Drug interactions with itraconazole, fluconazole, and terbinafine and their management

CLINICAL

REVIEWS

Drug interactions with itraconazole, fluconazole, and terbinafine and their management Aditya K. Gupta, MD, FRCPC,a H. Irving Katz, MD,b and Neil H. Shear, MD, FRCPCa,c Toronto, Ontario, Canada, and Minneapolis, Minnesota A drug interaction develops when the effect of a drug is increased or decreased or when a new effect is produced by the prior, concurrent, or subsequent administration of the other. Before prescribing a drug, it is important to obtain a thorough drug history of the prescription and nonprescription medications taken by the patient. The nonprescription medications may include items such as nutritional supplements and herbal medications. The risk of side effects is an inevitable consequence of drug use. The frequency of adverse reactions is increased in those patients receiving multiple medications. Drug interactions reported in animal or in vitro studies may not necessarily develop in humans. When drug interactions are observed with a particular agent, it cannot be automatically assumed that all closely related drugs will necessarily produce the same interaction. However, caution is advised until sufficient experience accrues. The prescriber should not overestimate or underestimate the potential for a given drug interaction on the basis of personal experience alone. Drug interactions will not necessarily occur in every patient who is given a particular combination of drugs known to produce an interaction. For a clinically significant drug interaction to be manifest, several other factors may be relevant other than just using the two drugs. In many instances drug interactions can be predicted and therefore avoided if the pharmacodynamic effects, the pharmacokinetic properties, and the mechanisms of action of the 2 drugs in question are known. In the case of contraindicated drugs, it may be possible to use an alternative agent. (J Am Acad Dermatol 1999;41:237-49.)

T

he newer oral antifungal agents fluconazole, itraconazole, and terbinafine were first introduced into clinical practice less than 10 years ago. Their combined use worldwide for all indications including systemic and superficial mycoses because their initial launch is approximately 100 million patients (fluconazole, 50 million patients; itraconazole, 40 million patients; terbinafine, 11 million patients). Itraconazole, fluconazole, and terbinafine have proved to be extremely safe with a high benefitto-risk ratio.1 With these oral antifungal agents only, some of the expected adverse reactions can be attributed to drug interactions.2 The risk of adverse From the Division of Dermatology, Department of Medicine, Sunnybrook and Women’s Health Science Center (Sunnybrook site) and the University of Toronto Medical School, Torontoa; the Department of Dermatology, University of Minnesota, Minneapolisb; and the Division of Clinical Pharmacology, Department of Medicine and Department of Pharmacology, Sunnybrook and Women’s Health Science Center (Sunnybrook site) and the University of Toronto Medical School, Toronto.c Reprints are not available from the authors. Correspondence: Aditya K. Gupta, MD, FRCPC, 490 Wonderland Rd South, Suite 6, London, Ontario, N6K 1L6, Canada. E-mail: agupta @execulink.com. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/97351

reactions can be minimized by obtaining a detailed history of both prescription and nonprescription drugs taken by the patient. In many instances it is possible to predict a drug interaction when the mechanism of action of the interacting agents, the pharmacodynamic effects, and the pharmacokinetic properties are known. When a drug interaction involves a contraindicated drug, in many instances alternative agents can be used safely. Improved understanding regarding the mechanism of drug interactions and their successful management is an important step in maintaining the high benefit-torisk ratio of the newer antifungal agents.

WHAT IS A DRUG INTERACTION? A potential drug interaction refers to the possibility that one drug may alter the intensity of pharmacologic effects of another drug that is given concurrently. The result may either be enhanced or reduced activity of the affected drug that may lead to toxicity or therapeutic failure, respectively. It is also possible that there is the appearance of a new effect that is not seen with either drug alone.

FREQUENCY OF DRUG INTERACTIONS The frequency of significant beneficial or adverse 237

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Table I. Drug interactions: Myths and realities Myth

Reality

If a drug-drug interaction is listed on a chart or in a reference text, then coadministration is contraindicated.

Some interactions are contraindications; others may be managed by dosage adjustments and/or serum level monitoring. Drugs in the same chemical or structural class may or may not “cross interact” with other drugs in the same manner. Many drug interactions have been substantiated by small pharmacokinetic studies or derived from collections of analyzed case reports after clinical experience. Significant interpatient variability in drug metabolism often creates variable degrees of response and clinical significance among patients.

