Action And Clinical Pharmacology: Verapamil is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist) which exerts 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.
Verapamil exerts antihypertensive effects by inducing peripheral vasodilation and reducing peripheral vascular resistance usually without reflex tachycardia. These effects are mediated by inhibition of calcium ion influx into smooth muscle cells of the arteriolar wall. Verapamil does not blunt hemodynamic response to isometric or dynamic exercise. Compared to baseline, verapamil administration did not affect electrolytes, glucose and creatinine. The hypotensive effect of verapamil is not blunted by an increase in sodium intake.
Pharmacokinetics: Immediate Release Formulations of Verapamil: With the immediate release formulations, more than 90% of the orally administered dose of verapamil is absorbed. Because of rapid biotransformation during its first pass through the portal circulation, bioavailability ranges from 20 to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg of verapamil every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 ng/mL, with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist. In initial dose titration with verapamil a relationship exists between verapamil plasma concentration and prolongation of the PR interval. After repetitive dosing, less than 10 consecutive doses given 6 hours apart, the mean elimination half-life ranged from 4.5 to 12 hours. Half-life of verapamil increases during titration due to saturation of hepatic enzyme systems as plasma verapamil levels rise.
Aging affects the pharmacokinetics of verapamil. Elimination half-life is prolonged in the elderly.
In healthy men, orally administered verapamil undergoes extensive metabolism in the liver through the cytochrome P450 system. The particular isoenzymes involved are: CYP-3A4, CYP-1A2, and the CYP-2C family. 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 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 Warnings, Hepatic Insufficiency and Dosage).
After 4 weeks of oral dosing (120 mg q.i.d.) verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficients of 0.06 for verapamil and 0.04 for norverapamil.
Verelan Sustained Release Capsules: In a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of Verelan Sustained Release Capsule 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 hours post-dose concentrations were approximately 30% higher. The steady-state pharmacokinetic data are summarized in Table I.
Food does not affect the extent or rate of the absorption of verapamil from the controlled release Verelan capsule. The Verelan 240 mg capsule when administered with food had a Cmax of 77 ng/mL which occurred 9 hours after dosing and an AUC(0-inf) of 1 387 ng.hr/mL. Verelan 240 mg under fasting conditions had a Cmax of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(0-inf) of 1 541 ng.hr/mL.
The time to reach maximum verapamil concentrations (Tmax) with Verelan Sustained Release Capsules has been found to be approximately 7 to 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.
Indications And Clinical Uses: In the treatment of mild to moderate essential hypertension. It should normally be used in those patients in whom treatment with diuretics or beta-blockers has been associated with unacceptable adverse effects.
Verelan can be tried as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated, or in patients with medical conditions in which these drugs frequently cause serious adverse effects.
Combination of verapamil with a diuretic has been found to be compatible and showed additive antihypertensive effect.
Verelan should not be used concurrently with beta-blockers in the treatment of hypertension (see Precautions, Drug Interactions).
Safety of concurrent use of Verelan Sustained Release Capsules with other antihypertensive agents has not been established and such use cannot be recommended at this time.
Contra-Indications: Severe hypotension or cardiogenic shock. Acute myocardial infarction; severe congestive heart failure and/or severe left ventricular dysfunction (unless secondary to a supraventricular tachycardia amenable to oral verapamil therapy); second- or third-degree AV block; sick sinus syndrome (see Warnings, Conduction Disturbance); marked bradycardia. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see Warnings, Accessory Bypass Tract). Hypersensitivity to the drug. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: General: In patients with angina or arrhythmias using antihypertensive drugs, the additional hypotensive effect of verapamil should be taken into consideration.
Heart Failure: Because of verapamil’s negative inotropic effect, the drug should not be used in patients with poorly compensated congestive heart failure, unless the failure is complicated by or caused by a dysrhythmia. If verapamil is used in such patients, they must be digitalized prior to treatment. It has been reported that digoxin plasma levels may increase with chronic verapamil administration (see Precautions, Drug Interactions – Digitalis).
The use of verapamil in the treatment of hypertension is not recommended in patients with heart failure caused by systolic dysfunction.
Hypotension: Hypotensive symptoms of lethargy and weakness with faintness have been reported following single oral doses, and even after some months of treatment. In some patients it may be necessary to reduce the dose.
