Composition

Metolar XR-12.5 Capsule
Each extended-release capsule contains
Metoprolol succinate equivalent to Metoprolol tartrate................ 12.5 mg

Metolar XR-25 Capsule
Each extended-release capsule contains
Metoprolol succinate equivalent to Metoprolol tartrate...................25 mg

Metolar XR-50 Capsule
Each extended-release capsule contains
Metoprolol succinate equivalent to Metoprolol tartrate......................50 mg

Metolar XR-100 Capsule
Each extended-release capsule contains
Metoprolol succinate equivalent to Metoprolol tartrate...................100 mg

Dosage Form

Extended-Release Capsule

Pharmacology

Pharmacodynamics

Metoprolol is a beta₁-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta₂-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 atrioventricular (AV) nodal conduction.

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 relative beta₁-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta₂-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 forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) significantly less than a nonselective beta-blocker, propranolol, at equivalent beta₁-receptor blocking doses.

In clinical trials, metoprolol extended-release administered once a day, and immediate-release metoprolol administered once to four times a day, provided comparable total beta₁-blockade over 24 hours (area under the beta₁-blockade versus time curve) in the dose range 100-400 mg. At a dosage of 50 mg once daily, metoprolol extended-release produced significantly higher total beta₁-blockade over 24 hours than immediate-release metoprolol. For metoprolol extended-release, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta₁-blockade increased with increasing doses from 50 to 300 mg daily. In contrast to metoprolol extended-release, immediate-release metoprolol given at a dose of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with metoprolol extended-release over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate-release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta₁-blocking effects of 50 mg immediate-release metoprolol administered t.i.d., 100 mg and 200 mg metoprolol extended-release once daily. A 50 mg dose of immediate-release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of metoprolol extended-release. A 200 mg dose of metoprolol extended-release 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.

The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an Emax model, the maximum effect is a 30% reduction in exercise heart rate, which is attributed to beta₁-blockade. Beta₁-blocking effects in the range of 30-80% of the maximal effect (approximately 8-23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The relative beta₁-selectivity of metoprolol diminishes and blockade of beta₂-adrenoceptors increases at plasma concentrations above 300 nmol/L.

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. Beta₂-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.

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

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.

Pharmacokinetics

Adults
In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol, however, approximate 50% of levels following intravenous (IV) administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood-brain barrier and has been reported in the cerebral spinal fluid (CSF) in a concentration 78% of the simultaneous plasma concentration.

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 IV 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.

In comparison to conventional metoprolol, the plasma metoprolol levels following administration of metoprolol extended-release 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 metoprolol extended-release 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 extended-release, 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, beta₁-blockade is comparable and dose-related. The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following metoprolol extended-release administration.

Pediatrics
The pharmacokinetic profile of metoprolol extended-release was studied in 120 pediatric hypertensive patients (6-17 years of age) receiving doses ranging from 12.5 mg to 200 mg once daily. The pharmacokinetics of metoprolol in pediatrics were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on metoprolol pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Metoprolol pharmacokinetics have not been investigated in patients less than 6 years of age.

Indications

Hypertension

METOLAR XR is indicated for the treatment of hypertension, to lower blood pressure. It may be administered with other antihypertensive agents.

Angina Pectoris

METOLAR XR is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.

Heart Failure

METOLAR XR is indicated for the treatment of stable, symptomatic [New York Heart Association (NYHA) Class II or III] heart failure of ischemic, hypertensive or cardiomyopathic origin. Metoprolol extended-release was studied in patients already receiving angiotensin converting enzyme (ACE) inhibitors, diuretics and in the majority of cases, digitalis. In this population, metoprolol extended-release decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.

Migraine Prophylaxis

Dosage and Administration

METOLAR XR is an extended-release capsule intended for only daily administration. For treatment of hypertension and angina, when switching from immediate-release metoprolol to METOLAR XR, use the same total daily dose of METOLAR XR. Individualize the dosage of METOLAR XR. Titration may be needed in some patients.

Hypertension

The usual initial dosage is 25 to 100 mg daily in a single dose. 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 one week of therapy. Dosages above 400 mg per day have not been studied.

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 systolic blood pressure (SBP)], however some other endpoints demonstrated effectiveness. If selected for treatment, the recommended starting dose of metoprolol extended-release is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. Doses above 2.0 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients.

Metoprolol extended-release is not recommended in pediatric patients

Angina Pectoris

The dosage should be individualized. 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. 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 1-2 weeks.

