Disopyramide Phosphate 100 mg Capsule, 100-count — NDC 51862-095-01 (Billing 51862-0095-01)

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 nonfatal 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%).

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 disopyramide and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of disopyramide as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.

Negative Inotropic Properties Heart Failure/Hypotension Disopyramide 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. Disopyramide 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 disopyramide, but careful attention must be given to the maintenance of cardiac function, including optimal digitalization. If hypotension occurs or congestive heart failure worsens, disopyramide 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 disopyramide administration; in such cases disopyramide 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 disopyramide. Hypoglycemia In rare instances significant lowering of blood-glucose values has been reported during disopyramide 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 disopyramide 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 anti… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS The adverse reactions which were reported in disopyramide phosphate 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 disopyramide 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 disopyramide therapy, with prompt return to normal mental status when therapy was stopped.

The physician should be aware of these possible reactions and should discontinue disopyramide phosphate therapy promptly if they occur. To report SUSPECTED ADVERSE EVENTS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Drug Interactions If phenytoin or other hepatic enzyme inducers are taken concurrently with disopyramide, 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 disopyramide.

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 disopyramide was coadministered with either propranolol or diazepam. Concomitant administration of disopyramide and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels.

Disopyramide 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 CYP3A4 (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 co-administration of disopyramide with inhibitors of CYP3A4 could result in potentially fatal interaction.

PRECAUTIONS General Atrial Tachyarrhythmias Patients with atrial flutter or fibrillation should be digitalized prior to disopyramide 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 disopyramide 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 disopyramide 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 disopyramide phosphate 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 ). 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 disopyramide.

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 disopyramide therapy. Drug Interactions If phenytoin or other hepatic enzyme inducers are taken concurrently with disopyramide, 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 disopyramide. 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 disopyramide was coadministered with either propranolol or diazepam. Concomitant administration of disopyramide and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels. Disopyramide 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 CYP3A4 (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 co-administration of disopyramide with inhibitors of CYP3A4 could result in potentially fatal interaction.

Carcinogenesis, Mutagenesis, Impairment of Fertility Eighteen months of disopyramide phosphate 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. Disopyramide, at doses up to 250 mg/kg/day, did not adversely af… [Excerpted — this section continues on DailyMed.]