Timolol GFS

1 INDICATIONS AND USAGE Timolol GFS 0.25% and 0.5% are indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Timolol GFS is a beta adrenergic blocker indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma ( 1 ).

2 DOSAGE AND ADMINISTRATION Instill one drop of Timolol GFS (either 0.25% or 0.5%) in the affected eye(s) once daily. Shake once before each use. Timolol GFS may be used alone or in combination with other intraocular pressure lowering medications. Concomitant topical ophthalmic medications should be administered at least 10 minutes before instilling Timolol GFS. Instill one drop in the affected eye(s) once daily ( 2 ).

4 CONTRAINDICATIONS Timolol GFS is contraindicated in patients with: • bronchial asthma • history of bronchial asthma • severe chronic obstructive pulmonary disease • sinus bradycardia • second or third degree atrioventricular block • overt cardiac failure • cardiogenic shock • hypersensitivity to any component of this product. • Bronchial asthma (or history of) ( 4 ) • Severe chronic obstructive pulmonary disease ( 4 ) • Sinus bradycardia ( 4 ) • Second or third degree atrioventricular block ( 4 ) • Overt cardiac failure ( 4 ) • Cardiogenic shock ( 4 ) • Hypersensitivity to any component of this product ( 4 )

5 WARNINGS AND PRECAUTIONS • Same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical ophthalmic administration ( 5.1 ). • Beta-adrenergic receptor inhibitors may mask signs and symptoms of hypoglycemia and should be administered with caution in diabetic patients subject to hypoglycemia ( 5.5 ). • Beta-adrenergic receptor inhibitors may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism ( 5.6 ). 5.1 Systemic Absorption As with many topically applied ophthalmic drugs, Timolol GFS is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical ophthalmic administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and death due to cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate [see Contraindications (4) ]. 5.2 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 failure. In patients without a history of cardiac failure, continued depression of the myocardium with beta-adrenergic receptor inhibitors over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Timolol GFS should be discontinued. 5.3 Bronchospasm and Obstructive Pulmonary Disease Bronchospasm may occur. Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which Timolol GFS is contraindicated [see Contraindications (4) ] ) should, in general, not receive beta-adrenergic receptor inhibitors, including Timolol GFS. 5.4 Surgical Anesthesia The necessity or desirability of withdrawal of beta-adrenergic receptor inhibitors prior to 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 inhibitors have experienced protracted, severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. In patients undergoing elective surgery, consider gradual withdrawal of beta-adrenergic receptor inhibitors. If necessary during surgery, the effects of beta-adrenergic receptor inhibitors may be reversed by sufficient doses of adrenergic agonists. 5.5 Diabetes Mellitus Beta-adrenergic receptor inhibitors should be administered with caution in diabetic patients subject to hypoglycemia who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor inhibitors may mask the signs and symptoms of acute hypoglycemia. 5.6 Thyrotoxicosis Beta-adrenergic receptor inhibitors 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 receptor inhibitors that might precipitate a thyroid storm. 5.7 Cerebrovascular Insufficiency Because of potential effects of beta-adrenergic receptor inhibitors on 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 Timolol GFS, alternative therapy should be considered. 5.8 Bacterial Keratitis Bacterial keratitis may occur with use of multiple dose containers of topical ophthalmic products when these containers are inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Instruct patients on appropriate instillation techniques [see Patient Counseling Information (17) ]. 5.9 Choroidal Detachment Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant (e.g., timolol) therapy. 5.10 Angle-Closure Glaucoma In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This may require constricting the pupil. Timolol GFS has little or no effect on the pupil and should not be used alone in the treatment of angle-closure glaucoma. 5.11 Atopy/Anaphylaxis While taking beta receptor inhibitors, 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. 5.12 Muscle Weakness Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

7 DRUG INTERACTIONS • Oral beta-adrenergic receptor inhibitors may have additive effects ( 7.1 ) • Digitalis and calcium antagonists may have additive effects ( 7.2 ) • Catecholamine-depleting drugs may have additive effects ( 7.3 ) • Quinidine may have additive effects ( 7.4 ) 7.1 Oral Beta-Adrenergic Receptor Inhibitors Patients who are receiving a beta-adrenergic receptor inhibiting agent orally and Timolol GFS should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. Patients should not usually receive two topical ophthalmic beta-adrenergic receptor inhibiting agents concurrently. 7.2 Digitalis and Calcium Antagonists The concomitant use of beta-adrenergic receptor inhibiting agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. Caution should be used in the co-administration of beta-adrenergic receptor inhibitors, such as Timolol GFS, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, or hypotension. In patients with impaired cardiac function, co-administration should be avoided. 7.3 Catecholamine-Depleting Drugs Close observation of the patient is recommended when a beta receptor inhibitor 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 result in vertigo, syncope, or postural hypotension. 7.4 Quinidine Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6. 7.5 Clonidine Oral beta-adrenergic receptor inhibiting agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate. 7.6 Injectable Epinephrine Patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions. [See Warnings and Precautions (5.11) ]

6 ADVERSE REACTIONS Most common adverse reactions (1% to 5%) occur upon instillation and include transient blurred vision, burning, and stinging ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 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, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials with Timolol GFS, transient blurred vision upon instillation of the drop was reported in approximately one in three patients. The frequency of patients reporting burning and stinging upon instillation was approximately one in eight patients which was comparable to that observed for TIMOPTIC*. Adverse reactions reported in 1% to 5% of patients were: Ocular: Blepharitis, conjunctivitis, crusting, discomfort, foreign body sensation, hyperemia, pruritus and tearing; Systemic: Headache, hypertension, and upper respiratory infections. In a 3-month, double-masked, active-controlled, multicenter study in pediatric patients, the adverse reactions profile of Timolol GFS 0.25% and 0.5% was comparable to that seen in adult patients. 6.2 Additional Potential Adverse Reactions Associated with Timolol Maleate The following additional adverse experiences have been reported with the ocular administration of this or other timolol maleate formulations: BODY AS A WHOLE Asthenia/fatigue and chest pain. CARDIOVASCULAR Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, dizziness, edema, claudication, Raynaud's phenomenon, and cold hands and feet. DIGESTIVE Nausea, diarrhea, dyspepsia, anorexia, and dry mouth. IMMUNOLOGIC Systemic lupus erythematosus. NERVOUS SYSTEM/PSYCHIATRIC Increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including confusion, hallucinations, anxiety, depression, disorientation, nervousness, and memory loss. SKIN Alopecia and psoriasiform rash or exacerbation of psoriasis. HYPERSENSITIVITY Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria and localized and generalized rash. RESPIRATORY Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, and cough. ENDOCRINE Masked symptoms of hypoglycemia in diabetic patients [see Warnings and Precautions (5.5) ] . SPECIAL SENSES Signs and symptoms of ocular irritation including blepharitis, keratitis, and dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration surgery [see Warnings and Precautions (5.9 )] ; and tinnitus. UROGENITAL Retroperitoneal fibrosis, decreased libido, impotence and Peyronie's disease.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women with timolol maleate to inform a drug-associated risk. Administration of oral timolol maleate to pregnant mice, rats and rabbits did not produce teratogenicity at clinically relevant systemic exposures (see Data). Because animal reproductive studies are not always predictive of human response, Timolol GFS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 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.