ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reaction occurring in approximately 25% of patients was mild taste following instillation. Other adverse reactions which occurred in to 5% of subjects were eye irritation, headache, and nasopharyngitis. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 mild taste following instillation. Other adverse reactions occurring in to 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 population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. The hypersensitivity reactions may include itching, body rash, and swelling of lips, tongue and/or throat.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-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 nominal dose of up to 200 mg/kg/day for 21 months or in rats receiving 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). MutagenesisThere 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 FertilityOral administration of bepotastine to male and female rats at doses up to 1000 mg/kg/day (5400 times higher than the maximum RHOD, on mg/m2 basis) 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 3300 times higher than that anticipated in humans at the RHOD).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Bepotastine is 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 seven days, bepotastine plasma concentrations peaked at approximately one to two 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 vitro metabolism studies with human liver microsomes demonstrated that bepotastine is minimally metabolized by CYP450 isozymes.In vitro studies 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 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 to 90% excreted unchanged in urine).

DESCRIPTION SECTION.

11 DESCRIPTION. Bepotastine Besilate Ophthalmic Solution, 1.5% is sterile, topically administered drug for ophthalmic use. Each mL of Bepotastine Besilate Ophthalmic Solution contains 15 mg bepotastine besilate. Bepotastine besilate is designated chemically as (+) -4-[[(S)-p-chloro-alpha -2-pyridylbenzyl]oxy]-1-piperidine butyric acid monobenzenesulfonate. The chemical structure for bepotastine besilate is:Bepotastine besilate is white or creamish white crystalline powder. The molecular weight of bepotastine besilate is 547.06 daltons. Bepotastine Besilate Ophthalmic Solution is supplied as sterile, aqueous 1.5% solution, with pH of 6.8. The osmolality of Bepotastine Besilate Ophthalmic Solution, 1.5% is approximately 290 mOsm/kg.Each mL of Bepotastine Besilate Ophthalmic Solution, 1.5% contains:Active: bepotastine besilate 15 mg (equivalent to 10.7 mg bepotastine)Preservative: benzalkonium chloride 0.005%Inactives: sodium chloride, sodium hydroxide to adjust pH, sodium phosphate monobasic dihydrate and water for injection.. structure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of bepotastine besilate 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 mothers clinical need for bepotastine besilate, and any potential adverse effects on the breastfed infant from bepotastine besilate. Animal Data Following single mg/kg oral dose (16 times the maximum RHOD, on mg/m2 basis) of radiolabeled bepotastine besilate to nursing rats 11 days after delivery, the maximum concentration of radioactivity in milk was 0.40 mcg-eq/mL 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-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 nominal dose of up to 200 mg/kg/day for 21 months or in rats receiving 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). MutagenesisThere 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 FertilityOral administration of bepotastine to male and female rats at doses up to 1000 mg/kg/day (5400 times higher than the maximum RHOD, on mg/m2 basis) 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 3300 times higher than that anticipated in humans at the RHOD).

PHARMACOKINETICS SECTION.

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 seven days, bepotastine plasma concentrations peaked at approximately one to two 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 vitro metabolism studies with human liver microsomes demonstrated that bepotastine is minimally metabolized by CYP450 isozymes.In vitro studies 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 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 to 90% excreted unchanged in urine).

