Brimonidine Tartrate/Timolol Maleate Ophthalmic Solution

5.4 Potentiation of Vascular Insufficiency Brimonidine tartrate/timolol maleate ophthalmic solution may potentiate syndromes associated with vascular insufficiency. Brimonidine tartrate/timolol maleate ophthalmic solution should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.

5.5 Increased Reactivity to Allergens While taking beta-blockers, 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.

5.6 Potentiation of Muscle Weakness Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

5.7 Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus Beta-adrenergic blocking agents should be administered with 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.

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 LEADING PHARMA, LLC AT 1-844-740-7500 or 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 cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Brimonidine Tartrate/Timolol Maleate Ophthalmic Solution In clinical trials of 12 months duration with brimonidine tartrate/timolol maleate ophthalmic solution, 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 cannot 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.

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 cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Brimonidine Tartrate/Timolol Maleate Ophthalmic Solution In clinical trials of 12 months duration with brimonidine tartrate/timolol maleate ophthalmic solution, 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.