Ganfort

Bimatoprost:

• Recent major changes
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Ganfort (Bimatoprost) reviews

RECENT MAJOR CHANGES

Warnings and Precautions, Intraocular Inflammation (5.3) 09/2014

1 INDICATIONS AND USAGE

Ganfort (Bimatoprost) ophthalmic solution, 0.03% is a prostaglandin analog indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension. (1)

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

2 DOSAGE AND ADMINISTRATION

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

The recommended dosage is one drop in the affected eye(s) once daily in the evening.

Ganfort (Bimatoprost) ophthalmic solution, 0.03% should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs 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.

Ganfort (Bimatoprost) ophthalmic solution, 0.03% 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.

3 DOSAGE FORMS AND STRENGTHS

Solution containing 0.3 mg/mL Ganfort (Bimatoprost). (3)

Ophthalmic solution containing Ganfort (Bimatoprost) 0.3 mg/mL.

4 CONTRAINDICATIONS

None. (4)

None

5 WARNINGS AND PRECAUTIONS

Pigmentation.

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

Ganfort (Bimatoprost) 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. Pigmentation is expected to increase as long as Ganfort (Bimatoprost) 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 Ganfort (Bimatoprost), 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 long term effects of increased pigmentation are not known.

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 Ganfort (Bimatoprost) ophthalmic solution, 0.03% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly .

5.2 Eyelash Changes

Ganfort ophthalmic solution, 0.03% 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.

5.3 Intraocular Inflammation

Prostaglandin analogs, including Ganfort (Bimatoprost), have been reported to cause intraocular inflammation. In addition, because these products may exacerbate inflammation, caution should be used in patients with active intraocular inflammation (e.g., uveitis).

5.4 Macular Edema

Macular edema, including cystoid macular edema, has been reported during treatment with Ganfort ophthalmic solution. Ganfort (Bimatoprost) ophthalmic solution, 0.03% 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 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, (17.3)].

5.6 Use with Contact Lenses

Contact lenses should be removed prior to instillation of Ganfort (Bimatoprost) ophthalmic solution, 0.03% and may be reinserted 15 minutes following its administration.

6 ADVERSE REACTIONS

Most common adverse reaction is conjunctival hyperemia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

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

In clinical trials, the most frequent events associated with the use of Ganfort (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, periorbital 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.

6.2 Postmarketing Experience

The following reactions have been identified during postmarketing use of Ganfort (Bimatoprost) ophthalmic solution, 0.03% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to Ganfort (Bimatoprost) ophthalmic solution, or a combination of these factors, include: abnormal hair growth, dizziness, eyelid edema, hypertension, nausea, and periorbital and lid changes associated with a deepening of the eyelid sulcus.

8 USE IN SPECIFIC POPULATIONS

Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use.

8.1 Pregnancy

Pregnancy Category C

Teratogenic effects:

In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of Ganfort which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels.

At doses at least 41 times the maximum 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 Ganfort (Bimatoprost) ophthalmic solution, 0.03% administration in pregnant women. Because animal reproductive studies are not always predictive of human response. Ganfort (Bimatoprost) ophthalmic solution, 0.03% should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Ganfort (Bimatoprost) ophthalmic solution, 0.03% is excreted in human milk, although in animal studies, Ganfort (Bimatoprost) has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when Ganfort (Bimatoprost) ophthalmic solution, 0.03% is administered to a nursing woman.

8.4 Pediatric Use

Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use.

8.5 Geriatric Use

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

8.6 Hepatic Impairment

In patients with a history of liver disease or abnormal ALT, AST and/or bilirubin at baseline, Ganfort (Bimatoprost) 0.03% had no adverse effect on liver function over 48 months.

10 OVERDOSAGE

No information is available on overdosage in humans. If overdose with Ganfort (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 Ganfort (Bimatoprost) ophthalmic solution, 0.03% for a 10 kg child.

11 DESCRIPTION

Ganfort (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 C₂₅H₃₇NO₄. Its chemical structure is:

Ganfort (Bimatoprost) is a powder, which is freely soluble in alcohol. Ganfort (Bimatoprost) ophthalmic solution, 0.03% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg.

Ganfort (Bimatoprost) ophthalmic solution, 0.03% contains Active: Ganfort (Bimatoprost) 0.3 mg/mL; Inactives: benzalkonium chloride 0.05 mg/mL; disodium hydrogen phosphate heptahydrate, citric acid monohydrate, sodium chloride and water for injection. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.9 to 7.6.

structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ganfort, a prostaglandin analog, is a synthetic structural analog of prostaglandin with ocular hypotensive activity. It selectively mimics the effects of naturally occurring substances, prostamides. Ganfort (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.

12.3 Pharmacokinetics

Absorption

After one drop of Ganfort ophthalmic solution, 0.03% was administered once daily to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean C_max and AUC_0-24hr values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng-hr/mL, respectively, indicating that steady state was reached during the first week of ocular dosing. There was no significant systemic drug accumulation over time.

Distribution

Ganfort (Bimatoprost) is moderately distributed into body tissues with a steady-state volume of distribution of 0.67 L/kg. In human blood, Ganfort (Bimatoprost) resides mainly in the plasma. Approximately 12% of Ganfort (Bimatoprost) remains unbound in human plasma.

