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. IMMEDIATE-RELEASE NORPACE DOSAGE INTERVAL FOR PATIENTS WITH RENAL INSUFFICIENCY Creatinine Clearance (ml/min) 40–30 30–15 Less than 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 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 p…

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 (e.g., 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 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 (e.g., 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 decom…

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.

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

Pregnancy Teratogenic Effects 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.

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.

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.