Flecainide

C01B - Antiarrhythmics ATC C01BC04 Small molecule approved 1985 Oral Narrow therapeutic index Black-box warning

JFDA label: Tambocor Inj

⚠ Black-Box Warning

Mortality:
Ventricular proarrhythmic effects in patients with atrial fibrillation/flutter:

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

Indications

Approved

Ventricular arrhythmias (prevention)

Off-label

Atrial fibrillation or flutter (pharmacologic cardioversion)

Contraindications

Source: Lexicomp

Hypersensitivity to flecainide or any component of the formulation Absolute
cardiogenic shock Absolute
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]) Absolute
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) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (7)

Common chest pain · edema · Palpitation · proarrhythmic · sinus node dysfunction · syncope · tachycardia

Nervous system disorders (14)

Very Common Dizziness

Common anxiety · ataxia · depression · fatigue · Headache · hypoesthesia · insomnia · malaise · nervousness additional symptoms occurring at a frequency between 1% and 3%: fever · paresis · somnolence · tinnitus · vertigo

Gastrointestinal disorders (5)

Common abdominal pain · anorexia · constipation · diarrhea · Nausea

Skin and subcutaneous tissue disorders (1)

Common Rash

Musculoskeletal and connective tissue disorders (3)

Common paresthesia · Tremor · weakness

Other (5)

Very Common Visual disturbances

Common blurred vision · Diplopia

Not Known corneal deposits · Tardive dyskinesia

Respiratory, thoracic and mediastinal disorders (1)

Very Common Dyspnea

Dosing

Source: Lexicomp

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: Note: May be used on an outpatient basis (“Pill-in-the-pocket”). 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 (AHA/ACC/HRS [January 2014]; Alboni 2004). ≥70 kg: 300 mg; may not repeat in ≤24 hours 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.

(For additional information see "Flecainide: Pediatric drug information") 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

Refer to adult dosing.

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)

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.

Warnings & Precautions

Source: Lexicomp

Proarrhythmic effects

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.

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.

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/HRS, flecainide should be avoided in patients with structural or ischemic heart disease (ACC/AHA/HRS [Page 2015]).

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

In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but 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.

Pregnancy & Lactation

Pregnancy

FDA category C

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]).

Lactation

Flecainide is excreted into breast milk. Concentrations of flecainide in breast milk are as high as 4 times those in the maternal serum. The estimated daily dose of flecainide to a nursing infant would be

Monitoring

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

Chemistry & Properties

Formula	C17H20F6N2O3
Molecular weight	414.35 g/mol
IUPAC name	N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
CAS	54143-55-4
PubChem CID	3356
InChIKey	`DJBNUMBKLMJRSA-UHFFFAOYSA-N`
logP	3.44 (XLogP 3.8)
Polar surface area	59.59 Å²
H-bond acceptors / donors	4 / 2
Drug-likeness (QED)	0.67
Lipinski violations	0

SMILES

O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
Kv1.7 (KCNA7)	Channel blocker	pKd 5.1

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT2 (Inhibitor)OCT3 (Inhibitor)P-gp (Inhibitor)MATE1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Anagrelide	major
Arsenic trioxide	major
Cabozantinib	major
Ceritinib	major
Chloroquine	major
Cisapride	major
Cobicistat	major
Crizotinib	major
Dolasetron	major
Eliglustat	major
Fingolimod	major
Halofantrine	major
Hydroxychloroquine	major
Ivosidenib	major
Lumefantrine	major
Macimorelin	major
Nilotinib	major
Osimertinib	major
Ozanimod	major
Panobinostat	major
Papaverine	major
Pasireotide	major
Ribociclib	major
Siponimod	major
Toremifene	major
Vandetanib	major
Vemurafenib	major
Abarelix	moderate
Abiraterone	moderate
Adalimumab	moderate
Alectinib	moderate
Alefacept	moderate
Alimemazine	moderate
Anakinra	moderate
Apalutamide	moderate
Astemizole	moderate
Bicalutamide	moderate
Bisacodyl	moderate
Bosutinib	moderate
Brigatinib	moderate

Showing 40 of 100+.

Registered Products (10)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Nailoren	Tablet 50.0 mg	60 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	3.930
Gultrima	Tablet 50 mg	60 tab pack varies	Amneal Pharmaceuticals,LLC	4.360
Gultrima	Tablet 100 mg	60 tab pack varies	Al-Omawai Drug Store	7.150
Gultrima	Tablet 50 mg	100 tab pack varies	Amneal Pharmaceuticals,LLC	7.270
Nailoren	Tablet 100.0 mg	60 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	9.620
Tambocor	Tablet 100 mg	60 tab	Sabbagh Drug Store	10.220
Gultrima	Tablet 150 mg	60 tab pack varies	Al-Omawai Drug Store	10.730
Gultrima	Tablet 100 mg	100 tab pack varies	Al-Omawai Drug Store	11.920
Tambocor Inj	Injection 10 mg/ml	15 ml	Khraim Drug Store	12.630
Gultrima	Tablet 150 mg	100 tab pack varies	Al-Omawai Drug Store	16.580