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Flecainide

Pronunciation

Pronunciation

(fle KAY nide)

Index Terms

  • Flecainide Acetate
  • Tambocor

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as acetate:

Tambocor: 50 mg [DSC], 100 mg [DSC], 150 mg [DSC]

Generic: 50 mg, 100 mg, 150 mg

Brand Names: U.S.

  • Tambocor [DSC]

Pharmacologic Category

  • Antiarrhythmic Agent, Class Ic

Pharmacology

Class Ic antiarrhythmic; slows conduction in cardiac tissue by altering transport of ions across cell membranes; causes slight prolongation of refractory periods; decreases the rate of rise of the action potential without affecting its duration; increases electrical stimulation threshold of ventricle, His-Purkinje system; possesses local anesthetic and moderate negative inotropic effects

Absorption

Oral: Nearly complete; decreased when administered with milk

Excretion

Urine (30% [range: 10% to 50%] as unchanged drug); feces (5%)

Time to Peak

Serum: ~3 hours (range: 1 to 6 hours)

Half-Life Elimination

Newborns: Up to ≤29 hours; 3 months: 11 to 12 hours; 12 months: 6 hours

Children: ~8 hours

Adolescents 12 to 15 years: ~11 to 12 hours

Adults: ~20 hours (range: 12 to 27 hours); increased in patients with heart failure (NYHA Class III) or renal dysfunction

Protein Binding

~40%

Use: Labeled Indications

Paroxysmal atrial fibrillation/flutter and paroxysmal supraventricular tachycardias (prevention): For the prevention of paroxysmal atrial fibrillation/flutter associated with disabling symptoms and paroxysmal supraventricular tachycardias (PSVT), including atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, and other supraventricular tachycardias of unspecified mechanism associated with disabling symptoms in patients without structural heart disease.

Ventricular arrhythmias (prevention): Prevention of documented life-threatening ventricular tachyarrhythmias (eg, sustained ventricular tachycardia) in patients without structural heart disease.

Limitations of use: Use of flecainide is not recommended in patients with less severe ventricular arrhythmias, even if symptomatic. Because of the proarrhythmic effects of flecainide, its use should be reserved for patients in whom the benefits of treatment outweigh the risks. Flecainide should not be used in patients with chronic atrial fibrillation (not adequately studied) or recent MI. No evidence from controlled trials have demonstrated favorable effects of flecainide on survival or the incidence of sudden death.

Use: Unlabeled

Atrial fibrillation or flutter (pharmacologic cardioversion)

Contraindications

Hypersensitivity to flecainide or any component of the formulation; pre-existing second- or third-degree AV block or with right bundle branch block when associated with a left hemiblock (bifascicular block) (except in patients with a functioning artificial pacemaker); cardiogenic shock; concurrent use of ritonavir

According to the American College of Cardiology/American Heart Association/European Society of Cardiology, the use of flecainide is considered contraindicated in patients with structural heart disease (ACC/AHA/ESC [Blomstrom-Lundqvist 2003]).

Dosing: Adult

Ventricular arrhythmias (prevention): Oral:

Initial: 100 mg every 12 hours; increase by 50 mg twice daily at 4-day intervals; maximum: 400 mg per day. Some patients inadequately controlled with or intolerant to dosing every 12 hours may require dosing every 8 hours. Note: Initiate therapy in a hospital setting in patients with sustained ventricular tachycardia. Use of higher initial doses and more rapid dosage adjustments have resulted in an increased incidence of proarrhythmic events and congestive heart failure, particularly during the first few days. Do not use a loading dose. Use very cautiously in patients with history of congestive heart failure or myocardial infarction.

Paroxysmal atrial fibrillation/flutter and paroxysmal supraventricular tachycardias (prevention): Oral: Initial: 50 mg every 12 hours; increase by 50 mg twice daily at 4-day intervals; maximum total dose: 300 mg. The AHA/ACC/HRS atrial fibrillation guidelines recommend a maximum total daily dose of 400 mg (AHA/ACC/HRS [January 2014]).

Atrial fibrillation or flutter (pharmacological cardioversion) (off-label dose): Oral: Outpatient: "Pill-in-the-pocket" dose: Note: May not repeat in ≤24 hours (Alboni 2004; AHA/ACC/HRS [January 2014]). An initial inpatient cardioversion trial should have been successful before sending patient home on this approach. Patient must be taking an AV nodal-blocking agent (eg, beta-blocker, nondihydropyridine calcium channel blocker) prior to initiation of antiarrhythmic.

