Disopyramide

Name: Disopyramide

Warnings

Black Box Warnings

National Heart, Lung, and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST): Excessive mortality or nonfatal cardiac arrest (7.7%) shown with encainide or flecainide compared with placebo (3%)

CAST was a long-term, multicenter, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction (MI) >6 days but <2 yr previously

Average duration of treatment with encainide or flecainide in CAST was 10 months

Applicability of CAST results to other populations (eg, patients without recent MI) is uncertain

Reserve use of Class IC antiarrhythmics for life-threatening ventricular arrhythmias: Considering the known proarrhythmic properties of disopyramide & lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, disopyramide use, as well as other antiarrhythmic agents, should be reserved for patients with life-threatening ventricular arrhythmias

Contraindications

Hypersensitivity

Cardiogenic shock, preexisting second or third degree heart block, congenital QT syndrome, sick sinus syndrome

Cautions

CHF, ECG abnormalities, electrolyte abnormalities (hypo/hyper K), glaucoma, hypoglycemia, myasthenia gravis, sick sinus syndrome, BPH/urinary retention, need normal potassium prior to use, hypotension, cardiac myopathies, heart failure, prostatic enlargement, Wolff-Parkinson-White syndrome, bundle branch block, hepatic/renal impairment

Hypotension may occur

May cause QTc prolongation and subsequent torsade de pointes

Can both precipitate and exacerbate HF due to marked myocardial depressant effects in HF

Disopyramide Overview

Disopyramide is a prescription medication used to treat life-threatening abnormal heart rhythms (arrhythmias). This medication belongs to a group of drugs called antiarrhythmics. It works by affecting sodium channels in the heart which slows electrical signals, stabilizing heart rhythm.

Disopyramide comes in capsule form. It is taken 3 to 4 times daily. It is also available in a long-acting form, which is taken twice daily. The long-acting capsules should be swallowed whole.

Common side effects include dry mouth, difficult urination, blurred vision, and dizziness. Do not drive or operate heavy machinery until you know how disopyramide affects you.

 

Disopyramide Precautions

Serious side effects have been reported with disopyramide including the following: 

  • Heart Failure/Hypotension. Disopyramide may cause or worsen congestive heart failure or produce severe low blood pressure. Norpace should not be given to patients uncompensated or marginally compensated congestive heart failure or hypotension unless the congestive heart failure or hypotension is secondary to cardiac arrhythmia.
  • QRS Widening. Disopyramide may widen the QRS complex. If this happens, your doctor will stop disopyramide. 
  • Q-T Prolongation. Disopyramide may cause prolongation of the QT interval. Your doctor will monitor you closely.
  • Low blood sugar. Disopyramide may lower blood sugar levels.
  • Heart block. If first degree block develops, your doctor will reduce your disopyramide dose. 
  • Anticholinergic activity. Disopyramide should not be used in patients with glaucoma, myasthenia gravis, or urinary retention.

Do not take disopyramide if you:

  • are allergic to disopyramide or any of its ingredients
  • have cardiogenic shock
  • have a preexisting second- or third-degree AV block (if no pacemaker is present)
  • have congenital Q-T prolongation

Disopyramide Food Interactions

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of disopyramide, there are no specific foods that you must exclude from your diet when receiving this medication.

What other drugs will affect disopyramide?

Many drugs can interact with disopyramide. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using, especially:

  • ketoconazole;

  • an antibiotic--clarithromycin, erythromycin; or

  • other heart rhythm medicines--encainide, flecainide, propranolol, propafenone, quinidine.

This list is not complete and many other drugs can interact with disopyramide. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Precautions While Using disopyramide

Your doctor should check your progress at regular visits to make sure the medicine is working properly.

Do not stop taking disopyramide without first checking with your doctor. Stopping suddenly may cause a serious change in heart function .

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. This is due to lowered blood pressure. Getting up slowly may help. This effect does not occur often at doses of disopyramide usually used; however, make sure you know how you react to disopyramide before you drive, use machines, or do anything else that could be dangerous if you are not alert. If the problem continues or gets worse, check with your doctor.

Disopyramide may rarely cause hypoglycemia (low blood sugar) in some people. (See the Side Effects of disopyramide section below.) If these signs appear, eat or drink a food containing sugar and call your doctor right away.

disopyramide may cause blurred vision or other vision problems. If any of these occur, do not drive, use machines, or do anything else that could be dangerous if you are not able to see well.

