Drug Information

Brimonidine and timolol

Brimonidine and timolol

Brand Names: U.S.

  • Combigan®
Brand Names: Canada

  • Combigan®
Pharmacologic Category

  • Alpha2; Agonist, Ophthalmic
  • Beta Blocker, Nonselective;
  • Ophthalmic Agent, Antiglaucoma
Dosing: AdultGlaucoma, ocular hypertension: Ophthalmic: Instill 1 drop into affected eye(s) twice daily

Dosing: PediatricGlaucoma, ocular hypertension: Children ≥2 years: Ophthalmic: Instill 1 drop into affected eye(s) twice daily

Note: In the Canadian labeling, use in children (at any age) is not recommended

Dosing: GeriatricRefer to adult dosing.

Dosage Forms: U.S.Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, ophthalmic [drops]:

Combigan®: Brimonidine tartrate 0.2% and timolol maleate 0.5% (5 mL,10 mL) [contains benzalkonium chloride]

Dosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, ophthalmic [drops]:

Combigan®: Brimonidine tartrate 0.2% and timolol maleate 0.5% (2.5 mL, 5 mL,10 mL) [contains benzalkonium chloride]

Generic Equivalent Available: U.S.No

AdministrationAdminister approximately every 12 hours. Remove contact lenses prior to administration; wait 15 minutes before reinserting if using products containing benzalkonium chloride. Separate administration of other ophthalmic agents by 5-10 minutes.

UseReduction of intraocular pressure (IOP) in patients with glaucoma or ocular hypertension

Medication Safety Issues

Sound-alike/look-alike issues:

Combigan® may be confused with Combivent®, Comtan®

Adverse Reactions SignificantPercentages as reported with combination product. Also see individual agents.

>10%: Ocular: Conjunctival hyperemia (15%), burning sensation (11%)

1% to 10%:

Cardiovascular: Hypertension

Central nervous system: Somnolence (2%; children 25% to 83%), headache (1%), depression

Gastrointestinal: Xerostomia (2%)

Neuromuscular & skeletal: Weakness (2%)

Ocular: Stinging (6%), pruritus (6%), allergic conjunctivitis (5%), conjunctival folliculosis (5%), blurred vision (4%), blepharitis (3%), corneal erosion (3%), dry eyes (3%), epiphora (3%), eye discharge (3%), eyelid edema (3%), eyelid erythema (3%), superficial punctuate keratitis (3%), eye pain (2%), foreign body sensation (1%), eye irritation, eyelid pruritus

<1%: Conjunctival edema, follicular conjunctivitis

ContraindicationsHypersensitivity to brimonidine, timolol, or any other component of the formulation; current or history of bronchial asthma, severe chronic obstructive pulmonary disease (COPD); sinus bradycardia, second- or third-degree atrioventricular block, overt cardiac failure, cardiogenic shock. Also see individual agents.

Canadian labeling: Additional contraindications (not in U.S. labeling): Monoamine oxidase (MAO) inhibitor therapy (concurrent or within 14 days)

Warnings/Precautions Concerns related to adverse effects:

• Anaphylactic reactions: Use caution with history of severe anaphylaxis to a variety of allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.

• Bacterial keratitis: Inadvertent contamination of multiple-dose ophthalmic solutions has the potential to cause bacterial keratitis.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Ocular effects: Use of agents that reduce/suppress aqueous humor production has been associated with choroidal detachment after filtration procedures. Discontinue use in patients with chronic or recurrent choroidal detachment.

• Orthostatic hypotension: Use with caution. Signs and symptoms of hypotension may be enhanced.

Disease-related concerns:

• Angle-closure glaucoma: Appropriate use: Not for use alone to treat acute angle-closure glaucoma (has no effect on papillary constriction).

• Bronchospastic disease: In general, patients with bronchospastic disease (eg, asthma, COPD) should not receive beta-blockers; if used at all, should be used cautiously with close monitoring.

• Conduction abnormalities: Consider pre-existing conditions such as sick sinus syndrome before initiating.

• Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms.

• Heart failure: Use with caution in patients with compensated heart failure and monitor for a worsening of the condition.

• Hepatic impairment: Use with caution in patients with hepatic impairment; not studied.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may worsen myasthenia-related muscle weakness.

• Peripheral vascular disease (PVD) and Raynaud's disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud's disease. Use with caution and monitor for progression of arterial obstruction.

• Psychiatric disease: Use with caution in patients with a history of psychiatric illness; may cause or exacerbate CNS depression.

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• Renal Impairment: Use with caution in patients with renal impairment; not studied.

• Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If thyrotoxicosis is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm.

Concurrent drug therapy issues:

• Beta-blockers: Concomitant use with other topical beta-blockers should be avoided; monitor for increased effects (systemic or intraocular) with concomitant use of a systemic beta-blocker.

• Calcium channel blockers: Use with caution in patients on concurrent verapamil or diltiazem; bradycardia or heart block can occur.

• Cardiac glycosides: Use with caution in patients receiving digoxin; bradycardia or heart block can occur.

• Inhaled anesthetic agents: Use with caution in patients receiving inhaled anesthetic agents known to depress myocardial contractility.

Special populations:

• Contact lens wearers: Product contains benzalkonium chloride which may be absorbed by soft contact lenses; remove lens prior to administration and wait 15 minutes before reinserting.

• Pediatrics: Safety and efficacy have not been established in children <2 years of age; use in children <2 years of age is not recommended. Note: In the Canadian labeling, use in children (at any age) is not recommended. Serious adverse reactions (eg, bradycardia, hypotension, apnea, dyspnea, cyanosis) resulting in hospitalization have been reported in association with brimonidine administration in infants ages 28 days to 3 months.

