24 Hr Metoprolol Succinate 100 Mg (as Metoprolol Succinate 95 Mg Equivalent To 100 Mg Metoprolol Tartrate) Extended Release Oral Tablet

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.g., 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.

Pediatric  Hypertensive  Patients  ≥  6  Years  of  age:A pediatric clinical hypertension study in patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstrated effectiveness [see Use in Specific Populations (8.4)] . If selected for treatment, the recommended starting dose of metoprolol succinate is 1 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Adjust dosage according to blood pressure response. Doses above 2 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients [see Use in Specific Populations (8.4)and Clinical Pharmacology (12.3)].  

Metoprolol succinate has not been studied in pediatric patients < 6 years of age [see Use in Specific Populations (8.4)].

50 mg tablets: White to off-white color, round shaped, biconvex coated tablets, debossed with "565" on one side and break line on the other side.

100 mg tablets: White to off-white color, round shaped, biconvex coated tablets, debossed with "566" on one side and break line on other side.

200 mg tablets: White to off-white color, oval shaped, biconvex coated tablets, debossed with "5" and "67" on either side of break line and plain on the other side.

Patients with first-degree atrioventricular block, sinus node dysfunction, conduction disorders (including Wolff- Parkinson-White) or on concomitant drugs that cause bradycardia [see Drug Interactions (7.3)], may be at increased risk. Monitor heart rate in patients receiving metoprolol succinate. If severe bradycardia develops, reduce or stop metoprolol succinate.

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery: however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

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 in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of metoprolol succinate 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 group and greater than placebo by more than 0.5%, regardless of the assessment of causality.

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, photosensitivity, taste disturbance.

Potential Adverse Reactions:In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol succinate.

Central  Nervous  System:Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics.

Hematologic:Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Hypersensitive  Reactions:Laryngospasm, respiratory distress.

If clonidine and a beta blocker, such as metoprolol are co-administered, 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.

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 ²basis.

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 ²basis, 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.

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. There is no information regarding the effects of metoprolol on milk production.

Clinical consideration

Monitoring for adverse reactions

Monitor the breastfed infant for bradycardia and other symptoms of beta-blockade such as listlessness (hypoglycemia).

Data

Based on published case reports, the estimated infant daily dose of metoprolol received from breast milk 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.

In two women who were taking unspecified amount of metoprolol, milk samples were taken after one dose of metoprolol. The estimated amount of metoprolol and alpha hydroxy metoprolol 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 to 158.7). The average relative infant dosage was 0.5% of the mother's weight-adjusted dosage.

Based on the published literature, beta-blockers (including metoprolol) may cause erectile dysfunction and inhibit sperm motility.

No evidence of impaired fertility due to metoprolol was observed in rats [see Nonclinical Toxicology (13.1)].

Of the 1,990 patients with heart failure randomized to metoprolol succinate 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.

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 FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta ₁-receptor blocking doses.

Hypertension: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.

The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Beta ₁-blocking effects in the range of 30 to 80% of the maximal effect (approximately 8 to 23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30 to 540 nmol/L. The relative beta ₁-selectivity of metoprolol diminishes and blockade of beta ₂-adrenoceptors increases at plasma concentration above 300 nmol/L.

In five controlled studies in normal healthy subjects, extended-release metoprolol succinate administered once a day, and immediate-release metoprolol administered once to four times a day, provided comparable total beta ₁-blockade over 24 hours (area under the beta ₁-blockade versus time curve) in the dose range 100 to 400 mg. In another controlled study, 50 mg once daily for each product, extended-release metoprolol succinate produced significantly higher total beta ₁-blockade over 24 hours than immediate-release metoprolol. For extended-release metoprolol succinate, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta ₁-blockade increased with increasing doses from 50 to 300 mg daily.

A controlled cross-over study in heart failure patients compared the plasma concentrations and beta ₁-blocking effects of 50 mg immediate-release metoprolol administered t.i.d., and 100 mg and 200 mg extended-release metoprolol succinate once daily. Extended-release metoprolol succinate 200 mg once daily produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate-release metoprolol.

In other studies, treatment with metoprolol succinate produced an improvement in left ventricular ejection fraction. Metoprolol succinate was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment.

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-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.

The peak plasma levels following once-daily administration of metoprolol succinate 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 metoprolol succinate, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol.

The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following metoprolol succinate administration.

The peak plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism.

Distribution

Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Only a small fraction of the drug (about 12%) is bound to human serum albumin.

Metabolism

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

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%.

Specific Populations

Patients with Renal Impairment

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.

Pediatric Patients

The pharmacokinetic profile of metoprolol succinate was studied in 120 pediatric hypertensive patients (6 to 17 years of age) receiving doses ranging from 12.5 to 200 mg once daily. The pharmacokinetics of metoprolol were similar to those described previously in adults. Metoprolol pharmacokinetics have not been investigated in patients < 6 years of age.

Body Weight, Age, and Race

Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Age, gender, and race had no significant effects on metoprolol pharmacokinetics.

Drug Interactions

CYP2D6

Metoprolol is metabolized predominantly by CYP2D6. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a potent CYP2D6 inhibitor, 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 steady-state concentration of metoprolol 2- to 5-fold what is seen with metoprolol alone. 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)] .

All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative.

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 ²basis, the daily dose of 200 mg in a 60-kg patient.

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 to 450 mg daily. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, produces similar β1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, metoprolol succinate extended-release tablets administered at a dose of 50 mg once daily lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate-release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected both supine and standing blood pressure. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration.

The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p=0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p=0.00012). 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. Nonetheless, subgroup analyses can be difficult to interpret, and it is not known whether these represent true differences or chance effects.