Rampini E, Schiazza L, Occella C, et al: Falsely elevated urinary level of vanillylmandelic acid induced by griseofulvin. Arch Dermatol 125:269-270, 1989 74. Rosen T Debilitating edema associated with itraconazole therapy [letter]. Arch Dermatol 130:260261, 1994 75. Rossi SJ, Schroeder TJ, Hariharan S, et al: Prevention and management of the adverse effects associated with immunosuppressive therapy. Drug Safety 9:104-131, 1993 76. Sahai J, Gallicano K, Pakuts A, et al: Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus. J Infect Dis 169:1103-1107, 1994 77. Sandimmune package insert prescribing information, East Hanover, NJ, Sandoz Pharmaceuticals, 1995 78. Sandoz Pharmaceuticals, data on file, East Hanover, NJ, 1996 79. Schaffner A, Bohler A Amphotericin B refractory aspergillosis after itraconazole: Evidence for significant antagonism. Mycoses 36421-424, 1993 80. Seldane package insert prescribing information, Kansas City, MO, Hoechst Marion Roussel, 1995
81. Shenfield GM, Griffin JM: Clinical pharmacokinetics of contraceptive steroids. An update [review]. Clin Pharmacokinet 20:15-37,1991 82. SIaughter RL, Edwards DJ: Recent advances: The cytochrome P450 enzymes. Ann Pharmacother 29619624, 1995 83. Spatzenegger M, Jaeger W Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab Rev 27397417,1995 84. Sporanox package insert prescribing information, Titusville, NJ, Janssen Pharmaceutica, 1996 85. Tailor SA, Gupta AK, Walker SE, et al: Peripheral edema due to nifedipine-itraconazole interaction: A case report [letter]. Arch Dermatol 132:350-352, 1996 86. Tett S, Carey D, Lee H S Drug interactions with fluconazole [letter]. Med J Aust 156365, 1992 87. Thompson D, Oster G: Use of terfenadine and contraindicated drugs. JAMA 275:1339-1341, 1996 88. Tucker RM, Denning DW, Hanson LH, et al: Interaction of azoles with rifampin, phenytoin, and carbamazepine: In vitro and clinical observations. Clin Infect Dis 14165-174, 1992 89. Ulrich B, Frey FJ, Speck RF, et al: Pharmacokmetics/ pharmacodynamics of ketoconazole-prednisoloneinteraction. J Pharmacol Exp Ther 260:487490, 1992 90. Xanax package insert prescribing information, Kalamazoo, MI, Pharmacia & Upjohn Company, 1996 91. Yeh J, So0 SC, Summerton C, et al: Potentiation of action of warfarin by itraconazole. BMJ 301:669,1990 92. Zurcher RM, Frey BM, Frey FJ: Impact of ketoconazole on the metabolism of prednisolone [see comments]. Clin Pharmacol Ther 45:366-372, 1989
Address reprint requests to H. Irving Katz, MD Minnesota Clinical Study Center 7205 University Avenue Northeast Fridley, MN 55432
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Bruce H. Thiers, MD,Consulting Editor
ORAL ANTIFUNGAL DRUG INTERACTIONS H. Irving Katz, MD, and Aditya K. Gupta, MD
Drug interactions can cause iatrogenic disease. Dermatologists may be lulled into a false sense of security with the medication they prescribe because, by and large, their patients are in good health. If concurrent medications are taken, however, the potential exists for a drug interaction to occur. Renewed interest in the topic of drug interactions has been generated by the recent approval of two oral antifungal agents, itraconazole (Sporanox) and terbinafine (Lamisil),for the treatment of onychomycosis. These two agents, along with other oral antifungal medications such as griseofulvin (Fulvicin, Grisactin) and ketoconazole (Nizoral), can be involved in drug interactions (Table 1). The consequences of these drug interactions vary in clinical significance, extent, and effect. Some interactions are theoretical whereas others may lead to severe iatrogenic adverse experiences including lethal consequences. The purpose of this review of oral antifungal agents is to alert the medical practitioner to potential drug interactions that may occur when oral antifungal agents are prescribed for onychomycosis. The pharmacologic basis and clinical significance of these interactions of the oral antifungal medications are reviewed. The pharmacologic mechanisms underlying the most significant oral antifungals interactions are illustrative of
those that may be involved for many other medications. Dermatologists and their patients should be aware of the potential pitfalls that may occur when an oral antifungal is prescribed with concurrent medications. WHAT ARE DRUG INTERACTIONS?
