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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Flecainide may be confused with fluconazole
Tambocor™ may be confused with Pamelor®, Temodar®, tamoxifen
Pronunciation
(fle KAY nide)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Prevention and suppression of documented life-threatening ventricular arrhythmias (eg, sustained ventricular tachycardia); controlling symptomatic, disabling supraventricular tachycardias in patients without structural heart disease in whom other agents fail
Pregnancy Risk Factor
C
Lactation
Enters breast milk/compatible
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; coronary artery disease (based on CAST study results); concurrent use of ritonavir or amprenavir
Warnings/Precautions
Boxed warnings:
• Atrial flutter: Appropriate use: See “Disease-related concerns” below.
• CAST trial: See “Other warnings/precautions” below.
• Proarrhythmic effects: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Proarrhythmic effects: [U.S. Boxed Warning]: Watch for proarrhythmic effects; monitor and adjust dose to prevent QTc prolongation. Not recommended for patients with chronic atrial fibrillation.
Disease-related concerns:
• Atrial flutter: Appropriate use: [U.S. 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.
• Conduction disturbances: Use with caution in patients with sick sinus syndrome; dose-related increases in PR and QRS intervals occur.
• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.
• Heart failure (HF): Use with caution in patients with HF; may precipitate or exacerbate condition.
• Hepatic impairment: Use with caution in patients with significant hepatic impairment.
Other warnings/precautions:
• CAST trial: [U.S. 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.
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): Bradycardia, paradoxical increase in ventricular rate in atrial fibrillation/flutter, heart block, increased P-R, QRS duration, ventricular arrhythmia, CHF, flushing, AV block, angina, hyper-/hypotension, amnesia, confusion, decreased libido, depersonalization, euphoria, apathy, nervousness, twitching, neuropathy, weakness, taste disturbance, urticaria, exfoliative dermatitis, pruritus, alopecia, flatulence, xerostomia, blood dyscrasias, possible hepatic dysfunction, paresthesia, eye pain, photophobia, bronchospasm, pneumonitis, swollen lips/tongue/mouth, arthralgia, myalgia, polyuria, urinary retention, leukopenia, granulocytopenia, thrombocytopenia, metallic taste, alters pacing threshold
Postmarketing and/or case reports: Tardive dyskinesia, corneal deposits
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), 2D6 (major); Inhibits CYP2D6 (weak)
Drug Interactions
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Amiodarone: May decrease the metabolism of Flecainide. Risk D: Consider therapy modification
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Carbonic Anhydrase Inhibitors: May decrease the excretion of Flecainide. Exceptions: Brinzolamide; Dorzolamide. Risk C: Monitor therapy
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Ritonavir: May decrease the metabolism of Flecainide. Risk X: Avoid combination
Sodium Bicarbonate: May diminish the arrhythmogenic effect of Flecainide. Sodium Bicarbonate may increase the serum concentration of Flecainide. Risk C: Monitor therapy
Sodium Lactate: May increase the serum concentration of Flecainide. Risk C: Monitor therapy
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tipranavir: May increase the serum concentration of Flecainide. Risk X: Avoid combination
Tromethamine: May increase the serum concentration of Flecainide. Risk C: Monitor therapy
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Food: Clearance may be decreased in patients following strict vegetarian diets due to urinary pH ?8. Dairy products (milk, infant formula, yogurt) may interfere with the absorption of flecainide in infants; there is one case report of a neonate (GA 34 weeks PNA >6 days) who required extremely large doses of oral flecainide when administered every 8 hours with feedings (“milk feeds”); changing the feedings from “milk feeds” to 5% glucose feeds alone resulted in a doubling of the flecainide serum concentration and toxicity.
