FDA label ab789dec-c39e-4dcf-9e51-618cc239dafc

5 WARNINGS AND PRECAUTIONS Abrupt cessation may exacerbate myocardial ischemia. ( 5.1 ) May worsen congestive heart failure. ( 5.2 ) Bronchospasm: Avoid beta-blockers. ( 5.3 ) Bradycardia.( 5.4 ) Avoid discontinuing therapy prior to major surgery.( 5.5 ) May mask symptoms of hypoglycemia.( 5.6 ) Monitor serum electrolytes and creatinine periodically. ( 5.7 ) Peripheral vascular disease: Can aggravate symptoms of arterial insufficiency. ( 5.9 ) Pheochromocytoma: First initiate therapy with an alpha blocker. ( 5.10 ) Abrupt withdrawal in thyrotoxicosis might precipitate a thyroid storm.( 5.11 ) 5.1 Abrupt Cessation of Therapy Following abrupt cessation of therapy with beta adrenergic blockers, exacerbations of angina pectoris and myocardial infarction may occur. When discontinuing chronically administered DUTOPROL, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly resume therapy and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abrupt discontinuation of DUTOPROL in patients treated only for hypertension. 5.2 Heart Failure Worsening cardiac failure may occur during up-titration of beta-blockers. If such symptoms occur, increase diuretics and restore clinical stability (compensated heart failure) before advancing the dose of DUTOPROL [see Dosage and Administration ( 2 )] . It may be necessary to lower the dose of DUTOPROL or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of DUTOPROL. 5.3 Bronchospasm Beta adrenergic blockers can cause bronchospasm. Patients with bronchospastic disease should, in general, not receive beta adrenergic blockers. Because of its relative beta 1 cardio-selectivity, however, metoprolol-containing products including DUTOPROL may be used in patients with bronchospastic disease who do not respond to or cannot tolerate other antihypertensive treatment. Because beta 1 - selectivity is not absolute, in such patients use the lowest possible DUTOPROL dose and have bronchodilators (e.g., beta 2 -agonists) readily available or administer concomitantly. 5.4 Bradycardia Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of Dutoprol. Patients with first-degree atrioventricular block, sinus node dysfunction, conduction disorders (including Wolff-Parkinson-White) or on concomitant drugs that cause bradycardia [see Drug Interactions ( 7.1 )] may be at increased risk. Monitor heart rate in patients receiving Dutoprol. If severe bradycardia develops, reduce or stop Dutoprol. 5.5 Risks of Use in Major Surgery Avoid initiation of high-dose regimen of DUTOPROL in patients with cardiovascular risk factors undergoing non-cardiac surgery, since use in such patients has been associated with bradycardia, hypotension, stroke and death. Chronically administered beta adrenergic blockers should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures [see Warnings and Precautions ( 5.1 )]. 5.6 Masked Signs of Hypoglycemia Beta adrenergic blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. 5.7 Electrolyte and Metabolic Effects DUTOPROL contains hydrochlorothiazide which can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Monitor serum electrolytes periodically. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide reduces clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels. 5.8 Renal Impairment Patients with chronic kidney disease, severe heart failure, or volume depletion may be at increased risk for developing acute renal failure on drugs containing hydrochlorothiazide, including DUTOPROL. 5.9 Peripheral Vascular Disease Beta adrenergic blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. 5.10 Pheochromocytoma If DUTOPROL is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle. 5.11 Thyrotoxicosis Beta adrenergic blockers may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of a beta adrenergic blocker may precipitate a thyroid storm. 5.12 Anaphylactic Reaction While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction. 5.13 Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause acute transient myopia and acute angle-closure glaucoma (idiosyncratic reactions). Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of hydrochlorothiazide initiation. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. Untreated acute angle-closure glaucoma can lead to permanent vision loss. Given that DUTOPROL contains hydrochlorothiazide, if these symptoms occur, discontinue DUTOPROL. Consider prompt medical or surgical treatment if the intraocular pressure remains uncontrolled. 5.14 Exacerbation of Systemic Lupus Erythematosus Hydrochlorothiazide can exacerbate or activate systemic lupus erythematosus.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in labeling: • Worsening angina or myocardial infarction. [see Warnings and Precautions ( 5 )] • Worsening heart failure. [see Warnings and Precautions ( 5 )] • Worsening A V block. [see Contraindications ( 4 )] Adverse events which occurred greater than 1% more frequently in patients treated with DUTOPROL than placebo were: nasopharyngitis and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Concordia Pharmaceuticals at 1-877-370-1142 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Metoprolol succinate extended release/hydrochlorothiazide The metoprolol succinate extended release and hydrochlorothiazide combination was evaluated for safety in 891 patients with hypertension in clinical trials. In a randomized, double-blind, placebo-controlled, factorial trial (Study 1), 843 patients were treated with various combinations of metoprolol succinate (doses of 25 to 200 mg) and hydrochlorothiazide (doses of 6.25 to 25 mg) [see Clinical Studies ( 14 )] . Adverse events which occurred more than 1% more frequently in patients treated with DUTOPROL than placebo were: nasopharyngitis (3.4% vs 1.3%) and fatigue (2.6% vs 0.7%). The adverse reactions of metoprolol succinate extended release are a mixture of dose-dependent phenomena (primarily bradycardia and fatigue) and those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with DUTOPROL will be associated with both sets of dose independent reactions. Laboratory Abnormalities Liver Enzyme Tests —Increases in liver enzymes or serum bilirubin. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of DUTOPROL, metoprolol succinate extended release, and/or hydrochlorothiazide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. Metoprolol The following adverse reactions have been reported for immediate release metoprolol tartrate. Most adverse reactions have been mild and transient. Central Nervous System : Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia, dizziness Cardiovascular : Shortness of breath, bradycardia, cold extremities; arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain, hypotension. Respiratory : Dyspnea, wheezing (bronchospasm). Gastrointestinal : Diarrhea, nausea, dry mouth, gastric pain, constipation, flatulence, heartburn, hepatitis, vomiting. Hypersensitivity Reactions : Pruritus, rash Miscellaneous : Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, taste disturbance, depression Potential Adverse Reaction : In addition, adverse reactions not listed above, that have been reported with other beta-adrenoceptor blockers and should be considered potential adverse reactions to DUTOPROL. Central Nervous System : Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics. Hematologic : Non-thrombocytopenic purpura, thrombocytopenic purpura, agranulocytosis. Hypersensitivity Reactions : Laryngospasm, and respiratory distress Hydrochlorothiazide Adverse reactions that have been reported with hydrochlorothiazide are listed below: Body as a Whole : Weakness Cardiovascular : Orthostatic hypotension Digestive : Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation, anorexia Hematologic : Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Hypersensitivity Reactions : Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria Metabolic : Glycosuria Musculoskeletal : Muscle spasm Nervous System/Psychiatric : Vertigo, paresthesias, restlessness Renal : Interstitial nephritis Skin : Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses : Transient blurred vision, xanthopsia Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.