Timoptic Drug Information

Preservative-free timolol maleate ophthalmic solution USP in the unit dose vial is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Preservative-free timolol maleate ophthalmic solution USP in the unit dose vial may be used when a patient is sensitive to the preservative in timolol maleate ophthalmic solution USP, benzalkonium chloride, or when use of a preservative-free topical medication is advisable.

Preservative-free timolol maleate ophthalmic solution USP in the unit dose vial is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be guaranteed after the individual unit is opened, the remaining contents should be discarded immediately after administration.

Preservative-free timolol maleate ophthalmic solution in the unit dose vial is available in concentrations of 0.25% and 0.5%. The usual starting dose is one drop of 0.25% preservative-free timolol maleate ophthalmic solution in the unit dose vial in the affected eye(s) administered twice a day. Apply enough gentle pressure on the individual vial to obtain a single drop of solution. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5% solution in the affected eye(s) administered twice a day.

Since in some patients the pressure-lowering response to preservative-free timolol maleate ophthalmic solution in the unit dose vial may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with preservative-free timolol maleate ophthalmic solution in the unit dose vial. 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. Dosages above one drop of 0.5% timolol maleate 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 other agent(s) for lowering intraocular pressure can be instituted taking into consideration that the preparation(s) used concomitantly may contain one or more preservatives. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)

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 USP 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 pre-existing 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 USP or other ORAL beta blocking agents, and may be considered potential effects of ophthalmic timolol maleate USP: 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 Nordic Pharma, Inc. at 1-844-267-4641 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Although timolol maleate ophthalmic solution USP used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with timolol maleate ophthalmic solution USP and epinephrine has been reported occasionally. Beta-adrenergic blocking agents : Patients who are receiving a beta-adrenergic blocking agent orally and preservative-free timolol maleate ophthalmic solution USP in the unit dose vial 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 preservative-free timolol maleate ophthalmic solution USP in the unit dose vial, 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 )

• Pregnancy: Teratogenic Effects : 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 1,000 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. Preservative-free timolol maleate ophthalmic solution USP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pediatric Use Safety and effectiveness of timolol maleate ophthalmic solution USP have been established when administered in pediatric patients aged 2 years and older. Use of timolol maleate ophthalmic solution USP in these children is supported by evidence from adequate and well- controlled studies in children and adults. Safety and efficacy in pediatric patients below the age of 2 years have not been established.

Preservative-free timolol maleate ophthalmic solution USP in the unit dose vial is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease (see WARNINGS ); sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure (see WARNINGS ); cardiogenic shock; or hypersensitivity to any component of this product.

There have been reports of inadvertent overdosage with timolol maleate ophthalmic solution USP 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 (see also ADVERSE REACTIONS ). Overdosage has been reported with timolol maleate USP tablets. A 30 year old female ingested 650 mg of timolol maleate USP tablets (maximum recommended oral daily dose is 60 mg) and experienced second and third degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block.

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.