Norpace Information
Norpace () Description
Norpace () (disopyramide phosphate) is an antiarrhythmic drug available for oral administration in immediate-release and controlled-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 Norpace () is:
Norpace () 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.
Norpace () is a racemic mixture of and isomers. This drug is not chemically related to other antiarrhythmic drugs.
Norpace () CR (controlled-release) capsules are designed to afford a gradual and consistent release of disopyramide. Thus, for maintenance therapy, Norpace () CR provides the benefit of less-frequent dosing (every 12 hours) as compared with the every-6-hour dosage schedule of immediate-release Norpace () capsules.
Inactive ingredients of Norpace () include corn starch, edible ink, FD&C Red No. 3, FD&C Yellow No. 6, gelatin, lactose, talc, and titanium dioxide; the 150-mg capsule also contains FD&C Blue No. 1.
Inactive ingredients of Norpace () CR include corn starch, D&C Yellow No. 10, edible ink, ethylcellulose, FD&C Blue No. 1, gelatin, shellac, sucrose, talc, and titanium dioxide; the 150-mg capsule also contains FD&C Red No. 3 and FD&C Yellow No. 6.
Norpace () Clinical Pharmacology
Following oral administration of immediate-release Norpace () , disopyramide phosphate is rapidly and almost completely absorbed, and peak plasma levels are usually attained within 2 hours. The usual therapeutic plasma levels of disopyramide base are 2 to 4 mcg/ml, and at these concentrations protein binding varies from 50% to 65%. Because of concentration-dependent protein binding, it is difficult to predict the concentration of the free drug when total drug is measured.
The mean plasma half-life of disopyramide in healthy humans is 6.7 hours (range of 4 to 10 hours). In six patients with impaired renal function (creatinine clearance less than 40 ml/min), disopyramide half-life values were 8 to 18 hours.
After the oral administration of 200 mg of disopyramide to 10 cardiac patients with borderline to moderate heart failure, the time to peak serum concentration of 2.3 ± 1.5 hours (mean ± SD) was increased, and the mean peak serum concentration of 4.8 ± 1.6 mcg/ml was higher than in healthy volunteers. After intravenous administration in these same patients, the mean elimination half-life was 9.7 ± 4.2 hours (range in healthy volunteers of 4.4 to 7.8 hours). In a second study of the oral administration of disopyramide to 7 patients with heart disease, including left ventricular dysfunction, the mean plasma half-life was slightly prolonged to 7.8 ± 1.9 hours (range of 5 to 9.5 hours).
In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite, and 10% as the other metabolites. The plasma concentration of the major metabolite is approximately one tenth that of disopyramide. Altering the urinary pH in man does not affect the plasma half-life of disopyramide.
In a crossover study in healthy subjects, the bio-availability of disopyramide from Norpace () CR capsules was similar to that from the immediate-release capsules. With a single 300-mg oral dose, peak disopyramide plasma concentrations of 3.23 ± 0.75 mcg/ml (mean ± SD) at 2.5 ± 2.3 hours were obtained with two 150-mg immediate-release capsules and 2.22 ± 0.47 mcg/ml at 4.9 ± 1.4 hours with two 150-mg Norpace () CR capsules. The elimination half-life of disopyramide was 8.31 ± 1.83 hours with the immediate-release capsules and 11.65 ± 4.72 hours with Norpace () CR capsules. The amount of disopyramide and mono-N-dealkylated metabolite excreted in the urine in 48 hours was 128 and 48 mg, respectively, with the immediate-release capsules, and 112 and 33 mg, respectively, with Norpace () CR capsules. The differences in the urinary excretion of either constituent were not statistically significant.
Following multiple doses, steady-state plasma levels of between 2 and 4 mcg/ml were attained following either 150 mg every-6-hour dosing with immediate-release capsules or 300 mg every-12-hour dosing with Norpace () CR capsules.
Norpace () Indications And Usage
Norpace () and Norpace () CR are indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgment of the physician, are life-threatening. Because of the proarrhythmic effects of Norpace () and Norpace () CR, their use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.
Initiation of Norpace () or Norpace () CR treatment, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital. Norpace () CR should not be used initially if rapid establishment of disopyramide plasma levels is desired.
Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.
Norpace () 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.
Norpace () Warnings
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 non-life-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 (e.g., those without recent myocardial infarction) is uncertain. Considering the known proarrhythmic properties of Norpace () or Norpace () CR and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of Norpace () or Norpace () CR as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.
Norpace () Precautions
If phenytoin or other hepatic enzyme inducers are taken concurrently with Norpace () or Norpace () CR, 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 Norpace () . Excessive widening of the QRS complex and/or prolongation of the Q-T interval may occur in these situations (see ). In healthy subjects, no significant drug-drug interaction was observed when Norpace () was coadministered with either propranolol or diazepam. Concomitant administration of Norpace () and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels. Norpace () 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 cytochrome P450 3A4 (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 coadministration of disopyramide with inhibitors of cytochrome 3A4 could result in potentially fatal interaction.
Clinical studies of Norpace () /Norpace () 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 ). 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 and ).
Norpace () Adverse Reactions
The adverse reactions which were reported in Norpace () clinical trials encompass observations in 1,500 patients, including 90 patients studied for at least 4 years. The most serious adverse reactions are hypotension and congestive heart failure. The most common adverse reactions, which are dose dependent, are associated with the anticholinergic properties of the drug. These may be transitory, but may be persistent or can be severe. Urinary retention is the most serious anticholinergic effect.