<70 kg: 200 mg

≥70 kg: 300 mg

Conversion from another antiarrhythmic agent: Allow for 2 to 4 half-lives of the other agent after discontinuation to pass before initiating flecainide therapy.

Dosage adjustment for concomitant therapy: Amiodarone: Reduce the flecainide dose by 50% and monitor the patient closely for adverse effects; monitoring of plasma concentrations is strongly recommended to guide dosage.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Arrhythmias (prevention): Manufacturer's labeling: BSA-directed dosing: Use caution with dose titration, as small change in dose may result in disproportionate increase in plasma concentrations.

Infants ≤6 months: Oral: Initial: 50 mg/m2/day divided every 8 to 12 hours; may titrate dose at 4 day intervals; maximum daily dose: 200 mg/m2/day; higher doses have been associated with an increased risk of proarrhythmic effects

Infants >6 months, Children, and Adolescents: Oral: Initial: 100 mg/m2/day divided every 8 to 12 hours; may titrate dose at 4 day intervals; maximum daily dose: 200 mg/m2/day; higher doses have been associated with an increased risk of proarrhythmic effects

Dosing: Renal Impairment

CrCl >35 mL/minute/1.73 m2: Adults: Initial: 100 mg every 12 hours; consider obtaining plasma concentrations to guide dosage adjustments. Dose increases should be made very cautiously at intervals >4 days.

CrCl ≤35 mL/minute/1.73 m2: Adults: Initial: 100 mg once daily or 50 mg every 12 hours; obtain plasma concentrations to guide dosage adjustments. Dose increases should be made very cautiously at intervals >4 days and serum trough concentrations monitored frequently. In patients with end stage renal disease, renal clearance is very low as compared to patients with moderate renal impairment and the plasma half-life may extend up to 58 hours (Conard 1984).

Hemodialysis: Removal by hemodialysis is negligible (only ~1% of an oral dose)

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however elimination from the plasma may be slower in patients with hepatic impairment. Use with caution; obtain plasma concentrations to guide dosage adjustments. Dose increases should be made very cautiously at intervals >4 days and serum concentrations monitored frequently. Frequent plasma level monitoring is required in patients with severe hepatic impairment; if unavailable, use is not recommended.

Extemporaneously Prepared

A 20 mg/mL oral liquid suspension may be made from tablets and one of three different vehicles (cherry syrup, a 1:1 mixture of Ora-Sweet® and Ora-Plus®, or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®). Crush twenty-four 100 mg tablets in a mortar and reduce to a fine powder. Add 20 mL of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well” and “protect from light”. Stable for 60 days when stored in amber plastic prescription bottles in the dark at room temperature or refrigerated.

Allen LV and Erickson III MA, “Stability of Baclofen, Captopril, Diltiazem, Hydrochloride, Dipyridamole, and Flecainide Acetate in Extemporaneously Compounded Oral Liquids,” Am J Health Syst Pharm. 1996, 53:2179-84.8879325

Storage

Store at 20°C to 25°C (68°F to 77°F) in a tight, light-resistant container

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Amiodarone: May enhance the QTc-prolonging effect of Flecainide. Amiodarone may increase the serum concentration of Flecainide. Management: Decrease flecainide dose by 50% in the presence of amiodarone. Monitor for adverse effects of flecainide and consider monitoring for elevated serum concentrations during concomitant therapy. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Flecainide. Management: Canadian labeling recommends avoiding this combination. Monitor therapy

Asunaprevir: May increase the serum concentration of Flecainide. Avoid combination

Boceprevir: May increase the serum concentration of Flecainide. Monitor therapy

Carbonic Anhydrase Inhibitors: May increase the serum concentration of Flecainide. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Digoxin: Flecainide may increase the serum concentration of Digoxin. Monitor therapy

Etravirine: May decrease the serum concentration of Flecainide. Monitor therapy

Fosamprenavir: May increase the serum concentration of Flecainide. Management: Concurrent use of ritonavir-boosted fosamprenavir with flecainide is contraindicated. The use of non-ritonavir-boosted fosamprenavir with flecainide is not specifically contraindicated but should only be undertaken with caution. Avoid combination

