"Mutations in the TTN gene, which are commonly found in idiopathic dilated cardiomyopathy, also seem common in peripartum cardiomyopathyâ€”which may finally help explain why the latter condition occurs, new research suggests.
In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study in patients with asymptomatic nonlife-threatening ventricular arrhythmias who had had a myocardial infarction more than 6 days but less than 2 years previously, an excessive mortality or non-fatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to carefully matched placebo-treated groups (3.0%). The average duration of treatment with encainide or flecainide in this study was 10 months.
The applicability of the CAST results to other populations (eg, those without recent myocar-dial infarction) is uncertain. Considering the known proarrhythmic properties of Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.
Negative Inotropic Properties
Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR may cause or worsen congestive heart failure or produce severe hypoten-sion as a consequence of its negative inotropic properties. Hypotension has been observed primarily in patients with primary cardiomyopathy or inadequately compensated congestive heart failure. Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR should not be used in patients with uncompensated or marginally compensated congestive heart failure or hypo-tension unless the congestive heart failure or hypotension is secondary to cardiac arrhythmia. Patients with a history of heart failure may be treated with Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR, but careful attention must be given to the maintenance of cardiac function, including optimal digitalization. If hypotension occurs or congestive heart failure worsens, Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR should be discontinued and, if necessary, restarted at a lower dosage only after adequate cardiac compensation has been established.
Although it is unusual, significant widening (greater than 25%) of the QRS complex may occur during Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR administration; in such cases Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR should be discontinued.
As with other Type 1 antiarrhythmic drugs, prolongation of the Q-T interval (corrected) and worsening of the arrhythmia, including ventricular tachycardia and ventricular fibrillation, may occur. Patients who have evidenced prolongation of the Q-T interval in response to quinidine may be at particular risk. As with other Type 1A antiar-rhythmics, disopyramide phosphate has been associated with torsade de pointes.
If a Q-T prolongation of greater than 25% is observed and if ectopy continues, the patient should be monitored closely, and consideration be given to discontinuing Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR.
In rare instances significant lowering of blood glucose values has been reported during Norpace (disopyramide phosphate) administration. The physician should be alert to this possibility, especially in patients with congestive heart failure, chronic malnutrition, hepatic, renal or other diseases, or drugs (eg, beta adrenocep-tor blockers, alcohol) which could compromise preservation of the normal glucoregulatory mechanisms in the absence of food. In these patients the blood glucose levels should be carefully followed.
Concomitant Antiarrhythmic Therapy
The concomitant use of Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR with other Type 1A antiarrhythmic agents (such as quinidine or procainamide), Type 1C antiar-rhythmics (such as encainide, flecainide or propafenone), and/or propranolol 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.
If first-degree heart block develops in a patient receiving Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR, 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 degrees of heart block. Development of second- or third-degree AV block or uni-fascicular, bifascicular, or trifascicular block requires discontinuation of Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR therapy, unless the ventricular rate is adequately controlled by a temporary or implanted ventricular pacemaker.
Because of its anticholinergic activity, disopyr-amide phosphate should not be used in patients with glaucoma, myasthenia gravis, or urinary retention unless adequate overriding measures are taken; these consist of the topical application of potent miotics (eg, pilocarpine) for patients with glaucoma, and catheter drainage or operative relief for patients with urinary retention. Urinary retention may occur in patients of either sex as a consequence of Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR administration, but males with benign prostatic hypertrophy are at particular risk. In patients with a family history of glaucoma, intraocular pressure should be measured before initiating Norpace or Norpace CR therapy. Disopyramide phosphate should be used with special care in patients with myasthenia gravis since its anticholinergic properties could precipitate a myasthenic crisis in such patients.
Patients with atrial flutter or fibrillation should be digitalized prior to Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR administration to ensure that drug-induced enhancement of AV conduction does not result in an increase of ventricular rate beyond physiologically acceptable limits.
Care should be taken when prescribing Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR 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.
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 Norpace (disopyramide phosphate) should not be given to such patients, and initial dosage and subsequent dosage adjustments should be made under close supervision (see DOSAGE AND ADMINISTRATION).
More than 50% of disopyramide is excreted in the urine unchanged. Therefore Norpace (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).
Norpace (disopyramide phosphate) CR is not recommended for patients with severe renal insufficiency (creatinine clearance 40 ml/min or less).
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 Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR.
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 Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR therapy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Eighteen months of Norpace (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. Nor-pace, at doses up to 250 mg/kg/day, did not adversely affect fertility of rats.
Teratogenic Effects: Pregnancy Category C. Norpace (disopyramide phosphate) 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. Nor-pace or Norpace (disopyramide phosphate) CR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects:Norpace (disopyramide phosphate) 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 Norpace (disopyramide phosphate) or Nor-pace CR 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.
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 Norpace (disopyramide phosphate) or Norpace (disopyramide phosphate) CR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drugto the mother.
Safety and effectiveness in pediatric patients have not been established (see DOSAGE AND ADMINISTRATION).
Clinical studies of Norpace (disopyramide phosphate) /Norpace (disopyramide phosphate) CR 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).This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/4/2017
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