Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/447
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Verapamil Hydrochloride (Injection, Solution)
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FOR INTRAVENOUS USE
ONLY. VERAPAMIL HYDROCHLORIDE INJECTION SHOULD BE GIVEN AS A SLOW INTRAVENOUS
INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME UNDER CONTINUOUS ELECTROCARDIOGRAPHIC
(ECG) AND BLOOD PRESSURE MONITORING. The recommended intravenous
doses of verapamil hydrochloride injection are as follows: Adult: Initial
dose���5 to 10 mg (0.075 to 0.15 mg/kg body weight) given
as an intravenous bolus over at least 2 minutes. Repeat dose���10 mg (0.15 mg/kg
body weight) 30 minutes after the first dose if the initial response is not
adequate. An optimal interval for subsequent I.V. doses has not been determined,
and should be individualized for each patient. Older patients���The dose should
be administered over at least 3 minutes to minimize the risk of untoward drug
effects. Pediatric: Initial dose: 0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual
single dose range: 0.75 to 2 mg) should be administered as an intravenous
bolus over at least 2 minutes under continuous ECG
monitoring. 1 to
15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range:
2 to 5 mg) should be administered as an intravenous bolus over at least 2
minutes. Do not exceed 5 mg. Repeat dose: 0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual
single dose range: 0.75 to 2 mg) 30 minutes after the first dose if the initial
response is not adequate (under continuous ECG monitoring). An optimal interval for subsequent I.V. doses has not been determined,
and should be individualized for each patient. 1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual
single dose range: 2 to 5 mg) 30 minutes after the first dose if the initial
response is not adequate. Do not exceed 10 mg as
a single dose. An optimal interval for subsequent I.V. doses has
not been determined, and should be individualized for each patient. Note: Parenteral drug products should be inspected
visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. Use only if solution is clear and
vial seal is intact. Unused amount of solution should be discarded immediately
following withdrawal of any portion of contents. For
stability reasons this product is not recommended for dilution with Sodium
Lactate Injection, USP in polyvinyl chloride bags. Verapamil is physically
compatible and chemically stable for at least 24 hours at 25��C protected
from light in most common large volume parenteral solutions. Admixing verapamil
hydrochloride injection with albumin, amphotericin B, hydralazine hydrochloride
and trimethoprim with sulfamethoxazole should be avoided. Verapamil hydrochloride
injection will precipitate in any solution with a pH above 6.0.
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Verapamil hydrochloride is a calcium antagonist or slow-channel
inhibitor. Verapamil Hydrochloride Injection, USP is a sterile, nonpyrogenic
solution containing verapamil hydrochloride 2.5 mg/mL and sodium chloride
8.5 mg/mL in water for injection. The solution contains no bacteriostat or
antimicrobial agent and is intended for single-dose intravenous administration.
May contain hydrochloric acid for pH adjustment; pH is 4.9 (4.0 to 6.5). The
chemical name of Verapamil Hydrochloride, USP is benzeneacetonitrile,��-[3-[{2-(3,4-dimethoxyphenyl)ethyl}
methylamino] propyl]-3,4-dimethoxy-��-(1-methylethyl) hydrochloride.
Verapamil hydrochloride is a white or practically white crystalline powder.
It is practically odorless and has a bitter taste. It is soluble in water;
freely soluble in chloroform; sparingly soluble in alcohol; practically insoluble
in ether. It has the following structural formula: Molecular
weight: 491.07 Molecular formula: CHNO���HCl Verapamil hydrochloride is not chemically related
to other antiarrhythmic drugs. The plastic syringe is
molded from a specially formulated polypropylene. Water permeates from inside
the container at an extremely slow rate which will have an insignificant effect
on solution concentration over the expected shelf life. Solutions in contact
with the plastic container may leach out certain chemical components from
the plastic in very small amounts; however, biological testing was supportive
of the safety of the syringe material.
