Norpace (Disopyramide Phosphate) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Carcinogenesis, Mutagenesis, Impairment of Fertility

Eighteen months of Norpace 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. Norpace, at doses up to 250 mg/kg/day, did not adversely affect fertility of rats.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Norpace 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. Norpace or Norpace CR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

CONTRAINDICATIONS

Norpace and Norpace CR are contraindicated in the presence of cardiogenic shock, preexisting second- or third-degree AV block (if no pacemaker is present), congenital Q-T prolongation, or known hypersensitivity to the drug.