Xalcom

Latanoprost:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Xalcom (Latanoprost) reviews

1 INDICATIONS AND USAGE

Xalcom (Latanoprost) is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Xalcom (Latanoprost) is a prostaglandin F_2α analogue indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. (1)

2 DOSAGE AND ADMINISTRATION

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

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

Xalcom (Latanoprost) may be used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. Contact lenses should be removed prior to the administration of Xalcom (Latanoprost), and may be reinserted 15 minutes after administration

One drop in the affected eye(s) once daily in the evening. (2)

3 DOSAGE FORMS AND STRENGTHS

Sterile ophthalmic solution containing 50 mcg/mL Xalcom (Latanoprost).

Ophthalmic solution containing 50 mcg/mL Xalcom (Latanoprost) (0.005%). (3)

4 CONTRAINDICATIONS

Known hypersensitivity to Xalcom (Latanoprost), benzalkonium chloride, or any other ingredients in this product.

Known hypersensitivity to Xalcom (Latanoprost), benzalkonium chloride or any other ingredients in this product. (4)

5 WARNINGS AND PRECAUTIONS

• Pigmentation: pigmentation of the iris, periorbital tissue and eyelashes can occur. Iris pigmentation 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

Xalcom (Latanoprost) 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 Xalcom (Latanoprost) 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 Xalcom (Latanoprost), 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. Beyond 5 years the effects of increased pigmentation are not known [see Clinical Studies (14.2) ].

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 Xalcom (Latanoprost) can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly [see Patient Counseling Information (17) ].

5.2 Eyelash Changes

Xalcom 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 [see Patient Counseling Information (17) ].

5.3 Intraocular Inflammation

Xalcom (Latanoprost) 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 because inflammation may be exacerbated.

5.4 Macular Edema

Macular edema, including cystoid macular edema, has been reported during treatment with Xalcom. Xalcom (Latanoprost) 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.

5.5 Herpetic Keratitis

Reactivation of Herpes Simplex keratitis has been reported during treatment with Xalcom (Latanoprost). Xalcom (Latanoprost) should be used with caution in patients with a history of herpetic keratitis. Xalcom (Latanoprost) should be avoided in cases of active herpes simplex keratitis because inflammation may be exacerbated.

5.6 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 a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information ].

5.7 Use with Contact Lenses

Contact lenses should be removed prior to the administration of Xalcom (Latanoprost), and may be reinserted 15 minutes after administration.

6 ADVERSE REACTIONS

The following adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the label:

• Iris pigmentation changes [see Warnings and Precautions ]
• Eyelid skin darkening [see Warnings and Precautions (5.1) ]
• Eyelash changes (increased length, thickness, pigmentation, and number of lashes) [see Warnings and Precautions (5.2) ]
• Intraocular inflammation (iritis/uveitis) [see Warnings and Precautions (5.3) ]
• Macular edema, including cystoid macular edema [see Warnings and Precautions (5.4) ]

Most common adverse reactions (≥4%) from clinical trials are blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris, punctate keratitis, and upper respiratory tract infection/nasopharyngitis/influenza. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Xalcom (Latanoprost) was studied in three multicenter, randomized, controlled clinical trials. Patients received 50 mcg/mL Xalcom (Latanoprost) once daily or 5 mg/mL active-comparator (timolol) twice daily. The patient population studied had a mean age of 65±10 years. Seven percent of patients withdrew before the 6-month endpoint.

Less than 1% of the patients treated with Xalcom (Latanoprost) required discontinuation of therapy because of intolerance to conjunctival hyperemia.

The ocular event/signs and symptoms of blepharitis have been identified as "commonly observed" through analysis of clinical trial data.

