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Istalol

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Istalol

Istalol

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Potentiation of Respiratory Reactions Including Asthma

Istalol® 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).

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, Istalol® should be discontinued (see also CONTRAINDICATIONS).

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 Istalol® is contraindicated (see CONTRAINDICATIONS] should, in general, not receive beta-blocking agents, including Istalol® .

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.

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.

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.

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.

Contamination of Topical Ophthalmic Products After Use

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 PATIENT INFORMATION).

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 betaadrenergic receptor blocking agents. If necessary during surgery, the effects of betaadrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.

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. Istalol® should not be used alone in the treatment of angle-closure glaucoma.

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 Istalol®, alternative therapy should be considered.

Choroidal Detachment

Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.

In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day, (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.

Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.

Use In Specific Populations

Pregnancy

Teratogenic Effects - Pregnancy Category C

Teratogenicity studies have been performed in animals. 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 1000 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. Istalol® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Timolol has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from Istalol® in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Last reviewed on RxList: 7/1/2013
This monograph has been modified to include the generic and brand name in many instances.

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Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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