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-[1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is C₃₅H₂₇NO₄ . 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.

Contains: Active: bimatoprost 0.3 mg/mL; Preservative: Benzalkonium chloride 0.05 mg/mL; 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.

LUMIGAN® (bimatoprost ophthalmic solution) 0.03% is indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension.

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.

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
7.5 mL fill in 10 mL container - NDC 0023-9187-07

Storage: LUMIGAN® should be stored in the original container at 2º to 25ºC (36º to 77ºF).

Revised September 2006. Allergan, Inc. Irvine, CA 92612. FDA Rev date: 6/22/2006

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 punctate 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.

No information provided.

LUMIGAN® (bimatoprost ophthalmic solution) 0.03% 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, and growth of eyelashes. Pigmentation is expected to increase as long as LUMIGAN® is administered. After discontinuation of LUMIGAN® 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 effects of increased pigmentation beyond 5 years are not known.

General: LUMIGAN® (bimatoprost ophthalmic solution) 0.03% may gradually increase the pigmentation of the iris. The eye color change is due to increased melanin content in the stromal melanocytes of the iris rather than to an increase in the number of melanocytes. This change may not be noticeable for several months to years (see WARNINGS). 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 LUMIGAN® can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

During clinical trials, the increase in brown iris pigment has not been shown to progress further upon discontinuation of treatment, but the resultant color change may be permanent.

Eyelid skin darkening, which may be reversible upon discontinuation of the treatment has been reported in association with the use of LUMIGAN®.

LUMIGAN® 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.

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® has not been evaluated for the treatment of angle closure, inflammatory or neovascular glaucoma.

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 PRECAUTIONS, Information for Patients).

Contact lenses should be removed prior to instillation of LUMIGAN® and may be reinserted 15 minutes following its administration (see PRECAUTIONS, Information for Patients).

Carcinogenesis, Mutagenesis, Impairment of fertility: Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1mg/kg/day respectively (approximately 192 times 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 (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® 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® 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.

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/m² is at least 70 times higher than the accidental dose of one bottle of LUMIGAN® for a 10 kg child.

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

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 Cmax 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.

Results of dosing for up to five years with products in this drug class showed that the onset of noticeable increased iris pigmentation occurred within the first year of treatment for the majority of the patients who developed noticeable increased iris pigmentation. Patients continued to show signs of increasing iris pigmentation throughout the five years of the study. Observation of increased iris pigmentation did not affect the incidence, nature or severity of adverse events (other than increased iris pigmentation) recorded in the study. IOP reduction was similar regardless of the development of increased iris pigmentation during the study.

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 48 months.

(see WARNINGS and PRECAUTIONS): Patients should be advised about the potential for increased brown pigmentation of the iris, which may be permanent. Patients should also be informed about the possibility of eyelid skin darkening, which may be reversible after discontinuation of LUMIGAN®.

Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye during treatment with LUMIGAN®. These changes may result in a 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.

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.

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

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

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

BIMATOPROST SOLUTION - OPHTHALMIC

(bi-MAT-oh-prost)

COMMON BRAND NAME(S): Lumigan

USES: Bimatoprost is used to treat high pressure inside the eye due to glaucoma (open-angle type) or other eye diseases (e.g., ocular hypertension). Lowering high pressure inside the eye can help prevent blindness. This medication works by regulating the flow of fluid within the eye to maintain a normal pressure.

Bimatoprost is used after other medicines either caused very bothersome side effects or did not fully work to lower the pressure in the eye.

HOW TO USE: Apply this medication in the affected eye(s), usually once a day in the evening, or as directed by your doctor. Do not use bimatoprost more often because it will not work as well.

To apply eye drops, wash your hands first. To avoid contamination, do not touch the dropper tip or let it touch your eye or any other surface.

Bimatoprost contains a preservative that may stain contact lenses. If you are wearing contact lenses, remove them before using your eye drops. Wait at least 15 minutes after each dose before putting your lenses back in.

Tilt your head back, look upward, and pull down the lower eyelid to make a pouch. Hold the dropper directly over your eye and place one drop into the pouch. Look downward and gently close your eyes for 1 to 2 minutes. Place one finger at the corner of your eye (near the nose) and apply gentle pressure. This will prevent the medication from draining out. Try not to blink and do not rub your eye. Repeat these steps for your other eye if so directed.

Do not rinse the dropper. Replace the dropper cap after each use, and keep the cap tightly closed.

If you are using another kind of eye medication (e.g., drops or ointments), wait at least 5 minutes before applying other medications. Use eye drops before eye ointments to allow the eye drops to enter the eye.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day. It is important to continue using bimatoprost even if you feel well. Most people with glaucoma or high pressure in the eye do not have symptoms.

SIDE EFFECTS: Burning/stinging/irritation/redness of the eye, feeling as if something is in your eye, dry eyes, watering eyes, and increased sensitivity to light may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

This medication may slowly (over months to years) cause brown discoloration of the colored portion of the eye (iris). If you are using bimatoprost in only one eye, only that iris may change color. An increase in eyelash number/length/thickness and darkening of the eyelashes/eyelids may also occur in the treated eye. These changes may be permanent, but the long-term effects are uncertain. Notify your doctor if this occurs, and schedule regular eye exams to monitor it.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: vision changes, eye pain/swelling, swelling/redness of the eyelids.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using bimatoprost, tell your doctor or pharmacist if you are allergic to it; or to similar drugs (e.g., latanoprost, travoprost); or to the preservative benzalkonium chloride; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: eye problems (e.g., macular edema, iritis, uveitis, lens extraction/aphakia).

If you develop an eye infection or injury, or have eye surgery, check with your doctor about the continued use of your current bottle of bimatoprost. You may be advised to start using a new bottle.

This drug may cause temporary unstable vision. Use caution engaging in activities requiring alertness and clear vision such as driving or using machinery.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. This medicine may be harmful if swallowed.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., eye exams) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store between 36-77 degrees F (2-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.