All drugs in the same chemical or structural class interact with other drugs in the same manner. All drug interactions have been carefully evaluated and proved to occur through prospective trials and detailed pharmacokinetic studies. All patients experience the same interactions in the same manner.

drug interactions is difficult to assess. Surveys that include data obtained in vitro, in animals, and in case reports tend to predict a frequency of interactions that is higher than actually occurs.3 In one surveillance program there were 3600 adverse drug reactions (4.3%) in 83,000 drug exposures.4 Drug interactions were believed to occur in 234 cases (0.3%). In general, the incidence of clinically significant drug interactions depends on several factors including the age of the individual, pre-existing medical status, concomitant polypharmaceutic exposures, nature of the specific drugs being taken, and whether an inpatient or outpatient population is being considered.

ASSESSMENT OF RISK IN THE CLINICAL OUTCOME OF DRUG INTERACTIONS A physician may underestimate or overestimate the clinical importance of a specific drug interaction, because such an assessment is often based on the clinical experience gained from the use of the particular drug combination.5 For example, if no adverse effect is observed after several patients have been prescribed a particular drug combination, then there may be a tendency to consider the interaction clinically unimportant although in fact the interaction may produce serious adverse effects in a small proportion of the patients.5 Alternatively, if the physician has a patient who experiences a serious adverse effect after the use of a particular drug combination, there may be the tendency to avoid this combination of drugs; however, in practice, the incidence of such a reaction is actually uncommon.5 Some drug interaction myths and realities are listed in Table I.

PATIENTS AT INCREASED RISK FOR DRUG INTERACTIONS Some patient groups may be at an increased risk for the development of drug interactions. Older indi-

viduals are more likely to experience an adverse effect because of the physiologic changes associated with the aging process and the higher frequency of the use of multiple drugs for a wide range of ailments, many of which require long-term treatment.6 Patients who are seeing multiple prescribers, patients who are infrequently or inadequately monitored, patients with impaired pathways of drug elimination, and patients with certain pharmacogenetic patterns are at increased risk for drug interactions. In general, patients with the following diseases that may require more than one medication are more likely to have an adverse drug reaction: cardiovascular, connective tissue, gastrointestinal, lipid, infectious, psychiatric, respiratory, or seizure disorders.7

DRUG-DRUG INTERACTIONS Understanding the mechanism of drug interactions may help the prescriber to avoid them. Drug interactions are considered clinically significant if the therapeutic effectiveness of one of the interacting drugs is decreased or if an adverse reaction manifests itself.8 The more important adverse drug-drug interactions occur with drugs that have a serious toxicity and low therapeutic index.3 In such instances relatively small changes in the drug level may have important adverse consequences. Drug interactions may be either pharmacokinetic or pharmacodynamic.3 In a pharmacokinetic drug-drug interaction, a drug may alter the absorption, distribution, metabolism, or elimination of another medication.9 As a consequence, there may be an increase or decrease in the concentration of drug at the site of action. Because individuals may vary in the rate of disposition of a given drug, the extent of a drug interaction that alters pharmacokinetic parameters are not always predictable.3 However, the consequences can be quite significant. A pharmacodynamic interaction

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occurs when a medication induces a change in a patient’s response to a drug without altering the pharmacokinetics of the object drug, for example, decreased receptor sensitivity.9 It has been suggested that such reactions may not be drug interactions unless an adverse reaction occurs.9

HOW DRUG METABOLISM MAY RESULT IN DRUG INTERACTIONS Drugs may be divided into water-soluble (polar) and lipid-soluble compounds.10 Although polar compounds are usually excreted unchanged through the kidneys, lipid compounds generally have to be metabolized to more polar metabolites before they can be excreted in the urine.10 Drug metabolism takes place mainly in the liver but to a lesser extent in other tissues (eg, the intestine, skin, lungs, kidneys, blood, and brain).10 When a drug is being metabolized to more polar compounds, a range of biochemical reactions can occur. Metabolic reactions may be subdivided into phase I and phase II reactions. In the former, polar groups are incorporated into the drug (eg, by oxidation, reduction, or hydrolysis), with oxidation being the most common pathway.10 Phase II reactions include conjugation reactions. Oxidative metabolism of many drugs and other compounds (eg, prostaglandin, fatty acids and steroids) occurs through the cytochrome P-450 system. This is a collective term for a group of related enzymes or isozymes.10