Drug interactions are alterations in an expected pharmacologic response of a drug or drugs when two or more agents (such as a food, chemical, or drug[s]) are administered concurrently. The altered response may be of little significance or may result in a clinically significant adverse experience. Drug interactions are a common problem that may not necessarily get the attention that they deserve.3,13, 23, 36, 72,87 Many patients take one or more medications daily. As medical practitioners who focus on the skin, we may be particularly vulnerable to a knowledge gap in this rapidly expanding branch of pharmacologic science. Drug interactions are classified as being either pharmacokinetic or pharmacodynamic. Pharrnacokinetic interactions involve either the absorption, distribution, biotransformation, or elimination of therapeutic agents that ultimately affect the plasma drug concentration. Pharmacodynamic drug interactions are
From the Department of Dermatology, University of Minnesota, Minneapolis, Minnesota (HIK); and the Division of Dermatology, Department of Medicine, Sunnybrook Health Science Center and the University of Toronto, Toronto, Ontario, Canada (AKG)
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Table 1. ORAL ANTIFUNGALS THAT MAY BE USED TO TREAT ONYCHOMYCOSIS Griseofulvin lmidazole antifungals ltraconazole Fluconazole Ketoconazole Terbinafine
not dependent on drug concentration per se but involve competition for similar receptors or a physiologic system that may have either synergistic or antagonist effects. As discussed in the following section, alterations in the pharmacokinetics involving gastrointestinal absorption and biotransformation are relevant for the drug interactions involving oral antifungal agents used to treat onychomycosis. ORAL ANTIFUNGAL GASTROINTESTINAL ABSORPTION Medications that are taken by mouth must first be absorbed from the gastrointestinal tract. Most drugs are weak acids or bases, and in their non-ionized form are lipophilic, which facilitates their absorption. Substances that bind to lipophilic agents such as foods, polyvalent cations, resins, or activated charcoal may interfere with the absorption of medications from the gastrointestinal tract. Some oral antifungal agents are best absorbed with meals and are dependent on the gastric pH. For example, alteration of gastric pH by an antacid or an H2blocker may influence the bioavailability of medications such as itraconazole or ketoconazole, which require an acid milieu for optimal absorption. Impaired gastrointestinal absorption may result in decreased drug plasma levels and possibly a reduction in antifungal therapeutic efficacy. ORAL ANTIFUNGAL DRUG DISTRIBUTION Once a drug is absorbed, it is distributed via the circulatory system to tissue sites either in a free unbound form or, more commonly, bound to a plasma protein such as albumin. Generally, it is only the free form of the drug that has pharmacologic activity. Although some of the oral antifungal agents are highly protein bound, protein displacement interac-
tions are not clinically significant for any of the oral antifungal agents per se. ORAL ANTIFUNGAL BIOTRANSFORMATION (METABOLISM) Biotransformation is the metabolic conversion process that changes a lipophilic parent drug into a water-soluble metabolite(s) that is more readily eliminated. Biotransformation may begin in the gut wall, but the majority of such metabolism usually occurs in the liver. The orderly breakdown of drugs occurs during phase I and phase I1 biotransformation enzymatic processes. Phase I biotransformation involves oxidative, reduction, and hydrolysis reactions revealing or forming a functional group within a parent drug that alters its intramolecular makeup as is demonstrated in the example of a phase I biotransformation: Cytochrome P450 catalyzed reaction (intramolecular dealkylation, hydroxylation, and oxidation) CYP enzyme Parent substrate drug- SH + H' + O2 -+ Metabolized drug - OH + HzO Phase I reactions are catalyzed by the cytochrome P450 family of heme-containing enzymes.21,36, s ~s3* Cytochrome P450 enzyme biological functions are the biotransformation of endogenous agents such as corticosteroids and the biotransformation of exogenous agents such as drugs and other chemicals. There are more than 30 individual cytochrome P450 enzymes (singular isoforms) with distinctive chemical specificity. One or more cytochrome P450 enzyme pathways may be involved in biotransformation of a specific drug. Therefore, cytochrome P450 enzymes may exert a rate-limiting effect on a drug metabolism, especially if only one isoenzyme is required for such biotransformation. The prefix CYP connotes all cytochrome P450 enzymes that are subclassified into families, subfamilies, and isoforms according to their amino acid makeup and molecular specifi~ity.8~ Families have at least 40% identical amino acid sequencing and are designated by an Arabic number (ie, CYP1, CYP2, and CYP3 are the most important for drug biotransformation). Subfamilies have at least 55% amino acid identity and are denoted by a capital letter following the first Arabic number (ie,
