Verapamil Hydrochloride (Capsule, Extended Release)
Essential Hypertension: Verapamil capsules (PM) should be administered once daily at bedtime. Clinical trials studied doses of 100 mg, 200 mg, 300 mg and 400 mg. The usual daily dose of verapamil capsules (PM) in clinical trials has been 200 mg given by mouth once daily at bedtime. In rare instances, initial doses of 100 mg a day may be warranted in patients who have an increased response to verapamil [e.g. patients with impaired renal function , impaired hepatic function, elderly, small people, etc.]. Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of verapamil capsules (PM) are evident within the first week of therapy. If an adequate response is not obtained with 200 mg of verapamil capsules (PM), the dose may be titrated upward in the following manner: When verapamil capsules (PM) are 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 verapamil capsules (PM) would be just prior to bedtime. As with immediate-release and sustained-release verapamil, dosages of verapamil capsules (PM) should be individualized and titration may be needed in some patients.<br/>Sprinkling the Capsule Contents on Food: Verapamil capsules (PM) may also be administered by carefully opening the capsule and sprinkling the beads onto one tablespoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the beads. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Any beads /applesauce mixture should be used immediately and not stored for future use. Absorption of the beads sprinkled onto other foods has not been tested. This method of administration may be beneficial for patients who have difficulty swallowing whole capsules or tablets. Subdividing the contents of a verapamil capsule (PM) is not recommended.
Verapamil hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verapamil hydrochloride extended-release capsules (PM) are available for oral administration as a 100 mg, 200 mg or 300 mg hard-shell gelatin capsule. Verapamil is administered as a racemic mixture of the R and S enantiomers. The structural formula of verapamil hydrochloride is: Chemical name: Benzeneacetonitrile,��-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-��-(1-methylethyl)-,monohydrochloride,(��)-. Verapamil hydrochloride, USP is an almost white crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform, and methanol. Verapamil hydrochloride is not structurally related to other cardioactive drugs. In addition to verapamil hydrochloride, the verapamil hydrochloride extended-release capsules (PM) contain the following inactive ingredients: ammonium hydroxide, colloidal anhydrous silica, dibutyl sebacate, diethyl phthalate, ethylcellulose, hypromellose, maltodextrin, methacrylic acid copolymer, oleic acid, polyethylene glycol, povidone, silicon dioxide, sugar spheres, sodium lauryl sulfate and talc. Each of the empty gelatin capsules for the 100 mg, 200 mg and 300 mg capsule strengths contain the following: D&C Red No. 28 aluminum lake, D&C Red No. 33 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Red No. 40 aluminum lake, gelatin, and titanium dioxide. In addition, the 200 mg empty gelatin capsule contains FD&C Yellow No. 6 aluminum lake. The imprinting ink contains the following: 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.
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.<br/>System Components and Performance: Verapamil capsules (PM) are designed for bedtime dosing, and it incorporates a delayed drug delivery system. This slow onset results in an average maximum plasma concentration (C) of verapamil in the morning hours (approximately 9 to 12 hours following product administration). These pellet-filled capsules provide for extended-release of the drug in the gastrointestinal tract. This delay is introduced by the release-controlling polymers applied to drug loaded beads. The release-controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer coated beads, the water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of drug. The rate of release is essentially independent of posture and food. Multiparticulate systems such as Verapamil capsules (PM) have been shown to be independent of gastrointestinal motility.<br/>Mechanism of Action:<br/>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.<br/>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. During isometric or dynamic exercise verapamil does not alter systolic cardiac function in patients with normal ventricular function. Verapamil 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. 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.<br/>Effects in Hypertension: Verapamil capsules (PM) were evaluated in two placebo-controlled, parallel design, double-blind studies of patients with mild to moderate hypertension. In the clinical trials, 413 evaluable patients were randomized to either placebo, 100 mg, 200 mg, 300 mg, or 400 mg and treated for up to 8 weeks. Verapamil capsules (PM) or placebo was given once daily between 9 pm and 11 pm (nighttime) and blood pressure changes were measured with 36 hour ambulatory blood pressure monitoring (ABPM). The results of these studies demonstrate that verapamil capsules (PM) at 200, 300 and 400 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 to 10 pm) were dose related, and ranged from 3.8 to 10 mm Hg after 8 weeks of therapy. Although verapamil capsules (PM) 100 mg was not effective in reducing diastolic BP at trough when measured by ABPM, efficacy was demonstrated in reducing diastolic BP when measured manually at trough and peak and, from 6 am to 12 noon over 24 hours when measured by ABPM . There were no apparent treatment differences between patient subgroups of different age (older or younger than 65 years), sex and race. For severity of hypertension, "moderate" hypertensives (mean daytime diastolic BP���105 mm Hg and���114 mm Hg) appeared to respond better than "mild" hypertensives (mean daytime diastolic BP���90 mm Hg and���104 mm Hg). However, sample size for the subgroup comparisons were limited.