CYTOCHROME P-450 ISOENZYME NOMENCLATURE The cytochrome P-450 isoenzymes (isoforms) are a group of heme-containing proteins that exist as gene superfamilies. They encode isoforms with distinct but overlapping substrate specificities. When carbon monoxide binds to the enzyme in the reduced state, the maximum spectral absorbance is observed at or near 450 nm, hence the name.11 Cytochrome P-450 isoforms are present in many tissues, with the highest concentration in the endoplasmic reticulum of hepatocytes. These metabolic enzymes are also present in high concentrations in enterocytes of the small intestine with smaller amounts in extrahepatic tissues such as the kidneys, lung and brain.12 The nomenclature for cytochrome P-450 isoforms that is widely used today was first suggested by Nebert et al13 in 1987 and discussed by Michalets12 in 1998. It uses a 3-tier classification.14,15 The first tier of classification is the family (Arabic numeral, >36% homology in amino acid sequence); the second tier is the subfamily (capital letter, 77% homology), and the third tier is the individual gene (Arabic numeral). At least 12 cytochrome P-450 gene families and 31 apparently functional gene products have been identified in humans.15 The

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major cytochrome P-450 isoforms responsible for human drug metabolism are CYP 3A4, CYP 2D6, CYP 1A2, CYP 2C9, and CYP 2C19. Substrates Some drug are metabolized by more than one isoform. For example, the pharmacologically active enantiomer S-warfarin is metabolized by the CYP 2C9 isoform and R-warfarin is metabolized by the CYP 3A4 and CYP 1A2 isoform.12,16,17 It is also possible for a drug to inhibit or induce the activity of one isoform although it is not a substrate at that particular site (eg, quinidine is metabolized by the CYP 3A4 isoform but is a potent inhibitor of CYP 2D6).11,12,18 Enzyme induction The time course of induction is in part dependent on the half-life of the inducer (eg, rifampin has a short half-life with enzyme induction [CYP 3A4, CYP 2C] developing within 24 hours); however, phenobarbital has a longer half-life of 3 to 5 days, and consequently it takes approximately 7 days for induction (CYP 3A4, CYP 1A2, CYP 2C) to become manifest.12 Another limiting factor may be the time it takes for degradation of the cytochrome P-450 (eg, CYP 3A4 isoenzyme and new enzyme production). For CYP 3A4 this is typically 1 to 6 days.12,19 Enzyme induction may also be reduced in subjects with hepatitis or cirrhosis. Subsequently, the ability to induce drug metabolism may be reduced.12,20 Enzyme inhibition Enzyme inhibition may be the result of competitive or noncompetitive binding at the enzyme binding site. When the inhibition is competitive, the onset and offset of enzyme inhibition depend on the half-life and the time to steady state of the inhibitor drug (eg, cimetidine [CYP 1A2], chloramphenicol [CYP 2C9], and acute ethanol ingestion typically inhibit drug metabolism within 24 hours of a single dose). In contrast, amiodarone (CYP 2C9) has a long half-life; consequently, inhibitory interactions may not manifest for months.12,21 The time period elapsed before the drug interaction is maximal (onset and termination) and is also dependent on the time period required for the inhibited drug to reach a new steady state (eg, when cimetidine inhibits theophylline, maximal increases in theophylline concentration are not observed for 2 days because this is the time period over which theophylline achieves a new steady state).12,22,23 Noncompetitive inhibition occurs less commonly, and the duration of inhibition may last for a longer period if new CYP isoform has to be synthesized after discontinuation of the inhibitor drug.12,20

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Table II. Contraindicated drugs with itraconazole and possible alternatives Contraindicated drug

