Verkazia

1 INDICATIONS AND USAGE Verkazia ophthalmic emulsion is indicated for the treatment of vernal keratoconjunctivitis (VKC) in children and adults. Verkazia ophthalmic emulsion is a calcineurin inhibitor immunosuppressant indicated for the treatment of vernal keratoconjunctivitis in children and adults ( 1 )

2 DOSAGE AND ADMINISTRATION Instill one drop of Verkazia, 4 times daily (morning, noon, afternoon, and evening) in each affected eye ( 2 ) 2.1 General Dosing Information Gently shake the single-dose vial several times to obtain a uniform, white, opaque emulsion before use. Contact lenses should be removed before applying Verkazia and may be reinserted 15 minutes after administration. If a dose is missed, treatment should be continued as normal, at the next scheduled administration. If more than one topical ophthalmic product is being used, administer the eye drops at least 10 minutes apart to avoid diluting products. Administer Verkazia 10 minutes prior to using any eye ointment, gel or other viscous eye drops. Discard the vial immediately after use. 2.2 Recommended Dosage and Dose Administration Instill one drop of Verkazia, 4 times daily (morning, noon, afternoon, and evening) into each affected eye. Treatment can be discontinued after signs and symptoms are resolved and can be reinitiated if there is a recurrence. 2.1 General Dosing Information Gently shake the single-dose vial several times to obtain a uniform, white, opaque emulsion before use. Contact lenses should be removed before applying Verkazia and may be reinserted 15 minutes after administration. If a dose is missed, treatment should be continued as normal, at the next scheduled administration. If more than one topical ophthalmic product is being used, administer the eye drops at least 10 minutes apart to avoid diluting products. Administer Verkazia 10 minutes prior to using any eye ointment, gel or other viscous eye drops. Discard the vial immediately after use. 2.2 Recommended Dosage and Dose Administration Instill one drop of Verkazia, 4 times daily (morning, noon, afternoon, and evening) into each affected eye. Treatment can be discontinued after signs and symptoms are resolved and can be reinitiated if there is a recurrence.

4 CONTRAINDICATIONS None None ( 4 )

5 WARNINGS AND PRECAUTIONS To avoid the potential for eye injury and contamination, advise patient not to touch the vial tip to the eye or other surfaces ( 5.1 ) 5.1 Potential for Eye Injury and Contamination To avoid the potential for eye injury or contamination, advise patients not to touch the vial tip to the eye or other surfaces. 5.1 Potential for Eye Injury and Contamination To avoid the potential for eye injury or contamination, advise patients not to touch the vial tip to the eye or other surfaces.