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Mechanism of Action: Verapamil
inhibits the calcium ion (and possibly sodium ion) influx through slow channels
into conductile and contractile myocardial cells and vascular smooth muscle
cells. The antiarrhythmic effect of verapamil appears to be due to its effect
on the slow channel in cells of the cardiac conduction system. The vasodilatory
effect of verapamil appears to be due to its effect on blockade of calcium
channels as well as��receptors. In the isolated
rabbit heart, concentrations of verapamil that markedly affect SA nodal fibers
or fibers in the upper and middle regions of the AV node have very little
effect on fibers in the lower AV node (NH region) and no effect on atrial
action potentials or His bundle fibers. Electrical activity
in the SA and AV nodes depends, to a large degree, upon calcium influx through
the slow channel. By inhibiting this influx, verapamil slows AV conduction
and prolongs the effective refractory period within the AV node in a rate-related
manner. This effect results in a reduction of the ventricular rate in patients
with atrial flutter and/or atrial fibrillation and a rapid ventricular response. By
interrupting reentry at the AV node, verapamil can restore normal sinus rhythm
in patients with paroxysmal supraventricular tachycardias (PSVT), including
PSVT associated with Wolff-Parkinson-White syndrome. Verapamil
does not induce peripheral arterial spasm. Verapamil
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. Verapamil does not alter total serum calcium
levels. Hemodynamics: Verapamil
reduces afterload and myocardial contractility. The commonly used intravenous
doses of 5 to 10 mg verapamil hydrochloride produce transient, usually asymptomatic,
reduction in normal systemic arterial pressure, systemic vascular resistance
and contractility; left ventricular filling pressure is slightly increased.
In most patients, including those with organic cardiac disease, the negative
inotropic action of verapamil is countered by reduction of afterload, and
cardiac index is usually not reduced. However, in patients with moderately
severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm
Hg, ejection fraction less than 30%), acute worsening of heart failure may
be seen. Peak therapeutic effects occur within 3 to 5 minutes after a bolusinjection. Pharmacokinetics: Intravenously administered verapamil hydrochloride has been shown
to be rapidly metabolized. Following intravenous infusion in man, verapamil
is eliminated bi-exponentially, with a rapid early distribution phase (half-life
about 4 minutes) and a slower terminal elimination phase (half-life 2 to 5
hours). In healthy men, orally administered verapamil hydrochloride undergoes
extensive metabolism in the liver, with 12 metabolites having been identified,
mostin only trace amounts. The major metabolites have been identified as
various N- and O-dealkylated products of verapamil. Approximately 70% of an
administered dose is excreted in the urine and 16% more in the feces within
5 days. About 3% to 4% is excreted as unchanged drug. Aging
may affect the pharmacokinetics of verapamil given to hypertensive patients.
Elimination half-life may be prolonged in the elderly.
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Verapamil hydrochloride injection is contraindicated in: 1.
Severe hypotension or cardiogenic shock. 2. Second-
or third-degree AV block (except in patients with a functioning artificial
ventricular pacemaker). 3. Sick sinus syndrome (except
in patients with a functioning artificial ventricular pacemaker). 4.
Severe congestive heart failure (unless secondary to a supraventricular tachycardia
amenable to verapamil therapy). 5. Patients receiving intravenous beta-adrenergic blocking drugs (e.g.,
propranolol). Intravenous verapamil and intravenous beta-adrenergic blocking drugs should
not be administered in close proximity to each other (within a few hours),
since both may have a depressant effect on myocardial contractility and AV
conduction. 6. Patients with atrial flutter
or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White,
Lown-Ganong-Levine syndromes) are at risk to develop ventricular tachyarrhythmia
including ventricular fibrillation if verapamil is administered. Therefore,
the use of verapamil in these patients is contraindicated. 7.
Ventricular tachycardia: Administration of intravenous verapamil to patients
with wide-complex ventricular tachycardia (QRS���0.12 sec) can result
in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy
diagnosis and differentiation from wide-complex supraventricular tachycardia
is imperative in the emergency room setting. 8. Known
hypersensitivity to verapamil hydrochloride.
