DESCRIPTION

LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% is a synthetic prostamide analog with ocular hypotensive activity. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[1 E ,3 S )-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. LUMIGAN ^® is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg.

Each mL contains: Active: bimatoprost 0.3 mg; Preservative: Benzalkonium chloride 0.05 mg; Inactives: Sodium chloride; sodium phosphate, dibasic; citric acid; and purified water. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Bimatoprost is a prostamide, 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.

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 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.

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 a diverse variety of metabolites.

Elimination:    Following an intravenous dose of radiolabeled bimatoprost (3.12 µg/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.

Clinical Studies:

In clinical studies of patients with open angle glaucoma or ocular hypertension with a mean baseline IOP of 26 mmHg, the IOP-lowering effect of LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% once daily (in the evening) was 7-8 mmHg.

In patients with a history of liver disease or abnormal ALT, AST and/or bilirubin at baseline, LUMIGAN ^® had no adverse effect on liver function over 24 months.

INDICATIONS AND USAGE

LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% is indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another intraocular pressure lowering medication.

CONTRAINDICATIONS

LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% is contraindicated in patients with hypersensitivity to bimatoprost or any other ingredient in this product.

WARNINGS

LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% has been reported to cause changes to pigmented tissues. These reports include increased pigmentation and growth of eyelashes and increased pigmentation of the iris and periorbital tissue (eyelid). These changes may be permanent.

LUMIGAN ^® (bimatoprost ophthalmic solution) may gradually change eye color, increasing the amount of brown pigment in the iris by increasing the number of melanosomes (pigment granules) in melanocytes. The long-term effects on the melanocytes and the consequences of potential injury to the melanocytes and/or deposition of pigment granules to other areas of the eye are currently unknown. The change in iris color occurs slowly and may not be noticeable for several months to years. Patients should be informed of the possibility of iris color change.

Eyelid skin darkening has also been reported in association with the use of LUMIGAN ^® .

LUMIGAN ^® (bimatoprost ophthalmic solution) may gradually change eyelashes; these changes include increased length, thickness, pigmentation, and number of lashes.

Patients who are expected to receive treatment in only one eye should be informed about the potential for increased brown pigmentation of the iris, periorbital tissue, and eyelashes in the treated eye and thus, heterochromia between the eyes. They should also be advised of the potential for a disparity between the eyes in length, thickness, and/or number of eyelashes.

PRECAUTIONS

General:    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 a concurrent corneal disease or a disruption of the ocular epithelial surface (see Information for Patients ).

Patients may slowly develop increased brown pigmentation of the iris. This change may not be noticeable for several months to years (see Warnings ). Typically the brown pigmentation around the pupil is expected to spread concentrically towards the periphery in affected eyes, but the entire iris or parts of it may also become more brownish. Until more information about increased brown pigmentation is available, patients should be examined regularly and, depending on the clinical situation, treatment may be stopped if increased pigmentation ensues. The increase in brown iris pigment is not expected to progress further upon discontinuation of treatment, but the resultant color change may be permanent. Neither nevi nor freckles of the iris are expected to be affected by treatment.

LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% should be used with caution in patients with active intraocular inflammation (e.g., uveitis).

Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution. LUMIGAN ^® 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.

LUMIGAN ^® (bimatoprost ophthalmic solution) has not been evaluated for the treatment of angle closure, inflammatory or neovascular glaucoma.

LUMIGAN ^® should not be administered while wearing contact lenses.

Information for Patients:    Patients should be informed that LUMIGAN ^® (bimatoprost ophthalmic solution) has been reported to cause increased growth and darkening of eyelashes and darkening of the skin around the eye in some patients. These changes may be permanent.

Some patients may slowly develop darkening of the iris, which may be permanent.

When only one eye is treated, patients should be informed of the potential for a cosmetic difference between the eyes in eyelash length, darkness or thickness, and/or color changes of the eyelid skin or iris.

Patients should be instructed 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.

Patients should also be advised that if they develop an intercurrent ocular condition (e.g., trauma or infection) or have ocular surgery, they should immediately seek their physician's advice concerning the continued use of the multidose container.

Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice.

Contact lenses should be removed prior to instillation of LUMIGAN ^® and may be reinserted 15 minutes following its administration. Patients should be advised that LUMIGAN ^® (bimatoprost ophthalmic solution) contains benzalkonium chloride, which may be absorbed by soft contact lenses.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications.

Carcinogenesis, Mutagenesis, Impairment of fertility: Carcinogenicity studies were not performed with bimatoprost.

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 (approximately 103 times the recommended human exposure based on blood AUC levels).

Pregnancy: Teratogenic Effects: Pregnancy Category C.    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 intended human exposure based on blood AUC levels.

At doses 41 times the 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 LUMIGAN ^® administration in pregnant women. Because animal reproductive studies are not always predictive of human response, LUMIGAN ^® (bimatoprost ophthalmic solution) should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers:    It is not known whether LUMIGAN ^® 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 LUMIGAN ^® (bimatoprost ophthalmic solution) is administered to a nursing woman.

Pediatric Use:    Safety and effectiveness in pediatric patients have not been established.

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

ADVERSE REACTIONS

In clinical trials, the most frequent events associated with the use of LUMIGAN ^® (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 punctuate keratitis, eyelid 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.

OVERDOSAGE

No information is available on overdosage in humans. If overdose with LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% occurs, treatment should be symptomatic.

In oral (by gavage) mouse and rat 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 LUMIGAN ^® for a 10 kg child.

DOSAGE AND ADMINISTRATION

The recommended dosage is one drop in the affected eye(s) once daily in the evening. The dosage of LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% should not exceed once daily since it has been shown that more frequent administration may decrease the intraocular pressure lowering effect.

Reduction of the intraocular pressure starts approximately 4 hours after the first administration with maximum effect reached within approximately 8 to 12 hours.

LUMIGAN ^® 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.

HOW SUPPLIED

LUMIGAN ^® (bimatoprost ophthalmic solution) 0.03% is supplied sterile in opaque white low density polyethylene ophthalmic dispenser bottles and tips with turquoise polystyrene caps in the following sizes: 2.5 mL fill in 5 mL container - NDC 0023-9187-03; 5 mL fill in 10 mL container - NDC 0023-9187-05; or 7.5 mL fill in 10 mL container - NDC 0023-9187-07.

Rx only

Storage: LUMIGAN ^® should be stored in the original container at 2° to 25°C (36° to 77°F).

^® Marks owned by Allergan, Inc. US Pat. No. 5,688,819 and 6,403,649.

Revised August 2004

©2004 Allergan, Inc.

Irvine, CA 92612

Allergan