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are no available human data for the use of bepotastine besilate 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 mg/m2 basis) [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 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.DataAnimal DataIn embryofetal development studies, oral administration of bepotastine besilate to pregnant rabbits throughout organogenesis did not produce teratogenic effects at maternal doses up to 500 mg/kg/day (approximately 5400 times the maximum RHOD, on mg/m2 basis). maternal no observed adverse effect level (NOAEL) was not identified in this study due to spontaneous abortion observed at the lowest dose tested, 20 mg/kg/day (approximately 215 times higher than the maximum RHOD, on mg/m2 basis). Oral administration of bepotastine besilate to pregnant rats throughout organogenesis produced skeletal anomalies at 1000 mg/kg/day (5400 times higher than the maximum RHOD, on mg/m2 basis), dose that also produced maternal toxicity and lethality. No teratogenic effects were observed in rats at maternal doses up to 200 mg/kg/day (corresponding to an estimated blood plasma concentration 3300 times higher than that anticipated in humans at the maximum RHOD). maternal NOAEL was observed at 10 mg/kg/day (54 times higher than the maximum RHOD, on mg/m2 basis). Following single mg/kg oral dose in rats (16 times higher than the maximum RHOD, on mg/m2 basis), the concentration of radio-labeled bepotastine besilate was similar in fetal liver and maternal blood plasma. The concentration in other fetal tissues was one-third to one-tenth the concentration in maternal blood plasma. In pre/postnatal development study, oral administration of bepotastine besilate to rats during the perinatal and lactation periods produced an increase in stillbirths and decreased growth and development in offspring at maternal dose of 1000 mg/kg/day (5400 times higher than the maximum RHOD, on mg/m2 basis). There were no observed adverse effects on offspring of rats treated with 100 mg/kg/day (540 times higher than the maximum RHOD, on mg/m2 basis). Effects on parturition and maternal lethality were observed at 100 mg/kg/day and 1000 mg/kg/day, respectively. maternal NOAEL was observed at 10 mg/kg/day (54 times higher than the maximum RHOD, on mg/m2 basis).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary There are no available human data for the use of bepotastine besilate 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 mg/m2 basis) [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 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.DataAnimal DataIn embryofetal development studies, oral administration of bepotastine besilate to pregnant rabbits throughout organogenesis did not produce teratogenic effects at maternal doses up to 500 mg/kg/day (approximately 5400 times the maximum RHOD, on mg/m2 basis). maternal no observed adverse effect level (NOAEL) was not identified in this study due to spontaneous abortion observed at the lowest dose tested, 20 mg/kg/day (approximately 215 times higher than the maximum RHOD, on mg/m2 basis). Oral administration of bepotastine besilate to pregnant rats throughout organogenesis produced skeletal anomalies at 1000 mg/kg/day (5400 times higher than the maximum RHOD, on mg/m2 basis), dose that also produced maternal toxicity and lethality. No teratogenic effects were observed in rats at maternal doses up to 200 mg/kg/day (corresponding to an estimated blood plasma concentration 3300 times higher than that anticipated in humans at the maximum RHOD). maternal NOAEL was observed at 10 mg/kg/day (54 times higher than the maximum RHOD, on mg/m2 basis). Following single mg/kg oral dose in rats (16 times higher than the maximum RHOD, on mg/m2 basis), the concentration of radio-labeled bepotastine besilate was similar in fetal liver and maternal blood plasma. The concentration in other fetal tissues was one-third to one-tenth the concentration in maternal blood plasma. In pre/postnatal development study, oral administration of bepotastine besilate to rats during the perinatal and lactation periods produced an increase in stillbirths and decreased growth and development in offspring at maternal dose of 1000 mg/kg/day (5400 times higher than the maximum RHOD, on mg/m2 basis). There were no observed adverse effects on offspring of rats treated with 100 mg/kg/day (540 times higher than the maximum RHOD, on mg/m2 basis). Effects on parturition and maternal lethality were observed at 100 mg/kg/day and 1000 mg/kg/day, respectively. maternal NOAEL was observed at 10 mg/kg/day (54 times higher than the maximum RHOD, on mg/m2 basis).. 8.2 Lactation. Risk SummaryThere are no data on the presence of bepotastine besilate 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 mothers clinical need for bepotastine besilate, and any potential adverse effects on the breastfed infant from bepotastine besilate. Animal Data Following single mg/kg oral dose (16 times the maximum RHOD, on mg/m2 basis) of radiolabeled bepotastine besilate to nursing rats 11 days after delivery, the maximum concentration of radioactivity in milk was 0.40 mcg-eq/mL 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Contamination of Solution: Do not touch the dropper tip to any surface. Keep bottle tightly closed when not in use. (5.1) Contact Lens Wear: Bepotastine besilate ophthalmic solution should not be used to treat contact lens-related irritation. (5.2) Contamination of Solution: Do not touch the dropper tip to any surface. Keep bottle tightly closed when not in use. (5.1) Contact Lens Wear: Bepotastine besilate ophthalmic solution should not be used to treat contact lens-related irritation. (5.2) 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.