Hoechst Marion Roussel
Action And Clinical Pharmacology: In both animal and man the electrophysiological and hemodynamic effects of disopyramide are qualitatively similar to those of quinidine and procainamide.
Although the exact mechanism of action has not been completely elucidated, it would appear from animal studies that disopyramide exerts its antiarrhythmic activity in the following manner: 1. Reduces automaticity in cardiac Purkinje fibers by depressing the slope of Phase 4 diastolic depolarization. The action manifests itself both in normal Purkinje fibers and in fibers damaged by either ischemia or infarction. 2. Depresses conduction velocity in atria, AV node, Purkinje fibers and ventricular muscle by decreasing the rate of rise of phase 0 depolarization in these fibers. 3. Prolongs action potential duration and effective refractory period in atria, Purkinje fibers and ventricular muscle. 4. Depresses excitability of both atrial and ventricular muscles by its direct effect on the myocardium. 5. Although the anticholinergic action of disopyramide may cause an increase in the sinus rate of normal hearts, the usual effect on the rapid cardiac rate associated with an arrhythmia is a decrease with possibly a reduction in blood pressure. Disopyramide exerts a negative inotropic action on cardiac muscle.
Disopyramide is rapidly absorbed after oral administration and reaches peak levels in about 1 to 2 hours. Absorption is slower with the long acting form, peak levels being reached in 4.5 to 6.2 hours.
Serum levels of disopyramide are correlated with antiarrhythmic activity. Usual therapeutic plasma levels are 2 to 4 g/mL. At these concentrations, disopyramide in the blood is about equally distributed between plasma and erythrocytes. Plasma protein binding of disopyramide in humans varies with drug concentration. At therapeutic concentrations, protein binding is about 50%. Toxic plasma levels have not been defined in man, but are thought to exceed 10.5 g/mL.
Mean plasma half-life of disopyramide in healthy humans is 6.7 hours (range of 4 to 10 hours) while with the long acting form it is 14.5 hours, and even longer in ill, hospitalized patients. Patients with impaired renal function (creatinine clearance less than 40 mL/minute), have demonstrated disopyramide half-lives of 10 to 18 hours. Hepatic impairment may also prolong the half-life. Little or no tissue accumulation occurs.
In healthy humans, urinary and fecal excretion of disopyramide and its metabolites account for about 80% and 10% of the dose, respectively. Forty percent (40%) to 60% of a given dose is excreted in the urine as the unchanged drug and 15% to 25% as the mono-N-dealkylated metabolite. The remainder of a given dose is excreted via the bile into the feces. The plasma concentration of this metabolite is about 1/10th that of disopyramide.
Indications And Clinical Uses:
No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risks and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias.
Disopyramide is indicated for the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. Disopyramide may also be used for the treatment of patients with documented symptomatic ventricular arrhythmias when the symptoms are of sufficient severity to require treatment. Because of the proarrhythmic effects of disopyramide its use should be reserved for patients in whom, in the opinion of the physician, the benefit of treatment clearly outweighs the risks.
For patients with sustained ventricular tachycardia, disopyramide therapy should be initiated in the hospital. Hospitalization may also be required for certain other patients depending on their cardiac status and underlying cardiac disease.
The effects of disopyramide in patients with recent myocardial infarction have not been adequately studied and, therefore, its use in this condition cannot be recommended.
Contra-Indications: In the presence of shock, renal failure, severe intraventricular conduction defects, pre-existing second and third degree AV block (if no pacemaker is present), known hypersensitivity to the drug.
Disopyramide should not be used in the presence of uncompensated or inadequately compensated congestive heart failure (see Warnings).
Disopyramide is contraindicated in most patients with extensive myocardial disease, but may on occasion be used in these patients under the close supervision of a cardiologist if in his opinion the patient’s condition justifies it. When used in these patients continuous ECG monitoring in a CCU facility is mandatory.
