Included as part of the PRECAUTIONS section.
Potential For Severe Respiratory Or Cardiac Reactions
COMBIGAN® contains timolol maleate; and although
administered topically can be absorbed systemically. Therefore, the same types
of 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]. Additionally, ophthalmic beta-blockers
may impair compensatory tachycardia and increase risk of hypotension.
Sympathetic stimulation may be essential for support of
the circulation in individuals with diminished myocardial contractility, and
its inhibition by 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, COMBIGAN® should be discontinued [see 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 COMBIGAN® is
contraindicated [see CONTRAINDICATIONS]) should, in general, not receive
beta-blocking agents, including COMBIGAN®.
Potentiation Of Vascular Insufficiency
COMBIGAN® may potentiate syndromes associated with
vascular insufficiency. COMBIGAN® should be used with caution in
patients with depression, cerebral or coronary insufficiency, Raynaud's
phenomenon, orthostatic hypotension, or thromboangiitis obliterans.
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
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
betaadrenergic blocking agents that might precipitate a thyroid storm.
Ocular hypersensitivity reactions have been reported with
brimonidine tartrate ophthalmic solutions 0.2%, with some reported to be
associated with an increase in intraocular pressure [see CONTRAINDICATIONS].
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 betaadrenergically 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
beta-adrenergic blocking agents may be reversed by sufficient doses of
Carcinogenesis, Mutagenesis, Impairment Of Fertility
With brimonidine tartrate, no compound-related
carcinogenic effects were observed in either mice or rats following a 21-month
and 24-month study, respectively. In these studies, dietary administration of
brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1 mg/kg/day in
rats achieved 150 and 210 times, respectively, the plasma Cmax drug
concentration in humans treated with one drop of COMBIGAN® into both
eyes twice daily, the recommended daily human dose.
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 25,000 times the maximum recommended human ocular dose of 0.012
mg/kg/day on a mg/kg basis (MRHOD)].
Similar differences were not observed in rats
administered oral doses equivalent to approximately 8,300 times the daily dose
of COMBIGAN® in humans.
In a lifetime oral study of timolol maleate 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 42,000 times the MRHOD), but
not at 5 or 50 mg/kg/day (approximately 420 to 4,200 times higher,
respectively, than the MRHOD). 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.
Brimonidine tartrate was not mutagenic or clastogenic in
a series of in vitro and in vivo studies including the Ames bacterial reversion
test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and
three in vivo studies in CD-1 mice: a host-mediated assay, cytogenetic study,
and dominant lethal assay.
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 with timolol
maleate and in rats with brimonidine tartrate demonstrated no adverse effect on
male or female fertility at doses up to approximately 100 times the systemic
exposure following the maximum recommended human ophthalmic dose of COMBIGAN®.
Use In Specific Populations
Teratogenicity studies have been performed in animals.
Brimonidine tartrate was not teratogenic when given orally during gestation
days 6 through 15 in rats and days 6 through 18 in rabbits. The highest doses
of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5 mg/kg/day)
achieved AUC exposure values 580 and 37-fold higher, respectively, than similar
values estimated in humans treated with COMBIGAN®, 1 drop in both
eyes twice daily.
Teratogenicity studies with timolol in mice, rats, and
rabbits at oral doses up to 50 mg/kg/day [4,200 times the maximum recommended
human ocular dose of 0.012 mg/kg/day on a mg/kg basis (MRHOD)] 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 (83,000 times the MRHOD)
were maternotoxic in mice and resulted in an increased number of fetal
resorptions. Increased fetal resorptions were also seen in rabbits at doses
8,300 times the MRHOD without apparent maternotoxicity.
There are no adequate and well-controlled studies in
pregnant women; however, in animal studies, brimonidine crossed the placenta
and entered into the fetal circulation to a limited extent. Because animal
reproduction studies are not always predictive of human response, COMBIGAN® should
be used during pregnancy only if the potential benefit to the mother justifies
the potential risk to the fetus.
Timolol has been detected in human milk following oral
and ophthalmic drug administration. It is not known whether brimonidine
tartrate is excreted in human milk, although in animal studies, brimonidine
tartrate has been shown to be excreted in breast milk. Because of the potential
for serious adverse reactions from COMBIGAN® 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.
COMBIGAN® is contraindicated in children under the
age of 2 years [see CONTRAINDICATIONS]. During post-marketing
surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia,
lethargy, pallor, respiratory depression, and somnolence have been reported in
infants receiving brimonidine. The safety and effectiveness of brimonidine
tartrate and timolol maleate have not been studied in children below the age of
The safety and effectiveness of COMBIGAN® have
been established in the age groups 2 – 16 years of age. Use of COMBIGAN® in
these age groups is supported by evidence from adequate and well-controlled
studies of COMBIGAN® in adults with additional data from a study of the
concomitant use of brimonidine tartrate ophthalmic solution 0.2% and timolol
maleate ophthalmic solution in pediatric glaucoma patients (ages 2 to 7 years).
In this study, brimonidine tartrate ophthalmic solution 0.2% was dosed three
times a day as adjunctive therapy to beta-blockers. The most commonly observed
adverse reactions were somnolence (50%-83% in patients 2 to 6 years) and
decreased alertness. In pediatric patients 7 years of age or older ( > 20 kg),
somnolence appears to occur less frequently (25%). Approximately 16% of
patients on brimonidine tartrate ophthalmic solution discontinued from the
study due to somnolence.
No overall differences in safety or effectiveness have
been observed between elderly and other adult patients.