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Terbinafine Hydrochloride Tablets
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 Prescribing Information
treatment (mycological cure plus 0% nail involvement or >5mm of new unaffected nail growth); 38% of patients demonstrated mycological cure plus clinical cure (0% DESCRIPTION
Terbinafine hydrochloride tablets contain the synthetic allylamine antifungal In a second toenail study of dermatophytic onychomycosis, in which non-dermatophytes were also cultured, similar efficacy against the dermatophytes was demonstrated.
Chemically, terbinafine hydrochloride is (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N- The pathogenic role of the non-dermatophytes cultured in the presence of methyl-1-naphthalenemethanamine hydrochloride. The empirical formula dermatophytic onychomycosis has not been established. The clinical significance C21H26CIN with a molecular weight of 327.90, and the following structural formula: 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 six months after achieving clinical cure and at least one year after completing terbinafine hydrochloride therapy, the clinical relapse rate was 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 INDICATIONS AND USAGE
Terbinafine hydrochloride tablets are indicated for the treatment of onychomycosis Each tablet contains:
of the toenail or fingernail due to dermatophytes (tinea unguium) (see DOSAGE Active Ingredients: terbinafine hydrochloride (equivalent to 250 mg base) AND ADMINISTRATION and CLINICAL STUDIES).
Inactive Ingredients: colloidal silicon dioxide, NF; hypromellose, USP; magnesium Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH stearate, NF; microcrystalline cellulose, NF; sodium starch glycolate, NF.
preparation, fungal culture, or nail biopsy) should be obtained to confirm the CLINICAL PHARMACOLOGY
CONTRAINDICATIONS
Pharmacokinetics
Terbinafine hydrochloride tablets are contraindicated in individuals with hyper- Following oral administration, terbinafine is well absorbed (>70%) and the sensitivity to terbinafine or to any other ingredients of the formulation.
bioavailability of terbinafine hydrochloride tablets as a result of first-pass metabolism is approximately 40%. Peak plasma concentrations of 1 µg/mL appear within 2 h WARNINGS
after a single 250 mg dose; the AUC (area under the curve) is approximately 4.56 Rare cases of liver failure, some leading to death or liver transplant, have occurred µg·h/mL. An increase in the AUC of terbinafine of less than 20% is observed when with the use of terbinafine hydrochloride tablets for the treatment of onychomycosis terbinafine hydrochloride is administered with food. No clinically relevant age-dependent in individuals with and without pre-existing liver disease.
changes in steady-state plasma concentrations of terbinafine have been reported. In In the majority of liver cases reported in association with terbinafine hydrochloride patients with renal impairment (creatinine clearance ≤ 50mL/min) or hepatic cirrhosis, use, the patients had serious underlying systemic conditions and an uncertain the clearance of terbinafine is decreased by approximately 50% compared to normal causal association with terbinafine hydrochloride. The severity of hepatic events volunteers. No effect of gender on the blood levels of terbinafine was detected in clinical and/or their outcome may be worse in patients with active or chronic liver disease trials. In plasma, terbinafine is >99% bound to plasma proteins and there are no (see PRECAUTIONS). Treatment with terbinafine hydrochloride tablets should be specific binding sites. At steady-state, in comparison to a single dose, the peak discontinued if biochemical or clinical evidence of liver injury develops (see 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.
There have been isolated reports of serious skin reactions (e.g., Stevens-Johnson Terbinafine is distributed to the sebum and skin. A terminal half-life of 200-400 h may Syndrome and toxic epidermal necrolysis). If progressive skin rash occurs, treatment represent the slow elimination of terbinafine from tissues such as skin and adipose.
with terbinafine hydrochloride should be discontinued.
Prior to excretion, terbinafine is extensively metabolized. No metabolites have been identified that have antifungal activity similar to terbinafine. Approximately 70% of the PRECAUTIONS
administered dose is eliminated in the urine.
