Bepreve (Page 2 of 2)

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

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 bottle with a sterile linear low density polyethylene controlled dropper tip and a white polypropylene cap in the following sizes:

NDC 24208-629-02 5 mL Bottle
NDC 24208-629-01 10 mL Bottle

Storage:

Store at 15° to 25°C (59° to 77°F).

17 PATIENT COUNSELING INFORMATION

Sterility of Dropper Tip
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
Bausch Health US, LLC
Bridgewater, NJ 08807 USA

Manufactured by:
Bausch & Lomb Incorporated
Tampa, FL 33637 USA
Under license from:
Senju Pharmaceutical Co., Ltd.
Osaka, Japan 541-0046
U.S. Patent Numbers: 8,784,789 and 8,877,168


BEPREVE is a trademark of Bausch & Lomb Incorporated or its affiliates.
© 2019 Bausch & Lomb Incorporated or its affiliates

9291103 (folded)
9291003 (flat)

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 24208-629-02

BEPREVE®

(bepotastine besilate
ophthalmic solution) 1.5%

Sterile 5 mL

Rx only FOR TOPICAL OPHTHALMIC USE

BAUSCH + LOMB

CARTON 5
(click image for full-size original)

NDC 24208-629-01

BEPREVE®

(bepotastine besilate
ophthalmic solution) 1.5%

Sterile 10 mL

Rx only FOR TOPICAL OPHTHALMIC USE

BAUSCH + LOMB

CARTON 10
(click image for full-size original)
BEPREVE bepotastine besilate solution/ drops
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:24208-629
Route of Administration OPHTHALMIC DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
BEPOTASTINE BESILATE (BEPOTASTINE) BEPOTASTINE BESILATE 15 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
BENZALKONIUM CHLORIDE 0.05 mg in 1 mL
SODIUM PHOSPHATE, MONOBASIC, DIHYDRATE
SODIUM CHLORIDE
SODIUM HYDROXIDE
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:24208-629-02 1 BOTTLE, DROPPER in 1 CARTON contains a BOTTLE, DROPPER
1 5 mL in 1 BOTTLE, DROPPER This package is contained within the CARTON (24208-629-02)
2 NDC:24208-629-01 1 BOTTLE, DROPPER in 1 CARTON contains a BOTTLE, DROPPER
2 10 mL in 1 BOTTLE, DROPPER This package is contained within the CARTON (24208-629-01)
3 NDC:24208-629-03 1 BOTTLE, DROPPER in 1 CARTON contains a BOTTLE, DROPPER
3 1 mL in 1 BOTTLE, DROPPER This package is contained within the CARTON (24208-629-03)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA022288 09/08/2009
Labeler — Bausch & Lomb Incorporated (196603781)
Establishment
Name Address ID/FEI Operations
Bausch & Lomb Incorporated 079587625 MANUFACTURE (24208-629)

Revised: 09/2019 Bausch & Lomb Incorporated

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