Antiarrhythmic – Antianginal – Antihypertensive
Action And Clinical Pharmacology: Angina and Arrhythmia: Verapamil, a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist) is believed to exert its antiarrhythmic and antianginal effects by selectively inhibiting transmembrane influx of calcium ions in cardiac muscle, coronary and systemic arteries and in cells of the intracardiac conduction system. Verapamil blocks the transmembrane influx of calcium through the slow channel (calcium ion antagonism) without significantly affecting transmembrane influx of sodium through the fast channel. The result is a reduction of free calcium ions available within the cells of the above tissues.
Verapamil exerts antihypertensive effects by inducing vasodilation and reducing peripheral vascular resistance usually without reflex tachycardia. Verapamil does not blunt hemodynamic response to isometric or dynamic exercise.
Verapamil’s action on the sinoatrial and atrioventricular nodes is believed to be responsible for the drug’s antiarrhythmic effects. Verapamil slows AV nodal conduction and prolongs functional refractory periods. The normal atrial action potential or intra-ventricular conduction time is not altered by verapamil, but amplitude, velocity of depolarization and conduction in depressed atrial fibers is reduced. It is through this action that verapamil interrupts re-entrant pathways and slows ventricular rate.
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.
Verapamil is a potent smooth muscle relaxant with vasodilator properties, and a depressant of myocardial contractility. These effects are largely independent of autonomic influence. The antianginal action of verapamil in exertional angina is believed to result from a decrease in resistance in the systemic vasculature as well as from a direct effect on myocardial contraction. A decrease in myocardial oxygen consumption is the net pharmacologic effect. Verapamil’s effectiveness in vasospastic angina is due to a decrease in coronary vascular tone.
Essential Hypertension: Verapamil induces its antihypertensive effect by peripheral vasodilation and reducing peripheral vascular resistance usually without reflex tachycardia. These effects are brought about by inhibition of calcium ion influx into smooth muscle cells of the arteriolar wall. Verapamil does not affect the hemodynamic response to isometric or dynamic exercise. Verapamil administration did not affect electrolytes, glucose, and creatinine compared to baseline. An increase in sodium intake does not hinder the hypotensive effect of verapamil.
Compared to baseline, verapamil does not affect electrolytes, glucose, and creatinine. The hypotensive effect of verapamil is not blunted by an increase in sodium intake.
In hypertensive normolipidemic patients, verapamil had no effects on plasma lipoprotein fractions.
Pharmacodynamics: In a study in 5 healthy males, the S enantiomer was found to be 8 to 20 times more active than the R enantiomer in slowing AV conduction. In another study using septal strips isolated from the left ventricle of 5 patients with mitral disease, the S enantiomer was 8 times more potent than the R enantiomer in reducing myocardial contractility.
Pharmacokinetics: Verapamil Tablets: Verapamil is rapidly absorbed. From a comparison of the areas under the time concentration curves of total radioactivity, following oral and i.v. administration as well as based on cumulative urinary excretion, absorption has been calculated at approximately 92%. Despite its almost complete absorption, the oral bioavailability of verapamil is only about 10 to 35% due to its extensive first pass metabolism.
Intersubject verapamil plasma concentrations vary after oral administration. Following long-term oral administration of 120 mg conventional tablets every 6 hours to healthy adults, the average steady state plasma concentrations ranged from 125 to 400 ng/mL. The average time to peak plasma concentration (Tmax) is between 1 and 2 hours and the therapeutic range is considered to be 60 to 70 ng/mL or higher. A nonlinear correlation exists between the dose of verapamil administered and verapamil plasma levels. In the initial dose titration with verapamil, a relationship exists between verapamil plasma concentration and prolongation of the PR interval. Administration with meals slows absorption and decreases the relative bioavailability slightly.
