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Commercially viable manufacturing process for Flecainide Acetate (I) conforming to regulatory specification and cost effective process is reported. Specifically, an improved process for the preparation of Flecainide Acetate allows isolation of anhydrous hydrochloride salt of Compound III, which facilitates the reduction of the pyridine ring with the only catalytic amount of platinum on carbon within 2 hours Therefore, simplifies the synthesis and isolation of Flecainide acetate on a commercial scale to a considerable extent.

Pharmacologic management of atrial fibrillation (AF) is a pressing problem. This arrhythmia afflicts >5 million individuals in the United States and prevalence is estimated to rise to 12 million by 2050. Although the pill-in-the-pocket regimen for self-administered AF cardioversion introduced over a decade ago has proven useful, significant drawbacks exist. Among these are the relatively long latency of effects in the range of hours along with potential for hypotension and other adverse effects. This experience prompted development of a new strategy for increasing plasma concentrations of antiarrhythmic drugs rapidly and for a limited time, namely, pulmonary delivery. In preclinical studies in Yorkshire pigs, intratracheal administration of flecainide was shown to cause a rapid, reproducible increase in plasma drug levels. Moreover, pulmonary delivery of flecainide converted AF to normal sinus rhythm by prolonging atrial depolarization, which slows intra-atrial conduction and seems to be directly correlated with efficacy in converting AF. The rapid rise in plasma flecainide levels optimizes its anti-AF effects while minimizing adverse influences on ventricular depolarization and contractility. A more concentrated and soluble formulation of flecainide using a novel cyclodextrin complex excipient reduced net drug delivery for AF conversion when compared to the acetate formulation. Inhalation of the beta-adrenergic blocking agent metoprolol slows ventricular rate and can also terminate AF. In human subjects, oral inhalation of flecainide acetate with a hand-held, breath-actuated nebulizer results in signature prolongation of the QRS complex without serious adverse events. Thus, pulmonary delivery is a promising advance in pharmacologic approach to management of AF.

The availability of liquid oral preparations compounded by pharmacists is essential to meet paediatric needs which remain unanswered by the pharmaceutical industry. Unfortunately, compendial monographs are often not available and, in many cases, pre-formulation studies (e.g., compatibility with other excipients and solubility evaluations) are not performed in-depth, leading, in some rare cases, to the inadvertent administration of a toxic dose. In this study, the preparation of an oral liquid formulation for paediatric use, containing flecainide acetate at different strengths, was considered, taking into account the possible effects of conventionally used excipients. First, the optimal vehicle was selected based on a solubility study, evidencing some unexpected formations of precipitates. As a matter of fact, the buffers commonly used for oral solutions significantly reduced flecainide solubility, and the concomitant presence of citrate buffer and methylparaben even caused the formation of non-resuspendable crystals. Then, chemical, physical, and microbiological stability were assessed. Solutions at strengths of 10 and 20 mg/mL flecainide acetate were stable up to 8 weeks when compounded by using a 40% sucrose solution as a vehicle. Microbiological data showed that the use of methylparaben was not necessary over this time period.

The article considers the use of flecainide, an antiarrhythmic agent. The results of comparing the bioequivalence of Lixarit, flecainide acetate generic drug (flecainide acetate, 100 mg tablets, Laboratorios Normon SA, Spain), and Apocard®, flecainide acetate reference drug (Health Care Ltd, UK, 100 mg tablets), are presented., У статті розкривається тема використання антиаритмічного препарату флекаїніду. Наведені результати порівняння біоеквівалентності генеричного препарату флекаїніду ацетату Ліксарит (флекаїніду ацетат, таблетки по 100 мг, Laboratorios Normon SA, Іспанія) і референтного препарату флекаїніду ацетату Апокард® (Health Care Ltd, Велика Британія, таблетки по 100 мг).

