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Lamisil Oral Granules

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Lamisil Oral Granules

CLINICAL PHARMACOLOGY

Mechanism Of Action

Terbinafine is an allylamine antifungal.

Pharmacodynamics

The pharmacodynamics of Lamisil ® (terbinafine hydrochloride) Oral Granules is unknown.

Pharmacokinetics

The pharmacokinetics in children 4 to 8 years of age with tinea capitis was investigated in a pharmacokinetic study after single and repeated (for 42 days) oral administration of Lamisil Oral Granules (terbinafine hydrochloride) (N=16), once daily, using the body weight groups and doses described in section 2.2. The systemic exposure (Cmax and AUC0-24) of terbinafine in children had a relatively high inter-individual variability (ranging from 36 % to 64 %). At steady state the AUC0-24 increased by a mean factor of 1.9 to 2.1 across doses. The mean (SD) effective half-life obtained from the observed accumulation was 26.7 (13.8) hrs and 30.5 (9.3) hrs for the 125 mg and 187.5 mg doses, respectively.

Systemic exposure to terbinafine in the children did not exceed the highest values of the systemic exposure in adults receiving repeated once daily doses of 250 mg Lamisil (terbinafine) Tablets. A population pharmacokinetic evaluation of oral terbinafine that included children 4-12 years of age and adults 18-45 years of age (N=113) found that clearance (CL/F) of terbinafine is dependent on body weight in a nonlinear manner. For a typical child of 25 kg CL/F was predicted to be 19 L/h and for a typical adult of 70 kg body weight it was predicted to be 27 L/h. Over the weight range for pediatric patients included in the analysis (14.1 kg-68 kg), the predicted CL/F ranged between 15.6 - 26.7 L/hr. In plasma, terbinafine is > 99% bound to plasma proteins. Prior to excretion, terbinafine is rapidly and 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 adult 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 [see Warnings and PRECAUTIONS].

Microbiology

Terbinafine, an allylamine antifungal, inhibits biosysnthesis 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 tested in vitro, terbinafine may be fungicidal. However, the clinical significance of in vitro data is unknown.

Lamisil Oral Granules (terbinafine hydrochloride) has been studied in tinea capitis [see Clinical Studies].

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 2-3x those seen in humans at the MRHD. Higher doses were not tested.

In a 52 week oral toxicology study conducted in juvenile maturing dogs, increased heart and liver weights were noted in males and signs of CNS disturbance including 3 cases of single episodes of seizures were noted in females at the highest dose tested, 100 mg/kg/day [19X (males) and 10X (females) the MRHD based on AUC comparisons of the parent terbinafine]. No treatment related findings were noted at 30 mg/kg/day [1.6X (males) and 1.9X (females) the MRHD based on AUC comparisons of the parent terbinafine] in this study.

Clinical Studies

Two randomized, multinational trials were conducted to investigate the safety and efficacy of Lamisil (terfinafine hydrochloride) Oral Granules in the treatment of subjects 4 to 12 years old with tinea capitis. Lamisil Oral Granules (terbinafine hydrochloride) was dosed based on body weight. Griseofulvin dosed at 10-20 mg/kg was used as a comparator. Subjects were dosed for 6 weeks and followed for an additional 4 weeks.

The two trials enrolled 50% of subjects from the U.S. Additionally, among those with positive cultures, 65% and 54% of infections were due to T. tonsurans, and 19% and 17% due to M. canis in Studies 1 and 2, respectively.

The primary efficacy endpoint was the proportion of subjects with complete cure (negative KOH, negative culture and absence of clinical signs of infection) at week 10. Table 3 below lists the efficacy results for Studies 1 and 2 overall and according to the dermatophyte species (T. tonsurans, M. canis, or Other).

Table 3. Primary Efficacy Results by Dermatophyte Species


  Study 1 Study 2
Terbinafine Griseofulvin Terbinafine Griseofulvin
All Dermatophytes (N=411) (N=197) (N=441) (N=237)
  Complete Cure 190 (46.2%) 67 (34.0%) 194 (44.0%) 103 (43.5%)
T. tonsurans (N = 264) (N = 131) (N = 243) (N = 126)
  Complete Cure 148 (56.1%) 45 (34.4%) 116 (47.7%) 46 (36.5%)
M. canis (N = 80) (N = 37) (N = 72) (N = 45)
  Complete Cure 19 (23.8%) 13 (35.1%) 22 (30.6%) 23 (51.1%)
Other* (N = 67) (N = 29) (N = 126) (N =66 )
  Complete Cure 23 (34.2%) 9 (31.0%) 56 (44.4%) 34 (51.5%)
* T. violaceum, M. audouinii, T. mentagrophytes, T. rubrum, M. gypseum, and M. vanbreuseghemii.

Last reviewed on RxList: 7/2/2013
This monograph has been modified to include the generic and brand name in many instances.

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