Microbiology
Terbinafine hydrochloride tablets are not recommended for patients with chronic or Terbinafine hydrochloride is a synthetic allylamine derivative. Terbinafine active liver disease. Before prescribing terbinafine hydrochloride tablets, pre-existing hydrochloride is hypothesized to act by inhibiting squalene epoxidase, thus liver disease should be assessed. Hepatotoxicity may occur in patients with and blocking the biosynthesis of ergosterol, an essential component of fungal cell without pre-existing liver disease. Pretreatment serum transaminase (ALT and membranes. In vitro, mammalian squalene epoxidase is only inhibited at higher AST) tests are advised for all patients before taking terbinafine hydrochloride (4000 fold) concentrations than is needed for inhibition of the dermatophyte tablets. Patients prescribed terbinafine hydrochloride tablets should be warned to enzyme. Depending on the concentration of the drug and the fungal species test in report immediately to their physician any symptoms of persistent nausea, anorexia, vitro, terbinafine hydrochloride may be fungicidal. However, the clinical significance fatigue, vomiting, right upper abdominal pain or jaundice, dark urine or pale stools (see WARNINGS). Patients with these symptoms should discontinue taking oral terbinafine, and the patient’s liver function should be immediately evaluated.
Terbinafine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the In patients with renal impairment (creatinine clearance ≤50 mL/ min), the use of terbinafine hydrochloride has not been adequately studied, and therefore, is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
During post-marketing experience, precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported infrequently in patients taking The following in vitro data are available, but their clinical significance is unknown.
terbinafine hydrochloride. Terbinafine hydrochloride therapy should be discontinued In vitro, terbinafine exhibits satisfactory MIC’s against most strains of the following in patients with clinical signs and symptoms suggestive of lupus erythematosus.
microorganisms; however, the safety and efficacy of terbinafine in treating clinical infections due to these microorganisms have not been established in adequate and Changes in the ocular lens and retina have been reported following the use of terbinafine hydrochloride tablets in controlled trials. The clinical significance of Transient decreases in absolute lymphocyte counts (ALC) have been observed in controlled clinical trials. In placebo-controlled trials, 8/465 terbinafine hydrochloride- treated patients (1.7%) and 3/137 placebo-treated patients (2.2%) had decreases in CLINICAL STUDIES
ALC to below 1000/mm3 on two or more occasions. The clinical significance of this The efficacy of terbinafine hydrochloride tablets in the treatment of onychomycosis observation is unknown. However, in patients with known or suspected immuno- is illustrated by the response of patients with toenail and/or fingernail infections deficiency, physicians should consider monitoring complete blood counts in individuals who participated in three US/Canadian placebo-controlled clinical trials. using terbinafine hydrochloride therapy for greater than six weeks.
Results of the first toenail study, as assessed at week 48 (12 weeks of treatment Isolated cases of severe neutropenia have been reported. These were reversible upon discontinuation of terbinafine hydrochloride, 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 hydrochloride should be discontinued and supportive management 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 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.
In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and In vivo drug-drug interaction studies conducted in healthy volunteer subjects * Liver enzyme abnormalities ≥ 2x the upper limit of the normal range.
showed that terbinafine does not affect the clearance of antipyrine or digoxin.
Adverse events, based on worldwide experience with terbinafine hydrochloride Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the tablets use, include: idiosyncratic and symptomatic hepatic injury and more rarely, cases of liver failure, some leading to death or liver transplant, (see WARNINGS There have been spontaneous reports of increase or decrease in prothrombin times and PRECAUTIONS), serious skin reactions (see WARNINGS), severe neutropenia in patients concomitantly taking oral terbinafine and warfarin, however, a causal (see PRECAUTIONS), thrombocytopenia, angioedema and allergic reactions relationship between terbinafine hydrochloride tablets and these changes has not (including anaphylaxis). Psoriasiform eruptions or exacerbation of psoriasis, acute generalized exanthematous pustulosis and precipitation and exacerbation of Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer, cutaneous and systemic lupus erythematosus have been reported in patients taking and decreased 33% by cimetidine, a CYP450 enzyme inhibitor. Terbinafine clearance terbinafine hydrochloride. Terbinafine hydrochloride may cause taste disturbance (including taste loss) which usually recovers within several weeks after discontinuation of the drug. There have been reports of prolonged (greater than one year) taste There is no information available from adequate drug-drug interaction studies with disturbance. Taste disturbances associated with oral terbinafine have been reported the following classes of drugs: oral contraceptives, hormone replacement therapies, to be severe enough to result in decreased food intake leading to significant and hypoglycemics, theophyllines, phenytoins, thiazide diuretics, and calcium channel Other adverse reactions which have been reported include malaise, fatigue, vomiting, Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 28-month oral carcinogenicity study in rats, an increase in the incidence of Clinical adverse effects reported spontaneously since the drug was marketed include liver tumors was observed in males at the highest dose tested, 69 mg/kg/day [2x altered prothrombin time (prolongation and reduction) in patients concomitantly the Maximum Recommended Human Dose (MRHD) based on AUC comparisons of treated with warfarin and terbinafine hydrochloride tablets and agranulocytosis (rare).