ORAL ANTIFUNGAL DRUG INTERACTIONS
CYPlA, CYP2D, and CYP3A). Individual isoforms are noted by an Arabic number after the capital letter (ie, CYPlA2, CYP2D6, and CYP3A4). The quantity, quality, and efficiency of CYP may be influenced by the genetic makeup of the individual, disease states, exogenous chemicals, and drugs. Many of the more clinically significant and potentially serious drug interactions of the oral antifungal agents involve alteration of CYP3A4 isoenzymes. A person with a sufficient quantity and activity of a particular CYP isoform, such as CYP3A4, allows the metabolism of substrate drugs such as terfenadine, astemizole, or cisapride to proceed in a normal fashion and is considered a ”normal metabolizer.” Examples of parent substrate drugs that are dependent on optimal activity of CYP3A are illustrated in Table 2. If excess CYP3A is present, then a person is termed a ”fast metabolizer.” On the other hand, if a person has an insufficient activity of CYP3A (owing to a quantitative decrease or inhibition of activity), then a person can be classified as a ”slow metabolizer.” A normal metabolizer may be transformed into a fast metabolizer by inducing the formation of more CYP (enzyme induction). A normal or fast metabolizer may be transformed into a slow metabolizer by the destruction, competitive utilization, or repression of CYP activity (enzyme inhibition). Some drugs, such as phenobarbital, phenytoin, and rifampin, may produce enzyme in-
537
duction. CYP3A subfamily enzyme inducers (Table 2) increase the quantity or the efficiency of the CYP, resulting in increased biotransformation. An enzyme inducer may decrease the blood levels of a substrate drug, reducing its activity, and lead to therapeutic failure. The clinically relevant consequences of enzyme inducers may take weeks to become apparent because of synthetic processes involved in producing more CYP. Inhibitors of CYP3A subfamily are found in Table 2 and include drugs such as cimetidine, itraconazole, ketoconazole, and erythromycin. Enzyme inhibitors can produce decreased drug metabolism within a day or two. The reasons for CYP inhibition include stereochemical interference, competition among drugs for the enzyme, or the actual destruction of the enzyme. The result of CYP inhibition may be increased blood levels of a substrate drug, decreased levels of its metabolite, and resultant drug toxicity. Drug toxicity is especially relevant when the concomitant medication has a narrow therapeutic window or is dependent on almost complete first-pass metabolism following absorption from the gastrointestinal tract (Table 3). An example of such a clinically significant drug interaction is the combination of ketoconazole and terfenadine. Ketoconazole is a known potent inhibitor of CYP3A4. Terfenadine is normally almost completely biotransformed during its first pass through the liver by CYP3A4, with generally undetectable levels of the parent
Table 2. EXAMPLES OF CYP3A SUBFAMILY INDUCERS, INHIBITORS, OR SUBSTRATES CYPBA Inducers
CYP3A Inhibitors
CYP3A Substrates
Carbamazepine Cortisol Dexamethasone (Decadron) Griseofulvin Phenobarbital Phenylbutazone Phenytoin Prednisone Rifabutin (Mycobutin) Rifampicin Rifampin
Cimetidine Clarithromycin Diltiazem (Cardizem) Erythromycin (E-Mycin, Ilosone) Fluconazole (large doses) Fluoxetine (Prozac) Fluvoxamine (Luvox) Gestodene Interferon-gamma (Actimmune) ltraconazole Ketoconazole Miconazole Nefazodone (Serzone) Nifedipine Omeprazole (Prilosec) Propoxyphene (Darvon, Datvocet N) Ritonavir Sertraline (Zoloft) Troleandomycin (Tao) Verapamil (Calan, Verelan)
Alprazolam Astemizole Cisapride Digoxin Erythromycin Felodipine (Plendil) Ketoconazole Loratadine Lovastatin Miconazole Midazolam Nifedipine Pimozide (Orap) Prednisone Quinidine Rifampin Simvastatin Tacrolimus Terfenadine Triazolam Warfarin
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Table 3. SELECTED EXAMPLES OF DRUGS THAT HAVE A NARROW THERAPEUTIC WINDOW -~
Medication