The following reactions were reported in 10% to 40% of patients:
Anticholinergic: dry mouth (32%), urinary hesitancy (14%), constipation (11%)
The following reactions were reported in 3% to 9% of patients:
Anticholinergic: blurred vision, dry nose/eyes/throat
Genitourinary: urinary retention, urinary frequency and urgency
Gastrointestinal: nausea, pain/bloating/gas
General: dizziness, general fatigue/muscle weakness, headache, malaise, aches/pains
The following reactions were reported in 1% to 3% of patients:
Genitourinary: impotence
Cardiovascular: hypotension with or without congestive heart failure, increased congestive heart failure (see ), cardiac conduction disturbances (see ), edema/weight gain, shortness of breath, syncope, chest pain
Gastrointestinal: anorexia, diarrhea, vomiting
Dermatologic: generalized rash/dermatoses, itching
Central nervous system: nervousness
Other: hypokalemia, elevated cholesterol/triglycerides
The following reactions were reported in less than 1%:
Depression, insomnia, dysuria, numbness/tingling, elevated liver enzymes, AV block, elevated BUN, elevated creatinine, decreased hemoglobin/hematocrit
Hypoglycemia has been reported in association with Norpace () administration (see ).
Infrequent occurrences of reversible cholestatic jaundice, fever, and respiratory difficulty have been reported in association with disopyramide therapy, as have rare instances of thrombocytopenia, reversible agranulocytosis, and gynecomastia. Some cases of LE (lupus erythematosus) symptoms have been reported; most cases occurred in patients who had been switched to disopyramide from procainamide following the development of LE symptoms. Rarely, acute psychosis has been reported following Norpace () therapy, with prompt return to normal mental status when therapy was stopped. The physician should be aware of these possible reactions and should discontinue Norpace () or Norpace () CR therapy promptly if they occur.
Norpace () Overdosage
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 LD of disopyramide phosphate is 580 and 700 mg/kg for rats and mice, respectively.
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.
Norpace () Dosage And Administration
The dosage of Norpace () or Norpace () CR must be individualized for each patient on the basis of response and tolerance. The usual adult dosage of Norpace () or Norpace () CR is 400 to 800 mg per day given in divided doses. The recommended dosage for most adults is 600 mg/day given in divided doses (either 150 mg every 6 hours for immediate-release Norpace () or 300 mg every 12 hours for Norpace () CR). For patients whose body weight is less than 110 pounds (50 kg), the recommended dosage is 400 mg/day given in divided doses (either 100 mg every 6 hours for immediate-release Norpace () or 200 mg every 12 hours for Norpace () CR). 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.
For patients with moderate renal insufficiency (creatinine clearance greater than 40 ml/min) or hepatic insufficiency, the recommended dosage is 400 mg/day given in divided doses (either 100 mg every 6 hours for immediate-release Norpace () or 200 mg every 12 hours for Norpace () CR).
For patients with severe renal insufficiency (C 40 ml/min or less), the recommended dosage regimen of immediate-release Norpace () is 100 mg at intervals shown in the table below, with or without an initial loading dose of 150 mg.
The above dosing schedules are for Norpace () immediate-release capsules; Norpace () CR is not recommended for patients with severe renal insufficiency.
For patients in whom rapid control of ventricular arrhythmia is essential, an initial loading dose of 300 mg of immediate-release Norpace () (200 mg for patients whose body weight is less than 110 pounds) is recommended, followed by the appropriate maintenance dosage. Therapeutic effects are usually attained 30 minutes to 3 hours after administration of a 300-mg loading dose. If there is no response or evidence of toxicity within 6 hours of the loading dose, 200 mg of immediate-release Norpace () every 6 hours may be prescribed instead of the usual 150 mg. If there is no response to this dosage within 48 hours, either Norpace () should then be discontinued or the physician should consider hospitalizing the patient for careful monitoring while subsequent immediate-release Norpace () doses of 250 mg or 300 mg every 6 hours are given. A limited number of patients with severe refractory ventricular tachycardia have tolerated daily doses of Norpace () up to 1600 mg per day (400 mg every 6 hours), resulting in disopyramide plasma levels up to 9 mcg/ml. If such treatment is warranted, it is essential that patients be hospitalized for close evaluation and continuous monitoring.
Norpace () CR should not be used initially if rapid establishment of disopyramide plasma levels is desired.
Norpace () How Supplied
Norpace () (disopyramide phosphate) is supplied in hard gelatin capsules containing either 100 mg or 150 mg of disopyramide base, present as the phosphate.
Norpace () 100-mg capsules are white and orange, with markings SEARLE, 2752, Norpace () , and 100 MG.
Norpace () 150-mg capsules are brown and orange, with markings SEARLE, 2762, Norpace () , and 150 MG.
Norpace () CR (disopyramide phosphate) Controlled-Release is supplied as specially prepared controlled-release beads in hard gelatin capsules containing either 100 mg or 150 mg of disopyramide base, present as the phosphate.
Norpace () CR 100-mg capsules are white and light green, with markings SEARLE, 2732, Norpace () CR, and 100 mg.
Norpace () CR 150-mg capsules are brown and light green, with markings SEARLE, 2742, Norpace () CR, and 150 mg.
Norpace ()
Norpace () Principal Display Panel - Mg Bottle Label
Norpace () Principal Display Panel - Mg Bottle Label
Norpace () Principal Display Panel - Mg Bottle Label
Norpace () Principal Display Panel - Mg Bottle Label
