Terbinafine (Page 2 of 4)

6.2 Postmarketing Experience

The following adverse events have been identified during post-approval use of terbinafine tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Pancytopenia, agranulocytosis, severe neutropenia, thrombocytopenia, anemia, thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome [see Warnings and Precautions (5.5, 5.8)]

Immune system disorders: Serious hypersensitivity reactions e.g., angioedema and allergic reactions (including anaphylaxis), precipitation and exacerbation of cutaneous and systemic lupus erythematosus [see Warnings and Precautions (5.7)], serum sickness-like reaction
Psychiatric disorders: Anxiety and depressive symptoms independent of taste disturbance have been reported with use of terbinafine tablets. In some cases, depressive symptoms have been reported to subside with discontinuance of therapy and to recur with reinstitution of therapy [see Warnings and Precautions (5.4)].
Nervous system disorders: Cases of taste disturbance, including taste loss, have been reported with the use of terbinafine tablets. It can be severe enough to result in decreased food intake, weight loss, anxiety, and depressive symptoms. Cases of smell disturbance, including smell loss, have been reported with the use of terbinafine tablets [see Warnings and Precautions (5.2, 5.3)]. Cases of paresthesia and hypoesthesia have been reported with the use of terbinafine tablets.
Eye disorders: Visual field defects, reduced visual acuity

Ear and labyrinth disorders: Hearing impairment, vertigo, tinnitus

Vascular disorders: Vasculitis

Gastrointestinal disorders: Pancreatitis, vomiting

Hepatobiliary disorders: Cases of liver failure some leading to liver transplant or death [see Warnings and Precautions (5.1)], idiosyncratic and symptomatic hepatic injury. Cases of hepatitis, cholestasis, and increased hepatic enzymes [see Warnings and Precautions (5.1)] have been seen with the use of terbinafine tablets.

Skin and subcutaneous tissue disorders: Serious skin reactions [e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, bullous dermatitis, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome] [see Warnings and Precautions (5.6)], acute generalized exanthematous pustulosis, psoriasiform eruptions or exacerbation of psoriasis, photosensitivity reactions, hair loss

Musculoskeletal and connective tissue disorders: Rhabdomyolysis, arthralgia, myalgia

General disorders and administration site conditions: Malaise, fatigue, influenza-like illness, pyrexia

Investigations: Altered prothrombin time (prolongation and reduction) in patients concomitantly treated with warfarin and increased blood creatine phosphokinase have been reported

7 DRUG INTERACTIONS

7.1 Drug-Drug Interactions

In vivo studies have shown that terbinafine is an inhibitor of the CYP450 2D6 isozyme. Drugs predominantly metabolized by the CYP450 2D6 isozyme include the following drug classes: tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers, antiarrhythmics class 1C (e.g., flecainide and propafenone) and monoamine oxidase inhibitors Type B. Coadministration of terbinafine tablets should be done with careful monitoring and may require a reduction in dose of the 2D6-metabolized drug. In a study to assess the effects of terbinafine on desipramine in healthy volunteers characterized as normal metabolizers, the administration of terbinafine resulted in a 2-fold increase in C max and a 5-fold increase in area under the curve (AUC). In this study, these effects were shown to persist at the last observation at 4 weeks after discontinuation of terbinafine tablets. In studies in healthy subjects characterized as extensive metabolizers of dextromethorphan (antitussive drug and CYP2D6 probe substrate), terbinafine increases the dextromethorphan/dextrorphan metabolite ratio in urine by 16- to 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolizers to poor metabolizer status.

In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, cyclosporine, cisapride and fluvastatin. In vivo drug-drug interaction studies conducted in healthy volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%.
The influence of terbinafine on the pharmacokinetics of fluconazole, cotrimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline was not considered to be clinically significant.
Coadministration of a single dose of fluconazole (100 mg) with a single dose of terbinafine resulted in a 52% and 69% increase in terbinafine C max and AUC, respectively. Fluconazole is an inhibitor of CYP2C9 and CYP3A enzymes. Based on this finding, it is likely that other inhibitors of both CYP2C9 and CYP3A4 (e.g., ketoconazole, amiodarone) may also lead to a substantial increase in the systemic exposure (C max and AUC) of terbinafine when concomitantly administered.
There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between terbinafine tablets and these changes has not been established.
Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer, and decreased 33% by cimetidine, a CYP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, phenytoins, thiazide diuretics, and calcium channel blockers.

7.2 Food Interactions

An evaluation of the effect of food on terbinafine tablets was conducted. An increase of less than 20% of the AUC of terbinafine was observed when terbinafine tablets were administered with food. Terbinafine tablets can be taken with or without food.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from postmarketing cases on the use of terbinafine tablets in pregnant women are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, terbinafine did not cause malformations or any harm to the fetus when administered to pregnant rabbits and rats during the period of organogenesis at oral doses up to 12 and 23 times the maximum recommended human dose (MRHD) of 250 mg/day, respectively (see data).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received orally (by gavage) doses of terbinafine up to 300 mg/kg/day, during the period of organogenesis. There were no maternal or embryo-fetal effects in either species up to the maximum dose tested. The 300 mg/kg/day dose level in rats and rabbits corresponds to 23 and 12 times the MRHD [based on body surface area (BSA) comparisons], respectively.

In a rat peri- and postnatal development study, terbinafine doses of up to 300 mg/kg/day (12 times the MRHD based on BSA comparisons) given by oral gavage during late pregnancy and lactation (Day 15 of gestation to day 20 post-partum) had no adverse effects on parturition and lactation.

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