Potential Consequences if Therapeutic Window Is Exceeded
Alprazolam Astemizole Carbamazepine Cisapride Cyclosporine Digoxin Glipizide Glyburide Lovastatin Midazolarn Phenytoin Tacrolimus Terfenadine Tolbutamide Triazolam Warfarin
Prolonged sedation, CNS depression Cardiotoxicity, QT-interval prolongation, ventricular arrhythmias CNS toxicity Cardiotoxicity, QT-interval prolongation, ventricular arrhythmias Nephrotoxicity, hypertension Cardiotoxicity, gastrointestinal distress Hypoglycemia Hypoglycemia Myopathy, rhabdomyolysis Prolonged sedation, CNS depression CNS toxicity, cardiotoxicity Nephrotoxicity, hypertension Cardiotoxicity, QT-interval prolongation, ventricular arrhythmias Hypoglycemia Prolonged sedation, CNS depression Increased prothrombin time, hemorrhage
drug in the circ~lation.~~, 84 Nonmetabolized terfenadine can exert a quinidine-like effect on the heart, with resultant prolongation of the QT interval, ventricular arrhythmias, torsades de pointes, and even death.41Therefore, the concurrent use of ketoconazole and terfenadine is contraindicated because lifethreatening cardiac arrhythmias may result from elevated blood levels of the nonmetabolized parent drug owing to impaired first84 pass metab~lisrn.~~, Phase I1 metabolism involves the conjugation or linkage of functional groups to the original parent compound or to one resulting from phase I biotransformation with glucuronic acid, sulfate, or other compounds. This yields highly polar water-soluble conjugates that are readily eliminated.
ment of dermatophyte infections of the skin, hair, and nails.39The gastrointestinal absorption of griseofulvin is variable. Optimal absorption is achieved if griseofulvin is given after ingestion of a fatty meal. Griseofulvin is a known enzyme inducer. Griseofulvin may rarely be associated with hepatotoxic, nephrotoxic, and hematotoxic adverse experiences. In addition, griseofulvin may cause phototoxicity. Hence, persons taking griseofulvin should avoid excessive exposure to ultraviolet light and other potential phototoxic agents such as methoxsalen, sulfonamides, and quinolone and tetracycline antibiotics. Examples of the potential griseofulvin drug interactions are shown in Table 4. lmidazole Oral Antifungal Agents
ORAL ANTIFUNGAL ELIMINATION
Oral antifungal elimination can occur via the gut or the kidney. Alterations in drug clearance owing to the aging process, disease, iatrogenic adverse experiences, or drug interactions may lead to modifications in the blood levels of a drug. Impaired renal function may require closer drug monitoring. SPECIFIC ORAL ANTIFUNGAL DRUG INTERACTIONS Griseofulvin
Griseofulvin is a narrow spectrum oral antifungal agent that is approved for the treat-
Imidazoles are synthetic antifungal agents that include ketoconazole, which is an azole, along with fluconazole and itraconazole, which are triazole derivatives. The imidazoles are broad-spectrum oral antifungal agents. The imidazoles interfere with the CYP fungal Ianosterol-14-demethylase activity, thereby impeding ergosterol synthesis and proper membrane formation. Oral administration of imidazoles (except for fluconazole) is dependent on the presence of acid pH for optimal gastrointestinal absorption to occur. The imidazoles are CYP3A4 substrates and may act as competitive inhibitors of this isoenzyme (see Table 2). Fluconazole may inhibit CYP3A4, but it does so to a lesser degree than either itraconazole or ketoconazole unless it is given at high doses.30Hence the imidazole
ORAL ANTIFUNGAL DRUG INTERACTIONS
539
Table 4. POTENTIAL GRISEOFULVIN DRUG INTERACTIONS
Drug Alcohol Aspirin Cyclosporine (Sandirnrnune, Neoiral) Oral contraceptives Phenobarbital Vanillylrnandelic acid testing Warfarin (Cournadin)
Possible Consequences of Concurrent Griseofulvin Administration
Avoid alcohol if possible because disulfirarn-like reactions with tachycardia, diaphoresis, and flushing may OCCUP Monitor because decreased aspirin absorption and decreased salicylate efficacy may occurB6 Monitor because decreased cyclosporine blood levels may occur1i, 39 Monitor because increased biotransforrnation may result in decreased efficacy of oral contraceptives, interrnenstrual bleeding, or unintended pregnancy3*. Monitor because decreased griseofulvin absorption may lead to decreased griseofulvin efficacy’. False-positivespectrometric vanillylrnandelic acid assay Monitor because decreased anticoagulant effects may occur; monitor anticoagulant effectsz6.39,63
