Data from FDA - Curated by EPG Health - Last updated 01 June 2018

Indication(s)

1 INDICATIONS AND USAGE Terbinafine 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 [potassium hydroxide (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). ( 1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Terbinafine tablets are contraindicated in patients with: Terbinafine tablets are contraindicated in patients with: • History of allergic reaction to oral terbinafine because of the risk of anaphylaxis • History of allergic reaction to oral terbinafine because of the risk of anaphylaxis [see Adverse Reactions (6.2)] • Chronic or active liver disease [see Warnings and Precautions (5.1)] History of allergic reaction to oral terbinafine because of the risk of anaphylaxis. ( 4) Chronic or active liver disease. ( 4)
Adverse reactions
6 ADVERSE REACTIONS Common (greater than 2% of 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 Cipla Ltd. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot 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 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. *Liver enzyme abnormalities greater than or equal to 2x the upper limit of normal range. Image 1 6.2 Postmarketing Experience The following adverse events have been identified during postapproval 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 and 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Prior to administering, evaluate patients for evidence of chronic or active liver disease. ( 2.1) Fingernail onychomycosis: One 250 mg tablet, once daily for 6 weeks. ( 2.2) Toenail onychomycosis: One 250 mg tablet, once daily for 12 weeks. ( 2.2) 2.1 Assessment Prior to Initiation Before administering terbinafine tablets, evaluate patients for evidence of chronic or active liver disease [see Contraindications (4) and Warnings and Precautions (5.1)]. 2.2 Dosage 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.
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 tablets 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 maximum recommended human dose (MRHD), in rabbits and rats, respectively, based on body surface area (BSA) comparisons] 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 tablets is not recommended in women who are nursing. 8.4 Pediatric Use The safety and efficacy of terbinafine tablets have not been established in pediatric patients with onychomycosis. 8.5 Geriatric Use Clinical studies of terbinafine tablets did not include sufficient numbers of subjects aged 65 years 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. 8.6 Renal Impairment In patients with renal impairment (creatinine clearance less than or equal to 50 mL/min), the use of terbinafine tablets has not been adequately studied. 8.7 Hepatic Impairment Terbinafine tablets are contraindicated for patients with chronic or active liver disease [see Contraindications (4) and Warnings and Precautions (5.1)] . Cases of liver failure, some leading to liver transplant or death, have occurred with the use of terbinafine tablets in individuals with and without preexisting liver disease. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease.
Pregnancy and lactation
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 tablets is not recommended in women who are nursing.

Interactions

7 DRUG INTERACTIONS Terbinafine is an inhibitor of CYP450 2D6 isozyme and has an effect on metabolism of desipramine. Drug interactions have also been noted with cimetidine, fluconazole, cyclosporine, rifampin, and caffeine. ( 7.1) 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.

More information

Category Value
Authorisation number ANDA077533
Agency product number 012C11ZU6G
Orphan designation No
Product NDC 70518-1191
Date Last Revised 15-05-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 313222
Marketing authorisation holder REMEDYREPACK INC.