METOPROLOL TARTRATE

Metoprolol tartrate Injection, USP, is a selective beta 1 -adrenoreceptor blocking agent, available in 5 mL vials for intravenous administration. Each vial contains a sterile solution of metoprolol tartrate USP, 5 mg, and sodium chloride USP, 45 mg. Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol (2:1) dextro -tartrate salt, and its structural formula is: Metoprolol tartrate USP is a white, practically odorless, crystalline powder with a molecular weight of 684.83. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. Chemical Structure

Metoprolol tartrate Injection is indicated in the treatment of definite or suspected acute myocardial infarction in hemodynamically stable patients to reduce cardiovascular mortality when used in conjunction with oral metoprolol maintenance therapy. Metoprolol tartrate is a beta-adrenergic receptor inhibitor indicated for the treatment of definite or suspected acute myocardial infarction in hemodynamically stable patients to reduce cardiovascular mortality when used in conjunction with oral metoprolol maintenance therapy. ( 1 )

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Initiate treatment 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 each; give the injections at approximately 2-minute intervals. During the intravenous administration of Metoprolol tartrate, monitor blood pressure, heart rate, and electrocardiogram. Initiate therapy in a coronary care or similar unit immediately after the patients hemodynamic condition has stabilized. ( 2 ) Begin treatment with an intravenous administration of three bolus injections of 5 mg each, at approximately 2-minute intervals. Monitor blood pressure, heart rate and electrocardiogram. ( 2 ) Following administration of Metoprolol tartrate Injection, transition the patient to an oral formulation of metoprolol. ( 2 ) Transition to Oral Metoprolol: Following administration of Metoprolol tartrate Injection, transition patients to an oral formulation of metoprolol. See prescribing information for oral metoprolol for dose selection.

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). Metoprolol tartrate is contraindicated in patients with a heart rate <45 beats/min; second- and third-degree heart block (unless a functioning pacemaker is present); significant first-degree heart block (P-R interval ≥0.24 sec); systolic blood pressure <100 mmHg; or decompensated cardiac failure. Known hypersensitivity to product components. ( 4 ) Severe bradycardia, greater than first degree heart block, or sick sinus syndrome without a pacemaker. ( 4 ) Cardiogenic shock or decompensated heart failure. ( 4 )

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 AV block [see Contraindications (4) ] Most common adverse reactions: tiredness, dizziness, shortness of breath, bradycardia, hypotension, pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 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. 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 a randomized comparison of Metoprolol tartrate and placebo, 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. Miscellaneous: Unstable diabetes and claudication have been reported. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of metoprolol. 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. Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, and hypotension. Respiratory: Wheezing (bronchospasm), dyspnea. Central Nervous System: Confusion, short-term memory loss, headache, nightmares, insomnia, nervousness, hallucinations. Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting. Hypersensitive Reactions: Pruritus. Miscellaneous: Musculoskeletal pain, arthritis, blurred vision, decreased libido, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie's disease, photosensitivity.

Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. ( 7.1 ) Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. ( 7.2 ) CYP2D6 Inhibitors are likely to increase metoprolol concentration. ( 7.3 ) Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. ( 7.4 ) Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. ( 7.4 ) 7.1 Catecholamine Depleting Drugs and Monoamine Oxidate (MAO) Inhibitors Catecholamine depleting drugs (e.g., reserpine) and monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with metoprolol plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. 7.2 Epinephrine 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. 7.3 CYP2D6 Inhibitors Drugs that are strong inhibitors of CYP2D6, such as quinidine, fluoxetine, paroxetine, and propafenone, were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol [see Clinical Pharmacology (12.3) ]. Monitor patients closely, when the combination cannot be avoided. 7.4 Digitalis, Clonidine, and Calcium Channel Blockers and Other Drugs that Decrease Heart Rate Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant administration of beta-blockers with these and other drugs known to decrease heart rate such as sphingosine-1-phosphate receptor modulators (e.g. fingolimod) may result in additive heart rate lowering effects. If clonidine and metoprolol are coadministered, withdraw the metoprolol several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped . 7.5 Drugs that Decrease Blood Pressure Concomitant administration of beta-blockers with other drugs known to decrease blood pressure may result in an enhanced hypotensive effect.

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]. Do not freeze. PROTECT FROM LIGHT. Retain in carton until time of use. Discard unused portion.