Mechanism of Action
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
Pharmacodynamics/Kinetics
Absorption: Oral: Rapid
Distribution: Adults: Vd: 5-13.4 L/kg
Protein binding: Alpha1 acid glycoprotein: 40% to 50%
Metabolism: Hepatic
Bioavailability: 85% to 90%
Half-life elimination: Infants: 11-12 hours; Children: 8 hours; Adults: 7-22 hours, increased with congestive heart failure or renal dysfunction; End-stage renal disease: 19-26 hours
Time to peak, serum: ~1.5-3 hours
Excretion: Urine (80% to 90%, 10% to 50% as unchanged drug and metabolites)
Dosage
Oral:
Children:
Initial: 3 mg/kg/day or 50-100 mg/m2/day in 3 divided doses
Usual: 3-6 mg/kg/day or 100-150 mg/m2/day in 3 divided doses; up to 11 mg/kg/day or 200 mg/m2/day for uncontrolled patients with subtherapeutic levels
Adults:
Life-threatening ventricular arrhythmias:
Initial: 100 mg every 12 hours
Increase by 50-100 mg/day (given in 2 doses/day) every 4 days; maximum: 400 mg/day.
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.
Prevention of paroxysmal supraventricular arrhythmias in patients with disabling symptoms but no structural heart disease: Initial: 50 mg every 12 hours; increase by 50 mg twice daily at 4-day intervals; maximum: 300 mg/day
Paroxysmal atrial fibrillation: Outpatient: "Pill-in-the-pocket" dose (unlabeled dose): 200 mg (weight <70 kg), 300 mg (weight ?70 kg). May not repeat in ?24 hours. Note: An initial inpatient conversion 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.
Dosing adjustment in severe renal impairment: GFR ?50 mL/minute: Decrease dose by 50%; dose increases should be made cautiously at intervals >4 days and serum levels monitored frequently.
Hemodialysis: No supplemental dose recommended.
Peritoneal dialysis: No supplemental dose recommended.
Dosing adjustment/comments in hepatic impairment: Monitoring of plasma levels is recommended because of significantly increased half-life.
When transferring from another antiarrhythmic agent, allow for 2-4 half-lives of the agent to pass before initiating flecainide therapy.
Administration: Oral
Administer around-the-clock to promote less variation in peak and trough serum levels.
Monitoring Parameters
ECG, blood pressure, pulse, periodic serum concentrations, especially in patients with renal or hepatic impairment
Reference Range
Therapeutic: 0.2-1 mcg/mL; pediatric patients may respond at the lower end of the recommended therapeutic range
Patient Education
Take exactly as directed, around-the-clock. Do not discontinue without consulting prescriber. You will require frequent monitoring while taking this medication. You may experience lightheadedness, nervousness, dizziness, visual disturbances (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or nausea, vomiting, or loss of appetite (small frequent meals may help). Report palpitations, chest pain, excessively slow or rapid heartbeat; acute nervousness, headache, or fatigue; unusual weight gain; unusual cough; respiratory difficulty; swelling of hands or ankles; or muscle tremor, numbness, or weakness. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant.
Geriatric Considerations
Decreased clearance and, therefore, prolonged half-life is possible; however, studies have shown no difference in response to usual doses in the elderly despite slight decrease in clearance; calculate or measure GFR since elderly patients may have GFR ?50 mL/minute.
Anesthesia and Critical Care Concerns/Other Considerations
Based on adverse outcomes noted with flecainide in the CAST trial, the FDA recommends that use of flecainide be limited to patients with life-threatening ventricular arrhythmias.
Cardiovascular Considerations
Flecainide is a Class Ic antiarrhythmic with a very narrow therapeutic index and with considerable proarrhythmic properties. The CAST trial, evaluating flecainide in the treatment of asymptomatic ventricular extrasystoles after myocardial infarction, showed a significant increase in mortality. In lower doses, flecainide has sometimes been used for maintenance of sinus rhythm in patients with severe refractory atrial fibrillation, without structural heart disease.
