7
`
`
`
`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
`
`------------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)
`
`
`
`-----------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)
`
`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: 08/2009
`
`
`_____________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION:
`11
`DESCRIPTION
`
`
`CONTENTS*
`CLINICAL PHARMACOLOGY
`12
`
`
`
`
`12.1 Mechanism of Action
`1
`INDICATIONS AND USAGE
`
` Pharmacokinetics
`12.3
`DOSAGE AND ADMINISTRATION
`2
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`NONCLINICAL TOXICOLOGY
`13
`
`
`
`Carcinogenesis, Mutagenesis and Impairment
`13.1
`4
`CONTRAINDICATIONS
`of Fertility
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Contamination of Tip and Solution
`CLINICAL STUDIES
`
`
`
`5.2 Contact Lens Use
`HOW SUPPLIED/STORAGE AND
`
`
`
`5.3 Topical Ophthalmic Use Only
`HANDLING
`
`6
`ADVERSE REACTIONS
`PATIENT COUNSELING INFORMATION
`
`
`
`Topical Ophthalmic Use Only
`8
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`Sterility of Dropper Tip
`
`
`
`
`8.3 Nursing Mothers
`Concomitant Use of Contact Lenses
`
`8.4
`Pediatric Use
`
`8.5 Geriatric Use
`
`
`17
`17.1
`
`17.2
`17.3
`
`*Sections or subsections omitted from the full
`prescribing information are not listed
`____________________________________________________________________________________________
`
`14
`
`16
`
`
`.
`
`
`
`
`
`
`

`

`8
`
`
`
`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
`None.
`
`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
`
`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.
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`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 radiolabeled 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 µg 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
`
`

`

`9
`
`
`
`
`8.5
`
`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.
`
` Geriatric Use
`
`
`No overall difference in safety or effectiveness
`has 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:
`
`
`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 besilate15 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
`
`concentration for the 1% and 1.5% strengths
`were 5.1 ± 2.5 ng/mL and 7.3 ± 1.9 ng/mL,
`
`respectively. Plasma concentration at 24 hours
`post-instillation were the below quantifiable
`limit (2ng/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 substrate 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).
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis and
`
`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. Theses dose levels represent systemic
`
`exposures approximating 350 and 200 times
`that achieved with human topical ocular use.
`The no observable adverse effect level for
`
`

`

`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 541-004
`
`
`® and ™ marks owned by ISTA
`
`Pharmaceuticals, Inc.
`U.S. Patents: 6,307,052; 6,780,877
`
`
`
`10
`
`
`
`
`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.
`
`
`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 sizes:
`
`
`2.5 mL (NDC 67425-007-12)
`
`5 mL (NDC 67425-007-50)
`
`10 mL (NDC 67425-007-75)
`
`
`STORAGE
`
`
`Store at 15º – 25ºC (59º – 77ºF).
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`17.1 Topical Ophthalmic Use Only
`
`For topical ophthalmic administration only.
`
`
`
`
`
`
`
`