Adverse effects
The most common adverse effects affecting 5 to 15% of the patients include allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging. 1 to 5% of the patients in clinical trials experienced asthenia, blepharitis, corneal erosion, depression, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body sensation, headache, hypertension, oral dryness, somnolence, superficial punctate keratitis, and visual disturbance. Contraindications
Contraindications of Combigan include the following: reactive airway disease including bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, secondary or third degree atrioventricular block, overt cardiac failure, cardiogenic shock, age less than 2 years, and hypersensitivity to any component of Combigan. Pharmacology
Combigan is composed of brimonidine, a selective alpha-2 adrenergic receptor agonist, and timolol, a non-selective beta-adrenergic receptor inhibitor. Elevated IOP is considered the only modifiable risk factor in the pathogenesis of glaucoma. Brimonidine exerts its ocular hypotensive effect by decreasing aqueous humor production and increasing uveoscleral outflow, while timolol acts by reducing aqueous humor production. Combigan has a fast onset of action, and the peak IOP lowering effect occurs at two hours after administration. Preclinical studies
No carcinogenic effects were found with brimonidine tartrate in mice or rats.
With timolol maleate, 300 mg/kg/day in rats (equivalent to about 42,000 times systemic exposure following the maximum recommended ocular dose in human [MRHOD]) was associated with significantly increased incidence of adrenal pheochromocytomas in a two-year study; in a lifetime study in mice, 500 mg/kg/day (equivalent to about 71,000 times systemic exposure following the MRHOD) but not 5 or 50 mg/kg/day (about 700 or 7,000 times systemic exposure following the MRHOD) of timolol maleate was associated with significantly increased incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas. Neither brimonidine tartrate nor timolol maleate was mutagenic in in vitro and in vivo studies. Reproduction and fertility studies in rats did not reveal any adverse effects on male or female fertility with brimonidine tartrate or timolol maleate. Clinical trials
Two prospective, randomized, double-blinded, phase III clinical trials were conducted at 53 sites in the United States to compare the IOP-lowering efficacy and safety of 0.2% brimonidine tartrate/0.5% timolol maleate fixed combination twice daily with 0.2% brimonidine tartrate three times daily or 0.5% timolol maleate twice daily in patients aged 18 or older who had ocular hypertension or glaucoma. When assessed over a 3-month period, pooled results from a total of 1159 patients showed significantly greater mean IOP decrease from baseline with the brimonidine/timolol combination (4.9-7.6 mmHg) than with brimonidine monotherapy (3.1-5.5 mmHg) or timolol monotherapy (4.3-6.2 mmHg) across all follow-up visits.