Professional Information — Norpace Cr

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.

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). 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 (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 (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.

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 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 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.

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

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.

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.

Drug Interactions

Effects of other drugs on disopyramide pharmacokinetics: 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.

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 life-saving. 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.

Description

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%. 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 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.

Clinical Pharmacology

Mechanisms of Action

Norpace (disopyramide phosphate) is a Type 1 antiarrhythmic drug (i.e., 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 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 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.

Drug Interactions

Effects of other drugs on disopyramide pharmacokinetics: 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.

How Supplied / Storage and Handling

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.]