Norpace (disopyramide phosphate) is an anti-arrhythmic 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%. The structural formula of Norpace is:

α-[2-(diisopropylamino) ethyl]-α-phenyl-2-pyridineacetamide phosphate

Norpace is freely soluble in water, and the free base (pKa 10.4) has an aqueous solubility of 1mg/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 anti-arrhythmic drugs.

Norpace CR (controlled-release) capsules are designed to afford a gradual and consistent release of disopyramide. Thus, for maintenance therapy, Nor-pace 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.

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.

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 Nor-pace 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). In the event of increased anticholinergic side effects, plasma levels of disopyramide should be monitored and the dose of the drug adjusted accordingly. A reduction of the dose by one third, from the recommended 600 mg/day to 400 mg/day, would be reasonable, without changing the dosing interval.

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 (cre-atinine clearance greater than 40 ml/min) or hepat-ic 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 (C_cr 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

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 Nor-pace 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 250 mg 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 procaina-mide 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 pro-cainamide.

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. Disopyr-amide 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*

Norpace CR capsules should not be used to prepare the above suspension.

Norpace (disopyramide phosphate) is supplied in hard gelatin capsules containing either 100 mg or 150 mg of disopyramide base, present as the phosphate.

Norpace 100-mg capsules are white and orange, with markings SEARLE, 2752, NORPACE, and 100 MG.

 Norpace 150-mg capsules are brown and orange, with markings SEARLE, 2762, NORPACE, and 150 MG.

Norpace CR (disopyramide phosphate) Controlled-Release is supplied as specially prepared controlled-release beads in hard gelatin capsules containing either 100 mg or 150 mg of disopyramide base, present as the phosphate.

Norpace CR 100-mg capsules are white and light green, with markings SEARLE, 2732, NORPACE CR, and 100 mg.

Norpace CR 150-mg capsules are brown and light green, with markings SEARLE, 2742, NORPACE CR, and 150 mg.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.]

Revised: September 2001. G.D. Searle LLC, A subsidiary of Pharmacia Corporation, Chicago, IL 60680, USA. FDA revision date: 5/17/2000

The adverse reactions which were reported in Nor-pace clinical trials encompass observations in 1,500 patients, including 90 patients studied for at least 4 years. The most serious adverse reactions are hypo-tension 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 procaina-mide 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.

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 inef-fective therapy. Other antiarrhythmic drugs (eg, quinidine, procainamide, lidocaine, propranolol) have occasionally been used concurrently with Nor-pace. 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.

Until data on possible interactions between ve-rapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Although potent inhibitors of cytochrome P450 3A4 (eg, ketoconazole) have not been studied clinically, in vitro studies have shown that erythromycin and oleandomycin inhibit the metabolism of diso-pyramide. Cases of life-threatening interactions have been reported for disopyramide when given with clarithromycin and erythromycin indicating that co-administration of disopyramide with inhibitors of cy-tochrome 3A4 could result in potentially fatal interaction.

Negative Inotropic Properties

Heart Failure/Hypotension

Norpace or Norpace CR may cause or worsen congestive heart failure or produce severe hypoten-sion 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 hypo-tension 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 antiar-rhythmics, 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 adrenocep-tor 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 antiar-rhythmics (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 uni-fascicular, 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, disopyr-amide 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.

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.

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. Nor-pace, 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. Nor-pace 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 Nor-pace 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 drugto the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see DOSAGE AND ADMINISTRATION).

Geriatric Use

Clinical studies of Norpace/Norpace CR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Because of its anticholinergic activity, disopyramide phosphate should not be used in patients with glaucoma, urinary retention, or benign prostatic hypertrophy (medical conditions commonly associated with the elderly) unless adequate overriding measures are taken (see WARNINGS: Anticholinergic Activity). In the event of increased anticholinergic side effects, plasma levels of disopyramide should be monitored and the dose of the drug adjusted accordingly. A reduction of the dose by one third, from the recommended 600 mg/day to 400 mg/day, would be reasonable, without changing the dosing interval.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).

Symptoms

Deliberate or accidental overdosage of oral diso-pyramide 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, hypo-tension, 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, hemoper-fusion 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, endocar-dial 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.

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.

Mechanisms of Action

Norpace (disopyramide phosphate) is a Type 1 anti-arrhythmic drug (ie, similar to procainamide and quinidine). In animal studies Norpace decreases the rate of diastolic depolarization (phase4) 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 (creati-nine clearance less than 40 ml/min), disopyramide half-life values were 8 to 18 hours.

After the oral administration of 200 mg of diso-pyramide 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 diso-pyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metab-olite, 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 bio-availability 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 disopyr-amide 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.

Drug Interactions

Effects of other drugs on disopyramide pharmaco-kinetics: In vitro metabolic studies indicated that disopyramide is metabolized by cytochrome P450 3A4 and that inhibitors of this enzyme may result in elevation of plasma levels of disopyramide. Although specific drug interaction studies have not been done, cases of life-threatening interactions have been reported for disopyramide when given with clarithromycin and erythromycin.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DISOPYRAMIDE - ORAL

(dye-so-PIR-uh-mide)

COMMON BRAND NAME(S): Norpace

WARNING: Although this medication and others like it are used to treat certain kinds of abnormal heartbeats, they may rarely cause serious (sometimes fatal) irregular heartbeats. Therefore, disopyramide should be used carefully only in selected patients. Consult your doctor or pharmacist for more information.