Antihistamines: astemizole, terfenadine GI motility agent: cisapride

Cholesterol-lowering agents: simvastatin, lovastatin

Benzodiazepines: oral triazolam, midazolam

Possible alternatives

Hydroxyzine, cetirizine, fexofenadine, loratadine, other antihistamines Antacids or H2-antagonists (itraconazole administered 1 or 2 h beforehand), lifestyle modifications. (Note: The cisapride alternatives do not truly duplicate what is accomplished pharmacologically by cisapride.) Pravastatin, fluvastatin, or temporarily withhold cholesterol-lowering agent. (Note: Atorvastatin and cerivastatin are metabolized in the liver by cytochrome P450 3A4. The use of these two drugs should be temporarily discontinued during itraconazole therapy.) Zolpidem

Note: This is only a guideline. Consult product monograph or up-to-date source for contraindicated drugs because the list may change with time. The list of possible alternatives may be updated as more information regarding drug interactions becomes available. Authoritative and current sources should be consulted before patient use. (Adapted from Gupta AK, Shear NH. An update: the risk-benefit of the newer antifungal agents in the management of onychomycosis. Drug Safety In press.)

ITRACONAZOLE AND FLUCONAZOLE Absorption interactions The absorption of itraconazole, when administered as the capsule formulation, is enhanced by coadministration with food.24-28 Agents that increase gastric alkalinity (eg, histamine2 [H2]-blockers, antacids, proton pump inhibitors, and oral didanosine) reduce itraconazole capsule absorption. Itraconazole should be administered 1 to 2 hours before an H2-blocker (eg, cimetidine, ranitidine) or an antacid. Coadministration of an acidic beverage with itraconazole may improve its bioavailability in patients who have hypochlorhydria.29,30 Itraconazole is a weak base (pKa = 3.7) and a 325-mL can of Coca Cola Classic or Pepsi (pH 2.5) enables the triazole to be ionized.31 Some beverages do not have a pH of less than 3, suggesting that these may not be as effective (eg, Diet Coca Cola, Diet Pepsi, Diet 7-Up, Diet Canada Dry Ginger Ale, Diet Canada Dry Orange juice, 7-Up, Canada Dry Ginger Ale, and Canada Dry Orange juice).31,32 Didanosine is formulated with buffers to prevent its destruction by gastric acid.33 Itraconazole should be spaced at least 2 hours apart from the didanosine for optimal absorption.33,34 Proton pump inhibitors may reduce absorption of itraconazole. Therefore when a patient is receiving a proton pump inhibitor it is especially important to ensure that itraconazole is taken after a full meal or a Coke Classic or Pepsi beverage. Itraconazole solution absorption is not significantly influenced by the degree of gastric acidity.35,36 In fact, for best absorption the itraconazole solution should be administered in the fasting state.

When fluconazole is administered with the antacid magnesium hydroxide, there was no effect on the absorption or elimination of fluconazole.37,38 The pKa of fluconazole is 1.5, whereas that of ketoconazole has two values, 2.9 and 6.5.39,40 Cimetidine and antacids can markedly reduce ketoconazole absorption.41,42 When antacids are given concurrently with fluconazole, plasma levels of fluconazole may be reduced, possibly as a result of decreased absorption.41-43 However, this change may not be clinically significant.43 Treatment with omeprazole may not interfere with the absorption and plasma pharmacokinetics of fluconazole.44 Interactions with CYP enzymes The CYP 3A4 isoform is the most common cytochrome isoform found in the liver. It accounts for 60% and 70% of hepatic and enterocyte cytochrome enzymes, respectively. With itraconazole, the basis of some of the drug interaction is the inhibition/induction of CYP 450 3A4 isoform. Fluconazole may inhibit both the CYP 450 3A4 and 2C9 isoforms. The interactions between fluconazole and phenytoin, tolbutamide, and warfarin may be explained by the triazole-inhibiting CYP 2C9 isoform. Higher doses of fluconazole may inhibit CYP 3A4 to a greater extent compared with lower doses of the triazole. The drugs that are contraindicated with itraconazole and possible alternatives are listed in Table II.45 For both itraconazole and fluconazole, the drug interactions described are those reported with continuous dosing schedules.

