Timolol maleate 5 mg/mL Solution/ Drops — NDC 70069-707-01 (Billing 70069-0707-01)

WARNINGS As with many topically applied ophthalmic drugs, this drug 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 reactions 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 ophthalmic administration of timolol maleate [see CONTRAINDICATIONS].

Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition of beta-adrenergic receptor blockade may precipitate more severe 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. At the first sign or symptom of cardiac failure, timolol maleate ophthalmic solution should be discontinued.

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, in which timolol maleate ophthalmic solution is contraindicated [see CONTRAINDICATIONS]) should, in general, not receive beta-blockers, including timolol maleate ophthalmic solution. Major Surgery The necessity or desirability of withdrawal of beta-adrenergic blocking agents 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 blocking agents have experienced protracted severe hypotension during anesthesia.

Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of 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 that might precipitate a thyroid storm.

ADVERSE REACTIONS The most frequently reported adverse experiences have been burning and stinging upon instillation (approximately one in eight patients). The following additional adverse experiences have been reported less frequently with ocular administration of this or other timolol maleate formulations: Body as a Whole Headache, 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, 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 anaphylaxis, angioedema, urticaria, and localized and generalized rash. Respiratory Bronchospasm (predominantly in patients with preexisting bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections.

Endocrine Masked symptoms of hypoglycemia in diabetic patients [see WARNINGS] . 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 PRECAUTIONS, General ]; and tinnitus. Urogenital Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.

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 pigmentation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties.

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

Drug Interactions Although timolol maleate ophthalmic solution used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with timolol maleate ophthalmic solution and epinephrine has been reported occasionally. 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.

Calcium antagonists: Caution should be used in the coadministration 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, coadministration should be avoided. 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.

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. CYP2D6 inhibitors: Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol. 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. Injectable epinephrine: [see PRECAUTIONS, General , Anaphylaxis] .

PRECAUTIONS General Because of potential effects of beta-adrenergic blocking agents 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 maleate ophthalmic solution, 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 [see PRECAUTIONS, Information for Patients] . Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol). Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle.

This requires constricting the pupil. Timolol maleate has little or no effect on the pupil. Timolol maleate ophthalmic solution should not be used alone in the treatment of angle-closure glaucoma.

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. 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 rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms. 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, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, 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 [see PRECAUTIONS, General ]. Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container. 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 [see CONTRAINDICATIONS] .

Patients should be advised that timolol maleate ophthalmic solution contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following timolol maleate ophthalmic solution administration.

Drug Interactions Although timolol maleate ophthalmic solution used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with timolol maleate ophthalmic solution and epinephrine has been reported occasionally. 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.

Calcium antagonists: Caution should be used in the coadministration of beta-adrenergic blocking agents, such as timolol maleate ophthalmic solution, and oral or intravenous calcium antagonists… [Excerpted — this section continues on DailyMed.]