Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 26 January 2017

Indication(s)

1 INDICATIONS AND USAGE Terbinafine hydrochloride tablets, USP are indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

Terbinafine tablets are an allylamine antifungal indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium)

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Advisory information

contraindications
4 CONTRAINDICATIONS Terbinafine hydrochloride tablets are contraindicated in individuals with a history of allergic reaction to oral terbinafine because of the risk of anaphylaxis. Terbinafine tablets are contraindicated in individuals with a history of allergic reaction to oral terbinafine because of the risk of anaphylaxis. (4)
Adverse reactions

6 ADVERSE REACTIONS Common (>2 % in patients treated with terbinafine tablets) reported adverse events include headache, diarrhea, rash, dyspepsia, liver enzyme abnormalities, pruritus, taste disturbance, nausea, abdominal pain, and flatulence.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Apotex at 1-800-667-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most frequently reported adverse events observed in the three US/Canadian placebo-controlled trials are listed in the table below.

The adverse events reported encompass gastrointestinal symptoms (including diarrhea, dyspepsia, and abdominal pain), liver test abnormalities, rashes, urticaria, pruritus, and taste disturbances.

Changes in the ocular lens and retina have been reported following the use of terbinafine hydrochloride tablets in controlled trials.

The clinical significance of these changes is unknown.

In general, the adverse events were mild, transient, and did not lead to discontinuation from study participation.

Adverse Event Discontinuation Terbinafine Hydrochloride Tablets Placebo Terbinafine Hydrochloride Tablets Placebo (%) (%) (%) (%) n=465 n=137 n=465 n=137 Headache 12.9 9.5 0.2 0.0 Gastrointestinal Symptoms: Diarrhea 5.6 2.9 0.6 0.0 Dyspepsia 4.3 2.9 0.4 0.0 Abdominal Pain 2.4 1.5 0.4 0.0 Nausea 2.6 2.9 0.2 0.0 Flatulence 2.2 2.2 0.0 0.0 Dermatological Symptoms: Rash 5.6 2.2 0.9 0.7 Pruritis 2.8 1.5 0.2 0.0 Urticaria 1.1 0.0 0.0 0.0 Liver Enzyme Abnormalities * 3.3 1.4 0.2 0.0 Taste Disturbance 2.8 0.7 0.2 0.0 Visual Disturbance 1.1 1.5 0.9 0.0 * Liver enzyme abnormalities?

2x the upper limit of normal range.

6.2 Postmarketing Experience The following adverse events have been identified during post-approval use of terbinafine hydrochloride 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.

Adverse events, based on worldwide experience with terbinafine hydrochloride use, include: idiosyncratic and symptomatic hepatic injury and more rarely, cases of liver failure, some leading to death or liver transplant,, serious skin reactions (e.g., Stevens-Johnson Syndrome and toxic epidermal necrolysis), severe neutropenia, thrombocytopenia, agranulocytosis, pancytopenia, anemia, angioedema and allergic reactions (including anaphylaxis) [see Warnings and Precautions (5.1, 5.5, and 5.6)].

Psoriasiform eruptions or exacerbation of psoriasis, acute generalized exanthematous pustulosis and precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported in patients taking terbinafine [see Warnings and Precautions (5.7)] Cases of taste disturbance, including taste loss, have been reported with the use of terbinafine hydrochloride tablets.

It can be severe enough to result in decreased food intake, weight loss, and depressive symptoms [see Warnings and Precautions (5.2)].

Depressive symptoms independent of taste disturbance have been reported with use of terbinafine hydrochloride 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)].

Cases of smell disturbance, including smell loss, have been reported with the use of terbinafine tablets [see Warnings and Precautions (5.3)].

Other adverse reactions which have been reported include malaise, fatigue, vomiting, arthralgia, myalgia, rhabdomyolysis, reduced visual acuity, visual field defect, hair loss, serum sickness-like reaction, vasculitis, pancreatitis, influenza-like illness, pyrexia and increased blood creatine phosphokinase and photosensitivity reactions.

Altered prothrombin time (prolongation and reduction) in patients concomitantly treated with warfarin has been reported.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION Fingernail onychomycosis: One 250 mg tablet once daily for 6 weeks.

Toenail onychomycosis: One 250 mg tablet once daily for 12 weeks.

The optimal clinical effect is seen some months after mycological cure and cessation of treatment.

This is related to the period required for outgrowth of healthy nail.

Fingernail onychomycosis: One 250 mg tablet, once daily for 6 weeks Toenail onychomycosis: One 250 mg tablet, once daily for 12 weeks.

Use in special populations

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, and because treatment of onychomycosis can be postponed until after pregnancy is completed, it is recommended that terbinafine not be initiated during pregnancy.

Oral reproduction studies have been performed in rabbits and rats at doses up to 300 mg/kg/day (12x to 23x the MRHD, in rabbits and rats, respectively, based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to terbinafine.

8.3 Nursing Mothers After oral administration, terbinafine is present in breast milk of nursing mothers.

The ratio of terbinafine in milk to plasma is 7:1.

Treatment with terbinafine hydrochloride is not recommended in nursing mothers.

8.4 Pediatric Use The safety and efficacy of terbinafine hydrochloride have not been established in pediatric patients with onychomycosis.

8.5 Geriatric Use Clinical studies of terbinafine hydrochloride tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Interactions

7 DRUG INTERACTIONS Terbinafine is an inhibitor of CYP4502D6 isozyme and has an effect on metabolism of desipramine, cimetidine, fluconazole, cyclosporine, rifampin, and caffeine.

(7.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling 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 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

Cmax and a 5-fold increase in AUC.

In this study, these effects were shown to persist at the last observation at 4 weeks after discontinuation of terbinafine.

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.

Co-administration of a single dose of fluconazole (100 mg) with a single dose of terbinafine resulted in a 52 % and 69 % increase in terbinafine Cmax 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 (Cmax 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 hydrochloride 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 hydrochloride tablets was conducted.

An increase of less than 20 % of the AUC (i.e. area under the curve) of terbinafine was observed when terbinafine hydrochloride tablets were administered with food.

Terbinafine hydrochloride tablets can be taken with or without food.

More information

Category Value
Authorisation number ANDA078199
Orphan designation No
Product NDC 54868-5794
Date Last Revised 07-05-2012
Type HUMAN PRESCRIPTION DRUG
RXCUI 313222
Marketing authorisation holder Physicians Total Care, Inc.