DISOPYRAMIDE PHOS
DESCRIPTION:
* Considering the known proarrhythmic *
* properties of Norpace or Norpace CR and the *
* lack of evidence of improved survival for *
* any antiarrhythmic drug in patients without *
* life-threatening arrhythmias, the use of *
* Norpace or Norpace CR as well as other *
* antiarrhythmic agents should be reserved *
* for patients with life-threatening *
* ventricular arrhythmias. *
* *
*************************************************
Norpace (disopyramide phosphate) is an antiarrhythmic drug available for oral
administration in immediate-release and controlled-release capsules containing
100 mg or 150 mg of disopyramide base, present as the phosphate. The base
content of the phosphate salt is 77.6%.
alpha-(2-(diisopropylamino) ethyl)-alpha-phenyl- 2-pyridine-
acetamide phosphate
Norpace is freely soluble in water, and the free base (pKa 10.4) has an aqueous
solubility of 1 mg/ml. The chloroform:water partition coefficient of the base is
3.1 at pH 7.2.
Norpace is a racemic mixture of D- and L-isomers. This drug is not chemically
related to other antiarrhythmic drugs.
Norpace CR (controlled-release) capsules are designed to afford a gradual and
consistent release of disopyramide. Thus, for maintenance therapy, Norpace CR
provides the benefit of less- frequent dosing (every 12 hours) as compared with
the every-6-hour dosage schedule of immediate- release Norpace capsules.
Inactive ingredients of Norpace include corn starch, edible ink, FD&C Red No. 3,
FD&C Yellow No. 6, gelatin, lactose, talc, and titanium dioxide; the 150-mg
capsule also contains FD&C Blue No. 1.
Inactive ingredients of Norpace CR include corn starch, D&C Yellow No. 10,
edible ink, ethylcellulose, FD&C Blue No. 1, gelatin, shellac, sucrose, talc,
and titanium dioxide; the 150-mg capsule also contains FD&C Red No. 3 and FD&C
Yellow No. 6.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISMS OF ACTION
Norpace (disopyramide phosphate) is a Type 1 antiarrhythmic drug (ie, similar to
procainamide and quinidine). In Animal Studies Norpace decreases the rate of
diastolic depolarization (phase 4) in cells with augmented automaticity,
decreases the upstroke velocity (phase 0) and increases the action potential
duration of normal cardiac cells, decreases the disparity in refractoriness
between infarcted and adjacent normally perfused myocardium, and has no effect
on alpha- or beta-adrenergic receptors.
ELECTROPHYSIOLOGY
In man, Norpace at therapeutic plasma levels shortens the sinus node recovery
time, lengthens the effective refractory period of the atrium, and has a minimal
effect on the effective refractory period of the AV node. Little effect has been
shown on AV-nodal and His-Purkinje conduction times or QRS duration. However,
prolongation of conduction in accessory pathways occurs.
HEMODYNAMICS
At recommended oral doses, Norpace rarely produces significant alterations of
blood pressure in patients without congestive heart failure (see Warnings). With
intravenous Norpace, either increases in systolic/diastolic or decreases in
systolic blood pressure have been reported, depending on the infusion rate and
the patient population. Intravenous Norpace may cause cardiac depression with an
approximate mean 10% reduction of cardiac output, which is more pronounced in
patients with cardiac dysfunction.
ANTICHOLINERGIC ACTIVITY
The In Vitro anticholinergic activity of Norpace is approximately 0.06% that of
atropine; however, the usual dose for Norpace is 150 mg every 6 hours and for
Norpace CR 300 mg every 12 hours, compared to 0.4 to 0.6 mg for atropine (see
Warnings and Adverse Reactions for anticholinergic side effects).
PHARMACOKINETICS
Following oral administration of immediate- release Norpace, disopyramide
phosphate is rapidly and almost completely absorbed, and peak plasma levels are
usually attained within 2 hours. The usual therapeutic plasma levels of
disopyramide base are 2 to 4 mcg/ml, and at these concentrations protein binding
varies from 50% to 65%. Because of concentration-dependent protein binding, it
is difficult to predict the concentration of the free drug when total drug is
measured.
