Verapamil Hydrochloride

VERAPAMIL HYDROCHLORIDE- verapamil hydrochloride capsule, extended release
Mylan Pharmaceuticals Inc.

DESCRIPTION

Verapamil hydrochloride extended-release capsules, USP are a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verapamil hydrochloride extended-release capsules are available for oral administration as a 120 mg hard gelatin capsule (bluish green opaque cap and white opaque body), a 180 mg hard gelatin capsule (bluish green opaque cap and light green opaque body) and a 240 mg hard gelatin capsule (bluish green opaque cap and bluish green opaque body). These bead filled capsules provide an extended-release of the drug in the gastrointestinal tract.

The structural formula of verapamil HCl is given below:

C₂₇ H₃₈ N₂ O₄ • HCl M.W. 491.07

Chemical name: (±)-5-[(3,4-Dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile monohydrochloride.

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

In addition to verapamil HCl the verapamil hydrochloride extended-release capsules contain the following inactive ingredients: ammonium hydroxide, dibutyl sebacate, diethyl phthalate, ethylcellulose, FD&C Green No. 3, gelatin, hypromellose, maltodextrin, methacrylic acid copolymer Type A and B, oleic acid, polyethylene glycol, povidone, silicon dioxide, sodium lauryl sulfate, sugar spheres (which contain cornstarch and sucrose), talc and titanium dioxide, the 180 mg capsules also contain D&C Yellow No. 10.

In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

CLINICAL PHARMACOLOGY

Verapamil hydrochloride extended-release capsules are a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exert its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells.

Normal sinus rhythm is usually not affected by verapamil HCl. However in patients with sick sinus syndrome, verapamil HCl 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.) Verapamil HCl 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 HCl may shorten the antegrade effective refractory period of accessory bypass tracts. 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 HCl 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.

Mechanism of Action

Essential Hypertension

Verapamil HCl exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/minute is uncommon). Verapamil HCl regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works.

Pharmacokinetics and Metabolism

With the immediate release formulations, more than 90% of the orally administered dose is absorbed, and peak plasma concentrations of verapamil are observed 1 to 2 hours after dosing. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, the absolute bioavailability ranges from 20% to 35%. Chronic oral administration of the highest recommended dose (120 mg every 6 hours) resulted in plasma verapamil levels ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the verapamil HCl dose administered and verapamil plasma levels does exist.

During initial dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. The quantitative relationship between plasma verapamil concentrations and blood pressure reduction has not been fully characterized.

In a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of verapamil hydrochloride extended-release capsules 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24 hour post-dose concentrations were approximately 30% higher. At a total daily dose of 240 mg, verapamil hydrochloride extended-release capsules were shown to have a similar extent of verapamil bioavailability based on the AUC-24 as that obtained with the conventional immediate-release tablets. In this same study verapamil hydrochloride extended-release capsules doses of 120 mg, 240 mg and 360 mg once daily were compared after multiple doses. The ratios of the verapamil and norverapamil AUCs for the verapamil hydrochloride extended-release capsules 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng•hr/mL):3 (1660 ng•hr/mL):5 (2729 ng•hr/mL) and 1 (621 ng•hr/mL):3 (1614 ng•hr/mL):4 (2535 ng•hr/mL) respectively, indicating that the AUC increased non-proportionately with increasing doses.

Food does not affect the extent or rate of the absorption of verapamil from the controlled release verapamil hydrochloride extended-release capsule. The verapamil hydrochloride extended-release 240 mg capsule when administered with food had a C_max of 77 ng/mL which occurred 9.0 hours after dosing, and an AUC(_0-inf ) of 1387 ng•hr/mL. Verapamil hydrochloride extended-release capsules 240 mg under fasting conditions had a C_max of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(_0-inf ) of 1541 ng•hr/mL.

The bioequivalence of verapamil hydrochloride extended-release capsules 240 mg, administered as the beads sprinkled on applesauce and as the intact capsule, was demonstrated in a single-dose, cross-over study in 32 healthy adults. Comparative ratios (sprinkled/intact) of verapamil were 0.95, 1.02, and 1.01 for C_max , T_max , and AUC(_0-inf ) respectively. When the contents of the verapamil hydrochloride extended-release capsule were administered by sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the same dose when administered as an intact capsule. Similar results were observed with norverapamil.

The time to reach maximum verapamil concentrations (T_max ) with verapamil hydrochloride extended-release capsules have been found to be approximately 7-9 hours in each of the single dose (fasting), single dose (fed), the multiple dose (steady state) studies and dose proportionality pharmacokinetic studies. Similarly the apparent half-life (t_1/2 ) has been found to be approximately 12 hours independent of dose. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly.

In healthy man, orally administered verapamil HCl undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The biologic activity of norverapamil appears to be approximately 20% that of verapamil.

Approximately 70% of an administered dose of verapamil HCl 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. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS), the volume of distribution is increased and plasma clearance reduced to about 30% of normal. 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 (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.

In 10 healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg), resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg/dL) compared with placebo. (See PRECAUTIONS: Drug Interactions.)

The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg•hr/dL). Verapamil AUCs were positively correlated (r = 0.71) to increased ethanol blood AUC values.