Professional Information

Flecainide (Systemic)

VA CLASSIFICATION
Primary: CV300

Commonly used brand name(s): Tambocor.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Antiarrhythmic. —

Indications

Accepted

Arrhythmias, supraventricular (prophylaxis)¹—In patients without structural heart disease, flecainide is indicated for the prevention of paroxysmal supraventricular tachycardias, including atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, and other supraventricular tachycardias of unspecified mechanism associated with disabling symptoms. It is also indicated for the prevention of paroxysmal atrial fibrillation/flutter associated with disabling symptoms in patients without structural heart disease. ^{39}

Arrhythmias, ventricular (prophylaxis and treatment)—Flecainide is indicated for the prevention and suppression of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia ^{01} ^{02} ^{05} ^{15} ^{22} ^{39}.

Unaccepted
Use of flecainide is no longer accepted for treatment of less severe arrhythmias such as nonsustained ventricular tachycardias or frequent premature ventricular contractions, even if patients are symptomatic, because of results of a trial that found increased mortality in patients with non–life-threatening arrhythmias treated with flecainide ^{01} ^{37}.

Flecainide is not accepted for use in the treatment of chronic atrial fibrillation because of the increased risk for development of ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation. ^{39}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    474.40

pKa—
    9.3

Mechanism of action/Effect:

Decreases excitability, conduction velocity, and automaticity as a result of slowed atrial, atrioventricular (AV) nodal, His-Purkinje, and intraventricular conduction ^{01} ^{03} ^{04} ^{05} ^{10} ^{15} ^{17}, and causes a slight but significant prolongation of refractory periods in these tissues ^{01} ^{02} ^{03} ^{04} ^{05} ^{06} ^{10} ^{17} ^{34}. The greatest effect is on the His-Purkinje system ^{01} ^{03} ^{05}. Decreases the rate of rise of the action potential ^{07} without affecting its duration ^{02} ^{03} ^{04} ^{07}. In the Vaughan Williams classification of antiarrhythmics, flecainide is considered to be a class IC agent ^{01} ^{02} ^{03} ^{04} ^{05}.

Other actions/effects:

Mild to moderate negative inotropic effect ^{01} ^{02} ^{03} ^{05} ^{09} ^{19} ^{28}; local anesthetic activity ^{01} ^{09}.

Absorption:

Nearly complete ^{01} ^{02} ^{03} ^{05} ^{12}; not affected by food or antacids ^{01} ^{02} ^{03} ^{12}.

Protein binding:

Moderate (40%) ^{01} ^{03} ^{05} ^{12}.

Biotransformation:

Hepatic ^{01} ^{03} ^{12}.

Half-life:

Elimination—Approximately 20 hours (range, 12 to 27 hours) ^{01} ^{05} ^{08} ^{12} ^{22} ^{25} ^{32}; increased with renal or hepatic function impairment or congestive heart failure ^{01} ^{03} ^{04} ^{05} ^{12}. In addition, elimination is slowed significantly in those rare conditions where urinary pH is 8 or higher (e.g., renal tubular acidosis, strict vegetarian diet) ^{01}.

Time to peak plasma concentration

Single dose—Approximately 3 hours (range, 1 to 6 hours) ^{01} ^{03} ^{05} ^{08} ^{12}.

Time to steady-state plasma concentration

Multiple doses—3 to 5 days ^{01}.

Therapeutic trough plasma concentration

0.2 to 1.0 mcg per mL ^{02} ^{08} ^{25} ^{32} ^{33}.

Elimination:
    Renal—Approximately 30% (range, 10 to 50%) unchanged ^{01} ^{03} ^{12}.
    Fecal—5% ^{01} ^{03} ^{12}.
    In dialysis—Hemodialysis removes only about 1% of a dose as unchanged drug ^{01} ^{02} ^{03} ^{05} ^{12}.

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other amide-type anesthetics may rarely be sensitive to flecainide also. Cross-sensitivity with procainamide or quinidine has not been reported.

Carcinogenicity

Studies with flecainide in rats and mice at doses up to 8 times the usual human dose found no evidence of carcinogenicity ^{01}.

Mutagenicity

Mutagenicity studies (Ames test, mouse lymphoma, in vivo cytogenetics) found no evidence of mutagenicity ^{01}.

