Data from FDA - Curated by EPG Health - Last updated 22 December 2016

Indication(s)

1 INDICATIONS AND USAGE COMBIGAN® (brimonidine tartrate/timolol maleate ophthalmic solution) 0.2 %/0.5 % is an alpha-adrenergic receptor agonist with a beta-adrenergic receptor inhibitor indicated for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP; the IOP-lowering of COMBIGAN® dosed twice a day was slightly less than that seen with the concomitant administration of 0.5 % timolol maleate ophthalmic solution dosed twice a day and 0.2 % brimonidine tartrate ophthalmic solution dosed three times per day.

COMBIGAN® is an alpha-adrenergic receptor agonist with a beta-adrenergic receptor inhibitor indicated for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP; the IOP-lowering of COMBIGAN® dosed twice a day was slightly less than that seen with the concomitant administration of timolol maleate ophthalmic solution, 0.5 % dosed twice a day and brimonidine tartrate ophthalmic solution, 0.2 % dosed three times per day.

(1)

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Advisory information

contraindications

4 CONTRAINDICATIONS Bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease.

(4.1, 5.1, 5.3) Sinus bradycardia, atrioventricular block, overt cardiac failure, cardiogenic shock.

(4.2, 5.2) Neonates and infants (under the age of 2 years).

(4.3) Hypersensitivity to any component of this product.

(4.4) 4.1 Reactive Airway Disease Including Asthma, COPD COMBIGAN® is contraindicated in patients with reactive airway disease including bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease [see Warnings and Precautions (5.1, 5.3)].

4.2 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 [see Warnings and Precautions (5.2)]; cardiogenic shock.

4.3 Neonates and Infants (Under the Age of 2 Years) COMBIGAN® is contraindicated in neonates and infants (under the age of 2 years).

4.4 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.

Adverse reactions

6 ADVERSE REACTIONS Most common adverse reactions occurring in approximately 5 to 15 % of patients included allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug can not be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

COMBIGAN® In clinical trials of 12 months duration with COMBIGAN®, the most frequent reactions associated with its use occurring in approximately 5 % to 15 % of the patients included: allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging.

The following adverse reactions were reported in 1 % to 5 % of patients: 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.

Other adverse reactions that have been reported with the individual components are listed below.

Brimonidine Tartrate (0.1 % - 0.2 %) Abnormal taste, allergic reaction, blepharoconjunctivitis, blurred vision, bronchitis, cataract, conjunctival blanching, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness, dyspepsia, dyspnea, fatigue, flu syndrome, follicular conjunctivitis, gastrointestinal disorder, hypercholesterolemia, hypotension, infection (primarily colds and respiratory infections), hordeolum, insomnia, keratitis, lid crusting, lid disorder, muscular pain, nasal dryness, ocular allergic reaction, pharyngitis, photophobia, rash, rhinitis, sinus infection, sinusitis, superficial punctate keratopathy, tearing, upper respiratory symptoms, visual field defect, vitreous detachment, vitreous disorder, vitreous floaters

and worsened visual acuity.

Timolol (Ocular Administration) Body as a whole: chest pain; Cardiovascular: Arrhythmia, bradycardia, cardiac arrest, cardiac failure, cerebral ischemia, cerebral vascular accident, claudication, cold hands and feet, edema, heart block, palpitation, pulmonary edema, Raynaud 's phenomenon, syncope, and worsening of angina pectoris; Digestive: anorexia, diarrhea, nausea; Immunologic: Systemic lupus erythematosus; Nervous System/Psychiatric: Increase in signs and symptoms of myasthenia gravis, insomnia, nightmares, paresthesia, behavioral changes and psychic disturbances including confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss; Skin: Alopecia, psoriasiform rash or exacerbation of psoriasis;

Hypersensitivity: Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria, and generalized and localized rash; Respiratory: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease) [see Contraindications (4.1)], dyspnea, nasal congestion, respiratory failure, upper respiratory infections; Endocrine: Masked symptoms of hypoglycemia in diabetes patients [see Warnings and Precautions (5.7)]; Special Senses: diplopia, choroidal detachment following filtration surgery, cystoid macular edema, decreased corneal sensitivity, pseudopemphigoid, ptosis, refractive changes, tinnitus; Urogenital: Decreased libido, impotence, Peyronie 's disease, retroperitoneal fibrosis.

6.2 Postmarketing Experience The following reactions have been identified during post-marketing use of brimonidine tartrate ophthalmic solutions, timolol ophthalmic solutions, or both in combination, in clinical practice.

Because they are reported voluntarily from a population of unknown size, estimates of frequency can not be made.

The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, timolol ophthalmic solutions, or a combination of these factors, include: eyelid erythema extending to the cheek or forehead, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, rash, and vasodilation), and tachycardia.

In infants, apnea, bradycardia, coma, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported [see Contraindications (4.3) and Use in Specific Populations (8.4)].

