terbinafine 250 MG Oral Tablet

Generic Name: TERBINAFINE HYDROCHLORIDE
Brand Name: TERBINAFINE HYDROCHLORIDE
  • Substance Name(s):
  • TERBINAFINE HYDROCHLORIDE

DRUG INTERACTIONS

7 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 hydrochloride 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 Cmax 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 hydrochloride 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 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 of terbinafine was observed when terbinafine hydrochloride tablets were administered with food.

Terbinafine hydrochloride tablets can be taken with or without food.

OVERDOSAGE

10 Clinical experience regarding overdose with oral terbinafine 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.

DESCRIPTION

11 Terbinafine hydrochloride tablets contain the synthetic allylamine antifungal compound terbinafine hydrochloride.

Chemically, terbinafine hydrochloride is (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine hydrochloride.

The empirical formula C21H26ClN with a molecular weight of 327.90, and the following structural formula: Terbinafine hydrochloride is a white to off-white 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: microcrystalline cellulose, NF; hypromellose 6 cps, USP; sodium starch glycolate, NF; colloidal silicon dioxide, NF; magnesium stearate, NF Image

CLINICAL STUDIES

14 The efficacy of terbinafine hydrochloride tablets in the treatment of onychomycosis is illustrated by the response of subjects with toenail and/or fingernail infections who participated in 3 US/Canadian placebo-controlled clinical trials.

Results of the first toenail trial, 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 subjects.

Fifty-nine percent (59%) of subjects experienced effective treatment (mycological cure plus 0% nail involvement or greater than 5mm of new unaffected nail growth); 38% of subjects demonstrated mycological cure plus clinical cure (0% nail involvement).

In a second toenail trial of dermatophytic onychomycosis, in which nondermatophytes were also cultured, similar efficacy against the dermatophytes was demonstrated.

The pathogenic role of the nondermatophytes cultured in the presence of dermatophytic onychomycosis has not been established.

The clinical significance of this association is unknown.

Results of the fingernail trial, as assessed at week 24 (6 weeks of treatment with 18 weeks follow-up after completion of therapy), demonstrated mycological cure in 79% of subjects, effective treatment in 75% of the subjects, and mycological cure plus clinical cure in 59% of the subjects.

The mean time to overall success was approximately 10 months for the first toenail trial and 4 months for the fingernail trial.

In the first toenail trial, for subjects evaluated at least 6 months after achieving clinical cure and at least 1 year after completing therapy with terbinafine hydrochloride tablets, the clinical relapse rate was approximately 15%.

HOW SUPPLIED

16 /STORAGE AND HANDLING Terbinafine hydrochloride tablets 250 mg, supplied as white circular, bi-convex, bevelled tablets embossed with ‘W’ on one side and ‘743’ on other side.

Bottles of 30 tablets NDC 64679-743-01 Bottles of 100 tablets NDC 64679-743-03 Bottles of 1000 tablets NDC 64679-743-02 Unit-dose blister pack of 10 x 10 tablets NDC 64679-743-04 Store between 20°-25°C (68°-77°F) (See USP Controlled Room Temperature) in a tight container.

Protect from light.

RECENT MAJOR CHANGES

Dosage and Administration: Assessment Prior to Initiation (2.1) 8/2016 Contraindications (4) 8/2016 Warnings and Precautions: Hepatotoxicty (5.1) 8/2016 Warnings and Precautions: Thrombotic Microangiopathy (5.8) 1/2017

GERIATRIC USE

8.5 Geriatric Use Clinical studies of terbinafine hydrochloride 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.

DOSAGE FORMS AND STRENGTHS

3 Terbinafine hydrochloride tablets 250 mg, supplied as white circular, bi-convex, bevelled tablets embossed with ‘W’ on one side and ‘743’ on other side.

Tablet, 250 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Terbinafine is an allylamine antifungal [see Clinical Pharmacology (12.4)].

INDICATIONS AND USAGE

1 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 [potassium hydroxide (KOH) preparation, fungal culture, or nail biopsy] should be obtained to confirm the diagnosis of onychomycosis.

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

(1)

PEDIATRIC USE

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

PREGNANCY

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 hydrochloride 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.

NUSRING MOTHERS

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 tablets is not recommended in women who are nursing.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Liver failure, sometimes leading to liver transplant or death, has occurred with the use of oral terbinafine.

Obtain pretreatment serum transaminases.

Prior to initiating treatment and periodically during therapy, assess liver function tests.

Discontinue terbinafine hydrochloride tablets if liver injury develops.

(5.1) Taste disturbance, including taste loss, has been reported with the use of terbinafine hydrochloride tablets.

Taste disturbance can be severe, may be prolonged, or may be permanent.

Discontinue terbinafine hydrochloride tablets if taste disturbance occurs.

(5.2) Smell disturbance, including loss of smell, has been reported with the use of terbinafine hydrochloride tablets.

Smell disturbance may be prolonged, or may be permanent.

Discontinue terbinafine hydrochloride tablets if smell disturbance occurs.

