TAMBOCOR (Page 2 of 4)

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.

WARNINGS

Mortality. TAMBOCOR was included in the National Heart Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a longterm, multicenter, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously. An excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with TAMBOCOR compared with that seen in patients assigned to a carefully matched placebo-treated group. This rate was 16/315 (5.1%) for TAMBOCOR and 7/309 (2.3%) for the matched placebo. The average duration of treatment with TAMBOCOR in this study was ten months.

The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain, but at present, it is prudent to consider the risks of Class IC agents (including TAMBOCOR), coupled with the lack of any evidence of improved survival, generally unacceptable in patients without life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.

Ventricular Pro-arrhythmic Effects in Patients with Atrial Fibrillation/Flutter. A review of the world literature revealed reports of 568 patients treated with oral TAMBOCOR for paroxysmal atrial fibrillation/flutter (PAF). Ventricular tachycardia was experienced in 0.4% (2/568) of these patients. Of 19 patients in the literature with chronic atrial fibrillation (CAF), 10.5% (2) experienced VT or VF. FLECAINIDE IS NOT RECOMMENDED FOR USE IN PATIENTS WITH CHRONIC ATRIAL FIBRILLATION. Case reports of ventricular proarrhythmic effects in patients treated with TAMBOCOR for atrial fibrillation/flutter have included increased PVCs, VT, ventricular fibrillation (VF), and death.

As with other Class I agents, patients treated with TAMBOCOR for atrial flutter have been reported with 1:1 atrioventricular conduction due to slowing the atrial rate. A paradoxical increase in the ventricular rate also may occur in patients with atrial fibrillation who receive TAMBOCOR. Concomitant negative chronotropic therapy such as digoxin or beta-blockers may lower the risk of this complication.

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.)

HEART FAILURE

TAMBOCOR has a negative inotropic effect and may cause or worsen CHF, particularly in patients with cardiomyopathy, preexisting severe heart failure (NYHA functional class III or IV) or low ejection fractions (less than 30%). In patients with supraventricular arrhythmias new or worsened CHF developed in 0.4% (1/225) of patients. In patients with sustained ventricular tachycardia during a mean duration of 7.9 months of TAMBOCOR therapy, 6.3% (20/317) developed new CHF. In patients with sustained ventricular tachycardia and a history of CHF, during a mean duration of 5.4 months of TAMBOCOR therapy, 25.7% (78/304) developed worsened CHF. Exacerbation of preexisting CHF occurred more commonly in studies which included patients with class III or IV failure than in studies which excluded such patients. TAMBOCOR should be used cautiously in patients who are known to have a history of CHF or myocardial dysfunction. The initial dosage in such patients should be no more than 100 mg bid (see Dosage and Administration) and patients should be monitored carefully. Close attention must be given to maintenance of cardiac function, including optimization of digitalis, diuretic, or other therapy. In cases where CHF has developed or worsened during treatment with TAMBOCOR, the time of onset has ranged from a few hours to several months after starting therapy. Some patients who develop evidence of reduced myocardial function while on TAMBOCOR can continue on TAMBOCOR with adjustment of digitalis or diuretics, others may require dosage reduction or discontinuation of TAMBOCOR. When feasible, it is recommended that plasma flecainide levels be monitored. Attempts should be made to keep trough plasma levels below 0.7 to 1.0 μg/mL.

Effects on Cardiac Conduction. TAMBOCOR slows cardiac conduction in most patients to produce dose-related increases in PR, QRS, and QT intervals. PR interval increases on average about 25% (0.04 seconds) and as much as 118% in some patients. Approximately one-third of patients may develop new first-degree AV heart block (PR interval ≥0.20 seconds). The QRS complex increases on average about 25% (0.02 seconds) and as much as 150% in some patients. Many patients develop QRS complexes with a duration of 0.12 seconds or more. In one study, 4% of patients developed new bundle branch block while on TAMBOCOR. The degree of lengthening of PR and QRS intervals does not predict either efficacy or the development of cardiac adverse effects. In clinical trials, it was unusual for PR intervals to increase to 0.30 seconds or more, or for QRS intervals to increase to 0.18 seconds or more. Thus, caution should be used when such intervals occur, and dose reductions may be considered. The QT interval widens about 8%, but most of this widening (about 60% to 90%) is due to widening of the QRS duration. The JT interval (QT minus QRS) only widens about 4% on the average. Significant JT prolongation occurs in less than 2% of patients. There have been rare cases of Torsade de Pointes-type arrhythmia associated with TAMBOCOR therapy.

Clinically significant conduction changes have been observed at these rates: sinus node dysfunction such as sinus pause, sinus arrest and symptomatic bradycardia (1.2%), second-degree AV block (0.5%) and third-degree AV block (0.4%). An attempt should be made to manage the patient on the lowest effective dose in an effort to minimize these effects. (See Dosage and Administration) If second- or third-degree AV block, or right bundle branch block associated with a left hemiblock occur, TAMBOCOR therapy should be discontinued unless a temporary or implanted ventricular pacemaker is in place to ensure an adequate ventricular rate.

Sick Sinus Syndrome (Bradycardia-Tachycardia Syndrome). TAMBOCOR should be used only with extreme caution in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pause, or sinus arrest.

Effects on Pacemaker Thresholds. TAMBOCOR is known to increase endocardial pacing thresholds and may suppress ventricular escape rhythms. These effects are reversible if flecainide is discontinued. It should be used with caution in patients with permanent pacemakers or temporary pacing electrodes and should not be administered to patients with existing poor thresholds or nonprogrammable pacemakers unless suitable pacing rescue is available.

The pacing threshold in patients with pacemakers should be determined prior to instituting therapy with TAMBOCOR, again after one week of administration and at regular intervals thereafter. Generally threshold changes are within the range of multiprogrammable pacemakers and, when these occur, a doubling of either voltage or pulse width is usually sufficient to regain capture.

Electrolyte Disturbances. Hypokalemia or hyperkalemia may alter the effects of Class I antiarrhythmic drugs. Preexisting hypokalemia or hyperkalemia should be corrected before administration of TAMBOCOR.

Pediatric Use. The safety and efficacy of TAMBOCOR in the fetus, infant, or child have not been established in double-blind, randomized, placebo-controlled trials. The proarrhythmic effects of TAMBOCOR, as described previously, apply also to children. In pediatric patients with structural heart disease, TAMBOCOR has been associated with cardiac arrest and sudden death. TAMBOCOR should be started in the hospital with rhythm monitoring. Any use of TAMBOCOR in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children.

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