Timolol Hemihydrate

1 INDICATIONS AND USAGE Timolol maleate ophthalmic solution 0.5% is a non-selective beta-adrenergic receptor blocking agent indicated in the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. Timolol maleate ophthalmic solution is a non-selective beta-adrenergic receptor blocking agent indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma (1)

DOSAGE AND ADMINISTRATION Timolol Ophthalmic Solution is available in concentration of 0.5 percent. The usual starting dose is one drop of 0.25 percent timolol ophthalmic solution 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 timolol ophthalmic solution may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with timolol ophthalmic solution. Dosages above one drop of 0.5 percent timolol ophthalmic solution 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.

3 DOSAGE FORMS AND STRENGTHS Topical ophthalmic solution, USP containing 5 mg/mL timolol (6.8 mg/mL of timolol maleate). Topical ophthalmic solution containing timolol maleate, 0.5% (5 mg/mL) (3)

4 CONTRAINDICATIONS Bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease . (4.1, 5.1, 5.3) Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock . (4.2, 5.2) Hypersensitivity to any component of this product (4.3) 4.1 Asthma, COPD Timolol maleate ophthalmic solution is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease [see Warnings and Precautions, (5.1, 5.3)] . 4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Timolol maleate ophthalmic solution is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure; cardiogenic shock [see Warnings and Precautions, (5.2)] . 4.3 Hypersensitivity Reactions Timolol maleate ophthalmic solution is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this product in the past.

6 ADVERSE REACTIONS The most frequently reported adverse reactions have been burning and stinging upon instillation in 38% of patients treated with timolol maleate ophthalmic solution. Additional reactions reported with timolol maleate ophthalmic solution at a frequency of 4 to 10% include: blurred vision, cataract, conjunctival injection, headache, hypertension, infection, itching and decreased visual acuity . (6) To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1-800-417-9175 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. The most frequently reported adverse reactions have been burning and stinging upon instillation in 38% of patients treated with timolol maleate ophthalmic solution. Additional reactions reported with timolol maleate ophthalmic solution at a frequency of 4 to 10% include: blurred vision, cataract, conjunctival injection, headache, hypertension, infection, itching and decreased visual acuity. The following additional adverse reactions have been reported less frequently with ocular administration of this or other timolol maleate formulations. Timolol (Ocular Administration) Body as a Whole: Asthenia/fatigue and chest pain; Cardiovascular: Bradycardia, arrhythmia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, 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: Dizziness, increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including depression, confusion, hallucinations, anxiety, disorientation, nervousness and memory loss; Skin: Alopecia and psoriasiform rash or exacerbation of psoriasis; Hypersensitivity: Signs and symptoms of systemic allergic reactions, including angioedema, urticaria, and localized and generalized rash; Respiratory: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections; Endocrine: Masked symptoms of hypoglycemia in diabetic patients [see Warnings and Precautions (5.6)] ; Special Senses: Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain, discharge (e.g., crusting), foreign body sensation, itching and tearing, 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, (5.12)] ; Urogenital: Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease. 6.2 Postmarketing Experience Oral Timolol/Oral Beta-Blockers The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic timolol maleate: Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular: Worsening of arterial insufficiency, vasodilatation; Digestive : Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Hematologic : Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigme …

7 DRUG INTERACTIONS Concomitant use with systemic beta-blockers may potentiate systemic beta- blockade. (7.1) Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension . (7.2) Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked bradycardia . (7.3) Digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. (7.4) Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol. (7.5) 7.1 Beta-Adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent orally and timolol maleate ophthalmic solution should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. 7.2 Calcium Antagonists Caution should be used in the co-administration of beta-adrenergic blocking agents, such as timolol maleate ophthalmic solution, 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. 7.3 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 result in vertigo, syncope, or postural hypotension. 7.4 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. 7.5 CYP2D6 Inhibitors Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine) and timolol. 7.6 Clonidine Oral beta-adrenergic blocking 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Teratogenicity studies have been performed in animals. 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 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. Timolol maleate ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Timolol has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from timolol maleate ophthalmic solution in nursing infants, 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. 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.

12.1 Mechanism of Action Timolol maleate is a beta 1 and beta 2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. 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 blockade 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 activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous. Timolol maleate ophthalmic solution, when applied topically on 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. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. The onset of reduction in intraocular pressure following administration of timolol maleate ophthalmic solution can usually be detected within one-half hour after a single dose. The maximum effect usually occurs in one to two hours and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours with a single dose. Repeated observations over a period of one year indicate that the intraocular pressure lowering effect of timolol maleate ophthalmic solution is well maintained. The precise mechanism of the ocular hypotensive action of timolol maleate ophthalmic solution is not clearly established at this time. Tonography and fluorophotometry studies 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.

11 DESCRIPTION Timolol maleate ophthalmic solution 0.5% is a non-selective beta-adrenergic receptor blocking agent. Its chemical name is (-)-1-( tert -butylamino) -3- [(4-morpholino 1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. 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 432.49. It is a white or almost white, crystalline powder which is soluble in water, sparingly soluble in ethanol, slightly soluble in chloroform, practically insoluble in ether. Timolol maleate ophthalmic solution is stable at room temperature. Timolol maleate ophthalmic solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in a single strength. It has a pH of 6.5-7.5 and an osmolality of 275-330 mOsm/kg. Each mL of timolol maleate ophthalmic solution contains the active ingredient 5 mg of timolol (6.8 mg of timolol maleate) with the inactive ingredients benzalkonium chloride (0.05 mg/mL), monobasic sodium phosphate monohydrate, potassium sorbate 0.47%, sodium chloride, sodium hydroxide, and purified water. Image

10 OVERDOSAGE There have been reports of inadvertent overdosage with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. 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.

HOW SUPPLIED Timolol ophthalmic solution is a clear, colorless solution. Timolol ophthalmic solution 0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows: NDC 70069- 696 -01 5 mL fill in 5 mL bottle NDC 70069- 697 -01 10 mL fill in 10 mL bottle NDC 70069- 698 -01 15 mL fill in 15 mL bottle Rx Only STORAGE Store at 15° to 25°C (59° to 77°F). Do not freeze. Protect from light.