Verapamil

Brand names: Calan, Isoptin

Pharmacology

Antihypertensive - Antianginal - Antiarrhythmic

Angina and Arrhythmia:
Verapamil is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist). The mechanism of the antianginal and antiarrhythmic effects of verapamil is believed to be related to its specific cellular action of selectively inhibiting transmembrane influx of calcium 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 affecting, to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within cells of the above tissues.

Verapamil's antiarrhythmic effects are believed to be brought about largely by its action on the sinoatrial (SA) and atrioventricular (AV) nodes. Verapamil depresses AV nodal conduction and prolongs functional refractory periods. 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. Through this action, it interrupts re-entrant pathways and slows the 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 vasodilatory properties, as well as a depressant of myocardial contractility, and these effects are largely independent of autonomic influences. Its antianginal action in exertional angina seems to result from a decrease in resistance in the systemic vasculature, as well as from a direct effect on myocardial contraction. The net pharmacologic effect is a decrease in myocardial oxygen consumption. Verapamil's effectiveness in vasospastic angina is due to a decrease in coronary vascular tone.

Essential Hypertension:
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:
Isoptin:

More than 90% of the orally administered dose of verapamil is absorbed. Because of rapid biotransformation of verapamil 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.

The mean elimination half-life in single-dose studies 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). 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. 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 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. 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 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.

Isoptin SR:
In a single dose comparative study using standard release 120 mg tablets (dose adjusted to 240 mg) and the 240 mg SR tablets, peak verapamil plasma levels of 203 ng/mL at 1.1 hours and 80.1 ng/mL at 5.5 hours were obtained respectively.

The steady-state pharmacokinetic data from a study in which 11 volunteers were treated with the sustained release formulation twice daily at 12 hourly intervals and with the standard release formulation 3 times daily at 8 hourly intervals for 5 days is summarized in Table I.

---------------------------------------------------------------
Table I
 
                Standard        Sustained      Sustained 
                Release         Release         Release
                Tablet**        Tablet**        Tablet*
                 120 mg          240 mg          240 mg 
Parameters    (360 mg daily)  (360 mg daily)  (480 mg daily)
C max            289.4            250.5          298.4 (ng/mL)
C min             80.1            110.7          152.0 (ng/mL)
T max              1.4              4.5            4.4 (hours)
T 1/2              6.1              8.2            8.7 (hours)
AUC 0-infinity    1850             3466           4484 (ng/mL/hr)
AUC 0-36          1809             3154           4116 (ng/mL/hr)
 
----------------------------------------------------------------
  * last dose=240 mg
 ** last dose=120 mg
----------------------------------------------------------------

The data have been calculated from samples taken at frequent intervals for 36 hours after the last dose.

Influence of Food:
Administration of Isoptin tablets or Isoptin-SR with food results in marked prolongation of T(max) (45 to 75%) and slight decreases in C(max) (about 15%) and AUC (1 to 8%). Food thus produces a slight decrease in bioavailability (AUC), but a narrower peak-to-trough ratio.

Indications

Isoptin:
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. Verapamil should normally be used in those patients in whom treatment with diuretics or beta-blockers has been associated with unacceptable adverse effects.

Verapamil 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.

Verapamil should not be used concurrently with beta-blockers in the treatment of hypertension (see 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.

Isoptin SR:
In the treatment of mild to moderate essential hypertension. Isoptin SR should normally be used in those patients in whom treatment with diuretics or beta-blockers has been associated with unacceptable adverse effects.

Isoptin SR 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 Isoptin SR with a diuretic has been found to be compatible and showed additive antihypertensive effect.

Isoptin SR should not be used concurrently with beta-blockers in the treatment of hypertension (see Drug Interactions).

Safety of concurrent use of Isoptin SR with other antihypertensive agents has not been established and such use cannot be recommended at this time.

Contraindications

Acute myocardial infarction; severe congestive heart failure and/or severe left ventricular dysfunction (unless secondary to a supraventricular tachycardia amenable to oral verapamil therapy); cardiogenic shock; severe hypotension; second or third degree AV block; sick sinus syndrome (see Warnings); marked bradycardia; hypersensitivity to the drug; patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see Warnings).

Warnings

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 the drug's negative inotropic effect, verapamil 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 Drug Interactions). 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 a 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 (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. 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 Use with Beta-blockers:
Generally, oral verapamil should not be given to patients receiving beta-blockers since the depressant effects on myocardial contractility, heart rate and AV conduction may be additive. However, in exceptional cases when in the opinion of the physician, concomitant use in angina and arrhythmias is considered essential, such use should be instituted gradually 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 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 was seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension, abnormally high (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see Drug Interactions) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second degree AV block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction, 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 (SGOT), ALT (SGPT) 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 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 vercuronium. 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 (>=65 years) especially those prone to developing hypotension or those with a history of cerebrovascular insufficiency. The incidence of adverse reactions is approximately 4% higher in the elderly. The adverse reactions occurring more frequently include dizziness and constipation.

