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Pronunciation:

(dye soe PEER a mide)

U.S. Brand Names:

Norpace®; Norpace® CR

Synonyms:

Disopyramide Phosphate

Generic Available:

Yes

Canadian Brand Names:

Norpace®; Rythmodan®; Rythmodan®-LA

Use:

Suppression and prevention of unifocal and multifocal atrial and premature, ventricular premature complexes, coupled ventricular tachycardia; effective in the conversion of atrial fibrillation, atrial flutter, and paroxysmal atrial tachycardia to normal sinus rhythm and prevention of the recurrence of these arrhythmias after conversion by other methods

Pregnancy Risk Factor:

Lactation:

Enters breast milk/compatible

Contraindications:

Hypersensitivity to disopyramide or any component of the formulation; cardiogenic shock; pre-existing second- or third-degree heart block (except in patients with a functioning artificial pacemaker); congenital QT syndrome; sick sinus syndrome

Warnings/Precautions:

Monitor and adjust dose to prevent QTc prolongation. Watch for proarrhythmic effects. May precipitate or exacerbate CHF. Due to significant anticholinergic effects, do not use in patients with urinary retention, BPH, glaucoma, or myasthenia gravis. Reduce dosage in renal or hepatic impairment. The extended release form is not recommended for Clcr<40 mL/minute. In patients with atrial fibrillation or flutter, block the AV node before initiating. Use caution in Wolff-Parkinson-White syndrome or bundle branch block. Correct hypokalemia before initiating therapy. Hypokalemia may worsen toxicity. Monitor closely for hypotension during the initiation of therapy. Avoid concurrent use with other medications with prolong QT interval or decrease myocardial contractility.

Adverse Reactions:

The most common adverse effects are related to cholinergic blockade. The most serious adverse effects of disopyramide are hypotension and CHF.

>10%:

Gastrointestinal: Xerostomia (32%), constipation (11%)

Genitourinary: Urinary hesitancy (14% to 23%)

1% to 10%:

Cardiovascular: CHF, hypotension, cardiac conduction disturbance, edema, syncope, chest pain

Central nervous system: Fatigue, headache, malaise, dizziness, nervousness

Dermatologic: Rash, generalized dermatoses, pruritus

Endocrine & metabolic: Hypokalemia, elevated cholesterol, elevated triglycerides

Gastrointestinal: Dry throat, nausea, abdominal distension, flatulence, abdominal bloating, anorexia, diarrhea, vomiting, weight gain

Genitourinary: Urinary retention, urinary frequency, urinary urgency, impotence (1% to 3%)

Neuromuscular & skeletal: Muscle weakness, muscular pain

Ocular: Blurred vision, dry eyes

Respiratory: Dyspnea

<1% (Limited to important or life-threatening): Agranulocytosis, arrhythmia (new or worsened, proarrhythmic effect); AV block, BUN increased, cholestatic jaundice, creatinine increased, depression, dysuria, fever, gynecomastia, hematocrit decreased, hemoglobin decreased, hepatotoxicity, hypoglycemia, insomnia, numbness, paresthesia, psychotic reaction, respiratory distress, serum creatinine increased, thrombocytopenia, tingling, transaminases increased. Rare cases of lupus have been reported (generally in patients previously receiving procainamide).

Postmarketing and/or case reports: Peripheral neuropathy, psychosis, pupillary dilation, toxic cutaneous blisters

Overdosage/Toxicology:

Has a low toxic:therapeutic ratio and may easily produce fatal intoxication (acute toxic dose: 1 g in adults). Symptoms of overdose include sinus bradycardia, sinus node arrest or asystole, P-R, QRS, or QT interval prolongation, torsade de pointes (polymorphous ventricular tachycardia) and depressed myocardial contractility, which along with alpha-adrenergic or ganglionic blockade, may result in hypotension and pulmonary edema. Other effects are anticholinergic (dry mouth, dilated pupils, and delirium), as well as seizures, coma, and respiratory arrest.