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Itraconazole Anticonvulsants (eg, phenytoin, phenobarbital, carbamazepine).43,46-48 Coadministration with itraconazole may be associated with reduced serum concentration of the triazole. Phenytoin may enhance the first-pass metabolism and hepatic metabolism of the triazole by CYP 3A4.7,46 The pharmacologic effects of hydantoins (phenytoin, ethotoin, and mephenytoin) may be increased as a result of inhibition of hydantoin metabolism.43 Antihistamines (astemizole, terfenadine).49-55 Concurrent administration of astemizole and itraconazole is contraindicated because elevated concentrations of astemizole and its principal metabolite, desmethylastemizole, may result. 49,50 Similarly, coadministration with terfenadine results in increased plasma levels of the antihistamine. Both of these antihistamines are contraindicated with itraconazole because of an increased risk of torsades de pointes ventricular tachycardia.51-53 Antimycobacterial agents (rifampin, isoniazid, rifabutin).56-58 Coadministration with itraconazole may be associated with decreased serum itraconazole concentration because the metabolism of the triazole is induced. In addition, itraconazole may increase serum rifabutin levels. Benzodiazepines (eg, midazolam, triazolam, alprazolam).59-67 Concurrent administration with itraconazole may result in elevated levels of the benzodiazepine because the triazole may decrease the metabolism of certain benzodiazepines and the firstpass effect of triazolam. Oral midazolam and oral triazolam are contraindicated with itraconazole. Compared with oral midazolam, the interaction between itraconazole and intravenous midazolam is weaker.64 When bolus doses of midazolam are given for short-time sedation, the effect of midazolam is not increased to a clinically significant degree, and it can be used in normal doses. However, the use of large doses of intravenous midazolam increases the risk of clinically significant interactions.64 The prescribing information for alprazolam indicates that the drug is contraindicated with itraconazole.67 Buspirone.68 Buspirone is a non-benzodiazepine anxiolytic agent that acts as a partial antagonist at serotonin receptors of the 5-HT1A type. Itraconazole increases plasma busiprone concentrations by inhibiting CYP 3A4-mediated first-pass metabolism. Busulfan.69 Concurrent administration with itraconazole may result in increased busulfan levels. Calcium channel blockers of the dihydropyridine class (eg, amlodipine, felodipine, nifedipine).70-72 Concurrent administration with itraconazole may result in edema of the ankles and legs because of elevated levels of the calcium chan-

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nel blocker. Itraconazole may inhibit CYP 3A4 during the first-pass and elimination phases of felodipine metabolism. Cyclosporine.73-80 Coadministration with itraconazole may increase cyclosporine serum concentrations. Because nephrotoxicity can occur, cyclosporine concentrations and renal function should be monitored. Digoxin.81-91 Coadministration with itraconazole may be associated with elevated digoxin levels and the potential for toxicity. Fluoxetine.92 There is a case report of an interaction between fluoxetine and itraconazole. Gastrointestinal motility agent (cisapride).43 Coadministration of cisapride with itraconazole is contraindicated and may lead to increased plasma cisapride concentrations. Life-threatening cardiac arrhythmias, including torsades de pointes, QT prolongation, ventricular tachycardia, and fibrillation may develop in patients who are coadministered the two drugs. HIV protease inhibitors (eg, ritonavir, indinavir)93,94 and other HIV drugs (eg, zidovudine). Coadministration of itraconazole with protease inhibitors that are metabolized primarily by CYP 3A4 (eg, ritonavir, indinavir) may result in changes in plasma concentrations of both the triazole and HIV protease inhibitor. Caution is therefore advised when using the two concomitantly. Zidovudine. The pharmacokinetics of zidovudine may not be affected with concomitant itraconazole administration. HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, pravastatin).95-102 Coadministration of itraconazole with lovastatin and simvastatin is contraindicated. Itraconazole inhibits the metabolism of lovastatin, resulting in significantly elevated plasma concentrations of lovastatin or lovastatin acid, and this has been associated with rhabdomyolysis.95-97 Itraconazole may also inhibit simvastatin.102 The use of atorvastatin and cerivastatin with itraconazole may not be recommended because these drugs are also metabolized by the hepatic CYP 3A4.100,101 Fluvastatin is metabolized by the CYP 450 2C isoform, and concomitant use with itraconazole is not likely to result in a clinically significant drug interaction.98 In addition, itraconazole has only a minor effect on pravastatin.102 Methylprednisolone.103,104 The adrenal response to corticotropin in patients treated with itraconazole 100 mg/day and 200 mg/day has been evaluated.103 No impairment of cortisol synthesis was demonstrated. In some susceptible patients, the adverse effects of steroids (eg, myopathy, diabetes

