VERAPAMIL
DESCRIPTION:
ISOPTIN (verapamil hydrochloride) is a calcium ion influx inhibitor (slow
channel blocker or calcium ion antagonist). ISOPTIN is available for oral
administration as round, scored, film-coated tablets containing 40 mg, 80 mg or
120 mg of verapamil hydrochloride.
The empirical formula of verapamil HCl is C27H38N2O4.HCl and M.W. is 491.08.
Verapamil HCl is Benzeneacetonitrile,alpha- (3-((2-(3,4-dimethoxyphenyl)
ethyl)methylamino)propyl)-3,4-dimethoxy-alpha- (1-methylethyl)hydrochloride.
Verapamil HCl is an almost white, crystalline powder, practically free of odor,
with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil
HCl is not chemically related to other cardioactive drugs.
In addition to verapamil HCl, ISOPTIN tablets may contain: colloidal silicon
dioxide, corn starch, dibasic calcium phosphate, lactose, gelatin,
microcrystalline cellulose, sodium carboxymethylcellulose, talc, and magnesium
stearate. The film coating used for ISOPTIN 40mg, 80mg and 120mg tablets
contains hydroxypropyl methylcellulose, polyethylene glycol, propylene glycol,
titanium dioxide and polysorbate 80.
ISOPTIN 80mg tablets also contain D&C yellow #10 Lake dye. The ISOPTIN 40mg
tablet contains FD&C blue #2 Aluminum Lake dye.
ACTIONS/CLINICAL PHARMACOLOGY:
ISOPTIN is a calcium ion influx inhibitor (slow channel blocker or calcium ion
antagonist) that 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
Angina
The precise mechanism of action of ISOPTIN as an antianginal agent remains to be
fully determined, but includes the following two mechanisms:
1. RELAXATION AND PREVENTION OF CORONARY ARTERY SPASM
ISOPTIN 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
or dilation of coronary arteries is not an important factor in classical angina.
2. REDUCTION OF OXYGEN UTILIZATION
ISOPTIN regularly reduces the total peripheral resistance (afterload) against
which the heart works both at rest and at a given level of exercise by dilating
peripheral arterioles. This unloading of the heart reduces myocardial energy
consumption and oxygen requirements and probably accounts for the effectiveness
of ISOPTIN in chronic stable effort angina.
Arrhythmia
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. This property accounts for the ability of
ISOPTIN to slow the ventricular rate in patients with chronic atrial flutter or
atrial fibrillation.
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
decreases the frequency of episodes of paroxysmal supraventricular tachycardia.
ISOPTIN does not alter the normal atrial action potential or intraventricular
conduction time, but in depressed atrial fibers it decreases amplitude, velocity
of depolarization and conduction velocity. 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.
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.
PHARMACOKINETICS AND METABOLISM: 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 ng/mL with higher
values reported occasionally. A nonlinear correlation between the verapamil dose
administered and verapamil plasma levels does exist.
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 healthy men, 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 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. However, in patients with severe left
ventricular dysfunction (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.
INDICATIONS AND USAGE:
ISOPTIN tablets are indicated for the treatment of the following:
ANGINA
1. Angina at rest including:
. Vasospastic (Prinzmetal's, variant) angina
. Unstable (crescendo, pre-infarction) angina
2. Chronic stable angina (classic effort- associated angina)
ARRHYTHMIAS
1. In association with digitalis, for the control of ventricular rate at rest
and during stress in patients with chronic atrial flutter and/or atrial
fibrillation (see WARNINGS: Accessory Bypass Tract)
2. Prophylaxis of repetitive paroxysmal supraventricular tachycardia
ESSENTIAL HYPERTENSION
CONTRAINDICATIONS:
Verapamil HCl tablets are contraindicated in:
1. Severe left ventricular dysfunction (see WARNINGS)
2. Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock
3. Sick sinus syndrome (except in patients with a functioning artificial
ventricular pacemaker)
4. Second- or third-degree AV block (except in patients with a functioning
artificial ventricular pacemaker)
5. Patients with atrial flutter or atrial fibrillation and an accessory bypass
tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see Warnings)
6. Patients with known hypersensitivity to verapamil hydrochloride
WARNINGS:
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., pulmonary wedge pressure above 20 mmHg or
ejection fraction less than 30%) or moderate to 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, if 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 with continued
verapamil treatment. Several cases of hepatocellular injury related to verapamil
have been proven by rechallenge; half of these cases 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 cause asymptomatic first-degree AV block and transient bradycardia,
sometimes accompanied by nodal escape rhythms. PR interval prolongation is
correlated with verapamil plasma concentrations, especially during the early
titration phase 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 HCl 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 (greater than 20 mmHg) 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 and only rarely did verapamil
have to be discontinued.
