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terbinafine hydrochloride tablet
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Terbinafine hydrochloride tablets 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.
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.
3 DOSAGE FORMS AND STRENGTHS
Terbinafine hydrochloride tablets, equivalent to 250 mg base, are supplied as white to off-white, round shaped, bevelled edge tablets; on one side debossed “93” and debossed “7294” on the other side of the tablet.
Terbinafine hydrochloride tablets are contraindicated in individuals with a history of allergic reaction to oral terbinafine because of the risk of anaphylaxis.
5 WARNINGS AND PRECAUTIONS
Cases of liver failure, some leading to liver transplant or death, have occurred with the use of terbinafine hydrochloride tablets in individuals with and without preexisting liver disease.
In the majority of liver cases reported in association with terbinafine use, the patients had serious underlying systemic conditions. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease. Treatment with terbinafine hydrochloride tablets should be discontinued if biochemical or clinical evidence of liver injury develops.
Terbinafine hydrochloride tablets are not recommended for patients with chronic or active liver disease. Before prescribing terbinafine hydrochloride tablets, preexisting liver disease should be assessed. Hepatotoxicity may occur in patients with and without preexisting liver disease. Patients prescribed terbinafine hydrochloride tablets should be warned to report immediately to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine or pale stools. Patients with these symptoms should discontinue taking oral terbinafine, and the patient’s liver function should be immediately evaluated.
5.2 Taste Disturbance Including Loss of Taste
Taste disturbance, including taste loss, has 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. Taste disturbance may resolve within several weeks after discontinuation of treatment, but may be prolonged (greater than one year). If symptoms of a taste disturbance occur, terbinafine hydrochloride tablets should be discontinued.
5.3 Depressive Systems
Depressive symptoms have occurred during postmarketing use of terbinafine. Prescribers should be alert to depressive symptoms, and patients should be instructed to report depressive symptoms to their physician.
5.4 Hematologic Effects
Transient decreases in absolute lymphocyte counts (ALC) have been observed in controlled clinical trials. In placebo-controlled trials, 8/465 terbinafine-treated patients (1.7%) and 3/137 placebo-treated patients (2.2%) had decreases in ALC to below 1000/mm3 on two or more occasions. In patients with known or suspected immunodeficiency, physicians should consider monitoring complete blood counts if treatment continues for more than six weeks. Cases of severe neutropenia have been reported. These were reversible upon discontinuation of terbinafine, with or without supportive therapy. If clinical signs and symptoms suggestive of secondary infection occur, a complete blood count should be obtained. If the neutrophil count is ≤ 1,000 cells/mm3, terbinafine should be discontinued and supportive management started.
5.5 Skin Reactions
There have been postmarketing reports of serious skin reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis). If progressive skin rash occurs, treatment with terbinafine hydrochloride tablets should be discontinued.
5.6 Lupus Erythematosus
During postmarketing experience, precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported in patients taking terbinafine hydrochloride tablets. Terbinafine hydrochloride tablets should be discontinued in patients with clinical signs and symptoms suggestive of lupus erythematosus.
6 ADVERSE REACTIONS
6.1 Clinical Studies 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 U.S./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.
6.2 Postmarketing Experience
The following adverse events have been identified during post-approval use of terbinafine. 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 tablets 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, 5.4, 5.5)].
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 hydrochloride [see Warnings and Precautions (5.6)]. 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 the 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 (5.3)].
Other adverse reactions which have been reported include malaise, fatigue, vomiting, arthralgia, myalgia, acute pancreatitis, rhabdomyolysis, reduced visual acuity, visual field defect, and hair loss.
Altered prothrombin time (prolongation and reduction) in patients concomitantly treated with warfarin has 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 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 hydrochloride tablets. In studies in healthy subjects characterized as extensive metabolizers of dextromethorphan, terbinafine increases the dextromethorphan/dextrorphan metabolite ratio in urine by 16 to 97 fold on average. 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, trimethoprim, sulfamethoxazole, zidovudine or theophylline was not considered to be clinically significant. Coadministration of a single dose of fluconazole (100mg) 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.
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 terfinabine 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 diruetics, 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.
8 USE IN SPECIFIC POPULATIONS
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 (12 to 23 times 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 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.
Clinical experience regarding overdose with terbinafine hydrochloride tablets is limited. Doses up to 5 grams (20 times the therapeutic daily dose) have been taken without inducing serious adverse reactions. The symptoms of overdose included nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache.
Terbinafine hydrochloride tablets contain the synthetic allylamine antifungal compound terbinafine hydrochloride.
