Xalatan (Latanoprost)

XALATAN™

Pharmacia & Upjohn

Latanoprost

Prostaglandin F2  Analogue

Action And Clinical Pharmacology: Latanoprost, a novel prostaglandin F2  analogue, is a selective prostanoid FP receptor agonist which reduces the intraocular pressure by increasing the outflow of aqueous humor. Studies in animals and man indicate that the main mechanism of action is increased uveoscleral outflow.

Primary open-angle glaucoma is a disease with characteristic optic nerve damage and a corresponding visual field defect. Increased intraocular pressure (IOP) is one of the main risk factors. However, disturbances in blood flow may also play a role in some cases. In ocular hypertension, patients may have increased IOP but without changes in the visual field or corresponding optic nerve damage. Results from phase III clinical trials (see Table I) have demonstrated that latanoprost is a very effective ocular hypotensive drug when applied once daily, particularly in the evening. Across these trials, 460 patients received latanoprost and 369 patients received timolol. At 6 months, latanoprost reduced IOP by 27 to 34% from the untreated baseline of 24.4 to 25.2 mmHg. Timolol reduced IOP by 20 to 33% from a baseline of 24.1 to 25.4 mmHg. The p-value for the difference between the IOP reduction by latanoprost versus timolol was p
Xalatan is a sterile, isotonic, buffered aqueous solution with a pH of approximately 6.7. Each mL contains 50 g of latanoprost, a colorless to slightly yellow oil. Latanoprost is an isopropyl ester prodrug which is well absorbed through the cornea and upon entering the aqueous humor is rapidly and completely hydrolyzed to the biologically active acid. Studies in humans indicate that the peak concentration in the aqueous humor is reached about 2 hours after topical administration.

Following topical administration in monkeys, latanoprost is primarily distributed in the anterior segment, conjunctiva and eyelids with only minute quantities reaching the posterior segment. Reduction of IOP following a single dose in humans starts about 3 to 4 hours following topical administration, and the maximum effect is reached after 8 to 12 hours. Pressure reduction is maintained for at least 24 hours.

There is practically no metabolism of the acid of latanoprost in the eye. The plasma clearance is rapid and occurs in the liver. In humans, the half-life of the biologically active acid in plasma is approximately 17 minutes. In animal studies, the main metabolites were the 1,2-dinor and the 1,2,3,4-tetranor metabolites which exerted only weak or no biologic activity, and were excreted primarily in urine.

Clinical trials have shown that latanoprost has no significant effect on production of aqueous humor and no effect on the blood-aqueous barrier. At clinical dose levels, latanoprost has negligible or no effects on intraocular blood circulation when studied in monkeys. However, mild to moderate conjunctival or episcleral hyperemia may occur as a result of topical administration.

Latanoprost has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes during short-term treatment.

Phase II clinical trials have also demonstrated that latanoprost is effective in combination with other drugs used for treatment of glaucoma. The IOP reducing effect of latanoprost is additive to that of beta-adrenergic antagonists (timolol), adrenergic agonists (dipivefrin, epinephrine), cholinergic agonists (pilocarpine) and carbonic anhydrase inhibitors (acetazolamide).

Indications And Clinical Uses: For the reduction of intraocular pressure in patients with open-angle glaucoma and ocular hypertension who are intolerant or insufficiently responsive to any other intraocular pressure lowering medication.

Contra-Indications: Known hypersensitivity to benzalkonium chloride or any other ingredient in this product.

Manufacturers’ Warnings In Clinical States: Latanoprost 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 is currently unknown.

This effect has predominantly been seen in patients with mixed colored irides (i.e., blue/gray-brown, green-brown, or yellow-brown). In patients with homogeneously blue, gray, green or brown eyes, the change has only rarely been seen during 2 years of treatment in clinical trials. 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. Patients who are expected to receive treatment in only one eye should be informed about the potential for increased brown pigmentation in the treated eye and thus, heterochromia between the eyes. The increased pigmentation may be permanent.

Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed in clinical trials.

Latanoprost has been reported to cause darkening, thickening and lengthening of eye lashes (see Adverse Effects).

Based on spontaneous reports, very rare cases of darkening of the palpebral skin have been reported (see Adverse Effects).

Pregnancy : 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. Latanoprost should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: The active substance in latanoprost and its metabolites may pass into breast milk, and latanoprost should therefore be used with caution in nursing women.

Children: The safety and efficacy of the use of latanoprost in children has not been established.

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 ocular epithelial surface (see Blue Section – Information for the Patient).