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mellitus, and Cushing’s syndrome) may become exaggerated when itraconazole is associated with the treatment.104 In one case, cyclosporine and methylprednisolone was administered after itraconazole 400 mg/day for 3 weeks, and a steroid myopathy developed.104 The itraconazole was stopped with improvement in the myopathy. The authors indicate that when a patient receiving itraconazole and exogenous steroids experiences steroid-related side effects, then the steroid dosage should be reduced.104 Oral contraceptives.105-107 Isolated cases of contraceptive failure have been reported, although there may be no scientific basis for such an interaction.105,106 In one study, itraconazole did not have any inducing effects on the metabolism of ethinylestradiol and norethisterone.107 The report concluded that itraconazole may not affect contraceptive effectiveness.107 Oral hypoglycemic agents (eg, sulfonylureas: tolbutamide, glimepiride, acetohexamide, chlorpropamide, tolazamide, glipizide, and glyburide; non-sulfonyl urea agents: acarbose, metformin, troglitazone, and repaglinide).108-118 Severe hypoglycemia has been reported in patients receiving azoles and oral hypoglycemic agents concomitantly. Blood glucose concentrations should be monitored when itraconazole is coadministered with oral hypoglycemic agents. Tolbutamide and glimeripide may be metabolized through CYP 2C9 rather than CYP 3A4.108-113 The other sulfonylureas (acetohexamide, chlorpropamide, tolazamide, glipizide, and glyburide) are metabolized by the liver, but their hepatic CYP 450 activity is not reported. Some antidiabetic agents that are not sulfonylureas include acarbose, metformin, troglitazone, and repaglinide. Metformin does not appear to have hepatic metabolism and may be excreted unchanged in the urine.114 Acarbose has no liver metabolism and is metabolized mainly by intestinal bacteria and digestive enzymes.115 Troglitazone is metabolized by the liver but not by CYP 450.116 However, it may induce drug metabolism by CYP 3A4. Repaglinide undergoes hepatic metabolism and is a substrate of CYP 3A4.117 Verspeelt et al118 reviewed available clinical data, literature, and postmarketing information and found no strong association between the development of hypoglycemia in patients receiving both itraconazole and antidiabetic agents concomitantly.118 Postmarketing surveillance data reveal that there were 189 diabetic patients of a total of 2359 patients who were treated with itraconazole. The number of patients with hyperglycemia (37 patients) in the adverse events database was twice as high as the number of subjects

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with hypoglycemia (17 patients).118 The ratio was similar regardless of antidiabetic treatment, in particular, insulin, oral antidiabetics, or no antidiabetic drugs.118 Verspeelt et al118 reasoned that if itraconazole truly inhibits the metabolism of antidiabetic drugs then there would be a preponderance of cases of hypoglycemia. Oxybutynin.119 Itraconazole moderately increases serum concentrations of oxybutynin, possibly by inhibiting CYP 3A-mediated metabolism. Quinidine.120,121 Concurrent administration with itraconazole may result in an increased quinidine concentration as the result of inhibition of metabolism by CYP 3A4. This may lead to tinnitus. Sildenafil citrate.122 Sildenafil citrate is cleaved predominantly by the CYP 3A4 (major route) and CYP 2C9 (minor route). Inhibitors of these isoforms may reduce sildenafil clearance. The package insert indicates that concomitant use of itraconazole may be associated with a 200% increase in plasma levels of sildenafil; therefore it is suggested that the starting dose be reduced by one half in this situation. Tacrolimus (FK506).123-125 Metabolism of tacrolimus may be inhibited by itraconazole. Vincristine.126,127 Itraconazole may aggravate vincristine-induced toxicity. Warfarin.128 Coadministration of warfarin with itraconazole may result in an increased anticoagulant effect, possibly by inhibiting warfarin metabolism. Fluconazole Antidepressants, tricyclic (eg, amitriptyline, nortriptyline).129,130 Three case reports with fluconazole appeared to significantly raise serum levels of amitriptyline. Fluconazole may interfere with amitriptyline demethylation by the CYP 2C9 isoform. Antihistamines (eg, terfenadine, astemizole).131-134 Coadministration of fluconazole at multiple doses of 400 mg or higher with terfenadine is contraindicated. Coadministration of fluconazole at doses lower than 400 mg/day should be carefully monitored. Use of fluconazole in patients concurrently taking astemizole may result in elevated levels of the latter. In the absence of definitive information, care should be taken when administering astemizole with fluconazole. Patients should be carefully monitored. Anti-HIV drugs (eg, didanosine, zidovudine, and protease inhibitors).135-137 There is no interaction. Zidovudine. Fluconazole increases zidovudine serum concentration, possibly by inhibiting its metabolism. Protease inhibitors.138-141 In a crossover study, 13 healthy male and female patients were assessed

