Bimatoprost

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: • Effects on Intraocular Pressure [see Warnings and Precautions ( 5.1 )] • Iris Pigmentation [see Warnings and Precautions ( 5.2 )] • Lid Pigmentation [see Warnings and Precautions ( 5.3 )] • Hair Growth Outside the Treatment Area [see Warnings and Precautions ( 5.4 )] • Intraocular Inflammation [see Warnings and Precautions ( 5.5 )] • Macular Edema [see Warnings and Precautions ( 5.6 )] • Hypersensitivity [see Contraindications ( 4 )] Most common adverse reactions (incidence approximately 3% to 4%) are eye pruritus, conjunctival hyperemia, and skin hyperpigmentation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. The following information is based on clinical trial results from a multicenter, double-masked, randomized, vehicle-controlled, parallel study including 278 adult patients for four months of treatment. The most frequently reported adverse reactions were eye pruritus, conjunctival hyperemia, skin hyperpigmentation, ocular irritation, dry eye symptoms, and periorbital erythema. These reactions occurred in less than 4% of patients. Additional adverse reactions seen in clinical trials experience include foreign body sensation, hair growth abnormal, and iris hyperpigmentation. Additional adverse reactions reported with bimatoprost ophthalmic solution (Lumigan ® ) for the reduction of intraocular pressure include, ocular dryness, visual disturbance, ocular burning, eye pain, blepharitis, cataract, superficial punctate keratitis, eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, conjunctival edema, iritis, infections (primarily colds and upper respiratory tract infections), headaches, and asthenia. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bimatoprost ophthalmic solution. 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 include: dry skin of the eyelid and/or periocular area, eye swelling, eyelid edema, hordeolum, hypersensitivity (local allergic reactions), lacrimation increased, madarosis and trichorrhexis (temporary loss of a few lashes to loss of sections of eyelashes, and temporary eyelash breakage, respectively), periorbital and lid changes associated with periorbital fat atrophy and skin tightness resulting in deepening of eyelid sulcus and eyelid ptosis, rash (including macular and erythematous), skin discoloration (periorbital), skin exfoliation of the eyelid and/or periorbital area, trichiasis, and vision blurred.

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

11 DESCRIPTION Bimatoprost ophthalmic solution, 0.03% is a synthetic prostaglandin analog. Its chemical name is ( Z )-7-[(1 R ,2 R ,3 R ,5 S )-3,5-Dihydroxy-2-[(1 E ,3 S )-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]- N -ethyl-5-heptenamide, 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 is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg. Contains: Active: Bimatoprost 0.3 mg/mL; Preservative: Benzalkonium chloride 0.05 mg/mL; Inactives: Citric acid, purified water, sodium chloride and sodium phosphate dibasic. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8 to 7.8. chemicalstructure

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. 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 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. ( 2 )

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 is a prostaglandin analog, indicated to treat hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness. ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bimatoprost is a structural prostaglandin analog. Although the precise mechanism of action is unknown, the growth of eyelashes is believed to occur by increasing the percent of hairs in, and the duration of the anagen or growth phase. 12.3 Pharmacokinetics Absorption After one drop of bimatoprost ophthalmic solution 0.03% was administered once daily into both eyes (cornea and/or conjunctival sac) of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean C max and AUC 0-24hr values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng.hr/mL, respectively, indicating that steady state was reached during the first week of ocular dosing. There was no significant systemic drug accumulation over time. Distribution Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost remains unbound in human plasma. Elimination Metabolism Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation. Bimatoprost then undergoes oxidation, N-deethylation, and glucuronidation to form a diverse variety of metabolites. Excretion Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/kg) to six healthy subjects, the maximum blood concentration of unchanged drug was 12.2 ng/mL and decreased rapidly with an elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1.5 L/hr/kg. Up to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces.

12.1 Mechanism of Action Bimatoprost is a structural prostaglandin analog. Although the precise mechanism of action is unknown, the growth of eyelashes is believed to occur by increasing the percent of hairs in, and the duration of the anagen or growth phase.

12.3 Pharmacokinetics Absorption After one drop of bimatoprost ophthalmic solution 0.03% was administered once daily into both eyes (cornea and/or conjunctival sac) of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean C max and AUC 0-24hr values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng.hr/mL, respectively, indicating that steady state was reached during the first week of ocular dosing. There was no significant systemic drug accumulation over time. Distribution Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost remains unbound in human plasma. Elimination Metabolism Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation. Bimatoprost then undergoes oxidation, N-deethylation, and glucuronidation to form a diverse variety of metabolites. Excretion Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/kg) to six healthy subjects, the maximum blood concentration of unchanged drug was 12.2 ng/mL and decreased rapidly with an elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1.5 L/hr/kg. Up to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces.

