METOPROLOL TARTRATE

Warnings and Precautions, Hypoglycemia ( 5.5 ) 05/2024 Warnings and Precautions, Hypoglycemia ( 5.5 ) 05/2024

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 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 )

DOSAGE & ADMINISTRATION Myocardial Infarction Early Treatment During the early phase of definite or suspected acute myocardial infarction, initiate treatment with metoprolol tartrate 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 each; give the injections at approximately 2-minute intervals. During the intravenous administration of metoprolol tartrate injection, 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 continued for 48 hours. Thereafter, the maintenance dosage is 100 mg orally twice daily. Start patients who appear not to tolerate the full intravenous 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.

3 DOSAGE FORMS AND STRENGTHS Injection: 5 mg Metoprolol Tartrate as a clear liquid supplied in 5 mL single dose vials. Also available in oversized vials (10 mL) with large mouth (20 mm). Injection: 5 mg Metoprolol Tartrate supplied in 5 mL single dose vials. Also available in oversized vials (10 mL) with large mouth (20 mm) ( 3 )

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

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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 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 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 and placebo, the following adverse reactions were reported: Metoprolol Tartrate Injection 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.

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 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 …

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.

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, …

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 …

Mechanism of Action Metoprolol is a beta 1 -selective (cardioselective) adrenergic receptor blocker. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta 2 -adrenoreceptors, chiefly located in the bronchial and vascular musculature. Clinical pharmacology studies have demonstrated the beta-blocking activity of metoprolol, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia. Hypertension The mechanism of the antihypertensive effects of beta-blocking agents has not been fully elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity. Angina Pectoris By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris. Myocardial Infarction The precise mechanism of action of metoprolol in patients with suspected or definite myocardial infarction is not known.

DESCRIPTION Metoprolol Tartrate Injection, USP, is a selective beta 1 -adrenoreceptor blocking agent, available in 5 mL single dose vials for intravenous administration. Each vial contains a sterile solution of Metoprolol Tartrate, USP, 5 mg, Sodium Chloride, USP, 45 mg, and Water for Injection, USP. Metoprolol Tartrate, USP is (±)-1-(Isopropylamino)-3-[ p -(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is: Molecular Formula: (C 15 H 25 NO 3 ) 2 •C 4 H 6 O 6 Metoprolol Tartrate, USP is a white, practically odorless, crystalline powder with a molecular weight of 684.82. 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

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.

HOW SUPPLIED METOPROLOL TARTRATE INJECTION, USP is supplied in the following dosage forms. NDC 51662-1478-1 METOPROLOL TARTRATE INJECTION, USP 5mg/5mL (1mg PER mL) 5mL VIAL HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Metoprolol Tartrate Injection, USP is available as: 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. METOPROLOL TARTRATE INJECTION, USP is supplied in the following dosage forms. NDC 51662-1478-2 METOPROLOL TARTRATE INJECTION, USP 5mg/5mL (1mg PER mL) 5mL (POUCH) HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms METOPROLOL TARTRATE INJECTION, USP is supplied in the following dosage forms. NDC 51662-1478-3 METOPROLOL TARTRATE INJECTION, USP 5mg/5mL (1mg PER mL) (CASE OF 10) HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1113-1.0 8/2017 HOW SUPPLIED LOGO