The mean plasma half-life of disopyramide in healthy humans is 6.7 hours (range
of 4 to 10 hours). In six patients with impaired renal function (creatinine
clearance less than 40 ml/min), disopyramide half-life values were 8 to 18
hours.
After the oral administration of 200 mg of disopyramide to 10 cardiac patients
with borderline to moderate heart failure, the time to peak serum concentration
of 2.3 (+/-) 1.5 hours (mean (+/-) SD) was increased, and the mean peak serum
concentration of 4.8 (+/-) 1.6 mcg/ml was higher than in healthy volunteers.
After intravenous administration in these same patients, the mean elimination
half-life was 9.7 (+/-) 4.2 hours (range in healthy volunteers of 4.4 to 7.8
hours). In a second study of the oral administration of disopyramide to 7
patients with heart disease, including left ventricular dysfunction, the mean
plasma half-life was slightly prolonged to 7.8 (+/-) 1.9 hours (range of 5 to
9.5 hours).
In healthy men, about 50% of a given dose of disopyramide is excreted in the
urine as the unchanged drug, about 20% as the mono-N- dealkylated metabolite,
and 10% as the other metabolites. The plasma concentration of the major
metabolite is approximately one tenth that of disopyramide. Altering the urinary
pH in man does not affect the plasma half-life of disopyramide.
In a crossover study in healthy subjects, the bioavailability of disopyramide
from Norpace CR capsules was similar to that from the immediate- release
capsules. With a single 300-mg oral dose, peak disopyramide plasma
concentrations of 3.23 (+/-) 0.75 mcg/ml (mean (+/-) SD) at 2.5 (+/-) 2.3 hours
were obtained with two 150-mg immediate-release capsules and 2.22 (+/-) 0.47
mcg/ml at 4.9 (+/-) 1.4 hours with two 150-mg Norpace CR capsules. The
elimination half-life of disopyramide was 8.31 (+/-) 1.83 hours with the
immediate-release capsules and 11.65 (+/-) 4.72 hours with Norpace CR capsules.
The amount of disopyramide and mono-N-dealkylated metabolite excreted in the
urine in 48 hours was 128 and 48 mg, respectively, with the immediate-release
capsules, and 112 and 33 mg, respectively, with Norpace CR capsules. The
differences in the urinary excretion of either constituent were not
statistically significant.
Following multiple doses, steady-state plasma levels of between 2 and 4 mcg/ml
were attained following either 150 mg every-6-hour dosing with immediate-release
capsules or 300 mg every- 12-hour dosing with Norpace CR capsules.
INDICATIONS AND USAGE:
Norpace and Norpace CR are indicated for the treatment of documented ventricular
arrhythmias, such as sustained ventricular tachycardia, that, in the judgment of
the physician, are life- threatening. Because of the proarrhythmic effects of
Norpace and Norpace CR, their use with lesser arrhythmias is generally not
recommended. Treatment of patients with asymptomatic ventricular premature
contractions should be avoided.
Initiation of Norpace or Norpace CR treatment, as with other antiarrhythmic
agents used to treat life-threatening arrhythmias, should be carried out in the
hospital. Norpace CR should not be used initially if rapid establishment of
disopyramide plasma levels is desired.
Antiarrhythmic drugs have not been shown to enhance survival in patients with
ventricular arrhythmias.
CONTRAINDICATIONS:
Norpace and Norpace CR are contraindicated in the presence of cardiogenic shock,
preexisting second- or third-degree AV block (if no pacemaker is present),
congenital Q-T prolongation, or known hypersensitivity to the drug.