Treatment is symptomatic and effects usually respond to conventional therapies. Note: Do not use other Type 1A or 1C antiarrhythmic agents to treat ventricular tachycardia. Sodium bicarbonate may treat wide QRS intervals or hypotension. Markedly impaired conduction or high degree AV block, unresponsive to bicarbonate, indicates consideration of a pacemaker.

Drug Interactions:

Substrate of CYP3A4 (major)

Beta-blockers may cause additive/excessive negative inotropic activity.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of disopyramide. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of disopyramide. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Erythromycin and clarithromycin increase disopyramide blood levels; may cause QRS widening and/or QT interval prolongation.

Procainamide, quinidine, propafenone, or flecainide can cause increased/excessive negative inotropic effects or prolonged conduction.

Drugs which may prolong the QT interval (amiodarone, amitriptyline, bepridil, cisapride, disopyramide, erythromycin, haloperidol, imipramine, pimozide, quinidine, sotalol, and thioridazine) may be additive with disopyramide; use with caution.

Sparfloxacin, gatifloxacin, and moxifloxacin may result in additional prolongation of the QT interval; concurrent use is contraindicated.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: St John's wort may decrease disopyramide levels. Avoid ephedra (may worsen arrhythmia).

Stability:

Extemporaneously prepared suspension is stable for 4 weeks refrigerated

Mechanism of Action:

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

Pharmacodynamics/Kinetics:

Onset of action: 0.5-3.5 hours

Duration: 1.5-8.5 hours

Absorption: 60% to 83%

Protein binding (concentration dependent): 20% to 60%

Metabolism: Hepatic to inactive metabolites

Half-life elimination: Adults: 4-10 hours; prolonged with hepatic or renal impairment

Excretion: Urine (40% to 60% as unchanged drug); feces (10% to 15%)

Dosage:

Oral:

Children:

<1 year: 10-30 mg/kg/24 hours in 4 divided doses

1-4 years: 10-20 mg/kg/24 hours in 4 divided doses

4-12 years: 10-15 mg/kg/24 hours in 4 divided doses

12-18 years: 6-15 mg/kg/24 hours in 4 divided doses

Adults:

<50 kg: 100 mg every 6 hours or 200 mg every 12 hours (controlled release)

>50 kg: 150 mg every 6 hours or 300 mg every 12 hours (controlled release); if no response, increase to 200 mg every 6 hours. Maximum dose required for patients with severe refractory ventricular tachycardia is 400 mg every 6 hours.

Elderly: Dose with caution, starting at the lower end of dosing range

Dosing adjustment in renal impairment: 100 mg (nonsustained release) given at the following intervals, based on creatinine clearance (mL/minute):

Clcr 30-40 mL/minute: Administer every 8 hours

Clcr 15-30 mL/minute: Administer every 12 hours

Clcr<15 mL/minute: Administer every 24 hours

or alter the dose as follows:

Clcr 30-<40 mL/minute: Reduce dose 50%

Clcr 15-30 mL/minute: Reduce dose 75%

Dialysis: Not dialyzable (0% to 5%) by hemo- or peritoneal methods; supplemental dose is not necessary.

Dosing interval in hepatic impairment: 100 mg every 6 hours or 200 mg every 12 hours (controlled release)

Administration:

Do not break or chew controlled release capsules. Administer around-the-clock to 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

Monitoring Parameters:

ECG, blood pressure, urinary retention, CNS anticholinergic effects (confusion, agitation, hallucinations, etc)

Reference Range:

Therapeutic concentration:

Atrial arrhythmias: 2.8-3.2 mcg/mL

Ventricular arrhythmias 3.3-7.5 mcg/mL

Toxic concentration: >7 mcg/mL

Dietary Considerations:

Should be taken on an empty stomach.

Patient Education:

Take as directed, at regular intervals around-the-clock on an empty stomach. Do not alter dosage or discontinue therapy without consulting prescriber. Do not crush or chew extended release form. Avoid (or limit) alcohol and caffeine. You may experience dizziness or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or dry mouth (frequent mouth care or sucking on lozenges may help). Report any change in urinary pattern or difficulty urinating; chest pain, palpitations, irregular heartbeat; unusual cough, respiratory difficulty, swelling of extremities; muscle tremors or weakness; confusion or acute lethargy; or skin rash. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant.

