5.1 Contamination of Tip and Solution

To minimize contaminating the dropper tip and solution, advise the patient not to touch the eyelids or surrounding areas with the dropper tip of the bottle and to keep the bottle tightly closed when not in use.

5.2 Contact Lens Wear

Bepotastine Besilate Ophthalmic Solution should not be used to treat contact lens-related irritation.

Bepotastine Besilate Ophthalmic Solution should not be instilled while wearing contact lenses. Patient should remove contact lenses prior to instillation of Bepotastine Besilate Ophthalmic Solution, because benzalkonium chloride may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of Bepotastine Besilate 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 clinical practice.

The most common reported adverse reaction occurring in approximately 25% of subjects was a mild taste following instillation. Other adverse reactions occurring in 2-5% of subjects were eye irritation, headache, and nasopharyngitis.

6.2 Post-Marketing Experience

Hypersensitivity reactions have been reported rarely during the post-marketing use of Bepotastine Besilate Ophthalmic Solution. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The hypersensitivity reactions may include itching, body rash, and swelling of lips, tongue and/or throat.

8.1 Pregnancy

Risk Summary

There are no available human data for the use of Bepotastine Besilate Ophthalmic Solution during pregnancy to inform any drug-associated risks.

Oral administration of bepotastine besilate to pregnant rats or rabbits during organogenesis or during the pre/postnatal period did not produce adverse embryofetal or offspring effects at clinically relevant systemic exposures. Maternal toxicity was observed in the rabbits at the lowest dose administered, 20 mg/kg/day (215 times the maximum recommended human ophthalmic dose, RHOD, on a mg/m 2basis) [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.

8.2 Lactation

Risk Summary

There are no data on the presence of Bepotastine Besilate Ophthalmic Solution in human milk, the effects on the breastfed infant or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for Bepotastine Besilate Ophthalmic Solution, and any potential adverse effects on the breastfed infant from Bepotastine Besilate Ophthalmic Solution.

Animal Data

Following a single 3 mg/kg oral dose (16 times the maximum RHOD, on a mg/m2 basis) of radio-labeled bepotastine besilate to nursing rats 11 days after delivery, the maximum concentration of radioactivity in milk was 0.40 mcg-eq/mL 1 hour after administration; at 48 hours after administration, the radioactivity concentration was below detection limits. The milk radioactivity concentration was higher than the maternal blood plasma radioactivity concentration at each time of measurement. It is not known whether bepotastine besilate would be present in maternal milk following topical ocular administration.

8.4 Pediatric Use

Safety and efficacy of Bepotastine Besilate Ophthalmic Solution, 1.5% have not been established in pediatric patients under 2 years of age. Efficacy in pediatric patients under 10 years of age was extrapolated from clinical trials conducted in pediatric patients greater than 10 years of age and from adults.

8.5 Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

12.1 Mechanism of Action

Bepotastine is a topically active, direct H1-receptor antagonist and an inhibitor of the release of histamine from mast cells.

12.3 Pharmacokinetics

Absorption:The extent of systemic exposure to bepotastine following topical ophthalmic administration of bepotastine besilate 1% and 1.5% ophthalmic solutions was evaluated in 12 healthy adults. Following one drop of 1% or 1.5% bepotastine besilate ophthalmic solution to both eyes four times daily (QID) for 7 days, bepotastine plasma concentrations peaked at approximately 1 to 2 hours post-instillation. Maximum plasma concentrations for the 1% and 1.5% strengths were 5.1 ± 2.5 ng/mL and 7.3 ± 1.9 ng/mL, respectively. Plasma concentrations at 24 hours post-instillation were below the quantifiable limit (2 ng/mL) in 11/12 subjects in the two dose groups.

Distribution:The extent of protein binding of bepotastine is approximately 55% and independent of bepotastine concentration.

Metabolism:In vitrometabolism studies with human liver microsomes demonstrated that bepotastine is minimally metabolized by CYP450 isozymes. In  vitrostudies demonstrated that bepotastine besilate does not inhibit the metabolism of various cytochrome P450 substrates via inhibition of CYP3A4, CYP2C9, and CYP2C19. The effect of bepotastine besilate on the metabolism of substrates of CYP1A2, CYP2C8, and CYP2D6 was not studied. Bepotastine besilate has a low potential for drug interaction via inhibition of CYP3A4, CYP2C9, and CYP2C19.

Excretion:The main route of elimination of bepotastine besilate is urinary excretion (with approximately 75-90% excreted unchanged in urine).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term dietary studies in mice and rats were conducted to evaluate the carcinogenic potential of bepotastine besilate. Bepotastine besilate did not significantly induce neoplasms in mice receiving a nominal dose of up to 200 mg/kg/day for 21 months, or in rats receiving a nominal dose of up to 97 mg/kg/day for 24 months. These dose levels correspond to systemic exposures approximately 350 and 200 times higher than that achieved at the RHOD, respectively.

The no observable adverse effect level for bepotastine besilate based on nominal dose levels in carcinogenicity tests were 18.7 to 19.9 mg/kg/day in mice and 9.6 to 9.8 mg/kg/day in rats (corresponding to systemic exposures approximately 60 and 20 times higher than that anticipated in humans at RHOD, respectively).

Mutagenesis

There was no evidence of genotoxicity in the Ames test (mutagenicity), in CHO cells (chromosome aberration), in mouse hepatocytes (unscheduled DNA synthesis), or in the mouse micronucleus test.

Impairment of Fertility

Oral administration of bepotastine to male and female rats at doses up to 1,000 mg/kg/day (5,400 times higher than the maximum RHOD, on a mg/m 2basis) resulted in reduction in fertility index and surviving fetuses. Oral administration of bepotastine besilate produced no observed adverse effects on fertility or reproduction in rats at oral doses up to 200 mg/kg/day (corresponding to an estimated blood plasma concentration 3,300 times higher than that anticipated in humans at the RHOD).