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for the potential drug interaction between ritonavir administered alone (200 mg for 4 days) and in combination fluconazole (400 mg on day 1 and 200 mg on days 2-5; personal communication with Pfizer Inc, January 1998). The pharmacokinetics of ritonavir were assessed for the 24-hour period after the dose on day 4. Small (≤ 15%), but statistically significant, mean increases in ritonavir area under the curve (12%) and maximum concentration (15%) were found with concomitant fluconazole administration. Mean values of half-life and time of maximum concentration were not significantly affected. Based on this study, dosage adjustment of ritonavir appears unnecessary. The effect of ritonavir on fluconazole pharmacokinetics was not evaluated (personal communication, Pfizer Inc, January 1998). In the absence of further clinical information, it may be prudent to monitor any patient receiving fluconazole and any protease inhibitor for objective and subjective alterations in response to either drug (personal communication, Pfizer Inc, January 1998). Antimycobacterial agents (eg, rifampin, rifabutin).142-148 Rifampin may reduce levels of fluconazole by increasing its elimination; fluconazole may increase levels of rifabutin possibly by inhibition of CYP 3A4. Benzodiazepines (eg, midazolam, triazolam).149-153 Fluconazole may increase the concentration and effect of midazolam. Metabolism of midazolam is inhibited more strongly when the drug is administered by the oral than by the intravenous route.150,151 Fluconazole may enhance the effect of triazolam, although not to the same extent as ketoconazole or itraconazole.152,153 Cyclosporine.154-164 Fluconazole (at doses of >100 mg/day) may increase cyclosporine levels, and toxicity may result, possibly by inhibiting CYP 3A4 levels. Therefore cyclosporine concentrations and serum creatinine should be carefully monitored. Gastrointestinal motility agent (eg, cisapride). Coadministration with fluconazole has been associated with cardiac events including torsades de pointes as the result of elevated serum levels of cisapride. The coadministration of cisapride with fluconazole is contraindicated. Hydrocholorothiazide. An increase in fluconazole plasma levels is attributed to decreased renal clearance. Oral contraceptives.165,166 When fluconazole is administered with oral contraceptives containing ethinylestradiol and levonorgestrel, an overall mean increase in levels of both has been reported; however, in some instances decreased levels may occur. Clinical significance of these effects is presently not known.

Oral hypoglycemic agents (eg, tolbutamide, glyburide, glipizide).167,168 Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When fluconazole is used concomitantly with sulfonylurea oral hypoglycemia agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary.168 Phenytoin.169-176 Fluconazole may increase plasma concentrations of phenytoin, which may lead to toxicity in some patients, possibly by inhibiting hepatic metabolism of the hydantoin (phenytoin, ethotoin, mephenytoin). Phenytoin is metabolized by CYP 2C9; therefore fluconazole could be a possible inhibitor of CYP 2C.176 Careful monitoring of phenytoin concentration is recommended. Tacrolimus (FK506).177-181 Coadministration with fluconazole (100 mg/day) may result in elevated levels of the immunosuppressive agent. Fluconazole inhibits metabolism of tacrolimus through CYP 3A4. Theophylline.182 Intravenous aminophylline given with oral fluconazole decreased the clearance of theophylline and increased its half-life. This interaction may occur through CYP 1A2. Warfarin.16,17,183-189 Fluconazole enhances the effect of warfarin by inhibiting its hepatic metabolism. The more potent S enantiomer is metabolized by the CYP 2C9 pathway, and (R)-10-hydroxy-warfarin is metabolized by CYP 3A4. Fluconazole appears to inhibit both these pathways.16,17,189

