ORAL ANTIFUNGAL DRUG INTERACTIONS

Current Therapy Bruce H. Thiers, MD, Consulting Editor

0733-8635/97 $0.00 + .20

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. Re- newed interest in the topic of drug interactions has been generated by the recent ap- proval 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 (Ful- vicin, 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 prac- titioner 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 mecha- nisms 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 ex- pected 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 de- serve.3, 13, 23, 36, 72, 87 Many patients take one or more medications daily. As medical prac- titioners 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)

DEWTOLOGIC CLINICS

VOLUME 15 * NUMBER 3 * JULY 1997 535

536 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 char- coal 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 H2 blocker 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 conver- sion 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 re- vealing 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 spec- ifi~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 537

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 effi- ciency of CYP may be influenced by the ge- netic 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 isoen- zymes.

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.” Exam- ples of parent substrate drugs that are dependent on optimal activity of CYP3A are illus- trated 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 insuffi- cient activity of CYP3A (owing to a quantita- tive 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 induc- tion). A normal or fast metabolizer may be transformed into a slow metabolizer by the destruction, competitive utilization, or repres- sion of CYP activity (enzyme inhibition).

Some drugs, such as phenobarbital, phenytoin, and rifampin, may produce enzyme in-

duction. CYP3A subfamily enzyme inducers (Table 2) increase the quantity or the effi- ciency 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 be- come 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 stereo- chemical 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

538 KATZ & GUPTA

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.41 Therefore, the concurrent use of ketoconazole and terfenadine is contraindicated because life- threatening cardiac arrhythmias may result from elevated blood levels of the nonmetabolized parent drug owing to impaired first- pass metab~lisrn.~~, 84

Phase I1 metabolism involves the conjuga- tion or linkage of functional groups to the original parent compound or to one resulting from phase I biotransformation with glucu- ronic acid, sulfate, or other compounds. This yields highly polar water-soluble conjugates that are readily eliminated.

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

Griseof ulvi n

Griseofulvin is a narrow spectrum oral antifungal agent that is approved for the treat-

ment of dermatophyte infections of the skin, hair, and nails.39 The 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, nephro- toxic, and hematotoxic adverse experiences. In addition, griseofulvin may cause phototox- icity. Hence, persons taking griseofulvin should avoid excessive exposure to ultravio- let light and other potential phototoxic agents such as methoxsalen, sulfonamides, and quin- olone and tetracycline antibiotics. Examples of the potential griseofulvin drug interactions are shown in Table 4.

lmidazole Oral Antifungal Agents

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.30 Hence the imidazole


Table 4. POTENTIAL GRISEOFULVIN DRUG INTERACTIONS

Drug Possible Consequences of Concurrent Griseofulvin Administration

Alcohol

Aspirin

Cyclosporine

Oral contraceptives (Sandirnrnune, Neoi

Phenobarbital

Vanillylrnandelic acid

Warfarin (Cournadin) testing

Avoid alcohol if possible because disulfirarn-like reactions with tachycardia,

Monitor because decreased aspirin absorption and decreased salicylate

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-positive spectrometric vanillylrnandelic acid assay

Monitor because decreased anticoagulant effects may occur; monitor

diaphoresis, and flushing may OCCUP

efficacy may occurB6

ral)

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 ac- celerated 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 idiosyn- cratic hepatitis. Examples of potential drug interactions for the imidazole oral antifungal agents are shown in Table 5.

Terbinafine

Terbinafine hydrochloride is a synthetic al- lylamine antifungal Terbinafine inhibits the fungal enzyme squalene epoxidase that results in the accumulation of squalene and reduced ergosterol synthesis. Squa- lene 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. Terbi- nafine may be a CYP substrate because its clearance may be altered by cimetidine (CYP inhibitor) and rifampin (CYP inducer). Terbi- nafine 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 an i t i d i~~e .~~ More 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 dis- turbances, severe neutropenia, and idiosyn- cratic 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

540 KATZ & GUPTA

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 Ketoconazole

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)

Corticosteroids such as methylprednisolone, prednisolone, prednisone (deltasone)

Corticotropin

Cyclosporine

Digoxin (Lanoxin)

Fexofenadine (Allegra)

Gastric pH alkalinizers such as antacids (Maalox), H2 blockers, lansoprazole (Prevacid), sucralfate (Carafate), didanosine (Videx)

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 CYP3A4- dependent biotransformation, especially with high doses of fluconazole", 35

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

Inconsistent effects with adrenocorticotropic hormonestimulated cortisol response testing may OCCUP

Monitor because increased cyclosporine blood levels may occurp~ TI

Fluconazole absorption is not affected by gastric pH alteration per se". 53 (see cimetidine for additional information)

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 CYP3A4- dependent biotransforma- tion17, 27. 90

Monitor because edema reported with dihydropyridine class calcium channel blocker types of agents". 74. w, 85

itraconazole blood levels may

absorption can OCCUP

Monitor because decreased

~ccurl5. 65. BB

Decreased itraconazole

Contraindicated because serious cardiac arrhythmias (torsades de pointes) have occurred32, 71.