(5.3) Depressive symptoms have been reported with terbinafine use.

Prescribers should be alert to the development of depressive symptoms.

(5.4) Severe neutropenia has been reported.

If the neutrophil count is less than or equal to 1000 cells/mm3, terbinafine hydrochloride tablets should be discontinued.

(5.5) Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, bullous dermatitis, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with oral terbinafine use.

If signs or symptoms of drug reaction occur, treatment with terbinafine hydrochloride tablets should be discontinued.

(5.6) 5.1 Hepatotoxicity Terbinafine hydrochloride tablets are contraindicated for patients with chronic or active liver disease.

Before prescribing terbinafine hydrochloride tablets, perform liver function tests because hepatotoxicity may occur in patients with and without preexisting liver disease.

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 use of terbinafine hydrochloride tablets, 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.

Periodic monitoring of liver function tests is recommended.

Discontinue terbinafine hydrochloride tablets if biochemical or clinical evidence of liver injury develops.

Warn patients prescribed terbinafine hydrochloride tablets and/or their caregivers to report immediately to their healthcare providers any symptoms or signs of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine, or pale stools.

Advise patients with these symptoms to discontinue taking oral terbinafine, and immediately evaluate the patient’s liver function.

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, anxiety, and depressive symptoms.

Taste disturbance may resolve within several weeks after discontinuation of treatment, but may be prolonged (greater than 1 year), or may be permanent.

If symptoms of a taste disturbance occur, terbinafine hydrochloride tablets should be discontinued.

5.3 Smell Disturbance Including Loss of Smell Smell disturbance, including loss of smell, has been reported with the use of terbinafine hydrochloride tablets.

Smell disturbance may resolve after discontinuation of treatment, but may be prolonged (greater than 1 year), or may be permanent.

If symptoms of a smell disturbance occur, terbinafine hydrochloride tablets should be discontinued.

5.4 Depressive Symptoms Depressive symptoms have occurred during postmarketing use of terbinafine hydrochloride tablets.

Prescribers should be alert to the development of depressive symptoms, and patients should be instructed to report depressive symptoms to their physician.

5.5 Hematologic Effects Transient decreases in absolute lymphocyte counts (ALCs) have been observed in controlled clinical trials.

In placebo-controlled trials, 8/465 subjects receiving terbinafine hydrochloride tablets (1.7%) and 3/137 subjects receiving placebo (2.2%) had decreases in ALC to below 1000/mm3on 2 or more occasions.

In patients with known or suspected immunodeficiency, physicians should consider monitoring complete blood counts if treatment continues for more than 6 weeks.

Cases of severe neutropenia have been reported.

These were reversible upon discontinuation of terbinafine hydrochloride tablets, 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 less than or equal to 1000 cells/mm3, terbinafine hydrochloride tablets should be discontinued and supportive management started.

5.6 Serious Skin/Hypersensitivity Reactions There have been postmarketing reports of serious skin/hypersensitivity 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].

Manifestations of DRESS syndrome may include cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more organ complications such as hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis.

If progressive skin rash or signs/symptoms of the above drug reactions occur, treatment with terbinafine hydrochloride tablets should be discontinued.

5.7 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.

5.8 Thrombotic Microangiopathy Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with terbinafine.

Discontinue terbinafine if clinical symptoms and laboratory findings consistent with TMA occur.

The findings of unexplained thrombocytopenia and anemia should prompt further evaluation and consideration of diagnosis of TMA.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-Approved Medication Guide.

Patients taking terbinafine hydrochloride tablets should receive the following information and instructions: Advise patients to immediately report to their physician or get emergency help if they experience any of the following symptoms: hives, mouth sores, blistering and peeling of skin, swelling of face, lips, tongue, or throat, difficulty swallowing or breathing.

terbinafine hydrochloride tablets treatment should be discontinued.

Advise patients to immediately report to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine, or pale stools.

Terbinafine hydrochloride tablets treatment should be discontinued.

Advise patients to report to their physician any signs of taste disturbance, smell disturbance and/or depressive symptoms, fever, skin eruption, lymph node enlargement, erythema, scaling, loss of pigment, and unusual photosensitivity that can result in a rash.

Terbinafine hydrochloride tablets treatment should be discontinued.

Advise patients to minimize exposure to natural and artificial sunlight (tanning beds or UVA/B treatment) while using terbinafine hydrochloride tablets.

Advise patients that if they forget to take terbinafine hydrochloride tablets, to take their tablets as soon as they remember, unless it is less than 4 hours before the next dose is due.

Advise patients to call their physician if they take too many terbinafine hydrochloride tablets.

Manufactured by: Wockhardt Limited H-14/2, M.I.D.C.

Area, Waluj, Aurangabad, Maharashtra, India.

Distributed by: Wockhardt USA LLC.

20 Waterview Blvd.

Parsippany, NJ 07054 USA.

Rev.201117

DOSAGE AND ADMINISTRATION

2 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 hydrochloride 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.