Disopyramide may cause dryness of the eyes, mouth, and nose. For temporary relief of mouth dryness, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if dry mouth continues for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and oral yeast infections.

disopyramide often will make you sweat less, allowing your body temperature to increase. Use extra care not to become overheated during exercise or hot weather while you are taking disopyramide, since becoming overheated could possibly result in heatstroke.

Disopyramide Description

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:

C21H29N3O∙H3PO4                                               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.

Precautions

General

Atrial Tachyarrhythmias

Patients with atrial flutter or fibrillation should be digitalized prior to Disopyramide administration to ensure that drug-induced enhancement of AV conduction does not result in an increase of ventricular rate beyond physiologically acceptable limits.

Conduction Abnormalities

Care should be taken when prescribing Disopyramide for patients with sick sinus syndrome (bradycardia-tachycardia syndrome), Wolff-Parkinson-White syndrome (WPW), or bundle branch block. The effect of Disopyramide phosphate in these conditions is uncertain at present.

Cardiomyopathy

Patients with myocarditis or other cardiomyopathy may develop significant hypotension in response to the usual dosage of Disopyramide phosphate, probably due to cardiodepressant mechanisms. Therefore, a loading dose of Disopyramide should not be given to such patients, and initial dosage and subsequent dosage adjustments should be made under close supervision (see DOSAGE AND ADMINISTRATION).

Renal Impairment

More than 50% of Disopyramide is excreted in the urine unchanged. Therefore Disopyramide phosphate dosage should be reduced in patients with impaired renal function (see DOSAGE AND ADMINISTRATION). The electrocardiogram should be carefully monitored for prolongation of PR interval, evidence of QRS widening, or other signs of overdosage (see OVERDOSAGE).

Hepatic Impairment

Hepatic impairment also causes an increase in the plasma half-life of Disopyramide. Dosage should be reduced for patients with such impairment. The electrocardiogram should be carefully monitored for signs of overdosage (see OVERDOSAGE).

Patients with cardiac dysfunction have a higher potential for hepatic impairment; this should be considered when administering Disopyramide.

Potassium Imbalance

Antiarrhythmic drugs may be ineffective in patients with hypokalemia, and their toxic effects may be enhanced in patients with hyperkalemia. Therefore, potassium abnormalities should be corrected before starting Disopyramide therapy.

Drug Interactions

If phenytoin or other hepatic enzyme inducers are taken concurrently with Disopyramide, lower plasma levels of Disopyramide may occur. Monitoring of Disopyramide plasma levels is recommended in such concurrent use to avoid ineffective therapy. Other antiarrhythmic drugs (e.g., quinidine, procainamide, lidocaine, propranolol) have occasionally been used concurrently with Disopyramide. Excessive widening of the QRS complex and/or prolongation of the Q-T interval may occur in these situations (see WARNINGS). In healthy subjects, no significant drug-drug interaction was observed when Disopyramide was coadministered with either propranolol or diazepam. Concomitant administration of Disopyramide and quinidine resulted in slight increases in plasma Disopyramide levels and slight decreases in plasma quinidine levels. Disopyramide does not increase serum digoxin levels.

Until data on possible interactions between verapamil and Disopyramide phosphate are obtained, Disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Although potent inhibitors of CYP3A4 (e.g., ketoconazole) have not been studied clinically, in vitro studies have shown that erythromycin and oleandomycin inhibit the metabolism of Disopyramide. Cases of life-threatening interactions have been reported for Disopyramide when given with clarithromycin and erythromycin indicating that co-administration of Disopyramide with inhibitors of CYP3A4 could result in potentially fatal interaction.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Eighteen months of Disopyramide phosphate administration to rats, at oral doses up to 400 mg/kg/day (about 30 times the usual daily human dose of 600 mg/day, assuming a patient weight of at least 50 kg), revealed no evidence of carcinogenic potential. An evaluation of mutagenic potential by Ames test was negative. Disopyramide, at doses up to 250 mg/kg/day, did not adversely affect fertility of rats.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Disopyramide was associated with decreased numbers of implantation sites and decreased growth and survival of pups when administered to pregnant rats at 250 mg/kg/day (20 or more times the usual daily human dose of 12 mg/kg, assuming a patient weight of at least 50 kg), a level at which weight gain and food consumption of dams were also reduced. Increased resorption rates were reported in rabbits at 60 mg/kg/day (5 or more times the usual daily human dose). Effects on implantation, pup growth, and survival were not evaluated in rabbits. There are no adequate and well-controlled studies in pregnant women. Disopyramide phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Disopyramide has been reported to stimulate contractions of the pregnant uterus. Disopyramide has been found in human fetal blood.

