TAMBOCOR™
(flecainide acetate)

TABLETS

TAMBOCOR™ (flecainide acetate) is an antiarrhythmic drug available in tablets of 50, 100, or 150 mg for oral administration. Flecainide acetate is benzamide, N-(2-piperidinylmethyl)-2,5-bis (2,2,2-trifluoroethoxy)-monoacetate. The structural formula is given below.

Flecainide acetate is a white crystalline substance with a pKa of 9.3. It has an aqueous solubility of 48.4 mg/mL at 37°C.

TAMBOCOR tablets also contain: croscarmellose sodium, hydrogenated vegetable oil, magnesium stearate, microcrystalline cellulose and starch.

TAMBOCOR has local anesthetic activity and belongs to the membrane stabilizing (Class 1) group of antiarrhythmic agents; it has electrophysiologic effects characteristic of the IC class of antiarrhythmics.

In two randomized, crossover, placebo-controlled clinical trials of 16 weeks double-blind duration, 79% of patients with paroxysmal supraventricular tachycardia (PSVT) receiving flecainide were attack free, whereas 15% of patients receiving placebo remained attack free. The median time-before-recurrence of PSVT in patients receiving placebo was 11 to 12 days, whereas over 85% of patients receiving flecainide had no recurrence at 60 days.

In two randomized, crossover, placebo-controlled clinical trials of 16 weeks double-blind duration, 31% of patients with paroxysmal atrial fibrillation/flutter (PAF) receiving flecainide were attack free, whereas 8% receiving placebo remained attack free. The median time-before-recurrence of PAF in patients receiving placebo was about 2 to 3 days, whereas for those receiving flecainide the median time-before-recurrence was 15 days.

In patients without structural heart disease, TAMBOCOR is indicated for the prevention of

– paroxysmal supraventricular tachycardias (PSVT), including atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia and other supraventricular tachycardias of unspecified mechanism associated with disabling symptoms

– paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms

TAMBOCOR is also indicated for the prevention of

– documented ventricular arrhythmias, such assustained ventricular tachycardia (sustained VT), that in the judgment of the physician are life-threatening.

Use of TAMBOCOR for the treatment of sustained VT, like other antiarrhythmics, should be initiated in the hospital. The use of TAMBOCOR is not recommended in patients with less severe ventricular arrhythmias even if the patients are symptomatic.

Because of the proarrhythmic effects of TAMBOCOR, its use should be reserved for patients in whom, in the opinion of the physician, the benefits of treatment outweigh the risks.

TAMBOCOR should not be used in patients with recent myocardial infarction. (See Boxed Warnings.)

Use of TAMBOCOR in chronic atrial fibrillation has not been adequately studied and is not recommended. (See Boxed Warnings.)

As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of TAMBOCOR favorably affects survival or the incidence of sudden death.

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.

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 forsustainedventricular 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 forsustainedVT (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 withsustainedVT 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 withsustainedVT and serious underlying heart disease, and the need for careful titration and monitoring, requires that therapy of patients withsustainedVT be started in the hospital. (See Dosage and Administration.)

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 withsustainedventricular tachycardia during a mean duration of 7.9 months of TAMBOCOR therapy, 6.3% (20/317) developed new CHF. In patients withsustainedventricular 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.

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, pruritis, 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.

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.

For patients withsustainedVT, no matter what their cardiac status, TAMBOCOR, like other antiarrhythmics, should be initiated in-hospital with rhythm monitoring.

Flecainide has a long half-life (12 to 27 hours in patients). Steady-state plasma levels, in patients with normal renal and hepatic function, may not be achieved until the patient has received 3 to 5 days of therapy at a given dose. Therefore, increases in dosage should be made no more frequently than once every four days, since during the first 2 to 3 days of therapy the optimal effect of a given dose may not be achieved.

For patients with PSVT and patients with PAF the recommended starting dose is 50 mg every 12 hours. TAMBOCOR doses may be increased in increments of 50 mg bid every four days until efficacy is achieved. For PAF patients, a substantial increase in efficacy without a substantial increase in discontinuations for adverse experiences may be achieved by increasing the TAMBOCOR dose from 50 to 100 mg bid. The maximum recommended dose for patients with paroxysmal supraventricular arrhythmias is 300 mg/day.

