Pharmacokinetics

In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism.

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. 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 clinical significance. 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 dosage is usually needed in patients with chronic renal failure.

Metoprolol is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers.

Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of metoprolol than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of metoprolol seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of metoprolol contribute significantly to its beta-blocking effect.

Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.

Equivalent maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio of approximately 2.5:1.

There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration.

In several studies of patients with acute myocardial infarction, intravenous followed by oral administration of metoprolol caused a reduction in heart rate, systolic blood pressure, and cardiac output. Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure remained unchanged.

In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the oral dose within the range of 50 to 400 mg. Exercise heart rate and systolic blood pressure are reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise capacity and the reduction in left ventricular ischemia are also significantly related to the logarithm of the oral dose.

In elderly subjects with clinically normal renal and hepatic function, there are no significant differences in metoprolol pharmacokinetics compared to young subjects.

Hypertension

Metoprolol tartrate tablets, USP are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents.

Angina Pectoris

Metoprolol tartrate tablets, USP are indicated in the long-term treatment of angina pectoris.

Myocardial Infarction

Metoprolol tartrate tablets, USP are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality. Treatment with intravenous metoprolol can be initiated as soon as the patient’s clinical condition allows (see and Alternatively, treatment can begin within 3 to 10 days of the acute event (see , , DOSAGE AND ADMINISTRATIONCONTRAINDICATIONS). WARNINGS). DOSAGE AND ADMINISTRATION

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 tartrate 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.

Pheochromocytoma (see ). WARNINGS

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 ≥ 0.24 sec); systolic blood pressure < 100 mmHg; or moderate-to-severe cardiac failure (see ). WARNINGS

Hypertension and Angina

: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics, metoprolol should be administered cautiously. Cardiac Failure

: Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic. The response should be observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, metoprolol should be withdrawn. In Patients Without a History of Cardiac Failure

General

Metoprolol should be used with caution in patients with impaired hepatic function.

Information for Patients

Patients should be advised to take metoprolol regularly and continuously, as directed, with or immediately following meals. If a dose should be missed, the patient should take only the next scheduled dose (without doubling it). Patients should not discontinue metoprolol without consulting the physician.

Patients should be advised (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with metoprolol has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking metoprolol.

Drug Interactions

Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with metoprolol plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Risk of Anaphylactic Reaction:

General Anesthetics

Some inhalation anesthetics may enhance the cardiodepressant effect of beta- blockers (see ). WARNINGS, Major Surgery

CYP2D6 Inhibitors

Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of metoprolol. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer (see Caution should therefore be exercised when coadministering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine. , ). CLINICAL PHARMACOLOGYPharmacokinetics section

Clonidine

If a patient is treated with clonidine and metoprolol concurrently, and clonidine treatment is to be discontinued metoprolol should be stopped several days before clonidine is withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.

All mutagenicity tests performed (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) were negative.

No evidence of impaired fertility due to metoprolol was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg.

Pregnancy Category C

Metoprolol has been shown to increase postimplantation loss and decrease neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm exposure of the fetus when metoprolol is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Metoprolol is excreted in breast milk in a very small quantity. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Caution should be exercised when metoprolol is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical trials of metoprolol in hypertension did not include sufficient numbers of elderly patients to determine whether patients over 65 years of age differ from younger subjects in their response to metoprolol. Other reported clinical experience in elderly hypertensive patients has not identified any difference in response from younger patients.

In worldwide clinical trials of metoprolol in myocardial infarction, where approximately 478 patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety and effectiveness were found. Other reported clinical experience in myocardial infarction has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some elderly individuals taking metoprolol cannot be categorically ruled out. Therefore, in general, it is recommended that dosing proceed with caution in this population.

Hypertension and Angina

Most adverse effects have been mild and transient.

: Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported. Central Nervous System

: Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100 patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported very rarely. (see and Cardiovascular, , CONTRAINDICATIONSWARNINGS.) PRECAUTIONS

: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see Rhinitis has also been reported. Respiratory). WARNINGS

: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients. Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported. Gastrointestinal

: Pruritus or rash have occurred in about 5 of 100 patients. Very rarely, photosensitivity and worsening of psoriasis has also been reported. Hypersensitive Reactions

: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, and tinnitus have also been reported. Miscellaneous

There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis relationship to metoprolol has not been definitely established put.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with metoprolol.

Myocardial Infarction

: Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced libido have also been reported, but a drug relationship is not clear. Central Nervous System

: In the randomized comparison of metoprolol and placebo described in the section, the following adverse reactions were reported: CardiovascularCLINICAL PHARMACOLOGY

: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients. Respiratory

: Nausea and abdominal pain have been reported in fewer than 1 of 100 patients. Gastrointestinal

: Rash and worsened psoriasis have been reported, but a drug relationship is not clear. Dermatologic

: Unstable diabetes and claudication have been reported, but a drug relationship is not clear. Miscellaneous

Potential Adverse Reactions

A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol.

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

: Intensification of AV block (see Cardiovascular). CONTRAINDICATIONS

: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Hematologic

: Fever combined with aching and sore throat, laryngospasm, and respiratory distress. Hypersensitive Reactions

Acute Toxicity

Several cases of overdosage have been reported, some leading to death.

Oral LD ’s (mg/kg): mice, 1158 to 2460; rats, 3090 to 4670. 50

Signs and Symptoms

Potential signs and symptoms associated with overdosage with metoprolol are bradycardia, hypotension, bronchospasm, and cardiac failure.

Treatment

There is no specific antidote.

In general, patients with acute or recent myocardial infarction may be more hemodynamically unstable than other patients and should be treated accordingly (see , ). WARNINGSMyocardial Infarction

On the basis of the pharmacologic actions of metoprolol, the following general measures should be employed:

: Gastric lavage should be performed. Elimination of the Drug

: Atropine should be administered. If there is no response to vagal blockade, isoproterenol should be administered cautiously. Bradycardia

: A vasopressor should be administered, e.g., norepinephrine or dopamine. Hypotension

: A beta -stimulating agent and/or a theophylline derivative should be administered. Bronchospasm2

: A digitalis glycoside and diuretic should be administered. In shock resulting from inadequate cardiac contractility, administration of dobutamine, isoproterenol, or glucagon may be considered. Cardiac Failure

Hypertension

The dosage of metoprolol tartrate tablets, USP should be individualized. Metoprolol tartrate tablets, USP should be taken with or immediately following meals.

The usual initial dosage 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 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. 1

Angina Pectoris

The dosage of metoprolol tartrate tablets, USP should be individualized. Metoprolol tartrate tablets, USP should be taken with or immediately following meals.

The usual initial dosage 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 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

: During the early phase of definite or suspected acute myocardial infarction, treatment with metoprolol tartrate tablets, USP 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. Early Treatment

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 USP, 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 below). Late Treatment

Patients who appear not to tolerate the full intravenous dose should be started on metoprolol tartrate tablets, USP 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

: 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, USP,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. Late Treatment