DISOPYRAMIDE PHOSPHATE- disopyramide phosphate capsule
Actavis Pharma, Inc.
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:
Disopyramide Phosphate Structural Formula
C21 H29 N3 O•H3 PO4 M.W. 437.47
(±)-α-[2-(Diisopropylamino)ethyl]-α-phenyl-2-pyridineacetamide phosphate (1:1).
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.
Disopyramide phosphate capsules (equivalent to 100 mg Disopyramide Base) and Disopyramide phosphate capsules (equivalent to 150 mg Disopyramide Base) contain the following inactive ingredients: magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The capsule shells contain gelatin, methylparaben, propylparaben, silicon dioxide, sodium lauryl sulfate and titanium dioxide.
The 100 mg capsule shell also contains D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1 and FD&C Red No. 40.
The 150 mg capsule shell also contains black iron oxide and red iron oxide.
Disopyramide phosphate is a Type 1 antiarrhythmic drug (i.e., similar to procainamide and quinidine). In animal studies disopyramide 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.
In man, disopyramide 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.
At recommended oral doses, disopyramide rarely produces significant alterations of blood pressure in patients without congestive heart failure (see WARNINGS). With intravenous disopyramide, 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 may cause cardiac depression with an approximate mean 10% reduction of cardiac output, which is more pronounced in patients with cardiac dysfunction.
The in vitro anticholinergic activity of disopyramide is approximately 0.06% that of atropine; however, the usual dose for disopyramide (as the 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).
Following oral administration of immediate-release 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.
Effects of other drugs on disopyramide pharmacokinetics: In vitro metabolic studies indicated that disopyramide is metabolized by CYP3A4 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.
Disopyramide phosphate capsules 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 disopyramide, its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.
Initiation of disopyramide 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.
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.
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.
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.
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