PAZEO Ophthalmic solution Ref.[11062] Active ingredients: Olopatadine

In healthy subjects, topical ocular dosing of 1 drop of PAZEO once daily for 7 days into both eyes resulted in mean ± SD (range) steady state plasma olopatadine C_max and AUC_0-12 of 1.6 ± 0.9 ng/mL (0.6 to 4.5 ng/mL) and 9.7 ± 4.4 ng*h/mL (3.7 to 21.2 ng*h/mL), respectively. The olopatadine C_max and AUC_0-12 after the first dose were similar to those measured on day 7 in these subjects, suggesting that there was no systemic accumulation of olopatadine after repeated topical ocular dosing with PAZEO. The median (range) time to achieve peak olopatadine concentrations (T_max) was 2.0 hours (0.25 to 4 hours). The mean ± SD (range) elimination half‑life of olopatadine was 3.4 ± 1.2 hours (2 to 8 hours). N-oxide olopatadine (M3) was detected during the first 4 hours after bilateral topical ocular dosing of PAZEO in approximately half of the subjects and in less than 10% of the total plasma samples collected, at concentrations not exceeding 0.121 ng/mL on day 1 and 0.174 ng/mL on day 7. None of the plasma samples from these subjects had mono-desmethyl olopatadine (M1) concentrations that were above the lower limit of quantitation (0.05 ng/mL) of the PK assay.

Carcinogenicity

Olopatadine administered orally was not carcinogenic in mice and rats in doses up to 500 mg/kg/day and 200 mg/kg/day, respectively. Based on a 35 μL drop size and a 60 kg person, these doses are approximately 4,500 and 3,600 times the MRHOD, on a mg/m² basis.

Mutagenesis

No mutagenic potential was observed when olopatadine was tested in an in vitro bacterial reverse mutation (Ames) test, an in vitro mammalian chromosome aberration assay or an in vivo mouse micronucleus test.

Impairment of fertility

Olopatadine administered at an oral dose of 400 mg/kg/day (approximately 7,200 times the MRHOD) produced toxicity in male and female rats, and resulted in a decrease in the fertility index and reduced implantation rate. No effects on reproductive function were observed at 50 mg/kg/day (approximately 900 times the MRHOD).

The efficacy of PAZEO was established in two randomized, double-masked, placebo-controlled, conjunctival allergen challenge (CAC) clinical studies in patients with a history of allergic conjunctivitis (Studies 1 and 2).

In Study 1, patients were randomized to receive one of the following study treatments: PAZEO, PATADAY, or vehicle ophthalmic solutions. In Study 2, patients were randomized to receive one of the following study treatments: PAZEO, PATADAY, PATANOL, 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 the mean ocular itching severity scores after ocular administration of a specific antigen using the CAC model in Studies 1 and 2, respectively. A one unit difference compared to vehicle is considered a clinically meaningful change in the ocular itching severity score.

PAZEO demonstrated statistically significantly improved relief of ocular itching compared to vehicle at 30-34 minutes, 16 hours, and 24 hours after study treatment. PAZEO demonstrated statistically significantly improved relief of ocular itching compared to PATADAY at 24 hours after study treatment, but not at 30-34 minutes after study treatment.

Table 1. Itching Scores by Treatment Group and Treatment Difference* in Mean Itching:

^* Mean score estimates, treatment differences and corresponding 95% confidence intervals (CIs) were based on analysis of repeated measures using a mixed model with itching scores from each eye (left or right) as the dependent variable and fixed effect terms for investigator, treatment, eye-type (left or right), time, and treatment-by-time interaction;
The ocular itching score range is 0-4, where 0 is none and 4 is incapacitating itch.