USES: This medication is used to treat serious, possibly life-threatening, abnormally fast heartbeats (e.g., persistent ventricular tachycardia). Disopyramide belongs to a class of drugs known as antidysrhythmics. It works by blocking the abnormal electrical activity of an abnormal heartbeat so that the normal heartbeat can occur.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat certain other types of irregular heartbeat (atrial fibrillation/flutter).

HOW TO USE: This medication may be started at a low dose in the hospital so that your doctor can determine the best dose, increase it gradually as needed, and monitor you closely for side effects.

Take this medication exactly as prescribed by your doctor.

If you are taking the immediate-release form of disopyramide, take it by mouth, usually 4 times daily or as directed by your doctor.

If you are taking the extended-release product, take it with a full glass of water, usually twice a day or as directed by your doctor. Do not cut, crush or chew the extended-release capsules or tablets. Doing so may increase side effects.

Dosage is based on your age, kidney/liver function, medical condition, and response to therapy.

This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, take it at the same times each day.

Do not take more or less of this drug than prescribed or stop taking it (or other heart medicines) even for a short time unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause your abnormal heartbeat to return. Do not run out of this medication. Order your refills several days early to avoid running out of pills.

Contact your doctor immediately and seek emergency medical attention (e.g., call -911, have someone else drive you to a hospital emergency room) if your condition persists or worsens.

SIDE EFFECTS: See also Warning section.

Dry mouth, problems starting the flow of urine, and constipation may occur. Less common side effects may include nausea, abdominal pain/gas/bloating, blurred vision, dry nose/eyes/throat, urge to urinate often, tiredness, muscle weakness, headache, body aches/pain. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: inability to urinate, worsening symptoms of heart failure (e.g., ankle/leg swelling, increased tiredness, increased shortness of breath when lying down), loss of appetite, diarrhea, vomiting.

Seek immediate medical attention if any of these unlikely but serious side effects occur: chest pain, severe dizziness, fainting, sudden change in heartbeat (unusually faster/slower/more irregular).

Tell your doctor immediately if any of these rare but very serious side effects occur: mental/mood changes (e.g., unusual thoughts/behavior, nervousness, depression), shakiness with unusual hunger/headache/sweating, signs of liver problems (e.g., persistent nausea/vomiting, stomach/abdominal pain, yellowing eyes/skin, dark urine, severe tiredness), easy bleeding/bruising, signs of serious infection (e.g., fever, severe chills, persistent sore throat), signs of low red blood cells (e.g., worsening tiredness, pale skin/lips, fast heartbeat while resting), enlargement of male breasts, muscle cramping/weakness, butterfly-shaped facial rash with unusual tiredness and joint/muscle aches, numbness/tingling in hands/feet.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking disopyramide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain heart problems (second- or third-degree atrioventricular block, QT prolongation in the EKG), shock due to the heart not pumping well (e.g., very low blood pressure and loss of consciousness), heart failure with severe symptoms (e.g., swelling of feet/legs, severe tiredness, shortness of breath).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: other heart problems (heart failure, cardiomyopathy, very slow heartbeat), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death), decreased kidney/liver function, diabetes, glaucoma, myasthenia gravis, urine blockage due to prostate enlargement, decreased ability to urinate, certain heart rhythm problems (e.g., atrial fibrillation/flutter, sick sinus syndrome, Wolff-Parkinson-White syndrome, bundle-branch block), low levels of potassium or magnesium in the blood.

Contact your doctor immediately if you develop other illnesses/conditions such as prolonged or large quantities of diarrhea, excessive sweating, vomiting, prolonged loss of appetite or desire to drink water. These conditions could cause you to have serious changes in blood minerals leading to increased side effects from disopyramide.

This drug may rarely make you dizzy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

This drug may decrease your blood sugar levels. If you have diabetes, chronic heart failure, decreased kidney/liver function, or nutrition problems, your blood sugar levels may need to be checked regularly and your diet changed as directed by your doctor. Tell your doctor immediately if you have symptoms of low blood sugar such as shakiness, headache, or unusual sweating/hunger. If you have diabetes, your anti-diabetic medication may need to be adjusted.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially urination problems.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Disopyramide has rarely started early labor during pregnancy.

This medication passes into breast milk and may have undesirable effects on a nursing infant. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not usually be used with the following medications because very serious interactions may occur: drugs that may affect the heart rhythm (QTc prolonging drugs such as dofetilide, ziprasidone, gatifloxacin, moxifloxacin, amiodarone, lidocaine, quinidine, procainamide, encainide, flecainide, sotalol, mexiletine, levomethadyl, halofantrine, droperidol, haloperidol, ranolazine, bepridil, pimozide, ibutilide, propafenone, chlorpromazine, amitriptyline, doxepin, methadone, cisapride, venlafaxine, voriconazole, ketoconazole).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting disopyramide.

Other drugs besides disopyramide and those drugs listed above may affect the heart rhythm (QT prolongation in the EKG). Before using disopyramide, report all medications you are currently using to your doctor or pharmacist. QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical attention. Ask your doctor or pharmacist for more details and for instructions on how you may reduce the risk of this effect.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: etravirine, propranolol, warfarin, vardenafil, telithromycin, tolterodine, tacrolimus, quinupristin/dalfopristin, phenytoin, rifampin, macrolide antibiotics (e.g., erythromycin, clarithromycin), verapamil, certain "water pills" (potassium-wasting diuretics such as hydrochlorothiazide, furosemide).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: fainting, slowed or stopped breathing.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., EKG, disopyramide blood level) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.