Disopyramide Drug Information

Disopyramide phosphate is 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 disopyramide phosphate, its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.

Initiation of disopyramide phosphate treatment, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital. Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.

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 phosphate 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 phosphate 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 REACTIONS, contact Teva at 1-888-838-2872 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 phosphate, 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 phosphate.

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 phosphate was coadministered with either propranolol or diazepam. Concomitant administration of disopyramide phosphate and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels. disopyramide phosphate 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 P450 3A4 could result in potentially fatal interaction.

Pregnancy Teratogenic Effects Disopyramide phosphate 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.

Disopyramide phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Disopyramide phosphate has been reported to stimulate contractions of the pregnant uterus. Disopyramide has been found in human fetal blood.

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

Disopyramide phosphate is 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.

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 LD 50 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.