<br/>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 . Verapamil 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 . 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.<br/>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 five subjects with oral immediate-release verapamil, the systemic bioavailability was from 33% to 65% for the R enantiomer and from 13% to 34% for theS enantiomer. Following oral administration of an immediately releasing formulation every 8 hours in 24 subjects, the relative systemic availability of the S enantiomer compared to the R enantiomer was approximately 13% following a single day's administration and approximately 18% following administration to steady-state. The degree of stereoselectivity of metabolism for verapamil capsules (PM) was similar to that for the immediately releasing formulation. 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 to 50 times the activity of the R enantiomer in reducing myocardial contractility in isolated blood-perfused dog papillary muscle, respectively, and twice the effect in reducing peripheral resistance. In isolated septal strip preparations from five 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) or areas under the plasma concentration vs. time curves (AUC). Although some evidence of lack of dose linearity was observed for verapamil capsules (PM) this non-linearity was enantiomer specific, with the R enantiomer showing the greatest degree of non-linearity. Racemic verapamil is released from verapamil capsules (PM) by diffusion following the gradual solubilization of the water soluble polymer. The rate of solubilization of the water soluble polymer produces a lag period in drug release for approximately 4 to 5 hours. The drug release phase is prolonged with the peak plasma concentration (C) 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 achieved by day 5 of dosing. In healthy volunteers, following administration of verapamil capsules (PM) (200 mg per day), steady-state pharmacokinetics of the R and S enantiomers of verapamil is as follows: Mean Cof the R isomer was 77.8 ng/mL and 16.8 ng/mL for the S isomer; AUCof the R isomer was 1037 ng���h/mL and 195 ng���h/mL for the S isomer. In general, bioavailability of verapamil is higher and half-life longer in older (>65 yrs) subjects. Lean body weight also affects its pharmacokinetics inversely. It was not possible to observe a gender difference in the clinical trials of verapamil capsules (PM) due to the small sample size. However, there are conflicting data in the literature suggesting that verapamil clearance decreased with age in women to a greater degree than in men. Consumption of a high fat meal just prior to dosing in the morning had no effect on the extent of absorption and a modest effect on the rate of absorption from verapamil capsules (PM). The rate of absorption was not affected by whether the volunteers were supine 2 hours after night-time dosing or non-supine for 4 hours following morning dosing. Administering verapamil capsules (PM) in the morning increased the extent of absorption of verapamil and/or decreased the metabolism to norverapamil. When the contents of the verapamil capsules (PM) 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. Orally administered verapamil undergoes extensive metabolism in the liver. Verapamil is metabolized by O-demethylation (25%) and N-dealkylation (40%), and is subject to pre-systemic hepatic metabolism with elimination of up to 80% of the dose. The metabolism is mediated by hepatic cytochrome P, and animal studies have implied that the mono-oxygenase is the specific isoenzyme of the Pfamily. 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. For verapamil capsules (PM) the norverapamil R enantiomer reached steady-state plasma concentrations similar to the verapamil R enantiomer, but the norverapamil S enantiomer concentrations were approximately twice that of the verapamil S enantiomer concentrations. 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 . 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 4 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.<br/>Geriatric Use: The pharmacokinetics of verapamil GITS were studied after five consecutive nights of dosing 180 mg in 30 healthy young (19 to 43 years) versus 30 healthy elderly (65 to 80 years) male and female subjects. Older subjects had significantly higher mean verapamil C, Cand AUCcompared to younger subjects. Older subjects had mean AUCs that were approximately 1.7 to 2 times higher than those of younger subjects as well as a longer average verapamil t(approximately 20 hr vs. 13 hr).<br/>Hemodynamics: 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 (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 .<br/>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.