Due to its anticholinergic activity, disopyramide is contraindicated in most patients with glaucoma or in patients in whom urinary retention is present (see Precautions).
Manufacturers’ Warnings In Clinical States: Mortality: The results of Cardiac Arrhythmia Suppression Trial (CAST) in post-myocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in non-fatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine and placebo arms only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine treated group.
The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present it is prudent to consider these results when using any antiarrhythmic agent.
Negative Inotropic Properties: Heart Failure: Because of its negative inotropic effect disopyramide may cause or worsen congestive heart failure. Therefore, this drug should not be used in patients with heart failure, and should be especially avoided in patients with a previous history of heart failure except in the very special circumstances described below:
In patients in whom the failure is exacerbated or caused by an arrhythmia, disopyramide may be used to suppress the ectopy but it must be borne in mind that any such benefit on cardiac function may be overcome by the depressant effect on cardiac output, and thereby result in even worse failure even though routine methods of anti-failure therapy including optimal digitalization are attempted. Careful monitoring is essential under these circumstances.
Patients with compensated heart failure may be treated with disopyramide, but careful attention must be given to the maintenance of cardiac function including optimal digitalization. Close observation is mandatory, as any benefit of disopyramide either therapeutic or prophylactic could be accompanied by an unacceptable lowering of cardiac output.
For most patients the encroachment on their cardiac reserve may be of minimal clinical consequence, but in patients with a limited reserve as a result of pump dysfunction and/or imbalanced work load, even a minor encroachment on reserve can precipitate clinically evident failure or make its control more difficult, and even result in a gross low output congestive cardiac failure state (see Precautions, Drug Interactions).
Hypotension: On rare occasions disopyramide has caused syncope with sudden loss of consciousness. In the cases reported, this was believed to be due to an excessive hypotensive action of the drug or, in some cases, due to concomitant use with other hypotensive or negative inotropic agents.
Severe hypotension following disopyramide administration has been observed usually in patients with primary myocardial disease (cardiomyopathy), and also in inadequately compensated congestive heart failure or advanced myocardial disease with low output state, or in patients on other hypotensive medication e.g., beta-adrenergic blockers or verapamil. An oral loading dose of disopyramide should not be given to such patients; initial dosage and subsequent dosage adjustments should be made under close supervision.
If severe hypotension develops, disopyramide should be discontinued promptly (see Precautions, Drug Interactions).
Other Cardiac Effects: QRS Widening: Significant widening (greater than 25%) of the QRS complex may occur during disopyramide administration; in such cases disopyramide should be discontinued.
Q-T Prolongation: As with other quinidine-like antiarrhythmic drugs, prolongation of the Q-T interval (corrected) and worsening of the arrhythmia may occur with disopyramide, particularly in response to higher doses. Patients who have evidenced prolongation of the Q-T interval in response to quinidine may be at particular risk. If a Q-T prolongation greater than 25% is observed and if ectopy continues, the patient should be monitored closely, and consideration be given to discontinuing disopyramide.
Disopyramide, as with other quinidine-like antiarrhythmic drugs, has been associated with torsades de pointes.
Heart Block: If first degree heart block develops in a patient receiving disopyramide, 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 degree of heart block. Development of second or third degree AV block or unifascicular or trifascicular block requires discontinuation of disopyramide therapy, unless the ventricular rate is adequately controlled by a temporary or implanted ventricular pacemaker.
Precautions: Patients with Special Diseases or Conditions: Atrial Tachyarrhythmias: Disopyramide is usually ineffective in atrial flutter and its usefulness in atrial fibrillation is not proven. If atrial flutter or fibrillation is present, the patient should be fully digitalized prior to disopyramide use so that drug-induced changes in AV conduction do not result in an increase of ventricular rate beyond physiologically acceptable limits.