For sustained VT the recommended starting dose is 100 mg every 12 hours. This dose may be increased in increments of 50 mg bid every four days until efficacy is achieved. Most patients with sustained VT do not require more than 150 mg every 12 hours (300 mg/day) and the maximum dose recommended is 400 mg/day.

In patients with sustained VT, use of higher initial doses and more rapid dosage adjustments have resulted in an increased incidence of proarrhythmic events and CHF, particularly during the first few days of dosing (see Warnings). Therefore, a loading dose is not recommended.

Intravenous lidocaine has been used occasionally with TAMBOCOR while awaiting the therapeutic effect of TAMBOCOR. No adverse drug interactions were apparent. However, no formal studies have been performed to demonstrate the usefulness of this regimen.

An occasional patient not adequately controlled by (or intolerant to) a dose given at 12-hour intervals may be dosed at eight-hour intervals.

Once adequate control of the arrhythmia has been achieved, it may be possible in some patients to reduce the dose as necessary to minimize side effects or effects on conduction. In such patients, efficacy at the lower dose should be evaluated.

TAMBOCOR should be used cautiously in patients with a history of CHF or myocardial dysfunction (see Warnings).

Any use of TAMBOCOR in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. Because of the evolving nature of information in this area, specialized literature should be consulted. Under six months of age, the initial starting dose of TAMBOCOR in children is approximately 50 mg/M² body surface area daily, divided into two or three equally spaced doses. Over six months of age, the initial starting dose may be increased to 100 mg/M² per day. The maximum recommended dose is 200 mg/M² per day. This dose should not be exceeded. In some children on higher doses, despite previously low plasma levels, the level has increased rapidly to far above therapeutic values while taking the same dose. Small changes in dose may also lead to disproportionate increases in plasma levels. Plasma trough (less than one hour pre-dose) flecainide levels and electrocardiograms should be obtained at presumed steady state (after at least five doses) either after initiation or change in TAMBOCOR dose, whether the dose was increased for lack of effectiveness, or increased growth of the patient. For the first year on therapy, whenever the patient is seen for reasons of clinical follow-up, it is suggested that a 12-lead electrocardiogram and plasma trough flecainide level are obtained. The usual therapeutic level of flecainide in children is 200-500 ng/mL. In some cases, levels as high as 800 ng/mL may be required for control.

In patients with severe renal impairment (creatinine clearance of 35 mL/min/1.73 square meters or less), the initial dosage should be 100 mg once daily (or 50 mg bid); when used in such patients, frequent plasma level monitoring is required to guide dosage adjustments (see Plasma Level Monitoring). In patients with less severe renal disease, the initial dosage should be 100 mg every 12 hours; plasma level monitoring may also be useful in these patients during dosage adjustment. In both groups of patients, dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days), observing the patient closely for signs of adverse cardiac effects or other toxicity. It should be borne in mind that in these patients it may take longer than four days before a new steady-state plasma level is reached following a dosage change.

Based on theoretical considerations, rather than experimental data, the following suggestion is made: when transferring patients from another antiarrhythmic drug to TAMBOCOR allow at least two to four plasma half-lives to elapse for the drug being discontinued before starting TAMBOCOR at the usual dosage. In patients where withdrawal of a previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, the physician should consider hospitalizing the patient.

When flecainide is given in the presence of amiodarone, reduce the usual flecainide dose by 50% and monitor the patient closely for adverse effects.

Plasma level monitoring is strongly recommended to guide dosage with such combination therapy (see below).

All tablets are embossed with 3M on one side and TR 50, TR 100 or TR 150 on the other side.

Tambocor, 50 mg per white, round tablet, is available in

      Bottles of 100 – NDC #0089-0305-10

Tambocor, 100 mg per white, round, scored tablet, is available in

      Bottles of 100 – NDC #0089-0307-10

Tambocor, 150 mg per white, oval, scored tablet, is available in

      Bottles of 100 – NDC #0089-0314-10

Store at controlled room temperature 15°-30°C (59°-86°F) in a tight, light-resistant container.

Rx only

600900 JUNE 1998

Manufactured by

3M Pharmaceuticals

Northridge, CA 91324 3M