Conduction Disturbance: Verapamil slows conduction across the AV node and rarely may produce second- or third-degree AV block, bradycardia and in extreme cases, asystole.
Verapamil causes dose-related suppression of the SA node. In some patients, sinus bradycardia may occur, especially in patients with sick sinus syndrome (SA nodal disease), which is more common in older patients (see Contraindications).
Bradycardia: The total incidence of bradycardia (ventricular rate less than 50 beats/min) was 1.4% in controlled studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately (see Overdose: Symptoms and Treatment).
Accessory Bypass Tract: Verapamil may result in significant acceleration of ventricular response during atrial fibrillation or atrial flutter in the Wolff-Parkinson White (WPW) or Lown-Ganong-Levine Syndromes after receiving i.v. verapamil. 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).
Concomitant Therapy with Beta-adrenergic Blockers: Generally, oral verapamil should not be given to patients receiving beta-blockers since the depressant effects on myocardial contractility, heart rate and atrioventricular conduction may be additive.
Verapamil gives no protection against the dangers of abrupt beta-blocker withdrawal and such withdrawal should be done by the gradual reduction of the dose of beta-blocker. Then verapamil may be started with the usual dose.
Patients with Hypertrophic Cardiomyopathy: In 120 patients with hypertrophic cardiomyopathy who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died due to 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 mmHg) pulmonary wedge pressure and a marked left ventricular outlfow obstruction were present in most of these patients.
Concomitant administration of quinidine (see Precautions, 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 should be appreciated that this group of patients had a serious disease with high mortality rate. Most adverse effects responded well to dose reduction, but in some cases verapamil had to be discontinued.
Elevated Liver Enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Several published cases of hepatocellular injury produced by verapamil have been proven by rechallenge. Clinical symptoms of malaise, fever, and/or right upper quadrant pain, in addition to elevation of AST, ALT and alkaline phosphatase have been reported. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.
Hepatic Insufficiency: Since verapamil is extensively metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Impaired hepatic function prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours. A decreased dosage should be used in patients with hepatic insufficiency and careful monitoring for abnormal prolongation of the PR interval or other signs of excessive, pharmacologic effect should be carried out (see Pharmacology, Pharmacokinetics and Dosage).
Renal Insufficiency: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. In one study in healthy volunteers, the total body clearance after i.v. administration of verapamil was 12.08 mL/min/kg, while in patients with advanced renal disease it was reduced to 5.33 mL/min/kg. This pharmacokinetic finding suggests that renal clearance of verapamil in patients with renal disease is decreased. In 2 studies with oral verapamil no difference in pharmacokinetics could be demonstrated. Therefore, until further data are available, verapamil should be used with caution in patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect (see Dosage).
Precautions: Atypical lens changes and cataracts were observed in beagle dog studies at high doses. This has been concluded to be species-specific for the beagle dog. (These ophthalmological changes were not seen in a second study.) No similar changes have been observed in long-term prospective human ophthalmological trials.
Verapamil does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may decrease the therapeutic effect of verapamil.
Patients with Attenuated (Decreased) Neuromuscular Transmission: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.
Geriatrics: Caution should be exercised when verapamil is administered to elderly patients (Â³65 years) especially those prone to developing hypotension or those with a history of cerebrovascular insufficiency (see Pharmacology, Pharmacokinetics, and Dosage, Geriatrics). The incidence of adverse reactions is approximately 4% higher in the elderly. The adverse reactions occurring more frequently include dizziness and constipation. Serious adverse events associated with heart block have occurred in the elderly.
Pregnancy: Teratology and reproduction studies have been performed with verapamil in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity or impaired fertility. In rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats.
There are no studies in pregnant women. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verelan Sustained Release Capsules are not recommended for use in pregnant women unless the anticipated benefits outweigh the potential risks to mother and fetus.
Labor and Delivery: 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, increases the need for forceps delivery or other obstetric intervention.
Lactation: Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while the drug is administered.
Children: The safety and dosage regimen of verapamil in children has not yet been established.
Drug Interactions: As with all drugs, care should be exercised when treating patients with multiple medications.
Calcium channel blockers undergo biotransformation by the cytochrome P450 system. Coadministration of verapamil with other drugs which follow the same route of biotransformation may result in altered bioavailability of verapamil or these drugs.
Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered verapamil to maintain optimum therapeutic blood levels.
Drugs known to be inhibitors of the cytochrome P450 system include: asole antifungals cimetidine, cyclosporine, erythromycin, quinidine, terfenadine, warfarin.
Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, penytoin, rifampin.
Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, theophylline.
Alcohol: Verapamil may increase blood alcohol concentrations and prolong its effects.
Antihypertensive Agents: Verapamil administered concomitantly with other antihypertensive agents may have an additive effect on lowering blood pressure. In patients with hypertension, combination with a diuretic has been found to be compatible; however, combination with other antihypertensive agents has not been established. Verapamil should not be combined with beta-blockers for the treatment of hypertension.
Antineoplastic Agents: Verapamil inhibits P-glycoprotein mediated transport of antineoplastic agents out of tumor cells, resulting in their decreased metabolic clearance. Dosage adjustments of antineoplastic agents should be considered when verapamil is administered concomitantly.
Concomitant administration of R-verapamil can decrease the clearance of paclitaxil.
ASA: Potential adverse reactions in terms of bleeding due to antiplatelet effects of the two agents should be taken into consideration in patients taking verapamil and ASA concomitantly.
Beta-Adrenergic Blockers: The concomitant administration of verapamil with beta-blockers can result in severe adverse effects (see Warnings).
Carbamazepine: The concomitant oral administration of verapamil and carbamazepine may potentiate the effects of carbamazepine neurotoxicity. Symptoms include nausea, diplopia, headache, ataxia or dizziness.
Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been adequately studied. Variable results on clearance have been obtained in acute studies of healthy volunteers.
Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine.
Digitalis: Verapamil treatment increases serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and nonrenal clearance of digitoxin by 27 and 29% respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over- or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of verapamil use, the patient should be reassessed to avoid underdigitalization.
Disopyramide: Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.
Inhalation Anesthetics: When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully because additive hemodynamic depressive effects have been observed.
Lithium: Oral verapamil therapy may result in a lowering of serum lithium levels in patients receiving chronic, oral lithium therapy. A dose adjustment of the lithium may be necessary.
Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.
Nitrates, Diuretics: No cardiovascular adverse effects have been attributed to any interaction between these agents and verapamil.
Phenobarbital: Phenobarbital therapy may increase verapamil clearance.
Quinidine: In a small number of patients with hypertrophic cardiomyopathy, concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.
The electrophysiologic effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.
Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.
Sulfinpyrazone: Oral clearance of verapamil following single and multiple doses in volunteers was increased, with an associated decrease in bioavailability.
Theophylline: Increased plasma theophylline concentrations due to verapamil administration have been reported.
Adverse Reactions: In controlled clinical trials involving 285 hypertensive patients treated with Verelan sustained release capsules, the overall incidence of adverse events irrespective of causality was 26% and the rate of discontinuation from these trials due to adverse events was 2%. The following adverse reactions were reported in greater than 1% of the patients: constipation (7.4%), headache (5.3%), dizziness (4.2%), lethargy (3.2)%, dyspepsia (2.5%), rash (1.4%), ankle edema (1.4%), sleep disturbance (1.4%) and myalgia (1.1%).
In clinical trials with other formulations of verapamil HCl, (n=4 954), the following adverse reactions divided by body system have been reported. The most serious adverse reactions reported with verapamil are heart failure (1.8%), hypotension (2.5%), AV block (1.2%) and rapid ventricular response (see Warnings).
Cardiovascular: hypotension (2.5%), edema (2.1%) CHF/pulmonary edema (1.9%), bradycardia (1.4%), AV block, total (first, second and third degree) (1.2%) or second and third degree (0.8%).
CNS: dizziness (3.2%), headache (2.2%), fatigue (1.7%).
Gastrointestinal: constipation (7.3%), nausea (2.7%).
The following reactions were reported in 1% or less of patients: Cardiovascular: flushing, angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura, syncope, severe tachycardia, developing or worsening of heart failure, development of rhythm disturbances, ventricular dysrhythmias, painful coldness or numbness of extremities.
CNS: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence, excitation, depression, rotary nystagmus, vertigo, tremor, extrapyramidal disorders, muscle fatigue, hyperkinesis.
Gastrointestinal: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia, vomiting.