Pregnancy/Reproduction
Fertility—
A reproduction study in male and female rats given flecainide in doses up to 50 mg per kg of body weight (mg/kg) per day (7 times the usual human dose) did not reveal fertility impairment. ^{39}

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

Studies in New Zealand White rabbits given doses of 30 and 35 mg/kg per day revealed teratogenic and embryotoxic effects. Teratogenic effects did not occur in Dutch Belted rabbits at the same dose or in rats and mice given doses up to 50 and 80 mg/kg per day, respectively. However, delayed sternebral and vertebral ossification was seen at the high dose in rats. ^{39}

FDA Pregnancy Category C. ^{01}

Breast-feeding

Flecainide is distributed into human breast milk in concentrations as high as 4 times the corresponding plasma concentrations. The potential dose to a nursing infant, assuming a maternal plasma concentration of 1 mcg per mL (mcg/mL) and infant ingestion of 700 mL of breast milk over 24 hours, would be less than 3 mg. ^{39}

Pediatrics

Appropriate studies on the relationship of age to the effects of flecainide have not been performed in the pediatric population. Safety and efficacy have not been established.

Geriatrics

The half-life of flecainide may be somewhat prolonged in the elderly ^{01} ^{02} ^{03}, although dosage adjustment is usually not necessary ^{01}. In addition, incidence of proarrhythmic effects may be increased in the elderly, who are more likely to have underlying cardiac function impairment ^{35}. Elderly patients are also more likely to have age-related renal function impairment, which may require caution in patients receiving flecainide ^{36}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acidifiers, urinary    (by decreasing urine pH, may increase elimination of flecainide; dosage adjustment of flecainide may be necessary ^{38})

Alkalizers, urinary    (by increasing urine pH, may decrease elimination of flecainide; dosage adjustment of flecainide may be necessary ^{38})

» Antiarrhythmics, other    (concurrent use with flecainide may produce additive cardiac effects ^{01} ^{02} ^{05}; irreversible ventricular tachycardia/fibrillation has been reported in patients with hypotensive ventricular tachycardia ^{02} ^{05} ^{18})

    (concurrent use of amiodarone with flecainide has resulted in a twofold or greater increase in plasma flecainide concentrations; it is recommended that the usual dose of flecainide be reduced by 50% and plasma flecainide concentrations monitored carefully during concurrent use ^{01})

Beta-adrenergic blocking agents    (concurrent use with flecainide may result in additive negative inotropic effects ^{01} ^{02} ^{13}; in addition, concurrent use of propranolol with flecainide has resulted in increased plasma concentrations of both ^{01} ^{02} ^{05} ^{13}, but less depression of heart rate than occurs with propranolol alone ^{01} ^{02} ^{03})

Bone marrow depressants (See Appendix II )    (although problems have not been reported, concurrent use with flecainide may increase the risk of leukopenia and thrombocytopenia)

Digoxin    (concurrent use with flecainide has resulted in transiently increased plasma digoxin concentrations; no adverse effects have been reported ^{01} ^{02} ^{03} ^{05} ^{13})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Electrocardiogram (ECG) changes such as:
QRS widening and
PR prolongation and
QT prolongation secondary to QRS widening^{01}^{05}^{10}^{33}^{34}    (occur in most patients ^{01} ^{02} ^{05} ^{06} ^{08} ^{09} ^{14} ^{15} ^{16} ^{17} ^{18} ^{24} ^{26})

Note: ECG changes produced by flecainide do not necessarily indicate efficacy, toxicity, or overdose ^{01}.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Atrioventricular (AV) block, pre-existing second or third degree without pacemaker or
» Right bundle branch block associated with a left hemiblock (bifascicular block) without pacemaker    (risk of complete heart block ^{01} ^{05})

Risk-benefit should be considered when the following medical problems exist
» Cardiogenic shock    (negative inotropic effect of flecainide; increased risk of flecainide-induced arrhythmias ^{01} ^{34})

Congestive heart failure    (may be aggravated as a result of small negative inotropic effect ^{01} ^{02} ^{03} ^{05} ^{09} ^{19} ^{21}; elimination may be delayed ^{01} ^{02} ^{03} ^{22}; increased risk of flecainide-induced arrhythmias ^{01} ^{02} ^{05}; dosage reduction may be necessary ^{34})

» Hepatic function impairment    (elimination may be significantly slowed; the interval between dosage increments should be greater than 4 days, and dosage reduction may be necessary; dosage adjustments should be made on the basis of plasma flecainide determinations ^{01} ^{03})