Conduction Abnormalities: Disopyramide therapy in patients with sick sinus syndrome (including bradycardia-tachycardia syndrome), Wolff-Parkinson White (WPW) syndrome or bundle branch block requires care, since the effect of disopyramide in these conditions is difficult to predict. Sinoatrial node function deterioration has been reported in 6 sick sinus syndrome patients treated with disopyramide.
Digitalis Intoxication: Since disopyramide has not been studied in patients with digitalis intoxication, it should be used with caution in these patients.
Anticholinergic Activity: Glaucoma: In patients with a family history of angle-closure glaucoma, intraocular pressure should be measured before initiating disopyramide therapy. Disopyramide should not be administered to patients with angle-closure glaucoma unless topical application of miotics (e.g. pilocarpine ophthalmic drops) is used to counteract the anticholinergic effects of the drug.
Urinary Retention: Urinary retention may occur in patients of either sex, but males with benign prostatic hypertrophy are at particular risk. If acute urinary retention develops, disopyramide therapy should be temporarily discontinued, except in occasional instances, in which continued control of the arrhythmia with disopyramide is considered mandatory. In such cases, overriding measures should be taken (e.g., catheter drainage or operative relief). If disopyramide is discontinued, and later reintroduced, a lower dose should be used.
Myasthenia Gravis: Disopyramide should be used with special care in myasthenia gravis since its anticholinergic properties could precipitate a myasthenic crisis.
Renal Impairment: More than 50% of disopyramide is excreted unchanged in urine. Therefore, in impaired renal function reduce the dose and increase the dosing interval (see Dosage); ECG should be carefully monitored for prolongation of PR interval, QRS widening, or other signs of overdosage (see Pharmacology and Overdose: Symptoms and Treatment).
Rythmodan-LA tablets should not be used in patients with severe renal impairment.
Hepatic Impairment: Hepatic impairment also increases disopyramide plasma half-life; reduce dosage for patients with such impairment. The ECG should be carefully monitored for signs of overdosage.
Rythmodan-LA tablets should not be used in severe hepatic impairment.
Hypokalemia: Although there is no experience with disopyramide in severe hypokalemia, other antiarrhythmic agents are frequently ineffective in such patients; a significant potassium deficit should be corrected before instituting disopyramide therapy.
Hypoglycemia: Significant lowering of blood glucose has occasionally been reported during disopyramide administration. The physician should be alert to this possibility, especially in patients with congestive heart failure, chronic malnutrition, hepatic, renal or other diseases, or who are taking drugs (e.g., b-adrenergic blockers, alcohol) which could compromise preservation of the normal gluco-regulatory mechanisms in the absence of food. In these patients blood glucose levels should be carefully monitored (see Drug Interactions).
Pregnancy: Animal studies have not demonstrated any teratogenic effect and only minimal evidence of impaired fertility.
Disopyramide has been reported to stimulate contraction of the pregnant uterus.
Disopyramide should be used in pregnant women only when it is clearly indicated and the benefit/risk ratio has been carefully evaluated.
Lactation: Disopyramide is excreted in human milk. Therefore, if use of the drug is deemed essential in lactating women, an alternative method of infant feeding should be instituted.
Children: The safety and effectiveness of disopyramide in children have not been established.
Drug Interactions: Concomitant Antiarrhythmic Therapy: The concomitant use of disopyramide with other Class I antiarrhythmic agent and/or b-adrenergic blockers 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.
Administer disopyramide cautiously to patients who have recently received other antiarrhythmic drugs. Disopyramide should not be started until at least one half-life after stopping the other antiarrhythmic agent. (Half-life of quinidine is about 6 hours. Half-life of procainamide is about 3 hours.) In these cases loading dose of disopyramide should not be used. Excessive widening of QRS or excessive negative inotropic effect may occur.
Quinidine: Concomitant administration of disopyramide and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels.
Verapamil: Although the interaction is poorly documented, the concurrent use of verapamil and disopyramide may aggravate or precipitate congestive heart failure or result in excessive hypotension (see Warnings).
