`
` NDA 22-288/S-003
`
`Page 3
`
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed
`
`to use BEPREVE® (bepotastine besilate ophthalmic
`
`
`solution) 1.5% safely and effectively. See full prescribing
`
`information for Bepreve™.
`
`
`BEPREVE® (bepotastine besilate ophthalmic solution)
`
`
`1.5%
`
`Initial U.S. Approval: 2009
`
`
`--------------RECENT MAJOR CHANGES----------------
`
`
`
`Contraindications (4)
`06/2012
`
`
`--------------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.
`(BID). (2)
`----------DOSAGE FORMS AND STRENGTHS--------­
`
` Solution containing bepotastine besilate, 1.5%. (3)
`--------------CONTRAINDICATIONS----------------­
`
`Hypersensitivity to any component of this product. (4)
`
`
`
`
`
`
`
`
`-----------WARNINGS AND PRECAUTIONS-------­
`
`
`  To minimize the risk of contamination, do not touch
`
` dropper tip to any surface. Keep bottle tightly
`closed when not in use. (5.1)
`
` BEPREVE® should not be used to treat contact
`
` lens-related irritation. (5.2)
`
`
` Remove contact lenses prior to instillation of
`
` BEPREVE®. (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
`ISTA Pharmaceuticals, Inc. at 1-877-788-2020, or FDA at 1­
`
`800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`Revised: 06/2012
`
`
`_____________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`11
`DESCRIPTION
`1
`INDICATIONS AND USAGE
`12
`CLINICAL PHARMACOLOGY
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`12.1 Mechanism of Action
`
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`
` 12.3 Pharmacokinetics
`
`4
`CONTRAINDICATIONS
`13
`NONCLINICAL TOXICOLOGY
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`
`5.1 Contamination of Tip and Solution
`Fertility
`CLINICAL STUDIES
`14
`
`
`
`5.2 Contact Lens Use
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`5.3 Topical Ophthalmic Use Only
`6
`ADVERSE REACTIONS
`17
`PATIENT COUNSELING INFORMATION
`
`
`6.1 Clinical Trials Experience
`
`
` 17.1 Topical Ophthalmic Use Only
`
`
`
`Post-Marketing Experience
`6.2
`
`
` 17.2 Sterility of Dropper Tip
`USE IN SPECIFIC POPULATIONS
`8
`
`
` 17.3 Concomitant Use of Contact Lenses
`
`
`8.1
`Pregnancy
`
`
`
`8.3 Nursing Mothers
`
`
`*Sections or subsections omitted from the full prescribing
`
`
`8.4
`Pediatric Use
`
`information are not listed
`8.5 Geriatric Use
`
`____________________________________________________________________________________________
`
`
`
`
`
`
`Reference ID: 3151309
`
`

`

`
`
` NDA 22-288/S-003
`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 (BID).
`
`3 DOSAGE FORMS AND STRENGTHS
`Topical ophthalmic solution containing bepotastine besilate 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, care should be taken not to touch
`the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed
`when not in use.
`
`
`5.2 Contact Lens Use
`Patients should be advised not to wear a contact lens if their eye is red. BEPREVE should
`not be used to treat contact lens-related irritation.
`
`BEPREVE should not be instilled while wearing contact lenses. Remove contact lenses prior
`to instillation of BEPREVE®. The preservative in BEPREVE®, benzalkonium chloride,
`may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes
`following administration of BEPREVE.
`
`
`5.3 Topical Ophthalmic Use Only
`BEPREVE is for topical ophthalmic use only.
`
`
`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
`
`
`
`
`Reference ID: 3151309
`
`
`
`