Introduction: Oral and intravenous (IV) flecainide are recommended as first line therapy for pharmacological cardioversion of recent-onset atrial fibrillation (AF) in patients without known relevant structural heart disease. In the present open-label, dose-escalation study, the feasibility of using flecainide acetate inhalation solution (FlecIH) for acute conversion of recent-onset AF to sinus rhythm (SR) was evaluated. Hypothesis: We hypothesized that FlecIH quickly gives rise to plasma concentrations sufficient to rapidly restore SR in patients with recent-onset AF. Methods: Patients (n=95) with symptomatic AF (for ≤ 48 hours) were enrolled and self-administered FlecIH using a breath-actuated nebulizer (30 mg [n=10], 60 mg [n=20], 90 mg [n=21], 120 mg [n=17], and 120 mg in a formulation containing saccharin [n=27]). Blood samples were collected for flecainide plasma concentrations, electrocardiograms were obtained, cardiac rhythm with a 4-hour Holter and vital signs were monitored, and adverse events (AEs) were recorded. Patients who did not convert to SR were offered alternative treatment per the investigator’s discretion. Results: Conversion rates increased with dose and maximum plasma concentrations (C max ) of flecainide. At the highest dose, 45% of patients converted to normal SR. Patients with C max > 300 ng/mL had a conversion rate of 53% whereas those with C max < 200 ng/mL had a conversion rate of 33%. The median time to conversion was 3.5 min after FlecIH administration. AEs were typically mild and transient. Commonly reported AEs associated with inhalation of flecainide included: cough, throat pain, and throat irritation; at the highest dose with the formulation containing saccharin, these AEs were reported for 37%, 11%, and 4% of patients, respectively. Cardiac AEs consistent with those observed with oral and IV flecainide and considered serious were uncommon and included 2 post-conversion pauses and 1 bradycardia, and 1 atrial flutter with 1:1 atrioventricular conduction; none required treatment and all resolved without sequelae. Conclusions: FlecIH was well tolerated. Inhalation of FlecIH at the 120 mg dose yielded therapeutic plasma levels and conversion rates within the range reported for oral and IV administration.

We compared the pharmacokinetic (PK) profile and electrocardiographic (ECG) changes in response to intratracheal instillation of flecainide acetate into the left atrium and ventricle with intravenous (IV) flecainide acetate administration. In 12 closed-chest anesthetized Yorkshire pigs, we monitored the QRS complex and PR, JTc, and QTc intervals during sinus rhythm and correlated changes with venous plasma drug concentrations before and at 2, 5, 10, 15, and 30 minutes after drug administration. Intratracheal instillation of flecainide (0.75 and 1.5 mg/kg, rapid bolus) caused dose/concentration-dependent increases in the QRS complex duration of 10% and 19%, respectively, at 2 minutes, coinciding with peak venous plasma levels (1688 ± 177 and 2808 ± 217 ng/mL, respectively). IV infusion of flecainide (2 mg/kg) over 2 or 10 minutes similarly prolonged QRS complexes and PR intervals (both, P < 0.001). Intratracheal flecainide instillation increased PR interval briefly at 5 minutes. Neither intratracheal nor IV flecainide affected JTc or QTc intervals. Thus, the PK pattern of intratracheal instillation of flecainide is comparable to IV administration, although the absolute plasma concentrations were higher with IV infusion. Both modes of delivery elicited ECG changes that were consistent with the expected pharmacological activity of flecainide.

Objective To describe the treatment of persistent supraventricular tachycardia (SVT) in a young horse in endurance training. Case Summary A 6-year-old Arab gelding in endurance training presented for a dysrhythmia and decreased performance. SVT was diagnosed and conversion to a normal sinus rhythm was achieved following administration of a constant rate infusion of amiodarone. However, reversion to SVT occurred shortly after initiation of ridden exercise. A second attempt to convert the dysrhythmia with amiodarone failed, but normal sinus rhythm was achieved with transvenous electrical cardioversion (TVEC). Postmortem examination of the heart revealed extensive fibrous replacement of most of the left atrial myocardium; these changes likely provided the structural substrate for the dysrhythmia. The underlying cause of the fibrosis was not identified. New or Unique Information Provided SVT is a form of supraventricular tachyarrhythmia rarely diagnosed in the horse. A recent report has described sudden death of a horse following attempted conversion of SVT with oral flecainide acetate. In the present report, we describe short-term conversion of SVT in a horse using intravenous amiodarone with no significant adverse effects. When the dysrhythmia recurred, the animal was donated for teaching purposes and conversion was achieved with TVEC. Normal sinus rhythm persisted for 2 weeks until the horse was euthanized for postmortem evaluation of the heart. Intravenous amiodarone or TVEC could be considered as treatments for supraventricular tachyarrhyhmias other than atrial fibrillation in the horse.

Flecainide acetate is a Vaughan-Williams class IC antiarrhythmic drug prescribed for the treatment of supraventricular arrhythmias. It has a narrow therapeutic index and proarrhythmic effects even at therapeutic doses. Flecainide is metabolized by a CYP2D6 enzyme that exhibits polymorphism. In this case report, we present, to our best knowledge, the first case of toxicity contributed by genetic polymorphism in an infant. Our patient with recurrent supraventricular tachycardia was treated with a therapeutic dose of flecainide but developed heart block requiring extracorporeal membrane oxygenation support and subsequent treatment with lipid emulsion therapy. He was found to have supratherapeutic serum flecainide concentration, and gene testing revealed the patient to be an intermediate metabolizer. With this case report, we reinforce the importance of evaluating the CYP2D6 genotype before drug initiation in the neonatal population and recommend regular monitoring of serum flecainide levels and electrocardiograms in these patients.