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Mirabegron: May increase the serum concentration of Flecainide. Management: Monitor clinical response to flecainide closely. Dose adjustment may be necessary. Canadian mirabegron labeling recommends restricting the maximum adult mirabegron dose to 25 mg/day in patients receiving flecainide. Monitor therapy

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Pindolol: Flecainide may enhance the bradycardic effect of Pindolol. The negative inotropic effects of Pindolol may also be enhanced. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Ritonavir: May increase the serum concentration of Flecainide. Avoid combination

Saquinavir: May enhance the arrhythmogenic effect of Flecainide. Saquinavir may increase the serum concentration of Flecainide. Avoid combination

Simeprevir: May increase the serum concentration of Flecainide. Monitor therapy

Sodium Bicarbonate: May diminish the arrhythmogenic effect of Flecainide. Sodium Bicarbonate may increase the serum concentration of Flecainide. Monitor therapy

Sodium Lactate: May increase the serum concentration of Flecainide. Monitor therapy

Telaprevir: May enhance the adverse/toxic effect of Flecainide. Monitor therapy

Tipranavir: May increase the serum concentration of Flecainide. Avoid combination

Tromethamine: May increase the serum concentration of Flecainide. Monitor therapy

Verapamil: May enhance the adverse/toxic effect of Flecainide. In particular, this combination may significantly impair myocardial contractility and AV nodal conduction. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Dizziness (19% to 30%)

Ocular: Visual disturbances (16%)

Respiratory: Dyspnea (~10%)

1% to 10%:

Cardiovascular: Palpitation (6%), chest pain (5%), edema (3.5%), tachycardia (1% to 3%), proarrhythmic (4% to 12%), sinus node dysfunction (1.2%), syncope

Central nervous system: Headache (4% to 10%), fatigue (8%), nervousness (5%) additional symptoms occurring at a frequency between 1% and 3%: fever, malaise, hypoesthesia, paresis, ataxia, vertigo, somnolence, tinnitus, anxiety, insomnia, depression

Dermatologic: Rash (1% to 3%)

Gastrointestinal: Nausea (9%), constipation (1%), abdominal pain (3%), anorexia (1% to 3%), diarrhea (0.7% to 3%)

Neuromuscular & skeletal: Tremor (5%), weakness (5%), paresthesia (1%)

Ocular: Diplopia (1% to 3%), blurred vision

<1% (Limited to important or life-threatening): Alopecia, alters pacing threshold, amnesia, angina, AV block, bradycardia, bronchospasm, CHF, corneal deposits, depersonalization, euphoria, exfoliative dermatitis, granulocytopenia, heart block, increased P-R, leukopenia, metallic taste, neuropathy, paradoxical increase in ventricular rate in atrial fibrillation/flutter, paresthesia, photophobia, pneumonitis, pruritus, QRS duration, swollen lips/tongue/mouth, tardive dyskinesia, thrombocytopenia, urinary retention, urticaria, ventricular arrhythmia

ALERT: U.S. Boxed Warning

Mortality:

Flecainide was included in the National Heart Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had an MI more than 6 days but less than 2 years previously. An excessive mortality or nonfatal cardiac arrest rate was seen in patients treated with flecainide compared with that seen in patients assigned to a carefully matched placebo-treated group. This rate was 5.1% for flecainide and 2.3% for the matched placebo. The average duration of treatment with flecainide in this study was 10 months.

The applicability of the CAST results to other populations (eg, those without recent MI) is uncertain, but at present, it is prudent to consider the risks of Class ΙC agents (including flecainide), 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 proarrhythmic effects in patients with atrial fibrillation/flutter:

A review of the world literature revealed reports of 568 patients treated with oral flecainide for paroxysmal atrial fibrillation/flutter (PAF). Ventricular tachycardia was experienced in 0.4% of these patients. Of 19 patients in the literature with chronic atrial fibrillation (CAF), 10.5% experienced ventricular tachycardia (VT) or ventricular fibrillation (VF). Flecainide is not recommended for use in patients with CAF. Case reports of ventricular proarrhythmic effects in patients treated with flecainide for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, and death.

As with other Class Ι agents, patients treated with flecainide 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 flecainide. Concomitant negative chronotropic therapy such as digoxin or beta-blockers may lower the risk of this complication.

