Tambocor (Flecainide Acetate) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Drug Interactions. TAMBOCOR has been administered to patients receiving digitalis preparations or beta-adrenergic blocking agents without adverse effects. During administration of multiple oral doses of TAMBOCOR to healthy subjects stabilized on a maintenance dose of digoxin, a 13% - 19% increase in plasma digoxin levels occurred at six hours postdose.

In a study involving healthy subjects receiving TAMBOCOR and propranolol concurrently, plasma flecainide levels were increased about 20% and propranolol levels were increased about 30% compared to control values. In this formal interaction study, TAMBOCOR and propranolol were each found to have negative inotropic effects; when the drugs were administered together, the effects were additive. The effects of concomitant administration of TAMBOCOR and propranolol on the PR interval were less than additive. In TAMBOCOR clinical trials, patients who were receiving beta blockers concurrently did not experience an increased incidence of side effects. Nevertheless, the possibility of additive negative inotropic effects of beta blockers and flecainide should be recognized.

Flecainide is not extensively bound to plasma proteins. In vitro studies with several drugs which may be administered concomitantly showed that the extent of flecainide binding to human plasma proteins is either unchanged or only slightly less. Consequently, interactions with other drugs which are highly protein bound (e.g., anticoagulants) would not be expected. TAMBOCOR has been used in a large number of patients receiving diuretics without apparent interaction. Limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination. In healthy subjects receiving cimetidine (1 gm daily) for one week, plasma flecainide levels increased by about 30% and half-life increased by about 10%.

When amiodarone is added to flecainide therapy, plasma flecainide levels may increase two-fold or more in some patients, if flecainide dosage is not reduced. (See Dosage And Administration)

Drugs that inhibit cytochrome P450IID6, such as quinidine, might increase the plasma concentrations of flecainide in patients that are on chronic flecainide therapy; especially if these patients are extensive metabolizers.

There has been little experience with the coadministration of TAMBOCOR and either disopyramide or verapamil. Because both of these drugs have negative inotropic properties and the effects of coadministration with TAMBOCOR are unknown, neither disopyramide nor verapamil should be administered concurrently with TAMBOCOR unless, in the judgment of the physician, the benefits of this combination outweigh the risks. There has been too little experience with the coadministration of TAMBOCOR with nifedipine or diltiazem to recommend concomitant use.

OVERDOSAGE

No specific antidote has been identified for the treatment of TAMBOCOR overdosage. Overdoses ranging up to 8000 mg have been survived, with peak plasma flecainide concentrations as high as 5.3 μg/mL. Untoward effects in these cases included nausea and vomiting, convulsions, hypotension, bradycardia, syncope, extreme widening of the QRS complex, widening of the QT interval, widening of the PR interval, ventricular tachycardia, AV nodal block, asystole, bundle branch block, cardiac failure, and cardiac arrest. The spectrum of events observed in fatal cases was much the same as that seen in the non-fatal cases. Death has resulted following ingestion of as little as 1000 mg; concomitant overdose of other drugs and/or alcohol in many instances undoubtedly contributed to the fatal outcome. Treatment of overdosage should be supportive and may include the following: removal of unabsorbed drug from the gastrointestinal tract, administration of inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol; mechanically assisted respiration; circulatory assists such as intra-aortic balloon pumping; and transvenous pacing in the event of conduction block. Because of the long plasma half-life of flecainide (12 to 27 hours in patients receiving usual doses), and the possibility of markedly non-linear elimination kinetics at very high doses, these supportive treatments may need to be continued for extended periods of time.

Hemodialysis is not an effective means of removing flecainide from the body. Since flecainide elimination is much slower when urine is very alkaline (pH 8 or higher), theoretically, acidification of urine to promote drug excretion may be beneficial in overdose cases with very alkaline urine. There is no evidence that acidification from normal urinary pH increases excretion.

CONTRAINDICATIONS

TAMBOCOR is contraindicated in patients with pre-existing second- or third-degree AV block, or with right bundle branch block when associated with a left hemiblock (bifascicular block), unless a pacemaker is present to sustain the cardiac rhythm should complete heart block occur. TAMBOCOR is also contraindicated in the presence of cardiogenic shock or known hypersensitivity to the drug.

PROARRHYTHMIC EFFECTS

TAMBOCOR, like other antiarrhythmic agents, can cause new or worsened supraventricular or ventricular arrhythmias. Ventricular proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, e.g., tachycardia that is more sustained or more resistant to conversion to sinus rhythm, with potentially fatal consequences. In studies of ventricular arrhythmia patients treated with TAMBOCOR, three-fourths of proarrhythmic events were new or worsened ventricular tachyarrhythmias, the remainder being increased frequency of PVCs or new supraventricular arrhythmias. In patients treated with flecainide for sustained ventricular tachycardia, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. In studies of 225 patients with supraventricular arrhythmia (108 with paroxysmal supraventricular tachycardia and 117 with paroxysmal atrial fibrillation), there were 9 (4%) proarrhythmic events, 8 of them in patients with paroxysmal atrial fibrillation. Of the 9, 7 (including the one in a PSVT patient) were exacerbations of supraventricular arrhythmias (longer duration, more rapid rate, harder to reverse) while 2 were ventricular arrhythmias, including one fatal case of VT/VF and one wide complex VT (the patient showed inducible VT, however, after withdrawal of flecainide), both in patients with paroxysmal atrial fibrillation and known coronary artery disease.

It is uncertain if TAMBOCOR's risk of proarrhythmia is exaggerated in patients with chronic atrial fibrillation (CAF), high ventricular rate, and/or exercise. Wide complex tachycardia and ventricular fibrillation have been reported in two of 12 CAF patients undergoing maximal exercise tolerance testing.

In patients with complex ventricular arrhythmias, it is often difficult to distinguish a spontaneous variation in the patient's underlying rhythm disorder from drug-induced worsening, so that the following occurrence rates must be considered approximations. Their frequency appears to be related to dose and to the underlying cardiac disease.

Among patients treated for sustained VT (who frequently also had CHF, a low ejection fraction, a history of myocardial infarction and/or an episode of cardiac arrest), the incidence of proarrhythmic events was 13% when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In early studies in patients with sustained VT utilizing a higher initial dose (400 mg/day) the incidence of proarrhythmic events was 26%; moreover, in about 10% of the patients treated proarrhythmic events resulted in death, despite prompt medical attention. With lower initial doses, the incidence of proarrhythmic events resulting in death decreased to 0.5% of these patients. Accordingly, it is extremely important to follow the recommended dosage schedule. (See Dosage and Administration.)

The relatively high frequency of proarrhythmic events in patients with sustained VT and serious underlying heart disease, and the need for careful titration and monitoring, requires that therapy of patients with sustained VT be started in the hospital. (See Dosage and Administration.)