20230504

19

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

Bimatoprost Bimatoprost BIMATOPROST BIMATOPROST BENZALKONIUM CHLORIDE CITRIC ACID MONOHYDRATE HYDROCHLORIC ACID SODIUM CHLORIDE SODIUM HYDROXIDE SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage for 104 weeks at doses up to 2 mg/kg/day and 1 mg/kg/day, respectively (192 and 291 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily based on blood AUC levels). Mutagenesis Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests. Impairment of Fertility Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (103 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily based on blood AUC levels).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage for 104 weeks at doses up to 2 mg/kg/day and 1 mg/kg/day, respectively (192 and 291 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily based on blood AUC levels). Mutagenesis Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests. Impairment of Fertility Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (103 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily based on blood AUC levels).

ANDA202719

Bimatoprost

Bimatoprost

0781-6206

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

Bimatoprost Ophthalmic Solution 0.03%, Carton NDC 0781-6206-93 Bimatoprost Ophthalmic Solution 0.03% Rx Only FOR TOPICAL APPLICATION TO THE UPPER EYE LID Sterile 3 mL SANDOZ carton

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Nightly Application Inform patients that bimatoprost ophthalmic solution should be applied every night using only the accompanying sterile applicators. They should start by ensuring their face is clean, all makeup is removed, and their contact lenses removed (if applicable). Then, carefully place one drop of bimatoprost ophthalmic solution on the disposable sterile applicator and brush cautiously along the skin of the upper eyelid margin at the base of the eyelashes. If any bimatoprost ophthalmic solution gets into the eye proper, it will not cause harm. The eye should not be rinsed. Additional applications of bimatoprost ophthalmic solution will not increase the growth of eyelashes. Inform patients not to apply to the lower eyelash line. Any excess solution outside the upper eyelid margin should be blotted with a tissue or other absorbent material. The onset of effect is gradual but is not significant in the majority of patients until 2 months. Counsel patients that the effect is not permanent and can be expected to gradually return to the original level upon discontinuation of treatment with bimatoprost ophthalmic solution. Handling the Bottle and Applicator Instruct patients that the bimatoprost ophthalmic solution bottle must be maintained intact and to avoid allowing the tip of the bottle or applicator to contact surrounding structures, fingers, or any other unintended surface in order to avoid contamination of the bottle or applicator by common bacteria known to cause ocular infections. Instruct patients to only use the applicator supplied with the product once and then discard since reuse could result in using a contaminated applicator. Serious infections may result from using contaminated solutions or applicators. Potential for Intraocular Pressure Effects Bimatoprost ophthalmic solution may lower intraocular pressure although not to a level that will cause clinical harm. In patients using Lumigan ® or other prostaglandin analogs for the treatment of elevated intraocular pressure, the concomitant use of bimatoprost ophthalmic solution may interfere with the desired reduction in IOP. Patients using prostaglandin analogs for IOP reduction should only use bimatoprost ophthalmic solution after consulting with their physician. Potential for Eyelid Skin Darkening Inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of bimatoprost ophthalmic solution. Potential for Iris Darkening Advise patients about the potential for increased brown iris pigmentation which is likely to be permanent. Increased iris pigmentation has occurred when bimatoprost solution was administered. Potential for Unexpected Hair Growth or Eyelash Changes Inform patients of the possibility of hair growth occurring outside of the target treatment area if bimatoprost ophthalmic solution repeatedly touches the same area of skin outside the treatment area. They should also be informed of the possibility of disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are likely reversible upon discontinuation of treatment. When to Seek Physician Advice Advise patients that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden decrease in visual acuity, have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of bimatoprost ophthalmic solution. Patients on IOP-lowering medications should not use bimatoprost ophthalmic solution without prior consultation with their physician. Contact Lens Use Advise patients that bimatoprost ophthalmic solution contains benzalkonium chloride, which may be absorbed by and cause discoloration of soft contact lenses. Contact lenses should be removed prior to application of bimatoprost ophthalmic solution and may be reinserted 15 minutes following its administration. Manufactured by Alcon Laboratories, Inc. Fort Worth, Texas 76134 for Sandoz Inc. Princeton, NJ 08540