WARNINGS:
--------------------------------------------------------------------------------------------
* *
* MORTALITY: *
* IN THE NATIONAL HEART, LUNG AND BLOOD *
* INSTITUTE'S CARDIAC ARRHYTHMIA SUPPRESSION *
* TRIAL (CAST), A LONG-TERM, MULTI-CENTER, *
* RANDOMIZED, DOUBLE-BLIND STUDY IN PATIENTS *
* WITH ASYMPTOMATIC NON-LIFE-THREATENING *
* VENTRICULAR ARRHYTHMIAS WHO HAD HAD A *
* MYOCARDIAL INFARCTION MORE THAN 6 DAYS BUT *
* LESS THAN 2 YEARS PREVIOUSLY, AN EXCESSIVE *
* MORTALITY OR NON-FATAL CARDIAC ARREST RATE *
* (7.7%) WAS SEEN IN PATIENTS TREATED WITH *
* ENCAINIDE OR FLECAINIDE COMPARED WITH THAT *
* SEEN IN PATIENTS ASSIGNED TO CAREFULLY *
* MATCHED PLACEBO-TREATED GROUPS (3.0%). THE *
* AVERAGE DURATION OF TREATMENT WITH *
* ENCAINIDE OR FLECAINIDE IN THIS STUDY WAS *
* 10 MONTHS. *
* THE APPLICABILITY OF THE CAST RESULTS TO *
* OTHER POPULATIONS (EG, THOSE WITHOUT RECENT *
* MYOCARDIAL INFARCTION) IS UNCERTAIN. *
* CONSIDERING THE KNOWN PROARRHYTHMIC *
* PROPERTIES OF NORPACE OR NORPACE CR AND THE *
* LACK OF EVIDENCE OF IMPROVED SURVIVAL FOR *
* ANY ANTIARRHYTHMIC DRUG IN PATIENTS WITHOUT *
* LIFE-THREATENING ARRHYTHMIAS, THE USE OF *
* NORPACE OR NORPACE CR AS WELL AS OTHER *
* ANTIARRHYTHMIC AGENTS SHOULD BE RESERVED *
* FOR PATIENTS WITH LIFE-THREATENING *
* VENTRICULAR ARRHYTHMIAS. *
* *
---------------------------------------------------------------------------------------------------
NEGATIVE INOTROPIC PROPERTIES:
HEART FAILURE/HYPOTENSION
NORPACE OR NORPACE CR MAY CAUSE OR WORSEN CONGESTIVE HEART FAILURE OR PRODUCE
SEVERE HYPOTENSION AS A CONSEQUENCE OF ITS NEGATIVE INOTROPIC PROPERTIES.
HYPOTENSION HAS BEEN OBSERVED PRIMARILY IN PATIENTS WITH PRIMARY CARDIOMYOPATHY
OR INADEQUATELY COMPENSATED CONGESTIVE HEART FAILURE. NORPACE OR NORPACE CR
SHOULD NOT BE USED IN PATIENTS WITH UNCOMPENSATED OR MARGINALLY COMPENSATED
CONGESTIVE HEART FAILURE OR HYPOTENSION UNLESS THE CONGESTIVE HEART FAILURE OR
HYPOTENSION IS SECONDARY TO CARDIAC ARRHYTHMIA. PATIENTS WITH A HISTORY OF HEART
FAILURE MAY BE TREATED WITH NORPACE OR NORPACE CR, BUT CAREFUL ATTENTION MUST BE
GIVEN TO THE MAINTENANCE OF CARDIAC FUNCTION, INCLUDING OPTIMAL DIGITALIZATION.
IF HYPOTENSION OCCURS OR CONGESTIVE HEART FAILURE WORSENS, NORPACE OR NORPACE CR
SHOULD BE DISCONTINUED AND, IF NECESSARY, RESTARTED AT A LOWER DOSAGE ONLY AFTER
ADEQUATE CARDIAC COMPENSATION HAS BEEN ESTABLISHED.
QRS WIDENING
ALTHOUGH IT IS UNUSUAL, SIGNIFICANT WIDENING (GREATER THAN 25%) OF THE QRS
COMPLEX MAY OCCUR DURING NORPACE OR NORPACE CR ADMINISTRATION; IN SUCH CASES
NORPACE OR NORPACE CR SHOULD BE DISCONTINUED.
