ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reaction is conjunctival hyperemia (45%). (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Studies Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies 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 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 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 to 5% of patients, in descending order of incidence, included headaches, abnormal liver function tests, asthenia and hirsutism.. 6.2 Postmarketing Experience. The following reactions have been identified during postmarketing use of bimatoprost ophthalmic solution, 0.03% in clinical practice. Because they are reported voluntarily from population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to bimatoprost ophthalmic solution, or combination of these factors, include: abnormal hair growth, dizziness, eyelid edema, hypertension, nausea, and periorbital and lid changes associated with deepening of the eyelid sulcus.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Bimatoprost, prostaglandin analog, is 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 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.. 12.3 Pharmacokinetics. Absorption. After one drop of bimatoprost ophthalmic solution, 0.03% was administered once daily to both eyes 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 Cmax and AUC0-24hr values were similar on days and 14 at approximately 0.08 ng/mL and 0.09 ngohr/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 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.. Metabolism. Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form diverse variety of metabolites.. Elimination. 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.

DESCRIPTION SECTION.

11 DESCRIPTION. Bimatoprost ophthalmic solution, 0.03% is synthetic prostamide analog with ocular hypotensive activity. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-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 C25H37NO4. Its chemical structure is:Bimatoprost is powder, which is freely soluble in alcohol. Bimatoprost ophthalmic solution, 0.03% is clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg.Bimatoprost ophthalmic solution, 0.03% contains Active: bimatoprost 0.3 mg/mL; Inactives: benzalkonium chloride 0.05 mg/mL; disodium hydrogen phosphate heptahydrate, citric acid monohydrate, sodium chloride 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.. structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. One drop in the affected eye(s) once daily in the evening. (2). The recommended dosage is one drop in the affected eye(s) once daily in the evening. Bimatoprost ophthalmic solution, 0.03% should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect. Reduction of the intraocular pressure starts approximately hours after the first administration with maximum effect reached within approximately to 12 hours. Bimatoprost ophthalmic solution, 0.03% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Potential for Pigmentation. Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of bimatoprost ophthalmic solution, 0.03%.. 17.2 Potential for Eyelash Changes. Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with bimatoprost ophthalmic solution, 0.03%. These changes may result in disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.. 17.3 Handling the Container. Instruct patients to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.. 17.4 When to Seek Physician Advice. Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physicians advice concerning the continued use of bimatoprost ophthalmic solution, 0.03%.. 17.5 Use with Contact Lenses. Advise patients that bimatoprost ophthalmic solution, 0.03% contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of bimatoprost ophthalmic solution, 0.03% and may be reinserted 15 minutes following its administration.. 17.6 Use with Other Ophthalmic Drugs. Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications.. Marketed by:Lupin Pharmaceuticals, Inc.Baltimore, Maryland 21202United StatesManufactured by:Lupin LimitedPithampur (M.P.) 454 775IndiaMarch 2015 ID: 239313.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Bimatoprost, prostaglandin analog, is 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to mg/kg/day and mg/kg/day respectively (at least 192 and 291 times the recommended human exposure based on blood AUC levels respectively) for 104 weeks.Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests.Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (at least 103 times the recommended human exposure based on blood AUC levels).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. BIMATOPROST OPHTHALMIC SOLUTIONRx Only0.03%NDC 68180-429-012.5 mL Bottle LabelBIMATOPROST OPHTHALMIC SOLUTIONRx Only0.03%NDC 68180-429-012.5 mL Carton LabelBIMATOPROST OPHTHALMIC SOLUTIONRx Only0.03%NDC 68180-429-025 mL Bottle LabelBIMATOPROST OPHTHALMIC SOLUTIONRx Only0.03%NDC 68180-429-025 mL Carton LabelBIMATOPROST OPHTHALMIC SOLUTIONRx Only0.03%NDC 68180-429-037.5 mL Bottle LabelBIMATOPROST OPHTHALMIC SOLUTIONRx Only0.03%NDC 68180-429-037.5 mL Carton Label. 2.5 ml bottle. 2.5 ml carton. ml bottle. ml carton. 7.5 ml bottle. 7.5 ml carton.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption. After one drop of bimatoprost ophthalmic solution, 0.03% was administered once daily to both eyes 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 Cmax and AUC0-24hr values were similar on days and 14 at approximately 0.08 ng/mL and 0.09 ngohr/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 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.. Metabolism. Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form diverse variety of metabolites.. Elimination. 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.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category C. Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels.At doses at least 41 times the maximum intended human exposure based on blood AUC levels, the gestation length was reduced in the dams, the incidence of dead fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup body weights were reduced.There are no adequate and well-controlled studies of bimatoprost ophthalmic solution, 0.03% administration in pregnant women. 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 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. Pregnancy Category C. Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels.At doses at least 41 times the maximum intended human exposure based on blood AUC levels, the gestation length was reduced in the dams, the incidence of dead fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup body weights were reduced.There are no adequate and well-controlled studies of bimatoprost ophthalmic solution, 0.03% administration in pregnant women. 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.. 8.3 Nursing Mothers. It is not known whether bimatoprost ophthalmic solution, 0.03% is excreted in human milk, although in animal studies, bimatoprost has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when bimatoprost ophthalmic solution, 0.03% is administered to nursing woman.. 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 clinical differences in safety or effectiveness have been observed between elderly and other adult patients.. 8.6 Hepatic Impairment. In patients with history of liver disease or abnormal ALT, AST and/or bilirubin at baseline, bimatoprost 0.03% had no adverse effect on liver function over 48 months.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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 ophthalmic solution 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 bimatoprost ophthalmic solution, 0.03% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly [see PATIENT COUNSELING INFORMATION, (17.1)]. 5.2 Eyelash Changes. Bimatoprost ophthalmic solution, 0.03% 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. In addition, because these products may exacerbate inflammation, caution should be used in patients with active intraocular inflammation (e.g., uveitis).. 5.4 Macular Edema. Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution. Bimatoprost ophthalmic solution, 0.03% should be used with caution in aphakic patients, in pseudophakic patients with torn posterior lens capsule, or in patients with known risk factors for macular edema. 5.5 Bacterial Keratitis. There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had concurrent corneal disease or disruption of the ocular epithelial surface see PATIENT COUNSELING INFORMATION, (17.3)]. 5.6 Use with Contact Lenses. Contact lenses should be removed prior to instillation of bimatoprost ophthalmic solution, 0.03% and may be reinserted 15 minutes following its administration.