Istalol Drug Information

® is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. ISTALOL is a beta adrenergic blocker indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

One drop of ISTALOL should be administered in the affected eye(s) once a day in the morning (AM). If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart. One drop in the affected eye(s) once a day in the morning.

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 ISTALOL. Additional reactions reported with ISTALOL 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 ; 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 ; Urogenital: Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie’s disease.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ISTALOL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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.

Beta-Adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent orally

and ISTALOL 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 co-administration of beta-adrenergic blocking

agents, such as ISTALOL, 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.

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) has been reported

during combined treatment with CYP2D6 inhibitors (e.g., quinidine) 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.

Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women with timolol maleate to inform a drug-associated risk. Administration of oral timolol maleate to pregnant mice, rats and rabbits did not produce teratogenicity at clinically relevant systemic exposures (see Data). Because animal reproductive studies are not always predictive of human response, ISTALOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data Teratogenicity studies with timolol in pregnant 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 maternally toxic 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 without apparent maternal toxicity.

Pediatric Use The safety and effectiveness of ISTALOL in pediatric patients have not been established.

Asthma

COPD ISTALOL is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease .

Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock

ISTALOL is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure; cardiogenic shock .

Hypersensitivity Reactions

ISTALOL is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this product in the past.

There have been reports of inadvertent overdosage with ISTALOL 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. 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.