RESTASIS ophthalmic emulsion is indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.

Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs.

Invert the unit dose vial a few times to obtain a uniform, white, opaque emulsion before using. Instil one drop of RESTASIS ophthalmic emulsion twice a day in each eye approximately 12 hours apart.

RESTASIS can be used concomitantly with lubricant eye drops, allowing a 15-minute interval between products. Discard vial immediately after use.

Paediatric population

Safety and efficacy have not been established in paediatric patients below the age of 16.

Geriatric population

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

Be careful not to touch the vial tip to your eye or other surfaces to avoid potential for eye injury and contamination.

RESTASIS has not been adequately studied in patients with a history of recurrent herpes keratitis.

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.

No interaction studies have been performed.

Drugs that affect the cytochrome P-450 3A may alter cyclosporine metabolism.  There is no detectable systemic absorption of RESTASIS following ocular administration. Therefore, no interaction of topically applied RESTASIS with systemic drugs is expected to occur

Pregnancy

Risk Summary

Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically following topical ocular administration [see Clinical Pharmacology (12.3)], and maternal use is not expected to result in fetal exposure to the drug. Oral administration of cyclosporine to pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses [see Data].

Data

Animal Data

At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral solution (USP) was teratogenic as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal retardations. These doses (normalized to body surface area) are 5,000 and 32,000 times greater, respectively, than the daily recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic emulsion 0.05% twice daily 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 during organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively. These doses in rats and rabbits are approximately 3,000 and 10,000 times greater, respectively, than the daily recommended human dose.

An oral dose of 45 mg/kg/day cyclosporine administered to rats from Day 15 of pregnancy until Day 21 postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. This dose is 7,000 times greater than the daily recommended human dose. No adverse effects in dams or offspring were observed at oral doses up to 15 mg/kg/day (2,000 times greater than the daily recommended human dose).

Breastfeeding

Risk Summary

Cyclosporine is known to appear in human milk following systemic administration, but its presence in human milk following topical treatment has not been investigated. Although blood concentrations are undetectable following topical administration of RESTASIS ophthalmic emulsion [see Pharmacokinetic properties (5.2)], caution should be exercised when RESTASIS is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RESTASIS and any potential adverse effects on the breast-fed child from cyclosporine.

RESTASIS may cause transient blurring of vision which may impair the ability to drive or operate machines. The patient should wait until their vision has cleared before driving or using machinery.

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, the most common adverse reaction following the use of RESTASIS was ocular burning (17%).

Other reactions reported in 1% to 5% of patients included conjunctival hyperaemia, discharge, epiphora, eye pain, foreign body sensation, pruritus, stinging, and visual disturbance (most often blurring).

The frequency of adverse reactions observed during clinical trials involving 436 patients treated with RESTASIS is presented below.

The frequency of adverse reactions arising from clinical experience is given as follows:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from available data) adverse reactions are presented according to System Organ Class in Table 1.

Table 1 Tabulated summary of adverse reactions

Post-marketing Experience

The following adverse reactions have been identified during post approval use of RESTASIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases of severe angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea); and superficial injury of the eye (from the vial tip touching the eye during administration).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Reporting of suspected adverse reactions

Systemic overdose is unlikely to occur after ocular administration of RESTASIS. Due to undetectable systemic concentrations of cyclosporine after topical treatment with RESTASIS, systemic intoxication from topical overdose in humans is not expected.

ATC code: L04AD01

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.

Clinical Absorption and Distribution

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, twice daily, 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 ophthalmic emulsion.

RESTASIS has not been studied in patients with liver impairment. However, based on the low systemic availability of cyclosporine administered as an ophthalmic emulsion, and as there was no detectable drug accumulation in the blood during 12 months of treatment with RESTASIS, no dose adjustment or higher incidence of adverse drug reactions in patients with impaired liver function would be expected.

Patients with Renal Impairment

RESTASIS has not been studied in patients with renal impairment. However, based on the low systemic availability of cyclosporine administered as an ophthalmic emulsion, and as there was no detectable drug accumulation in the blood during 12 months of treatment with RESTASIS, no dose adjustment or higher incidence of adverse drug reactions in patients with impaired renal function would be expected.

Carcinogenesis

Systemic carcinogenicity studies were conducted 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 80 times greater (normalized to body surface area) than the daily recommended human dose of one drop (approximately 28 mcL) of 0.05% RESTASIS twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is absorbed.

Mutagenesis

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. 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).

Impairment of Fertility

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 2,000 times the human daily dose of 0.001 mg/kg/day normalized to body surface area) for 9 weeks (male) and 2 weeks (female) prior to mating.

The inactive ingredients of RESTASIS include: castor oil, glycerine, polysorbate 8, carbomer copolymer type A, sodium hydroxide (to adjust the pH) and purified water.

Not applicable.

Store below 25°C.

Store unused vials of RESTASIS (unit dose) in the original package (tray/carton).

RESTASIS ophthalmic emulsion is packaged in single use vials.  Each vial contains 0.4 mL fill in a 0.9 mL LDPE vial.  30 vials are packaged in a polypropylene tray with a peelable lid.  The entire contents of this tray (30 vials) must be dispensed as one unit

Pack size: 30 vials of 0.4 mL each.

The product should be discarded after the expiration date. Discard the vial immediately after use.  Any unused product or waste material should be disposed of in accordance with local requirements.