the parent terbinafine]; however, even though dose-limiting toxicity was not achieved at the highest tested dose, higher doses were not tested.
OVERDOSAGE
The results of a variety of in vitro (mutations in E. coli and S. typhimurium, DNA Clinical experience regarding overdose with terbinafine hydrochloride tablets is limited.
repair in rat hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome Doses up to 5 grams (20 times the therapeutic daily dose) have been taken without aberration and sister chromatid exchanges in Chinese hamster lung cells), and in inducing serious adverse reactions. The symptoms of overdose included nausea, vivo (chromosome aberration in Chinese hamsters, micronucleus test in mice) vomiting, abdominal pain, dizziness, rash, frequent urination, and headache.
genotoxicity tests gave no evidence of a mutagenic or clastogenic potential. Oral DOSAGE AND ADMINISTRATION
reproduction studies in rats at doses up to 300 mg/kg/day (approximately 12x the Terbinafine hydrochloride tablets, one 250 mg tablet, should be taken once daily for 6 MRHD based on body surface area comparisons, BSA) did not reveal any specific weeks by patients with fingernail onychomycosis. Terbinafine hydrochloride, one 250 mg effects on fertility or other reproductive parameters. Intravaginal application of tablet, should be taken once daily for 12 weeks by patients with toenail onychomycosis.
terbinafine hydrochloride at 150 mg/day in pregnant rabbits did not increase the The optimal clinical effect is seen some months after mycological cure and cessation incidence of abortions or premature deliveries nor affect fetal parameters.
of treatment. This is related to the period required for outgrowth of healthy nail.
Pregnancy
HOW SUPPLIED
Pregnancy Category B: Oral reproduction studies have been performed in rabbits
Terbinafine Hydrochloride Tablets
and rats at doses up to 300 mg/kg/day (12x to 23x the MRHD, in rabbits and rats, Supplied as white to off white round tablets debossed ‘AN’ above ‘543’ on one side respectively, based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to terbinafine. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not Bottles of 30 tablets……… NDC 67405-543-03 always predictive of human response, and because treatment of onychomycosis Bottles of 100 tablets……. NDC 67405-543-10 can be postponed until after pregnancy is completed, it is recommended that Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C terbinafine hydrochloride not be initiated during pregnancy.
(between 59°F and 86°F), in a tight container. Protect from light.
Nursing Mothers
ANIMAL TOXICOLOGY
After oral administration, terbinafine is present in breast milk of nursing mothers.
A wide range of in vivo studies in mice, rats, dogs, and monkeys, and in vitro studies The ratio of terbinafine in milk to plasma is 7:1. Treatment with terbinafine using rat, monkey, and human hepatocytes suggest that peroxisome proliferation in hydrochloride is not recommended in nursing mothers.
the liver is a rat-specific finding. However, other effects, including increased liver Pediatric Use
weights and APTT, occurred in dogs and monkeys at doses giving Css trough levels The safety and efficacy of terbinafine hydrochloride have not been established in of the parent terbinafine 2-3x those seen in humans at the MRHD. Higher doses ADVERSE REACTIONS
HARRIS Pharmaceutical, Inc.
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. In Amneal Pharmaceuticals
general, the adverse events were mild, transient, and did not lead to discontinuation

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