6.2 Postmarketing Experience

The following reactions have been identified during postmarketing use of Xalcom (Latanoprost) in clinical practice. Because they are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to Xalcom (Latanoprost), or a combination of these factors, include:

Nervous System disorders: Dizziness; headache; toxic epidermal necrolysis

Eye Disorders: Eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes); keratitis; corneal edema and erosions; intraocular inflammation (iritis/uveitis); macular edema, including cystoid macular edema; trichiasis; periorbital and lid changes resulting in deepening of the eyelid sulcus; iris cyst; eyelid skin darkening; localised skin reaction on the eyelids; conjunctivitis; pseudopemphigoid of the ocular conjunctiva

Respiratory, Thoracic and Mediastinal Disorders: Asthma and exacerbation of asthma; dyspnea

Skin and Subcutaneous Tissue Disorders: Pruritus

Infections and Infestations: Herpes keratitis

Cardiac Disorders: Angina; palpitations; angina unstable

General Disorders and Administration Site Conditions: Chest pain

7 DRUG INTERACTIONS

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

The combined use of two or more prostaglandins, or prostaglandin analogs including Xalcom (Latanoprost) is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the IOP lowering effect or cause paradoxical elevations in IOP.

In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with Xalcom (Latanoprost). If such drugs are used, they should be administered at least 5 minutes apart. (7)

8 USE IN SPECIFIC POPULATIONS

8.1 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. Xalcom should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 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 Xalcom (Latanoprost) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

10 OVERDOSAGE

Intravenous infusion of up to 3 mcg/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 mcg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea, and sweating.

If overdosage with Xalcom (Latanoprost) occurs, treatment should be symptomatic.

11 DESCRIPTION

Xalcom (Latanoprost) is a prostaglandin F_{2 α} 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:

Xalcom (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.

Xalcom (Latanoprost) (latanoprost ophthalmic solution) 0.005% is supplied as a sterile, isotonic, buffered aqueous solution of Xalcom (Latanoprost) with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Each mL of Xalcom (Latanoprost) contains 50 mcg of Xalcom (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 mcg of Xalcom (Latanoprost).

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Xalcom 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.

12.2 Pharmacodynamics

Reduction of the IOP in man starts about 3–4 hours after administration and maximum effect is reached after 8–12 hours. IOP reduction is present for at least 24 hours.

12.3 Pharmacokinetics

Absorption

Xalcom (Latanoprost) is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active.

Distribution

The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of Xalcom (Latanoprost) can be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration. Studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration.

Metabolism

Xalcom (Latanoprost), an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. The active acid of Xalcom (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 Xalcom (Latanoprost) from human plasma is rapid (t_1/2 = 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 are recovered in the urine after topical and intravenous dosing, respectively.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Xalcom (Latanoprost) was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 mcg/kg/day (approximately 2800 times the recommended maximum human dose) for up to 20 and 24 months, respectively.

Xalcom (Latanoprost) was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus tests. Chromosome aberrations were observed in vitro with human lymphocytes. Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative.

Xalcom (Latanoprost) has not been found to have any effect on male or female fertility in animal studies.

14 CLINICAL STUDIES

14.1 Elevated Baseline IOP

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

14.2 Progression of Increased Iris Pigmentation

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 Xalcom (Latanoprost) 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Xalcom (Latanoprost) is a clear, isotonic, buffered, preserved colorless solution of Xalcom (Latanoprost) 0.005% (50 mcg/mL). It is supplied as a 2.5 mL solution in a 5 mL clear low density polyethylene bottle with a clear 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 mcg/mL): Package of 1 bottle: NDC 0013-8303-04

Storage: Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be stored at room temperature up to 25°C (77°F) for 6 weeks.

17 PATIENT COUNSELING INFORMATION

Potential for Pigmentation

Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of Xalcom (Latanoprost) [ see Warnings and Precautions (5.1) ].

Potential for Eyelash Changes

Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with Xalcom (Latanoprost). 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.

Handling the Container

Instruct patients 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 [see Warnings and Precautions (5.6) ].

When to Seek Physician Advice

Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of the multiple-dose container.

Use with Contact Lenses

Advise patients that Xalcom (Latanoprost) 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 Xalcom (Latanoprost).

