Metoprolol succinate

RECENT MAJOR CHANGES SECTION WARNINGS AND PRECAUTIONS, Bradycardia ( 5.4 ) 04/2022

1 INDICATIONS AND USAGE Metoprolol succinate extended-release tablets, metoprolol succinate, is a beta 1 -selective adrenoceptor blocking agent. Metoprolol succinate extended-release tablets are indicated for the treatment of: 4. Hypertension,to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. (1.1 ) 5. Angina Pectoris (1.2) 6. Heart Failure - for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. (1.3) 1.1 Hypertension Metoprolol succinate extended-release tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Metoprolol succinate extended-release tablets may be administered with other antihypertensive agents. 1.2 Angina Pectoris Metoprolol succinate extended-release tablets are indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. 1.3 Heart Failure Metoprolol succinate extended-release tablets are indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, metoprolol succinate extended-release tablets decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.

Hypertension The dosage of metoprolol tartrate tablets should be individualized. Metoprolol tartrate tablets should be taken with or immediately following meals. The usual initial dosage of Metoprolol tartrate tablets is 100 mg daily in single or divided doses, whether used alone or added to a diuretic. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. The effective dosage range of Metoprolol tartrate tablets is 100 to 450 mg per day. Dosages above 450 mg per day have not been studied. While once-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and larger or more frequent daily doses may be required. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. Beta selectivity diminishes as the dose of metoprolol is increased. Angina Pectoris The dosage of metoprolol tartrate tablets should be individualized. Metoprolol tartrate tablets should be taken with or immediately following meals. The usual initial dosage of Metoprolol tartrate tablets is 100 mg daily, given in two divided doses. The dosage may be gradually increased at weekly intervals until optimum clinical response has been obtained or there is pronounced slowing of the heart rate. The effective dosage range of Metoprolol tartrate tablets is 100 to 400 mg per day. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, the dosage should be reduced gradually over a period of 1 to 2 weeks (see WARNINGS). Myocardial Infarction Early Treatment: During the early phase of definite or suspected acute myocardial infarction, 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. Treatment in this early phase should begin with the intravenous administration of three bolus injections of 5 mg of metoprolol tartrate each; the injections should be given at approximately 2-minute intervals. During the intravenous administration of metoprolol, blood pressure, heart rate,and electrocardiogram should be carefully monitored.In patients who tolerate the full intravenous dose (15 mg), metoprolol tartrate tablets, 50 mg every 6 hours, should be initiated 15 minutes after the last intravenous dose and continued for 48 hours. Thereafter, patients should receive a maintenance dosage of 100 mg twice daily (see Late Treatment below). Patients who appear not to tolerate the full intravenous dose should be started 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, treatment with metoprolol should be discontinued (see WARNINGS). Late Treatment: Patients with contraindications to treatment during the early phase of suspected or definite myocardial infarction, patients who appear not to tolerate the full early treatment, and patients in whom the physician wishes to delay therapy for any other reason should be started on metoprolol tartrate tablets, 100 mg twice daily, as soon as their clinical condition allows. Therapy should be continued for at least 3 months. Although the efficacy of metoprolol beyond 3 months has not been conclusively established, data from studies with other beta blockers suggest that treatment should be continued for 1 to 3 years. Special populations Pediatric patients: No pediatric studies have been performed. The safety and efficacy of Metoprolol Tartrate in pedi …

3 DOSAGE FORMS AND STRENGTHS 25 mg tablets: White to off-white, oval shaped, film coated scored tablets, debossed with I and 25 on either side of the score on one side and score on the other side free from physical defects. 50 mg tablets: White to off-white, round shaped, film coated scored tablets, debossed with I on one side of the score and debossed with 50 on the other side free from physical defects. 100 mg tablets: White to off-white, round shaped, film coated scored tablets, debossed with I one side of the score and debossed with 100 on the other side free from physical defects. 200 mg tablets: White to off-white, oval shaped, film coated scored tablets, debossed with I on one side of the score and 200 on the other side free from physical defects. Metoprolol succinate extended-release tablets: 25 mg, 50 mg, 100 mg and 200 mg. ( 3 )

Hypertension and Angina Metoprolol tartrate is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS). Hypersensitivity to metoprolol and related derivatives, or to any of the excipients; hypersensitivity to other beta-blockers (cross sensitivity between beta-blockers can occur). Sick-sinus syndrome. Severe peripheral arterial circulatory disorders. Myocardial Infarction Metoprolol 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 3 0.24 sec); systolic blood pressure < 100 mmHg; or moderate-to-severe cardiac failure (see WARNINGS).

6 ADVERSE REACTIONS • Most common adverse reactions: tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals LLC Toll-Free at 1-877-748-1970 or FDA at 1-800-FDA-1088 or Error! Hyperlink reference not valid. . 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) ]. 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. Hypertension and Angina: Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash. Heart Failure: In the MERIT-HF study comparing metoprolol succinate extended-release tablets in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of metoprolol succinate extended-release tablets patients discontinued for adverse reactions vs. 12.2% of placebo patients. The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of 1% in the metoprolol succinate extended-release tablets group and greater than placebo by more than 0.5%, regardless of the assessment of causality. Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥1% in the metoprolol succinate extended-release tablets Group and Greater Than Placebo by More Than 0.5% Metoprolol succinate extended-release tablet group; n=1990 % of patients Placebo; n=2001 % of patients Dizziness/vertigo 1.8 1.0 Bradycardia 1.5 0.4 Accident and/or injury 1.4 0.8 Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta–blocker therapy, metoprolol succinate extended-release tablets 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Metoprolol succinate extended-release tablets use was associated with a higher incidence of bradycardia (6.6% vs. 2.4%; HR, 2.74; 95% CI 2.19, 3.43), hypotension (15% vs. 9.7%; HR 1.55; 95% CI 1.37, 1.74), stroke (1.0% vs. 0.5%; HR 2.17; 95% CI 1.26, 3.74) and death (3.1% vs. 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of metoprolol succinate extended-release tablets or immediate-release 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, chest pain and hypotension. Respiratory: Wheezing (bronchospasm), dyspnea. Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia. Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting. Hypersensitive Reactions: Pruritus. Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie's disease, sweating, photosens …

