Bimatoprost

1 INDICATIONS AND USAGE Bimatoprost ophthalmic solution, 0.03% is indicated to treat hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness. Bimatoprost ophthalmic solution, for topical ophthalmic use is a prostaglandin analog, indicated to treat hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.

2 DOSAGE AND ADMINISTRATION Ensure the face is clean, makeup and contact lenses are removed. Once nightly, place one drop of bimatoprost ophthalmic solution, 0.03% on the disposable sterile applicator supplied with the package and apply evenly along the skin of the upper eyelid margin at the base of the eyelashes. The upper lid margin in the area of lash growth should feel lightly moist without runoff. Blot any excess solution runoff outside the upper eyelid margin with a tissue or other absorbent cloth. Dispose of the applicator after one use. Repeat for the opposite eyelid margin using a new sterile applicator. Do not reuse applicators and do not use any other brush/applicator to apply bimatoprost ophthalmic solution 0.03%. Do not apply to the lower eyelash line [ see Warnings and Precautions (5.3, 5.4 ] and Patient Counseling Information (17)]. Additional applications of bimatoprost ophthalmic solution 0.03% will not increase the growth of eyelashes. Upon discontinuation of treatment, eyelash growth is expected to return to its pre-treatment level. Apply nightly directly to the skin of the upper eyelid margin at the base of the eyelashes using the accompanying applicators. Blot any excess solution beyond the eyelid margin. Dispose of the applicator after one use. Repeat for the opposite eyelid margin using a new sterile applicator.

3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution containing bimatoprost 0.3 mg/mL . Ophthalmic solution containing 0.3 mg/mL of bimatoprost. ( 3 )

4 CONTRAINDICATIONS Bimatoprost ophthalmic solution 0.03% is contraindicated in patients with hypersensitivity to bimatoprost or to any of the ingredients [see Adverse Reactions ( 6.2 )] . Hypersensitivity. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: • Pigmentation [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 reaction (45%) is conjunctival hyperemia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 clinical trials, the most frequent events associated with the use of bimatoprost ophthalmic solution 0.03% occurring in approximately 15% to 45% of patients, in descending order of incidence, included conjunctival hyperemia, growth of eyelashes, and ocular pruritus. Approximately 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse events occurring in approximately 3 to 10% of patients, in descending order of incidence, included ocular dryness, visual disturbance, ocular burning, foreign body sensation, eye pain, pigmentation of the periocular skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, ocular irritation, and eyelash darkening. The following ocular adverse events reported in approximately 1 to 3% of patients, in descending order of incidence, included: eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, increases in iris pigmentation, and conjunctival edema. In less than 1% of patients, intraocular inflammation was reported as iritis. Systemic adverse events reported in approximately 10% of patients were infections (primarily colds and upper respiratory tract infections). The following systemic adverse events reported in approximately 1 to 5% of patients, in descending order of incidence, included headaches, abnormal liver function tests, asthenia and hirsutism. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bimatoprost ophthalmic solution 0.03%. 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. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to bimatoprost ophthalmic solution, or a combination of these factors, include: abnormal hair growth, asthma-like symptoms, dizziness, dyspnea, eyelid edema, hypersensitivity reaction including signs and symptoms of eye allergy and allergic dermatitis, hypertension, nausea, and 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 skin discoloration (non-periocular).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of bimatoprost ophthalmic solution 0.03% administration in pregnant women. There is no increase in the risk of major birth defects or miscarriages based on bimatoprost postmarketing experience. In embryofetal development 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 following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on the area under the curve (AUC). These adverse effects were not observed at 2.6 times (mice) and 47 times (rats) the human exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC. 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 following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC. No adverse effects were observed in rat offspring at exposures estimated at 14 times the human exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC. Because animal reproductive studies are not always predictive of human response bimatoprost ophthalmic solution 0.03% should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac 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 following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac 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 following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac 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 following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac 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 following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac 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 following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC). The NOAEL for postnatal development and mating performance of the offspring wa …

12.1 Mechanism of Action Bimatoprost, a prostaglandin analog, is a synthetic structural analog of prostaglandin with ocular hypotensive activity. It selectively mimics the effects of naturally occurring substances, prostamides. Bimatoprost is believed to lower intraocular pressure (IOP) in humans by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Elevated IOP presents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.

11 DESCRIPTION Bimatoprost ophthalmic solution 0.03% is a synthetic prostamide analog with ocular hypotensive activity. Its chemical name is ( Z )-7-[(1 R ,2 R ,3 R ,5 S )-3,5-Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5- N -ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is C 25 H 37 NO 4 . Its chemical structure is: Bimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. Bimatoprost ophthalmic solution 0.03% is clear, colorless solution, practically free from particles with an osmolality of approximately 290 mOsmol/kg. Bimatoprost ophthalmic solution 0.03% contains Active: Bimatoprost 0.3 mg/mL; Preservative: benzalkonium chloride 0.05 mg/mL; Inactives: sodium chloride; disodium hydrogen phosphate, heptahydrate, citric acid monohydrate and water for injection. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.9 to 7.6. bimatoprost_stru.jpg

10 OVERDOSAGE No information is available on overdosage in humans. If overdose with bimatoprost ophthalmic solution, 0.03% occurs, treatment should be symptomatic. In oral (by gavage) mouse and rat general toxicity studies, doses up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m 2 is at least 70 times higher than the accidental dose of one bottle of bimatoprost ophthalmic solution, 0.03% for a 10 kg child.

16 HOW SUPPLIED/STORAGE AND HANDLING Bimatoprost Ophthalmic Solution, 0.01% is a sterile, clear colourless solution filled in 5 mL or 10 mL low density polyethylene white opaque bottles with low density polyethylene white opaque new nozzle and high density polyethylene turquoise cap. It is available as follows: 2.5 mL in 5 mL Containers (Filled to 1/2 Capacity): NDC 60219-2149-1 5 mL in 5 mL Containers: NDC 60219-2149-4 7.5 mL in 10 mL Containers (Filled to 3/4 Capacity): NDC 60219-2149-2 Storage: Store at 2° to 25°C (36° to 77°F). After opening, bimatoprost ophthalmic solution 0.01% can be used until the expiration date on the bottle.