Verapamil is contraindicated in:
Verapamil Hydrochloride Extended-Release Capsules (PM) are available containing 100 mg, 200 mg or 300 mg of verapamil hydrochloride, USP. The 100 mg capsule is a hard-shell gelatin capsule with a red opaque cap and a white opaque body filled with white to off-white beads. The capsule is axially printed with MYLAN over 6201 in black ink on both the cap and the body. They are available as follows: NDC 0378-6201-93bottles of 30 capsules NDC 0378-6201-01bottles of 100 capsules NDC 0378-6201-05bottles of 500 capsules The 200 mg capsule is a hard-shell gelatin capsule with a red opaque cap and a light orange opaque body filled with white to off-white beads. The capsule is axially printed with MYLAN over 6202 in black ink on both the cap and the body. They are available as follows: NDC 0378-6202-93bottles of 30 capsules NDC 0378-6202-01bottles of 100 capsules NDC 0378-6202-05bottles of 500 capsules The 300 mg capsule is a hard-shell gelatin capsule with a red opaque cap and a red opaque body filled with white to off-white beads. The capsule is axially printed with MYLAN over 6203 in black ink on both the cap and the body. They are available as follows: NDC 0378-6203-93bottles of 30 capsules NDC 0378-6203-01bottles of 100 capsules NDC 0378-6203-05bottles of 500 capsules Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
dailymed-ingredient:D&C_Red_No._28_aluminum_lake, dailymed-ingredient:D&C_Red_No._33_aluminum_lake, dailymed-ingredient:D&C_Yellow_No._10_aluminum_lake, dailymed-ingredient:FD&C_Blue_No._1_aluminum_lake, dailymed-ingredient:FD&C_Blue_No._2_aluminum_lake, dailymed-ingredient:FD&C_Red_No._40_aluminum_lake, dailymed-ingredient:ammonium_hydroxide, dailymed-ingredient:black_iron_oxide, dailymed-ingredient:colloidal_anhydrous_silica, dailymed-ingredient:dibutyl_sebacate, dailymed-ingredient:diethyl_phthalate, dailymed-ingredient:ethylcellulose, dailymed-ingredient:gelatin, dailymed-ingredient:hypromellose, dailymed-ingredient:maltodextrin, dailymed-ingredient:methacrylic_acid_copolymer, dailymed-ingredient:oleic_acid, dailymed-ingredient:polyethylene_glycol, dailymed-ingredient:povidone, dailymed-ingredient:propylene_glycol, dailymed-ingredient:shellac_glaze, dailymed-ingredient:silicon_dioxide, dailymed-ingredient:sodium_lauryl_sulfate, dailymed-ingredient:sugar_spheres, dailymed-ingredient:talc, dailymed-ingredient:titanium_dioxide
Verapamil Hydrochloride (Capsule, Extended Release)
Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. The following reactions to orally administered verapamil capsules (PM) occurred at rates of 2% or greater or occurred at lower rates but appeared to be drug-related in clinical trials in hypertension. 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. In previous experience with other formulations of verapamil (N = 4,954) the following reactions have occurred at rates greater than 1% or occurred at lower rates but appeared clearly drug related in clinical trials in 4,954 patients. In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of 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 listed to alert the physician to a possible relationship: Cardiovascular: angina pectoris, atrioventricular dissociation, 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, extrapyramidal symptoms, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence. Respiratory: dyspnea. 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, impotence, increased urination, spotty menstruation. Other: allergy aggravated.<br/>Treatment of Acute Cardiovascular Adverse Reactions: 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; e.g., intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol hydrochloride (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine hydrochloride, metaraminol bitartrate, or methoxamine hydrochloride) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, inotropic agents (dopamine hydrochloride or dobutamine hydrochloride) may be administered. Actual treatment anddosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
Verapamil capsules (PM) are indicated for the management of essential hypertension.