Q-T PROLONGATION
AS WITH OTHER TYPE 1 ANTIARRHYTHMIC DRUGS, PROLONGATION OF THE Q-T INTERVAL
(CORRECTED) AND WORSENING OF THE ARRHYTHMIA, INCLUDING VENTRICULAR TACHYCARDIA
AND VENTRICULAR FIBRILLATION, MAY OCCUR. PATIENTS WHO HAVE EVIDENCED
PROLONGATION OF THE Q-T INTERVAL IN RESPONSE TO QUINIDINE MAY BE AT PARTICULAR
RISK. AS WITH OTHER TYPE 1A ANTIARRHYTHMICS, DISOPYRAMIDE PHOSPHATE HAS BEEN
ASSOCIATED WITH TORSADE DE POINTES.
IF A Q-T PROLONGATION OF GREATER THAN 25% IS OBSERVED AND IF ECTOPY CONTINUES,
THE PATIENT SHOULD BE MONITORED CLOSELY, AND CONSIDERATION BE GIVEN TO
DISCONTINUING NORPACE OR NORPACE CR.
HYPOGLYCEMIA
IN RARE INSTANCES SIGNIFICANT LOWERING OF BLOOD GLUCOSE VALUES HAS BEEN REPORTED
DURING NORPACE ADMINISTRATION. The physician should be alert to this
possibility, especially in patients with congestive heart failure, chronic
malnutrition, hepatic, renal, or other diseases, or drugs (eg, beta adrenoceptor
blockers, alcohol) which could compromise preservation of the normal
glucoregulatory mechanisms in the absence of food. In these patients the blood
glucose levels should be carefully followed.
CONCOMITANT ANTIARRHYTHMIC THERAPY
THE CONCOMITANT USE OF NORPACE OR NORPACE CR WITH OTHER TYPE 1A ANTIARRHYTHMIC
AGENTS (SUCH AS QUINIDINE OR PROCAINAMIDE), TYPE 1C ANTIARRHYTHMICS (SUCH AS
ENCAINIDE, FLECAINIDE OR PROPAFENONE), AND/OR PROPRANOLOL SHOULD BE RESERVED FOR
PATIENTS WITH LIFE-THREATENING ARRHYTHMIAS WHO ARE DEMONSTRABLY UNRESPONSIVE TO
SINGLE-AGENT ANTIARRHYTHMIC THERAPY. SUCH USE MAY PRODUCE SERIOUS NEGATIVE
INOTROPIC EFFECTS, OR MAY EXCESSIVELY PROLONG CONDUCTION. This should be
considered particularly in patients with any degree of cardiac decompensation or
those with a prior history thereof. Patients receiving more than one
antiarrhythmic drug must be carefully monitored.
HEART BLOCK
IF FIRST-DEGREE HEART BLOCK DEVELOPS IN A PATIENT RECEIVING NORPACE OR NORPACE
CR, THE DOSAGE SHOULD BE REDUCED. If the block persists despite reduction of
dosage, continuation of the drug must depend upon weighing the benefit being
obtained against the risk of higher degrees of heart block. Development of
second- or third- degree AV block or unifascicular, bifascicular, or
trifascicular block requires discontinuation of Norpace or Norpace CR therapy,
unless the ventricular rate is adequately controlled by a temporary or implanted
ventricular pacemaker.
ANTICHOLINERGIC ACTIVITY
BECAUSE OF ITS ANTICHOLINERGIC ACTIVITY, DISOPYRAMIDE PHOSPHATE SHOULD NOT BE
USED IN PATIENTS WITH GLAUCOMA, MYASTHENIA GRAVIS, OR URINARY RETENTION UNLESS
ADEQUATE OVERRIDING MEASURES ARE TAKEN; these consist of the topical application
of potent miotics (eg, pilocarpine) for patients with glaucoma, and catheter
drainage or operative relief for patients with urinary retention. Urinary
retention may occur in patients of either sex as a consequence of Norpace or
Norpace CR administration, but males with benign prostatic hypertrophy are at
particular risk. In patients with a family history of glaucoma, intraocular
pressure should be measured before initiating Norpace or Norpace CR therapy.
