NDA 22288/S-008
`Page 3
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed
`to use BEPREVE safely and effectively. See full
`prescribing information for BEPREVE.
`
`BEPREVE® (bepotastine besilate ophthalmic solution)
`1.5%, for topical ophthalmic use
`Initial U.S. Approval: 2009
`
`----------------- INDICATIONS AND USAGE ----------------­
`BEPREVE® is a histamine H1 receptor antagonist indicated for
`
`the treatment of itching associated with allergic conjunctivitis.
`(1)
`------------- DOSAGE AND ADMINISTRATION ------------­
`Instill one drop into the affected eye(s) twice a day. (2)
`Remove contact lenses prior to instillation of BEPREVE. (2)
`----------- DOSAGE FORMS AND STRENGTHS ----------­
`Ophthalmic solution containing bepotastine besilate,
`15 mg/mL (1.5%). (3)
`-------------------- CONTRAINDICATIONS -------------------­
`Hypersensitivity to any component of this product. (4)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Contamination of Tip and Solution
`5.2 Contact Lens Wear
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-Marketing Experience
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`
`------------- 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: BEPREVE should not be used to
`treat contact lens-related irritation. (5.2)
`
`
`-------------------- ADVERSE REACTIONS -------------------­
`The most common adverse reaction occurring in
`approximately 25% of patients was a mild taste following
`instillation. Other adverse reactions which occurred in 2-5% of
`subjects were eye irritation, headache, and nasopharyngitis.
`(6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Bausch + Lomb, a division of Valeant Pharmaceuticals
`North America LLC, at 1-800-321-4576 or FDA at 1-800­
`FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION
`Revised: 02/2018
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`Reference ID: 4218555
`
`

`

`NDA 22288/S-008
`Page 4
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`BEPREVE® (bepotastine besilate ophthalmic solution) 1.5% is a histamine H1 receptor
`antagonist indicated for the treatment of itching associated with signs and symptoms of allergic
`conjunctivitis.
`
`2 DOSAGE AND ADMINISTRATION
`Instill one drop of BEPREVE into the affected eye(s) twice a day.
`
`Remove contact lenses prior to instillation of BEPREVE.
`
`3 DOSAGE FORMS AND STRENGTHS
`Ophthalmic solution containing bepotastine besilate 15 mg/mL (1.5%).
`
`4 CONTRAINDICATIONS
`BEPREVE is contraindicated in patients with a history of hypersensitivity reactions to
`bepotastine or any of the other ingredients [see Adverse Reactions (6.2)].
`
`5 WARNINGS AND PRECAUTIONS
`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
`BEPREVE should not be used to treat contact lens-related irritation.
`
`BEPREVE should not be instilled while wearing contact lenses. Patient should remove contact
`lenses prior to instillation of BEPREVE, because benzalkonium chloride may be absorbed by
`soft contact lenses. Lenses may be reinserted after 10 minutes following administration of
`BEPREVE.
`
`6 ADVERSE REACTIONS
`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
`BEPREVE. 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
`
`Reference ID: 4218555
`
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`NDA 22288/S-008
`Page 5
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`drug exposure. The hypersensitivity reactions may include itching, body rash, and swelling of
`
`lips, tongue and/or throat.
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`There are no available human data for the use of BEPREVE 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/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
`2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.
`
`Data
`Animal Data
`In 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 a mg/m2 basis). A 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 a 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 a mg/m2 basis), a 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). A maternal NOAEL was observed at 10
`mg/kg/day (54 times higher than the maximum RHOD, on a mg/m2 basis). Following a single 3
`mg/kg oral dose in rats (16 times higher than the maximum RHOD, on a 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 a 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 a maternal dose of 1000 mg/kg/day (5400 times higher than the
`maximum RHOD, on a 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 a mg/m2 basis).
