General Information

Toprol-XL is a beta1-selective (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended release tablets. It has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. Hypertension The mechanism of the antihypertensive effects of beta-blocking agents is not fully known. 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 Metoprolol blocks the catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort. Heart failure Tthe precise mechanism for the beneficial effects of beta-blockers in heart failure is not known.

Toprol-XL is specifically indicated for: the treatment of hypertension, either alone or in combination with other antihypertensive agents, the long-term treatment of angina pectoris and the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin.

Toprol-XL is supplied as 25mg, 50mg, 100mg and 200mg tablets designed for oral administration. The recommended initial dose of the drug is as follows:<.p>

Hypertension
25 to 100 mg daily in a single dose, 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. Dosages above 400 mg per day have not been studied.

Angina Pectoris
The doseage should be individualized. The usual initial dosage is 100 mg daily, given in a single dose. The dosage may be gradually increased 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 to 2 weeks.

Heart Failure
Dosage must be individualized and closely monitored during up-titration. The recommended starting dose of 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. The dose should then be doubled every two weeks to the highest dosage level tolerated, up to 200 mg.

Clinical Results

FDA Approval

Hypertension
A double-blind study enrolled 1,092 subjects with mild-to-moderate hypertension who were randomized to once daily Toprol-XL (25, 100, or 400 mg), Plendil (felodipine extended release tablets), a combination of the two, or placebo. After 9 weeks, Toprol-XL alone decreased sitting blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of Toprol-XL with Plendil has greater effects on blood pressure. In controlled clinical studies, an immediate release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100-450 mg daily. Toprol-XL, in dosages of 100 to 400 mg once daily, produces similar ß1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, Toprol-XL 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.

Angina Pectoris
In controlled clinical trials, an immediate release formulation of metoprolol has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. Toprol-XL, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily.

Heart Failure
MERIT-HF was an international double-blind, placebo-controlled study and randomized 3,991 patients with NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. Prior to treatment, subjects were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of Toprol-XL was 159 mg. The primary endpoints were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. 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.

Mechanism of Action