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. 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:
Beta-Adrenergic Blockers:

The concomitant administration of verapamil with beta-blockers can result in severe adverse effects (see Warnings).

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 be 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.

Antihypertensive Agents:
Verapamil administered concomitantly with other antihypertensive agents 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. 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.

Antiarrhythmic Agents:
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.

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.

Other:
Nitrates, Diuretics:

No cardiovascular adverse effects have been attributed to any interaction between these agents and verapamil.

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.

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.

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.

Rifampin:
Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Phenobarbital:
Phenobarbital therapy may increase verapamil clearance.

Cyclosporine:
Verapamil therapy may increase serum levels of cyclosporine.

Theophylline:
Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

Sulfinpyrazone:
Increased clearance and decreased bioavailability of verapamil may occur.

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.

Adverse Effects

In 4826 patients treated with Isoptin 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 Isoptin SR tablets for hypertension the overall adverse reaction rate was 21.7% and the 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 Isoptin and 4.7% of patients on Isoptin SR.

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).

The following adverse reactions divided by body system have been reported in clinical trials or marketing experience. When incidences are shown, they are calculated based on the 4954 (4826+128) patient base.

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 and 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 (SGOT), ALT (SGPT), alkaline phosphatase]) and bilirubin levels, jaundice and associated symptoms of hepatitis with cholestasis have been reported (see Warnings).

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.

Overdose

Symptoms:
Based on reports of intentional overdosage of verapamil, the following symptoms have been observed. Hypotension occurs, varying from transient to severe. Conduction disturbances seen included: prolongation of AV conduction time, AV dissociation, nodal rhythm, ventricular fibrillation and ventricular asystole.

Treatment:
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.

Isoptin SR:
In case of overdosage with large amounts of Isoptin SR, 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.

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Table II
 
Suggested Treatment of Acute Cardiovascular Adverse Effects
                                                       Treatment with
Adverse                  Proven Effective              Good Theoretical      Supportive 
Effect                   Treatment                     Rationale             Treatment
Shock, cardiac failure,  Calcium salts,                Dopamine HCl i.v.*    I.V. fluids
severe hypotension       e.g., Calcium gluconate i.v.  Dobutamine HCl i.v.*  Trendelenburg
                             Metaraminol bitartrate i.v.*                        position
 
Bradycardia, AV block,   Isoproterenol HCl i.v.*              -              I.V. fluids
asystole                 Atropine sulfate i.v.                               (slow drip)
                         Cardiac pacing         
 
Rapid ventricular rate   DC cardioversion                     -              I.V. fluids
(due to antegrade        (high energy                                        (slow drip)
conduction in flutter/   may be required)
fibrillation with        Procainamide i.v.
WPW or LGL syndrome)     Lidocaine HCl i.v. 
 
--------------------------------------------------------------------------------------------

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 (marked by asterisks).

Dosage

Isoptin:
Isoptin should be taken with food (see Pharmacokinetics).

Angina Pectoris:
Usual starting dose in adults is 80 mg 3 to 4 times daily. This may be increased to 120 mg 3 to 4 times daily until optimum response is obtained. The dose should not be increased beyond 480 mg/day. In some cases the dose may be decreased following clinical improvement.

Obstructive Hypertrophic Cardiomyopathy:
Usual starting dose is 80 to 120 mg 3 to 4 times daily, and occasionally patients may require doses up to 600 to 720 mg/day.

Paroxysmal Supraventricular Tachycardia:
Oral treatment should replace i.v. therapy as soon as possible. It can be administered in adults in the same dosage schedule as for angina pectoris. Duration of treatment will depend on the underlying cause and history of recurrence. At this time there is insufficient data to establish a safe and effective oral dose for children.

Atrial Fibrillation and Flutter with Rapid Ventricular Response:
Verapamil 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 downward adjustment of the digoxin dose may be necessary (see Drug Interactions).

Mild to Moderate Essential Hypertension:
(see Indications).

The dosage should be individualized by titration depending on patient tolerance and responsiveness to verapamil.

The usual initial adult dose is 80 mg 3 times a day. If required, the dose may be increased up to 160 mg 3 times a day. A maximum daily dose of 480 mg should not be exceeded.

The antihypertensive effects of Isoptin tablets 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.

Geriatrics:
Lower dosage may be warranted in elderly patients (>=65 years) (see Precautions). The dosage should be carefully and gradually adjusted depending on patient tolerability and response. Consideration can be given to beginning titration using 1 Isoptin SR 120 mg tablet once a day since no suitable strength of standard tablet is available.

