Included as part of the "PRECAUTIONS" Section
Topical Ophthalmic Use Only
ZIRGAN is indicated for topical ophthalmic use only.
Avoidance Of Contact Lenses
Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during
the course of therapy with ZIRGAN.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1,000 mg/kg/day (approximately
3,000x and 160,000x the human ocular dose of 6.25 mcg/kg/day, assuming complete absorption). At the
dose of 1,000 mg/kg/day there was a significant increase in the incidence of tumors of the preputial
gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues
(ovaries, uterus, mammary gland, clitoral gland, and vagina) and liver in females. At the dose of 20
mg/kg/day, a slightly increased incidence of tumors was noted in the preputial and harderian glands in
males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in
mice administered ganciclovir at 1 mg/kg/day (160x the human ocular dose). Except for histocytic
sarcoma of the liver, ganciclovir-induced tumors were generally of epithelial or vascular origin.
Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human
counterparts, ganciclovir should be considered a potential carcinogen in humans. Ganciclovir increased
mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at concentrations
between 50 to 500 and 250 to 2,000 mcg/mL, respectively.
In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (IV)
(24,000x to 80,000x human ocular dose) but not 50 mg/kg (8,000x human ocular dose). Ganciclovir
was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5,000 mcg/mL.
Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of
embryolethality in female mice following intravenous doses of 90 mg/kg/day (approximately 14,000x
the human ocular dose of 6.25 mcg/kg/day). Ganciclovir caused decreased fertility in male mice and
hypospermatogenesis in mice and dogs following daily oral or intravenous administration of doses
ranging from 0.2 to 10 mg/kg (30x to 1,600x the human ocular dose).
Use In Specific Populations
Pregnancy Teratogenic Effects
Pregnancy Category C
Ganciclovir has been shown to be embryotoxic in rabbits and mice following
intravenous administration and teratogenic in rabbits. Fetal resorptions were present in at least 85% of
rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (approximately 10,000x and 17,000x the
human ocular dose of 6.25 mcg/kg/day), respectively, assuming complete absorption. Effects observed
in rabbits included: fetal growth retardation, embryolethality, teratogenicity, and/or maternal toxicity.
Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and
pancreas), hydrocephaly, and brachygnathia. In mice, effects observed were maternal/fetal toxicity and
embryolethality. Daily intravenous doses of 90 mg/kg/day (14,000x the human ocular dose)
administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of
the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the
nonglandular region of the stomach [see Carcinogenesis, Mutagenesis, Impairment Of Fertility].
There are no adequate and well-controlled studies in pregnant women. ZIRGAN should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether topical ophthalmic ganciclovir administration could result in sufficient systemic
absorption to produce detectable quantities in breast milk. Caution should be exercised when ZIRGAN
is administered to nursing mothers.
Safety and efficacy in pediatric patients below the age of 2 years have not been established.
No overall differences in safety or effectiveness have been observed between elderly and younger