Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action ZERVIATE, an antihistamine, is a histamine-1 (H1) receptor antagonist. Its effects are mediated via selective inhibition of H1 histamine receptors. The antihistaminic activity of cetirizine has been documented in a variety of animal and human models. In vivo and ex vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In vitro receptor binding studies have shown no measurable affinity for other than H1 receptors. Pharmacokinetics In healthy subjects, bilateral topical ocular dosing of one drop of ZERVIATE™ (cetirizine ophthalmic solution) 0.24% resulted in a mean cetirizine plasma Cmax of 1.7 ng/mL following a single dose and 3.1 ng/mL after twice-daily dosing for one week. The observed mean terminal half-life of cetirizine was 8.6 hours following a single dose and 8.2 hours after twice-daily dosing of ZERVIATE for one week. Clinical Studies The efficacy of ZERVIATE was established in three randomized, double-masked, placebo-controlled, conjunctival allergen challenge (CAC) clinical trials in patients with a history of allergic conjunctivitis. Onset and duration of action were evaluated in two of these trials in which patients were randomized to receive ZERVIATE or vehicle ophthalmic solutions. Patients were evaluated with an ocular itching severity score ranging from 0 (no itching) to 4 (incapacitating itch) at several time points after CAC administration. Table 1 displays data from the mean ocular itching severity scores after ocular administration of an antigen using the CAC model. A one unit difference compared to vehicle is considered a clinically meaningful change in the ocular itching severity score. Patients treated with ZERVIATE demonstrated statistically and clinically significantly less ocular itching compared to vehicle at 15 minutes and 8 hours after treatment. Table 1 : Itching Scores in the ITT Population by Treatment Group and Treatment Difference Statistics Study 1 Study 2 15 minutes post-treatment 8 hours post-treatment 15 minutes post-treatment 8 hours post-treatment ZERVIATE N=50 Vehicle N=50 ZERVIATE N=50 Vehicle N=50 ZERVIATE N=51 Vehicle N=50 ZERVIATE N=51 Vehicle N=50 3 Minute Post-CAC Mean 1.00 2.38 1.76 2.69 1.01 2.54 1.94 2.86 Treatment Difference (95% CI)1 -1.38 (-1.72, -1.05)* -0.93 (-1.26, -0.61)* -1.53 (-1.92, -1.15)* -0.92 (-1.25, -0.58)* 5 Minute Post-CAC Mean 1.18 2.43 1.85 2.74 1.17 2.51 2.03 1.82 Treatment Difference (95% CI)1 -1.25 (-1.58, -0.91)* -0.89 (-1.24, -0.54)* -1.34 (-1.71, -0.97)* -0.90 (-1.23, -0.57)* 7 Minute Post-CAC Mean 1.11 2.11 1.54 2.53 1.15 2.23 2.94 2.66 Treatment Difference (95% CI)1 -1.00 (-1.35, -0.65)* -0.99 (-1.40, -0.59)* -1.07 (-1.46, -0.69)* -0.84 (-1.21, -0.48)* 1 Treatment difference values shown are the group mean active minus the group mean vehicle at each post-CAC time point. * p < 0.05

ZERVIATE™ (cetirizine) Ophthalmic Solution DESCRIPTION ZERVIATE is a sterile ophthalmic solution containing cetirizine, which is a histamine-1 (H1) receptor antagonist, for topical administration to the eyes. Cetirizine hydrochloride is a white, crystalline, water-soluble powder with a molecular weight of 461.8 and a molecular formula of C21H25ClN2O3•2HCl. The chemical structure is presented below: Chemical Name: (RS)-2-[2-[4-[(4-Chlorophenyl) phenylmethyl] piperazin-1-yl] ethoxy] acetic acid, dihydrochloride Each mL of ZERVIATE contains an active ingredient [cetirizine 2.40 mg (equivalent to 2.85 mg of cetirizine hydrochloride)] and the following inactive ingredients: benzalkonium chloride 0.010% (preservative); glycerin; sodium phosphate, dibasic; edetate disodium; polyethylene glycol 400; polysorbate 80; hypromellose; hydrochloric acid/sodium hydroxide (to adjust pH); and water for injection. ZERVIATE solution has a pH of approximately 7.0 and osmolality of approximately 300 mOsm/kg.