Other warnings/precautions:

• Absorption: Systemic absorption of timolol and adverse effects may occur with ophthalmic use, including bradycardia and/or hypotension. Beta-blocker therapy should not be withdrawn abruptly in order to avoid acute tachycardia, hypertension, and/or ischemia. Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery.

Metabolism/Transport EffectsTimolol: Substrate of CYP2D6 (major); Inhibits CYP2D6 (weak)

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Risk D: Consider therapy modification

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Risk D: Consider therapy modification

Alpha2-Agonists: Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the alpha2-agonist is abruptly withdrawn. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Aminoquinolines (Antimalarial): May decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Risk C: Monitor therapy

Anilidopiperidine Opioids: May enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Risk C: Monitor therapy

Barbiturates: May decrease the serum concentration of Beta-Blockers. Risk C: Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Risk D: Consider therapy modification

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Risk C: Monitor therapy

Calcium Channel Blockers (Dihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Risk C: Monitor therapy

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Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil [Off Market]. Risk C: Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Risk D: Consider therapy modification

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Risk C: Monitor therapy

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Risk X: Avoid combination

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy

Insulin: Beta-Blockers may enhance the hypoglycemic effect of Insulin. Risk C: Monitor therapy

Lidocaine: Beta-Blockers may increase the serum concentration of Lidocaine. Risk C: Monitor therapy

Lidocaine (Systemic): Beta-Blockers may decrease the metabolism of Lidocaine (Systemic). Risk C: Monitor therapy

Lidocaine (Topical): Beta-Blockers may decrease the metabolism of Lidocaine (Topical). Risk C: Monitor therapy

MAO Inhibitors: May enhance the hypertensive effect of Alpha2-Agonists (Ophthalmic). Risk X: Avoid combination

MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Risk C: Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Risk X: Avoid combination

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Propafenone: May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity. Risk C: Monitor therapy

Propoxyphene: May decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

QuiNIDine: May decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Risk C: Monitor therapy

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Risk C: Monitor therapy

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Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Risk D: Consider therapy modification

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Pregnancy Risk Factor

Drug ratings in pregnancy (US Food & Drug Administration)
Category Interpretation
A Controlled studies show no risk
Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester with no evidence of risk in later trimesters. The possibility of fetal harm appears remote.
B No evidence of human risk in controlled studies
Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters.
C Risk cannot be ruled out
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefits justify the potential risk to the fetus.
D Positive evidence of risk
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
X Contraindicated in pregnancy
Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Reproduced with permission from: Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lexi-Comp Drug Information Handbook, 20th Edition. Hudson, OH: Lexi-Comp, 2011. Copyright © 2011.
Pregnancy ImplicationsThere are no adequate and well-controlled studies in pregnant women with the combination product. Use only if benefit outweighs risk. Also see individual agents.

LactationEnters breast milk (timolol)/not recommended

Breast-Feeding ConsiderationsTimolol has been detected in human breast milk following ophthalmic administration. It is not known if brimonidine is excreted in human milk.

Pricing: U.S. (www.drugstore.com)Solution (Combigan)

0.2-0.5% (5): $90.85

Monitoring ParametersIntraocular pressure; monitor for systemic effect of beta-blockade with ophthalmic administration; blood pressure

International Brand Names

  • Combigan (AR, AT, AU, BE, BR, CH, CN, CO, CZ, DE, DK, FI, FR, GB, GR, HK, HN, IE, IL, IT, KP, MY, NL, NO, NZ, PE, PH, PL, PT, SE, SG, TH, TW, ZA)
Mechanism of ActionBrimonidine: Selective agonism for alpha2-receptors; causes reduction of aqueous humor formation and increased uveoscleral outflow

Timolol: Blocks both beta1- and beta2-adrenergic receptors, reduces intraocular pressure by reducing aqueous humor production or possibly outflow; reduces blood pressure by blocking adrenergic receptors and decreasing sympathetic outflow, produces a negative chronotropic and inotropic activity by blocking beta1-adrenergic receptors

Pharmacodynamics/Kinetics 

REFERENCES

  1. Frampton JR, “Topical Brimonidine 0.2%/Timolol 0.5% Ophthalmic Solution In Glaucoma and Ocular Hypertension,” Drugs Aging, 2006, 23(9):753-61. [PubMed 17020399]
  2. Lang DM, “Anaphylactoid and Anaphylactic Reactions. Hazards of Beta-Blockers,” Drug Saf, 1995, 12(5):299-304. [PubMed 7669259]
  3. Larsson LI, “Aqueous Humor Flow in Normal Human Eyes Treated With Brimonidine and Timolol, Alone and in Combination,” Arch Ophthalmol, 2001, 119(4):492-5. [PubMed 11296014]
  4. Sherwood MB, Craven ER, Chou C, et al, “Twice-Daily 0.2% Brimonidine-0.5% Timolol Fixed-Combination Therapy vs Monotherapy With Timolol or Brimonidine in Patients With Glaucoma or Ocular Hypertension: A 12-Month Randomized Trial,” Arch Ophthalmol, 2006, 124(9):1230-8. [PubMed 16966616]
  5. Stewart WC, Stewart JA, and Jackson AL, “Cardiovascular Effects of Timolol Maleate, Brimonidine, or Brimonidine/Timolol Maleate in Concomitant Therapy,” Acta Ophthalmol Scand, 2002, 80(3):277-81. [PubMed 12059866]

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