`

`
`
` NDA 22-288/S-003
`Page 5
`
`
`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 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
`
`Pregnancy Category C: Teratogenicity studies have been performed in animals. Bepotastine
`besilate was not found to be teratogenic in rats during organogenesis and fetal development at
`oral doses up to 200 mg/kg/day (representing a systemic concentration approximately 3300
`times that anticipated for topical ocular use in humans), but did show some potential for
`causing skeletal abnormalities at 1000 mg/kg/day. There were no teratogenic effects seen in
`rabbits at oral does up to 500 mg/kg/day given during organogenesis and fetal development
`(>13,000 times the dose in humans on a mg/kg basis). Evidence of infertility was seen in rats
`given oral bepotastine besilate 1000 mg/kg/day, however, no evidence of infertility was
`observed in rats given 200 mg/kg/day (approximately 3300 times the topical ocular use in
`humans). The concentration of radio-labeled bepotastine besilate was similar in fetal liver and
`maternal blood plasma following a single 3 mg/kg oral dose. The concentration in other fetal
`tissues was one-third to one-tenth the concentration in maternal blood plasma.
`
`
`
`An increase in stillborns and decreased growth and development were observed in pups born
`from rats given oral doses of 1000 mg/kg/day during perinatal and lactation periods. There
`were no observed effects in rats treated with 100 mg/kg/day.
`
`There are no adequate and well-controlled studies of bepotastine besilate in pregnant women.
`Because animal reproduction studies are not always predictive of human response, BEPREVE
`(bepotastine besilate ophthalmic solution) 1.5% should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
`
`
`8.3 Nursing Mothers
`Following a single 3 mg/kg oral dose 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 concentration was below
`detection limits. The milk concentration was higher than the maternal blood plasma
`
`concentration at each time of measurement.
`
`It is not known if bepotastine besilate is excreted in human milk. Caution should be
`exercised when BEPREVE (bepotastine besilate ophthalmic solution) 1.5% is administered
`to a nursing woman.
`
`
`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.
`
`
`
`
`
`Reference ID: 3151309
`
`
`
`

`

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` NDA 22-288/S-003
`Page 6
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`
` 8.5 Geriatric Use
`No overall differences in safety or effectiveness have been observed between elderly and
`younger patients.
`
` 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:
`
`11
`
`
`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 time 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 (2ng/mL) in 11/12 subjects in the two dose groups.
`
`
`
`
`Reference ID: 3151309
`
`
`
`

`

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` NDA 22-288/S-003
`Page 7
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`
`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,
`
`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).
`
`
`
` NONCLINICAL TOXICOLOGY
`13
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`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 rats
`receiving a nominal dose of up to 97 mg/kg/day for 24 months. These dose levels represent
`systemic exposures approximating 350 and 200 times that achieved with human topical
`ocular use.
`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 (representing exposure margins of approximately 60 and 20 times the systemic
`exposure anticipated for human topical use).
`
`There was no evidence of genotoxicity in the Ames test, in CHO cells (chromosome
`aberrations), in mouse hepatocytes (unscheduled DNA synthesis), or in the mouse
`micronucleus test.
`
`When oral bepotastine was administered to male and female rats at doses up to 1,000
`mg/kg/day, there was a slight reduction in fertility index and surviving fetuses. Infertility
`was not seen in rats given 200 mg/kg/day oral bepotastine besilate (approximately 3300
`
`times the systemic concentration anticipated for topical ocular use in humans).
`
`
`
`14
`
` CLINICAL STUDIES
`
`Clinical efficacy was evaluated in 2 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
`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.
`
`
`
`
`Reference ID: 3151309
`
`
`
`

`

`
`
` NDA 22-288/S-003
`Page 8
`
`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 67425-007-50)
`
`10 mL (NDC 67425-007-75)
`
`
`
`
` STORAGE
`
`Store at 15º – 25ºC (59º – 77ºF).
`
`17 PATIENT COUNSELING INFORMATION
`17.1 Topical Ophthalmic Use Only
`
`For topical ophthalmic administration only.
`
`17.2 Sterility of Dropper Tip
`Patients should be advised to not touch dropper tip to any surface, as this may contaminate
`
` the contents.
`
`17.3 Concomitant Use of Contact Lenses
`Patients should be advised not to wear a contact lens if their eye is red. Patients should be
`
`advised 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.
`
`The preservative in BEPREVE, benzalkonium chloride, may be absorbed by soft contact
`
`lenses. Lenses may be reinserted after 10 minutes following administration of BEPREVE.
`
`
`©ISTA Pharmaceuticals, Inc.
`Manufactured for: ISTA Pharmaceuticals®, Inc.
`
`Irvine, CA 92618
`
`
`By: Bausch & Lomb Incorporated
`
`Tampa, FL 33637
`
`
`Under license from:
`
`Senju Pharmaceutical Co., Ltd.
`
`Osaka, Japan 541-0046
`
`
`® and ™ marks owned by ISTA Pharmaceuticals, Inc.
`U.S. Patents: 6,307,052; 6,780,877
`
`©2012 ISTA Pharmaceuticals, Inc.
`
`
`
`
`
`
`Reference ID: 3151309
`
`
`
`