RESTASIS ® ophthalmic emulsion has not been studied in patients with a history of herpes keratitis.
General: For ophthalmic use only.
Information for Patients:
The emulsion from one individual single-use vial is to be used immediately after opening for administration to one or both eyes, and the remaining contents should be discarded immediately after administration.
Do not allow the tip of the vial to touch the eye or any surface, as this may contaminate the emulsion.
RESTASIS ® should not be administered while wearing contact lenses. Patients with decreased tear production typically should not wear contact lenses. If contact lenses are worn, they should be removed prior to the administration of the emulsion. Lenses may be reinserted 15 minutes following administration of RESTASIS ® ophthalmic emulsion.
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Systemic carcinogenicity studies were carried out in male and female mice and rats. In the 78-week oral (diet) mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value.
In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. The low doses in mice and rats are approximately 1000 and 500 times greater, respectively, than the daily human dose of one drop (28 μL) of 0.05% RESTASIS ® BID into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is absorbed.
Cyclosporine has not been found mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE).
No impairment in fertility was demonstrated in studies in male and female rats receiving oral doses of cyclosporine up to 15 mg/kg/day (approximately 15,000 times the human daily dose of 0.001 mg/kg/day) for 9 weeks (male) and 2 weeks (female) prior to mating.
Pregnancy category C.
Teratogenic effects: No evidence of teratogenicity was observed in rats or rabbits receiving oral doses of cyclosporine up to 300 mg/kg/day during organogenesis. These doses in rats and rabbits are approximately 300,000 times greater than the daily human dose of one drop (28 μL) 0.05% RESTASIS ® BID into each eye of a 60 kg person (0.001mg/kg/day), assuming that the entire dose is absorbed.
Non-Teratogenic effects: Adverse effects were seen in reproduction studies in rats and rabbits only at dose levels toxic to dams. At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day), cyclosporine oral solution, USP, was embryo- and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardations. These doses are 30,000 and 100,000 times greater, respectively than the daily human dose of one-drop (28 μL) of 0.05% RESTASIS ® BID into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is absorbed. No evidence of embryofetal toxicity was observed in rats or rabbits receiving cyclosporine at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively, during organogenesis. These doses in rats and rabbits are approximately 17,000 and 30,000 times greater, respectively, than the daily human dose.
Offspring of rats receiving a 45 mg/kg/day oral dose of cyclosporine from Day 15 of pregnancy until Day 21 post partum, a maternally toxic level, exhibited an increase in postnatal mortality; this dose is 45,000 times greater than the daily human topical dose, 0.001 mg/kg/day, assuming that the entire dose is absorbed. No adverse events were observed at oral doses up to 15 mg/kg/day (15,000 times greater than the daily human dose).
There are no adequate and well-controlled studies of RESTASIS ® in pregnant women. RESTASIS ® should be administered to a pregnant woman only if clearly needed.
Cyclosporine is known to be excreted in human milk following systemic administration but excretion in human milk after topical treatment has not been investigated. Although blood concentrations are undetectable after topical administration of RESTASIS ® ophthalmic emulsion, caution should be exercised when RESTASIS ® is administered to a nursing woman.
The safety and efficacy of RESTASIS ® ophthalmic emulsion have not been established in pediatric patients below the age of 16.
No overall difference in safety or effectiveness has been observed between elderly and younger patients.