In single dose studies, the elimination half-life of verapamil ranged from 2.8 to 7.4 hours. In these same studies after repetitive dosing, the half-life increased to a range from 4.5 to 12 hours (after less than 10 consecutive doses given 6 hours apart). The 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 and elimination half-life is prolonged in the elderly. Verapamil and its metabolites are excreted predominantly (70%) in urine and the rest (16% or more) in feces within 5 days. Only 3 to 4% of the amount found in 48 hour pooled urine samples was found to be unchanged verapamil. Twelve metabolites produced by the biotransformation of verapamil have been identified in plasma with the chief one being norverapamil. Norverapamil can reach steady state plasma concentrations approximately equal to those of verapamil itself and appears to have approximately 20% of the cardiovascular activity of verapamil. Metabolism of verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours in patients with hepatic insufficiency (see Warnings and Dosage).
The degree of protein binding of verapamil varied from 88.7 to 92.0%. Verapamil and norverapamil levels were noted in the cerebrospinal fluid after 4 weeks of oral dosing (120 mg q.i.d.). The estimated partition coefficients were 0.06 for verapamil and 0.04 for norverapamil.
Verapamil Sustained Release Tablets: Verapamil sustained release tablets is a racemic mixture consisting of equal portions of the R enantiomer and the S enantiomer. More than 90% of the orally administered dose of verapamil sustained release is absorbed. Upon oral administration, there is rapid stereoselective biotransformation during the first pass of verapamil through the portal circulation. The systemic concentration of R and S enantiomers are dependent upon the route and the rate of administration and the rate and extent of release from the dosage forms.
The following bioavailability information was obtained from healthy volunteers and not from the populations most likely to be treated with verapamil.
In a study in 5 healthy volunteers with oral immediate-release verapamil, the systemic bioavailability varied from 33 to 65% for the R enantiomer and from 13 to 34% for the S enantiomer. The S enantiomer is pharmacologically more active than the R enantiomer (see Pharmacodynamics).
There is a nonlinear correlation between the verapamil dose administered and verapamil plasma levels. In early dose titration with verapamil, a relationship exists between total verapamil (R and S combined) plasma concentration and prolongation of the PR interval. The mean elimination half-life in single-dose studies of immediate release verapamil ranged from 2.8 to 7.4 hours. In these same studies, after steady state was reached, the half-life increased to a range from 4.5 to 12 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration. Aging decreases the clearance and elimination of verapamil.
In a randomized, multiple-dose study in 44 healthy young subjects, administration of verapamil sustained release 240 mg with food produced peak plasma concentrations at approximately 8 hours postdose of 188 and 76 mg/mL and AUC’s (0 to 24 hours) of 2 553 and 1 046 ng.h/mL for the R and S enantiomers, respectively. Similar results were demonstrated for plasma norverapamil.
In healthy men, orally administered verapamil undergoes extensive metabolism by the cytochrome P450 system. The particular isoenzyme involved are CYP 3A4, CYP 1A2, and the CYP 2C family. Thirteen metabolites have been identified in urine. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. 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. The degree of biotransformation during the first pass of verapamil may vary according to the status of the liver in different patient populations. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours (see Warnings and Dosage).
Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil is excreted in human milk.
A study was conducted in which 240 mg single oral doses of verapamil standard release (fasting) and verapamil sustained release (fed) tablets were given to 12 young, healthy males (19 to 37 years old) in a randomized, crossover (7-day washout) study. Serial blood samples for drug determination were taken over a 48-hour period.
The data was calculated from samples taken at frequent intervals for 36 hours after the last dose.
Influence of Food: Administration of verapamil SR tablets with food results in a prolongation of Tmax (45 to 75%), and slight decreases in Cmax (about 15%) and AUC (1 to 8%). Hence, food produces a slight decrease in bioavailability (AUC), but a narrower peak-to-trough ratio.
Indications And Clinical Uses: Novo-Veramil: May be used in the treatment of: chronic stable angina of effort; angina resulting from coronary artery spasm; obstructive hypertrophic cardiomyopathy where surgery is not otherwise indicated; atrial fibrillation or flutter with rapid ventricular response not otherwise controllable with digitalis preparations; follow-up treatment to the use of injectable verapamil in paroxysmal supraventricular tachycardia. Verapamil is indicated in the treatment of mild to moderate essential hypertension. It should be used in those patients in whom treatment with diuretics or beta-blockers produced unacceptable adverse effects.
