LAMISIL Terbinafine 250mg Tablet 1's

A few cases of overdosage (up to 5 g) have been reported, giving rise to headache, nausea, epigastric pain and dizziness.
The recommended treatment of overdosage consists of eliminating the drug, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy, if needed.

Women of child-bearing potential: Some cases of menstrual irregularities have been reported in patients taking terbinafine (Lamisil) tablets concomitantly with oral contraceptives, although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone.
There are no data to support special recommendations for women of child-bearing potential.
Pregnancy: Fetal toxicity studies with terbinafine in animals suggest no adverse effects. Since documented clinical experience in pregnant women is very limited, terbinafine (Lamisil) tablets should not be used during pregnancy unless the potential benefits outweigh any potential risks.
Breast-feeding: Terbinafine is excreted in breast milk; mothers receiving oral treatment with terbinafine (Lamisil) should therefore not breast-feed.
Fertility: There is no relevant information from human experience. Fertility studies in rats indicated no adverse findings in fertility or reproductive performance.

Incompatibilities: None known.

Store at temperatures not exceeding 30°C.

Pharmacology: Mechanism of action: Terbinafine is an allylamine which has a broad spectrum of activity against fungal pathogens of the skin, hair and nails including dermatophytes such as Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. tonsurans, T. violaceum), Microsporum (e.g. M. canis), Epidermophyton floccosum, and yeasts of the genera Candida (e.g. C. albicans) and Malassezia. At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi. Its activity against yeasts is fungicidal or fungistatic, depending on the species.
Terbinafine interferes specifically with fungal sterol biosynthesis at an early step. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane. The enzyme squalene epoxidase is not linked to the cytochrome P450 system.
Pharmacodynamics: When given orally, terbinafine accumulates in skin, hair and nails at levels associated with fungicidal activity.
Clinical Studies: Onychomycosis: The efficacy of terbinafine (Lamisil) tablets in the treatment of onychomycosis is illustrated by the response of patients with toenail and/or fingernail infections who participated in three US/Canadian placebo-controlled clinical trials (SFD301, SF5 and SF1508).
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 >5mm 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 treatment success for onychomycosis 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 (Lamisil) therapy, the clinical relapse rate was approximately 15%.
Tinea capitis: In the three comparative efficacy studies SF 8001, SFE 304, SF 8002 oral terbinafine (Lamisil) (62.5 - 250 mg daily) was given to a total of 117 evaluable patients, of whom over 97% were children. Single daily doses were given after the evening meal for 4 weeks (Terbinafine (Lamisil)) or 8 weeks (griseofulvin). Efficacy, demonstrated by negative mycology tests and a reduction in symptomatology, was evaluated at 8 weeks and at the follow-up examination (Week 12 for Studies SF 8001 and SFE 304, Week 24 for Study SF 8002). Negative mycology test results at follow-up were achieved by 85%, 88% and 72% of patients given terbinafine (Lamisil) in the three studies - the corresponding figures for griseofulvin were 73%, 89% and 69%. The derived variable "effective treatment" (negative mycology plus no, or only mild, symptoms and signs) was achieved in 82%, 78% and 69% of terbinafine-treated patients, compared with 66%, 74% and 59% in patients given griseofulvin; the difference was statistically significant in favor of terbinafine in Study SF 8001.
Two phase II treatment duration finding studies totaling 342 patients (mostly children) with T. capitis have been completed.
A 12-week randomized, double-blind, parallel group study was conducted in the United States and in Canada in children with Tinea capitis infection due to Trichophyton species (SFO327C T201). The objective of the study was to determine the optimal duration (1, 2 or 4 weeks) and safety of treatment with terbinafine (Lamisil) (tablets), given at weight adjusted doses once daily.
A second 16-week randomized, active-controlled, parallel-group, multicenter study was conducted in Europe in patients with Tinea capitis (>4 years) due to Microsporum species. The terbinafine (Lamisil) treatment duration arms (6, 8, 10, and 12 weeks) were double blinded, while the Griseofulvin active comparator arm was open-label (SFO327C T202). The objective of the study was to identify a safe and most appropriate treatment duration with terbinafine (tablets) in patients with Tinea capitis caused by Microsporum species. Dose administration of terbinafine was based on body weight in both studies as follows: <20 kg: 62.5 mg, 20-40 kg: 125 mg, >40 kg: 250 mg, given once daily. In both studies, terbinafine (Lamisil) was very well tolerated. Analysis of the efficacy data showed that both 2 and 4-week treatment duration provided good efficacy in T. capitis caused by Trichophyton species. In the Microsporum study, there was no significant difference in complete cure rates between the different treatment duration groups and 6-week treatment showed high complete cure rate (62%) with good tolerability and compliance. These results show that terbinafine (Lamisil) reduced treatment duration from 6-8 weeks to only 2-4 weeks in T. capitis caused by Trichophyton species compared to standard therapy with griseofulvin.
In phase II clinical studies conducted in Tinea capitis, adverse events reported from the 588 children enrolled were, in general, mild, relatively infrequent and often had an uncertain relationship to treatment. There were 11 reports of elevated SGPT levels and one of taste loss. Other events included mild gastrointestinal or skin symptoms, and laboratory findings indicative of intercurrent infections.
Fungal infections of the skin (tinea corporis, tinea cruris, tinea pedis) and yeast infections of the skin caused by the genus Candida (e.g. Candida albicans) where oral therapy is generally considered appropriate owing to the site, severity or extent of the infection: Three controlled, double blind, randomized, multicenter studies 5OR (4 week study), 6-7OR (4 week study) and 11-21OR (6 week study), evaluated efficacy and safety of Terbinafine (Lamisil) tablets in the treatment of Tinea corporis and cruris.
Two double blind, placebo controlled studies (85OR, 7OR) evaluated the efficacy of terbinafine (Lamisil) 125 mg b.i.d. in patients diagnosed with Tinea corporis/cruris. The studies included a total of 43 patients randomized to terbinafine (Lamisil) and 45 on placebo. There was no significant difference in terms of demographic and anamnestic data within groups. Efficacy, demonstrated by negative mycology tests and a reduction in clinical symptomatology, was evaluated at 4 weeks and at the follow-up examination. In both studies, minimal efficacy was demonstrated in patients treated with placebo compared to the efficacy of orally administered terbinafine at the end of therapy and at follow up.
The third study (11-21OR), a 6 weeks, double blind, randomized, multicenter study compared efficacy and safety of terbinafine (Lamisil) 125mg b.i.d. to griseofulvin 250mg b.i.d. One hundred twenty six (126) patients in each group were included in the efficacy analysis. This study showed high rate of mycological cure, reduction in signs and symptoms in the terbinafine treated study arm and significantly better (93-94%) overall efficacy at the end of therapy and at follow up of terbinafine 125 mg b.i.d. compared to 86-87% overall efficacy of comparator.
In summary, terbinafine (Lamisil) 125 mg b.i.d. administered for the period of 4-6 weeks demonstrated statistically superior efficacy compared to placebo and marketed drug griseofulvin in the treatment of Tinea corporis/cruris in the above major efficacy studies.
In a double blind, placebo controlled 4 weeks study SF 00438, terbinafine (Lamisil) 125 mg b.i.d was compared to placebo in patients with cutaneous candidiasis. Twenty two patients were randomized to each treatment arm, of which 19 were evaluated respectively. Of those, 29% of patients in the treatment arm and 17% of patients on placebo demonstrated mycological cure at the end of treatment and 67% of terbinafine-treated patients had negative mycological results at the end of follow up. Given the above response rates, 2 weeks therapy of terbinafine should be the minimum duration of treatment period and approximately half of the patients would require 3-4 weeks of treatment to achieve cure.
Two double blind, controlled studies compared terbinafine (Lamisil) 125 mg b.i.d. to placebo (39-40OR) and to griseofulvin 250 mg b.i.d. (20OR) in the treatment of Tinea pedis. Both studies recruited patients with chronic, recurrent disease. In the study 39-40OR, 65% of patients on terbinafine reported mycological cure at follow up whereas none of the placebo treated patients responded. In the study 20OR, terbinafine was shown to be highly effective with 88% of cure at follow up after 6 weeks therapy compared to 45% of patients on griseofulvin. These patients when observed after 10 months reported 94% cure rate, compared to 30% efficacy of griseofulvin in the same patient population. (See Table 1.)

