CONTRAINDICATIONS
Terbinafine hydrochloride is contraindicated in individuals with hypersensitivity to terbinafine.
WARNINGS
Rare cases of symptomatic hepatobiliary dysfunction including cholestatic hepatitis have been
reported. Treatment with terbinafine hydrochloride should be discontinued if hepatobiliary
dysfunction develops (see PRECAUTIONS.) There have been isolated reports of serious skin
reactions (e.g., Stevens-Johnson Syndrome and toxic epidermal necrolysis). If progressive skin rash
occurs, treatment with terbinafine hydrochloride should be discontinued.
PRECAUTIONS
General: Changes in the ocular lens and retina have been reported following the use of terbinafine
hydrochloride in controlled trials. The clinical significance of these changes is unknown. Hepatic
function (hepatic enzyme) tests are recommended in patients administered terbinafine hydrochloride
for more than six weeks (see WARNINGS.)
In patients with either pre-existing liver disease or 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.)
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 ALC to below 1000/mm3 on two or more
occasions. The clinical significance of this observation is unknown. However, in patients with
known or suspected immunodeficiency, physicians should consider monitoring complete blood
counts in individuals using terbinafine hydrochloride therapy for greater than six weeks.
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 started.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: In a 28–month oral carcinogenicity
study in rats, a marginal increase in the incidence of liver tumors was observed in males at the
highest dose level, 69 mg/kg/day [13.8 times the maximum recommended human dose (MRHD)
based on body weight (BW) and 3.6 times the MRHD based on body surface area (BSA)]. There
was no dose-related trend and the mid-dose male rats (20 mg/kg/day; 4.0 times the MRHD based
on BW and 1.0 times the MRHD based on BSA) did not have any tumors. No increased incidence
in liver tumors was noted in female rats at dose levels up to 97 mg/kg/day (19.4 times the MRHD
based on BW and 4.5 times the MRHD based on BSA) or in male or female mice treated orally for
23 months at doses up to 156 mg/kg/day (31.2 times the MRHD based on BW and 3.9 times the
MRHD based on BSA).
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 the development of liver tumors in the high-dose male
rats may be associated with peroxisome proliferation, and support the conclusion that this is a
rat-specific finding. In vivo investigations included evaluations of the effects of terbinafine
hydrochloride on liver weight, morphology, and ultrastructure; hepatic cytochrome P450; and
peroxisome proliferation assessed morphologically and biochemically (peroxisomal enzymes) in
mice, rats, dogs, and monkeys. The effects of terbinafine hydrochloride and two known metabolites
on hepatic morphology and peroxisomal and P450 enzyme activities were also evaluated in vivo in
male rats and in vitro in primary hepatocyte cultures from male rats and humans and from
monkeys. The results of the in vivo investigations indicated that oral administration of terbinafine
hydrochloride (500 mg/kg/day) resulted in peroxisome proliferation in rats, and that these effects did
not occur in mice, dogs, or monkeys. Further, in vitro studies indicated that peroxisome proliferation
occurred in rat hepatocytes, but not in monkey or human hepatocytes.
Systemic exposure to terbinafine hydrochloride, assessed by the steady-state plasma unbound
fraction area under the curve (AUC) for terbinafine and metabolites, was 7.7 and 9.7 mcg·h/mL for
male and female rats, respectively, and 11.2 and 13.1 mcg·h/mL for male and female mice,
respectively, at doses comparable to the high doses in the carcinogenicity studies. In human subjects
at the MRHD (a daily dose of 250 mg of terbinafine hydrochloride), the unbound AUC was 0.466
mcg·h/mL. The resulting safety margins for humans, based on relative systemic exposure (AUC
inbound), in rats and mice were 17 to 21 and 24 to 28, respectively.
The results of a variety of in vitro and in vivo genotoxicity tests gave no evidence of a mutagenic
or clastogenic potential, and demonstrated the absence of tumor-initiating or cell-proliferating
activity.
Oral reproduction studies in rats at doses up to 300 mg/kg/day (60 times the MRHD based on BW
and approximately 12 times the MRHD based on 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.
Pregnancy Category B: Oral reproduction studies have been performed in rabbits and rats at
doses up to 300 mg/kg/day (60 times the MRHD based on BW and 9 times to 12 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. There are, however, no adequate and well-controlled studies
in pregnant women. Because animal reproduction studies are not always predictive of human
response, and because treatment of anychomycosis can be postponed until after pregnancy is
completed, it is recommended that terbinafine hydrochloride not be initiated during pregnancy.
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.
Pediatric Use: The safety and efficacy of terbinafine hydrochloride have not been established in
pediatric patients.