Sustained Release Oral Tablets
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
ISOPTIN SR (verapamil hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist).
ISOPTIN SR is available for oral administration as light green, capsule shaped, scored, film-coated tablets containing
240 mg verapamil hydrochloride, as light pink, oval shaped, scored, film-coated tablets containing 180 mg verapamil
hydrochloride, and as light violet, oval shaped, film-coated tablets containing 120 mg verapamil hydrochloride. The
tablets are designed for sustained release of the drug in the gastrointestinal tract; sustained release characteristics are
not altered when the tablet is divided in half.
The structural formula of verapamil HCI is given below:
chloroform and methanol. Verapamil HCI is not chemically related to other cardioactive drugs.
In addition to verapamil HCI, the ISOPTIN SR tablet contains the following ingredients: alginate, hydroxypropyl
methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, talc, and
titanium dioxide. The following are the color additives per tablet strength:
Strength (mg) Color Additive(s) 120 Iron Oxide 180 Iron Oxide 240 D&C; yellow #1 0 Lake dye, and FD&C; blue #2 Lake dye
ISOPTIN is a calcium ion influx inhibitor (slow channel 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.
Mechanism of Action
Essential Hypertension
ISOPTIN exerts antihypertensive effects, by decreasing systemic vascular resistance, usually without orthostatic
decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During
isometric or dynamic exercise ISOPTIN does not alter systolic cardiac function in patients with normal ventricular
function. ISOPTIN does not alter total serum calcium levels. However, one report suggested that calcium levels above
the normal range may alter the therapeutic effect of ISOPTIN.
Other Pharmacological Actions of ISOPTIN Include the Following
ISOPTIN (verapamil HCl) dilates the main coronary arteries and coronary arterioles. both in normal and ischemic
regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property
increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of
ISOPTIN in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest. Whether this effect plays any role in
classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum
exercise rate pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of
spasm of dilation of coronary arteries is not an important factor in classical angina.
ISOPTIN regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a
given level of exercise by dilating peripheral arterioles.
Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel.
By decreasing the influx of calcium, ISOPTIN prolongs the effective refractory period within the AV node and slows AV
conduction in a rate-related manner.
Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, ISOPTIN may interfere with sinus
node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients
without preexisting conduction defects (see WARNINGS).
ISOPTIN does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude,
velocity of depolarization and conduction in depressed atrial fibers. ISOPTIN may shorten the antegrade effective
refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been
reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration
of verapamil (see WARNINGS).
ISOPTIN has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether
this action is important at the doses used in man.
Pharmacokinetics and Metabolism: With the immediate release formulation, more than 90% of the orally
administered dose of ISOPTIN 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 ISOPTIN every 6 hours resulted in plasma
levels of verapamil ranging from 125 to 400 mg/mL with higher values reported occasionally, A nonlinear correlation
between the verapamil dose administered and verapamil plasma levels does exist. No relationship has been established
between the plasma concentration of verapamil and a reduction in blood pressure.
In early dose titration with verapamil a relationship exists between verapamil plasma concentrations and the
prolongation of the PR interval. However, during chronic administration this relationship may disappear. The 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 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-
life of verapamil may increase during titration.
Aging may affect the pharmacokinetics of verapamil, Elimination half-life may be prolonged in the elderly.
In multiple dose studies under fasting conditions the bioavailability measured by AUC of ISOPTIN SR was similar to
ISOPTIN immediate release; rates of absorption were, of course, different. In a randomized, single-dose, crossover
study using healthy volunteers, administration of 240 mg ISOPTIN SR with food produced peak plasma verapamil
concentrations of 79 ng/mL, time to peak plasma verapamil concentration of 7.71 hours, and AUC (0-24 hr) of 841 ng-hr/
mL. When ISOPTIN SR was administered to fasting subjects, peak plasma verapamil concentration was 164 ng/mL; time
to peak plasma verapamil concentration was 5.21 hours; and AUC (0-24 hr) was 1,478 ng-hr/mL. Similar results were
demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak to
trough ratio. Good correlation of dose and response is not available, but controlled studies of ISOPTIN SR have shown
effectiveness of doses similar to the effective doses of ISOPTIN (immediate release).
In healthy man, orally administered ISOPTIN 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
of immediate release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS);
the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance
values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third
of the oral daily dose required for patients with normal liver function.
After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid
with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.
Hemodynamics and Myocardial Metabolism: ISOPTIN reduces afterload and myocardial contractility. Improved left
ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with
ISOPTIN therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of
ISOPTIN is countered by reduction of afterload and cardiac index is usually not reduced. In patients with severe left
ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mmHg or ejection fraction lower than 30%),
or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function
may occur (see DRUG INTERACTIONS).
Pulmonary Function: ISOPTIN does not induce bronchoconstriction and hence, does not impair ventilatory function.
ISOPTIN SR (verapamil HCI) is indicated for the management of essential hypertension.