PRECAUTIONS:
GENERAL
Use In Patients With Impaired Hepatic Function: 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 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: Controlled studies in small numbers of patients suggest that the
concomitant use of ISOPTIN and oral beta-adrenergic blocking agents may be
beneficial in certain patients with chronic stable angina or hypertension, but
available information is not sufficient to predict with confidence the effects
of concurrent treatment in patients with left ventricular dysfunction or cardiac
conduction abnormalities. Concomitant therapy with beta-adrenergic blockers and
verapamil may result in additive negative effects on heart rate,
atrioventricular conduction and/or cardiac contractility.
In one study involving 15 patients treated with high doses of propranolol
(median dose: 480 mg/day, range 160 to 1280 mg/day) for severe angina, with
preserved left ventricular function (ejection fraction greater than 35%), the
hemodynamic effects of additional therapy with verapamil HCl were assessed using
invasive methods. The addition of verapamil to high-dose beta blockers induced
modest negative inotropic and chronotropic effects which were not severe enough
to limit short-term (48 hours) combination therapy in this study. These modest
cardiodepressant effects persisted for greater than 6, but less than 30 hours
after abrupt withdrawal of beta blockers and were closely related to plasma
levels of propranolol. The primary verapamil/beta-blocker interaction in this
study appeared to be hemodynamic rather than electrophysiologic.
In other studies, verapamil did not generally induce significant negative
inotropic, chronotropic, or dromotropic effects in patients with preserved left
ventricular function receiving low or moderate doses of propranolol (less than
or equal to 320 mg/day); in some patients, however, combined therapy did produce
such effects. Therefore, if combined therapy is used, close surveillance of
clinical status should be carried out. Combined therapy should usually be
avoided in patients with atrioventricular conduction abnormalities and those
with depressed left ventricular function.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has
been observed in a patient receiving concomitant timolol (a beta- adrenergic
blocker) eyedrops and oral verapamil.
A decrease in metoprolol clearance has been observed when verapamil and
metoprolol were administered together. A similar effect has not 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.
However, 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 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. Upon discontinuation of ISOPTIN (verapamil HCl),
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 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.
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. There has been a report of increased quinidine
levels during verapamil therapy.
OTHER
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.
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: Pharmacokinetic and pharmacodynamic interactions between oral verapamil
and lithium have been reported. The former may result in a lowering of serum
lithium levels in patients receiving chronic stable oral lithium therapy. The
latter may result in an increased sensitivity to the effects of 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.
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 each 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 if clearly needed.
Verapamil 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 verapamil in Europe in the
treatment of cardiac side effects of beta-adrenergic agonist agents used to
treat premature labor.
NURSING MOTHERS: Verapamil 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.
DRUG INTERACTIONS:
Beta Blockers: Controlled studies in small numbers of patients suggest that the
concomitant use of ISOPTIN and oral beta-adrenergic blocking agents may be
beneficial in certain patients with chronic stable angina or hypertension, but
available information is not sufficient to predict with confidence the effects
of concurrent treatment in patients with left ventricular dysfunction or cardiac
conduction abnormalities. Concomitant therapy with beta-adrenergic blockers and
verapamil may result in additive negative effects on heart rate,
atrioventricular conduction and/or cardiac contractility.
In one study involving 15 patients treated with high doses of propranolol
(median dose: 480 mg/day, range 160 to 1280 mg/day) for severe angina, with
preserved left ventricular function (ejection fraction greater than 35%), the
hemodynamic effects of additional therapy with verapamil HCl were assessed using
invasive methods. The addition of verapamil to high-dose beta blockers induced
modest negative inotropic and chronotropic effects which were not severe enough
to limit short-term (48 hours) combination therapy in this study. These modest
cardiodepressant effects persisted for greater than 6, but less than 30 hours
after abrupt withdrawal of beta blockers and were closely related to plasma
levels of propranolol. The primary verapamil/beta-blocker interaction in this
study appeared to be hemodynamic rather than electrophysiologic.