7 DRUG INTERACTIONS • Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. ( 7.1 ) • CYP2D6 Inhibitors are likely to increase metoprolol concentration. ( 7.2 ) • Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. ( 7.3 ) • Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. ( 7.3 ) 7.1 Catecholamine Depleting Drugs Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with metoprolol succinate extended-release tablets plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. 7.2 CYP2D6 Inhibitors Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol. 7.3 Digitalis, Clonidine, and Calcium Channel Blockers Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia. If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker 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 [see Warnings and Precautions (5.11) ].

8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: Consider initiating metoprolol succinate extended-release therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events. ( 8.6 ) 8.1 Pregnancy Risk Summary Untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations ) . Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with metoprolol use during pregnancy. However, there are inconsistent reports of intrauterine growth restriction, preterm birth, and perinatal mortality with maternal use of beta-blockers, including metoprolol, during pregnancy (see Data ) . 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 post-partum 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 3rd 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 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 definitively 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 ranges 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. Th …

12.1 Mechanism of Action Metoprolol is a beta 1 -selective (cardioselective) adrenergic receptor blocking agent. 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. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction. The relative beta 1 -selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta 2 -mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEV 1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta 1 -receptor blocking doses. Hypertensio n: The mechanism of the antihypertensive effects of beta-blocking agents has not been 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. Heart Failure : The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.

11 DESCRIPTION Metoprolol succinate, is a beta 1 -selective (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended release tablets. Metoprolol succinate has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate extended-release tablets in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, respectively. Its chemical name is (±)1- (isopropyl amino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is: Metoprolol succinate, USP is a white to off white powder with a molecular weight of 652.8. It is freely soluble in water; soluble in methanol; sparingly soluble in alcohol and slightly soluble in isopropyl alcohol. Each metoprolol succinate extended-release tablet intended for oral administration contains metoprolol succinate equivalent to 25 mg, 50 mg, 100 mg or 200 mg of metoprolol tartrate. In addition, each tablet contains the following inactive ingredients: Colloidal silicon dioxide, croscarmellose sodium, ethyl cellulose, glycerin, hypromellose, magnesium stearate, methyl cellulose, microcrystalline cellulose, polyethylene glycol, povidone and talc. Additionally, each metoprolol succinate extended-release tablets contain opadry II white 03B28796 which contains hypromellose, polyethylene glycol and titanium dioxide. Meets USP Dissolution Test 4. figure

10 OVERDOSAGE Signs and Symptoms - Overdosage of metoprolol succinate extended-release tablets 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. Seek consultation with a regional poison control center and a medical toxicologist as needed. 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. There is very limited experience with the use of hemodialysis to remove metoprolol, however metoprolol is not highly protein bound. 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 α 1 receptor agonistic drugs added in presence of vasodilation. Bronchospasm: Can usually be reversed by bronchodilators.

16 HOW SUPPLIED/STORAGE AND HANDLING Metoprolol Succinate Extended-Release Tablets USP, 25 mg are white film coated oval shape tablets, scored on two sides, debossed with “Y” and “H” on one side and debossed with “164” on the other side. They are supplied in bottles of 100, 500 and 1,000 tablets. Bottles of 100 tablets with child-resistant closure, NDC 42806-724-01 Bottles of 500 tablets with child-resistant closure, NDC 42806-724-05 Bottles of 1,000 tablets with child-resistant closure, NDC 42806-724-10 Metoprolol Succinate Extended-Release Tablets USP, 50 mg are white film coated oval shape tablets, scored on two sides, debossed with “Y” and “H” on one side and debossed with “165” on the other side. They are supplied in bottles of 100, 500 and 1,000 tablets. Bottles of 100 tablets with child-resistant closure, NDC 42806-725-01 Bottles of 500 tablets with child-resistant closure, NDC 42806-725-05 Bottles of 1,000 tablets, NDC 42806-725-10 Metoprolol Succinate Extended-Release Tablets USP, 100 mg are white film coated oval shape tablets, scored on one side and debossed with “Y” and “H”, debossed with “163” on the other side. They are supplied in bottles of 100, 500 and 1,000 tablets. Bottles of 100 tablets with child-resistant closure, NDC 42806-726-01 Bottles of 500 tablets, NDC 42806-726-05 Bottles of 1,000 tablets, NDC 42806-726-10 Metoprolol Succinate Extended-Release Tablets USP, 200 mg are white film coated oval shape tablets, scored on one side and debossed with “Y” and “H”, debossed with “161” on the other side. They are supplied in bottles of 100, 500 and 1,000 tablets. Bottles of 100 tablets with child-resistant closure, NDC 42806-727-01 Bottles of 500 tablets, NDC 42806-727-05 Bottles of 1,000 tablets, NDC 42806-727-10 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. As with all medications, keep out of the reach of children.