antifungals in certain situations may potentially impair the biotransformation and lead to decreased clearance and increased plasma levels of many other CYP3A4 substrate drugs. In addition, the imidazoles may potentially have their respective biotransformations accelerated by certain CYP3A4 inducers.30, 84 Adverse experiences with the oral imidazoles are uncommon and include gastrointestinal distress, malaise, cutaneous eruptions, reversible elevated liver function tests, and the rare occurrence of edema and reversible idiosyncratic hepatitis. Examples of potential drug interactions for the imidazole oral antifungal agents are shown in Table 5. Terbinafine
Terbinafine hydrochloride is a synthetic allylamine antifungal Terbinafine inhibits the fungal enzyme squalene epoxidase that results in the accumulation of squalene and reduced ergosterol synthesis. Squalene epoxidase is not a cytochrome P450 enzyme. Following oral administration, more than 70% of terbinafine is absorbed, with greater than 99% bound to plasma proteins, and ultimately undergoes extensive hepatic metabolism prior to renal elimination. Terbinafine may be a CYP substrate because its clearance may be altered by cimetidine (CYP inhibitor) and rifampin (CYP inducer). Terbinafine is not metabolized by CYP3A4, however. Renal or hepatic impairment, or impairment of both may decrease terbinafine clearance by 50% compared with normal volunteers. Terbinafine use is not recommended in persons with impaired renal or hepatic
function.49 In vitro tests have not demonstrated inhibition of the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vivo studies in normal volunteers have not revealed any alteration of the clearance of antipyrine, digoxin, terfenadine, or warfarin. There are no formal prospective systematic drug interaction studies conducted for the oral contraceptives, hypoglycemics, theophylline, phenytoin, thiazide diuretics, beta-blockers, or calcium channel blockers as of this review.” A recent terbinafine postmarketing surveillance study of 25,884 patients done in the United Kingdom, The Netherlands, Germany, and Austria, however, did not reveal any clinically apparent drug interactions with oral contraceptives, oral tolbutamide, terfenadine, astemizole, or r a n i t i d i ~ ~More e . ~ ~ than 40% of these subjects were taking one or more concurrent medications. No new drug interactions associated with terbinafine were identified. Adverse experiences with terbinafine are uncommon and include gastrointestinal distress, malaise, cutaneous eruptions, reversible elevated liver function test results, taste aberration, and rarely the occurrence of reversible ocular disturbances, severe neutropenia, and idiosyncratic hepatitis. Examples of potential terbinafine drug interactions are shown in Table 6. DISCUSSION
In order to avoid untoward drug interactions, both the medical professional and the patient must be active participants. All parties should be vigilant and informed. It is important for the medical professional to know
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Table 5. EXAMPLES OF POTENTIAL DRUG INTERACTIONS FOR THE IMIDAZOLE ORAL ANTIFUNGAL AGENTS Possible Consequences of Concurrent lmidazole Antifungal Agent Administration' Individual Drug or Drug Class
Fluconazole
ltraconazole
Alcohol Amphotericin B
Astemizole (Hismanal)
Benzodiazepines such as alprazolam (Xanax), chlordiazepoxide (Librium), diazepam (Valium), midazolam (Versed), triazolam (Halcion)
Calcium channel blockers (dihydropyridine class calcium) such as felodipine (Plendil), nifedipine (Adalat, Procardia) Carbamazepine (Tegretol) Cimetidine (Tagamet)
Cisapride (Propulsid)
Clarithromycin(Biaxin) Corticosteroidssuch as methylprednisolone, prednisolone, prednisone (deltasone) Corticotropin
Cyclosporine
Combination not recommended because increased risk of ventricular arrhythmias (torsades de pointes) may theoretically occur, especially with high doses of fluconazole-'. Avoid if possible or monitor closely because increased sedation may theoretically occur with those benzodiazepines that undergo CYP3A4dependent biotransformation, especially with high doses of fluconazole", 35
Case report of decreased amphotericin B efficacy for aspergillosis if itraconazole is given initially78 Contraindicated because ventricular arrhythmias (torsade de pointes) may theoretically occuP4
May be contraindicated (ie, oral midazolamw and triazolamw) or monitor closely because increased sedation may occur with those benzodiazepines that undergo CYP3A4dependent biotransformation17,27. 90
Ketoconazole