Digoxin: Concomitant digoxin and disopyramide therapy has not resulted in changes in serum digoxin levels.
Anticholinergic Agents: The anticholinergic effect of disopyramide may be additive with that of other agents having anticholinergic properties.
Drugs Affecting Hepatic Microsomal Enzymes: Drugs (e.g.: phenobarbital, rifampin, phenytoin) that induce hepatic microsomal enzymes may accelerate the metabolism of disopyramide, resulting in lower plasma concentrations. When microsomal enzymes inducers are used concomitantly with disopyramide, serum concentrations of disopyramide should be closely monitored to avoid subtherapeutic concentrations.
Erythromycin: There are 2 reported cases of patients with clinically stable cardiac condition under disopyramide therapy where the addition of erythromycin resulted in polymorphic ventricular tachycardia, QTc prolongation, and elevation of disopyramide serum levels. Erythromycin appears to inhibit disopyramide metabolism in the liver. Additional documentation is needed to substantiate this possible interaction. However closer monitoring is advised when the two drugs are combined.
Ethanol: In healthy subjects, ethanol did not affect the half-life or total body clearance of disopyramide. However, combination could result in hypoglycemia in patients at risk (see Precautions).
Insulin: There has been 1 report of potentiation of the hypoglycemic effect of insulin by disopyramide (see Hypoglycemia).
Warfarin: Potentiation of the hypoprothrombinemic effect of warfarin has been reported in several patients receiving disopyramide and warfarin. However, in a study in several patients receiving disopyramide and warfarin concomitantly, the hypoprothrombinemic effect of warfarin was not increased and, in 2 patients, actually was decreased slightly. Further study is needed to determine whether a potential interaction exists.
Adverse Reactions: Rare occurrence of congestive heart failure, hypotension, widening QRS, sinus arrest, nodal rhythm dissociation, cardiac arrest and cardiovascular collapse have been reported. An occasional paradoxical ventricular tachycardia evolving sometimes to fibrillation has been observed. A definite relationship to the drug was not always established in the above cardiovascular effects.
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 and can be severe. Urinary retention is the most serious anticholinergic effect.
The following reactions were reported in more than 10% of patients:
- Anticholinergic: dry mouth (16 to 30%), urinary retention (7 to 13%), constipation.
- Gastrointestinal: nausea, indigestion, vomiting, diarrhea, flatulence, bad taste in the mouth, anorexia.
- The following reactions were reported in 1 to 10% of patients: Anticholinergic: blurred vision, dry eyes/nose/throat.
- Cardiovascular: hypotension with or without CHF, increased CHF, cardiac conduction disturbances, proarrhythmic effects (6%), edema, dyspnea, cyanosis, chest pain.
- Dermatologic: skin reactions including pruritus, urticaria, morbilliform eruption, abdominal rash, photosensitization.
- General: dizziness, vertigo, drowsiness, profuse sweating.
- Genitourinary: urinary hesitancy and frequency.
Other: raised AST levels.
The following were reported in less than 1% of patients: dysuria, headache, feeling of warmth, pallor, peripheral paresthesia, fatigue, malaise, insomnia, confusion, transitory psychosis, elevated BUN, elevated creatinine, decreased hemoglobin/hematocrit, hypoglycemia, neutropenia, idiosyncratic reaction to drug. In a few instances cholestatic jaundice has been reported. A definite causal relationship has not been established.
A high plasma concentration has been associated with impotence.
Symptoms And Treatment Of Overdose: Symptoms: Five patients who took deliberate overdoses of oral disopyramide presented with an early loss of consciousness after an apneic period, cardiac arrhythmias and loss of spontaneous respiration, leading to death. Serum levels in these patients were as high as 114 mg/L taken at various times after ingestion, including post-mortem.
Toxic plasma levels of disopyramide produce excessive widening of QRS complex and QT interval, worsening of congestive heart failure, hypotension, varying kinds and degrees of conduction disturbance, bradycardia and finally asystole. Obvious anticholinergic effects are also observed.