Heart Failure

Dosage must be individualized and closely monitored during up-titration. Prior to initiation of Metolar XR, stabilize the dose of other heart failure drug therapy. The recommended starting dose 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 very two weeks to the highest dosage level tolerated by the or up to 200 mg of METOLAR XR. Initial difficulty with titration should not preclude later attempts to introduce Metolar XR. If patients experience symptomatic bradycardia, reduce the dose of METOLAR XR. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of Metolar XR or temporarily discontinuing it. The dose of Metolar XR should not be increased until symptoms of worsening heart failure have been stabilized.

Migraine Prophylaxis

The dosage is 100-200 mg once daily in the morning.

Contraindications

Warnings and Precautions

Drug Interactions

Catecholamine Depleting Drugs [e.g. reserpine, monoamine oxidase (MAO) inhibitors]
Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. Observe patients treated with Metolar XR plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

CYP2D6 Inhibitors
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, co-administration 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, co-administration of propafenone 150 mg t.i.d with immediate-release metoprolol 50 mg t.i.d resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol.

Digitalis Glycosides
Digitalis glycosides slow AV conduction & decrease heart rate. Concomitant use with beta-blockers can increase the risk of bradycardia.

Clonidine
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, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.

Calcium Channel Blockers
Concomitant use of calcium channel blockers with beta-blockers can increase the risk of bradycardia. Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.

Ischemic Heart Disease

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 Metolar XR, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1-2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, Metolar XR should be reinstated promptly, and measures appropriate for the management of unstable angina should be taken. Warn patients not to interrupt therapy without their physicians advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing METOLAR XR in patients treated only for hypertension.

Bronchospastic Diseases

Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative beta₁-selectivity, however, METOLAR XR may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta₁-selectivity is not absolute, use the lowest possible dose of METOLAR XR. Bronchodilators, including beta₂-agonists, should be readily available or administered concomitantly.

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.

Diabetes and Hypoglycemia

Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.

Thyrotoxicosis

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

Peripheral Vascular Disease

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

Pheochromocytoma

If METOLAR XR is 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 vasodilation in skeletal muscle.

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.

Heart Failure

Worsening cardiac failure may occur during up-titration of METOLAR XR . If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose ofMETOLAR XR. It may be necessary to lower the dose of METOLAR XR or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of METOLAR XR.

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.

Hepatic Impairment

No studies have been performed with METOLAR XR in patients with hepatic impairment. Because, metoprolol extended-release is metabolized by liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Consider initiating METOLAR XR therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events.

Pregnancy

Category C
There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Lactation

Metoprolol is excreted in breast milk in 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 metoprolol extended-release is administered to a nursing woman.

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 extended-release (0.2, 1.0 or 2.0 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:

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.

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 extended-release have not been established in patients <6 years of age.

Geriatric Use

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.

Undesirable Effects

The following are the adverse reactions:

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

Post-Operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta-blocker therapy, metoprolol extended-release 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Metoprolol extended-release 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.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of metoprolol extended-release or immediate-release metoprolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension.

Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia.

Respiratory: Wheezing (bronchospasm), dyspnea.

Gastrointestinal: Nausea, dry mouth, constipations, 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 extended-release.

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

Laboratory Test Findings

Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase and lactate dehydrogenase.

Overdosage

Signs and Symptoms

Overdosage of METOLAR XR may lead to severe bradycardia, hypotension and cardiogenic shock. Clinical presentation can also include: AV block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting.

Treatment

Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Seek consultation with a regional poison control center and a medical toxicologist as needed. Beta-blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. On the basis of the pharmacologic actions of metoprolol employ the following measures.

There is very limited experience with the use of hemodialysis to remove metoprolol, however metoprolol is not highly protein bound.

Bradycardia: Administer IV atropine; repeat to effect. If the response is inadequate, consider intravenous isoproterenol or other positive chronotropic agents. Evaluate the need for transvenous pacemaker insertion.

Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine.

Bronchospasm: Administer a beta₂-agonist, including albuterol inhalation, or an oral theophylline derivative.

Cardiac Failure: Administer diuretics or digoxin for congestive heart failure. For cardiogenic shock, consider IV dobutamine, isoproterenol or glucagon.

Packaging Information

METOLAR XR-12.5: Blister pack of 10 capsules
METOLAR XR-25: Blister pack of 10 capsules
METOLAR XR-50: Blister pack of 15 capsules
METOLAR XR-100: Blister pack of 10 capsules