A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Isoptin Side Effects, and Drug Interactions - Verapamil HCl
Isoptin Side Effects, and Drug Interactions - Verapamil HCl
SIDE EFFECTS
Serious adverse reactions are uncommon when Calan 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) non-obstructive, paralytic
ileus has been infrequently reported in association with the use of verapamil.
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% Dyspnea 1.4% Dizziness 3.3% Bradycardia
Nausea 2.7% (HR<50/min) 1.4% Hypotension 2.5% AV block Headache 2.2% total
(1°,2°,3°) 1.2% Edema 1.9% 2° and 3° 0.8% CHF, Pulmonary Rash 1.2% edema 1.8%
Flushing 0.6% Fatigue 1.7% 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 rates 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, atrioventricu-lar dissociation,
chest pain, claudication, myo-cardial infarction, palpitations, purpura (vascu-litis),
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,
macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multi-forme.
Special senses: blurred vision, tinnitus. Urogenital: gynecomastia,
galactorrhea/hyper-prolactinemia, increased urination, spotty menstruation,
impotence.
Treatment of acute cardiovascular adverse reactions: The
frequency of cardiovascular adverse reactions that require therapy is rare;
hence, experience with their treatment is limited. Whenever severe hypotension
or complete AV block occurs following oral administration of verapamil, the
appropriate emergency measures should be applied immediately; eg, 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 bitar-trate, 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 dobu-tamine HCl may be administered. Actual
treatment and dosage should depend on the severity of the clinical situation
and the judgment and experience of the treating physician.
DRUG INTERACTIONS
Alcohol: Verapamil may increase blood alcohol concentrations
and prolong its effects.
Beta-blockers: Controlled studies in small numbers
of patients suggest that the concomitant use of Calan 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 1,280 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 that
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, chrono-tropic, 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 and propranolol clearance has been
observed when either drug is administered concomitantly with verapamil. A variable
effect has been seen when verap-amil 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. On discontinuation of Calan use, the patient should
be reassessed to avoid underdigitalization.
Antihypertensive agents: Verapamil administered concomitantly
with oral antihypertensive agents (eg, 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 withhypertrophic
cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in
significant hypotension. Until further data are obtained, combined therapy of
verap-amil 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
quini-dine 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: Increased sensitivity to the effects of lithium
(neurotoxicity) has been reported during concomitant verapamil-lithium therapy;
lithium levels have been observed sometimes to increase, sometimes to decrease,
and sometimes to be unchanged. Patients receiving both drugs must be monitored
carefully.
Carbamazepine: Verapamil therapy may increase carbamazepine
concentrations during combined therapy. This may produce carbam-azepine 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 the-ophylline.
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 tumor-igenic
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/day or approximately
1, 3.5, and 12 times, respectively, the maximum recommended human daily dose
(480 mg/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 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 verap-amil,
nursing should be discontinued while verapamil is administered.
Pediatric use: Safety and effectiveness in pediatric
patients have not been established.
Animal pharmacology and/or animal toxicology: In chronic
animal toxicology studies verap-amil 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 in the rat. Development of cataracts due to verapamil
has not been reported in man.
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