 

Pharmacokinetics: Absorption: Following oral administration, terbinafine is well absorbed (>70%). A single oral dose of 250 mg terbinafine resulted in a mean peak plasma concentration of 1.3 microgram/mL within 1.5 hours of administration. At steady-state (70% steady state is achieved in approximately 28 days), in comparison to a single dose, peak concentration of terbinafine was on average 25% higher and plasma AUC increased by a factor of 2.3.
Distribution: Terbinafine binds strongly to plasma proteins (99%). It rapidly diffuses through the dermis and accumulates in the lipophilic stratum corneum. Terbinafine is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and sebum-rich skin. There is also evidence that terbinafine is distributed into the nail plate within the first few weeks after commencing therapy.
Biotransformation/Metabolism: Terbinafine is metabolized rapidly and extensively by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. Biotransformation results in metabolites with no antifungal activity.
Elimination: The metabolites are excreted predominantly in the urine. From the increase in plasma AUC at steady state an effective half-life of Yulex30 hours was calculated. Multiple dose administration followed by extended blood sampling revealed a triphasic elimination with a terminal half-life of approximately 16.5 days.
Bioavailability: The absolute bioavailability of terbinafine from Lamisil tablets as a result of first-pass metabolism is approximately 50%.
Special populations: No clinically relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been observed.
Single dose pharmacokinetic studies in patients with renal impairment (creatinine clearance <50 mL/min) or with pre-existing liver disease have shown that the clearance of terbinafine (Lamisil) tablets may be reduced by about 50%.
Toxicology: Non-Clinical Safety Data: In long-term studies (up to 1 year) in rats and dogs no marked toxic effects were seen in either species up to oral doses of about 100 mg/kg a day. At high oral doses, the liver and possibly also the kidneys were identified as potential target organs.
In a two-year oral carcinogenicity study in mice, no neoplastic or other abnormal findings attributable to treatment were made up to doses of 130 (males) and 156 (females) mg/kg a day. In a two-year oral carcinogenicity study in rats, an increased incidence of liver tumors was observed in males at the highest dose level of 69 mg/kg a day. The changes, which may be associated with peroxisome proliferation have been shown to be species-specific since they were not seen in the carcinogenicity study in mice or in other studies in mice, dogs or monkeys.
During high-dose studies in monkeys, refractile irregularities were observed in the retina at the higher doses (non-toxic effect level 50 mg/kg). These irregularities were associated with the presence of a terbinafine metabolite in ocular tissue and disappeared after drug discontinuation. They were not associated with histological changes.
An 8-week oral study in juvenile rats provided a no-toxic-effect level (NTEL) of close to 100 mg/kg/day, with the only finding being slightly increased liver weights, while in maturing dogs at ≥100 mg/kg/day (AUC values about 13x (m) and 6x (f) those in children), signs of central nervous system (CNS) disturbance including single episodes of convulsions in individual animals were observed. Similar findings have been observed at high systemic exposure upon intravenous administration of terbinafine to adult rats or monkeys.
A standard battery of in vitro and in vivo genotoxicity tests revealed no evidence of mutagenic or clastogenic potential.
No adverse effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.