Disopyramide Phosphate ER

DISOPYRAMIDE PHOSPHATE ER- disopyramide phosphate capsule, extended release
ETHEX

Rx Only

DESCRIPTION

Disopyramide phosphate is an antiarrhythmic drug available for oral administration in extended-release capsules equivalent to 150 mg of disopyramide present as the phosphate. The base content of the phosphate salt is 77.66%. The structural formula of disopyramide phosphate is:

C₂₁ H₂₉ N₃ O.H₃ PO₄ M.W.437.48

(±)-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 Extended-release Capsules, USP are designed to afford a gradual and consistent release of disopyramide. Thus, for maintenance therapy, Disopyramide Phosphate Extended-release Capsules, USP provide the benefit of less frequent dosing (every 12 hours) as compared with the every-6-hour dosage schedule of immediate-release capsules.

Inactive ingredients: aluminum hydrate, black iron oxide, calcium stearate, D&C Red No. 28, D&C Yellow No. 10, dibutyl sebacate, ethylcellulose, FD&C Blue No. 1, FD&C Red No. 40, gelatin, lecithin, pharmaceutical glaze, povidone, simethicone, starch, sucrose, talc and titanium dioxide.

This product meets USP Drug Release Test 2.

CLINICAL PHARMACOLOGY

Mechanisms of Actions

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.

Electrophysiology

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.

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 and for disopyramide phosphate extended-release 300 mg every 12 hours compared to 0.4 to 0.6 mg for atropine (see WARNINGS and ADVERSEREACTIONS for anticholinergic side effects).

Pharmacokinetics

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 immediate release disopyramide to 10 cardiac patients with borderline to moderate heart failure, the time to peak serum concentration was increased and the mean peak serum concentration 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.

In a single-dose crossover study in 12 healthy subjects, the mean peak serum concentration of disopyramide following a single 150 mg oral dose of KV’s Disopyramide Phosphate Extended-release Capsules, USP was 2.39 (±0.89) mcg/mL, achieved at 5.58 (±1.44) hours. Following multiple doses (300 mg every 12 hours) of KV’s Disopyramide Phosphate Extended-release capsules, USP steady-state plasma levels of between 2 and 4 mcg/mL were attained. Total bioavailability was shown to be similar to an immediate-release product.

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.

INDICATIONS AND USAGE

Disopyramide Phosphate Extended-release Capsules, USP are indicated for the treatment of documented ventricular arrhythmias such as sustained ventricular tachycardia, that in the judgement 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. The extended-release capsules should not be used initially if rapid establishment of disopyramide plasma levels is desired.

Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.

CONTRAINDICATIONS

Disopyramide phosphate is contraindicated in the presence of cardiogenic shock, pre-existing second- or third-degree AV block (if no pacemaker is present), congenital Q-T prolongation, or known hypersensitivity to the drug.

WARNINGS