DISOPYRAMIDE PHOSPHATE

Disopyramide phosphate is an antiarrhythmic drug available for oral administration in immediate-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 disopyramide phosphate is: α-[2-(diisopropylamino) ethyl]-α-phenyl- 2-pyridineacetamide phosphate Disopyramide phosphate 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. Disopyramide phosphate is a racemic mixture of d- and l- isomers. This drug is not chemically related to other antiarrhythmic drugs. Inactive ingredients of disopyramide phosphate 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. Chemical Structure

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 dosage of disopyramide phosphate must be individualized for each patient on the basis of response and tolerance. The usual adult dosage of disopyramide phosphate 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 (150 mg every 6 hours for immediate-release disopyramide phosphate). For patients whose body weight is less than 110 pounds (50 kg), the recommended dosage is 400 mg/day given in divided doses (100 mg every 6 hours for immediate-release disopyramide phosphate). 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 disopyramide phosphate 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 (100 mg every 6 hours for immediate-release disopyramide phosphate). For patients with severe renal insufficiency (C cr 40 ml/min or less), the recommended dosage regimen of immediate-release disopyramide phosphate is 100 mg at intervals shown in the table below, with or without an initial loading dose of 150 mg. IMMEDIATE-RELEASE DISOPYRAMIDE PHOSPHATE 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 For patients in whom rapid control of ventricular arrhythmia is essential, an initial loading dose of 300 mg of immediate-release disopyramide phosphate (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 disopyramide phosphate every 6 hours may be prescribed instead of the usual 150 mg. If there is no response to this dosage within 48 hours, either disopyramide phosphate should then be discontinued or the physician should consider hospitalizing the patient for careful monitoring while subsequent immediate-release disopyramide phosphate 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 disopyramide phosphate 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. Transferring to disopyramide phosphate immediate release 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 disopyramide phosphate therapy: Disopyramide phosphate 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 disopyramide phosphate to Norpace CR, the maintenance schedule of Norpace CR may be started 6 hours after the last dose of immediate-release disopyramide phosphate. 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. SUGGESTED TOTAL DAILY DOSAGE Dosage is expressed in milligrams of disopyramide base. Since disopyramide phosphate 100-mg capsules contain 100 mg of disopyramide base, the pharmacist can readily prepare a 1-mg/ml to 10-mg/ml liquid suspension by adding the entire contents of disopyramide phosphate capsules to cherry syrup. (Prepare cherry syrup as follows: cherry juice, 475 ml; sucrose 800 g; alcohol, 20 ml; purified water, a sufficient quantity to make 1000 ml.) The resulting suspension, when refrigerated, is stable for one month and should be thoroughly shaken before the measurement of each dose. The suspension should be dispensed in an amber glass bottle with a child-resistant closure. Age (years) Disopyramide (mg/kg body weight/day) Under 1 10 to 30 1 to 4 10 to 20 4 to 12 10 to 15 12 to 18 6 to 15

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.

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.

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 3A4 could result in potentially fatal interaction.

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