Covera-HS has a unique delivery system, designed for bedtime dosing, incorporating a 4 to 5-hour delay in drug delivery. The unique controlled-onset, extended- release (COER) delivery system, which is designed for bedtime dosing, results in a maximum plasma concentration (Cmax) of verapamil in the morning hours.

Verapamil is a calcium ion influx inhibitor (L-type calcium channel blocker or calcium channel antagonist). Verapamil exerts its pharmacologic effects by selectively inhibiting the transmembrane influx of ionic calcium into arterial smooth muscle as well as in conductile and contractile myocardial cells without altering serum calcium concentrations.

Mechanism of action

In vitro: Verapamil binding is voltage-dependent with affinity increasing as the vascular smooth muscle membrane potential is reduced. In addition, verapamil binding is frequency dependent and apparent affinity increases with increased frequency of depolarizing stimulus.

The L-type calcium channel is an oligomeric structure consisting of five putative subunits designated alpha-1, alpha-2, beta, tau, and epsilon. Biochemical evidence points to separate binding sites for 1,4-dihydropyridines, phenylalkylamines, and the benzothiazepines (all located on the alpha-1 subunit). Although they share a similar mechanism of action, calcium channel blockers represent three heterogeneous categories of drugs with differing vascular-cardiac selectivity ratios.

Essential hypertension: Verapamil produces its antihypertensive effect by a combination of vascular and cardiac effects. It acts as a vasodilator with selectivity for the arterial portion of the peripheral vasculature. As a result the systemic vascular resistance is reduced and usually without orthostatic hypotension or reflex tachycardia. Bradycardia (rate less than 50 beats/min) is uncommon (<1% with Covera-HS as assessed by ECG). During isometric or dynamic exercise Covera-HS does not alter systolic cardiac function in patients with normal ventricular function.

Covera-HS does not alter total serum calcium levels. However, one report has suggested that calcium levels above the normal range may alter the therapeutic effect of verapamil.

Covera-HS regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles.

Effects in hypertension: Covera-HS was evaluated in two placebo-controlled, parallel design, double-blind studies of 382 patients with mild to moderate hypertension.

In a clinical trial, 287 patients were randomized to placebo, 120 mg, 180 mg, 360 mg, or 540 mg and treated for 8 weeks (the two higher doses were titrated from low doses and maintained for 6 and 4 weeks, respectively). Covera-HS or placebo was given once daily at 10 pm and blood pressure changes were measured with 36-hour ambulatory blood pressure monitoring (ABPM). The results of these studies demonstrate that Covera-HS, at 180–540 mg, is a consistently and significantly more effective antihypertensive agent than placebo in reducing ambulatory blood pressures. Over this dose range, the placebo-subtracted net decreases in diastolic BP at trough (averaged over 6–10 pm) were dose-related, ranged from 4.5 to 11.2 mm Hg after 4–8 weeks of therapy, and correlated well with sitting cuff blood pressures.

These studies demonstrate that clinically and statistically significant blood pressure reductions are achieved with Covera-HS throughout the 24-hour dosing period.

There were no significant treatment differences between patient subgroups of different age (older or younger than 65 years), sex, race (Caucasian and non Caucasian) and severity of hypertension at baseline (cuff BP below and above 105 mm Hg).

Angina: Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm and is responsible for the effectiveness of verapamil in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina.

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