Use with Other Ophthalmic Drugs

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

Pfizer Manufacturing Belgium NV

Puurs, Belgium

LAB-0135-13.0

Logo

Xalcom (Latanoprost) ^®

Xalcom (Latanoprost)

ophthalmic solution

Sterile

0.005%

125 mcg/2.5 mL

8Q4237

Timolol Maleate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Xalcom (Timolol Maleate) reviews

DESCRIPTION

Xalcom (Timolol Maleate)^® (timolol ophthalmic solution), 0.25% and 0.5%, is a non-selective beta-adrenergic antagonist for ophthalmic use. The chemical name of the active ingredient is (S)-1-[(1,1-dimethylethyl)amino]-3-[(4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol. Xalcom (Timolol Maleate) hemihydrate is the levo isomer. Specific rotation is [α]²⁵ _405nm=-16° (C=10% as the hemihydrate form in 1N HCl).

The molecular formula of Xalcom (Timolol Maleate) is Formula C₁₃H₂₄N₄O₃S and its structural formula is:

Xalcom (Timolol Maleate) (as the hemihydrate) is a white, odorless, crystalline powder which is slightly soluble in water and freely soluble in ethanol. Xalcom (Timolol Maleate) hemihydrate is stable at room temperature.

Xalcom (Timolol Maleate)^® is a clear, colorless, isotonic, sterile, microbiologically preserved phosphate buffered aqueous solution.

It is supplied in two dosage strengths, 0.25% and 0.5%.

Each mL of Xalcom (Timolol Maleate)^® 0.25% contains 2.56 mg of Xalcom (Timolol Maleate) hemihydrate equivalent to 2.5 mg Xalcom (Timolol Maleate).

Each mL of Xalcom (Timolol Maleate)^® 0.5% contains 5.12 mg of Xalcom (Timolol Maleate) hemihydrate equivalent to 5.0 mg Xalcom (Timolol Maleate).

Inactive ingredients: monosodium and disodium phosphate dihydrate to adjust pH (6.5 - 7.5) and water for injection, benzalkonium chloride 0.01% added as preservative.

The osmolality of Xalcom (Timolol Maleate)^® is 260 to 320 mOsmol/kg.

Chemical Structure

CLINICAL PHARMACOLOGY

Xalcom is a non-selective beta-adrenergic antagonist.

It blocks both beta₁-and beta₂-adrenergic receptors. Xalcom (Timolol Maleate) does not have significant intrinsic sympathomimetic activity, local anesthetic (membrane-stabilizing) or direct myocardial depressant activity.

Xalcom (Timolol Maleate), when applied topically in the eye, reduces normal and elevated intraocular pressure (IOP) whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of IOP, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. The predominant mechanism of ocular hypotensive action of topical beta-adrenergic blocking agents is likely due to a reduction in aqueous humor production.

In general, beta-adrenergic blocking agents reduce cardiac output both in healthy subjects and patients with heart diseases. In patients with severe impairment of myocardial function, beta-adrenergic receptor blocking agents may inhibit sympathetic stimulatory effect necessary to maintain adequate cardiac function. In the bronchi and bronchioles, beta-adrenergic receptor blockade may also increase airway resistance because of unopposed parasympathetic activity.

Pharmacokinetics

When given orally, Xalcom (Timolol Maleate) is well absorbed and undergoes considerable first pass metabolism. Xalcom (Timolol Maleate) and its metabolites are primarily excreted in the urine. The half-life of Xalcom (Timolol Maleate) in plasma is approximately 4 hours.

Clinical Studies

In two controlled multicenter studies in the U.S., Xalcom (Timolol Maleate)^® 0.25% and 0.5% were compared with respective Xalcom (Timolol Maleate) maleate eyedrops. In these studies, the efficacy and safety profile of Xalcom (Timolol Maleate)^® was similar to that of Xalcom (Timolol Maleate) maleate.

INDICATIONS AND USAGE

Xalcom (Timolol Maleate)^® is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

CONTRAINDICATIONS

Xalcom (Timolol Maleate)^® is contraindicated in patients with overt heart failure, cardiogenic shock, sinus bradycardia, second- or third-degree atrioventricular block, bronchial asthma or history of bronchial asthma, or severe chronic obstructive pulmonary disease, or hypersensitivity to any component of this product.