Labor and Delivery

It is not known whether the use of Disopyramide during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention.

Nursing Mothers

Studies in rats have shown that the concentration of Disopyramide and its metabolites is between one and three times greater in milk than it is in plasma. Following oral administration, Disopyramide has been detected in human milk at a concentration not exceeding that in plasma. Because of the potential for serious adverse reactions in nursing infants from Disopyramide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see DOSAGE AND ADMINISTRATION).

Geriatric Use

Clinical studies of Disopyramide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Because of its anticholinergic activity, Disopyramide phosphate should not be used in patients with glaucoma, urinary retention, or benign prostatic hypertrophy (medical conditions commonly associated with the elderly) unless adequate overriding measures are taken (see WARNINGS: Anticholinergic Activity). 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).

Overdosage

Symptoms

Deliberate or accidental overdosage of oral Disopyramide may be followed by apnea, loss of consciousness, cardiac arrhythmias, and loss of spontaneous respiration. Death has occurred following overdosage.

Toxic plasma levels of Disopyramide produce excessive widening of the QRS complex and Q-T interval, worsening of congestive heart failure, hypotension, varying kinds and degrees of conduction disturbance, bradycardia, and finally asystole. Obvious anticholinergic effects are also observed.

The approximate oral LD50 of Disopyramide phosphate is 580 and 700 mg/kg for rats and mice, respectively.

Treatment

Experience indicates that prompt and vigorous treatment of overdosage is necessary, even in the absence of symptoms. Such treatment may be life-saving. No specific antidote for Disopyramide phosphate has been identified. Treatment should be symptomatic and may include induction of emesis or gastric lavage, administration of a cathartic followed by activated charcoal by mouth or stomach tube, intravenous administration of isoproterenol and dopamine, insertion of an intra-aortic balloon for counterpulsation, and mechanically assisted ventilation. Hemodialysis or, preferably, hemoperfusion with charcoal may be employed to lower serum concentration of the drug.

The electrocardiogram should be monitored, and supportive therapy with cardiac glycosides and diuretics should be given as required.

If progressive AV block should develop, endocardial pacing should be implemented. In case of any impaired renal function, measures to increase the glomerular filtration rate may reduce the toxicity (Disopyramide is excreted primarily by the kidney).

The anticholinergic effects can be reversed with neostigmine at the discretion of the physician.

Altering the urinary pH in humans does not affect the plasma half-life or the amount of Disopyramide excreted in the urine.

Index Terms

  • Disopyramide Phosphate

Pharmacologic Category

  • Antiarrhythmic Agent, Class Ia

Pharmacology

Class Ia antiarrhythmic: Decreases myocardial excitability and conduction velocity; reduces disparity in refractory between normal and infarcted myocardium; possesses anticholinergic, peripheral vasoconstrictive, and negative inotropic effects

Absorption

60% to 83%

Distribution

Vd: Children: 1 L/kg; Adults: 0.8-2 L/kg

Metabolism

Hepatic; N-dealkylation to the active metabolite N-despropyldisopyramide (or mono-N-dealkylated [MND] metabolite) and other inactive metabolites

Excretion

Urine (~50% as unchanged drug; ~20% as MND; 10% other metabolites); feces (10% to 15%)

Clearance: Children: 3.76 mL/minute/kg (greater than adults)

Duration of Action

Immediate release: 1.5-8.5 hours

Half-Life Elimination

Children: 3.15 hours; Adults: 4-10 hours (prolonged with heart failure and hepatic or renal impairment)

Protein Binding

Concentration dependent: 20% to 60%

Administration

Do not break or chew controlled release capsules. Administer around-the-clock rather than 4 times/day (ie, 12-6-12-6, not 9-1-5-9) to promote less variation in peak and trough serum levels. Should be taken on an empty stomach.

Dietary Considerations

Should be taken on an empty stomach.

