• Glaucoma

Combigan Generic Name & Formulations

General Description

Brimonidine tartrate 0.2%, timolol (as maleate) 0.5%; oph soln; contains benzalkonium chloride.

Pharmacological Class

Alpha-2 agonist + noncardioselective beta-blocker.

How Supplied

Soln—5mL, 10mL, 15mL

How Supplied

Combigan is supplied sterile, in white opaque plastic LDPE bottles and tips, with blue high impact polystyrene (HIPS) caps as follows: 5mL in 10mL bottle; 10mL in 10mL bottle; 15mL in 15mL bottle.


Store at 15°-25°C (59°-77°F). Protect from light.


Combigan Indications


To reduce elevated intraocular pressure (IOP) in glaucoma or ocular hypertension where adjunctive or replacement therapy is warranted.

Combigan Dosage and Administration

Adults and Children

<2yrs: contraindicated. ≥2yrs: 1 drop every 12 hours.

Combigan Contraindications


Bronchial asthma or history of. Severe COPD. 2nd- or 3rd-degree AV block. Overt cardiac failure. Cardiogenic shock. Sinus bradycardia. Neonates and infants <2yrs of age.

Combigan Boxed Warnings

Not Applicable

Combigan Warnings/Precautions


Potential for severe respiratory or cardiac reactions. Discontinue at 1st sign of cardiac failure and before surgery. Mild to moderate COPD, bronchospastic disease: not recommended. Depression. Cerebral or coronary insufficiency. Raynaud's phenomenon. Orthostatic hypotension. Thromboangiitis obliterans. Myasthenia gravis. Renal or hepatic impairment. May mask hypoglycemia, thyrotoxicosis. Soft contact lenses (remove; may reinsert 15 minutes after instillation). Separate dosing of other oph drugs by ≥5 minutes. Pregnancy (Cat.C). Nursing mothers: not recommended.


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. Additionally, ophthalmic beta-blockers may impair compensatory tachycardia and increase risk of hypotension.

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.

  • Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure in patients without a history of cardiac failure. Discontinue Combigan at the first sign or symptom of cardiac failure.

Obstructive Pulmonary Disease

  • Combigan is contraindicated in 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

Potentiation of Vascular Insufficiency

  • May potentiate syndromes associated with vascular insufficiency. 

  • Use caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans. 

Increased Reactivity to Allergens

  • 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 (eg, 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 Mellitus 

  • Use 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

  • May mask certain clinical signs (eg, tachycardia) of hyperthyroidism. 

  • Manage carefully in patients suspected of developing thyrotoxicosis to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm. 

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.

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.

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. 

  • 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. 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.

Pregnancy Considerations

  • 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. 

  • Combigan should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus because animal reproduction studies are not always predictive of human response.

Nursing Mother Considerations

  • 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. 

Pediatric Considerations

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.

Geriatric Considerations

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

Renal Impairment Considerations

Combigan has not been studied in patients with renal impairment. A study of patients with renal failure showed that timolol was not readily removed by dialysis. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not known. Following oral administration of timolol maleate, the plasma half-life of timolol is essentially unchanged in patients with moderate renal insufficiency.

Hepatic Impairment Considerations

Combigan has not been studied in patients with hepatic impairment.

Combigan Pharmacokinetics


Plasma concentrations of brimonidine peaked at 1 to 4 hours after ocular dosing. Peak plasma concentrations of timolol occurred approximately 1 to 3 hours post-dose.


The protein binding of timolol is approximately 60%. The protein binding of brimonidine has not been studied.




Renal. Half-life: ~3 hours (brimonidine), ~7 hours (timolol).

Combigan Interactions


Avoid other topical β-blockers. May potentiate, or be potentiated by, other CNS depressants, systemic β-blockers, reserpine, quinidine, SSRIs, other CYP2D6 inhibitors. Caution with antihypertensives, systemic β-blockers, MAOIs, tricyclics. May cause conduction defects (eg, prolonged AV conduction) with digoxin, calcium channel blockers (avoid concomitant use in impaired cardiac function). May block systemic epinephrine.

Combigan Adverse Reactions

Adverse Reactions

Allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, pruritus, ocular burning/stinging, asthenia, corneal erosion, depression, epiphora, visual disturbance, headache, hypertension, dry mouth, somnolence, blepharitis, ocular hypersensitivity.

Combigan Clinical Trials

Clinical Trials

Clinical studies were conducted to compare the IOP-lowering effect over the course of the day of Combigan administered twice a day (BID) to individually-administered brimonidine tartrate ophthalmic solution, 0.2% administered three times per day (TID) and timolol maleate ophthalmic solution, 0.5% BID in patients with glaucoma or ocular hypertension. Combigan BID provided an additional 1 to 3 mm Hg decrease in IOP over brimonidine treatment TID and an additional 1 to 2 mm Hg decrease over timolol treatment BID during the first 7 hours post dosing. However, the IOP-lowering of Combigan BID was less (approximately 1-2 mm Hg) than that seen with the concomitant administration of 0.5% timolol BID and 0.2% brimonidine tartrate TID. Combigan administered BID had a favorable safety profile versus concurrently administered brimonidine TID and timolol BID in the self-reported level of severity of sleepiness for patients over age 40.

Combigan Note

Not Applicable

Combigan Patient Counseling

Patient Counseling

  • Advise patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure not to take this product.

  • Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions or by inadvertent contact with the dropper tip. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.

  • Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (eg, trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container. 

  • Administer by at least 5 minutes apart if more than one topical ophthalmic drug is being used. 

  • Advise patients that Combigan may be absorbed by soft contact lenses. Remove contact lenses prior to administration of the solution. May reinsert lenses 15 minutes following administration of Combigan. 

  • As with other similar medications, Combigan may cause fatigue and/or drowsiness in some patients. Patients who engage in hazardous activities should be cautioned of the potential for a decrease in mental alertness.