`Effects on parturition and maternal lethality were observed at 100 mg/kg/day and 1000
`mg/kg/day, respectively. A maternal NOAEL was observed at 10 mg/kg/day (54 times higher
`than the maximum RHOD, on a mg/m2 basis).
`
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`NDA 22288/S-008
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`8.2 Lactation
`Risk Summary
`There are no data on the presence of BEPREVE 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 BEPREVE, and any potential adverse effects on the breastfed infant
`from BEPREVE.
`
`Animal Data
`Following a single 3 mg/kg oral dose (16 times the maximum RHOD, on a 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 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 BEPREVE (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.
`
`11 DESCRIPTION
`BEPREVE® (bepotastine besilate ophthalmic solution) 1.5% is a sterile, topically administered
`drug for ophthalmic use. Each mL of BEPREVE 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:
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`NDA 22288/S-008
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`Bepotastine besilate is a white or pale yellowish crystalline powder. The molecular weight of
`
`bepotastine besilate is 547.06 daltons. BEPREVE ophthalmic solution is supplied as a sterile,
`
`aqueous 1.5% solution, with a pH of 6.8.
`
`
`The osmolality of BEPREVE (bepotastine besilate ophthalmic solution) 1.5% is approximately
`
`290 mOsm/kg.
`
`
`Each mL of BEPREVE (bepotastine besilate ophthalmic solution) 1.5% contains:
`
` Active: bepotastine besilate 15 mg (equivalent to 10.7 mg bepotastine)
`
` Preservative: benzalkonium chloride 0.005%
`
`Inactives: monobasic sodium phosphate dihydrate, sodium chloride, sodium hydroxide to
`
`
`adjust pH, and water for injection, USP.
`
`12 CLINICAL PHARMACOLOGY
`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 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 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 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis
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`NDA 22288/S-008
`Page 8
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`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 1000 mg/kg/day (5400
`times higher than the maximum RHOD, on a 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).
`
`14 CLINICAL STUDIES
`
`Clinical efficacy was evaluated in two conjunctival allergen challenge (CAC) studies (237
`
`patients). BEPREVE (bepotastine besilate ophthalmic solution) 1.5% was more effective than its
`vehicle for relieving ocular itching induced by an ocular allergen challenge, both at a CAC 15
`
`minutes post-dosing and a CAC 8 hours post-dosing of BEPREVE.
`
`
`The safety of BEPREVE was evaluated in a randomized clinical study of 861 subjects over a
`period of 6 weeks.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`BEPREVE® (bepotastine besilate ophthalmic solution) 1.5% is supplied in a white low density
`
`polyethylene plastic squeeze bottle with a white controlled dropper tip and a white
`
`polypropylene cap in the following size:
`
`
`5 mL (NDC 24208-629-02)
`
`10 mL (NDC 24208-629-01)
`
`
`STORAGE
`
`Store at 15°C to 25°C (59°F to 77°F).
`
`
`17 PATIENT COUNSELING INFORMATION
` Sterility of Dropper Tip
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`Reference ID: 4218555
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`NDA 22288/S-008
`Page 9
`
`Advise patients not to touch the dropper tip to any surface, as this may contaminate the
`
`solution and to keep the bottle tightly closed when not in use.
` Concomitant Use of Contact Lenses
`Advise patients not to wear a contact lens if their eye is red and that BEPREVE should not be
`used to treat contact lens-related irritation. Patients should also be advised to remove contact
`lenses prior to instillation of BEPREVE, which may be reinserted after 10 minutes following
`administration.
`
`Distributed by:
`Bausch + Lomb, a division of
`
`Valeant Pharmaceuticals North America LLC
`
`Bridgewater, NJ 08807 USA
`
`
`Under license from:
`
`Senju Pharmaceutical Co., Ltd.
`
`Osaka, Japan 541-0046
`
`Bepreve is a trademark of Bausch & Lomb Incorporated or its affiliates.
`
`©Bausch & Lomb Incorporated
`
`
`New component number
`
`Reference ID: 4218555
`
`