Verapamil can be used 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.
Concomitant use of verapamil with a diuretic or an angiotensin converting enzyme inhibitor has been shown to be compatible and to have additive blood pressure lowering effects.
Verapamil should not be concurrently used with beta-blockers in the treatment of hypertension (see Precautions, Drug Interactions).
Safety of concurrent use of verapamil with other antihypertensive agents has not been established and such use cannot be recommended at this time.
Novo-VeramiL SR (Sustained Release) Tablets: Treatment of mild to moderate essential hypertension. Verapamil sustained release tablets should normally be used in those patients in whom treatment with diuretics or beta-blockers has been associated with unacceptable adverse effects.
Verapamil sustained release tablets 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 sustained release with a diuretic or an angiotensin converting enzyme inhibitor has been found to be compatible and showed additive antihypertensive effect.
Verapamil sustained release tablets should not be used concurrently with beta-blockers in the treatment of hypertension (see Precautions, Drug Interactions).
Safety of concurrent use of verapamil sustained release tablets with other antihypertensive agents has not been established and such use cannot be recommended at this time.
Contra-Indications: In patients with: complicated myocardial infarction (patients who have ventricular failure manifested by pulmonary congestion); severe congestive heart failure and/or severe left ventricular dysfunction (unless secondary to a supraventricular tachycardia amendable to verapamil therapy); cardiogenic shock; severe hypotension; second or third degree AV block; sick sinus syndrome (see Warnings); marked bradycardia; hypersensitivity to the drug; atrial flutter or atrial fibrillation and an accessory bypass tract, (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see Warnings).
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: Verapamil has a negative inotropic effect and should not be used in patients with poorly compensated congestive heart failure, unless the failure is complicated by or caused by an arrhythmia. If verapamil or verapamil sustained release is to be used in such patients, they must be digitalized prior to treatment and monitored continuously. Digoxin plasma levels may increase significantly with chronic oral verapamil therapy (see Precautions, Drug Interactions).
In the treatment of hypertension, verapamil 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 of verapamil and even after some months of treatment. It may be necessary to reduce the dose in these patients.
The additional hypotensive effect of verapamil should be taken into consideration in patients with angina or arrhythmias using antihypertensive drugs.
Conduction Disturbance: Because verapamil slows conduction across the AV node, it rarely may produce second or third degree AV block, bradycardia and in extreme cases asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in the elderly (see Contraindications).
Verapamil causes dose-related suppression of the SA node. In some patients, sinus bradycardia may occur, especially in patients with a sick sinus syndrome (SA nodal disease), which is more common in the elderly (see Contraindications).
Bradycardia: Bradycardia (ventricular rate less than 50 beats/min) had a total incidence of less than 2% 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 recovery does not occur promptly, appropriate treatment should be initiated immediately (see Overdose: Symptoms and Treatment).
Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine): 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. The safety of verapamil in individual patients with WPW or Lown-Ganong-Levine syndrome should be established by electrophysiologic testing before use. Such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see Contraindications).
Concomitant Use with Beta-blockers: The concomitant use of oral verapamil with beta-blockers is not recommended since the depressant effects on myocardial contractility, heart rate and AV conduction may be additive. In general, verapamil and verapamil sustained release tablets should not be given to patients receiving beta-blockers. However, when in the opinion of the physician, concomitant use of verapamil and beta-blockers is considered essential, institute such use gradually in a hospital setting under careful supervision. If combined therapy is used, close surveillance of vital signs and clinical status should be carried out and the need for continued concomitant treatment periodically assessed.
Verapamil provides no protection against the dangers of abrupt beta-blocker withdrawal. When changing patients from beta-blockers to verapamil, withdraw beta-blockers by gradually reducing the dose, 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 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 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 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, but in some cases, verapamil use had to be discontinued.