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Verapamil Hydrochloride Injection, USP 2.5 mg/mL is supplied
in single-dose containers as follows: Store at 20 to 25��C (68 to 77��F). [See USP Controlled
Room Temperature.] Protect from light by retaining in
package until ready to use. HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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Drug Interactions:: (See WARNINGS: Concomitant Antiarrhythmic Therapy.) Verapamil
hydrochloride injection has been used concomitantly with other cardioactive
drugs (especially digitalis) without evidence of serious negative drug interactions.
In rare instances, including when patients with severe cardiomyopathy, congestive
heart failure, or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly
with intravenous verapamil, serious adverse
effects have occurred. Concomitant use ofverapamil hydrochloride with��-adrenergic
blockers may result in an exaggerated hypotensive response. Such an effect
was observed in one study, following the concomitant administration of verapamil
and prazosin. It may be necessary to decrease the dose of verapamil and/or
dose of the neuromuscular blocking agent when the drugs are used concomitantly.
As verapamil is highly bound to plasma proteins, it should be administered
with caution to patients receiving other highly protein-bound drugs. Other Cimetidine: The interaction between cimetidine and chronically administered
verapamil has not been studied. 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. The
addition of verapamil, however, 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. 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 depolarizing and nondepolarizing neuromuscular
blocking agents. 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. Dantrolene: Two animal studies suggest concomitant
intravenous use of verapamil and dantrolene sodium may result in cardiovascular
collapse. There has been one report of hyperkalemia and myocardial depression
following the coadministration of oral verapamil and intravenous dantrolene.<br/>Pregnancy:: Teratogenic Effects:Pregnancy Category C. Reproduction studies have
been performed in rabbits and rats at oral verapamil 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, 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,
however, 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.<br/>Labor and Delivery:: There have been few controlled studies to determine 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 hydrochloride injection in Europe in the treatment of
cardiac side effects of beta-adrenergic agonist agents used to treat premature
labor.<br/>Nursing Mothers:: Verapamil crosses the placental barrier and can be detected
in umbilical vein blood at delivery. Also, 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.<br/>Pediatric Use:: Controlled studies with verapamil have not been conducted
in pediatric patients, but uncontrolled experience with intravenous administration
in more than 250 patients, about half under 12 months of age and about 25%
newborn, indicates that results of treatment are similar to those in adults. In rare instances, however, severe hemodynamic side effects���some of them fatal���have occurred following the intravenous
administration of verapamil to neonates and infants. Caution should therefore
be used when administering verapamil to this group of pediatric patients. The most commonly used single doses in patients up to 12 months
of age have ranged from 0.1 to 0.2 mg/kg of body weight, while in patients
aged 1 to 15 years, the most commonly used single doses ranged from 0.1 to
0.3 mg/kg of body weight. Most of the patients received the lower dose of
0.1 mg/kg once, but in some cases, the dose was repeated once or twice every
10 to 30 minutes.
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Treatment of overdosage should be supportive and individualized.
Beta-adrenergic stimulation and/or parenteral administration of calcium injections
may increase calcium ion flux across the slow channel, and have been effectively
used in treatment of deliberate overdosage with oral verapamil hydrochloride.
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 isoproterenol hydrochloride, other
vasopressor agents, or cardiopulmonary resuscitation (see ADVERSE REACTIONS:
Suggested Treatment of Acute Cardiovascular Adverse Reactions).
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Verapamil Hydrochloride
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Verapamil Hydrochloride (Injection, Solution)
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The following reactions were reported with verapamil hydrochloride
injection used in controlled U.S. clinical trials involving 324 patients: Cardiovascular: Symptomatic hypotension (1.5%);
bradycardia (1.2%); severe tachycardia (1.0%). The worldwide experience in
open clinical trials in more than 7,900 patients was similar. Central Nervous System Effects: Dizziness (1.2%);
headache (1.2%). Occasional cases of seizures during verapamil injection have
been reported. Gastrointestinal: Nausea (0.9%); abdominal discomfort (0.6%). In
rare cases of hypersensitive patients, broncho/laryngeal spasm accompanied
by itch and urticaria has been reported. The following
reactions have been reported at low frequency: emotional depression, rotary
nystagmus, sleepiness, vertigo, muscle fatigue, diaphoresis, and respiratory
failure. *Actual treatment and dosage should depend on the severity
of the clinical situation and the judgment and experience of the treating
physician.
