Combigan Special Precautions

As with other topically applied ophthalmic agents, the active substances (brimonidine tartrate and timolol) in COMBIGAN may be absorbed systemically. No enhancement of the systemic absorption of the individual active substance has been observed.
Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur.
Respiratory and cardiac reaction have been reported including, rarely, death due to bronchospasm or associated with cardiac failure.
COMBIGAN has not been studied in children under the age of 18 years. However, in a 3-month phase 3 study in children (ages 2-7 years) with glaucoma inadequately controlled by beta-blockers, the use of brimonidine tartrate ophthalmic solution 0.2% led to a high incidence and severity of somnolence in children 2 years of age and above, especially those weighing ≤20 kg (see Use in Children as follows).
Delayed ocular hypersensitivity reactions have been reported with brimonidine tartrate ophthalmic solution 0.2%, with some reported to be associated with an increase in IOP.
Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease (e.g., coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension. Cardiac failure should be adequately controlled before beginning therapy. Patients with a history of severe cardiac disease should be watched for sign of cardiac failure and have their pulse rates checked. Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block. Cardiac and respiratory reactions, including death due to bronchospasm in patients with asthma, and, rarely, death in association with cardiac failures have been reported following administration of timolol maleate.
Beta-blockers may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension.
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.
COMBIGAN should be used with caution in patients with depression, cerebral or coronary insufficiency, with severe peripheral circulatory disturbance/disorders (i.e Raynaud's phenomenon), orthostatic hypotension.
Patients with chronic obstructive pulmonary disease of mild or moderate severity should, in general, not receive products containing beta-blockers, including COMBIGAN; however, if COMBIGAN is deemed necessary in such patients, it should be administered with caution.
While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens. Such patients may be unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.
As with systemic beta-blockers, if discontinuation of treatment is needed in patients with coronary heart disease, therapy should be withdrawn gradually to avoid rhythm disorders, myocardial infarct or sudden death.
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).
Caution should be exercised when used concomitantly with systemic beta-adrenergic blocking agents because of the potential for additive effects on systemic beta-blockade.
The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended.
Ophthalmic beta-blockers may impair compensatory tachycardia and increase risk of hypotension when used in conjunction with anesthetics. The anesthetist must be informed if the patient is using COMBIGAN.
The preservative in COMBIGAN, benzalkonium chloride, may cause eye irritation. Patients wearing soft (hydrophilic) contact lenses should be instructed to remove contact lenses prior to application and wait at least 15 minutes after instilling COMBIGAN before reinsertion. Benzalkonium chloride is known to be absorbed by and discolour soft contact lenses. Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures to avoid eye injury and contamination of eye drops.
COMBIGAN has not been studied in patients with hepatic or renal impairment. Therefore, caution should be used in treating such patients.
Effects on ability to drive and use machines: As with other similar medications, COMBIGAN may cause fatigue and/or drowsiness in some patients. Patients who engage in activities such as driving and operating machinery should be cautioned of the potential for a decrease in mental alertness. COMBIGAN may also cause blurred vision or visual disturbance. The patient should wait until these symptoms have cleared before driving or using machinery.
Use in Children: COMBIGAN should not be used in neonates.
The safety and effectiveness of COMBIGAN in children and adolescents have not been established and therefore, its use is not recommended in children or adolescents.
There are no adequate and well-controlled studies with COMBIGAN in children (less than 18 years old). In a 3-month, Phase 3 study in children (ages 2-7 years) with glaucoma inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with brimonidine tartrate ophthalmic solution 0.2% as adjunctive treatment to topical beta-blockers. This was severe in 8% of the children and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, the least being in the 7 year old age group (25%), but was more affected by weight, occurring more frequently in children weighing ≤20 kg (63%) compared to those weighing >20 kg (25%).
During post-marketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in neonates, infants, and children receiving brimonidine either for congenital glaucoma or by accidental ingestion (see Contraindications).
Use in the Elderly: No overall differences in safety and effectiveness have been observed between elderly and other adult patients.