Timoptic-XE

INDICATIONS AND USAGE TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

DOSAGE AND ADMINISTRATION Patients should be instructed to invert the closed container and shake once before each use. It is not necessary to shake the container more than once. Other topically applied ophthalmic medications should be administered at least 10 minutes before TIMOPTIC-XE [see PRECAUTIONS , Information for Patients and accompanying INSTRUCTIONS FOR USE ]. TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is available in concentrations of 0.25% and 0.5%. The dose is one drop of TIMOPTIC-XE (either 0.25% or 0.5%) in the affected eye(s) once a day. Because in some patients the pressure-lowering response to TIMOPTIC-XE may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with TIMOPTIC-XE. Dosages higher than one drop of 0.5% TIMOPTIC-XE once a day have not been studied. If the patient’s intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy can be considered. The concomitant use of two topical beta-adrenergic blocking agents is not recommended [see PRECAUTIONS , Drug Interactions , Beta-Adrenergic Blocking Agents ]. When patients have been switched from therapy with TIMOPTIC administered twice daily to TIMOPTIC-XE administered once daily, the ocular hypotensive effect has remained consistent.

CONTRAINDICATIONS TIMOPTIC-XE is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease [see WARNINGS , Obstructive Pulmonary Disease ]; (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure [see WARNINGS , Cardiac Failure ]; (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

ADVERSE REACTIONS In clinical trials, transient blurred vision upon instillation of the drop was reported in approximately one in three patients (lasting from 30 seconds to 5 minutes). Less than 1% of patients discontinued from the studies due to blurred vision. The frequency of patients reporting burning and stinging upon instillation was comparable between TIMOPTIC-XE and TIMOPTIC (approximately one in eight patients). Adverse experiences reported in 1-5% of patients were: Ocular: Pain, conjunctivitis, discharge (e.g., crusting), foreign body sensation, itching and tearing; Systemic: Headache, dizziness, and upper respiratory infections. 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, cerebrovascular 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 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, 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 , Diabetes Mellitus ]. 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 PRECAUTIONS , Genera l ]; 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 Bausch & Lomb Incorporated at 1-800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. OVERDOSAGE No data are available in regard to human overdosage with or accidental oral ingestion of TIMOPTIC‐XE. There have been reports of inadvertent overdosage with TIMOPTIC Ophthalmic Solution resulting in systemic effect …

Drug Interactions Beta-Adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent orally and TIMOPTIC-XE 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 TIMOPTIC‐XE, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, or 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 ]

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. TIMOPTIC-XE, 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 and optic nerve damage. The precise mechanism of the ocular hypotensive action of TIMOPTIC-XE is not clearly established at this time. Tonography and fluorophotometry studies of TIMOPTIC ® (timolol maleate ophthalmic solution) 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 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.

DESCRIPTION TIMOPTIC-XE ® (timolol maleate ophthalmic gel forming solution) 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. The optical rotation of timolol maleate is: 25° [α] in 1.0N HCl (C = 5%) = -12.2° (-11.7° to -12.5°). 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 432.49. It is a white, odorless, crystalline powder which is soluble in water; sparingly soluble in ethanol; slightly soluble in chloroform; practically insoluble in ether. TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths. The pH of the solution is approximately 7.0, and the osmolarity is 260-330 mOsm. Each mL of TIMOPTIC-XE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of TIMOPTIC-XE 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: gellan gum, tromethamine, mannitol, and water for injection. Preservative: benzododecinium bromide 0.012%. The gel forming solution contains a purified anionic heteropolysaccharide derived from gellan gum. An aqueous solution of gellan gum, in the presence of a cation, has the ability to gel. Upon contact with the precorneal tear film, TIMOPTIC-XE forms a gel that is subsequently removed by the flow of tears. chem

HOW SUPPLIED TIMOPTIC-XE (timolol maleate ophthalmic gel forming solution) is a colorless to nearly colorless, slightly opalescent, and slightly viscous solution. TIMOPTIC-XE (timolol maleate ophthalmic gel forming solution), 0.25% timolol equivalent, is supplied in a white low density polyethylene (LDPE) dispenser with a controlled drop tip and a yellow polypropylene cap as follows: NDC 24208-814-25, 5 mL in a 7.5 mL capacity bottle. TIMOPTIC-XE (timolol maleate ophthalmic gel forming solution), 0.5% timolol equivalent, is supplied in a white low density polyethylene (LDPE) dispenser with a controlled drop tip and a yellow polypropylene cap as follows: NDC 24208-816-05, 5 mL in a 7.5 mL capacity bottle. Storage Store at 15°C to 25°C (59°F to 77°F). Avoid freezing. Protect from light. Distributed by: Bausch & Lomb Americas Inc. Bridgewater, NJ 08807 USA Manufactured by: Bausch & Lomb Incorporated Tampa, FL 33637 USA TIMOPTIC and TIMOPTIC-XE are trademarks of Bausch & Lomb Incorporated or its affiliates. © 2022 Bausch & Lomb Incorporated or its affiliates Revised: 03/2022 9752801