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Propafenone (Propafenone Hydrochloride) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Quinidine

Small doses of quinidine completely inhibit the hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers (see CLINICAL PHARMACOLOGY). There is, as yet, too little information to recommend concomitant use of propafenone and quinidine.

Local Anesthetics

Concomitant use of local anesthetics (i.e., during pacemaker implantations, surgery, or dental use) may increase the risks of central nervous system side effects.

Digitalis

Propafenone hydrochloride produces dose-related increases in serum digoxin levels ranging from about 35% at 450 mg/day to 85% at 900 mg/day of propafenone without affecting digoxin renal clearance. These elevations of digoxin levels were maintained for up to 16 months during concomitant administration. Plasma digoxin levels of patients on concomitant therapy should be measured, and digoxin dosage should ordinarily be reduced when propafenone is started, especially if a relatively large digoxin dose is used or if plasma concentrations are relatively high.

Beta-Antagonists

In a study involving healthy subjects, concomitant administration of propafenone and propranolol has resulted in substantial increases in propranolol plasma concentration and elimination half-life with no change in propafenone plasma levels from control values. Similar observations have been reported with metoprolol. Propafenone appears to inhibit the hydroxylation pathway for the two beta-antagonists (just as quinidine inhibits propafenone metabolism). Increased plasma concentrations of metoprolol could overcome its relative cardioselectivity. In propafenone clinical trials, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects. While the therapeutic range for beta-blockers is wide, a reduction in dosage may be necessary during concomitant administration with propafenone.

Warfarin

In a study of eight healthy subjects receiving propafenone and warfarin concomitantly, mean steady-state warfarin plasma concentrations increased 39% with a corresponding increase in prothrombin times of approximately 25%. It is therefore recommended that prothrombin times be routinely monitored and the dose of warfarin be adjusted if necessary.

Cimetidine

Concomitant administration of propafenone and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone with no detectable changes in electrocardiographic parameters beyond that measured on propafenone alone.

Desipramine

Concomitant administration of propafenone and desipramine may result in elevated serum desipramine levels. Both desipramine, a tricyclic antidepressant, and propafenone are cleared by oxidative pathways of demthylation and hydroxylation carried out by the hepatic P-450 cytochrome.

Cyclosporin

Propafenone therapy may increase levels of cyclosporin.

Theophylline

Propafenone may increase theophylline concentration during concomitant therapy with the development of theophylline toxicity.

Rifampin

Rifampin may accelerate the metabolism and decrease the plasma levels and antiarrhythmic efficacy of propafenone.

Other

Limited experience with propafenone combined with calcium antagonists and diuretics has been reported without evidence of clinically significant adverse reactions. Drugs that inhibit CYP2D6, CYP1A2 and CYP3A4 might lead to increased plasma levels of propafenone. When propafenone is administered with inhibitors of these enzymes, the patients should be closely monitored and the dose adjusted accordingly.

OVERDOSAGE

The symptoms of overdosage, which are usually most severe within 3 hours of ingestion, may include hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and rarely convulsions and high grade ventricular arrhythmias. Defibrillation as well as infusion of dopamine and isoproterenol have been effective in controlling rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary.

CONTRAINDICATIONS

Propafenone HCl is contraindicated in the presence of uncontrolled congestive heart failure, cardiogenic shock, sinoatrial, atrioventricular and intraventricular disorders of impulse generation and/or conduction (e.g., sick sinus node syndrome, atrioventricular block) in the absence of an artificial pacemaker, bradycardia, marked hypotension, bronchospastic disorders, manifest electrolyte imbalance, and known hypersensitivity to the drug.

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