Disopyramide phosphate should be used with special care in patients with
myasthenia gravis since its anticholinergic properties could precipitate a
myasthenic crisis in such patients.
PRECAUTIONS:
GENERAL
ATRIAL TACHYARRHYTHMIAS
Patients with atrial flutter or fibrillation should be digitalized prior to
Norpace or Norpace CR administration to ensure that drug-induced enhancement of
AV conduction does not result in an increase of ventricular rate beyond
physiologically acceptable limits.
CONDUCTION ABNORMALITIES
Care should be taken when prescribing Norpace or Norpace CR for patients with
sick sinus syndrome (bradycardia-tachycardia syndrome), Wolff- Parkinson-White
syndrome (WPW), or bundle branch block. The effect of disopyramide phosphate in
these conditions is uncertain at present.
CARDIOMYOPATHY
Patients with myocarditis or other cardiomyopathy may develop significant
hypotension in response to the usual dosage of disopyramide phosphate, probably
due to cardiodepressant mechanisms. Therefore, a loading dose of Norpace should
not be given to such patients, and initial dosage and subsequent dosage
adjustments should be made under close supervision (see Dosage And
Administration).
RENAL IMPAIRMENT
More than 50% of disopyramide is excreted in the urine unchanged. Therefore
Norpace dosage should be reduced in patients with impaired renal function (see
Dosage And Administration). The electrocardiogram should be carefully monitored
for prolongation of PR interval, evidence of QRS widening, or other signs of
overdosage (see Overdosage).
Norpace CR is not recommended for patients with severe renal insufficiency
(creatinine clearance 40 ml/min or less).
HEPATIC IMPAIRMENT
Hepatic impairment also causes an increase in the plasma half-life of
disopyramide. Dosage should be reduced for patients with such impairment. The
electrocardiogram should be carefully monitored for signs of overdosage (see
Overdosage).
Patients with cardiac dysfunction have a higher potential for hepatic
impairment; this should be considered when administering Norpace or Norpace CR.
POTASSIUM IMBALANCE
Antiarrhythmic drugs may be ineffective in patients with hypokalemia, and their
toxic effects may be enhanced in patients with hyperkalemia. Therefore,
potassium abnormalities should be corrected before starting Norpace or Norpace
CR therapy.
DRUG INTERACTIONS
If phenytoin or other hepatic enzyme inducers are taken concurrently with
Norpace or Norpace CR, lower plasma levels of disopyramide may occur. Monitoring
of disopyramide plasma levels is recommended in such concurrent use to avoid
ineffective therapy. Other antiarrhythmic drugs (eg, quinidine, procainamide,
lidocaine, propranolol) have occasionally been used concurrently with Norpace.
Excessive widening of the QRS complex and/or prolongation of the Q-T interval
may occur in these situations (see Warnings). In healthy subjects, no
significant drug-drug interaction was observed when Norpace was coadministered
with either propranolol or diazepam. Concomitant administration of Norpace and
quinidine resulted in slight increases in plasma disopyramide levels and slight
decreases in plasma quinidine levels. Norpace does not increase serum digoxin
levels.
Patients taking disopyramide phosphate and erythromycin concomitantly may
develop increased serum concentrations of disopyramide resulting in excessive
widening of the QRS complex and/or prolongation of the Q-T interval (see
Warnings). Patients taking disopyramide phosphate and hepatic enzyme inhibitors
concomitantly should be closely monitored.
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.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Eighteen months of Norpace administration to rats, at oral doses up to 400
mg/kg/day (about 30 times the usual daily human dose of 600 mg/day, assuming a
patient weight of at least 50 kg), revealed no evidence of carcinogenic
potential. An evaluation of mutagenic potential by Ames test was negative.
Norpace, at doses up to 250 mg/kg/day, did not adversely affect fertility of
rats.