Chemically, terbinafine hydrochloride is (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-Nmethyl-1-naphthalenemethanamine hydrochloride. It has the following structural formula:
C21H26ClN M.W. 327.90
Terbinafine hydrochloride is a white to off-white fine crystalline powder. It is freely soluble in methanol and methylene chloride, soluble in ethanol, and slightly soluble in water.
Each tablet contains:
Active Ingredients: terbinafine hydrochloride (equivalent to 250 mg base).
Inactive Ingredients: hypromellose, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium starch glycolate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Terbinafine is an allylamine antifungal [see Clinical Pharmacology (12.4)].
Following oral administration, terbinafine is well absorbed (> 70%) and the bioavailability of terbinafine hydrochloride tablets as a result of first-pass metabolism is approximately 40%. Peak plasma concentrations of 1 mcg/mL appear within 2 hours after a single 250 mg dose; the AUC (area under the curve) is approximately 4.56 mcg•h/mL. An increase in the AUC of terbinafine of less than 20% is observed when terbinafine hydrochloride is administered with food.
In plasma, terbinafine is > 99% bound to plasma proteins and there are no specific binding sites. At steady state, in comparison to a single dose, the peak concentration of terbinafine is 25% higher and plasma AUC increases by a factor of 2.5; the increase in plasma AUC is consistent with an effective half-life of ~36 hours. Terbinafine is distributed to the sebum and skin. A terminal half-life of 200 to 400 hours may represent the slow elimination of terbinafine from tissues such as skin and adipose. Prior to excretion, terbinafine is extensively metabolized by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. No metabolites have been identified that have antifungal activity similar to terbinafine. Approximately 70% of the administered dose is eliminated in the urine.
In patients with renal impairment (creatinine clearance < 50 mL/min) or hepatic cirrhosis, the clearance of terbinafine is decreased by approximately 50% compared to normal volunteers. No effect of gender on the blood levels of terbinafine was detected in clinical trials. No clinically relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been reported.
Terbinafine, an allyylamine antifungal, inhibits biosynthesis of ergosterol, an essential component of fungal cell membrane, via inhibition of squalene epoxidase enzyme. This results in fungal cell death primarily due to the increased membrane permeability mediated by the accumulation of high concentrations of squalene but not due to ergosterol deficiency. Depending on the concentration of the drug and the fungal species test in vitro, terbinafine hydrochloride may be fungicidal. However, the clinical significance of in vitro data is unknown.
Terbinafine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:
The following in vitro data are available, but their clinical significance is unknown. In vitro, terbinafine exhibits satisfactory MIC’s against most strains of the following microorganisms; however, the safety and efficacy of terbinafine in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 28 month oral carcinogenicity study in rats, an increase in the incidence of liver tumors was observed in males at the highest dose tested, 69 mg/kg/day [2 times the Maximum Recommended Human Dose (MRHD) based on AUC comparisons of the parent terbinafine]; however, even though dose-limiting toxicity was not achieved at the highest tested dose, higher doses were not tested.
The results of a variety of in vitro (mutations in E. coli and S. typhimurium, DNA repair in rat hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome aberration and sister chromatid exchanges in Chinese hamster lung cells), and in vivo (chromosome aberration in Chinese hamsters, micronucleus test in mice) genotoxicity tests gave no evidence of a mutagenic or clastogenic potential.
Oral reproduction studies in rats at doses up to 300 mg/kg/day (approximately 12 times the MRHD based on body surface area comparisons, BSA) did not reveal any specific effects on fertility or other reproductive parameters. Intravaginal application of terbinafine hydrochloride at 150 mg/day in pregnant rabbits did not increase the incidence of abortions or premature deliveries nor affect fetal parameters.
13.2 Animal Toxicology and/or Pharmacology
A wide range of in vivo studies in mice, rats, dogs, and monkeys, and in vitro studies using rat, monkey, and human hepatocytes suggest that peroxisome proliferation in the liver is a rat-specific finding. However, other effects, including increased liver weights and APTT, occurred in dogs and monkeys at doses giving Css trough levels of the parent terbinafine 2 to 3 times those seen in humans at the MRHD. Higher doses were not tested.
14 CLINICAL STUDIES
The efficacy of terbinafine hydrochloride tablets in the treatment of onychomycosis is illustrated by the response of patients with toenail and/or fingernail infections who participated in 3 U.S./Canadian placebo-controlled clinical trials.
