Latanoprost is a prostaglandin F_2α analogue. Its chemical name is isopropyl-(Z)-7 [(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5- heptenoate. Its molecular formula is C₂₆H₄₀O₅ and its chemical structure is:

Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol and octanol. It is practically insoluble in water.

XALATAN Sterile Ophthalmic Solution (latanoprost ophthalmic solution) is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Each mL of XALATAN contains 50 micrograms of latanoprost. Benzalkonium chloride, 0.02% is added as a preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water for injection. One drop contains approximately 1.5 µg of latanoprost.

Last updated on RxList: 4/11/2008

XALATAN Sterile Ophthalmic Solution is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

The recommended dosage is one drop (1.5 µg) in the affected eye(s) once daily in the evening. If one dose is missed, treatment should continue with the next dose as normal.

The dosage of XALATAN Sterile Ophthalmic Solution should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including XALATAN Sterile Ophthalmic Solution is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the intraocular pressure lowering effect or cause paradoxical elevations in IOP.

Reduction of the intraocular pressure starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours.

XALATAN 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.

XALATAN Sterile Ophthalmic Solution is a clear, isotonic, buffered, preserved colorless solution of latanoprost 0.005% (50 µg/mL). It is supplied as a 2.5 mL solution in a 5 mL clear low density polyethylene bottle with a clear low density polyethylene dropper tip, a turquoise high density polyethylene screw cap, and a tamper-evident clear low density polyethylene overcap.

2.5 mL fill, 0.005% (50 µg/mL)

Multi-Pack of 3 bottles..............................NDC 0013-8303-01

Storage: Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 46°F). Once a bottle is opened for use, it may be stored at room temperature up to 25°C (77°F) for 6 weeks.

Distributed by: Pharmacia & Upjohn Company, Division of Pfizer Inc, .NY, NY 10017. Manufactured by: Cardinal Health Woodstock, IL 60098, USA. Revised November 2006. FDA Rev date:

Last updated on RxList: 4/11/2008

Adverse events referred to in other sections of this insert

Eyelash changes (increased length, thickness, pigmentation, and number of lashes); eyelid skin darkening; intraocular inflammation (iritis/uveitis); iris pigmentation changes; and macular edema, including cystoid macular edema (see WARNINGS and PRECAUTIONS).

Controlled Clinical Trials

The ocular adverse events and ocular signs and symptoms reported in 5 to 15% of the patients on XALATAN Sterile Ophthalmic Solution in the three 6-month, multi-center, double-masked, active-controlled trials were blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris, and punctate epithelial keratopathy.

Local conjunctival hyperemia was observed; however, less than 1% of the patients treated with XALATAN required discontinuation of therapy because of intolerance to conjunctival hyperemia.

In addition to the above listed ocular events/signs and symptoms, the following were reported in 1 to 4% of the patients: dry eye, excessive tearing, eye pain, lid crusting, lid discomfort/pain, lid edema, lid erythema, and photophobia.

The following events were reported in less than 1% of the patients: conjunctivitis, diplopia and discharge from the eye.

During clinical studies, there were extremely rare reports of the following: retinal artery embolus, retinal detachment, and vitreous hemorrhage from diabetic retinopathy.

The most common systemic adverse events seen with XALATAN were upper respiratory tract infection/cold/flu, which occurred at a rate of approximately 4%. Chest pain/angina pectoris, muscle/joint/back pain, and rash/allergic skin reaction each occurred at a rate of 1 to 2%.

Clinical Practice

The following events have been identified during postmarketing use of XALATAN in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to XALATAN, or a combination of these factors, include: asthma and exacerbation of asthma; corneal edema and erosions; dyspnea; eyelash and vellus hair changes (increased length, thickness, pigmentation, and number); eyelid skin darkening; herpes keratitis; intraocular inflammation (iritis/uveitis); keratitis; macular edema, including cystoid macular edema; misdirected eyelashes sometimes resulting in eye irritation; dizziness, headache, and toxic epidermal necrolysis.

In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with XALATAN. If such drugs are used they should be administered at least five (5) minutes apart.

Last updated on RxList: 4/11/2008

XALATAN Sterile 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, and growth of eyelashes. Pigmentation is expected to increase as long as XALATAN is administered. After discontinuation of XALATAN, 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: XALATAN Sterile Ophthalmic Solution 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 XALATAN 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, has been reported in association with the use of XALATAN (see WARNINGS).

XALATAN may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment.

XALATAN should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation.

Macular edema, including cystoid macular edema, has been reported during treatment with XALATAN. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. XALATAN should be used with caution in patients who do not have an intact posterior capsule or who have known risk factors for macular edema.

There is limited experience with XALATAN in 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 the administration of XALATAN, and may be reinserted 15 minutes after administration (see PRECAUTIONS, Information for Patients).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Latanoprost was not mutagenic in bacteria, in mouse lymphoma or in mouse micronucleus tests.

Chromosome aberrations were observed in vitro with human lymphocytes.

Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 µg/kg/day (approximately 2,800 times the recommended maximum human dose) for up to 20 and 24 months, respectively.

Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative. Latanoprost has not been found to have any effect on male or female fertility in animal studies.

Pregnancy: Teratogenic Effects: Pregnancy Category C.

Reproduction studies have been performed in rats and rabbits. In rabbits an incidence of 4 of 16 dams had no viable fetuses at a dose that was approximately 80 times the maximum human dose, and the highest nonembryocidal dose in rabbits was approximately 15 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. XALATAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when XALATAN is administered to a nursing woman.