Metabolism

Ganfort is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Ganfort (Bimatoprost) then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites.

Elimination

Following an intravenous dose of radiolabeled Ganfort (Bimatoprost) (3.12 mcg/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 Ganfort (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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Ganfort (Bimatoprost) was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times the recommended human exposure based on blood AUC levels respectively) for 104 weeks.

Ganfort (Bimatoprost) was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests.

Ganfort (Bimatoprost) did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (at least 103 times the recommended human exposure based on blood AUC levels).

14 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 Ganfort (Bimatoprost) ophthalmic solution, 0.03% once daily (in the evening) was 7 to 8 mmHg.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ganfort (Bimatoprost) ophthalmic solution, 0.03% is supplied sterile in opaque white low density polyethylene bottle which is closed with white low density polyethylene nozzle and then with turquoise colored high density polyethylene cap in the following sizes:

2.5 mL fill in a 5 mL container - NDC 68180-429-01

5 mL fill in a 10 mL container - NDC 68180-429-02

7.5 mL fill in a 10 mL container - NDC 68180-429-03

Storage: Ganfort (Bimatoprost) ophthalmic solution, 0.03% should be stored at 2 to 25°C (36 to 77°F).

17 PATIENT COUNSELING INFORMATION

17.1 Potential for Pigmentation

Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of Ganfort ophthalmic solution, 0.03%.

17.2 Potential for Eyelash Changes

Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with Ganfort (Bimatoprost) ophthalmic solution, 0.03%. 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.

17.3 Handling the Container

Instruct patients 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.

17.4 When to Seek Physician Advice

Advise patients that if they develop an intercurrent ocular condition, 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 Ganfort (Bimatoprost) ophthalmic solution, 0.03%.

17.5 Use with Contact Lenses

Advise patients that Ganfort (Bimatoprost) ophthalmic solution, 0.03% contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of Ganfort (Bimatoprost) ophthalmic solution, 0.03% and may be reinserted 15 minutes following its administration.

17.6 Use with Other Ophthalmic Drugs

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

Marketed by:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Pithampur (M.P.) - 454 775

India

March 2015 ID#: 239313

Ganfort (Bimatoprost) OPHTHALMIC SOLUTION

Rx Only

0.03%

NDC 68180-429-01

2.5 mL Bottle Label

Ganfort (Bimatoprost) OPHTHALMIC SOLUTION

Rx Only

0.03%

NDC 68180-429-01

2.5 mL Carton Label

Ganfort (Bimatoprost) OPHTHALMIC SOLUTION

Rx Only

0.03%

NDC 68180-429-02

5 mL Bottle Label

Ganfort (Bimatoprost) OPHTHALMIC SOLUTION

Rx Only

0.03%

NDC 68180-429-02

5 mL Carton Label

Ganfort (Bimatoprost) OPHTHALMIC SOLUTION

Rx Only

0.03%

NDC 68180-429-03

7.5 mL Bottle Label

Ganfort (Bimatoprost) OPHTHALMIC SOLUTION

Rx Only

0.03%

NDC 68180-429-03

7.5 mL Carton Label

2.5 ml bottle 2.5 ml carton 5 ml bottle 5 ml carton 7.5 ml bottle 7.5 ml carton

Timolol Maleate:

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

DESCRIPTION

Ganfort (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. Ganfort (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 Ganfort (Timolol Maleate) is Formula C₁₃H₂₄N₄O₃S and its structural formula is:

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

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

Each mL of Ganfort (Timolol Maleate)^® 0.5% contains 5.12 mg of Ganfort (Timolol Maleate) hemihydrate equivalent to 5.0 mg Ganfort (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 Ganfort (Timolol Maleate)^® is 260 to 320 mOsmol/kg.

Chemical Structure

CLINICAL PHARMACOLOGY

Ganfort is a non-selective beta-adrenergic antagonist.

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

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

Clinical Studies

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

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

Ganfort (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, Ganfort ^® 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. Ganfort (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 Ganfort ^®, 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. Ganfort (Timolol Maleate)^® has no effect on the pupil. Therefore, if Ganfort (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 Ganfort ^® 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 Ganfort ^® 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 Ganfort (Timolol Maleate) (as the maleate) has been studied in mice and rats. In a two-year study orally administrated Ganfort (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 Ganfort (Timolol Maleate) maleate is 1 mg/kg/day.

Mutagenic potential of Ganfort (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 Ganfort (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 Ganfort (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 Ganfort (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. Ganfort (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 Ganfort (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 Ganfort (Timolol Maleate)^® and Ganfort (Timolol Maleate) maleate (approximately one in eight patients).

The following adverse events were associated with use of Ganfort (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% Ganfort (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 Ganfort (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

Ganfort (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 Ganfort (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 Ganfort (Timolol Maleate)^® may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Ganfort (Timolol Maleate)^®.

Dosages above one drop of 0.5 percent Ganfort (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

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

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

NDC 68669-522-05	5.0mL	fill in 5 cc container
NDC 68669-522-10	10mL	fill in 11 cc container
NDC 68669-522-15	15mL	fill in 15 cc container

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

NDC 68669-525-05	5.0mL	fill in 5 cc container
NDC 68669-525-10	10mL	fill in 11 cc contalner
NDC 68669-525-15	15mL	fill in 15 cc container

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