WARNINGS
No information provided.
PRECAUTIONS
General
The efficacy of Famvir has not been established for initial
episode genital herpes infection, ophthalmic zoster, disseminated
zoster or in immunocompromised patients with herpes zoster.
Dosage adjustment is recommended when administering Famvir
to patients with creatinine clearance values <60 mL/min.
(see DOSAGE AND ADMINISTRATION). In patients with underlying
renal disease who have received inappropriately high doses
of Famvir for their level of renal function, acute renal
failure has been reported.
Information for Patients
Patients should be informed that Famvir is not a cure
for genital herpes. There are no data evaluating whether
Famvir will prevent transmission of infection to others.
As genital herpes is a sexually transmitted disease, patients
should avoid contact with lesions or intercourse when
lesions and/or symptoms are present to avoid infecting
partners. Genital herpes can also be transmitted in the
absence of symptoms through asymptomatic viral shedding.
If medical management of recurrent episodes is indicated,
patients should be advised to initiate therapy at the
first sign or symptom.
Drug Interactions
Concurrent use with probenecid or other drugs significantly
eliminated by active renal tubular secretion may result
in increased plasma concentrations of penciclovir.
The conversion of 6-deoxy penciclovir to penciclovir
is catalyzed by aldehyde oxidase. Interactions with other
drugs metabolized by this enzyme could potentially occur.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Famciclovir was administered orally unless otherwise
stated.
Carcinogenesis: Two-year dietary carcinogenicity
studies with famciclovir were conducted in rats and mice.
An increase in the incidence of mammary adenocarcinoma
(a common tumor in animals of this strain) was seen in
female rats receiving the high dose of 600 mg/kg/day (1.5
to 9.0x the human systemic exposure at the recommended
daily oral doses of 500 mg t.i.d., 250 mg b.i.d., or 125
mg b.i.d. based on area under the plasma concentration
curve comparisons [24 hr AUC] for penciclovir). No increases
in tumor incidence were reported in male rats treated
at doses up to 240 mg/kg/day (0.9 to 5.4x the human AUC),
or in male and female mice at doses up to 600 mg/kg/day
(0.4 to 2.4x the human AUC).
Mutagenesis: Famciclovir and penciclovir
(the active metabolite of famciclovir) were tested for
genotoxic potential in a battery of in vitro and in vivo
assays. Famciclovir and penciclovir were negative in in
vitro tests for gene mutations in bacteria (S. typhimurium
and E. coli) and unscheduled DNA synthesis in mammalian
HeLa 83 cells (at doses up to 10,000 and 5000 mcg/plate,
respectively). Famciclovir was also negative in the L5178Y
mouse lymphoma assay (5000 mcg/mL), the in vivo mouse
micronucleus test (4800 mg/kg), and rat dominant lethal
study (5000 mg/kg). Famciclovir induced increases in polyploidy
in human lymphocytes in vitro in the absence of chromosomal
damage (1200 mcg/mL). Penciclovir was positive in the
L5178Y mouse lymphoma assay for gene mutation/chromosomal
aberrations, with and without metabolic activation (1000
mcg/mL). In human lymphocytes, penciclovir caused chromosomal
aberrations in the absence of metabolic activation (250
mcg/mL). Penciclovir caused an increased incidence of
micronuclei in mouse bone marrow in vivo when administered
intravenously at doses highly toxic to bone marrow (500
mg/kg), but not when administered orally.
Impairment of Fertility: Testicular
toxicity was observed in rats, mice, and dogs following
repeated administration of famciclovir or penciclovir.
Testicular changes included atrophy of the seminiferous
tubules, reduction in sperm count, and/or increased incidence
of sperm with abnormal morphology or reduced motility.
The degree of toxicity to male reproduction was related
to dose and duration of exposure. In male rats, decreased
fertility was observed after 10 weeks of dosing at 500
mg/kg/day (1.9 to 11.4x the human AUC). The no observable
effect level for sperm and testicular toxicity in rats
following chronic administration (26 weeks) was 50 mg/kg/day
(0.2 to 1.2x the human systemic exposure based on AUC
comparisons). Testicular toxicity was observed following
chronic administration to mice (104 weeks) and dogs (26
weeks) at doses of 600 mg/kg/day (0.4 to 2.4x the human
AUC) and 1.50 mg/kg/day (1.7 to 10.2x the human AUC),
respectively.
Famciclovir had no effect on general reproductive performance
or fertility in female rats at doses up to 1000 mg/kg/day
(3.6 to 21.6x the human AUC). Two placebo- controlled
studies in a total of 130 otherwise healthy men with a
normal sperm profile over an 8-week baseline period and
recurrent genital herpes receiving oral Famvir (250 mg
b.i.d.) (n=66) or placebo (n=64) therapy for 18 weeks
showed no evidence of significant effects on sperm count,
motility or morphology during treatment or during an 8-week
follow-up.
Pregnancy
Teratogenic Effects— Pregnancy Category
B. Famciclovir was tested for effects on embryo-fetal
development in rats and rabbits at oral doses up to 1000
mg/kg/day (approximately 3.6 to 21.6x and 1.8 to 10.8x
the human systemic exposure to penciclovir based on AUC
comparisons for the rat and rabbit, respectively) and
intravenous doses of 360 mg/kg/day in rats (2 to 12x the
human dose based on body surface area [BSA] comparisons)
or 120 mg/kg/day in rabbits (1.5 to 9.0x the human dose
[BSA]). No adverse effects were observed on embryo-fetal
development. Similarly, no adverse effects were observed
following intravenous administration of penciclovir to
rats (80 mg/kg/day, 0.4 to 2.6x the human dose [BSA])
or rabbits (60mg/kg/day, 0.7 to 4.2x the human dose [BSA]).
There are, however, no adequate and well-controlled studies
in pregnant women. Because animal reproduction studies
are not always predictive of human response, famciclovir
should be used during pregnancy only if the benefit to
the patient clearly exceeds the potential risk to the
fetus.
Exposure Registry: To monitor maternal-fetal
outcomes of pregnant women exposed to Famvir SmithKline
Beecham maintains a Famvir Pregnancy Registry. Physicians
are encouraged to register their patients by calling (800)
366-8900, ext. 5231.
Nursing Mothers
Following oral administration of famciclovir to lactating
rats, penciclovir was excreted in breast milk at concentrations
higher than those seen in the plasma. It is not known
whether it is excreted in human milk. There are no data
on the safety of Famvir in infants.
Usage in Children
Safety and efficacy in children under the age of 18 years
have not been established.
Geriatric Use
Of 816 patients with herpes zoster in clinical studies who
were treated with Famvir, 248 (30.4%) were ³65 years
of age and 103 (13%) were ³75 years of age. No overall
differences were observed in the incidence or types of adverse
events between younger and older patients.
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