Combigan

8.1        Pregnancy

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.

8.3        Nursing Mothers

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.

8.4        Pediatric Use

COMBIGAN® is contraindicated in children under the age of 2 years [see Contraindications ( 4.3)]. 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 2 years.

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.

8.5        Geriatric Use

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

5.1        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 ( 4.1)]. Additionally, ophthalmic beta-blockers may impair compensatory tachycardia and increase risk of hypotension. 

5.2        Cardiac Failure

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 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, COMBIGAN® should be discontinued [see Contraindications ( 4.2)].

5.3        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 ( 4.1)] should, in general, not receive beta-blocking agents, including COMBIGAN®. 

5.4        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.

5.5        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.

5.6        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.

5.7        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.

5.8        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.

5.9        Ocular Hypersensitivity

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 ( 4.4)].

5.10        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 Counseling Information ( 17)].

5.11        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 beta-adrenergic receptor blocking agents.

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