Respiratory: dyspnea, bronchospasm.
Urogenital: gynecomastia, increased frequency of urination, spotty menstruation, oligomenorrhea, impotence.
Hematologic and Lymphatic: ecchymosis or bruising.
Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson Syndrome, erythema multiforme, pruritus.
Special Senses: blurred vision, diplopia.
Hepatotoxicity with elevated enzymes [AST, ALT, alkaline phosphatase] and bilirubin levels, jaundice and associated symptoms of hepatitis with cholestasis have been reported (see Warnings).
Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty.
In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or flutter, ventricular rates below 50 at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.
Symptoms And Treatment Of Overdose: Symptoms: Based on reports of intentional overdosage with verapamil, the following symptoms have been observed. Hypotension occurs, varying from transient to severe. Conduction disturbances seen included: prolonged AV conduction time, AV dissociation, nodal rhythm, ventricular fibrillation and ventricular asystole. tag_Treatment
Treatment: In case of overdosage with Verelan, it should be noted that the release rate and absorption of verapamil from Verelan is prolonged (see Table I) due to the sustained release characteristics of the formulation.
Treatment of overdosage should be supportive (see Table II). Gastric lavage should be undertaken even later than 12 hours after ingestion, if no gastrointestinal motility is present. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion influx across the slow channel. These pharmacologic interventions have been effectively used in treatment of overdosage with verapamil. Clinically significant hypotensive reactions should be treated with vasopressor agents. AV block is treated with atropine and cardiac pacing. Asystole should be handled by the usual advanced cardiac life support measures including the use of vasopressor agents, e.g., isoproterenol HCl. Verapamil is not removed by hemodialysis.
Suggested Treatment of Acute Cardiovascular Adverse Effects: Actual treatment and dosage should depend on the severity of the clinical situation and the judgment of the treating physician. Patients with hypertrophic cardiomyopathy treated with verapamil should not be administered positive inotropic agents
Dosage And Administration: Mild to Moderate Essential Hypertension: The dosage should be individualized by titration depending on patient tolerance and responsiveness to Verelan. Titration should be based on therapeutic efficacy and safety, evaluated weekly and approximately 24 hours after the previous dose.
The usual initial adult dose is 180 to 240 mg/day, taken once a day, in the morning. If adequate response is not obtained, the dose may be titrated upward to 360 mg or to 480 mg taken once a day in the morning. Optimal doses are usually lower in patients also receiving diuretics since additive antihypertensive effects can be expected.
The maximum daily dose of 480 mg should not be exceeded.
The antihypertensive effects are evident within the first week of therapy.
Geriatrics: Initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (see Precautions, Geriatrics). The dosage should be carefully and gradually adjusted depending on patient tolerability and response. Patients with Impaired Liver or Renal Function: Verelan should be administered cautiously to patients with impaired liver or renal function. The dosage should be adjusted gradually depending on patient tolerance and response. These patients should be monitored for abnormal prolongation of the PR interval or other signs of overdosage. Verelan should not be used in severe hepatic dysfunction (see Warnings, Hepatic Insufficiency).
Availability And Storage: 120 mg: Each sustained release, pellet-filled capsule with yellow body and yellow cap contains: verapamil HCl 120 mg. Nonmedicinal ingredients: FD&C red #40, fumaric acid, gelatin, methylparaben, povidone, propylparaben, shellac, silicon dioxide, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide and yellow iron oxide. High density polyethylene bottles of 100.
180 mg: Each sustained release, pellet-filled capsule with yellow body and grey cap contains: verapamil HCl 180 mg. Nonmedicinal ingredients: black iron oxide, FD&C red #40, fumaric acid, gelatin, methylparaben, povidone propylparaben, shellac, silicon dioxide, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide and yellow iron oxide. High density polyethylene bottles of 100.
240 mg: Each sustained release, pellet-filled capsule with yellow body and blue cap contains: D&C red #28, FD&C blue #1, FD&C red #40, fumaric acid, gelatin, methylparaben, povidone, propylparaben, shellac, silicon dioxide, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide and yellow iron oxide. High density polyethylene bottles of 100.
Store at 15 to 25Â°C. Protect from moisture and light.
VERELANÂ® Wyeth-Ayerst Verapamil HCl Antihypertensive