Elevated Liver Enzymes: Elevation of transaminase 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: Because verapamil is extensively metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function, since the elimination half-life of verapamil in these patients is prolonged 4-fold (from 3.7 to 14.2 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 1 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 is 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: Precautions should be taken when treating any supraventricular arrhythmia on an emergency basis as it may be caused by an undiagnosed sick sinus syndrome (see Contraindications and Warnings).
Although verapamil does not alter serum calcium levels, one report suggested that calcium levels above the normal range may decrease the therapeutic effect of verapamil.
Beagle dogs administered high doses of verapamil were shown to have atypical lens changes and cataracts. This has been concluded to be species specific for the beagle dog. No similar changes have been observed in long-term prospective human ophthalmological trials.
Patients with Attenuated (Decreased) Neuromuscular Transmission: There have been reports that neuromuscular transmission in patients with Duchenne’s muscular dystrophy is decreased and recovery from the neuromuscular blocking agent vercuronium is prolonged by verapamil. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.
Geriatrics: The incidence of adverse reactions is approximately 4% higher in the elderly (Â³65 years); therefore, verapamil should be administered with caution to these patients, especially those prone to developing hypotension or those with a history of cerebrovascular insufficiency. Dizziness and constipation are the adverse reactions occurring most frequently.
Pregnancy: Teratology and reproduction studies have been performed 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. However, verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil is not recommended for use in pregnant women unless the potential benefits outweigh 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 or increases the need for forceps delivery or other obstetric intervention.
Lactation: Verapamil is excreted in human milk. Nursing should be discontinued while the drug is administered.
Children: The safety and dosage regimen of oral 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. 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: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, terfenadine, warfarin.
Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, 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.
Antineoplastic Agents: Verapamil inhibits P-glycoprotein mediated transport of antineoplastic agents out of tumor cells, resulting in their decreased metabolic clearance. Dosage adjustment of antineoplastic agents should be considered when verapamil is administered concomitantly.
Antihypertensive Agents: Verapamil administered concomitantly with other antihypertensive agents such as vasodilators, ACE inhibitors, and diuretics may have an additive effect on lowering blood pressure. In patients with angina or arrhythmias using antihypertensive drugs, this additional hypotensive effect should be taken into consideration. Verapamil should not be combined with beta-blockers for the treatment of hypertension. Concomitant use of verapamil and alpha-adrenoceptors blockers may result in excessive fall in blood pressure in some patients as observed in one study following the concomitant administration of verapamil and prazosin.
ASA: Potential adverse reactions in terms of bleeding due to synergistic antiplatelet effects of the two agents should be taken into consideration in patients taking ASA and verapamil 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: Two clinical trials have shown a lack of significant verapamil interaction with cimetidine. A third study showed cimetidine reduced verapamil clearance and increased elimination half-life.
Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine.
Digoxin: 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 extrarenal clearance of digitoxin by 27% and 29% respectively. Maintenance and digitalization doses should reduced when verapamil is administered and the patient should be reassessed 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 disopyramide and verapamil are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil.
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 AV 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: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.
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 be 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 bioavailability of verapamil.
Sulfinpyrazone: Increased clearance and decreased bioavailability of verapamil may occur.
Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of theophylline.
Adverse Reactions: In 4 826 patients treated with verapamil tablets for arrhythmias, angina or hypertension, the overall adverse reaction rate in these patients was 37.1% and the dropout rate was 10.2%. The majority of these patients were seriously ill and treated under emergency drug regulations.
In controlled pivotal studies with 128 patients treated with verapamil sustained release tablets for hypertension the overall adverse reaction rate was 21.7% and dropout rate was 3.9%.
The most common adverse reactions were: constipation (7.3%), dizziness (3.2%), and nausea (2.7%). In hypertension studies, constipation occurred in 18.5% of patients on verapamil and 4.7% of patients on verapamil sustained release.
