SIDE EFFECTS

In post-myocardial infarction patients with asymptomatic PVCs and non-sustained ventricular tachycardia, TAMBOCOR therapy was found to be associated with a 5.1% rate of death and non-fatal cardiac arrest, compared with a 2.3% rate in a matched placebo group. (See WARNINGS .)

Adverse effects reported for TAMBOCOR, described in detail in the Warnings section, were new or worsened arrhythmias which occurred in 1% of 108 patients with PSVT and in 7% of 117 patients with PAF; and new or exacerbated ventricular arrhythmias which occurred in 7% of 1330 patients with PVCs, non-sustained or sustained VT. In patients treated with flecainide for sustained VT, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. 198 patients with sustained VT experienced a 13% incidence of new or exacerbated ventricular arrhythmias when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In some patients, TAMBOCOR treatment has been associated with episodes of unresuscitatable VT or ventricular fibrillation (cardiac arrest). (See WARNINGS .) New or worsened CHF occurred in 6.3% of 1046 patients with PVCs, non-sustained or sustained VT. Of 297 patients with sustained VT, 9.1% experienced new or worsened CHF. New or worsened CHF was reported in 0.4% of 225 patients with supraventricular arrhythmias. There have also been instances of second- (0.5%) or third-degree (0.4%) AV block. Patients have developed sinus bradycardia, sinus pause, or sinus arrest, about 1.2% altogether (see WARNINGS ). The frequency of most of these serious adverse events probably increases with higher trough plasma levels, especially when these trough levels exceed 1.0 µg/mL.

There have been rare reports of isolated elevations of serum alkaline phosphatase and isolated elevations of serum transaminase levels. These elevations have been asymptomatic and no cause and effect relationship with TAMBOCOR has been established. In foreign postmarketing surveillance studies, there have been rare reports of hepatic dysfunction including reports of cholestasis and hepatic failure, and extremely rare reports of blood dyscrasias. Although no cause and effect relationship has been established, it is advisable to discontinue TAMBOCOR in patients who develop unexplained jaundice or signs of hepatic dysfunction or blood dyscrasias in order to eliminate TAMBOCOR as the possible causative agent.

Incidence figures for other adverse effects in patients with ventricular arrhythmias are based on a multicenter efficacy study, utilizing starting doses of 200 mg/day with gradual upward titration to 400 mg/day. Patients were treated for an average of 4.7 months, with some receiving up to 22 months of therapy. In this trial, 5.4% of patients discontinued due to non-cardiac adverse effects.

The following additional adverse experiences, possibly related to TAMBOCOR therapy and occurring in 1% to less than 3% of patients, have been reported in acute and chronic studies: Body as a Whole  malaise, fever; Cardiovascular tachycardia, sinus pause or arrest; Gastrointestinal  vomiting, diarrhea, dyspepsia, anorexia; Skin  rash; Visual diplopia; Nervous System  hypoesthesia, paresthesia, paresis, ataxia, flushing, increased sweating, vertigo, syncope, somnolence, tinnitus; Psychiatric  anxiety, insomnia, depression.

The following additional adverse experiences, possibly related to TAMBOCOR, have been reported in less than 1% of patients: Body as a Whole  swollen lips, tongue and mouth; arthralgia, bronchospasm, myalgia; Cardiovascular  angina pectoris, second-degree and third-degree AV block, bradycardia, hypertension, hypotension; Gastrointestinal  flatulence; Urinary System  polyuria, urinary retention; Hematologic  leukopenia, granulocytopenia, thrombocytopenia; Skin  urticaria, exfoliative dermatitis, pruritus, alopecia; Visual  eye pain or irritation, photophobia, nystagmus; Nervous System  twitching, weakness, change in taste, dry mouth, convulsions, impotence, speech disorder, stupor, neuropathy; Respiratory  pneumonitis/pulmonary infiltration possibly due to chronic flecainide treatment: Psychiatric amnesia, confusion, decreased libido, depersonalization, euphoria, morbid dreams, apathy.

For patients with supraventricular arrhythmias, the most commonly reported noncardiac adverse experiences remain consistent with those known for patients treated with TAMBOCOR for ventricular arrhythmias. Dizziness is possibly more frequent in PAF patients.

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.