PREGNANCY
TERATOGENIC EFFECTS: Pregnancy Category C. Norpace was associated with decreased
numbers of implantation sites and decreased growth and survival of pups when
administered to pregnant rats at 250 mg/kg/day (20 or more times the usual daily
human dose of 12 mg/kg, assuming a patient weight of at least 50 kg), a level at
which weight gain and food consumption of dams were also reduced. Increased
resorption rates were reported in rabbits at 60 mg/kg/day (5 or more times the
usual daily human dose). Effects on implantation, pup growth, and survival were
not evaluated in rabbits. There are no adequate and well-controlled studies in
pregnant women. Norpace or Norpace CR should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
NONTERATOGENIC EFFECTS: NORPACE HAS BEEN REPORTED TO STIMULATE CONTRACTIONS OF
THE PREGNANT UTERUS. Disopyramide has been found in human fetal blood.
LABOR AND DELIVERY
It is not known whether the use of Norpace or Norpace CR 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.
NURSING MOTHERS
Studies in rats have shown that the concentration of disopyramide and its
metabolites is between one and three times greater in milk than it is in plasma.
Following oral administration, disopyramide has been detected in human milk at a
concentration not exceeding that in plasma. Because of the potential for serious
adverse reactions in nursing infants from Norpace or Norpace CR, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established (see
Dosage And Administration).
DRUG INTERACTIONS:
If phenytoin or other hepatic enzyme inducers are taken concurrently with
Norpace or Norpace CR, lower plasma levels of disopyramide may occur. Monitoring
of disopyramide plasma levels is recommended in such concurrent use to avoid
ineffective therapy. Other antiarrhythmic drugs (eg, quinidine, procainamide,
lidocaine, propranolol) have occasionally been used concurrently with Norpace.
Excessive widening of the QRS complex and/or prolongation of the Q-T interval
may occur in these situations (see Warnings). In healthy subjects, no
significant drug-drug interaction was observed when Norpace was coadministered
with either propranolol or diazepam. Concomitant administration of Norpace and
quinidine resulted in slight increases in plasma disopyramide levels and slight
decreases in plasma quinidine levels. Norpace does not increase serum digoxin
levels.
Patients taking disopyramide phosphate and erythromycin concomitantly may
develop increased serum concentrations of disopyramide resulting in excessive
widening of the QRS complex and/or prolongation of the Q-T interval (see
Warnings). Patients taking disopyramide phosphate and hepatic enzyme inhibitors
concomitantly should be closely monitored.
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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The adverse reactions which were reported in Norpace clinical trials encompass
observations in 1,500 patients, including 90 patients studied for at least 4
years. The most serious adverse reactions are hypotension and congestive heart
failure. The most common adverse reactions, which are dose dependent, are
associated with the anticholinergic properties of the drug. These may be
transitory, but may be persistent or can be severe. Urinary retention is the
most serious anticholinergic effect.
The following reactions were reported in 10% to 40% of patients:
Anticholinergic: dry mouth (32%), urinary hesitancy (14%), constipation (11%)
The following reactions were reported in 3% to 9% of patients:
Anticholinergic: blurred vision, dry nose/eyes/throat
Genitourinary: urinary retention, urinary frequency and urgency
Gastrointestinal: nausea, pain/bloating/gas
General: dizziness, general fatigue/muscle weakness, headache, malaise,
aches/pains
The following reactions were reported in 1% to 3% of patients:
Genitourinary: impotence
Cardiovascular: hypotension with or without congestive heart failure, increased
congestive heart failure (see Warnings), cardiac conduction disturbances (see
Warnings), edema/weight gain, shortness of breath, syncope, chest pain
Gastrointestinal: anorexia, diarrhea, vomiting
Dermatologic: generalized rash/dermatoses, itching
Central nervous system: nervousness
Other: hypokalemia, elevated cholesterol/triglycerides
The following reactions were reported in less than 1%:
Depression, insomnia, dysuria, numbness/tingling, elevated liver enzymes, AV
block, elevated BUN, elevated creatinine, decreased hemoglobin/hematocrit
Hypoglycemia has been reported in association with Norpace administration (see
Warnings).