Monitor because increased cyclosporine blood levels may

Monitor because increased digoxin blood levels may

Monitor therapeutic efficacy because increased gastric pH can decrease itmwnazole blood levels and lead to itraconazole therapeutic failuresl8. lg, 53, 56, ea

Alcohol may cause a

Therapeutic antifungal disulfiram-like reaction', 6o

antagonism reported but the clinical significance is not known"

Contraindicated because ventricular arrhythmias (torsades de pointes) may occur60

May be contraindicated (ie, oral midazolamao and triazolam60) or monitor closely because increased sedation may occur with those benzodiazepines that undergo CYP3A4- dependent biotran~formation~~, 27 ,90

Monitor because decreased ketoconazole blood levels may O C C U ~ ~ ~ ~ ~ *

Decreased ketoconazole absorption can occuP

Contraindicated because serious cardiac arrhythmias (torsades de pointes) may OccUP, Bo. "

Monitor because decreased corticosteroid effect may OCC"r7.29.n. m. 88.82

Monitor because blunted increase in plasma cortisol level may occuP

Monitor because increased cyclosporine blood levels may oCcur6O

Monitor because increased digoxin blood levels may OCCUP

Increased fexofenadine blood levels may occur but no cardiotoxicity reportedz

Monitor therapeutic efficacy because increased gastric pH can decrease ketoconazole blood levels and lead to ketoconazole therapeutic

Table continued on opposite page failures7.18. 19.4S 51.53 Bo.BB.69


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 ltraconazole Ketoconazole

HIV protease inhibitors such as indinavir (Crixivan), ritonavir (Norvir)

HMG CoA reductase inhibitors such as lovastatin (Mevacor), simvastatin (Zocor)

Hydrochlorothiazide (H ydroD I U RI L)

Insulin

lsoniazid (Nydrazid, Rifamate)

Loratadine (Claritin)

Oral anticoagulants such as warfarin (Coumadin)

Oral hypoglycemics such as chlorpropamide, glipizide (Glucotrol), glyburide (DiaBeta, Micronase) tolbutamide

Phenytoin (Dilantin)

Quinidine (Quinidex)

Rifampin (Rifadin, Rifarnate)

Tacrolimus (Prograf)

Terfenadine (Seldane)

Theophylline (Primatene,

Vincristine (Oncovin)

Theo-Dur)

Zidovudine (Retrovir)

Monitor because increased fluconazole blood levels may occurm

Monitor because increased anticoagulant effect and bleeding may occurs,25. m,44

Avoid or monitor glucose levels closely because clinically significant increased hypoglycemia may OCCUP, 38,

Monitor because increased phenytoin blood levels", 72

or decreased fluconazole levelss5 may occur

Monitor because decreased fluconazole levels may occurs. 22.30.50

Nephrotoxicity reporteds. 43

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 may OCCUP. 36, 47, ss

Monitor because theoretically increased blood levels of both agents may occuP4, 52

Contraindicated because increased lovastatin blood levels may occur59 and also rhabdomyolysis reporteds2,

Monitor because decreased itraconazole blood levels may occur12. 84

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 O C C U P ". 88

Monitor because increased tacrolimus blood levels may occure4

ventricular arrhythmias may occur w, 84

Contraindicated because

Monitor because aggravation of vincristine-induced neutrotoxicity may occurf4

Monitor because increased zidovudine blood levels may OCCUP, 78

Monitor because theoretically increased blood levels of both agents may occurZ4~ 62

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 bleeding may OCCUP w,85

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

ventricular arrhythmias may occurw, so

Contraindicated because

'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

Drug

Caffeine Cimetidine Cyclosporine Niacinlnicotinic acid (Nicobid)

Rifampin

Terfenadine

Possible Consequences of Concurrent Terbinafine Administration ~ ____

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

Monitor clinical efficacy because 100% increased terbinafine clearance and

Small increase in terbinafine blood levels may occuPg

acid and terbinafine4

decreased terbinafine blood levels may occur49

the relevant pharmacologic information for the drugs in their therapeutic armamentar- ium. Drug interaction information is a dy- namic 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 dermato- mycoses. 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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ORAL ANTIFUNGAL DRUG INTERACTIONS