Itraconazole and terbinafine: Focus on drug interactions

March 2002

Onychomycosis is a general fungal infection of the nail unit that accounts for one-half of all nail disorders. The FDA has approved itraconazole (Sporanox, Janssen, Ortho Biotech) and terbinafine (Lamisil, Novartis) for the treatment of onychomycosis. Although other antifungals may also be effective, itraconazole and terbinafine are the most frequently used antifungal agents.

Despite its frequent use, both itraconazole and terbinafine are associated with numerous potentially serious drug interactions. In May 2001, the product labeling for terbinafine and itraconazole were modified to include information regarding such drug interactions. Physicians should be aware of potential drug interactions with these agents to minimize the risk of serious complications.

Itraconazole: pharmacokinetics

Adequate absorption of itraconazole capsules requires an acidic gastric environment. It is recommended that itraconazole be taken with a meal to maximize absorption. Additionally, administration should be separated from agents that reduce gastric acidity (eg, antacids, H-2 antagonists, proton pump inhibitors) by one to two hours. In contrast to the capsule formulation, itraconazole solution does not depend on gastric acidity for absorption, and does not need to be given with food.

During fasting conditions, the bioavailability and time to peak concentration of the oral solution are increased. Itraconazole is 99.8% bound to plasma proteins and has an extensive distribution in vivo. Drug concentrations up to three times plasma levels have been seen in skin, liver, adipose tissue, bone, endometrium, pus, cervical mucous and the vagina. Itraconazole concentrations persist in the nail for six to nine months after discontinuing therapy. Itraconazole undergoes extensive metabolism in the liver, primarily by the cytochrome P450 3A4 isoenzyme system. More than 30 metabolites have been identified, with hydroxy-itraconazole being the major active metabolite. It reaches higher plasma concentrations than the parent compound, and has demonstrated in vitro activity similar to itraconazole.

Itraconazole drug interactions

Because of extensive metabolism by the hepatic cytochrome P450 3A4 system, itraconazole and hydroxy-itraconazole potentially interact with drugs metabolized by this route. Itraconazole may decrease the elimination of drugs metabolized by CYP 3A4 resulting in elevated plasma concentrations, which may prolong and/or increase both the therapeutic and the adverse effects of these drugs. When coadministration of these drugs with itraconazole is necessary, careful monitoring of the patient for signs and symptoms of toxicity is prudent and dosage adjustments may be necessary.

Recently, dofetilide (Tikosyn, Pfizer) was added to the black box warning for itraconazole regarding cardiac related adverse events caused by drug interactions. Concomitant use with cisapride, pimozide (Orap, Gate), quinidine or dofetilide is contraindicated. Cardiac adverse events including QT prolongation, torsades de pointes, ventricular fibrillation, cardiac arrest, and/or sudden death have occurred with coadministration of these agents with itraconazole. Pharmacokinetic studies in vivo have demonstrated an increased risk of skeletal muscle toxicity including rhabdomyolysis when HMGCo-A reductase inhibitors (eg, lovastatin [Mevacor Merck] and simvastatin [Zocor, Merck]) are coadministered with itraconazole. Concomitant use of itraconazole with these agents is contraindicated. Itraconazole may increase plasma concentrations of benzodiazepines resulting in increased sedative and hypnotic effects. Coadministration of oral midazolam and triazolam with itraconazole is contraindicated. If midazolam is administered parenterally, the manufacturer recommends special precaution and patient monitoring.

Terbinafine pharmacokinetics

Following oral administration, terbinafine is well absorbed (70%). As a result of first pass metabolism, the bioavailability is 40%. Gastric acidity does not appear to affect the absorption. Terbinafine is highly lipophillic and is distributed extensively to the tissues. After oral administration, high concentrations of the drug are present in the adipose tissue, stratum corneum, dermis, epidermis and nails.

Terbinafine is 99% protein bound. In comparison to itraconazole, terbinafine is not as extensively metabolized by the cytochrome P450 system. It has been reported that metabolism of terbinafine involves <5% of the total cytochrome P450 capacity of the liver. Therapeutic concentrations are present in the nails for up to nine months after discontinuing therapy.

Terbinafine does not inhibit or induce CYP 3A4. However, it does appear to inhibit CYP 2D6. The product labeling was updated in May 2001 to include information regarding drug interactions. Terbinafine has demonstrated inhibition of CYP2D6 mediated metabolism in in vitro studies. Interactions with medications metabolized by CYP 2D6, such as tricyclic antidepressants, ß-blockers, selective seratonin reuptake inhibitors and monoamine oxidase inhibitors, may occur.

In vivo studies have shown that terbinafine inhibits the metabolism of cyclosporine by 15%. Although case reports demonstrate an interaction between warfarin and terbinafine, a causal relationship cannot be established at this time. Nonetheless, caution should be used when administering terbinafine to patients receiving warfarin. There are no adequate drug-drug interaction studies with oral contraceptives, hormone replacement therapies, hypoglycemics, theophylline, phenytoin, thiazide diuretics, ß-blockers, and calcium channel blockers. There are no absolute contraindications regarding the use of terbinafine with other drugs.

Conclusions

The induction and inhibition of cytochrome P450 enzymes is a common mechanism for many drug interactions. Itraconazole and terbinafine are associated with multiple drug-drug interactions because of their action on P450 enzymes. Caution should be used if concomitant administration with drugs known to interact with these agents is necessary. The measurement of serum drug concentrations and appropriate dosage adjustment may be required, and patients receiving these drugs should be monitored closely for signs and symptoms of toxicity.

For more information:

• Drake LA, Dinehart SM, Farmer ER, Goltz RR, Graham GF, et al. Guidelines of care for superficial mycotic infections of the skin: onychomycosis. J Am Acad Dermatol. 1996;34:116-21.
• De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs 2001;Supp 1:27-37.
• Gantmacher J, Mills-Bomford J, Williams T. Manufacturer does not agree that interaction was with terbinafine. BMJ 1998;317:205.
• Mossavi M, Bagheri B, Scher RK. Systemic antifungal therapy. Dermatologic Clinics 2001;19(1):35-48.
• Micromedex Healthcare Series. Itraconazole: Drug Evaluation. Micromedex, Inc., 2002.
• Product information: Sporanox, itraconazole. Janssen Pharmaceutica Inc., Titusville, NJ, 2002.
• Product information: Lamisil, terbinafine. Novartis Pharmaceuticals Corp., East Hanover, NJ, 2002.