Verapamil HCI is contraindicated in:
- Severe left ventricular dysfunction (see WARNINGS)
- Hypotension (less than 90 mmHg systolic pressure) or cardiogenic shock
- Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)
- Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
- Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (see WARNINGS)
- Patients with known hypersensitivity to verapamil hydrochloride.
Heart Failure: Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload
reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In
clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil
should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, pulmonary
wedge pressure above 20mm Hg, or severe symptoms of cardiac failure) and in patients with any degree of ventricular
dysfunction if they are receiving a beta adrenergic blocker (see DRUG INTERACTIONS). Patients with milder ventricular
dysfunction should, it possible, be controlled with optimum doses of digitalis and/ or diuretics before verapamil treatment
(Note interactions with digoxin under: PRECAUTIONS).
Hypotension: Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below
normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in
4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are
unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.
Elevated Liver Enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase
and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face
of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by
rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to
elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving
verapamil is therefore prudent.
Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/ or
chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade
conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or
ventricular fibrillation after receiving intravenous verapamil (or digitalis). 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).
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral ISOPTIN.
Atrioventricular Block: The effect of verapamil on AV conduction and the SA node may lead to asymptomtic first-
degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation
is correlated with verapamil plasma concentrations, especially the early titration phases of therapy. Higher degrees of AV
block, however, were infrequently (0.8%) observed. Marked first degree block or progressive development to
second- or third-degree AV block requires a reduction in dosage or, in rare instances. discontinuation of verapamil HCI
and institution of appropriate therapy depending upon the clinical situation.
Patients with Hypertrophic Cardiomyopathy (IHSS): In 120 patients with hypertrophic cardiomyopathy (most of them
refractory or intolerant to propranolol) 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 (over 20 mmHg) capillary 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 and only
rarely did verapamil have to be discontinued.
General
Use In Patients with Impaired Hepatic Functions: Since verapamil is highly metabolized by the liver, it should be
administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-
life of immediate release verapamil to about 14 to 16 hours, hence, approximately 30% of the dose given to patients with
normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR
interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out.
Use In 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.
Use In Patients with Impaired Renal Function: About 70% of an administered dose of verapamil is excreted as
metabolites in the urine. Verapamil is not removed by hemodialysis, Until further data are available, verapamil should be
administered cautiously to patients with impaired renal function. These patients should be carefully monitored for
abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE).
Drug Interactions
Beta Blockers: Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects
on heart rate, atrioventricular conduction, and/or cardiac contractility, The combination of sustained-release verapamil
and beta-adrenergic blocking agents has not been studied. However, there have been reports of excessive bradycardia
and AV block, including complete heart block, when the combination has been used for the treatment of hypertension,
For hypertensive patients, the risks of combined therapy may outweigh the potential benefits. The combination should
be used only with caution and close monitoring.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving
concomitant timolol (a beta -adrenergic blocker) eyed drops and oral verapamil.
A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly
with verapamil. A variable effect has been seen when verapamil and atenolol were given together.
Digitalis: Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses
are properly adjusted. Chronic verapamil treatment can increase 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 digitalis 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. Upon discontinuation of ISOPTIN (verapamil HCI), the patient
should be reassessed to avoid underdigitalization.
Antihypertensive Agents: Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators,
angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood
pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that
attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some
patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.
Antiarrhythmic Agents
Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained,
disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
Flecainide: A study of 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.
Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), 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 electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil
significantly counteracted the effects of quinidine 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.
Nitrates: Verapamil has been given concomitantly with short and long-acting nitrates without any undesirable drug
interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.
Other
Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable
results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either
reduced or unchanged.
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.
Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may
produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.
Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.
Phenobarbital: Phenobarbital therapy may increase verapamil clearance.
Cyclosporin: Verapamil therapy may increase serum levels of cyclosporin.
Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of theophylline.
Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by
decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium
antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility: An 18-month toxicity study in rats. at a low multiple (6 fold) of
the maximum recommended human dose, and not the maximum tolerated dose. did not suggest a tumorigenic potential,
There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of
10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human
daily dose (480 mg per day or 9.6 mg/kg/day).
Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.
Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did
not show impaired fertility. Effects on male fertility have not been determined.
Pregnancy: Pregnancy Category C. 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. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and
development, probably because of adverse maternal effects reflected in the reduced weight gains of the dams. This oral
dose has also been shown to cause hypotension in rats, There are no adequate and well-controlled studies in pregnant
women, Because animal reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only it clearly needed. ISOPTIN (verapamil HCI) crosses the placental barrier and can be detected in
umbilical vein blood at delivery.
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. Such adverse experiences have not been reported in the literature, despite a long history of
use of ISOPTIN in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat
premature labor.
Nursing Mothers: ISOPTIN is excreted in human milk. Because of the potential for adverse reactions in nursing infants
from verapamil, nursing should be discontinued while verapamil is administered.
Pediatric Use: Safety and efficacy of ISOPTIN in children below the age of 18 years have not been established.
