BEPREVE Ophthalmic solution Ref.[9955] Active ingredients:

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.

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.

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.

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).

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.

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.

No overall differences in safety or effectiveness have been observed between elderly and younger patients.