Metoprolol Tartrate Injection

1 INDICATIONS AND USAGE Metoprolol Tartrate Injection, USP 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 Injection, USP is a betaadrenergic 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).

2 DOSAGE AND ADMINISTRATION 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 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. Transition to Oral Metoprolol: Following administration of Metoprolol Tartrate Injection, USP transition patients to an oral formulation of metoprolol. See prescribing information for oral metoprolol for dose selection. 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 Lopressor injection, transition the patient to an oral formulation of metoprolol (2).

4 CONTRAINDICATIONS Hypersensitivity to Metoprolol Tartrate Injection, USP and related derivatives, or to any of the excipients; hypersensitivity to other beta blockers (cross sensitivity between beta blockers can occur). Metoprolol Tartrate Injection, USP 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 (PR 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)

5 WARNINGS AND PRECAUTIONS Worsening cardiac failure may occur. (5.1) Bronchospastic Disease: Avoid beta blockers. (5.2) Pheochromocytoma: First initiate therapy with an alpha blocker. (5.3) May aggravate symptoms of arterial insuffciency. (5.4) 5.1 Bradycardia Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of Metoprolol tartrate injection USP. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders may be at increased risk. Monitor heart rate and rhythm in patients receiving Metoprolol tartrate injection USP. If severe bradycardia develops, reduce or stop Metoprolol tartrate injection USP. 5.2 Heart Failure Worsening cardiac failure may occur during metoprolol use. If such symptoms occur, increase diuretics and restore clinical stability before administering the next dose of metoprolol [see Dosage and Administration (2)]. Such episodes do not preclude subsequent successful titration of oral metoprolol. 5.3 Bronchospastic Disease PATIENTS WITH BRONCHOSPASTIC DISEASES, IN GENERAL, SHOULD NOT RECEIVE BETA-BLOCKERS because they can exacerbate bronchospasm. Because of its relative beta1 cardio-selectivity, however, metoprolol may be used in patients with bronchospastic disease for initial treatment of myocardial infarction. Bronchodilators, including beta2 - agonists, should be readily available or administered concomitantly [see Dosage and Administration (2)]. 5.4 Pheochromocytoma If metoprolol tartrate 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. 5.5 Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. 5.6 Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insuffciency in patients with peripheral vascular disease.

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 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 Onesource at 1-888-217-8103 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 injection USP 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 injection USP and placebo, the following adverse reactions were reported: Metoprolol tartarate injection USP 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.

7 DRUG INTERACTIONS 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.

8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: Consider initiating metoprolol tartrate therapy at low doses while monitoring closely for adverse events. (8.6) 8.1 Pregnancy Risk Summary Available data from published observational studies have not demonstrated an association of adverse developmental outcomes with maternal use of metoprolol during pregnancy (see Data). Untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations). In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, approximately 24 times the daily dose of 200 mg in a 60-kg patient on a mg/m 2 basis. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical consideration Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and postpartum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. There is a risk for preterm birth with pregnant women with chronic heart failure in 3 rd trimester of pregnancy. Fetal/Neonatal adverse reactions Metoprolol crosses the placenta. Neonates born to mothers who are receiving metoprolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Observe neonates for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly. Data Human Data Data from published observational studies did not demonstrate an association of major congenital malformations and use of metoprolol in pregnancy. The published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of metoprolol during pregnancy; however, these studies have methodological limitations hindering interpretation. Methodological limitations include retrospective design, concomitant use of other medications, and other unadjusted confounders that may account for the study findings including the underlying disease in the mother. These observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Animal Data Metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, i.e. 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient. No fetal abnormalities were observed when pregnant rats received metoprolol orally up to a dose of 200 mg/kg/day, i.e. 10 times, the daily dose of 200 mg in a 60-kg patient. 8.2 Lactation Risk Summary Limited available data from published literature report that metoprolol is present in human milk. The estimated daily infant dose of metoprolol received from breastmilk range from 0.05 mg to less than 1 mg. The estimated relative infant dosage was 0.5% to 2% of the mother's weight-adjusted dosage (see Data). No adverse reactions of metoprolol on the breastfed infant have been identified. There is no information regarding the effects of metoprolol on milk production. Clinical consideration Monitoring for adverse reactions For a lactating woman who is a slow metabolizer of metoprolol, monitor the breastfed infant for bradycardia and other symptoms of beta blockade such as dry mouth, skin or eyes, diarrhea or constipation. In a report of 6 mothers taking metoprolol, none reported adverse effects in her breastfed infant. Data Limited published cases estimate the infant daily dose of metoprolol received from breast milk range from 0.05 mg to less than 1 mg. In 2 women who were taking unspecified amount of metoprolol, milk samples were taken after one dose of metoprolol. The estimated amount of metoprolol and alpha hydroxymetoprolol in breast milk is reported to be less than 2% of the mother's weight adjusted dosage. In a small study, breast milk was collected every 2 to 3 hours over one dosage interval, in three mothers (at least 3 months postpartum) who took metoprolol of unspecified amount. The average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 to 158.7). The average relative infant dosage was 0.5% of the mother's weight-adjusted dosage. 8.3 Females and Males of Reproductive Potential Risk Summary Based on the published literature, beta blockers (including metoprolol) may cause erectile dysfunction and inhibit sperm motility. In animal fertility studies, metoprolol has been associated with reversible adverse effects on spermatogenesis starting at oral dose level of 3.5 mg/kg in rats, which would correspond to a dose of 34 mg/day in humans in mg/m 2 equivalent, although other studies have shown no effect of metoprolol on reproductive performance in male rats. No evidence of impaired fertility due to metoprolol was observed in rats [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In worldwide clinical trials of Metoprolol tartrate in myocardial infarction, where approximately 478 patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety and effectiveness were found. Other reported clinical experience in myocardial infarction has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some elderly individuals taking Metoprolol tartrate injection USP, cannot be categorically ruled out. Therefore, in general, it is recommended that dosing proceed with caution in this population. 8.6 Hepatic Impairment No studies have been performed with metoprolol in patients with hepatic impairment. Because metoprolol is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication.

10 OVERDOSAGE Signs and Symptoms -Overdosage of metoprolol may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting. Treatment – Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Beta blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the following measures. Hemodialysis is unlikely to make a useful contribution to metoprolol elimination [see Clinical Pharmacology (12.3)]. Bradycardia: Evaluate the need for atropine, adrenergic-stimulating drugs or pacemaker to treat bradycardia and conduction disorders. Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine. Heart failure and shock: May be treated when appropriate with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), intravenous administration of adrenergic drugs such as dobutamine, with α1 receptor agonistic drugs added in presence of vasodilation. Bronchospasm: Can usually be reversed by bronchodilators.