Alcohol may cause a disulfiram-like reaction', 6o Therapeutic antifungal antagonism reported but the clinical significance is not known" Contraindicated because ventricular arrhythmias (torsades de pointes) may occur60
May be contraindicated (ie, oral midazolamaoand triazolam60)or monitor closely because increased sedation may occur with those benzodiazepines that undergo CYP3A4dependent 27 ,90 biotran~formation~~,
Monitor because edema reported with dihydropyridine class calcium channel blocker types of agents". 74. w,85 Monitor because decreased fluconazole blood levels may occurffi.88 Decreased fluconazole blood levels may occur with oral but not with intravenous administration= Avoid if possible or monitor closely because serious cardiac arrhythmias (torsades de pointes) may theoretically occur, especially with high doses of fluconazole=~ 7' Monitor because increased clarithromycin blood levels may occurlo
Monitor because decreased itraconazole blood levels may ~ccurl5.65. BB Decreased itraconazole absorption can OCCUP
Monitor because decreased ketoconazole blood levels may O C C U ~ ~ ~ ~ ~ * Decreased ketoconazole absorption can occuP
Contraindicated because serious cardiac arrhythmias (torsades de pointes) have occurred32,71.
Contraindicatedbecause serious cardiac arrhythmias (torsades de pointes) may OccUP, Bo. "
Monitor because decreased corticosteroid effect may OCC"r7.29.n. m. 88.82 Inconsistent effects with adrenocorticotropic hormonestimulated cortisol response testing may OCCUP Monitor because increased cyclosporine blood levels may occurp~TI
Monitor because blunted increase in plasma cortisol level may occuP Monitor because increased cyclosporine blood levels may
Monitor because increased cyclosporine blood levels may oCcur6O Monitor because increased digoxin blood levels may
Digoxin (Lanoxin)
Monitor because increased digoxin blood levels may
Fexofenadine(Allegra)
Increasedfexofenadine blood levels may occur but no cardiotoxicity reportedz Monitor therapeutic efficacy Monitor therapeutic efficacy because increased gastric pH because increased can decrease itmwnazole blood gastric pH can decrease levels and lead to itraconazole ketoconazoleblood therapeutic failuresl8.lg, 53,56, ea levels and lead to ketoconazoletherapeutic failures7.18.1 9 . 4 S 51.53 Bo.BB.69 Table continued on opposite page
OCCUP
Gastric pH alkalinizers such as antacids (Maalox), H2 blockers, lansoprazole (Prevacid), sucralfate (Carafate), didanosine (Videx)
Fluconazoleabsorption is not affected by gastric pH alteration per se". 53 (see cimetidine for additional information)
ORAL ANTIFUNGAL DRUG INTERACTIONS
541
Table 5. EXAMPLES OF POTENTIAL DRUG INTERACTIONS FOR THE IMIDAZOLE ORAL ANTIFUNGAL AGENTS (Continued). Possible Consequences of Concurrent lmidazole Antifungal Agent Administration' lndlvidual Drug or Drug Class
Fluconazole
Monitor because theoretically increased blood levels of both agents may occuP4,52 Contraindicated because increased lovastatin blood levels may occur59and also rhabdomyolysis reporteds2,
HIV protease inhibitors such as indinavir (Crixivan), ritonavir (Norvir) HMG CoA reductase inhibitors such as lovastatin (Mevacor), simvastatin (Zocor) Hydrochlorothiazide (HydroDIURIL)
ltraconazole
Monitor because decreased itraconazole blood levels may occur12.84
lsoniazid (Nydrazid, Rifamate) Loratadine (Claritin)
Oral hypoglycemics such as chlorpropamide, glipizide (Glucotrol), glyburide (DiaBeta, Micronase) tolbutamide Phenytoin (Dilantin)
Monitor because increased anticoagulant effect and m,44 bleeding may occurs,25. Avoid or monitor glucose levels closely because clinically significant increased hypoglycemia may OCCUP, 38, Monitor because increased phenytoin blood levels", 72 or decreased fluconazole levelss5may occur
Quinidine (Quinidex) Rifampin (Rifadin, Rifarnate)
Monitor because decreased fluconazole levels may occurs. 22.30.50
Monitor because increased anticoagulant effect and bleeding may occuP,ffi, e4, Monitor glucose levels because increased hypoglycemia may theoretically occur" Monitor because altered phenytoin blood levels or decreased itraconazole blood levels may occurw Monitor because tinnitus and decreased hearing may occure4 Monitor therapeutic efficacy because decreased itraconazole blood levels and therapeutic failure may OCCUP
Tacrolimus (Prograf)
Nephrotoxicity reporteds.43
Terfenadine (Seldane)
Avoid if possible or monitor closely because increased risk of ventricular arrhythmias (torsades de pointes) may theoretically occur, especially with high doses of fluconazolef'.30, .s, Monitor because increased theophylline blood levels 36,47, ss may OCCUP.