TERBINAFINE In contrast to ketoconazole, itraconazole, and fluconazole, terbinafine is an allylamine that demonstrates a weak substrate interaction with cytochrome P-450.78,190-202 Terbinafine acts as a substrate for a fraction of cytochrome P-450 by which it is rapidly metabolized. No significant reaction has been observed between terbinafine and terfenadine,203 midazolam,204 triazolam,152 nifedipine,205 digoxin,206 testosterone,207,208 glyburide,209 and antipyrine.210,211 Terbinafine does not inhibit CYP 3A4. The allylamine may cause a weak induction of some CYP isoforms with a decrease in the plasma concentrations of some coadministered drugs (substrates of CYP 3A4) by 10% to 30%.211 Examples are terfenadine acid metabolite203 and cyclosporin.212 Caffeine.213-216 Terbinafine decreases intravenously administered caffeine clearance by 19%. Caffeine is metabolized primarily to 1,7-paraxanthine through the CYP 1A2 isoform. Cimetidine. Cimetidine, an H2 blocker, decreases terbinafine clearance by 33%,200 possibly by inhibition of CYP 1A2–mediated metabolism.211

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Cyclosporine.195,217,218 Terbinafine increases cyclosporine clearance by 15%. Nortriptyline.219 One case report of interaction between terbinafine and nortriptyline, with an increase in the levels of the nortriptyline, can be found. A rechallenge test was performed, again with an increase in the concentration of nortriptyline. Rifampin. Terbinafine clearance is increased by 100% when taken concomitantly with terbinafine. Theophylline.195,215,220,221 Both caffeine and theophylline are methylxanthines and are metabolized by similar pathways. When theophylline is given concurrently with terbinafine, theophylline exposure (area under the serum concentration-time curve from time zero to infinity) increased by 16%; oral clearance decreased by 14%, and half-life increased by 24%.220 A possibility is that terbinafine may cause a disruption in the CYP 450 reductase membranes and consequently inhibit its action on theophylline metabolism mediated by the CYP 1A2 pathway.195,220,221 However, in one study terbinafine did not appear to alter the activity of CYP 1A2.215 Warfarin.196,197,222-225 Some studies and postmarketing surveillance data indicate no interaction with terbinafine. One case report relates that the anticoagulant effect of terbinafine was reduced when given concurrently with warfarin (the patient was also receiving glibenclamide, metformin, furosemide, and spironolactone therapy, the doses of which had not been changed in the previous 24 months)224; in another report the opposite occurred, with the prothrombin time being increased.225 In the latter case there may have been an interaction between terbinafine and warfarin, or terbinafine in the presence of cimetidine or thyroxine may have had an effect on warfarin.225 In a postmarketing surveillance study in 25,884 patients (42.8% patients were taking a concomitant medication) conducted in the United Kingdom, the Netherlands, Germany, and Austria, data were analyzed for interactions between terbinafine and any of the drugs given concomitantly to study patients for any indication. No evidence of clinically apparent drug-drug interactions was found.197 ADDENDUM: Terbinafine is an inhibitor of CYP 2D6 (Abdel-Rahman SM, Marcucci K, Boge T, Gotschall RR, Kearns GL, Leeder JS. Inhibition of cytochrome P450256 (CYP2D6) by terbinafine (TER) in vitro [abstract]. Clin Pharmacol Ther 1999;65:135; and Abdel-Rahman SM, Gotschall RR, Kauffman MS, Leeder JS, Kearns GL. Inhibition of cytochrome P4502D6 (CYP2D6) by terbinafine (TER) in vivo [abstract]. Clin Pharmacol Ther 1999;65:135). The clinical significance of this finding is not known. There is one case report of terbinafine inhibiting

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