Combigan Drug Information

The recommended dosage is one drop 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 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) , dyspnea, nasal congestion, respiratory failure, upper respiratory infections Endocrine : Masked symptoms of hypoglycemia in diabetes patients 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

Postmarketing Experience

The following reactions have been identified during postapproval use of brimonidine tartrate ophthalmic solutions, timolol ophthalmic solutions, or both in combination, in clinical practice. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Bradycardia, eyelid erythema extending to the cheek or forehead, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, rash, and vasodilation), syncope, and tachycardia.

Apnea, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions . 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

Antihypertensives/Cardiac Glycosides

Because COMBIGAN may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with COMBIGAN is advised.

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.

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.

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.

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.

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.

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.

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.

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.

Pregnancy Risk Summary There are no adequate and well-controlled studies with COMBIGAN in pregnant women. Limited available data from postmarketing safety reports and published literature reviews with COMBIGAN use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data). In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Oral administration of brimonidine tartrate or timolol maleate to pregnant rats and rabbits during organogenesis at dose exposures 580 and 37 times the recommended human ophthalmic dose (RHOD) resulted in no adverse developmental effects (see Data). Oral administration of timolol maleate to mice, rats, and rabbits during organogenesis at dose exposures up to 4,200 times the RHOD resulted in no evidence of fetal malformations (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Limited available data from postmarketing safety reports and published literature with topical use of brimonidine ophthalmic solution in pregnant women are insufficient to inform a drug-associated risk of pregnancy-related adverse outcomes including miscarriage, stillbirth, congenital anomaly, and events experienced by the breastfed infant.

Animal Data Embryofetal development studies were conducted with oral administration of brimonidine tartrate during organogenesis in rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18). No adverse developmental effects were observed in rats up to 2.5 mg/kg/day and rabbits up to 5 mg/kg/day. These doses represent exposures 580 and 37 times higher, respectively, than the recommended human ophthalmic dose (RHOD) of COMBIGAN at 1 drop in both eyes twice daily. Orally administered brimonidine crossed the placenta in pregnant rats and entered the fetal circulation to a limited extent.

Embryofetal development studies conducted with timolol during organogenesis in mice, rats, and rabbits at oral doses up to 50 mg/kg/day 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.

Pediatric Use COMBIGAN is contraindicated in pediatric patients younger than 2 years old . 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 COMBIGAN 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 have been established in pediatric patients aged 2 years and older. Use of COMBIGAN for this indication 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 well-controlled clinical 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% to 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.

Reactive Airway Disease I ncluding Asthma

COPD COMBIGAN is contraindicated in patients with reactive airway disease including 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 ( Pediatric Patients Younger than 2 Years Old )

COMBIGAN is contraindicated in neonates and infants (pediatric patients younger than 2 years old) .

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.

There have been reports of inadvertent overdosage with timolol ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. With the exception of hypotension, very limited information exists on accidental ingestion of brimonidine in adults. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine ophthalmic solutions as part of medical treatment of congenital glaucoma or by accidental oral ingestion . Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.