6 ADVERSE REACTIONS The most common adverse reactions following the use of Verkazia were eye pain (12%) and eye pruritus (8%) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Santen at 1-855-7-SANTEN (855-772-6836) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA‑approved patient labeling. 6.1 Clinical Trials Experience Since 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 the VEKTIS study, a multicenter, randomized, double-masked, placebo‑controlled trial, a total of 57 patients received Verkazia dosed four times a day (QID) for 4 months. Forty-two (42) patients received Verkazia in an 8 month extension, safety follow-up of the VEKTIS study. In the NOVATIVE study, a multicenter, randomized, double-masked, placebo‑controlled trial, 39 patients received Verkazia 1 mg/mL dosed QID for one month. A total of 53 patients received Verkazia 1 mg/mL QID during a 3-month safety follow‑up. The majority of the treated patients were male (79%). The most common adverse reactions reported in greater than 5% of patients were eye pain (12%) and eye pruritus (8%) which were usually transitory and occurred during instillation (Table 1). Table 1: Adverse Reactions Reported in ≥ 1% of Patients Receiving Verkazia (N=135) Eye Disorders Eye pain a 12% Eye pruritus b 8% Ocular discomfort c 6% Visual acuity reduced 5% Ocular hyperemia 4% Systemic Cough 5% Headache 4% Upper respiratory tract infection 2% a Including eye pain and instillation site pain b Including eye pruritus and instillation site pruritus c Including foreign body sensation and ocular discomfort 6.1 Clinical Trials Experience Since 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 the VEKTIS study, a multicenter, randomized, double-masked, placebo‑controlled trial, a total of 57 patients received Verkazia dosed four times a day (QID) for 4 months. Forty-two (42) patients received Verkazia in an 8 month extension, safety follow-up of the VEKTIS study. In the NOVATIVE study, a multicenter, randomized, double-masked, placebo‑controlled trial, 39 patients received Verkazia 1 mg/mL dosed QID for one month. A total of 53 patients received Verkazia 1 mg/mL QID during a 3-month safety follow‑up. The majority of the treated patients were male (79%). The most common adverse reactions reported in greater than 5% of patients were eye pain (12%) and eye pruritus (8%) which were usually transitory and occurred during instillation (Table 1). Table 1: Adverse Reactions Reported in ≥ 1% of Patients Receiving Verkazia (N=135) Eye Disorders Eye pain a 12% Eye pruritus b 8% Ocular discomfort c 6% Visual acuity reduced 5% Ocular hyperemia 4% Systemic Cough 5% Headache 4% Upper respiratory tract infection 2% a Including eye pain and instillation site pain b Including eye pruritus and instillation site pruritus c Including foreign body sensation and ocular discomfort

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of Verkazia 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 [see Data ] . Data Animal Data Oral administration of cyclosporine oral solution (USP) 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 320 and 2150 times higher than the daily maximum recommended human ophthalmic dose (MRHOD) of 0.015 mg/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 185 and 650 times higher than the MRHOD, respectively). An oral dose of 45 mg/kg/day cyclosporine (approximately 485 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 (160 times greater than MRHOD). 8.2 Lactation Risk Summary There is no information regarding the presence of cyclosporine in human milk following topical administration or on the effect of Verkazia on the breastfed infants and milk production. Administration of oral cyclosporine to rats during lactation did not produce adverse effects in offspring at clinically relevant doses [see Pregnancy ( 8.1 )] . The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Verkazia and any potential adverse effects on the breast-fed child from cyclosporine. 8.3 Females and Males of Reproductive Potential Infertility There are no data on the effects of Verkazia on human fertility. No impairment of fertility has been reported in animals receiving intravenous cyclosporine [ see Impairment of Fertility ( 13.1 ) ] . 8.4 Pediatric Use Verkazia’s safety and effectiveness has been established in patients from 4 through 18 years of age. 8.5 Geriatric Use The safety and effectiveness of Verkazia have not been studied in geriatric patients. 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of Verkazia 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 [see Data ] . Data Animal Data Oral administration of cyclosporine oral solution (USP) 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 320 and 2150 times higher than the daily maximum recommended human ophthalmic dose (MRHOD) of 0.015 mg/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 185 and 650 times higher than the MRHOD, respectively). An oral dose of 45 mg/kg/day cyclosporine (approximately 485 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 (160 times greater than MRHOD). 8.2 Lactation Risk Summary There is no information regarding the presence of cyclosporine in human milk following topical administration or on the effect of Verkazia on the breastfed infants and milk production. Administration of oral cyclosporine to rats during lactation did not produce adverse effects in offspring at clinically relevant doses [see Pregnancy ( 8.1 )] . The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Verkazia and any potential adverse effects on the breast-fed child from cyclosporine. 8.3 Females and Males of Reproductive Potential Infertility There are no data on the effects of Verkazia on human fertility. No impairment of fertility has been reported in animals receiving intravenous cyclosporine [ see Impairment of Fertility ( 13.1 ) ] . 8.4 Pediatric Use Verkazia’s safety and effectiveness has been established in patients from 4 through 18 years of age. 8.5 Geriatric Use The safety and effectiveness of Verkazia have not been studied in geriatric patients.