WARNINGS

As with other topically applied ophthalmic drugs, Xalcom ^® is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely, death in association with cardiac failure have been reported following systemic or topical administration of beta-adrenergic blocking agents.

Cardiac Failure

Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe cardiac failure.

In patients without a history of cardiac failure, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. Xalcom (Timolol Maleate)^® should be discontinued at the first sign or symptom of cardiac failure.

Obstructive Pulmonary Disease

Patients with chronic obstructive pulmonary disease of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma which are contraindications) should in general not receive beta-blocking agents.

Major Surgery

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to a major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, gradual withdrawal of beta-adrenergic receptor blocking agents is recommended. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of beta-adrenergic agonists.

Diabetes Mellitus

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis

Beta-adrenergic blocking agents may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents which might precipitate a thyroid storm.

PRECAUTIONS

General

Because of the potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Xalcom ^®, alternative therapy should be considered.

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.

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. dipIopia, ptosis, and generalized weakness). Beta-adrenergic blocking agents have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

In angle-closure glaucoma, the goal of the treatment is to reopen the angle. This requires constricting the pupil. Xalcom (Timolol Maleate)^® has no effect on the pupil. Therefore, if Xalcom (Timolol Maleate) is used in angle-closure glaucoma, it should always be combined with a miotic and not used alone.

Anaphylaxis

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

The preservative benzalkonium chloride may be absorbed by soft contact lenses. Patients who wear soft contact lenses should wait 5 minutes after instilling Xalcom ^® before they insert their lenses.

Information for Patients

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions can 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 requiring concomitant topical ophthalmic medications should be instructed to administer these at least 5 minutes apart.

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrioventricular block, or cardiac failure should be advised not to take this product

Drug Interactions

Beta-adrenergic blocking agents

Patients who are receiving a beta-adrenergic blocking agent orally and Xalcom ^® should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade.

Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently.

Catecholamine-depleting drugs

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Calcium antagonists

Caution should be used in the co-administration of beta-adrenergic blocking agents and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided.

Digitalis and calcium antagonists

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

Injectable Epinephrine

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity of Xalcom (Timolol Maleate) (as the maleate) has been studied in mice and rats. In a two-year study orally administrated Xalcom (Timolol Maleate) maleate (300mg/kg/day) (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose) in male rats caused a significant increase in the incidence of adrenal pheochromocytomas; the lower doses, 25 mg or 100 mg/kg daily did not cause any changes.

In a life span study in mice the overall incidence of neoplasms was significantly increased in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Furthermore, significant increases were observed in the incidences of benign and malignant pulmonary tumors, benign uterine polyps, as well as mammary adenocarcinomas. These changes were not seen at the daily dose level of 5 or 50 mg/kg (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). For comparison, the maximum recommended human oral dose of Xalcom (Timolol Maleate) maleate is 1 mg/kg/day.

Mutagenic potential of Xalcom (Timolol Maleate) was evaluated in vivo in the micronucleus test and cytogenetic assay and in vitro in the neoplastic cell transformation assay and Ames test. In the bacterial mutagenicity test (Ames test) high concentrations of Xalcom (Timolol Maleate) maleate (5000 and 10,000 g/plate) statistically significantly increased the number of revertants in Salmonella typhimurium TA100, but not in the other three strains tested. However, no consistent dose-response was observed nor did the number of revertants reach the double of the control value, which is regarded as one of the criteria for a positive result in the Ames test. In vivo genotoxicity tests (the mouse micronucleus test and cytogenetic assay) and in vitro the neoplastic cell transformation assay were negative up to dose levels of 800 mg/kg and 100 g/mL, respectively.

No adverse effects on male and female fertility were reported in rats at Xalcom (Timolol Maleate) oral doses of up to 150 mg/kg/day (21,000 times the systemic exposure following the maximum recommended human ophthalmic dose).