Patients with Impaired Hepatic and Renal Function:
Isoptin should be administered cautiously to patients with liver or renal function impairment. The dosage should be carefully and gradually adjusted depending on patient tolerance and response. These patients should be monitored carefully for abnormal prolongation of the PR interval or other signs of overdosage. At this time, Isoptin tablets should not be used in patients with severe hepatic dysfunction (see Warnings).

Isoptin SR:
Crushing or chewing Isoptin SR tablets is not recommended since the sustained-release effect will be altered by damage to the tablet structure. The Isoptin SR 240 mg tablet may be split in half.

Mild to Moderate Essential Hypertension:
(see Indications).

Isoptin SR should be taken with food (see 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 initial adult dose is 180 to 240 mg/day. 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.

Recommended dosing intervals for specific daily dosages are given in Table III.

---------------------------------------------------
Table III
 
Total Daily
Isoptin SR Dose    Recommended Dosing Intervals
180 mg             Once each morning with food
240 mg             Once each morning with food
360 mg             180 mg each morning plus
180 mg             each evening, with food
                    or
                   240 mg each morning plus
                   120 mg each evening, with food
 
480 mg             240 mg each morning plus
                   240 mg each evening, with food
---------------------------------------------------

The antihypertensive effects of Isoptin 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.

Geriatrics:
Lower dosages of Isoptin SR, i.e. 120 mg a day, may be warranted in elderly patients (i.e., 65 years and older) (see Precautions). The dosage should be carefully and gradually adjusted depending on patient tolerability and response.

Patients with Impaired Liver and Renal Function:
Isoptin SR should be administered cautiously to patients with liver or renal function impairment. The dosage should be carefully and gradually adjusted depending on patient tolerance and response. These patients should be monitored carefully for abnormal prolongation of the PR interval or other signs of overdosage. Isoptin SR should not be used in severe hepatic dysfunction (see Warnings).

Switching from Isoptin to Isoptin SR:
When switching from Isoptin to Isoptin SR the total daily dose in mg may remain the same.

Special Note to Pharmacists:
The Isoptin SR 240 mg tablet may be split in half. Crushing Isoptin SR tablets is not recommended since the sustained-release effect will be altered by damage to the tablet structure. Use of Isoptin SR 120 mg is recommended.

Supplied

Isoptin:
80 mg:

Each round, yellow, sugar-coated tablet contains: Verapamil HCl 80 mg. Nonmedicinal ingredients: Acacia, calcium carbonate, carnauba wax, cellulose, cornstarch, gelatin, lactose, magnesium stearate, povidone, quinoline yellow lake, silicon dioxide, sodium carboxymethylcellulose, sucrose, talc and titanium dioxide. Energy: 2.8 kJ (0.68 kcal)/tablet. Sodium: <1 mmol (0.054 mg)/tablet. Bottles of 250 and 1000.

120 mg:
Each round, white, sugar-coated tablet contains: Verapamil HCl 120 mg. Nonmedicinal ingredients: Acacia, calcium carbonate, carnauba wax, cellulose, cornstarch, gelatin, lactose, magnesium stearate, povidone, silicon dioxide, sodium carboxymethylcellulose, sucrose, talc and titanium dioxide. Energy: 5.3 kJ (1.26 kcal)/tablet. Sodium: <1 mmol (0.086 mg)/tablet. Bottles of 250 and 1000.

Isoptin SR:
120 mg:

Each off-white, biconvex, round, film-coated tablet, with 120 SR embossed on one side, KNOLL on the other side, contains: Verapamil HCl 120 mg. Nonmedicinal ingredients: Cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, povidone, sodium alginate, talc, titanium dioxide and wax. Energy: 0.06 kJ (0.015 kcal). Sodium: <1 mmol (0.015 mg). Bottles of 100.

180 mg:
Each light-pink, football-shaped, film-coated tablet with KNOLL on one side and SR, scored, 180 on the other, contains: Verapamil HCl 180 mg. Nonmedicinal ingredients: Cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, povidone, red iron oxide, sodium alginate, talc, titanium dioxide and wax. Energy: 0.09 kJ (0.023 kcal). Sodium: <1 mmol (0.023 mg). Bottles of 100.

240 mg:
Each light-green, scored, capsule-shaped, film-coated tablet, with 2 triangles embossed on one side, contains: Verapamil HCl 240 mg. Nonmedicinal ingredients: Cellulose, hydroxypropyl methylcellulose, indigotine lake, magnesium stearate, polyethylene glycol, povidone, quinoline yellow lake, sodium alginate, talc, titanium dioxide and wax. Energy: 0.11 kJ (0.03 kcal). Sodium: <1 mmol (0.03 mg). Bottles of 100 and 500.