Infrequent occurrences of reversible cholestatic jaundice, fever, and
respiratory difficulty have been reported in association with disopyramide
therapy, as have rare instances of thrombocytopenia, reversible agranulocytosis,
and gynecomastia. Some cases of LE (lupus erythematosus) symptoms have been
reported; most cases occurred in patients who had been switched to disopyramide
from procainamide following the development of LE symptoms. Rarely, acute
psychosis has been reported following Norpace therapy, with prompt return to
normal mental status when therapy was stopped. The physician should be aware of
these possible reactions and should discontinue Norpace or Norpace CR therapy
promptly if they occur.
OVERDOSAGE:
SYMPTOMS
Deliberate or accidental overdosage of oral disopyramide may be followed by
apnea, loss of consciousness, cardiac arrhythmias, and loss of spontaneous
respiration. Death has occurred following overdosage.
Toxic plasma levels of disopyramide produce excessive widening of the QRS
complex and Q-T interval, worsening of congestive heart failure, hypotension,
varying kinds and degrees of conduction disturbance, bradycardia, and finally
asystole. Obvious anticholinergic effects are also observed.
The approximate oral LD50 of disopyramide phosphate is 580 and 700 mg/kg for
rats and mice, respectively.
TREATMENT
Experience indicates that prompt and vigorous treatment of overdosage is
necessary, even in the absence of symptoms. Such treatment may be lifesaving. No
specific antidote for disopyramide phosphate has been identified. Treatment
should be symptomatic and may include induction of emesis or gastric lavage,
administration of a cathartic followed by activated charcoal by mouth or stomach
tube, intravenous administration of isoproterenol and dopamine, insertion of an
intra-aortic balloon for counterpulsation, and mechanically assisted
ventilation. Hemodialysis or, preferably, hemoperfusion with charcoal may be
employed to lower serum concentration of the drug.
The electrocardiogram should be monitored, and supportive therapy with cardiac
glycosides and diuretics should be given as required.
If progressive AV block should develop, endocardial pacing should be
implemented. In case of any impaired renal function, measures to increase the
glomerular filtration rate may reduce the toxicity (disopyramide is excreted
primarily by the kidney).
The anticholinergic effects can be reversed with neostigmine at the discretion
of the physician.
Altering the urinary pH in humans does not affect the plasma half-life or the
amount of disopyramide excreted in the urine.
DOSAGE AND ADMINISTRATION:
The dosage of Norpace or Norpace CR must be individualized for each patient on
the basis of response and tolerance. The usual adult dosage of Norpace or
Norpace CR is 400 to 800 mg per day given in divided doses. The recommended
dosage for most adults is 600 mg/day given in divided doses (either 150 mg every
6 hours for immediate- release Norpace or 300 mg every 12 hours for Norpace CR).
For patients whose body weight is less than 110 pounds (50 kg), the recommended
dosage is 400 mg/day given in divided doses (either 100 mg every 6 hours for
immediate- release Norpace or 200 mg every 12 hours for Norpace CR).
FOR PATIENTS WITH CARDIOMYOPATHY OR POSSIBLE CARDIAC DECOMPENSATION, A LOADING
DOSE, AS DISCUSSED BELOW, SHOULD NOT BE GIVEN, AND INITIAL DOSAGE SHOULD BE
LIMITED TO 100 MG OF IMMEDIATE- RELEASE NORPACE EVERY 6 TO 8 HOURS. Subsequent
dosage adjustments should be made gradually, with close monitoring for the
possible development of hypotension and/or congestive heart failure (see
Warnings).
For patients with moderate renal insufficiency (creatinine clearance greater
than 40 ml/min) or hepatic insufficiency, the recommended dosage is 400 mg/day
given in divided doses (either 100 mg every 6 hours for immediate-release
Norpace or 200 mg every 12 hours for Norpace CR).
