TOPROL_XL- metoprolol succinate_tablet, extended release

Hypertension: Heart Failure: Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, 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. Metoprolol is a beta 1 2 The relative beta 1 2 1 1 The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an E max 1 1 1 2 Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta 2 In other studies, treatment with TOPROL-XL produced an improvement in left ventricular ejection fraction. TOPROL-XL was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment. Adults: Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity. Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in metoprolol succinate dosage is usually needed in patients with chronic renal failure. Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Poor metabolizers and extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity [see Drug Interactions (7. 2) In comparison to conventional metoprolol, the plasma metoprolol levels following administration of TOPROL-XL are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once-daily administration of TOPROL-XL average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol, administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of TOPROL-XL, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol. Nevertheless, over the 24-hour dosing interval, beta 1 [see Clinical Pharmacology (12) Pediatrics:.

TOPROL-XL, metoprolol succinate, is a beta 1 TOPROL-XL is indicated for the treatment of: Hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. 1) Angina Pectoris. 2) Heart Failure - for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. 3) TOPROL-XL is 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 (e. , on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. TOPROL-XL may be administered with other antihypertensive agents. TOPROL-XL is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. TOPROL-XL is 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, TOPROL-XL decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.

TOPROL-XL is an extended-release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate-release metoprolol to TOPROL-XL, use the same total daily dose of TOPROL-XL. Individualize the dosage of TOPROL-XL. Titration may be needed in some patients. TOPROL-XL tablets are scored and can be divided; however, do not crush or chew the whole or half tablet. Administer once daily. Dosing of TOPROL-XL should be individualized. (2) Heart Failure: Recommended starting dose is 12. 5 mg or 25 mg doubled every two weeks to the highest dose tolerated or up to 200 mg. 3) Hypertension: Usual initial dosage is 25 to 100 mg once daily. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. Dosages above 400 mg per day have not been studied. 1) Angina Pectoris: Usual initial dosage is 100 mg once daily. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is an unacceptable bradycardia. 2) Switching from immediate-release metoprolol to TOPROL-XL: use the same total daily dose of TOPROL-XL. (2) Adults: Pediatric Hypertensive Patients >= 6 Years of age: [see Use in Specific Populations (8. 4) [see Clinical Pharmacology (12. 3) TOPROL-XL is not recommended in pediatric patients < 6 years of age [see Use in Specific Populations (8. 4) Individualize the dosage of TOPROL-XL. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 - 2 weeks [see Warnings and Precautions (5) Dosage must be individualized and closely monitored during up-titration. Prior to initiation of TOPROL-XL, stabilize the dose of other heart failure drug therapy. The recommended starting dose of TOPROL-XL is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12. 5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of TOPROL-XL. Initial difficulty with titration should not preclude later attempts to introduce TOPROL-XL. If patients experience symptomatic bradycardia, reduce the dose of TOPROL-XL. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of TOPROL-XL or temporarily discontinuing it. The dose of TOPROL-XL should not be increased until symptoms of worsening heart failure have been stabilized.

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, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash. 1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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: Heart Failure: The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of >= 1% in the TOPROL-XL 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 TOPROL-XL Group and Greater Than Placebo by More Than 0. 5% TOPROL-XL n=1990 % of patients Placebo n=2001 % of patients Dizziness/vertigo 1. 0 Bradycardia 1. 4 Accident and/or injury 1. 8 Post-operative Adverse Events: The following adverse reactions have been identified during post-approval use of TOPROL-XL 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: Respiratory: Central Nervous System: Gastrointestinal: Hypersensitive Reactions: Miscellaneous: Potential Adverse Reactions: Central Nervous System: Hematologic: Hypersensitive Reactions: Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.

TOPROL-XL is contraindicated in severe bradycardia, second or third degree heart block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product. Known hypersensitivity to product components. (4) Severe bradycardia. (4) Heart block greater than first degree. (4) Cardiogenic shock. (4) Decompensated cardiac failure. (4) Sick sinus syndrome without a pacemaker.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Use this drug during pregnancy only if clearly needed. 1) Nursing Mothers: Consider possible infant exposure. 3) Pediatrics: Safety and effectiveness have not been established in patients < 6 years of age. 4) Geriatrics: No notable difference in efficacy or safety vs. younger patients. 5) Hepatic Impairment: Consider initiating TOPROL-XL therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events. 6) Pregnancy Category C Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m 2 Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when TOPROL-XL is administered to a nursing woman. One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of TOPROL-XL (0. 0 mg/kg once daily) and followed for 4 weeks. The study did not meet its primary endpoint (dose response for reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including: Dose-response for reduction in DBP, 1 mg/kg vs. placebo for change in SBP, and 2 mg/kg vs. placebo for change in SBP and DBP. The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in some individuals [see Dosage and Administration (2. 1) No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years as compared with adult patients. Safety and effectiveness of TOPROL-XL have not been established in patients < 6 years of age. Clinical studies of TOPROL-XL in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients. Of the 1,990 patients with heart failure randomized to TOPROL-XL in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older and younger patients. 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. No studies have been performed with TOPROL-XL in patients with hepatic impairment. Because TOPROL-XL 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; and increase doses gradually in patients with impaired hepatic function. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure [see Clinical Pharmacology (12.

Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. 1) CYP2D6 Inhibitors are likely to increase metoprolol concentration. 2) Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. 3) Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. 3) Catecholamine depleting drugs (e. , reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with TOPROL-XL plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. 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. with immediate-release metoprolol 50 mg t. 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. 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.

OVERDOSAGE
Signs and Symptoms - Overdosage of TOPROL-XL 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 en dash 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 alpha 1 Bronchospasm: Can usually be reversed by bronchodilators.
NONCLINICAL TOXICOLOGY
Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m 2 2 All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella Salmonella No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m 2
CLINICAL STUDIES
In five controlled studies in normal healthy subjects, the same daily doses of TOPROL-XL and immediate-release metoprolol were compared in terms of the extent and duration of beta 1 1 1 1 1 1 1 1 In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized to once daily TOPROL-XL (25, 100, or 400 mg), PLENDIL registered In controlled clinical studies, an immediate-release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100-450 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, produces similar beta 1 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. In controlled clinical trials, an immediate-release formulation of metoprolol has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily. MERIT-HF was a double-blind, placebo-controlled study of TOPROL-XL conducted in 14 countries including the US. It randomized 3991 patients (1990 to TOPROL-XL) with ejection fraction <=0. 40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of TOPROL-XL was 159 mg. The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0. The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p= 0. The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class. The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects. Clinical Endpoints in the MERIT-HF Study Clinical Endpoint Number of Patients Relative Risk (95% Cl) Risk Reduction With TOPROL-XL Nominal P-value Placebo n=2001 TOPROL-XL n=1990 All-cause mortality plus all-caused hospitalization Time to first event 767 641 0. 00012 All-cause mortality 217 145 0. 00009 All-cause mortality plus heart failure hospitalization 439 311 0. 0000008 Cardiovascular mortality 203 128 0. 000022 Sudden death 132 79 0. 0002 Death due to worsening heart failure 58 30 0. 0023 Hospitalizations due to worsening heart failure Comparison of treatment groups examines the number of hospitalizations (Wilcoxon test); relative risk and risk reduction are not applicable. 451 317 N/A N/A 0. 0000076 Cardiovascular hospitalization 773 649 N/A N/A 0. 00028 Merit results graph.
REFERENCES
1. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet

Aphena Pharma Solutions - Tennessee, LLC

TOPROL_XL- metoprolol succinate_tablet, extended release Product manual source documgent