METOPROLOL

Metoprolol Tartrate Injection, USP, metoprolol tartrate USP is a selective beta 1 -adrenoreceptor blocking agent, available as 5 mL vials for intravenous administration. Each vial contains a sterile solution of metoprolol tartrate, 5 mg, and sodium chloride, 45 mg, and water for injection. Metoprolol tartrate is (±)-1-(Isopropylamino)-3-[ p -(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is Metoprolol tartrate is a white, practically odorless, crystalline powder with a molecular weight of 684.81. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. Structural Formula

Myocardial Infarction Metoprolol Tartrate Injection, USP is indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality when used in conjunction with oral metoprolol maintenance therapy. Treatment with intravenous metoprolol tartrate can be initiated as soon as the patient's clinical condition allows (see DOSAGE AND ADMINISTRATION , CONTRA-INDICATIONS , and WARNINGS ).

Myocardial Infarction Early Treatment: During the early phase of definite or suspected acute myocardial infarction, initiate treatment with metoprolol tartrate can be initiated as soon as possible after the patient's arrival in the hospital. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has stabilized. Begin treatment in this early phase with the intravenous administration of three bolus injections of 5 mg of Metoprolol Tartrate Injection, USP each; give the injections at approximately 2-minute intervals. During the intravenous administration of Metoprolol Tartrate Injection, USP, monitor blood pressure, heart rate, and electrocardiogram. In patients who tolerate the full intravenous dose (15 mg), initiate metoprolol tartrate tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the maintenance dosage is 100 mg orally twice daily. Start patients who appear not to tolerate the full intravenous dose on metoprolol tartrate tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose or as soon as their clinical condition allows. In patients with severe intolerance, discontinue metoprolol tartrate (see WARNINGS ). Special populations Pediatric patients: No pediatric studies have been performed. The safety and efficacy of metoprolol tartrate in pediatric patients have not been established. Renal impairment: No dose adjustment of metoprolol tartrate is required in patients with renal impairment. Hepatic impairment: Metoprolol tartrate blood levels are likely to increase substantially in patients with hepatic impairment. Therefore, metoprolol tartrate should be initiated at low doses with cautious gradual dose titration according to clinical response. Geriatric patients (>65 years): In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Method of administration: Parenteral administration of metoprolol tartrate should be done in a setting with intensive monitoring. Note : Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Hypersensitivity to metoprolol tartrate and related derivatives, or to any of the excipients; hypersensitivity to other beta-blockers (cross sensitivity between beta-blockers can occur). Myocardial Infarction Metoprolol Tartrate Injection, USP is contraindicated in patients with a heart rate <45 beats/min; second- and third-degree heart block; significant first-degree heart block (P-R interval ≥0.24 sec); systolic blood pressure <100 mmHg; or moderate-to-severe cardiac failure (see WARNINGS ).

Hypertension and Angina These adverse reactions were reported for treatment with oral metoprolol tartrate. Most adverse effects have been mild and transient. Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported. Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100 patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported very rarely. (See CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS. ) Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see WARNINGS ). Rhinitis has also been reported. Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients. Vomiting was a common occurrence. Post-marketing experience reveals very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported. Hypersensitive Reactions: Pruritus or rash have occurred in about 5 of 100 patients. Very rarely, photosensitivity and worsening of psoriasis has been reported. Miscellaneous: Peyronie's disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, and tinnitus have also been reported. There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis (relationship to metoprolol tartrate has not been definitely established). The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with metoprolol tartrate. Myocardial Infarction These adverse reactions were reported from treatment regimens where intravenous metoprolol tartrate was administered, when tolerated. Central Nervous System: Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced libido have also been reported, but a drug relationship is not clear. Cardiovascular: In the randomized comparison of metoprolol tartrate and placebo described in the CLINICAL PHARMACOLOGY section, the following adverse reactions were reported: Metoprolol Tartrate Placebo Hypotension (systolic BP <90 mmHg) 27.4% 23.2% Bradycardia (heart rate <40 beats/min) 15.9% 6.7% Second- or third-degree heart block 4.7% 4.7% First-degree heart block (P-R ≥0.26 sec) 5.3% 1.9% Heart failure 27.5% 29.6% Respiratory: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients. Gastrointestinal: Nausea and abdominal pain have been reported in fewer than 1 of 100 patients. Dermatologic: Rash and worsened psoriasis have been reported, but a drug relationship is not clear. Miscellaneous: Unstable diabetes and claudication have been reported, but a drug relationship is not clear. Potential Adverse Reactions A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol tartrate. Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS ). Hematologic: Agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura. Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and respiratory distress. Postmarketing Experience The following adverse reactions have been reported during postapproval use of metoprolol tartrate: confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

Catecholamine-depleting drugs: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents or monoamine oxidase (MAO) inhibitors. Observe patients treated with metoprolol tartrate plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. In addition, possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversible MAO inhibitor. Digitalis glycosides and beta blockers: Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Monitor heart rate and PR interval. Calcium channel blockers: Concomitant administration of a beta-adrenergic antagonist with a calcium channel blocker may produce an additive reduction in myocardial contractility because of negative chronotropic and inotropic effects.

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP controlled room temperature]. Do not freeze. Protect from light and heat. To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-877-725-2747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA Manufactured by: Baxter Pharmaceuticals India Private Ltd Ahmedabad 382213, India 2018-10-08 1400006477