Bimatoprost

ZOLYMBUS™ is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. ZOLYMBUS™ is a prostaglandin analog indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Ophthalmic gel: 0.01% bimatoprost as a colorless, opalescent gel in a single-dose container. Ophthalmic gel: 0.01% bimatoprost in a single-dose container.

ZOLYMBUS is contraindicated in patients with hypersensitivity to bimatoprost or to any of the ingredients [see Adverse Reactions (6.2) ] . Hypersensitivity.

Pigmentation : Pigmentation of the iris, periorbital tissue (eyelid) and eyelashes can occur. Iris pigmentation is likely to be permanent. ( 5.1 ) Eyelash Changes : Gradual change to eyelashes including increased length, thickness and number of lashes. Usually, reversible. ( 5.2 )

5.1 Pigmentation Bimatoprost has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as bimatoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of bimatoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known. Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with ZOLYMBUS can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

5.2 Eyelash Changes ZOLYMBUS may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment.

5.3 Intraocular Inflammation Prostaglandin analogs, including bimatoprost, have been reported to cause intraocular inflammation. ZOLYMBUS should be used with caution in patients with active intraocular inflammation (e.g., iritis/uveitis) because inflammation may be exacerbated.

5.4 Macular Edema Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic products. ZOLYMBUS should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

5.5 Contact Lens Use Contact lenses should be removed prior to the administration of ZOLYMBUS and may be reinserted 15 minutes after administration.

The following adverse reactions are described elsewhere in the labeling: Pigmentation including blepharal pigmentation and iris hyperpigmentation [see Warnings and Precautions (5.1) ] Eyelash Changes [see Warnings and Precautions (5.2) ] Intraocular Inflammation [see Warnings and Precautions (5.3) ] Macular Edema [see Warnings and Precautions (5.4) ] Hypersensitivity [see Contraindications (4) ] Most common adverse reactions (≥10%) are conjunctival hyperemia (14%) and eye irritation (11%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Thea Pharma Inc. at 1-833-838-4028 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 practice. In the two clinical trials conducted with ZOLYMBUS (bimatoprost ophthalmic gel) 0.01% comparing it to preserved bimatoprost ophthalmic solution 0.01%, the most frequently reported ocular adverse reactions were conjunctival hyperemia (14%), eye irritation (11%), eye pruritus (9%) and foreign body sensation in eyes (8%). Other adverse drug reactions (reported in 1% to 6% of patients) with ZOLYMBUS in the studies included dry eye, abnormal sensation in eye, lacrimation increased, eye pain, and vision blurred.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topical bimatoprost products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to bimatoprost, or a combination of these factors include: asthma-like symptoms, dizziness, dry eye, dyspnea, eye discharge, eye edema, foreign body sensation, headache, hypersensitivity including signs and symptoms of eye allergy and allergic dermatitis, hypertension, lacrimation increased, periorbital and lid changes associated with periorbital fat atrophy leading to skin tightness, deepening of the eyelid sulcus, eyelid ptosis, enophthalmos, and eyelid retraction; and photophobia.

Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. ( 8.4 )

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of ZOLYMBUS (bimatoprost ophthalmic gel) 0.01% administration in pregnant women. There is no increase in the risk of major birth defects or miscarriages based on bimatoprost post-marketing experience. In embryofetal developmental studies, administration of bimatoprost to pregnant mice and rats during organogenesis, resulted in abortion and early delivery at oral doses at least 33 times (mice) or 94 times (rats) the human exposure to bimatoprost solution 0.03% dosed bilaterally once daily (based on blood area under the curve [AUC] levels). These adverse effects were not observed at 2.6 times (mice) and 47 times (rats) the human exposure to bimatoprost 0.03% dosed bilaterally once daily (based on blood AUC levels). In pre/postnatal development studies, administration of bimatoprost to pregnant rats from organogenesis to the end of lactation resulted in reduced gestation length and fetal body weight, and increased fetal and pup mortality at oral doses at least 41 times the human systemic exposure to bimatoprost solution 0.03% dosed bilaterally once daily (based on blood AUC levels). No adverse effects were observed in rat offspring at exposures estimated at 14 times the human exposure to bimatoprost solution 0.03% dosed bilaterally once daily (based on blood AUC levels). Because animal reproductive studies are not always predictive of human response ZOLYMBUS should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 an embryofetal development rat study, abortion was observed in pregnant rats administered bimatoprost orally during organogenesis at 0.6 mg/kg/day (94 times the human systemic exposure to bimatoprost solution 0.03% dosed bilaterally once daily, based on AUC). The No Observed Adverse Effect Level (NOAEL) for abortion was 0.3 mg/kg/day (estimated at 47 times the human systemic exposure to bimatoprost solution 0.03% dosed bilaterally once daily, based on AUC). No abnormalities were observed in rat fetuses at doses up to 0.6 mg/kg/day. In an embryofetal development mouse study, abortion and early delivery were observed in pregnant mice administered bimatoprost orally during organogenesis at doses greater than or equal to 0.3 mg/kg/day (33 times the human systemic exposure to bimatoprost solution 0.03% dosed bilaterally once daily, based on AUC). The NOAEL for abortion and early delivery was 0.1 mg/kg/day (2.6 times the human systemic exposure to bimatoprost solution 0.03% dosed bilaterally once daily, based on AUC). No abnormalities were observed in mouse fetuses at doses up to 0.6 mg/kg/day (72 times the human systemic exposure to bimatoprost solution 0.03% dosed bilaterally once daily based on AUC). In a pre/postnatal development study, treatment of pregnant rats with bimatoprost orally from gestation day 7 to lactation day 20 resulted in reduced gestation length, increased late resorptions, fetal deaths, and postnatal pup mortality, and reduced pup body weight at doses greater than or equal to 0.3 mg/kg/day. These effects were observed at exposures at least 41 times the human systemic exposure to bimatoprost solution 0.03% dosed bilaterally once daily, based on AUC. The NOAEL for postnatal development and mating performance of the offspring was 0.1 mg/kg/day (estimated at 14 times the human systemic exposure to bimatoprost solution 0.03% dosed bilaterally once daily, based on AUC).

8.2 Lactation Risk Summary It is not known whether topical ocular treatment with ZOLYMBUS could result in sufficient systemic absorption to produce detectable quantities in human milk. In animal studies, bimatoprost has been shown to be present in breast milk of lactating rats at an intravenous dose (i.e., 1 mg/kg) 970 times the recommended human ophthalmic dose (on a mg/m 2 basis), however, no animal data is available at clinically relevant doses. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOLYMBUS and any potential adverse effects on the breastfed child from ZOLYMBUS.

8.4 Pediatric Use Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use.

8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and other adult patients.