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
Verelan PM Side Effects, and Drug Interactions - Verapamil
Verelan PM Side Effects, and Drug Interactions - Verapamil
SIDE EFFECTS
Serious adverse reactions are uncommon when verapamil therapy
I initiated with upward dose titration within the recommended single and total
daily dose.
The following reactions to orally administered VERELAN®
PM occurred at rates of 2.0% or greater or occurred at lower rates but appeared
to be drug-related in clinical trials in hypertension.
| |
Placebo N=116%< /p>
|
All Doses Studied N=297%< /p>
|
|
Headache
|
11.2
|
12.1
|
|
Infection
|
6.9
|
12.1*
|
|
Constipation
|
0.9
|
8.8*
|
|
Flu Syndrome
|
2.6
|
3.7
|
|
Peripheral edema
|
0.9
|
3.7
|
|
Dizziness
|
0.9
|
3.0
|
|
Pharyngitis
|
2.6
|
3.0
|
|
Sinusitis
|
2.6
|
3.0
|
|
Dyspepsia
|
1.7
|
2.7
|
|
Rhinitis
|
2.6
|
2.7
|
|
Diarrhea
|
1.7
|
2.4
|
|
Pain
|
1.7
|
2.4
|
|
Rash
|
2.6
|
2.7
|
|
Asthenia
|
3.4
|
2.0
|
|
ECG Abnormal
|
3.4
|
2.0
|
|
Hypertension
|
2.0
|
1.7
|
|
Edema
|
0.0
|
1.7
|
|
Nausea
|
0.0
|
1.7
|
|
Accidential Injury
|
0.0
|
1.5
|
*Infection primarily upper respiratory infection (URI) and
unrelated to study medication. Constipation was typically mild and easily manageable.
At the usual once-daily dose 0f 200 mg, the observed incidence of constipation
was 3.9%
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.
In previous experience with other formulation of verapamil
(N=4,954) the following reactions have 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%
|
|
Dizziness
|
3.3%
|
|
Nausea
|
2.7%
|
|
Hypotension
|
2.5%
|
|
Headache
|
2.2%
|
|
Edema
|
1.9%
|
|
CHF/Polumonary Edema
|
1.8%
|
|
Fatigue
|
1.7%
|
|
Bradycardia (HR<50/min)
|
1.4%
|
|
Rash
|
1.2%
|
|
AV block (total 1°
, 2° , 3° )
|
1.2%
|
|
AV block (2° and 3° )
|
0.8%
|
|
Flushing
|
0.6%
|
Elevated Liver Enzymes (See WARNINGS)
In clinical trials related to the control of ventricular response
in digitalized patients who had atrial fibrillation or atrial flutter, ventricular
rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension
occurred in 5% of patients.
The following reactions, reported with orally administered
verapamil in 2.0% or less of patients, occured 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 oectoris, 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.
Respiratory: dyspnea.
Skin: arthralgia and rash. Exanthema, hair loss, hyperkeratosis,
mascules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.
Special Senses: blurred vision, tinnitus.
Urogenital: gynecomastia, galactorrhea/hyperprolactinemia,
impotence, increased urination. Spotty menstruation.
Other: allergy aggravated.
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;
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, mataraminol bitartrate, or methoxamine HCl) should be used
tyo maintain blood pressure, and isoproterenol and norepinephrine should be
avoided. If further support is necessary, inotropic agents ( dopamine HCl or
dobutamine HCl) may be administered. Actual treatment and dosage should depend
on the severity of the clinical situation and the judgement and experience of
the treating physician.
DRUG INTERACTIONS
Effects of other drugs on verapamil pharmacokinetics: In vitro metabolic studies indicate that verapamil is metabolized by
cytochrome P450 CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of
CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g.,
rifampin) have caused a lowering of plasma levels of verapamil.
Alcohol: Verapamil has been found to significantly inhibit
ethanol elimination resulting in elevated blood ethanol concentrations that
may prolong the intoxicating effects of alcohol.
Antineoplastic agents: Verapamil can increase the efficacy
of doxorubicin both in tissue culture systems and in patients. It raises the
resum doxorubicin levels. The absorption of verapamil can be reduced by the
cyclophosphamide, oncovin, procarbazine, prednisone (COPP) and the vindesine,
adriamycin, cisplatin (VAC) cytotoxic drug regimens. Concomitant administration
of R verapamil of R verapamil can decrease the clearance of paclitaxel.
Aspirin: In a few reported cases, coadministration of verapamil
with aspirin has led to increased bleeding times greater than observed with
aspirin alone.
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 extended-release
verapamil and beta-adrenergic blocking agents has not been studied. However,
there have been reports of excess bradycardia and AV block, including complete
heart block, when the combination has been used for the treatment of hypertension.
For hypertensive patients, the risk of combined therapy may outweight the potential
benefits. The combination should be used only with caution and close monitoring.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial
pacemake 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 verapamil and atenolol were given together.
Digitalis: Clinical use of verapamil in digitalized patients
has shown the combination to be well tolerated if digoxen 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 indigitalis
toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin
kinetics is magnified. Verapamil may reduce total body clearance or 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 digoxin should be reduced or temporarily discontinued. On
discontinuation of verapamil use, the patient should be reassessed to avoid
underdigitalization. In previous clinical trials with other verapamil formulations
related to the control of ventricular response in digitalized patients who had
atrial fibrillation or atrial flutter, ventricular rates below 50/mm at rest
occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of
patients.
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 thses combinations should be appropriately monitored. Concomitant
use of agents that attenuate alpha-adrenergic function with verapamil may result
in 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 befor 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 ropolarization. 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.
Grapefruit juice: Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice
given to nine healthy volunteers increased S- and R- verapamil AUC0-12 by 36% and 28%, respectively.
Steady state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice
compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively.
Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared
to control. Grapefruit juice did not cause a significant difference in the PK of norverapamil. This increase
in verapamil plasma concentration is not expected to have any clinical consequences.
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 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 neuromuscular blocking agent when the drugs are
used concomitantly.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See
PRECAUTIONS
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