INDICATIONS ZERVIATE™ (cetirizine ophthalmic solution) 0.24% is indicated for the treatment of ocular itching associated with allergic conjunctivitis. DOSAGE AND ADMINISTRATION The recommended dosage of ZERVIATE is to instill one drop in each affected eye twice daily (approximately 8 hours apart). HOW SUPPLIED Dosage Forms And Strengths Cetirizine ophthalmic solution, 0.24% is a sterile, buffered, clear, colorless aqueous solution containing cetirizine 0.24% (equivalent to cetirizine hydrochloride 0.29%). Storage And Handling ZERVIATE is a sterile, buffered, clear, colorless aqueous solution containing cetirizine 0.24% (equivalent to cetirizine hydrochloride 0.29%) supplied in a white low-density polyethylene multi-dose ophthalmic bottle with a low-density polyethylene dropper tip and a white polypropylene cap. ZERVIATE is supplied in a 7.5 mL bottle that contains 5 mL and 10 mL bottle that contains 7.5 mL cetirizine ophthalmic solution, 2.40 mg [equivalent to 2.85 mg cetirizine hydrochloride in one mL solution]. 5 mL fill in a 7.5 mL bottle NDC XXXXX-XXXX-5 7.5 mL fill in a 10 mL bottle NDC XXXXX-XXXX-7 Storage Store at 15°C to 25°C (59°F to 77°F). Manufactured by: Akorn, Inc. Lake Forest, IL 60045. Revised: May 2017

OVERDOSE No information provided. CONTRAINDICATIONS None.

SIDE EFFECTS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates in practice. In seven clinical trials, patients with allergic conjunctivitis or those at a risk of developing allergic conjunctivitis received one drop of either cetirizine (N=511) or vehicle (N=329) in one or both eyes. The most commonly reported adverse reactions occurred in approximately 1-7% of patients treated with either ZERVIATE or vehicle. These reactions were ocular hyperemia, instillation site pain, and visual acuity reduced. DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Contamination Of Tip And Solution As with any eye drop, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle to prevent contaminating the tip and solution. Keep the bottle closed when not in use. Contact Lens Wear Patients should be advised not to wear a contact lens if their eye is red. ZERVIATE should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of ZERVIATE. The preservative in ZERVIATE, benzalkonium chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of ZERVIATE. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity In a 2-year carcinogenicity study in rats, orally administered cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 550 times the MRHOD, on a mg/m² basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign liver tumors in males at a dietary dose of 16 mg/kg (approximately 220 times the MRHOD, on a mg/m² basis). No increase in the incidence of liver tumors was observed in mice at a dietary dose of 4 mg/kg (approximately 55 times the MRHOD, on a mg/m² basis). The clinical significance of these findings during long-term use of cetirizine is not known. Mutagenesis Cetirizine was not mutagenic in the Ames test or in an in vivo micronucleus test in rats. Cetirizine was not clastogenic in the human lymphocyte assay or the mouse lymphoma assay. Impairment of Fertility In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 875 times the MRHOD on a mg/m² basis). Use In Specific Populations Pregnancy Risk Summary There were no adequate or well-controlled studies with ZERVIATE™ (cetirizine ophthalmic solution) 0.24% in pregnant women. Cetirizine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Data Animal Data Cetirizine was not teratogenic in mice, rats, or rabbits at oral doses up to 96, 225, and 135 mg/kg, respectively (approximately 1300, 4930, and 7400 times the maximum recommended human ophthalmic dose (MRHOD), on a mg/m² basis). Lactation Risk Summary Cetirizine has been reported to be excreted in human breast milk following oral administration. Multiple doses of oral dose cetirizine (10 mg tablets once daily for 10 days) resulted in systemic levels (Mean Cmax = 311 ng/mL) that were 100 times higher than the observed human exposure (Mean Cmax = 3.1 ng/mL) following twice-daily administration of cetirizine ophthalmic solution 0.24% to both eyes for one week [see CLINICAL PHARMACOLOGY]. Comparable bioavailability has been found between the tablet and syrup dosage forms. However, it is not known whether the systemic absorption resulting from topical ocular administration of ZERVIATE could produce detectable quantities in human breast milk. There is no adequate information regarding the effects of cetirizine on breastfed infants, or the effects on milk production to inform risk of ZERVIATE to an infant during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZERVIATE and any potential adverse effects on the breastfed child from ZERVIATE. Pediatric Use The safety and effectiveness of ZERVIATE has been established in pediatric patients two years of age and older. Use of ZERVIATE in these pediatric patients is supported by evidence from adequate and well-controlled studies of ZERVIATE in pediatric and adult patients. Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.