Results of the first toenail study, as assessed at week 48 (12 weeks of treatment with 36 weeks follow-up after completion of therapy), demonstrated mycological cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 70% of patients. Fifty-nine percent (59%) of patients experienced effective treatment (mycological cure plus 0% nail involvement or > 5 mm of new unaffected nail growth); 38% of patients demonstrated mycological cure plus clinical cure (0% nail involvement).
In a second toenail study of dermatophytic onychomycosis, in which non-dermatophytes were also cultured, similar efficacy against the dermatophytes was demonstrated. The pathogenic role of the non-dermatophytes cultured in the presence of dermatophytic onychomycosis has not been established. The clinical significance of this association is unknown.
Results of the fingernail study, as assessed at week 24 (6 weeks of treatment with 18 weeks follow-up after completion of therapy), demonstrated mycological cure in 79% of patients, effective treatment in 75% of the patients, and mycological cure plus clinical cure in 59% of the patients.
The mean time to overall success was approximately 10 months for the first toenail study and 4 months for the fingernail study. In the first toenail study, for patients evaluated at least 6 months after achieving clinical cure and at least 1 year after completing terbinafine hydrochloride therapy, the clinical relapse rate was approximately 15%.
16 HOW SUPPLIED/STORAGE AND HANDLING
Terbinafine hydrochloride tablets, equivalent to 250 mg base, are supplied as white to off-white, round shaped, bevelled edge tablets; on one side debossed “93” and debossed “7294” on the other side of the tablet. They are available in bottles of 30 and 100 tablets.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
17 PATIENT COUNSELING INFORMATION
[See FDA-Approved Patient Labeling (Patient Information).]
Patients taking terbinafine hydrochloride tablets should receive the following information and instructions:
Manufactured In Israel By:
TEVA PHARMACEUTICAL IND. LTD.
Jerusalem, 91010, Israel
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. A 12/2010
Terbinafine Hydrochloride Tablets
Read this Patient Information before you start taking terbinafine hydrochloride tablets and each time you get a refill. There may be new information. This information does not take the place of talking to you doctor about your medical condition or your treatment.
What are terbinafine hydrochloride tablets?
Terbinafine hydrochloride tablets are a prescription antifungal medicine used to treat fungal infections of the fingernails and toenails (onychomycosis). Your doctor should do tests to check you for fungal infection of your nails before you start terbinafine hydrochloride tablets. It is not known if terbinafine hydrochloride tablets are safe and effective in children for the treatment of onychomycosis.
Who should not take terbinafine hydrochloride tablets?
Do not take terbinafine hydrochloride tablets if you are allergic to terbinafine hydrochloride when taken by mouth.
What should I tell my doctor before taking terbinafine hydrochloride tablets?
Before you take terbinafine hydrochloride tablets, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Terbinafine hydrochloride tablets may affect the way other medicines work and other medicines may affect how terbinafine hydrochloride tablets work. Especially tell your doctor if you take:
If you are not sure if your medicine is one listed above, ask your doctor or pharmacist.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take terbinafine hydrochloride tablets?
What are the possible side effects of terbinafine hydrochloride tablets?
Terbinafine hydrochloride tablets may cause serious side effects, including:
Your doctor should do a blood test to check you for liver problems before you take terbinafine hydrochloride tablets.
The most common side effects of terbinafine hydrochloride tablets include: headache, diarrhea, rash, dyspepsia, liver enzyme abnormalities, pruritus, taste disturbance, nausea, abdominal pain, and flatulence.
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of terbinafine hydrochloride tablets. For information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How do I store terbinafine hydrochloride tablets?
Keep terbinafine hydrochloride tablets and all medicines out of the reach of children.
General information about the safe and effective use of terbinafine hydrochloride tablets.
Medicines are sometimes prescribed for purposes other than those listed in Patient Information. Do not use terbinafine hydrochloride tablets for a condition for which they were not prescribed. Do not give terbinafine hydrochloride tablets to other people, even if they have the same symptoms that you have. They may harm them.
This Patient Information summarizes that most important information about terbinafine hydrochloride tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for imformation about terbinafine hydrochloride tablets that is written for health professionals.
What are the ingredients in terbinafine hydrochloride tablets?
Active ingredient: terbinafine hydrochloride (equivalent to 250 mg base)
Inactive ingredients: hypromellose, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium starch glycolate.
All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.
Manufactured In Israel By:
TEVA PHARMACEUTICAL IND. LTD.
Jerusalem, 91010, Israel
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Principal Display Panel
Revised: 01/2011 TEVA Pharmaceuticals USA Inc
Reproduced with permission of U.S. National Library of Medicine
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