Rythmodan
Rythmodan Medication Information:
Rythmodan medication comes in several different strengths; click on the strength you need to view prices from pharmacies competing to earn your business.
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Rythmodan 100 mg
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Rythmodan 150 mg
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Rythmodan LA 250 mg
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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 µg/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 µg/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
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.
Precautions
Drug Interactions
Concomitant Antiarrhythmic Therapy: The concomitant use of disopyramide with other Class I antiarrhythmic agent and/or β-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.
Proarrhythmia and cardiac decompensation are special risks associated with the use of antiarrhythmic drugs in patients with structural heart disease. Special caution should be exercised when prescribing in this context (see Warnings, General).
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.
Drugs Associated with Risk of “torsade de pointes”: Combination with drugs associated with risk of “torsade de pointes” is not recommended (see Warnings, Other Cardiac Effects, Q-T Prolongation).
Anticholinergic Agents: The anticholinergic effect of disopyramide may be additive with that of other agents having anticholinergic properties (i.e. atropine).
Phosphodiesterase Type 5 Inhibitors: There is evidence that phosphodiesterase Type 5 inhibitors may be potentially associated with a risk of QT prolongation. Concomitant administration of disopyramide with such drugs may potentially enhance this QT prolongation effect and is not recommended.
Drugs Affecting Hepatic Microsomal Enzymes: There is some evidence that disopyramide is metabolized by hepatic CYP3A.
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.
When prescribing a drug metabolized by CYP3A (such as theophylline, H.I.V. protease inhibitors [e.g. ritonavir, indinavir, saquinavir], cyclosporin A, warfarin), it should be kept in mind that disopyramide is probably also a substrate of this isoenzyme and thus competitive inhibition of metabolism might occur, possibly increasing serum levels of these drugs.
Erythromycin: There are 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, Hypoglycemia).
Insulin: There have been reports of potentiation of the hypoglycemic effect of insulin by disopyramide (see Precautions, 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.
Hypokalemia Inducing Drugs: The concomitant use of stimulant laxatives is not recommended, as patients are at particular risk of hypokalemia. The use of another type of laxative is more appropriate (see Precautions, Patients with Special Diseases or Conditions, Hypokalemia).
Precaution should also be exercised in case of association with other hypokalemia inducing drugs, such as: potassium-depleting diuretics (e.g. thiazides, furosemide, ethacrinic acid), amphotericin B, cosyntropin (corticotrophin analogue), gluco and mineralo-corticoids (see Precautions, Patients with Special Diseases or Conditions, Hypokalemia).
Occupational Hazards
Driving a Vehicle or Performing Other Hazardous Tasks: Some adverse reactions may impair the patient’s ability to concentrate and react, and hence the ability to drive or operate machinery (see Adverse Effects).
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 Rythmodan or Rythmodan-LA in children have not been established and are therefore not recommended in this population.
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.
Supplied
Capsules
LA Tablets
Each circular, off-white, biconvex, film coated tablet with a breakline, marked RY and R on one side and the Roussel logo on the other, contains: disopyramide phosphate equivalent to 250 mg disopyramide base. Nonmedicinal ingredients: glyceryl monostearate, hydroxypropylmethylcellulose, magnesium stearate, povidone, propylene glycol, sorbitan monostearate, sucrose and titanium dioxide. Bottles of 100.
100 mg
Each green/yellow, hard gelatin capsule, marked RY RL contains: disopyramide 100 mg. Nonmedicinal ingredients: cornstarch, magnesium stearate, pregelatinized starch and talc; capsule body and head : FD&C Blue #2, gelatin, titanium dioxide and yellow iron oxide. Blister packs of 84 (6×14).
150 mg
Each opaque, white, hard gelatin capsule, marked RY 150, contains: disopyramide 150 mg. Nonmedicinal ingredients: cornstarch, magnesium stearate, pregelatinized starch and talc; capsule body and head: gelatin and titanium dioxide. Blister packs of 84 (6×14).
Contraindications
Disopyramide is contraindicated in the presence of shock, renal failure, severe intraventricular conduction defects (i.e. bundle-branch block associated with first-degree atrioventricular block, double block [left posterior or anterior hemiblock and right bundle-branch block]), pre-existing second and third degree A-V block (if no pacemaker is present), known hypersensitivity to the drug or to any ingredient in the formulation (for a complete list, see Supplied).
Disopyramide is contraindicated in patients with a pre-existing long QT (see Warnings, Other Cardiac Effects, Q-T Prolongation).
Disopyramide is contraindicated in patients with severe sinus node dysfunction (see Precautions, Patients with Special Disease or Conditions, Conductions Abnormalities).
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 their 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).
Rythmodan-LA is contraindicated in children or in patients with cardiomyopathies, severe renal or hepatic insufficiency.
Concomitant administration of disopyramide with other antiarrhythmics or other drugs liable to provoke ventricular arrhythmias and especially torsade de pointes is contraindicated (see Precautions, Drug Interactions, Concomitant Antiarrhythmic Therapy and Drugs Associated with Risk of «torsade de pointes»).
Warnings
General: All antiarrhythmic drugs can produce unwanted effects when they are used to treat symptomatic but not life threatening arrhythmia; the expected benefit should be balanced against their risks.
Proarrhythmia and cardiac decompensation are special risks associated with the use of antiarrhythmic drugs in patients with structural heart disease. Special caution should be exercised when prescribing in this context (see Precautions, Drug Interactions, Concomitant Antiarrhythmic Therapy).
Life threatening and haemodynamically significant arrhythmia are difficult to treat and affected patients are at high risk. Treatment of these arrhythmias, whatever modality, must be initiated in the hospital.
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.
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 (see Contraindications).
Adverse Effects
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.
Other atropine-like ocular adverse reactions were reported: disorders of accommodation, diplopia.
Epigastralgia has been also reported.
Genitourinary
urinary hesitancy and frequency.
Gastrointestinal
nausea, indigestion, vomiting, diarrhea, flatulence, bad taste in the mouth, anorexia.
The following reactions were reported in 1 to 10% of patients:
Skin Reactions
very rarely, rashes; isolated reports of anaphylactic-type reactions (e.g. angioedema) possibly culminating in shock (essentially reported in association with the injectable formulation).
General
dizziness, vertigo, drowsiness, profuse sweating.
Dermatologic
skin reactions including pruritus, urticaria, morbilliform eruption, abdominal rash, photosensitization.
Cardiovascular
hypotension with or without CHF, increased CHF, cardiac conduction disturbances, proarrhythmic effects (6%), edema, dyspnea, cyanosis, chest pain.
Anticholinergic
blurred vision, dry eyes/nose/throat.
Overdose
Symptoms
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.
The clinical signs of overdose may also include: bilateral mydriasis (suggestive of overdose); syncope, hypotension or shock; cardiac arrest due to intraventricular block or asystole; respiratory symptoms; coma (with bilateral mydriasis) in cases of massive intoxication.
Toxic plasma levels of disopyramide produce excessive widening of QRS complex and QT interval as a premonitory sign of other arrhythmias, in particular torsade de pointes which can result in repeated syncopes, worsening of CHF, 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
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 arrhythmias 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 1) should be based on the results of these determinations (see Precautions).
Table 1: Rythmodan
Dosage Interval for Patients with Renal Insufficiency (Rythmodan Capsules)
| Creatinine clearance (mL/min) | 40–30 | 30–15 | <15 |
| Approximate maintenance-dosing interval | q8h | q12h | q24h |
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 tablet 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 children or in patients with cardiomyopathies, or severe renal or hepatic insufficiency.
