Brimonidine tartrate and Timolol maleate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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Overview
Brimonidine tartrate and Timolol maleate is an an alpha-adrenergic receptor agonist with a beta-adrenergic receptor inhibitor that is FDA approved for the treatment of glaucoma, ocular hypertension; in patients requiring adjunctive or replacement therapy. Common adverse reactions include somnolence, allergic conjunctivitis, burning sensation in eye, conjunctival hyperemia, acute follicular conjunctivitis, itching of the eye.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Glaucoma, In patients requiring adjunctive or replacement therapy
- In patients requiring adjunctive or replacement therapy: instill 1 drop in the affected eye(s) twice daily, approximately 12 hr apart
Ocular hypertension, In patients requiring adjunctive or replacement therapy
- instill 1 drop in the affected eye(s) twice daily, approximately 12 hr apart
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Brimonidine tartrate and Timolol maleate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Brimonidine tartrate and Timolol maleate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
- The safety and efficacy of brimonidine tartrate and timolol maleate combination have not been established in children under 2 yrs old.
Glaucoma, In patients requiring adjunctive or replacement therapy
- instill 1 drop in the affected eye(s) twice daily, approximately 12 hr apart.
Ocular hypertension, In patients requiring adjunctive or replacement therapy
- instill 1 drop in the affected eye(s) twice daily, approximately 12 hr apart
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Brimonidine tartrate and Timolol maleate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Brimonidine tartrate and Timolol maleate in pediatric patients.
Contraindications
Asthma, COPD
- COMBIGAN® is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease.
Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock
- COMBIGAN® is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure; cardiogenic shock.
Neonates and Infants (Under the Age of 2 Years)
- COMBIGAN® is contraindicated in neonates and infants (under the age of 2 years).
Hypersensitivity Reactions
- Local hypersensitivity reactions have occurred following the use of different components of COMBIGAN®. COMBIGAN® is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past.
Warnings
There is limited information regarding Brimonidine tartrate and Timolol maleate Warnings' in the drug label.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Brimonidine tartrate and Timolol maleate Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Brimonidine tartrate and Timolol maleate Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Brimonidine tartrate and Timolol maleate Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Brimonidine tartrate and Timolol maleate in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brimonidine tartrate and Timolol maleate in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Brimonidine tartrate and Timolol maleate during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Brimonidine tartrate and Timolol maleate in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Brimonidine tartrate and Timolol maleate in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Brimonidine tartrate and Timolol maleate in geriatric settings.
Gender
There is no FDA guidance on the use of Brimonidine tartrate and Timolol maleate with respect to specific gender populations.
Race
There is no FDA guidance on the use of Brimonidine tartrate and Timolol maleate with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Brimonidine tartrate and Timolol maleate in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Brimonidine tartrate and Timolol maleate in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Brimonidine tartrate and Timolol maleate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Brimonidine tartrate and Timolol maleate in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Brimonidine tartrate and Timolol maleate Administration in the drug label.
Monitoring
There is limited information regarding Brimonidine tartrate and Timolol maleate Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Brimonidine tartrate and Timolol maleate and IV administrations.
Overdosage
There is limited information regarding Brimonidine tartrate and Timolol maleate overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Brimonidine tartrate and Timolol maleate Pharmacology in the drug label.
Mechanism of Action
- COMBIGAN® is comprised of two components: brimonidine tartrate and timolol. Each of these two components decreases elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve damage.
- COMBIGAN® is a relatively selective alpha-2 adrenergic receptor agonist with a non-selective beta-adrenergic receptor inhibitor. Both brimonidine and timolol have a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing for brimonidine and one to two hours for timolol.
- Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow.
- Timolol maleate is a beta1 and beta2 adrenergic receptor inhibitor that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity.
Structure
- COMBIGAN® (brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5%, sterile, is a relatively selective alpha-2 adrenergic receptor agonist with a non-selective beta-adrenergic receptor inhibitor (topical intraocular pressure lowering agent).
- The structural formulae are:
- In solution, COMBIGAN® (brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% has a clear, greenish-yellow color. It has an osmolality of 260-330 mOsmol/kg and a pH during its shelf life of 6.5-7.3.
- Brimonidine tartrate appears as an off-white, or white to pale-yellow powder and is soluble in both water (1.5 mg/mL) and in the product vehicle (3 mg/mL) at pH 7.2. Timolol maleate appears as a white, odorless, crystalline powder and is soluble in water, methanol, and alcohol.
- Each mL of COMBIGAN® contains the active ingredients brimonidine tartrate 0.2% and timolol 0.5% with the inactive ingredients benzalkonium chloride 0.005%; sodium phosphate, monobasic; sodium phosphate, dibasic; purified water; and hydrochloric acid and/or sodium hydroxide to adjust pH.