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

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

Last updated on RxList: 4/11/2008

Apart from ocular irritation and conjunctival or episcleral hyperemia, the ocular effects of latanoprost administered at high doses are not known. Intravenous administration of large doses of latanoprost in monkeys has been associated with transient bronchoconstriction; however, in 11 patients with bronchial asthma treated with latanoprost, bronchoconstriction was not induced. Intravenous infusion of up to 3 µg/kg in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment and no adverse reactions were observed. Intravenous dosages of 5.5 to 10 µg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea and sweating.

If overdosage with XALATAN Sterile Ophthalmic Solution occurs, treatment should be symptomatic.

Known hypersensitivity to latanoprost, benzalkonium chloride or any other ingredients in this product.

Last updated on RxList: 4/11/2008

Mechanism of Action

Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents 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/Pharmacodynamics

Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. Studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration.

Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration.

Metabolism: Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4- tetranor metabolites via fatty acid β-oxidation.

Excretion: The elimination of the acid of latanoprost from human plasma is rapid (t1/2 =17 min) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose is recovered in the urine after topical and intravenous dosing, respectively.

Animal Studies

In monkeys, latanoprost has been shown to induce increased pigmentation of the iris. The mechanism of increased pigmentation seems to be stimulation of melanin production in melanocytes of the iris, with no proliferative changes observed. The change in iris color may be permanent.

Ocular administration of latanoprost at a dose of 6 µg/eye/day (4 times the daily human dose) to cynomolgus monkeys has also been shown to induce increased palpebral fissure. This effect was reversible upon discontinuation of the drug.

Clinical Studies

Patients with mean baseline intraocular pressure of 24-25 mmHg who were treated for 6 months in multi-center, randomized, controlled trials demonstrated 6-8 mmHg reductions in intraocular pressure. This IOP reduction with XALATAN Sterile Ophthalmic Solution 0.005% dosed once daily was equivalent to the effect of timolol 0.5% dosed twice daily.

A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to evaluate the progression of increased iris pigmentation with continuous use of XALATAN once-daily as adjunctive therapy in 519 patients with open-angle glaucoma. The analysis was based on observed-cases population of the 380 patients who continued in the extension phase.

Results 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.

Last updated on RxList: 4/11/2008

(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 XALATAN.

Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye during treatment with XALATAN. 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 or surrounding structures because this could cause the tip to become contaminated 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 also should 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 multiple-dose container.

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

Patients should also be advised that XALATAN contains benzalkonium chloride, which may be absorbed by contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of XALATAN.

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

Last updated on RxList: 4/11/2008

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.

LATANOPROST - OPHTHALMIC SOLUTION

(lay-TAN-oh-prost)

COMMON BRAND NAME(S): Xalatan

USES: Latanoprost is used to treat high pressure inside the eye due to glaucoma (open angle type) or other eye diseases (e.g., ocular hypertension). It is similar to a natural chemical in the body (prostaglandin) and works by regulating the flow of fluid within the eye which results in lower pressure. Lowering high pressure inside the eye helps to prevent blindness.

HOW TO USE: Apply this medication in the affected eye(s) usually once daily in the evening, or as directed by your doctor. Do not use this medication more frequently than prescribed; using more can decrease effectiveness.

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.

The preservative in this product may be absorbed by contact lenses. If you wear contact lenses, remove them before using this medication and keep them out of your eyes for at least 15 minutes after applying latanoprost.

Tilt your head back, look upward and pull down the lower eyelid to make a pouch. Hold the dropper directly over your eye and apply the prescribed number of drops. Look downward and gently close your eye for 1 to 2 minutes. Place one finger at the inside 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.

Do not rinse the dropper. Replace the dropper cap after each use.

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 latanoprost even if you feel well. Most people with glaucoma or high pressure in the eye do not feel sick.

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

SIDE EFFECTS: Blurred vision, burning/stinging/itching/redness of the eye, feeling as if something is in the eye, changes in eyelash number/color/length/thickness, eyelid skin darkening, dry eye, lid crusting/discomfort, increased sensitivity to light, flu-like symptoms, or muscle/joint pain 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 latanoprost in only one eye, only that iris may change color. This color change 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: eye pain, suspected eye infection (unusual redness or swelling of eyes), chest pain.

Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: rapid vision changes (e.g., loss of vision).

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, severe itching, swelling, 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 latanoprost, tell your doctor or pharmacist if you are allergic to it; or to the preservative in this product (benzalkonium chloride); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: an active swelling process within the eye (e.g., iritis, uveitis).

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

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 latanoprost. You may be advised to start using a new bottle.

Use caution engaging in activities requiring clear vision such as driving or using machinery because your vision may be temporarily blurred or unstable after applying this drug. Alcohol may worsen this effect. Limit alcoholic beverages.

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 doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. 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, especially of eye drops which contain thimerosal as a preservative (consult your pharmacist). If such a product is used, wait at least 5 minutes between using it and latanoprost.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you 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 on the same day. If you do not remember until the next day, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: US Product: Store the unopened bottles in the refrigerator between 36-46 degrees F (2-8 degrees C). Once a bottle is opened for use, it may be stored at room temperature (up to 77 degrees F or 25 degrees C) for 6 weeks. Discard any opened, unused bottles after this time period.

Canadian Product: Store the unopened bottles in the refrigerator between 36-46 degrees F (2-8 degrees C). Once a bottle is opened for use, store it in a cool place (refrigerate if possible) for 6 weeks. Discard any opened, unused bottles after this time period.

Store 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.