Anesthesia and Critical Care Concerns/Other Considerations:

In patients with pre-existing cardiovascular disease, the incidence of proarrhythmic effects and mortality may be increased with Class Ia antiarrhythmic agents. Disopyramide has significant anticholinergic effects which also limits its role in patients with cardiovascular disease.

Cardiovascular Considerations:

Disopyramide has limited antiarrhythmic effects and has a very narrow therapeutic index. Close monitoring of ECG, particularly of the QT interval, should be conducted when initiating therapy. Increases in QT >25% over baseline should result in cessation or reduction in disopyramide dosing. In patients with pre-existing cardiovascular disease, the incidence of proarrhythmic effects and mortality may be increased with Class Ia antiarrhythmic agents.

Disopyramide has significant anticholinergic effects which also limits its role in patients with cardiovascular disease. Disopyramide is being used experimentally for the treatment of vasovagal syncope.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

May cause drowsiness or nervousness; rare reports of depression and psychosis

Mental Health: Effects on Psychiatric Treatment:

Contraindicated with ziprasidone; use cautiously with TCAs; may cause AV block or QT prolongation; phenobarbital and carbamazepine may decrease the effects of disopyramide via enzyme induction

Dosage Forms:

Capsule (Norpace®): 100 mg, 150 mg

Capsule, controlled release (Norpace® CR): 100 mg, 150 mg

Extemporaneously Prepared:

Extemporaneous suspensions in cherry syrup (1 mg/mL and 10 mg/mL) are stable for 4 weeks in amber glass bottles stored at 5°C, 30°C, or at room temperature; shake well before use; do not use extended release capsules for this suspension

Mathur LK, Lai PK, and Shively CD, "Stability of Disopyramide Phosphate in Cherry Syrup,"J Hosp Pharm, 1982, 39(2):309-10.

International Brand Names:

Dicorantil® (BR); Dicorynan® (ES); Dirythmin SA® (GB); Dirytmin® (BE, LU, NL); Diso-Duriles® (DE); Disomet® (FI); Disopyramide® (CY, GB, HR, SI); Durbis® [inj.] (DK, NO); Durbis® (NO, SE); Isomide® (GB); Isorythm® (FR); Isorythm LP® (FR); Norpace® (AU, CA, CH, DE, HK, ID, IN, TR, ZA); Palpitin-PP® (HU); Pyramide® (NZ); Ritmodan® (IT, PT); Ritmodan Retard® (IT, PT); Ritmoforine® (NL); Rythmical® (IL); Rythmodan® (AT, AU, BE, CA, CZ, FR, GB, HK, ID, IE, LU, NL, NZ, PL, RU, ZA); Rythmodan® [inj.] (GB); Rythmodan®-LA (CA); Rythmodan Retard® (GB, ZA); Rythmodul® (DE); Rytmilen® (CZ, ID)

References

Buxton AE, Lee KL, Fisher JD, et al, "A Randomized Study of the Prevention of Sudden Death in Patients With Coronary Artery Disease. Multicenter Unsustained Tachycardia Trial Investigators,"N Engl J Med, 1999, 341(25):1882-90.

Coplen SE, Antman EM, Berlin JA, et al, "Efficacy and Safety of Quinidine Therapy for Maintenance of Sinus Rhythm After Cardioversion. A Meta-analysis of Randomized Control Trials,"Circulation, 1990, 82(4):1106-16.

Flaker GC, Blackshear JL, McBride R, et al, "Antiarrhythmic Drug Therapy and Cardiac Mortality in Atrial Fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators,"J Am Coll Cardiol, 1992, 20(3):527-32.

Morganroth J and Goin JE, "Quinidine-Related Mortality in the Short-Term Treatment of Ventricular Arrhythmias. A Meta-analysis,"Circulation, 1991, 84(5):1977-83.

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