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VERAPAMIL HYDROCHLORIDE SHOULD
BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD
OF TIME (see DOSAGE AND ADMINISTRATION). Hypotension: Verapamil hydrochloride injection
often produces a decrease in blood pressure below baseline levels that is
usually transient and asymptomatic but may result in dizziness. Systolic pressure
less than 90 mm Hg and/or diastolic pressure less than 60 mm Hg was seen in
5% to 10% of patients in controlled U.S. trials in supraventricular tachycardia
and in about 10% of the patients with atrial flutter/fibrillation. The incidence
of symptomatic hypotension observed in studies conducted in the U.S. was approximately
1.5%. Three of the five symptomatic patients required intravenous pharmacologic
treatment (norepinephrine bitartrate, metaraminol bitartrate, or 10% calcium
gluconate). All recovered without sequelae. Extreme Bradycardia/Asystole: Verapamil hydrochloride
affects the AV and SA nodes and rarely may produce second- or third-degree
AV block, bradycardia, and, in extreme cases, asystole. This is more likely
to occur in patients with a sick sinus syndrome (SA nodal disease), which
is more common in older patients. Bradycardia associated with sick sinus syndrome
was reported in 0.3% of the patients treated in controlled double-blind trials
in the U.S. The total incidence of bradycardia (ventricular rate less than
60 beats/min) was 1.2% in these studies. Asystole in patients other than those
with sick sinus syndrome is usually of short duration (few seconds or less),
with spontaneous return toAV nodal or normal sinus rhythm. If this does not
occur promptly, appropriate treatment should be initiated immediately. (See
ADVERSE REACTIONS and Suggested Treatment of Acute Cardiovascular Adverse
Reactions.) Heart Failure: When heart failure is not severe or rate related, it should be
controlled with digitalis glycosides and diuretics, as appropriate, before
verapamil is used. In patients with moderately severe to severe cardiac dysfunction
(pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%),
acute worsening of heart failure may be seen. Concomitant Antiarrhythmic Therapy: Digitalis: Verapamil hydrochloride injection
has been used concomitantly with digitalis preparations without the occurrence
of serious adverse effects. However, since both drugs slow AV conduction,
patients should be monitored for AV block or excessive bradycardia. Procainamide: Verapamil hydrochloride injection
has been administered to a small number of patients receiving oral procainamide
without the occurrence of serious adverse effects. Quinidine: Verapamil hydrochloride injection
has been administered to a small number of patients receiving oral quinidine
without the occurrence of serious adverse effects. However, three patients
have been described in whom the combination resulted in an exaggerated hypotensive
response presumably from the combined ability of both drugs to antagonize
the effects of catecholamines on��-adrenergic receptors. Caution should
therefore be used when employing this combination of drugs. Beta-Adrenergic Blocking Drugs: Verapamil hydrochloride
injection has been administered to patients receiving oral beta-blockers without
the development of serious adverse effects. However, since both drugs may
depress myocardial contractility and AV conduction, the possibility of detrimental
interactions should be considered. The concomitant administration of intravenous beta-blockers and intravenous verapamil has resulted in serious adverse reactions (see CONTRAINDICATIONS),
especially in patients with severe cardiomyopathy, congestive heart failure,
or recent myocardial infarction. Disopyramide: Until data on possible interactions between verapamil and all
forms of disopyramide phosphate 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 reducing myocardial contractility, prolonging AV conduction, and prolonging
repolarization. Heart Block: Verapamil prolongs AV conduction time. While high-degree AV block
has not been observed in controlled clinical trials in the United States,
a low percentage (less than 0.5%) has been reported in the world literature.