Patients may slowly develop increased brown pigmentation of the iris. Patients are to be informed of this potential occurrence (see Blue Section – Information for the Patient). This change may not be noticeable for several months to years (see Warnings). Typically the brown pigmentation around the pupil spreads concentrically toward the periphery in affected eyes; however, 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. 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. Neither nevi nor freckles of the iris have been affected by treatment.

Latanoprost has been reported to cause darkening, thickening and lengthening of eye lashes.

Based on spontaneous reports, very rare cases of darkening of the palpebral skin have been reported.

There is no experience with latanoprost in the treatment of angle closure, inflammatory or neovascular glaucoma or congenital glaucoma, and only limited experience with pseudophakic patients and in pigmentary glaucoma.

Latanoprost has not been studied in patients with renal or hepatic impairment and should, therefore, be used with caution in such patients.

Drug Interactions: In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with latanoprost. If such drugs are used, they should be administered with an interval of at least 5 minutes between applications.

Adverse Reactions: The ocular adverse events and ocular signs and symptoms reported in 5 to 15% of the patients on latanoprost in the 6-month, multicenter, double-masked, active-controlled trials were blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased iris pigmentation and punctate epithelial keratopathy.

Local conjunctival hyperemia was observed; however, less than 1% of the latanoprost treated patients 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 edema, lid erythema, lid discomfort/pain 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 latanoprost were upper respiratory tract infection/cold/flu which occurred at a rate of approximately 4%. Pain in muscle/joint/back, chest pain/angina pectoris and rash/allergic skin reaction each occurred at a rate of 1 to 2%.

Macular edema in patients with aphakia or pseudophakia with anterior chamber lenses has been reported rarely during latanoprost treatment. Upon discontinuation of latanoprost treatment, visual acuity has improved, in some cases with concurrent treatment with topical steroidal and NSAIDs.

Latanoprost has been reported to cause darkening, thickening and lengthening of eye lashes.

Based on spontaneous reports, rare cases of iritis/uveitis and very rare cases of darkening of the palpebral skin have been reported.

During the period from Nov. 8, 1996 to Nov. 12, 1997, about 600 000 patients were treated with latanoprost. Fifty-five spontaneous reports of darkening, thickening and lengthening of eye lashes and 7 spontaneous reports of darkening of the skin of the eye lid/lids/periorbital region have been received; 16 cases of iritis and 10 cases of uveitis have been reported during this period.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Apart from ocular irritation and conjunctival or episcleral hyperemia, no other ocular side effects of latanoprost administered at high doses are known. I.V. infusion of up to 3 g/kg in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment and no adverse reactions were observed. I.V. doses of 5.5 to 10 g/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea and sweating.

In monkeys, latanoprost has been infused i.v. in doses of up to 500 g/kg without major effects on the cardiovascular system. I.V. administration in monkeys has been associated with transient bronchoconstriction. However, in patients with bronchial asthma, bronchoconstriction was not induced by latanoprost when administered topically to the eyes at a dose 7 times the recommended clinical dose. If overdosage with latanoprost occurs, treatment should be symptomatic.

Dosage And Administration: The recommended dose for adults including the elderly (over 60 years of age), is 1 drop in the affected eye(s) once daily. Optimal effect is obtained if latanoprost is administered in the evening.

The dose of latanoprost should not exceed once daily as it has been shown that more frequent administration decreases the IOP lowering effect. Reduction of IOP in humans starts about 3 to 4 hours after treatment and maximum effect is reached after 8 to 12 hours. Pressure reduction is maintained for at least 24 hours.

If 1 dose is missed, treatment should continue with the next dose the following day.

Use in Combination with Other Drugs: The product may be used concomitantly with other topical ophthalmic products to further lower intraocular pressure. If more than 1 topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart.

Availability And Storage: Each mL of a sterile, isotonic, buffered aqueous solution, for topical ophthalmic administration, contains: latanoprost 50 g. One drop contains approximately 1.5 g of latanoprost. Nonmedicinal ingredients: benzalkonium chloride, disodium hydrogen phosphate anhydrous, sodium chloride, sodium dihydrogen phosphate monohydrate and water for injection. Buffered to a pH of approximately 6.7 and is isotonic with lacrimal fluid. Plastic ophthalmic dispenser bottles of 5 mL with a dropper tip, screw cap and tamper-proof polyethylene overcap. Each bottle contains 2.5 mL of latanoprost corresponding to approximately 80 drops. Store unopened bottle under refrigeration (2 to 8°C). Protect from light. Once opened, store bottle in a cool place (refrigerate if possible) for up to 6 weeks.

XALATAN Pharmacia & Upjohn Latanoprost Prostaglandin F2  Analogue

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Glaucoma

General Illness Information Medical Term: GLAUCOMA Common Name: None Specified Description: Glaucoma is a term applied to a number of conditions causing optic nerve damage…