5.1 Potential for Eye Injury and Contamination

To avoid the potential for eye injury and/or contamination, patients should not touch the bottle tip to the eye or other surfaces.

5.2 Use with Contact Lenses

VEVYE should not be administered while wearing contact lenses. If contact lenses are worn, they should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of VEVYE ophthalmic solution.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials with 738 subjects receiving at least 1 dose of VEVYE, the most common adverse reactions were instillation site reactions (8%) and temporary decreases in visual acuity (3%).

8.1 Pregnancy

Risk Summary
There are no adequate and well-controlled studies of VEVYE administration in pregnant women to inform a drug-associated risk. Oral administration of cyclosporine to pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses. VEVYE doses are approximately 4,700 times lower than recommended oral doses, with blood concentrations being undetectable after topical administration.

Data
Animal Data
Oral administration of cyclosporine oral solution to pregnant rats or rabbits was teratogenic at maternally toxic doses of 30 mg/kg/day in rats and 100 mg/kg/day in rabbits, as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal retardations. These doses (normalized to body weight) were approximately 7,250 and 48,000 times higher than the daily maximum recommended human ophthalmic dose (MRHOD) of 0.67 mcg/kg/day, respectively.

No adverse embryofetal effects were observed in rats or rabbits receiving cyclosporine during organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively (approximately 4,100 and 14,500 times higher than the MRHOD, respectively).

An oral dose of 45 mg/kg/day cyclosporine (approximately 10,900 times higher than MRHOD) administered to rats from Day 15 of pregnancy until Day 21 postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. No adverse effects in mothers or offspring were observed at oral doses of up to 15 mg/kg/day (3600 times greater than MRHOD).

8.2 Lactation

Risk Summary
Cyclosporine is known to be excreted in human milk following systemic administration but excretion in human milk after topical treatment has not been investigated. VEVYE doses are approximately 4,700 times lower than recommended oral doses of cyclosporine, with blood concentrations being undetectable after topical administration. However, caution should be exercised when VEVYE is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

8.5 Geriatric Use

No overall difference in safety or effectiveness has been observed between elderly and younger patients.

12.1 Mechanism of Action

Cyclosporine, a calcineurin inhibitor, is a relatively selective immunomodulatory drug.

12.3 Pharmacokinetics

Following bilateral topical ocular dosing of one drop of VEVYE twice daily, the blood concentrations of cyclosporine were below the limit of quantification (0.1 ng/mL) at all timepoints.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Evaluation of the potential carcinogenicity of cyclosporine was conducted in male and female mice and rats. In a 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 a 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 were approximately 120 times higher than the maximum recommended human ophthalmic dose (0.67 mcg/kg/day), normalized to body surface area.

Mutagenesis
In genetic toxicity tests, cyclosporine has not been found to be 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. Cyclosporine was positive in an in vitro sister chromatid exchange (SCE) assay using human lymphocytes.

Impairment of Fertility
Oral administration of cyclosporine to rats for 12 weeks (male) and 2 weeks (female) prior to mating produced no adverse effects on fertility at doses up to 15 mg/kg/day (approximately 3,600 times higher than the maximum recommended human ophthalmic dose).