Development of second- or third-degree AV block or unifascicular, bifascicular,
or trifascicular bundle branch block requires reduction in subsequent doses
or discontinuation of verapamil and institution of appropriate therapy, if
needed. (See ADVERSE REACTIONS, Suggested Treatment of Acute Cardiovascular
Adverse Reactions.) Hepatic
and Renal Failure: Significant hepatic and renal failure should
not increase the effects of a single intravenous dose of verapamil hydrochloride
but may prolong its duration. Repeated injections of verapamil hydrochloride
injection in such patients may lead to accumulation and an excessive pharmacologic
effect of the drug. There is no experience to guide use of multiple doses
in such patients, and this generally should be avoided. If repeated injections
are essential, blood pressure and PR interval should be closely monitored
and smaller repeat doses should be utilized. Verapamil cannot be removed by
hemodialysis. Premature
Ventricular Contractions: During conversion to normal sinus rhythm,
or marked reduction in ventricular rate, a few benign complexes of unusual
appearance (sometimes resembling premature ventricular contractions) may be
seen after treatment with verapamil hydrochloride. Similar complexes are seen
during spontaneous conversion of supraventricular tachycardias, after D.C.-cardioversion
and other pharmacologic therapy. These complexes appear to have no clinical
significance. Duchenne's
Muscular Dystrophy: Verapamil hydrochloride injection can precipitate
respiratory muscle failure in these patients and should, therefore, be used
with caution. Increased
Intracranial Pressure: Verapamil hydrochloride injection has been
seen to increase intracranial pressure in patients with supratentorial tumors
at the time of anesthesia induction. Caution should be taken and appropriate
monitoring performed.
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Verapamil Hydrochloride Injection, USP is indicated for the
following: ���Rapid conversion to sinus rhythm
of paroxysmal supraventricular tachycardias, including those associated with
accessory bypass tracts (Wolff-Parkinson-White [W-P-W] and Lown-Ganong- Levine
[L-G-L] syndromes). When clinically advisable, appropriate vagal maneuvers
(e.g., Valsalva maneuver) should be attempted prior to verapamil hydrochloride
administration. ���Temporary control of rapid
ventricular rate in atrial flutter or atrial fibrillation except when the
atrial flutter and/or atrial fibrillation are associated with accessory bypass
tracts (Wolff-Parkinson-White (W-P-W) and Lown-Ganong-Levine (L-G-L) syndromes). In
controlled studies in the United States, about 60% of patients with supraventricular
tachycardia converted to normal sinus rhythm within 10 minutes after intravenous
verapamil hydrochloride. Uncontrolled studies reported in the world literature
describe a conversion rate of about 80%. About 70% of patients with atrial
flutter and/or fibrillation with a faster ventricular rate respond with a
decrease in ventricular rate of at least 20%. Conversion of atrial flutter
orfibrillation to sinus rhythm is uncommon (about 10%) after verapamil hydrochloride
and may reflect the spontaneous conversion rate, since the conversion rate
after placebo was similar. Slowing of the ventricular rate in patients with
atrial fibrillation/flutter lasts 30 to 60 minutes after a single injection. Because a small fraction (<1%) of patients treated with
verapamil hydrochloride respond with life-threatening adverse responses (rapid
ventricular rate in atrial flutter/fibrillation, and an accessory bypass tract,
marked hypotension, or extreme bradycardia/asystole���see CONTRAINDICATIONS
and WARNINGS), the initial use of verapamil hydrochloride injection should,
if possible, be in a treatment setting with monitoring and resuscitation facilities,
including D.C.-cardioversion capability (see ADVERSE REACTIONS, Suggested
Treatment of Acute Cardiovascular Adverse Reactions). As familiarity with
the patient's response is gained, use in an office setting may be acceptable. Cardioversion has been used safely and effectively
after verapamil hydrochloride injection.
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Verapamil Hydrochloride
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