Animal Pharmacology and/or Animal Toxicology: In chronic animal toxicology studies verapamil caused lenticular
and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog
but not the rat. Development of cataracts due to verapamil has not been reported in man.
Serious adverse reactions are uncommon when ISOPTIN (verapamil HCl) therapy is initiated with upward dose titration
within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension,
elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil)
nonobstructive, paralytic, ileus has been infrequently reported in association with the use of verapamil. The following
reactions to orally administered ISOPTIN occurred at rates greater than 1.0% or occurred at lower rates but appeared
clearly drug related in clinical trials in 4,954 patients.
Constipation 7.3% Fatigue 1.7% Dizziness 3.3% Dyspnea 1.4% Nausea 2.7% Bradycardia (HR <50/min) 1.4% Hypotension 2.5% AV Block-total 1º, 2º, 3º 1.2% Headache 2.2% 2º and 3º 0.8% Edema 1.9% Rash 1.2% CHF/Pulmonary Edema 1.8% Flushing 0.6% Elevated Liver Enzymes (see WARNING)
In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial
flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5%
of patients.
The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing
experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship.
Cardiovascular:
-
- angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction,
-
- palpitations, purpura (vasculitis), syncope.
Digestive System:
-
- diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.
Hemic and Lymphatic:
-
- ecchymosis or bruising.
Nervous System:
-
- cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, parathesia,
-
- psychotic symptoms, shakiness, somnolence.
-
- Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson
-
- syndrome, erythema multiforme.
Special Senses:
-
- blurred vision.
Urogenital:
- gynecomastia, impotence, galactorrhea/ hyperprolactinemia, increased urination, spotty menstruation.
Treatment of Acute Cardiovascular Adverse Reactions: The frequency of cardiovascular adverse reactions which
require therapy is rare, hence, experience with their treatment is limited. Whenever severe hypotension or complete AV
block occur following oral administration of verapamil the appropriate emergency measures should be applied
immediately, e.g., intravenously administered isoproterenol HCI, levarterenol bitartrate, atropine (all in the usual doses),
or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents
(phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol
and levarterenol should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be
administered. Actual treatment and dosage should depend on the severity and the clinical situation and the judgment
and experience of the treating physician.
Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially Isoptin SR),
preferably under continuous hospital care. Delayed pharmacodynamic consequences- may occur with the sustained
released formulation. Verapamil is known to decrease gastrointestinal transit time.
Treatment of overdosage should be supportive. Beta adrenergic stimulation or parenteral administration of calcium
solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of
deliberate overdosage with verapamil. Verapamil cannot be removed by hemodialysis, Clinically significant hypotensive
reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole
should be handled by the usual measures including cardiopulmonary resuscitation.
Essential Hypertension
The dose of ISOPTIN SR should be individualized by titration and the drug should be administered with food. Initiate
therapy with 180 mg of sustained-release verapamil HCI, ISOPTIN SR, given in the morning. Lower, initial doses of 120
mg a day may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small
people etc.). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24
hours after the previous dose. The antihypertensive effects of ISOPTIN SR are evident within the first week of therapy.
If adequate response is not obtained with 180 mg of ISOPTIN SR, the dose may be titrated upward in the following
manner:
- 240 mg each morning,
- 180 mg each morning plus 180 mg each evening, or
240 mg each morning plus 120 mg each evening - 240 mg every twelve hours.
When switching from immediate release ISOPTIN to ISOPTIN SR, the total daily dose in milligrams may remain the
same.
ISOPTIN® SR 240 mg tablets are supplied as light green, capsule shaped, scored, film-coated tablets containing 240 mg
of verapamil hydrochloride. The tablet is embossed with a double Knoll triangle on one side and “ISOPTIN SR” on the
other side. ISOPTIN® SR 180 mg tablets are supplied as light pink, oval shaped, scored, film-coated tablets containing
180 mg of verapamil hydrochloride. The tablet is embossed with “ISOPTIN SR” on one side, and “180 mg” on the other
side. The ISOPTIN® SR 120 mg tablets are supplied as light violet, oval shaped film-coated tablets containing 120 mg
of verapamil hydrochloride. The tablet is embossed with “KNOLL” on one side and “120 SR” on the other side.
240 mg (light green)- Bottle of 30- NDC #0044-1826-93 Bottle of 100- NDC #0044-1826-02 Hospital Unit Dose (100 Tablets- Strips of 10) - NDC #0044-1 826-10 180 mg (light pink)- Bottle of 100- NDC #0044-1825-02 Hospital Unit Dose (100 Tablets Strips of 10) - NDC # 0044-1825-12 120 mg (light violet)- Bottle of 100- NDC #0044-1827-02 Hospital Unit Dose (100 Tablets Strips of 10) - NDC #0044-1827-12
Storage: 59º-77ºF (15º-25ºC).
Protect from light and moisture.
Dispense in a tight, light-resistant container as defined in the USP.
