Metoprolol: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

25 mg tablets: 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.

50 mg tablets: 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.

100 mg tablets: White film coated oval shape tablets, scored on one side and debossed with “Y” and “H”, debossed with “163” on the other side.

200 mg tablets: White film coated oval shape tablets, scored on one side and debossed with “Y” and “H”, debossed with “161” on the other side.

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=1,990) to placebo (n=2,001), 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 Tablets n=1,990% of patients | Placebo n=2,001% of patients
Dizziness/vertigo | 1.8 | 1.0
Bradycardia | 1.5 | 0.4

Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8,351 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 were 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, 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 extended-release tablets.

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.

5.1 Abrupt Cessation of Therapy

Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate metoprolol succinate extended-release tablets, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing metoprolol succinate extended-release tablets in patients treated only for hypertension.

5.2 Heart Failure

Worsening cardiac failure may occur during up-titration of metoprolol succinate extended-release tablets. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of metoprolol succinate extended-release tablets [see Dosage and Administration ( 2)] . It may be necessary to lower the dose of metoprolol succinate extended-release tablets or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol succinate extended-release tablets.

5.3 Bronchospastic Disease

Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative beta ₁-cardio-selectivity, however, metoprolol succinate extended-release tablets may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta ₁-selectivity is not absolute, use the lowest possible dose of metoprolol succinate extended-release tablets. Bronchodilators, including beta ₂-agonists, should be readily available or administered concomitantly [see Dosage and Administration ( 2)] .

5.4 Bradycardia

Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of metoprolol succinate extended-release tablets. 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 extended-release tablets. If severe bradycardia develops, reduce or stop metoprolol succinate extended-release tablets.

5.5 Pheochromocytoma

If metoprolol succinate extended-release tablets are used in the setting of pheochromocytoma, it should be given in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.

5.6 Major Surgery

Avoid initiation of a high-dose regimen of extended-release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death.

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.

5.7 Hypoglycemia

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

5.8 Thyrotoxicosis

Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.

5.9 Peripheral Vascular Disease

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

5.10 Anaphylactic Reaction

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.

7.1 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 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.

7.3 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 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.

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/m² 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/m² 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. 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 17.0 to 158.7). The average relative infant dosage was 0.5% of the mother's weight-adjusted dosage.

8.3 Females and Males of Reproductive Potential

Risk Summary

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

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

8.4 Pediatric Use

One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of metoprolol succinate extended-release tablets (0.2, 1 or 2 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 metoprolol succinate extended-release tablets have not been established in patients <6 years of age.

8.5 Geriatric Use

Clinical studies of metoprolol succinate extended-release tablets 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 metoprolol succinate extended-release tablets 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.

8.6 Hepatic Impairment

No studies have been performed with metoprolol succinate extended-release tablets in patients with hepatic impairment. Because metoprolol succinate extended-release tablets are 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.

8.7 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. No reduction in dosage is needed in patients with chronic renal failure [see Clinical Pharmacology ( 12.3)] .

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. 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 α ₁ receptor agonistic drugs added in presence of vasodilation.

Bronchospasm: Can usually be reversed by bronchodilators.

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.

12.2 Pharmacodynamics

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.

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.