For Healthcare Professionals

Applies to disopyramide: compounding powder, oral capsule, oral capsule extended release

Gastrointestinal

Gastrointestinal side effects including anticholinergic side effects have been the most common cause of gastrointestinal complaints. Dry mouth (40%), constipation (11%) and nausea, pain/bloating/gas (3% to 9%) have been reported. Anorexia, diarrhea, and vomiting have occurred. Two cases of paralytic ileus have been reported. A case of oral mucosal ulceration has been associated with the (unapproved) sublingual use of disopyramide.[Ref]

Cardiovascular

Cardiovascular side effects have included arrhythmias, conduction disturbances, hypotension, and heart failure. Like other class I antiarrhythmic agents, disopyramide can be proarrhythmic and decrease cardiac contractility. The risk of proarrhythmias may be increased in patients with left ventricular dysfunction. Various ventricular tachyarrhythmias accompanied by disopyramide-induced QT interval prolongation, including ventricular tachycardia or fibrillation and torsades de pointes, have been associated with usual therapeutic doses. Evidence of QRS segment or QT widening are indications to either reduce the dose or stop the drug. Conduction disturbances, including AV block, have occurred, and are more likely in patients with preexisting conduction disorders.[Ref]

Contributing factors towards the development of torsades de pointes included female gender, hypokalemia, underlying arrhythmias, mitral valve abnormalities, or congestive heart failure.

Hypotension, pulmonary edema, and frank cardiogenic shock have been associated with both the oral and intravenous administration of disopyramide. Most affected patients had underlying congestive heart failure.[Ref]

Nervous system

A patient developed a severe sensory-motor polyneuropathy after receiving disopyramide 500 mg daily for 4 years. Symptoms did not respond to corticosteroids, but did resolve a few months after withdrawal of disopyramide.[Ref]

Nervous system side effects including anticholinergic symptoms have been reported. Other nervous system side effects have been rare, and included nervousness, insomnia, depression, and peripheral paresthesia or neuropathy.[Ref]

Genitourinary

Genitourinary side effects were related to anticholinergic properties of the drug. Urinary hesitancy (10% to 40%) has occurred. Urinary retention, frequency, and urgency has been reported in up to 9% of patients. Recommended management consisted of lowering the dose, discontinuing the drug, or if necessary, using a cholinergic drug to counteract this effect. Sexual impotence has been reported.[Ref]

Hepatic

Hepatic side effects including reversible, dose-independent intrahepatic cholestasis, hepatocellular damage, and nonspecific hepatic inflammatory changes have been reported in rare cases where venous congestion secondary to heart failure was reasonably excluded. Manifestations of liver dysfunction usually appeared during the first week of treatment (malaise, dark urine) and resolved promptly upon discontinuation of the drug. In one review, 20 cases were reported during a 14-year period.[Ref]

Endocrine

Endocrine side effect have included hypoglycemia due to stimulation of insulin secretion and rare cases of hypokalemia and dyslipidemia. Hypoglycemia can occur in nondiabetic patients at therapeutic plasma disopyramide levels.[Ref]

Elevated insulin levels have been measured during disopyramide-associated hypoglycemic episodes. Data have revealed that disopyramide blocks pancreatic ATP-sensitive potassium channels, enhancing insulin release. Other factors such as increased peripheral utilization of glucose or decreased glycogenolysis have not been fully evaluated.[Ref]

Immunologic

Immunologic side effects, such as the production of antinuclear antibodies and other immunologically-mediated changes associated with other class 1 antiarrhythmic agents, do not appear to occur during disopyramide therapy.[Ref]

Dermatologic

Dermatologic reactions have been reported rarely, usually presenting as a rash or pruritus.[Ref]

Ocular

Ocular side effects of blurred vision (3% to 9%) have been associated with the anticholinergic effects of disopyramide.[Ref]

General

General body symptoms of fatigue, muscle weakness, malaise, and aches/pains have been reported in 3% to 9% of patients administered disopyramide. Rarely, fever has occurred.[Ref]

Psychiatric

Psychiatric side effects including reversible psychiatric symptoms of psychosis have been reported rarely.[Ref]

Hematologic

Hematologic adverse effects of thrombocytopenia, and reversible agranulocytosis have occurred rarely.[Ref]

Other

Gynecomastia has been reported.[Ref]

Respiratory

Respiratory difficulty has been reported rarely.[Ref]

Some side effects of disopyramide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Renal Dose Adjustments

Immediate-release:
CrCl < 15 mL/min: Loading dose: 150 mg orally.
Maintenance dose: 100 mg orally every 24 hours.

CrCl 15-30 mL/min: Loading dose: 150 mg orally.
Maintenance dose: 100 mg orally every 12 hours.

CrCl 30-40 mL/min: Loading dose: 150 mg orally.
Maintenance dose: 100 mg orally every 8 hours.

CrCl > 40 mL/min: Loading dose: 200 mg orally.
Maintenance dose: 100 mg orally every 6 hours.

Extended-release:
CrCl <= 40 mL/min: not recommended
CrCl > 40 mL/min: Maintenance dose: 200 mg (extended-release) orally every 12 hours.

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