Hypokalemia or hyperkalemia    (effects of flecainide may be altered; pre-existing hypokalemia or hyperkalemia should be corrected before administration of flecainide ^{01})

Myocardial infarction, history of, with associated left ventricular function impairment    (increased risk of flecainide-induced arrhythmias ^{01} ^{05} ^{18} ^{33})

Renal function impairment^{01}^{02}^{03}    (reduced elimination; the interval between dosage increments should be greater than 4 days ^{01} ^{05} ^{06}, and dosage reduction may be necessary ^{02} ^{03} ^{04} ^{05}; dosage adjustments should be made on the basis of plasma flecainide determinations ^{01} ^{06})

Sensitivity to flecainide^{01}
» Sick sinus syndrome    (flecainide prolongs sinus node recovery time ^{05} ^{10}; may cause sinus bradycardia, sinus pause, or sinus arrest ^{01} ^{05})

Caution is also recommended in patients with permanent pacemakers or temporary pacing electrodes because flecainide increases endocardial pacing thresholds and may suppress ventricular escape rhythms^{01}^{02}^{05}^{10} ; use is not recommended in patients with existing high thresholds or nonprogrammable pacemakers unless suitable pacing rescue is available^{01} . In patients with pacemakers, it is recommended that the pacing threshold be determined prior to initiation of therapy, after one week of administration, and then at regular intervals^{01} .

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood counts    (recommended at periodic intervals to detect bone marrow depression ^{34})

» ECG    (Holter monitoring or 24-hour ambulatory ECG recommended prior to initiation of therapy and at periodic intervals during therapy to assess efficacy and detect possible proarrhythmic effects ^{01} ^{18} ^{34})

Plasma flecainide determinations, trough    (recommended at frequent intervals to aid in dosage adjustment in patients with severe renal or hepatic disease; may also be useful in patients with congestive heart failure or moderate renal disease ^{01})

Side/Adverse Effects

Note: In the National Heart Lung and Blood Institute's Cardiac Arrhythmias Suppression Trial (CAST), flecainide treatment was found to be associated with excessive mortality or increased nonfatal cardiac arrest rate as compared with placebo in patients with asymptomatic, non–life-threatening arrhythmias who had a recent myocardial infarction ^{01}.
Adverse cardiac effects reported with flecainide administration include new or exacerbated ventricular or supraventricular arrhythmias, new or exacerbated congestive heart failure, second or third degree atrioventricular (AV) block, and rarely, sinus bradycardia, sinus pause, or sinus arrest ^{01} ^{18} ^{21} ^{24}.
Incidence of cardiac and other effects is at least partially dose-related and is increased at plasma flecainide concentrations greater than 0.7 to 1.0 mcg per mL ^{01} ^{02} ^{03} ^{16} ^{18} ^{22} ^{31}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent

Arrhythmias, including new or worsened ventricular tachyarrhythmias, increased frequency of premature ventricular contractions, or new supraventricular arrhythmias^{01} (irregular heartbeat)

chest pain

congestive heart failure (shortness of breath; swelling of feet or lower legs)

trembling or shaking

Note: Arrhythmias are dose-related and potentially fatal; incidence increased in patients with congestive heart failure or history of myocardial infarction with associated left ventricular function impairment. ^{01} ^{02} ^{03} ^{05} ^{18}

Incidence rare

Hepatic function impairment (yellow eyes or skin)

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Blurred vision or seeing spots^{01}

dizziness or lightheadedness

Incidence less frequent

Anxiety or mental depression

constipation

headache

nausea or vomiting

skin rash

stomach pain or loss of appetite

unusual tiredness or weakness

Overdose
For specific information on the agents used in the management of flecainide overdose, see:
   • Dobutamine, Dopamine, or Isoproterenol in Sympathomimetic Agents–Cardiovascular Use (Parenteral-Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
To decrease absorption—Treatment should begin with immediate evacuation of the stomach.

Specific treatment—Treatment is primarily supportive and symptomatic ^{01} and may include oxygen, mechanical respiratory assistance, circulatory assistance (e.g., intra-aortic balloon pumping), transvenous conduction pacing, administration of inotropic agents (dopamine, dobutamine, or isoproterenol), cardioversion defibrillation if sustained ventricular tachycardia attributable to flecainide's effects occurs, and if the sustained ventricular tachycardia has caused or may lead to hemodynamic decomposition and/or ventricular fibrillation ^{35}.