In other studies, verapamil did not generally induce significant negative
inotropic, chronotropic, or dromotropic effects in patients with preserved left
ventricular function receiving low or moderate doses of propranolol (less than
or equal to 320 mg/day); in some patients, however, combined therapy did produce
such effects. Therefore, if combined therapy is used, close surveillance of
clinical status should be carried out. Combined therapy should usually be
avoided in patients with atrioventricular conduction abnormalities and those
with depressed left ventricular function.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has
been observed in a patient receiving concomitant timolol (a beta- adrenergic
blocker) eyedrops and oral verapamil.
A decrease in metoprolol clearance has been observed when verapamil and
metoprolol were administered together. A similar effect has not 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.
However, 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 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. Upon discontinuation of ISOPTIN (verapamil HCl),
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 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.
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. There has been a report of increased quinidine
levels during verapamil therapy.
OTHER
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.
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: Pharmacokinetic and pharmacodynamic interactions between oral verapamil
and lithium have been reported. The former may result in a lowering of serum
lithium levels in patients receiving chronic stable oral lithium therapy. The
latter may result in an increased sensitivity to the effects of 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.
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 each 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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Serious adverse reactions are uncommon when ISOPTIN 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. The following reactions to orally
administered verapamil 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 1 deg,
2 deg, 3 deg 1.2%
Headache 2.2% 2 deg and 3 deg 0.8%
Edema 1.9% Rash 1.2%
CHF, Pulmonary Flushing 0.6%
Edema 1.8%
Elevated Liver Enzymes (see WARNINGS)
In clinical trials related to the control of ventricular response in digitalized
patients who had atrial fibrillation or flutter, ventricular rate below 50 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, paresthesia, 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, increased urination, spotty menstruation, impotence.
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 norepinephrine bitartrate, atropine sulfate,
isoproterenol HCl (all in the usual doses), or calcium gluconate (10% solution).
In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents
(phenylephrine HCl, metaraminol bitartrate or methoxamine HCl) should be used to
maintain blood pressure, and isoproterenol and norepinephrine should be avoided.
If further support is necessary, dopamine HCl or dobutamine HCl 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.
OVERDOSAGE:
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 fixed 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.
DOSAGE AND ADMINISTRATION:
The dose of verapamil must be individualized by titration. ISOPTIN is available
in 40 mg, 80 mg, and 120 mg tablets. The usefulness and safety of dosages
exceeding 480 mg/day have not been established; therefore, this daily dosage
should not be exceeded. Since the half-life of verapamil increases during
chronic dosing, maximum response may be delayed.
ANGINA: Clinical trials show that the usual dose is 80 mg to 120 mg three times
a day. However, 40mg three times a day may be warranted in patients who may have
an increased response to verapamil (e.g., decreased hepatic function, elderly,
etc.). Upward titration should be based on therapeutic efficacy and safety
evaluated approximately eight hours after dosing. Dosage may be increased at
daily (e.g., patients with unstable angina) or weekly intervals until optimum
clinical response is obtained.
ARRHYTHMIAS: The dosage in digitalized patients with chronic atrial fibrillation
(see PRECAUTIONS) ranges from 240 to 320 mg per day in divided (t.i.d. or
q.i.d.) doses. The dosage for prophylaxis of PSVT (non-digitalized patients)
ranges from 240 to 480 mg in divided (t.i.d. or q.i.d.) doses. In general,
maximum effects for any given dosage will be apparent during the first 48 hours
of therapy.
ESSENTIAL HYPERTENSION: Dose should be individualized by titration. The usual
initial monotherapy dose in clinical trials was 80 mg three times a day (240
mg). Daily dosages of 360 and 480 mg have been used but there is no evidence
that doses beyond 360 mg provide added effect. Consideration should be given to
beginning titration at 40 mg, three times per day in patients who might respond
to lower doses, such as the elderly or people of small stature. The
antihypertensive effects of ISOPTIN are evident within the first week of
therapy. Upward titration should be based on therapeutic efficacy, assessed at
the end of the dosing interval.
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