Warnings/Precautions

Concerns related to adverse effects:

• Proarrhythmic effects: [US Boxed Warning]: Proarrhythmic effects (including increased premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, and death) have been reported in patients with atrial fibrillation/fibrillation who received flecainide; use is not recommended for patients with chronic atrial fibrillation. Flecainide can cause new or worsened supraventricular or ventricular arrhythmias in all patients; effect is dose-related. Patients with sustained ventricular tachycardia and serious underlying heart disease are at an increased risk; initiation of therapy should occur in a hospital setting.

Disease-related concerns:

• Atrial fibrillation (chronic): Use is not recommended in patients with chronic atrial fibrillation due to an increased risk of life-threatening ventricular arrhythmias.

• Atrial flutter: Appropriate use: [US Boxed Warning]: When treating atrial flutter, 1:1 atrioventricular conduction may occur; pre-emptive negative chronotropic therapy (eg, digoxin, beta-blockers) may lower the risk.

• Atrial fibrillation (chronic): Use is not recommended in patients with chronic atrial fibrillation due to an increased risk of life-threatening ventricular arrhythmias.

• Heart disease: Avoid use in patients with heart failure; may precipitate or exacerbate condition, increase the risk of proarrhythmia, and contribute to an increased risk of mortality (ACCF/AHA [Yancy 2013]). According to the manufacturer, use with extreme caution in patients with structural heart disease as the risk of death and cardiac events may be increased. According to the ACC/AHA/ESC, the use of flecainide is considered relatively contraindicated in patients with coronary artery disease, LV dysfunction, or other significant heart disease (ACC/AHA/ESC [Blomström-Lundqvist 2003]).

• Conduction disturbances: Dose-related increases in PR and QRS intervals occur. If second- or third-degree AV block, or right bundle branch block associated with a left hemiblock occur, flecainide therapy should be discontinued unless a temporary or implanted ventricular pacemaker is in place to ensure an adequate ventricular rate. Use with extreme caution in patients with sick sinus syndrome; treatment with flecainide may result in sinus bradycardia, sinus pause, or sinus arrest.

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.

• Hepatic impairment: Use with caution in patients with significant hepatic impairment; benefit should outweigh risk. Consider careful monitoring during initiation of therapy. Dose titration should occur only after steady state has been achieved (≥4 days after initiation). Frequent plasma level monitoring is required in patients with severe hepatic impairment; if unavailable, use is not recommended.

• Renal impairment: Use with caution in patients with significant renal impairment. Frequent plasma level monitoring is required in patients with severe renal impairment; if unavailable, use is not recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: Small changes in dose may lead to disproportionate increases in plasma concentrations in pediatric patients. Following initiation of therapy or changes in dose, obtain plasma trough concentrations and ECG once steady state has been achieved (>5 doses after initiation or change); regular monitoring of trough concentrations and ECG is recommended by the manufacturer during the first year of therapy.

Other warnings/precautions:

• CAST trial: [US Boxed Warning]: In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but <2 years ago) myocardial infarction patients with asymptomatic, non-life-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. The risks of class 1C agents and the lack of improved survival make use in patients without life-threatening arrhythmias generally unacceptable.

• Pacemakers: Use with caution in patients with permanent pacemakers or temporary pacing wires; can increase endocardial pacing thresholds and suppress ventricular escape rhythms. Do not use in patients with existing poor thresholds or nonprogrammable pacemakers unless suitable pacing rescue is available. The pacing threshold in patients with pacemakers should be determined at baseline, 1 week after initiation and at regular intervals thereafter.

Monitoring Parameters

ECG, blood pressure, pulse, periodic serum trough concentrations, especially in patients with renal or hepatic impairment, concomitant administration of amiodarone and pediatric patients.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Flecainide is recommended in the treatment of fetal tachycardia determined to be SVT. Flecainide may be also used for the ongoing management of SVT in highly symptomatic pregnant patients. The lowest effective dose is recommended; avoid use during the first trimester if possible (Page [ACC/AHA/HRS 2015]). Additional guidelines are available for management of cardiovascular diseases during pregnancy (ESG [Regitz-Zagrosek 2011]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache. Have patient report immediately to prescriber signs of hepatic impairment, angina, severe dizziness, syncope, arrhythmia, bradycardia, tachycardia, dyspnea, excessive weight gain, edema of extremities, tremors, vision changes, ecchymosis, or hemorrhaging (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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