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Flecainide (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to flecainide or amide-type anesthetics

Pregnancy—Teratogenic in rabbits

Use in the elderly—Increased duration of action; increased risk of proarrhythmic effects
Other medications, especially other antiarrhythmics
Other medical problems, especially hepatic function impairment

Proper use of this medication
» Compliance with therapy; taking as directed even if feeling well

» Importance of not missing doses and taking at evenly spaced intervals

» Proper dosing
Missed dose: Taking as soon as possible if remembered within 6 hours; not taking if remembered later; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress

Carrying medical identification card or bracelet

» Caution if any kind of surgery (including dental surgery) or emergency treatment is required

» Caution when driving or doing things requiring alertness because of possible dizziness

Checking with physician before discontinuing medication; gradual dosage reduction may be necessary

Side/adverse effects
Signs of potential side effects, especially arrhythmias, chest pain, congestive heart failure, trembling or shaking, and hepatic function impairment

General Dosing Information
Previous antiarrhythmic therapy should be withdrawn 2 to 4 half-lives before initiation of flecainide therapy (except lidocaine, which can be used for interim control) ^{35}.

Occasionally, patients intolerant to or not adequately controlled by every-twelve-hour dosing may be dosed at eight-hour intervals ^{01}.

Because of flecainide's long half-life, dosage increments should be made no more frequently than every 4 days ^{01} ^{03} ^{18}.

It is recommended that treatment be initiated in the hospital ^{01} because of the increased risk of proarrhythmic effects associated with flecainide administration ^{01} ^{18} ^{21}.

It is recommended that flecainide therapy be withdrawn if bone marrow depression occurs.

For treatment of adverse effects
Digitalis or diuretic therapy may be useful in patients with flecainide-induced or -aggravated congestive heart failure. Dosage reduction or withdrawal of flecainide may be necessary. ^{01}

Oral Dosage Forms

FLECAINIDE ACETATE TABLETS

Usual adult dose
Paroxysmal supraventricular tachycardias or paroxysmal atrial fibrillation/flutter
Oral, 50 mg every twelve hours, the dosage being increased in increments of 50 mg two times a day every four days as needed and tolerated. ^{39}

Sustained ventricular tachycardia
Initial: Oral, 100 mg every twelve hours, the dosage being increased in increments of 50 mg two times a day every four days as needed and tolerated. ^{01} ^{05}

Note: In patients with severe renal function impairment (creatinine clearance of 35 mL per minute per 1.73 square meters of body surface or less), an initial dose of 100 mg once a day or 50 mg every twelve hours is recommended, and dosage should be adjusted on the basis of frequent plasma concentration determinations ^{01}. In patients with less severe renal function impairment, an initial dose of 100 mg every twelve hours may be used; plasma concentration determinations may be useful in dosage adjustment ^{01}.

Maintenance: Oral, up to 150 mg every twelve hours. ^{01}

Usual adult prescribing limits
Paroxysmal supraventricular arrhythmias—Up to 300 mg per day. ^{39}

Sustained ventricular tachycardia—Up to 400 mg per day. ^{01}

Usual pediatric dose
Safety and efficacy have not been established ^{01} ^{39}.

Strength(s) usually available
U.S.—

50 mg (Rx) [Tambocor][Generic]

100 mg (Rx) [Tambocor (scored)][Generic]

150 mg (Rx) [Tambocor (scored)][Generic]

Canada—

50 mg (Rx) [Tambocor (scored)]

100 mg (Rx) [Tambocor (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from light.

Revised: 08/19/1997

References

Tambocor package insert (Riker—US), 11/88.

Tambocor package insert (Riker—US), 7/89.

Smith GH. Flecainide: a new class 1c antidysrhythmic. Drug Intell Clin Pharm 1985; 19: 703-7.

Holmes B, Heel RC. Flecainide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1985; 29: 1-33.

Weintraub M, Standish R. Flecainide: a new orally active antiarrhythmic agent. Hosp Form 1984; 19: 541-6.

Nappi JM, Anderson JL. Flecainide: a new prototype antiarrhythmic agent. Pharmacother 1985; 5: 209-21.

Anderson JL. A new antiarrhythmic agent: flecainide. Primary Cardiol 1984; May.

Abitbol H, Califano JE, Abate C, Beilis P, Castellanos H. Use of flecainide acetate in the treatment of premature ventricular contractions. Am Heart J 1983; 105: 227-30.