Theophylline (Primatene, Theo-Dur)
".
88
Monitor because increased tacrolimus blood levels may occure4 Contraindicated because ventricular arrhythmias may occur w,84
Monitor for hypoglycemia because ketoconazole may increase glucose toleranceE' Monitor because decreased ketoconazole blood levels may occurw Monitor because increased loratadine blood levels but no evidence of cardiac arrhythmiasm. Monitor because increased anticoagulant effect and w,85 bleeding may OCCUP Antidiabetics monitor because increased hypoglycemia may theoretically occur Monitor because altered phenytoin blood levels or decreased ketoconazole blood levels may occurQ
Avoid or monitor therapeutic efficacy because increased ketoconazole cl, decreased ketoconazole blood levels, and ketoconazole therapeutic failure may occurw,BB Monitor because incieased tacrolimus blood levels may occurw,7o Contraindicated because ventricular arrhythmias may occurw,so
Monitor because aggravation of vincristine-induced neutrotoxicity may occurf4
Vincristine (Oncovin) Zidovudine (Retrovir)
Monitor because theoretically increased blood levels of 62 both agents may occurZ4~
Monitor because increased fluconazole blood levels may occurm
Insulin
Oral anticoagulants such as warfarin (Coumadin)
Ketoconazole
Monitor because increased zidovudine blood levels may O C C U P , 78
'Note that in some instances a specific drug interaction or interactions are cited for only either one or two of the imidazole(s). It may, however, be medically prudent to observe for a similar interaction with the other imidazole class of drugs.
542
KATZ & GUPTA
Table 6. EXAMPLES OF POTENTIAL TERBINAFINE DRUG INTERACTIONS Possible Consequences of Concurrent Terbinafine Administration
Drug ~
Caffeine Cimetidine Cyclosporine Niacinlnicotinic acid (Nicobid) Rifampin Terfenadine
____
Increased caffeine blood levels may occur with intravenously administered caffeine49 Increased terbinafine blood levels may occuri6.54 Monitor because small decreases in cyclosporine blood levels may occurs~ 49, 54 One case report of hepatotoxicity possibly due to combination of niacinlnicotinic acid and terbinafine4 Monitor clinical efficacy because 100% increased terbinafine clearance and decreased terbinafine blood levels may occur49 Small increase in terbinafine blood levels may occuPg
the relevant pharmacologic information for the drugs in their therapeutic armamentarium. Drug interaction information is a dynamic and expanding universe of revisions. Much of this information is readily available from the manufacturer’s package insert, the Physicians’ Desk Reference, literature references, and commercially available drug interaction sources. In addition, pharmacists are a valuable resource for information on this topic. The prescriber should refer to the most current information, which may or may not be included in this article. Overall, the newer oral antifungal agents appear to be safe when used in the management of onychomycosis and other dermatomycoses. It is important to take a thorough medical history to rule out a hepatic, renal, or other condition (ie, allergy) that may affect a likely therapeutic interventi~n.~~, Relevant medication history including concomitant, concurrent, or prospective drug usage, including over-the-counter and prescription medications, should also be obtained. The potential consequences of drug interactions with the oral antifungal agents must be borne in mind.
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