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 ).

3 DOSAGE FORMS AND STRENGTHS Ophthalmic gel forming solution: slightly opalescent, colorless to nearly colorless solution containing 0.25% or 0.5% of timolol. Available in 5 mL size bottle filled with 2.5 mL or 5 mL solution. Ophthalmic gel forming solution containing 0.25% or 0.5% of timolol ( 3 ).

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 )

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.

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) ]

8 USE IN SPECIFIC POPULATIONS 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. 8.2 Lactation Risk Summary Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Timolol GFS and any potential adverse effects on the breastfed child from Timolol GFS. 8.4 Pediatric Use The safety and IOP-lowering effect of Timolol GFS 0.25% and 0.5% have been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-controlled trial. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.

12.1 Mechanism of Action Timolol maleate is a beta 1 and beta 2 (non-selective) adrenergic receptor inhibitor that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. Timolol GFS, when applied topically to the eye, has the action of reducing elevated, as well as normal, intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss and optic nerve damage. The precise mechanism of the ocular hypotensive action of Timolol GFS is not clearly established at this time. Tonography and fluorophotometry studies of Timolol GFS in man suggest that its predominant action may be related to reduced aqueous formation. However, in some studies, a slight increase in outflow facility was also observed. Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function beta-adrenergic receptor inhibitors may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function. Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed parasympathetic activities. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.

11 DESCRIPTION Timolol GFS (timolol maleate ophthalmic gel forming solution) is a non-selective beta-adrenergic receptor inhibitor. Its chemical name is (-)-1-( tert -butylamino)-3-[(4-morpholino-1,2,5-thia diazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided at the levo-isomer. The nominal optical rotation of timolol maleate is: [α] 25° in 0.1N HCl (C=5%) = -12.2° 405 nm Its molecular formula is C 13 H 24 N 4 O 3 S·C 4 H 4 O 4 and its structural formula is: Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Timolol GFS is a colorless to nearly colorless, slightly opalescent, and slightly viscous, is supplied as a sterile, isotonic, buffered, aqueous topical ophthalmic solution of timolol maleate in two dosage strengths. Timolol GFS has a pH of approximately 6.9 and an osmolality of approximately 290 mOsmol/kg. Each mL of Timolol GFS 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of Timolol GFS 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: boric acid, mannitol, polysorbate-80, tromethamine, xanthan gum, and purified water. Preservative: benzododecinium bromide 0.012%. Xanthan gum is a purified high molecular weight polysaccharide gum produced from the fermentation by bacterium Xanthomonas campestris. An aqueous solution of xanthan gum, in the presence of tear protein (lysozyme), forms a gel. Upon contact with the precorneal tear film, Timolol GFS forms a gel that is subsequently removed by the flow of tears. chemical

10 OVERDOSAGE No data are available with regard to human overdose with, or accidental oral ingestion of Timolol GFS. There have been reports of inadvertent overdose with Timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic receptor inhibitors such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest [see also Adverse Reactions (6) ]. Overdosage has been reported with timolol maleate tablets. A 30-year old female ingested 650 mg of timolol maleate tablets (maximum recommended oral daily dose is 60 mg) and experienced second and third degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block. An in vitro hemodialysis study, using 14 C timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily.

16 HOW SUPPLIED/STORAGE AND HANDLING Timolol GFS (timolol maleate ophthalmic gel forming solution) 0.25% and 0.5%, are both supplied as either a 2.5 mL or 5 mL slightly opalescent, colorless to nearly colorless solution in a 5 mL white polyethylene bottle with a natural polyethylene dropper tip and a yellow polypropylene overcap. Tamper evidence is provided with a shrink band around the closure and neck area of the bottle. • 0.25% 2.5 mL fill NDC 61314-224-25 5 mL fill NDC 61314-224-05 • 0.5% 2.5 mL fill NDC 61314-225-25 5 mL fill NDC 61314-225-05 Storage and Handling Store at 2°C to 25°C (36°F to 77°F). After opening, Timolol GFS can be used until the expiration date on the bottle. Protect from light.