Duff HJ, Roden DM, Maffucci RJ, et al. Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide. Am J Cardiol 1981; 48: 1133-40.

Legrand V, Vandormael M, Collignon P, Kulbertus HE. Hemodynamic effects of a new antiarrhythmic agent, flecainide (R-818), in coronary heart disease. Am J Cardiol 1983; 51: 422-6.

Estes NA, Garan H, Ruskin JN. Electrophysiologic properties of flecainide acetate. Am J Cardiol 1984; 53: 26B-29B.

Hellestrand KJ, Nathan AW, Bexton RS, Camm AJ. Electrophysiologic effects of flecainide acetate on sinus node function, anomalous atrioventricular connections, and pacemaker thresholds. Am J Cardiol 1984; 53: 30B-38B.

Conard GJ, Ober RE. Metabolism of flecainide. Am J Cardiol 1984; 53: 41B-51B.

Lewis GP, Holtzman JL. Interaction of flecainide with digoxin and propranolol. Am J Cardiol 1984; 53: 52B-57B.

Woosley RL, Siddoway LA, Duff HJ, Roden DM. Flecainide dose-response relations in stable ventricular arrhythmias. Am J Cardiol 1984; 53: 59B-65B.

Hodges M, Salerno DM, Granrud G. Am J Cardiol 1984; 53: 66B-71B.

Kjekshus J, Bathen J, Orning OM, Storstein L. A double-blind, crossover comparison of flecainide acetate and disopyramide phosphate in the treatment of ventricular premature complexes. Am J Cardiol 1984; 53: 72B-78B.

Anderson JL. Experience with electrophysiologically guided therapy of ventricular tachycardia with flecainide: summary of long-term follow-up. Am J Cardiol 1984; 53: 79B-86B.

Morganroth J, Horowitz LN. Flecainide: its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardiol 1984; 53: 89B-94B.

Josephson MA, Ikeda N, Singh BN. Effects of flecainide on ventricular function: clinical and experimental correlations. Am J Cardiol 1984; 53: 95B-100B.

Gentzkow GD, Sullivan JY. Extracardiac adverse effects of flecainide. Am J Cardiol 1984; 53: 101B-105B.

Reid PR, Griffith LS, Platia EV, Ord SE. Evaluation of flecainide acetate in the management of patients at high risk of sudden cardiac death. Am J Cardiol 1984; 53: 108B-111B.

Anderson JL, Stewart JR, Crevey BJ. A proposal for the clinical use of flecainide. Am J Cardiol 1984; 53: 112B-119B.

Hellestrand KJ, Nathan AW, Bexton RS, Spurrell RA, Camm AJ. Cardiac electrophysiologic effects of flecainide acetate for paroxysmal reentrant junctional tachycardias. Am J Cardiol 1983; 51: 771-6.

Salerno DM, Hodges M, Granrud G, Sharkey P. Comparison of flecainide with quinidine for suppression of chronic stable ventricular ectopic depolarizations. Ann Intern Med 1983; 98: 455-60.

Hodges M, Haugland JM, Granrud G, et al. Suppression of ventricular ectopic depolarizations by flecainide acetate, a new antiarrhythmic agent. Circulation 1982; 65: 879-85.

The flecainide-quinidine research group. Flecainide versus quinidine for treatment of chronic ventricular arrhythmias. Circulation 1983; 67: 1117-23.

Muhiddin KA, Turner P, Blackett A. Effect of flecainide on cardiac output. Clin Pharmacol Ther 1985; 37: 260-3.

Jackson N, Verma SP, Frais MA, et al. Hemodynamic dose-response effects of flecainide in acute myocardial infarction with and without left ventricular decompensation. Clin Pharmacol Ther 1985; 37: 619-24.

Bexton RS, Hellestrand KJ, Nathan AW, Spurrell RA, Camm AJ. A comparison of the antiarrhythmic effects on AV junctional reentrant tachycardia of oral and intravenous flecainide acetate. European Heart J 1983; 4: 92-102.

Anderson JL, Lutz JR, Allison SB. Electrophysiologic and antiarrhythmic effects of oral flecainide in patients with inducible ventricular tachycardia. J Am Coll Cardiol 1983; 2: 105-14.

Salerno D, Granrud G, Sharkey P, et al. Flecainide: correlation of side effects with drug plasma levels and ECG intervals. J Am Coll Cardiol 1984 (abstract); 3: 583.