Pregnancy Teratogenic effects

Category C

Teratogenicity of Xalcom (as the maleate) after oral administration was studied in mice and rabbits. No fetal malformations were reported in mice or rabbits at a daily oral dose of 50 mg/kg (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women. Xalcom (Timolol Maleate)^® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

Because of the potential for serious adverse reactions in nursing infants from Xalcom (Timolol Maleate), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

Safety and efficacy in pediatric patients have not been established.

ADVERSE REACTIONS

The most frequently reported ocular event in clinical trials was burning/stinging on instillation and was comparable between Xalcom (Timolol Maleate)^® and Xalcom (Timolol Maleate) maleate (approximately one in eight patients).

The following adverse events were associated with use of Xalcom (Timolol Maleate)^® in frequencies of more than 5% in two controlled, double-masked clinical studies in which 184 patients received 0.25% or 0.5% Xalcom (Timolol Maleate)^®:

OCULAR:

Dry eyes, itching, foreign body sensation, discomfort in the eye, eyelid erythema, conjunctival injection, and headache.

BODY AS A WHOLE:

Headache.

The following side effects were reported in frequencies of 1 to 5%:

OCULAR:

Eye pain, epiphora, photophobia, blurred or abnormal vision, corneal fluorescein staining, keratitis, blepharitis and cataract.

BODY AS A WHOLE:

Allergic reaction, asthenia, common cold and pain in extremities.

CARDIOVASCULAR:

Hypertension.

DIGESTIVE:

Nausea.

METABOLlC/NUTRITIONAL:

Peripheral edema.

NERVOUS SYSTEM/PSYCHIATRY:

Dizziness and dry mouth.

RESPIRATORY:

Respiratory infection and sinusitis.

In addition, the following adverse reactions have been reported with ophthalmic use of beta blockers:

OCULAR:

Conjunctivitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes, diplopia and retinal vascular disorder.

BODY AS A WHOLE:

Chest pain.

CARDIOVASCULAR:

Arrhythmia, palpitation, bradycardia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure and cardiac arrest.

DIGESTIVE:

Diarrhea.

ENDOCRINE:

Masked symptoms of hypoglycemia in insulin dependent diabetics.

NERVOUS SYSTEM/PSYCHIATRY:

Depression, impotence, increase in signs and symptoms of myasthenia gravis and paresthesia.

RESPIRATORY:

Dyspnea, bronchospasm, respiratory failure and nasal congestion.

SKIN:

AIOPecia, hypersensitivity including localized and generalized rash, urticaria.

OVERDOSAGE

No information is available on overdosage with Xalcom (Timolol Maleate)^®. Symptoms that might be expected with an overdose of a beta-adrenergic receptor blocking agent are bronchospasm, hypotension, bradycardia, and acute cardiac failure.

DOSAGE AND ADMINISTRATION

Xalcom (Timolol Maleate)^® Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Xalcom (Timolol Maleate)^® in the affected eye(s) twice a day. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) twice a day.

If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to one drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure, satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure at different times during the day.

Since in some patients the pressure-lowering response to Xalcom (Timolol Maleate)^® may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Xalcom (Timolol Maleate)^®.

Dosages above one drop of 0.5 percent Xalcom (Timolol Maleate)^® twice a day generally have not been shown to produce further reduction in intraocular pressure. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy with pilocarpine and other miotics, and/or epinephrine, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide, can be instituted.

HOW SUPPLIED

Xalcom ^® (timolol ophthalmic solution) is a clear, colorless solution.

Xalcom (Timolol Maleate)^® 0.25% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:

Xalcom (Timolol Maleate)^® 0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:

Rx Only

STORAGE

Store between 15-25°C (59-77°F). Do not freeze. Protect from light.

MARKETED BY:

VISTAKON^® Pharmaceuticals, LLC

Jacksonville, FL 32256 USA

MANUFACTURED BY:

Santen Oy, P.O. Box 33

FIN-33721 Tampere, Finland

November 2006 Version

3220660/5