14 CLINICAL STUDIES Bimatoprost ophthalmic solution was evaluated for its effect on overall eyelash prominence in a multicenter, double-masked, randomized, vehicle-controlled, parallel study including 278 adult patients for four months of treatment. The primary efficacy endpoint in this study was an increase in overall eyelash prominence as measured by at least a 1-grade increase on the 4-point Global Eyelash Assessment (GEA) scale, from baseline to the end of the treatment period (week 16). Bimatoprost ophthalmic solution was more effective than vehicle as measured by the GEA score, with statistically significant differences seen at 8-week, 12-week, and 16-week (primary endpoint) treatment durations. Table 2. Number (%) of subjects with at least a 1-grade increase from baseline in Global Eyelash Assessment (Primary Efficacy Endpoint - Week 16) Week Bimatoprost ophthalmic solution N=137 N(%) Vehicle N=141 N(%) 1 7 (5%) 3 (2%) 4 20 (15%) 11 (8%) 8 69 (50%) 21 (15%) 12 95 (69%) 28 (20%) 16 107 (78%) 26 (18%) 20 103 (79%) 27 (21%) In this study, patients were also evaluated for the effect of bimatoprost ophthalmic solution on the length, thickness and darkness of their eyelashes. Improvements from baseline in eyelash growth as measured by digital image analysis assessing eyelash length, fullness/thickness, and darkness were statistically significantly more pronounced in the bimatoprost group at weeks 8, 12, and 16. Table 3 Efficacy endpoint at Week 16 (Mean Change from Baseline) Bimatoprost ophthalmic solution Vehicle Eyelash growth (length) (mm; % increase) N=137 1.4; 25% N=141 0.1; 2% Fullness/thickness (mm 2 ; % increase) N=136 0.7; 106% N=140 0.1; 12% Eyelash darkness (intensity a negative value is representative of eyelash darkening ; % increase in darkness) N=135 -20.2; -18% N=138 -3.6; -3% After the 16-week treatment period, a 4-week post-treatment period followed during which the effects of bimatoprost started to return toward baseline. The effect on eyelash growth is expected to abate following longer term discontinuation.

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

8.4 Pediatric Use Use of bimatoprost ophthalmic solution was evaluated in a sixteen-week double-masked, randomized, vehicle-controlled study conducted in pediatric patients who were post-chemotherapy or had alopecia areata, and adolescents who had hypotrichosis with no associated medical condition. No new safety issues were observed. The results of the Global Eyelash Assessment (GEA) are provided in Table 1 . Table 1. Number (%) of subjects with at least a 1-grade increase from baseline at month 4 in Global Eyelash Assessment Age Range (years) Bimatoprost Ophthalmic Solution Vehicle Difference (95% CI) Adolescents with hypotrichosis (N=40) 15 - 17 19/26 (73%) 1/14 (7%) 66% (44%, 88%) Post Chemotherapy Pediatric Patients (N=16) 5 - 17 11/13 (85%) 3/3 (100%) -15% (-35%, 4%) Alopecia Areata Pediatric Patients (N=15) 5 - 17 4/9 (44%) 2/6 (33%) 11% (-39%, 61%)

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 was 0.1 mg/kg/day (estimated at 14 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).

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 was 0.1 mg/kg/day (estimated at 14 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). 8.2 Lactation Risk Summary It is not known whether topical ocular treatment with bimatoprost ophthalmic solution 0.03% 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) 324 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 bimatoprost ophthalmic solution 0.03% and any potential adverse effects on the breastfed child from bimatoprost ophthalmic solution 0.03%. 8.4 Pediatric Use Use of bimatoprost ophthalmic solution was evaluated in a sixteen-week double-masked, randomized, vehicle-controlled study conducted in pediatric patients who were post-chemotherapy or had alopecia areata, and adolescents who had hypotrichosis with no associated medical condition. No new safety issues were observed. The results of the Global Eyelash Assessment (GEA) are provided in Table 1 . Table 1. Number (%) of subjects with at least a 1-grade increase from baseline at month 4 in Global Eyelash Assessment Age Range (years) Bimatoprost Ophthalmic Solution Vehicle Difference (95% CI) Adolescents with hypotrichosis (N=40) 15 - 17 19/26 (73%) 1/14 (7%) 66% (44%, 88%) Post Chemotherapy Pediatric Patients (N=16) 5 - 17 11/13 (85%) 3/3 (100%) -15% (-35%, 4%) Alopecia Areata Pediatric Patients (N=15) 5 - 17 4/9 (44%) 2/6 (33%) 11% (-39%, 61%) 8.5 Geriatric Use No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Bimatoprost ophthalmic solution, 0.03% is supplied sterile in opaque white low-density polyethylene dispenser bottles and tips with turquoise polystyrene caps accompanied by sterile, disposable applicators: 3 mL in a 4 mL bottle with 70 applicators - NDC 0781-6206-93 5 mL in a 8 mL bottle with 140 applicators - NDC 0781-6206-75 Storage: Store at 2° to 25°C (36° to 77°F).