"Pill-in-the Pocket" administration approach: Patients with a history of palpitations with an abrupt onset, were hemodynamically stable, and had 1-12 episodes of atrial fibrillation within the previous year (and no other cardiac symptoms) were candidates for a clinical trial evaluating flecainide or propafenone for conversion of their rhythm (Alboni P, 2004). Patients had to have minimal, if any, heart disease. Only 12% of all patients evaluated for this trial were eligible for inclusion, thus this type of treatment is only for select patients meeting both inclusion and exclusion criteria. However, patients who had met inclusion criteria and were given either flecainide or propafenone in the hospital phase of the trial and converted to normal sinus rhythm were then enrolled into the ambulatory phase of the trial. Patients in this outpatient trial were to take either flecainide or propafenone at the first onset of palpitations. The doses were as follows: Flecainide 300 mg for patients ?70 kg and 200 mg for patients <70 kg; propafenone 600 mg for patients ?70 kg and 450 mg for patients <70 kg. Patients were instructed to sit or lie down after taking either drug until palpitations had stopped or for at least 4 hours. If palpitations had not subsided after 6–8 hours, then the patients were instructed to go to the emergency room. They were not to take more than one dose in a 24-hour period. This treatment regimen demonstrated that 94% of episodes in the 165 patients studied were successfully treated with a mean time to symptom resolution of 113 minutes. Adverse events were reported in 12 patients. One patient developed atrial flutter with a rapid ventricular response that required an emergency room visit. The other 11 patients complained of noncardiac side effects (eg, nausea, weakness, and vertigo). This therapy demonstrated a significant reduction in emergency room visits and hospitalization.
Selected patients with infrequent paroxysmal atrial fibrillation may be candidates for the “Pill-in-the-Pocket” regimen. Many patients may not be appropriate candidates for this regimen, based on previous clinical studies ? CAST, CAST 2, CASH; a number of exclusion criteria define the potential harm of these agents.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Flecainide is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Flecainide is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Flecainide is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
Mental Health: Effects on Mental Status
Dizziness is common; may cause sedation; may rarely cause nervousness
Mental Health: Effects on Psychiatric Treatment
Use beta-blockers with caution; may produce additive negative inotropic effect; use caution with TCAs; may affect cardiac conduction; CYP2D6 substrate; use caution with the SSRIs
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions. Monitor cardiac status. Assess results of laboratory tests, therapeutic effectiveness, and adverse reactions when beginning therapy, when titrating dosage, and periodically during long-term therapy. Note: Flecainide has a low toxic:therapeutic ratio and overdose may easily produce severe and life-threatening reactions. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as acetate: 50 mg, 100 mg, 150 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Flecainide Acetate)
100 mg (60): $83.98
150 mg (60): $114.98
Tablets (Tambocor)
50 mg (60): $146.26
100 mg (60): $229.24
150 mg (60): $324.83
Extemporaneously Prepared
A 5 mg/mL suspension compounded from tablets and an oral flavored commercially available diluent (Roxane®) was stable for up to 45 days when stored at 5°C or 25°C in amber glass bottles. Flecainide 20 mg/mL was found stable for up to 60 days at 5°C and 25°C in a 1:1 preparation of Ora-Sweet® and Ora-Plus®, in Ora-Sweet® SF and Ora-Plus® and in cherry syrup
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, 53:2179-84.
Wiest DB, Garner SS, and Pagacz LR, “Stability of Flecainide Acetate in an Extemporaneously Compounded Oral Suspension,” Am J Hosp Pharm, 1992, 49(6):1467-70.
References
Alboni P, Botto GL, Baldi N, et al, "Outpatient Treatment of Recent-Onset Atrial Fibrillation With the "Pill-in-the-Pocket" Approach," N Engl J Med, 2004, 351(23):2384-91.
Drug Prescribing in Renal Failure: Dosing Guidelines for Children and Adults, 5th ed, Aronoff GR, et al, eds, Philadelphia, PA: American College of Physicians, 2007.
Flaker GC, Blackshear JL, McBride R, et al, “Antiarrhythmic Drug Therapy and Cardiac Mortality in Atrial Fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators,” J Am Coll Cardiol, 1992, 20(3):527-32.
“Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression After Myocardial Infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators,” N Engl J Med, 1989, 321(6):406-12.
Fuster V, Ryden LE, Cannom DS, et al, “ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation-Executrive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society,” J Am Coll Cardiol, 2006, 48(4):854-906.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2009
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