Pharmacodynamics
There is limited information regarding Brimonidine tartrate and Timolol maleate Pharmacodynamics in the drug label.
Pharmacokinetics
Absorption
- Systemic absorption of brimonidine and timolol was assessed in healthy volunteers and patients following topical dosing with COMBIGAN®. Normal volunteers dosed with one drop of COMBIGAN® twice daily in both eyes for seven days showed peak plasma brimonidine and timolol concentrations of 30 pg/mL and 400 pg/mL, respectively. 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.
- In a crossover study of COMBIGAN®, brimonidine tartrate 0.2%, and timolol 0.5% administered twice daily for 7 days in healthy volunteers, the mean brimonidine area-under-the-plasma-concentration-time curve (AUC) for COMBIGAN® was 128 ± 61 pg•hr/mL versus 141 ± 106 pg•hr/mL for the respective monotherapy treatments; mean Cmax values of brimonidine were comparable following COMBIGAN® treatment versus monotherapy (32.7 ± 15 pg/mL versus 34.7 ± 22.6 pg/mL, respectively). Mean timolol AUC for COMBIGAN® was similar to that of the respective monotherapy treatment (2919 ± 1679 pg•hr/mL versus 2909 ± 1231 pg•hr/mL, respectively); mean Cmax of timolol was approximately 20% lower following COMBIGAN® treatment versus monotherapy.
- In a parallel study in patients dosed twice daily with COMBIGAN®, twice daily with timolol 0.5%, or three times daily with brimonidine tartrate 0.2%, one-hour post dose plasma concentrations of timolol and brimonidine were approximately 30-40% lower with COMBIGAN® than their respective monotherapy values. The lower plasma brimonidine concentrations with COMBIGAN® appears to be due to twice-daily dosing for COMBIGAN® versus three-times dosing with brimonidine tartrate 0.2%.
Distribution
- The protein binding of timolol is approximately 60%. The protein binding of brimonidine has not been studied.
Metabolism
- In humans, brimonidine is extensively metabolized by the liver. Timolol is partially metabolized by the liver.
Excretion
- In the crossover study in healthy volunteers, the plasma concentration of brimonidine declined with a systemic half-life of approximately 3 hours. The apparent systemic half-life of timolol was about 7 hours after ocular administration.
- Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of an orally-administered radioactive dose of brimonidine was eliminated within 120 hours, with 74% found in the urine. Unchanged timolol and its metabolites are excreted by the kidney.
Special Populations
- COMBIGAN® has not been studied in patients with hepatic impairment.
- 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.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- With brimonidine tartrate, no compound-related carcinogenic effects were observed in either mice or rats following a 21-month and 24-month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1 mg/kg/day in rats achieved 150 and 210 times, respectively, the plasma Cmax drug concentration in humans treated with one drop of COMBIGAN® into both eyes twice daily, the recommended daily human dose.
- In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day [approximately 25,000 times the maximum recommended human ocular dose of 0.012 mg/kg/day on a mg/kg basis (MRHOD)]. Similar differences were not observed in rats administered oral doses equivalent to approximately 8,300 times the daily dose of COMBIGAN® in humans.
- In a lifetime oral study of timolol maleate in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day, (approximately 42,000 times the MRHOD), but not at 5 or 50 mg/kg/day (approximately 420 to 4,200 times higher, respectively, than the MRHOD). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.
- The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.
- Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro and in vivo studies including the Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three in vivo studies in CD-1 mice: a host-mediated assay, cytogenetic study, and dominant lethal assay.
- Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.
- Reproduction and fertility studies in rats with timolol maleate and in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at doses up to approximately 100 times the systemic exposure following the maximum recommended human ophthalmic dose of COMBIGAN®.
Clinical Studies
- 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.
How Supplied
- COMBIGAN® is supplied sterile, in white opaque plastic LDPE bottles and tips, with blue high impact polystyrene (HIPS) caps as follows:
- 5 mL in 10 mL bottle- NDC 0023-9211-05
- 10 mL in 10 mL bottle- NDC 0023-9211-10
Storage
- Storage: Store at 15°-25°C (59°-77°F). Protect from light.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
- 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 should be advised not to take this product.
- Patients should be instructed 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. 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.
- Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.
- If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.
- Patients should be advised that COMBIGAN® contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 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.
Precautions with Alcohol
Alcohol-Brimonidine tartrate and Timolol maleate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Combigan
Look-Alike Drug Names
There is limited information regarding Brimonidine tartrate and Timolol maleate Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.