Brimonidine/timolol, sold under the brand name Combigan among others, is a fixed-dose combination medication eye drop used for the treatment of glaucoma. It is a combination of brimonidine (an α2 adrenergic agonist) and timolol (a β adrenergic blocker). In 2020, it was the 256th most commonly prescribed medication in the United States, with more than 1million prescriptions. Medical uses Brimonidine/timolol is used to reduce elevated intraocular pressure (IOP) in people with glaucoma or ocular hypertension who need adjunctive or replacement therapy. 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 brimonidine/timolol 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 brimonidine/timolol. Pharmacology Brimonidine/timolol 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. Brimonidine/timolol has a fast onset of action, and the peak IOP lowering effect occurs at two hours after administration. History 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