March 23, 2017
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"SYDNEY, AUSTRALIA ” A small randomized trial reports sharp blood-pressure reductions in untreated hypertensives using a single pill combining four BP-lowering drugs at one-quarter the usual dose.

Among 18 patients, mean 24-hour systol"...




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).


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.

Verapamil 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.

Effect in chronic stable angina

COVERA-HS was evaluated in two placebo-controlled, parallel design, double-blind studies of 453 patients with chronic stable angina.

In the first clinical trial, 277 patients were randomized to placebo, 180 mg, 360 mg, or 540 mg and treated for 4 weeks (the two higher doses were titrated from low doses and maintained for 3 and 2 weeks, respectively). A single dose of 240 mg was compared to placebo in a separate study of 176 patients. In these studies, COVERA-HS was significantly more effective than placebo in improvement of exercise tolerance. Placebo-adjusted net increases in median exercise times at the end of the dosing interval were 0.1 to 1.0 minute for symptom limited duration, 0.3 to 1.4 minutes for time to angina, and 0.1 to 1.1 minutes for time to ST change. Increases in exercise tolerance were in general greater at higher doses, but dose-response relationship was not well defined due to shorter treatment duration for high doses.

In addition, in the first study, 24% to 34% of patients treated with COVERA-HS did not experience exercise-limiting angina on exercise treadmill testing (ETT) versus 12% of patients on placebo.

Electrophysiologic effects

Electrical activity through the AV node depends, to a significant degree, upon the transmembrane influx of extracellular calcium through the L-type (slow) channel. By decreasing the influx of calcium, verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner.

Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil may interfere with sinus-node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS).

COVERA-HS does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers. Verapamil may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS).

Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man.

Pharmacokinetics and metabolism

Verapamil is administered as a racemic mixture of the R and S enantiomers. The systemic concentrations of R and S enantiomers, as well as overall bioavailability, are dependent upon the route of administration and the rate and extent of release from the dosage forms. Upon oral administration, there is rapid stereoselective biotransformation during the first pass of verapamil through the portal circulation. In a study in 5 subjects with oral immediate-release verapamil, the systemic bioavailability was from 33% to 65% for the R enantiomer and from 13% to 34% for the S enantiomer. The R and S enantiomers have differing levels of pharmacologic activity. In studies in animals and humans, the S enantiomer has 8 to 20 times the activity of the R enantiomer in slowing AV conduction. In animal studies, the S enantiomer has 15 and 50 times the activity of the R enantiomer in reducing myocardial contractility in isolated blood-perfused dog papillary muscle and isolated rabbit papillary muscle, respectively, and twice the effect in reducing peripheral resistance. In isolated septal strip preparations from 5 patients, the S enantiomer was 8 times more potent than the R in reducing myocardial contractility. Dose escalation study data indicate that verapamil concentrations increase disproportionally to dose as measured by relative peak plasma concentrations (Cmax) or areas under the plasma concentration vs. time curves (AUC).

Pharmacokinetic Characteristics of Verapamil Enantiomers After Administration of Escalating Doses

  Isomer Total Dose of Racemic Verapamil (mg)
120 180 360 540
Dose Ratio 1 1.5 3 4.5
Relative Cmax R 1 1.55 4.47 7.06
S 1 1.62 5.17 9.21
Relative AUC R 1 1.59 6.14 11.1
S 1 1.89 8.17 15.9

Pharmacokinetic Characteristics of Verapamil Enantiomers After Administration of a Single 180 mg Dose and at Steady State

  Isomer First Dose (Verapamil-naive subject) Steady State (Current verapamil exposure)
Cmax R 59.4 90.5
(ng/ml) S 11.7 21.2
AUC (0–24h) R 644 1,223
(ng•hr/ml) S 111 266

Racemic verapamil is released from COVERA-HS at a constant rate following solubilization and release of the delay coat through the tablet orifices. This delay coat produces a lag period in drug release for approximately 4–5 hours. The drug release phase is prolonged with the peak plasma concentration (Cmax) occurring approximately 11 hours after administration. Trough concentrations occur approximately 4 hours after bedtime dosing while the patient is sleeping. Steady-state pharmacokinetics were determined in healthy volunteers. Steady-state concentration is reached by the third or fourth day of dosing.

Steady-State Pharmacokinetics of Verapamil Enantiomers in Healthy Humans

  Isomer Verapamil Dose (mg)
180 240
Mean Cmax R 90.5 120
(ng/ml) S 21.2 28.7
AUC (0–24h) R 1,223 1,470
(ng•hr/ml) S 266 322

Consumption of a high fat meal just prior to dosing at night had no effect on the pharmacokinetics of COVERA-HS. The pharmacokinetics were also not affected by whether the volunteers were supine or ambulatory for the 8 hours following dosing. Administering COVERA-HS in the morning led to a slower rate of absorption and/or elimination, but did not affect the extent of absorption or extent of metabolism to norverapamil.

Orally administered verapamil undergoes extensive metabolism in the liver. Thirteen metabolites have been identified in urine. Norverapamil enantiomers can reach steady-state plasma concentrations approximately equal to those of the enantiomers of the parent drug. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. R-verapamil is 94% bound to plasma albumin, while Sverapamil is 88% bound. In addition, R-verapamil is 92% and S-verapamil 86% bound to alpha-1 acid glycoprotein. In patients with hepatic insufficiency, metabolism of immediate-release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours because of the extensive hepatic metabolism (see PRECAUTIONS). In addition, in these patients there is a reduced first-pass effect, and verapamil is more bioavailable. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one third of the oral daily dose required for patients with normal liver function.

After four weeks of oral dosing of immediate release verapamil (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.

Geriatric use

The pharmacokinetics of COVERA-HS were studied after 5 consecutive nights of dosing 180 mg in 30 healthy young (19–43 years) versus 30 healthy elderly (65–80 years) male and female subjects. Older subjects had significantly higher mean verapamil Cmax, Cmin, and AUC(0–24h) compared to younger subjects. Older subjects had mean AUCs that were approximately 1.7–2.0 times higher than those of younger subjects as well as a longer average verapamil t½ (approximately 20 hr vs. 13 hr). These results were typical of the age-related differences seen with many drug products in clinical medicine. Lean body mass was inversely related to AUC, but no gender difference was observed in the clinical trials of COVERA-HS. However, there are conflicting data in the literature suggesting that verapamil clearance may decrease with age in women to a greater degree than in men. Mean Tmax was similar in young and elderly subjects.


Verapamil reduces afterload and myocardial contractility. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by reduction of afterload and cardiac index remains unchanged. During isometric or dynamic exercise, verapamil does not alter systolic cardiac function in patients with normal ventricular function. Improved left ventricular diastolic function in patients with Idiopathic Hypertrophic Subaortic Stenosis (IHSS) and those with coronary heart disease has also been observed with verapamil. In patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure above 20 mm Hg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see PRECAUTIONS: DRUG INTERACTIONS).

Pulmonary function

Verapamil does not induce bronchoconstriction and, hence, does not impair ventilatory function.

Verapamil has been shown to have either a neutral or relaxant effect on bronchial smooth muscle.

Animal pharmacology and/or animal toxicology

In chronic animal toxicology studies, verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater, and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not in the rat. Development of cataracts due to verapamil has not been reported in man.

Last reviewed on RxList: 1/31/2017
This monograph has been modified to include the generic and brand name in many instances.

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