Included as part of the PRECAUTIONS section.
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).
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
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
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
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
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.
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.
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 after filtration procedures has been
reported with the administration of aqueous suppressant therapy (e.g. timolol).
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
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.
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.
Safety and effectiveness in pediatric patients have not
No overall differences in safety or effectiveness have
been observed between elderly and younger patients.