Covera-HS^®
(verapamil hydrochloride)
Extended-Release Tablets
Controlled-Onset

Covera-HS (verapamil hydrochloride) is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist). Covera-HS is available for oral administration as pale yellow, round, film-coated tablets containing 240 mg of verapamil hydrochloride and as lavender, round, film-coated tablets containing 180 mg of verapamil hydrochloride. Verapamil is administered as a racemic mixture of the R and S enantiomers. The structural formulae of the verapamil HCl enantiomers are:

Benzeneacetonitrile, (±)-α-[3 [[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride

Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform, and methanol. Verapamil HCl is not chemically related to other cardioactive drugs.

Inactive ingredients are black ferric oxide, BHT, cellulose acetate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, polyethylene oxide, polysorbate 80, povidone, sodium chloride, titanium dioxide, and coloring agents: 240-mg—FD&C Blue No. 2 Lake and D&C Yellow No. 10 Lake; 180-mg—FD&C Blue No. 2 Lake and D&C Red No. 30 Lake.

The Covera-HS formulation has been designed to initiate the release of verapamil 4–5 hours after ingestion. This delay is introduced by a layer between the active drug core and outer semipermeable membrane. As water from the gastrointestinal tract enters the tablet, this delay coating is solubilized and released. As tablet hydration continues, the osmotic layer expands and pushes against the drug layer, releasing drug through precision laser-drilled orifices in the outer membrane at a constant rate. This controlled rate of drug delivery in the gastrointestinal lumen is independent of posture, pH, gastrointestinal motility, and fed or fasting conditions.

The biologically inert components of the delivery system remain intact during GI transit and are eliminated in the feces as an insoluble shell.

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 (C_max) 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.

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 (C_max) or areas under the plasma concentration vs time curves (AUC).

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 (C_max) 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.

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 S-verapamil 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.

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 C_max, C_min, 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 t_1/2 (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 T_max 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 IHSS and those with coronary heart disease has also been observed with verapamil. In patients with severe left ventricular dysfunction (eg, 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 Drug interactions).

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.

Covera-HS is indicated for the management of hypertension and angina.

Covera-HS is contraindicated in:

• Severe left ventricular dysfunction (see Warnings)
• Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock
• Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)
• Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker)
• Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (See Warnings.)
• Patients with known hypersensitivity to verapamil hydrochloride.

Verapamil has a negative inotropic effect, which in most patients is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In previous clinical experience with 4,954 patients primarily with immediate-release verapamil, 1.8% developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (eg, ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker (see Drug interactions). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment is started. (Note interactions with digoxin under Precautions.)

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension. In previous verapamil clinical trials the incidence observed in 4,954 patients was 2.5%. In clinical studies of Covera-HS, 0.4% of hypertensive patients and 1.0% of angina patients developed significant hypotension. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt-table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevation of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see Contraindications). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed in previous verapamil clinical trials. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy, depending upon the clinical situation.

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see Drug interactions ) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction, and only rarely did verapamil use have to be discontinued.

Covera-HS tablets should be swallowed whole; do not break, crush, or chew. The medication in the Covera-HS tablet is released slowly through an outer shell that does not dissolve. The patient should not be concerned if they occasionally observe this outer shell in their stool as it passes from the body.

An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg/day or approximately 1, 3.5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of Covera-HS did not include sufficient numbers of subjects aged under 65 to determine whether they responded differently from older subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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.

Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See Warnings for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions to orally administered Covera-HS occurred at rates greater than 2.0% or occurred at lower rates but appeared drug-related in clinical trials in hypertension and angina:

In previous experience with other formulations of verapamil, the following reactions occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug related in clinical trials in 4,954 patients.

The following reactions, reported with orally administered verapamil in 2% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are uled to alert the physician to a possible relationship:

Cardiovascular: angina pectoris, AV block (2°& 3°), atrioventricular dissociation, CHF, pulmonary edema, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope.

Digestive system: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.

Hemic and lymphatic: ecchymosis or bruising.

Nervous system: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms.

Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.

Special senses: blurred vision, tinnitus.

Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence.

Other: allergy aggravated, dyspnea.

The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately; eg, intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol HCl (all in usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, dopamine HCl or dobutamine HCl may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgement and experience of the treating physician.

Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially sustained-release verapamil products), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulations. Verapamil is known to decrease gastrointestinal transit time.

Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation.

Covera-HS should be administered once daily at bedtime. Clinical trials explored dose ranges between 180 mg and 540 mg given at bedtime and found effects to persist throughout the dosing interval.

Covera-HS tablets should be swallowed whole and not chewed, broken, or crushed.

For both hypertension and angina the dose of Covera-HS should be individualized by titration. Initiate therapy with 180 mg of Covera-HS.

If an adequate response is not obtained with 180 mg of Covera-HS, the dose may be titrated upward in the following manner:

• a)240 mg each evening
• b)360 mg each evening (2 × 180 mg)
• c)480 mg each evening (2 × 240 mg)

When Covera-HS is administered at bedtime, office evaluation of blood pressure during morning and early afternoon hours is essentially a measure of peak effect. The usual evaluation of trough effect, which sometimes might be needed to evaluate the appropriateness of any given dose of Covera-HS, would be just prior to bedtime.

Covera-HS 240-mg tablets are pale yellow, round, film coated with COVERA-HS 2021 printed on one side, supplied as:

NDC Number       Size
0025-2021-31         bottle of 100
0025-2021-34         carton of 100 unit dose

Covera-HS 180-mg tablets are lavender, round, film coated, with COVERA-HS 2011 printed on one side, supplied as:

NDC Number       Size
0025-2011-31         bottle of 100
0025-2011-34         carton of 100 unit dose

Store at controlled room temperature 20°–25°C (68°–77°F) [see USP]. Dispense in tight, light-resistant containers.

Rx only

LAB-0267-4.0