The most serious adverse reactions reported with verapamil are heart failure (1.8%), hypotension (2.5%), AV block (1.3%) and rapid ventricular response (see Warnings).
The following reactions to orally administered verapamil were reported from clinical experience in 4 954 patients with angina, arrhythmia or hypertension.
Cardiovascular: hypotension (2.5%), peripheral edema (2.1%), total AV block (1st, 2nd and 3rd degree) (1.2%), AV block (2nd and 3rd degree) (0.8%), bradycardia (HR
Nervous System: 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: transient asystole, development of rhythm disturbances including ventricular dysrhythmias, angina pectoris, flushing, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura, syncope, severe tachycardia, developing or worsening of heart failure, painful coldness and numbness of extremities.
Nervous System: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence, excitation, depression, vertigo, rotary nystagmus, tremor, extrapyramidal disorders, muscle fatigue, hyperkinesis.
Gastrointestinal: vomiting, diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.
Hepatic: hepatotoxicity with elevation in enzymes (AST, ALT, alkaline phosphatase) and bilirubin levels, jaundice and associated symptoms of hepatitis with cholestasis have been reported (see Warnings).
Respiratory: bronchospasm and dyspnea.
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.
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: Transient to severe hypotension; prolonged AV conduction time; AV dissociation, nodal rhythm; ventricular fibrillation and ventricular asystole.
Treatment: Supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel. These pharmacologic interventions have been effectively used in treatment of overdosage with oral verapamil. Clinically significant hypotensive reactions should be treated with vasopressor agents and AV block should be treated with atropine and cardiac pacing. Asystole should be handled by the usual Advanced Cardiac Life Support measures including isoproterenol HCl, or other vasopressor agents. Verapamil is not removed by hemodialysis.
In case of overdosage with large amounts of sustained release verapamil, it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. Depending on the time of ingestion, incompletely dissolved tablets may be present along the entire length of the gastrointestinal tract which function as active drug depots. Extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage and high enemas.
Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. Patients with hypertrophic cardiomyopathy treated with verapamil should not be administered positive inotropic agents.
Dosage And Administration: Novo-Veramil: Verapamil should be taken with food (see Pharmacology, Pharmacokinetics).
Angina Pectoris: Usual starting dose in adults is 80 mg of verapamil 3 to 4 times daily. This may be increased to 120 mg 3 to 4 times daily until optimum response is obtained. Do not increase the dose beyond 480 mg/day. In some cases the dose may be decreased following clinical improvement.
Paroxysmal Supraventricular Tachycardias: Replace i.v. therapy with oral treatment as soon as possible. In adults, use the same dosage schedule as for angina pectoris. Duration of treatment will depend on the underlying cause and history of recurrence.
Atrial Fibrillation and Flutter with Rapid Ventricular Response: Verapamil tablets may be administered to adults not completely controlled with digitalis preparations. The same dosage as for angina pectoris can be used but the physician should be aware that digoxin plasma levels may increase with verapamil administration and the reduction of digoxin dose may be necessary (see Precautions, Drug Interactions).
Obstructive Hypertrophic Cardiomyopathy: Usual starting dose is 80 to 120 mg 3 to 4 times daily, and occasionally patients may require up to 600 to 720 mg/day.
Mild to Moderate Essential Hypertension: Verapamil should be individually titrated, depending on patient tolerance and responsiveness.
Initial dose is usually 80 mg 3 times a day. The dose may be increased up to 160 mg 3 times a day. The daily dose should not exceed 480 mg.
Antihypertensive effects will be evident within the first week of therapy. In patients also taking diuretics, the optimal doses should be lower due to additive antihypertensive effects.
Geriatrics: Lower dosages of verapamil may be warranted in elderly patients (i.e. 65 years) (see Precautions). The dosage should be carefully and gradually adjusted depending on patient tolerance and response. Elderly patients may be more sensitive to the effects of the usual adult dose. Consideration can be given to beginning titration using one-half of a Novo-Veramil SR Tablet (120 mg) once a day since no suitable strength of standard tablet is available.
