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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Disopyramide may be confused with desipramine, dipyridamole
Norpace® may be confused with Norpramin®
Pronunciation
(dye soe PEER a mide)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
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
Use: Unlabeled/Investigational
Hypertrophic obstructive cardiomyopathy (HOCM)
Pregnancy Risk Factor
C
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
Boxed warnings:
• CAST trial: See “Other warnings/precautions” below.
Concerns related to adverse effects:
• Hypotension: May occur during the initiation of therapy; monitor closely.
• Proarrhythmic effects: Watch for proarrhythmic effects; monitor and adjust dose to prevent QTc prolongation.
Disease-related concerns:
• Atrial fibrillation/flutter: Appropriate use: In patients with atrial fibrillation or flutter, block the AV node before initiating.
• BPH/urinary retention: Do not use in patients with BPH and/or urinary retention due to significant anticholinergic effects.
• Conduction disturbances: Use with caution in patients with bundle branch block or heart block.
• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.
• Glaucoma: Do not use in patients with glaucoma due to significant anticholinergic effects.
• Heart failure (HF): Use with caution in patients with HF; may precipitate or exacerbate condition.
• Hepatic impairment: Use with caution in patients with hepatic impairment; reduced dosage recommended.
• Myasthenia gravis: Do not use in patients with myasthenia gravis due to significant anticholinergic effects.
• Renal impairment: Use with caution in renal impairment; reduced dosage recommended. The extended release form is not recommended for Clcr <40 mL/minute.
• Wolff-Parkinson-White syndrome: Use with caution in patients with Wolff-Parkinson-White syndrome.
Concurrent drug therapy issues:
• Drugs with QT prolongation potential: Avoid concurrent use with other drugs known to prolong QTc interval or decrease myocardial contractibility.
Other warnings/precautions:
• CAST trial: [U.S. Boxed Warning]: In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but <2 years ago) myocardial infarction patients with asymptomatic, non-life-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.
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: Cholesterol increased, hypokalemia, triglycerides increased
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
Metabolism/Transport Effects
Substrate of CYP3A4 (major)
Drug Interactions
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Amiodarone: Antiarrhythmic Agents (Class Ia) may enhance the QTc-prolonging effect of Amiodarone. Amiodarone may increase the metabolism of Antiarrhythmic Agents (Class Ia). Risk D: Consider therapy modification
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Barbiturates: May increase the metabolism of Disopyramide. Risk D: Consider therapy modification
Beta-Blockers: Disopyramide may enhance the bradycardic effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Cannabinoids: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoids. Risk C: Monitor therapy
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Lidocaine: Disopyramide may enhance the arrhythmogenic effect of Lidocaine. Disopyramide may increase the serum concentration of Lidocaine. Specifically, the unbound/free fraction of lidocaine. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Macrolide Antibiotics: May enhance the QTc-prolonging effect of Disopyramide. Macrolide Antibiotics may decrease the metabolism of Disopyramide. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk X: Avoid combination
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Phenytoin: May increase the metabolism of Disopyramide. Risk D: Consider therapy modification
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Risk D: Consider therapy modification
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Rifamycin Derivatives: May increase the metabolism of Disopyramide. Risk D: Consider therapy modification
Secretin: Anticholinergic Agents may diminish the stimulatory effect of Secretin. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
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).
Storage
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%
Distribution: Vd: 0.8-2 L/kg
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
Time to peak, serum: Within 2 hours
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.
Hypertrophic obstructive cardiomyopathy (unlabeled use): Initial: Controlled release: 200 mg twice daily. If symptoms do not improve, increase by 100 mg/day at 2-week intervals to a maximum daily dose of 600 mg.
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: Oral
Do not break or chew controlled release capsules. Administer around-the-clock to promote less variation in peak and trough serum levels. Should be taken on an empty stomach.
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.
Geriatric Considerations
Due to changes in total clearance (decreased) in the elderly, monitor closely; the anticholinergic action may be intolerable and require discontinuation; monitor for CNS anticholinergic effects (confusion, agitation, hallucinations, etc). Note: Dose needs to be altered with Clcr <40 mL/minute which may be found frequently in older adults.
Clinical studies of Norpace®/Norpace® CR did not include sufficient numbers of subjects ?65 years of age to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between 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 hyperplasia (medical conditions commonly associated with the elderly) unless adequate overriding measures are taken. 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.
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.
Disopyramide may be used in the treatment of HOCM as it significantly reduces the left ventricular outflow gradient and improves symptoms. Some patients may not tolerate the anticholinergic effects such as dry mouth or urinary retention, frequency, and urgency. Up to 1/3 may not improve and will require other nonpharmacologic interventions.
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
Disopyramide is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Disopyramide is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Disopyramide is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
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
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions. Assess results of laboratory tests, therapeutic effectiveness, and adverse reactions when beginning therapy, when titrating dosage, and periodically during long-term therapy. Note: Disopyramide has a low toxic:therapeutic ratio and overdose may easily produce severe and life threatening reactions. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule (Norpace®): 100 mg, 150 mg
Capsule, controlled release (Norpace® CR): 100 mg, 150 mg
Pricing: U.S. (www.drugstore.com)
Capsule, 12-hour (Norpace CR)
100 mg (60): $102.29
150 mg (60): $118.00
Capsules (Disopyramide Phosphate)
100 mg (90): $36.99
150 mg (30): $19.99
Capsules (Norpace)
100 mg (90): $141.57
150 mg (30): $57.19
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,” Am J Hosp Pharm, 1982, 39(2):309-10.
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.
Maron BJ, "Hypertrophic Cardiomyopathy: A Systematic Review," JAMA, 2002, 287(10):1308-20.
Morganroth J and Goin JE, “Quinidine-Related Mortality in the Short-to-Medium Term Treatment of Ventricular Arrhythmias," Circulation, 1991, 84(5):1977-83.
Sherrid MV, Barac I, McKenna WJ, et al, "Multicenter Study of the Efficacy and Safety of Disopyramide in Obstructive Hypertrophic Cardiomyopathy," J Am Coll Cardiol, 2005, 45(8):1251-8.
International Brand Names
Lexi-Comp.com
Last full review/revision October 2009
Content last modified October 2009
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