Oral Timolol/Oral Beta-blockers The following additional adverse reactions have been reported in clinical experience with ORAL timolol maleate or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic timolol maleate: Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Body as a whole: Decreased exercise tolerance, extremity pain, weight loss; Cardiovascular: Vasodilatation, worsening of arterial insufficiency; Digestive: Gastrointestinal pain, hepatomegaly, ischemic colitis, mesenteric arterial thrombosis, vomiting; Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura; Endocrine: Hyperglycemia, hypoglycemia

Skin: Increased pigmentation, pruritus, skin irritation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: An acute reversible syndrome characterized by disorientation for time and place, decreased performance on neuropsychometrics, diminished concentration, emotional lability, local weakness, reversible mental depression progressing to catatonia, slightly clouded sensorium, vertigo; Respiratory: Bronchial obstruction, rales; Urogenital: Urination difficulties.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended dose is one drop of COMBIGAN® in the affected eye(s) twice daily approximately 12 hours apart. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart. One drop in the affected eye(s), twice daily approximately 12 hours apart. (2)
Use in special populations

8 USE IN SPECIFIC POPULATIONS Not for use in children below the age of 2 years.

Use with caution in children?

2 years of age.

(8.4) 8.1 Pregnancy Teratogenicity studies have been performed in animals.

Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in rats and days 6 through 18 in rabbits.

The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5 mg/kg/day) achieved AUC exposure values 580 and 37-fold higher, respectively, than similar values estimated in humans treated with COMBIGAN®, 1 drop in both eyes twice daily.

Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day [4,200 times the maximum recommended human ocular dose of 0.012 mg/kg/day on a mg/ kg basis (MRHOD)] demonstrated no evidence of fetal malformations.

Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring.

Doses of 1,000 mg/ kg/day (83,000 times the MRHOD) were maternotoxic in mice and resulted in an increased number of fetal resorptions.

Increased fetal resorptions were also seen in rabbits at doses 8,300 times the MRHOD without apparent maternotoxicity.

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.

Because animal reproduction studies are not always predictive of human response, COMBIGAN® should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

8.3 Nursing Mothers Timolol has been detected in human milk following oral and ophthalmic drug administration.

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.

8.4 Pediatric Use COMBIGAN® is contraindicated in children under the age of 2 years [see Contraindications (4.3)].

During post-marketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine.

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.

Use of COMBIGAN® in these age groups is supported by evidence from adequate and well-controlled studies of COMBIGAN® in adults with additional data from a study of the concomitant use of brimonidine tartrate ophthalmic solution 0.2 % and timolol maleate ophthalmic solution in pediatric glaucoma patients (ages 2 to 7 years).

In this study, brimonidine tartrate ophthalmic solution 0.2 % was dosed three times a day as adjunctive therapy to beta-blockers.

The most commonly observed adverse reactions were somnolence (50 % - 83 % in patients 2 to 6 years) and decreased alertness.

In pediatric patients 7 years of age or older (>20 kg), somnolence appears to occur less frequently (25 %).

Approximately 16 % of patients on brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.

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

Pregnancy and lactation

8.3 Nursing Mothers Timolol has been detected in human milk following oral and ophthalmic drug administration.

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.

Interactions

7 DRUG INTERACTIONS Antihypertensives/cardiac glycosides may lower blood pressure.

(7.1) Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade.

(7.2) Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension.

(7.3) Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked bradycardia.

(7.4) Use with CNS depressants may result in an additive or potentiating effect.

(7.5) Digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

(7.6) CYP2D6 inhibitors may potentiate systemic beta-blockade.

(7.7) Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine.

(7.8) Monoamine oxidase inhibitors may result in increased hypotension.

(7.9) 7.1 Antihypertensives/Cardiac Glycosides Because COMBIGAN® may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with COMBIGAN® is advised.

7.2 Beta-adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent either orally or intravenously and COMBIGAN® should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure.

The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

7.3 Calcium Antagonists Caution should be used in the co-administration of beta-adrenergic blocking agents, such as COMBIGAN®, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension.

In patients with impaired cardiac function, co-administration should be avoided.

7.4 Catecholamine-depleting Drugs Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.

7.5 CNS Depressants Although specific drug interaction studies have not been conducted with COMBIGAN®, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered.

7.6 Digitalis and Calcium Antagonists The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

7.7 CYP2D6 Inhibitors Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol.

7.8 Tricyclic Antidepressants Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine.

It is not known whether the concurrent use of these agents with COMBIGAN® in humans can lead to resulting interference with the IOP-lowering effect.

Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

7.9 Monoamine Oxidase Inhibitors Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an increased systemic side effect such as hypotension.

Caution, however, is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

More information

Category Value
Authorisation number NDA021398
Orphan designation No
Product NDC 0023-9211
Date Last Revised 19-11-2015
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Allergan, Inc.