For patients with severe renal insufficiency (Ccr 40 ml/min or less), the
recommended dosage regimen of immediate-release Norpace is 100 mg at intervals
shown in the table below, with or without an initial loading dose of 150 mg.
IMMEDIATE-RELEASE NORPACE
DOSAGE INTERVAL FOR PATIENTS
WITH RENAL INSUFFICIENCY
----------------------------------------------------------------------
Creatinine less
clearance than
(ml/min) 40-30 30-15 15
-----------------------------------------------------------------------
Approximate
maintenance-
dosing
interval q 8 hr q 12 hr q 24 hr
----------------------------------------------------------------------
The above dosing schedules are for Norpace immediate-release capsules; Norpace
CR is not recommended for patients with severe renal insufficiency.
For patients in whom rapid control of ventricular arrhythmia is essential, an
initial loading dose of 300 mg of immediate-release Norpace (200 mg for patients
whose body weight is less than 110 pounds) is recommended, followed by the
appropriate maintenance dosage. Therapeutic effects are usually attained 30
minutes to 3 hours after administration of a 300-mg loading dose. If there is no
response or evidence of toxicity within 6 hours of the loading dose, 200 mg of
immediate-release Norpace every 6 hours may be prescribed instead of the usual
150 mg. If there is no response to this dosage within 48 hours, either Norpace
should then be discontinued or the physician should consider hospitalizing the
patient for careful monitoring while subsequent immediate-release Norpace doses
of 250mg or 300 mg every 6 hours are given. A limited number of patients with
severe refractory ventricular tachycardia have tolerated daily doses of Norpace
up to 1600 mg per day (400 mg every 6 hours), resulting in disopyramide plasma
levels up to 9 mcg/ml. If such treatment is warranted, it is essential that
patients be hospitalized for close evaluation and continuous monitoring.
Norpace CR should not be used initially if rapid establishment of disopyramide
plasma levels is desired.
TRANSFERRING TO NORPACE OR NORPACE CR
The following dosage schedule based on theoretical considerations rather than
experimental data is suggested for transferring patients with normal renal
function from either quinidine sulfate or procainamide therapy (Type 1
antiarrhythmic agents) to Norpace or Norpace CR therapy:
Norpace or Norpace CR should be started using the regular maintenance schedule
WITHOUT A LOADING DOSE 6 to 12 hours after the last dose of quinidine sulfate or
3 to 6 hours after the last dose of procainamide.
In patients in whom withdrawal of quinidine sulfate or procainamide is likely to
produce life-threatening arrhythmias, the physician should consider
hospitalization of the patient. When transferring a patient from immediate-
release Norpace to Norpace CR, the maintenance schedule of Norpace CR may be
started 6 hours after the last dose of immediate-release Norpace.
PEDIATRIC DOSAGE
Controlled clinical studies have not been conducted in pediatric patients;
however, the following suggested dosage table is based on published clinical
experience.
Total daily dosage should be divided and equal doses administered orally every 6
hours or at intervals according to individual patient needs. Disopyramide plasma
levels and therapeutic response must be monitored closely. Patients should be
hospitalized during the initial treatment period, and dose titration should
start at the lower end of the ranges provided below.
SUGGESTED TOTAL DAILY DOSAGE*
---------------------------------------------------------------------------------
Age Disopyramide
(years) (mg/kg body weight/day)
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Under 1 10 to 30
1 to 4 10 to 20
4 to 12 10 to 15
12 to 18 6 to 15
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* Dosage is expressed in milligrams of
disopyramide base. Since Norpace (disopyramide
phosphate) 100-mg capsules contain 100 mg of
disopyramide base, the pharmacist can readily
prepare a 1-mg/ml to 10-mg/ml liquid suspension
by adding the entire contents of Norpace
capsules to cherry syrup, NF. The resulting
suspension, when refrigerated, is stable for
one month and should be thoroughly shaken
before the measurement of each dose. The
suspension should be dispensed in an amber
glass bottle with a child-resistant closure.
Norpace CR capsules should not be used to
prepare the above suspension.
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