Treatment: Discontinue drug and initiate gastric lavage; no specific antidote has been identified: treatment of overdosage should be symptomatic and may include the administration of isoproterenol, dopamine, intra-aortic balloon counterpulsation, mechanically assisted respiration and hemoperfusion with charcoal.
Hemodialysis may be employed to rapidly lower serum concentration of drug. In vitro studies with human blood have demonstrated good dialyzability. Its clearance was 33 mL/minute at a blood flow 250 mL/minute when an initial plasma concentration of 22 µg/mL was dialyzed using an artificial kidney (Cordis-DOW-4).
The ECG should be monitored and supportive therapy with vasopressors, sympathomimetics, cardiac glycosides and diuretics should be given, as required.
Should progressive heart block develop, endocardial pacing should be implemented. In case of any impaired renal function, measures to increase glomerular filtration rate may reduce the toxicity (disopyramide is excreted primarily by the kidney). Altering the urinary pH in man does not affect plasma half-life or the amount of disopyramide excreted in urine.
The anticholinergic effects could be reversed with neostigmine, at the discretion of the physician.
Dosage And Administration: The dosage should be individualized for each patient based upon response and tolerance and patient weight.
Capsules: Usual daily dose: 400 to 800 mg given in 4 divided doses. Rarely, control may be maintained on daily doses of less than 400 mg.
If rapid control of arrhythmia is essential, an initial dosage schedule for most adults is a single loading dose of 300 mg followed by 100 mg every 6 hours. If satisfactory control of the arrhythmia is not obtained with the maintenance dose of 100 mg every 6 hours, increase to 150 mg or subsequently to 200 mg every 6 hours if necessary.
For patients with cardiomyopathy or possible cardiac decompensation, loading doses should not be given, an initial dosage should be limited to 100 mg every 6 hours. Subsequent dosage adjustments should be made gradually with close monitoring for possible development of hypotension and/or congestive heart failure (see Warnings).
For patients of small stature (body weight less than 50 kg) and for patients with mild hepatic or renal insufficiency (creatinine clearance above 60 mL/minute) a loading dose of 200 mg is recommended followed by 100 mg every 6 hours. The recommended maintenance dose of these patients is 400 mg/day given in doses of 100 mg every 6 hours.
In patients with severe hepatic or renal insufficiency (creatinine clearance below 50 mL/minute) an initial loading dose of 100 mg is recommended. These patients are best managed with repeated plasma disopyramide determinations and subsequent dosage and frequency of administration (see Table I) should be based on the results of these determinations (see Precautions).
No loading dose should be given to patients who are being transferred from other oral antiarrhythmic agents such as quinidine or procainamide (see Precautions, Drug Interactions).
Long Acting Tablets: Rythmodan-LA should not be used to initiate therapy; the patient should be titrated to the appropriate disopyramide dosage level using disopyramide capsules. Patients stabilized on disopyramide to a dosage level of 500 to 600 mg/day can be transferred to Rythmodan-LA one 250 mg twice daily. Patients titrated to other dosage levels should remain on disopyramide capsules. The first Rythmodan-LA dose should be taken 6 hours after the last disopyramide capsule dose. Rythmodan-LA should not be used in patients with cardiomyopathies, or severe renal or hepatic insufficiency.
Availability And Storage: Capsules: Each hard gelatin capsule contains: disopyramide 100 mg (green/yellow, marked RY RL) or 150 mg (opaque white, marked RY 150). Bottles of 100.
LA Tablets: Each circular, off-white, biconvex, film-coated tablet with a break line contains: disopyramide phosphate equivalent to 250 mg disopyramide base. Tablets are marked RY and R on one side and the Roussel logo on the other. Bottles of 100. (Shown in Product Recognition Section)
RYTHMODAN® RYTHMODAN®-LA Hoechst Marion Roussel Disopyramide Antiarrhythmic Agent