BETIMOL

INDICATIONS AND USAGE Betimol ® is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

DOSAGE AND ADMINISTRATION Betimol® Ophthalmic Solution is available in concentrations of 0.25% and 0.5%. The usual starting dose is one drop of 0.25% Betimol® 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% 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 Betimol® may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Betimol®. Dosages above one drop of 0.5% Betimol® 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.

CONTRAINDICATIONS Betimol ® 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, Betimol ® 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. Betimol ® should be discontinued at the first sign or symptom of cardiac failure. Obstructive Pulmonary Disease 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 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 (especially those with labile diabetes) 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.

Drug Interactions Beta-adrenergic blocking agents Patients who are receiving a beta-adrenergic blocking agent orally and Betimol ® 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 (See PRECAUTIONS, General, Anaphylaxis .)

ADVERSE REACTIONS The most frequently reported ocular event in clinical trials was burning/stinging on instillation and was comparable between Betimol ® and timolol maleate (approximately one in eight patients). The following adverse events were associated with use of Betimol ® in frequencies of more than 5% in two controlled, double-masked clinical studies in which 184 patients received 0.25% or 0.5% Betimol ® : 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. METABOLIC/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 (See WARNINGS ). NERVOUS SYSTEM/PSYCHIATRY: Depression, impotence, increase in signs and symptoms of myasthenia gravis and paresthesia. RESPIRATORY: Dyspnea, bronchospasm, respiratory failure and nasal congestion. SKIN: Alopecia, hypersensitivity including localized and generalized rash, urticaria.

Pregnancy Teratogenic effects Category C Teratogenicity of timolol (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. Betimol ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.