Patients with Impaired Hepatic Function: Verapamil should be administered cautiously to patients with impaired hepatic function. The dosage should be carefully and gradually adjusted depending on patient tolerability and response. Careful monitoring for abnormal prolongation of the PR interval or other signs of overdosage should be carried out. At this time, verapamil should not be used in patients with severe hepatic dysfunction (see Warnings).
Patients with Impaired Renal Function: Verapamil should be administered cautiously to patients with impaired renal function. The dosage should be carefully and gradually adjusted depending on patient tolerability and response. These patients should also be monitored carefully for abnormal prolongation of the PR interval or other signs of overdosage.
Novo-Veramil SR: Crushing or chewing Novo-Veramil SR tablets is not recommended since the sustained-release effect will be altered by damage to the tablet structure. The Novo-Veramil SR 240 mg tablet may be split in half.
Mild to Moderate Essential Hypertension (see Indications): Novo-Veramil SR Tablets should be taken with food (see Pharmacology, Pharmacokinetics). The dosage should be individualized by titration depending on patient tolerance and responsiveness to verapamil. Titration should be based on therapeutic efficacy and safety, evaluated weekly and approximately 24 hours after the previous dose.
The usual daily dose of verapamil sustained release is 180 to 240 mg/day. Novo-Veramil SR Tablets are not available as a 180 mg strength but verapamil sustained release tablets are available through other manufacturers. If required, the dose may be increased up to 240 mg twice a day. A maximum daily dose of 480 mg should not be exceeded.
The antihypertensive effects of Novo-Veramil SR are evident within the first week of therapy. Optimal doses are usually lower in patients also receiving diuretics since additive antihypertensive effects can be expected.
Elderly patients (i.e. 65 years) should be given a lower dosage of verapamil sustained release. One-half tablet (120 mg) may be given. The dosage should be carefully and gradually adjusted depending on patient tolerability and response.
Patients with Impaired Liver and Renal Function: Verapamil sustained release should be administered cautiously to patients with liver or renal function impairment. Careful titration of dosage is required depending on patient tolerance and response. These patients should be monitored carefully for abnormal prolongation of the PR interval or other signs of overdosage. Verapamil sustained release should not be used in severe hepatic dysfunction (see Warnings).
Switching from Novo-Veramil to Novo-Veramil SR: The total daily dose in mg should be identical when switching from Novo-Veramil to Novo-Veramil SR tablets.
Special Note to Pharmacists: The Novo-Veramil SR 240 mg tablet may be split in half. Crushing Novo-Veramil SR tablets is not recommended since the sustained-release effect will be altered by damage to the tablet structure.
Availability And Storage: Novo-Veramil: 80 mg: Each yellow, round, sugar-coated tablet, imprinted N80 on one side, plain on the reverse, or unidentified contains: verapamil HCl 80 mg. Imprinted tablets: bottles of 100, 500 and 1 000. Boxes of 100 (as unit dose strips). Unidentified tablets: bottles of 100, 500 and 1 000.
120 mg: Each white, round, sugar-coated tablet, imprinted N120 on one side, plain on the reverse, or unidentified contains: verapamil HCl 120 mg. Imprinted tablets: bottles of 100, 500 and 1 000. Boxes of 100 (as unit dose strips). Unidentified tablets: bottles of 100, 500 and 1 000.
Novo-Veramil SR: Each pale green, capsule-shaped, biconvex, scored, film-coated tablet, engraved no/vo on one side and 2/40 on the reverse, contains: verapamil HCl 240 mg. Bottles of 100, 500 and 1 000. Boxes of 100 (as unit dose strips).
Store between 15 and 30°C and protect from light. Unit dose strips should be stored between 15 and 25°C, and protected from high humidity and light.
NOVO-VERAMIL NOVO-VERAMIL SR Novopharm Verapamil HCl Antiarrhythmic – Antianginal – AntihypertensiveAntihypertensive
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