Restasis Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Cyclosporine is an immunosuppressive agent when administered systemically.
In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator. The exact mechanism of action is not known.
Pharmacokinetics: Blood cyclosporine A concentrations were measured using a specific high pressure liquid chromatography-mass spectrometry assay. Blood concentrations of cyclosporine, in all the samples collected, after topical administration of RESTASIS 0.05% BID, in humans for up to 12 months, were below the quantitation limit of 0.1 ng/mL. There was no detectable drug accumulation in blood during 12 months of treatment with RESTASIS.
Clinical Evaluations: Four multicenter, randomized, adequate and well-controlled clinical studies were performed in approximately 1200 patients with moderate to severe keratoconjunctivitis sicca. RESTASIS demonstrated statistically significant increases in Schirmer wetting of 10 mm versus vehicle at six months in patients whose tear production was presumed to be suppressed due to ocular inflammation. This effect was seen in approximately 15% of RESTASIS treated patients versus approximately 5% of vehicle-treated patients. Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs.
No increase in bacterial or fungal ocular infections was reported following administration of RESTASIS.
Toxicology: Preclinical Safety Data: Effects in non-clinical studies were observed following systemic administration only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Carcinogenesis and Mutagenesis studies: 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 300 and 80 times greater (normalized to body surface area), respectively, than the daily human dose, or alternatively, 1000 and 500 times greater, respectively, than the daily human dose of one drop of 0.05% RESTASIS BID into each eye.
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 recent 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), at high concentrations in this system.
Fertility Studies: No impairment in fertility was demonstrated in studies in male and female rats.