Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Timolol maleate ophthalmic solution, USP 0.5% is supplied in white LDPE bottles with 15 mm HDPE yellow caps and 15 mm LDPE white dropper tips as follows: 5 mL in 10mL container (NDC 70069- 517 -01) 2.5 mL in 5mL container (NDC 70069- 516 -01) STORAGE Store at 15º – 25ºC (59º – 77ºF).; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Container Label – 2.5 mL NDC 70069-516-01 Rx only Timolol Maleate Ophthalmic Solution USP 0.5% 2.5 mL Sterile Carton Label – 2.5 mL NDC 70069-516-01 Rx only Timolol Maleate Ophthalmic Solution USP 0.5% For topical application in the eye 2.5 mL Sterile Container Label – 5 mL NDC 70069-517-01 Rx only Timolol Maleate Ophthalmic Solution USP 0.5% 5 mL Sterile Carton Label – 5 mL NDC 70069-517-01 Rx only Timolol Maleate Ophthalmic Solution USP 0.5% For topical application in the eye 5 mL Sterile Image Image Image Image
- 16 HOW SUPPLIED/STORAGE AND HANDLING Timolol maleate ophthalmic solution, USP 0.5% is supplied in white LDPE bottles with 15 mm HDPE yellow caps and 15 mm LDPE white dropper tips as follows: 5 mL in 10mL container (NDC 70069- 517 -01) 2.5 mL in 5mL container (NDC 70069- 516 -01) STORAGE Store at 15º – 25ºC (59º – 77ºF).
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Container Label – 2.5 mL NDC 70069-516-01 Rx only Timolol Maleate Ophthalmic Solution USP 0.5% 2.5 mL Sterile Carton Label – 2.5 mL NDC 70069-516-01 Rx only Timolol Maleate Ophthalmic Solution USP 0.5% For topical application in the eye 2.5 mL Sterile Container Label – 5 mL NDC 70069-517-01 Rx only Timolol Maleate Ophthalmic Solution USP 0.5% 5 mL Sterile Carton Label – 5 mL NDC 70069-517-01 Rx only Timolol Maleate Ophthalmic Solution USP 0.5% For topical application in the eye 5 mL Sterile Image Image Image Image
Overview
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
Indications & 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 & Administration
One drop of timolol maleate ophthalmic solution 0.5% should be administered in the affected eye(s) once a day in the AM. One drop in the affected eye(s) once a day in the AM (2)
Warnings & Precautions
Potentiation of Respiratory Reactions Including Asthma (5.1) Cardiac Failure (5.2) Obstructive Pulmonary Disease (5.3) Increased Reactivity to Allergens (5.4) Potentiation of Muscle Weakness (5.5) Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus (5.6) Masking of Thyrotoxicosis (5.7) 5.1 Potentiation of Respiratory Reactions Including Asthma Timolol maleate ophthalmic solution contains timolol maleate; and although administered topically, it can be absorbed systemically. Therefore, 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, (4.1)] . 5.2 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 [see contraindications, (4.2)] . 5.3 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, (4.2)] should, in general, not receive beta-blocking agents, including timolol maleate ophthalmic solution. 5.4 Increased Reactivity to Allergens 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. 5.5 Potentiation of 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. 5.6 Masking of Hypoglycemic Symptoms in Patients with 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. 5.7 Masking of 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. 5.8 Contamination of Topical Ophthalmic Products After Use There have been reports of bacterial keratitis associated with the use of multidose 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 Patient Counseling Information, (17)]. 5.9 Impairment of Beta-adrenergically Mediated Reflexes During 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. 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 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. 5.11 Cerebrovascular Insufficiency 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. 5.12 Choroidal Detachment Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).
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.
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 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.
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.
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