disopyramide 250 MG Extended Release Oral Tablet

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION 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

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 disopyramide phosphate and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of disopyramide phosphate as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias. Negative Inotropic Properties Heart Failure/Hypotension Disopyramide phosphate 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 phosphate 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 phosphate, but careful attention must be given to the maintenance of cardiac function, including optimal digitalization. If hypotension occurs or congestive heart failure worsens, disopyramide phosphate 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 phosphate administration; in such cases, disopyramide phosphate 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 disopyramide phosphate. Hypoglycemia In rare instances significant lowering of blood-glucose values has been reported during disopyramide phosphate 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 phosphate 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 antiarrhythmic drug must be carefully monitored. Heart Block If first-degree heart block develops in a patient receiving disopyramide phosphate, the dosage should be reduced. If the block persists despite reduction of dosage, continuation of the drug must depend upon weighing the benefit being obtained against the risk of higher degrees of heart block. Development of second- or third-degree AV block or unifascicular, bifascicular, or trifascicular block requires discontinuation of disopyramide phosphate therapy, unless the ventricular rate is adequately controlled by a temporary or implanted ventricular pacemaker. Anticholinergic Activity Because of its anticholinergic activity, disopyramide phosphate should not be used in patients with glaucoma, myasthenia gravis, or urinary retention unless adequate overriding measures are taken; these consist of the topical application of potent miotics (e.g., pilocarpine) for patients with glaucoma, and catheter drainage or operative relief for patients with urinary retention. Urinary retention may occur in patients of either sex as a consequence of disopyramide phosphate administration, but males with benign prostatic hypertrophy are at particular risk. In patients with a family history of glaucoma, intraocular pressure should be measured before initiating disopyramide phosphate therapy. Disopyramide phosphate should be used with special care in patients with myasthenia gravis since its anticholinergic properties could precipitate a myasthenic crisis in such patients.

CONTRAINDICATIONS Disopyramide phosphate capsules 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.

CLINICAL PHARMACOLOGY Mechanisms of Action Disopyramide phosphate is a Type 1 antiarrhythmic drug (i.e., similar to procainamide and quinidine). In animal studies, disopyramide phosphate 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, disopyramide phosphate 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, disopyramide phosphate rarely produces significant alterations of blood pressure in patients without congestive heart failure (see WARNINGS ). With intravenous disopyramide phosphate, either increases in systolic/diastolic or decreases in systolic blood pressure have been reported, depending on the infusion rate and the patient population. Intravenous disopyramide phosphate 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 disopyramide phosphate is approximately 0.06% that of atropine; however, the usual dose for disopyramide phosphate is 150 mg every 6 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 disopyramide phosphate, 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. 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.