We present a patient with non-cardiac sarcoidosis complicated with manifest ventricular preexcitation. Initially, cardiac involvement of sarcoidosis was suspected from the echocardiographic findings showing localized hypokinesia at the left ventricular basal inferior wall. We, however, considered that the hypokinesia was a preexcitation-induced mechanical dyssynchrony rather than cardiac sarcoidosis, because polarities of the delta-waves indicated a left ventricular inferior accessory pathway. Temporal administration of oral flecainide acetate eliminated the basal left ventricular motion abnormality. Accordingly, we could successfully differentiate the mechanism of hypokinesia. In this context, we could rule out cardiac sarcoidosis, and initiation of glucocorticoid therapy was reasonably withheld.

Background Flecainide acetate (FlecAc) is an antiarrhythmic drug, effective in children and fetal tachyarrhythmias. FlecAc is commercially available as 50 mg–150 mg oral tablets or intravenous injectable solutions, approved only for use in adults. For paediatric use, an extemporaneous preparation has to be compounded, using the pure active principle or, when this is lacking, the ground tablet. Few examples of extemporaneous FlecAc preparations are reported in the literature, normally at a dose of 20 mg/mL. Nevertheless, in the case of neonates and infants, a lower concentration is useful. Purpose The aim of this work was to compound FlecAc oral liquids (2 mg/mL) using pure powder (API) or ground commercial tablets (GCT) and to evaluate the chemical stability of the active principle. Material and methods Oral solutions were compounded using either a preserved simple syrup (PSS) with the addition of a suspending phase or a ready-to-use commercial suspending vehicle, ORA-Plus ORA-Sweet (OPOS), to be stored at 4°C or 25°C, respectively. Four types of aqueous solutions were compounded following hospital standard operating procedures. In three different pharmacies, seven hospital pharmacists compounded a total of 28 preparations (n=28): 1) PSS-API, 2) PSS-GCT, 3) OPOS-API and 4) OPOS-GCT. The samples were stored at 4°C (PSS), 25°C (OPOS) and 40°C (both) for 42 days. The FlecAc content was determined using a stability indicating the high-performance liquid chromatography method. Results At time t=0, the mean FlecAc content of all samples was 1.82±0.10 mg/mL, against a labelled content of 2.00 mg/mL. A significant difference in FlecAc content was observed only in the case of GCT preparations (OPOS-GCT: 1.87±0.07 mg/mL; PSS-GCT: 1.79±0.15 mg/mL, p=0.03). Based on these results, duration and method of stirring were further investigated and improved in a second batch, which showed a higher mean content and reduced variability (1.92±0.06 mg/mL). FlecAc was stable over the entire period. Conclusion FlecAc is completely solubilised in the proposed vehicles and stable for 42 days. A suspending agent is therefore necessary only to mask the excipients of the tablet, if not completely solubilised. Normally suggested storage in a refrigerator when PSS is compounded should be carefully considered, because of the influence of the reduced temperature on FlecAc solubility. References and/or acknowledgements No conflict of interest.

In this work, two stability-indicating chromatographic methods have been developed and validated for determination of flecainide acetate (an antiarrhythmic drug) in the presence of its degradation products (flecainide impurities; B and D). Flecainide acetate was subjected to a stress stability study including acid, alkali, oxidative, photolytic and thermal degradation. The suggested chromatographic methods included the use of thin layer chromatography (TLC-densitometry) and high-performance liquid chromatography (HPLC). The TLC method employed aluminum TLC plates precoated with silica gel G.F254 as the stationary phase and methanol-ethyl acetate-33% ammonia (3:7:0.3, by volume) as the mobile phase. The chromatograms were scanned at 290 nm and visualized in daylight by the aid of iodine vapor. The developed HPLC method used a RP-C18 column with isocratic elution. Separation was achieved using a mobile phase composed of phosphate buffer pH 3.3-acetonitrile-triethylamine (53:47:0.03, by volume) at a flow rate of 1.0 mL/min and UV detection at 292 nm. Factors affecting the efficiency of HPLC method have been studied carefully to reach the optimum conditions for separation. The developed methods were validated according to the International Conference on Harmonization guidelines and were applied for bulk powder and dosage form. Copyright © 2016 John Wiley & Sons, Ltd.

Background Pulmonary delivery of antiarrhythmic agents has the potential to increase rapidly targeted drug concentrations in pulmonary veins and left atrium to terminate atrial fibrillation (AF). Objective We evaluated the efficacy of flecainide administered via intratracheal instillation in terminating AF in a reliable preclinical model. Methods In 11 closed-chest anesthetized Yorkshire pigs, AF was induced by intrapericardial administration of acetylcholine (1 mL of 102.5 mM solution) followed by burst pacing and allowed to continue for 2 minutes before intratracheal flecainide (0.4 or 0.75 mg/kg) administration. Results Both the 0.4- and 0.75-mg/kg doses of intratracheal flecainide significantly reduced AF duration by 35% (P = .02) and 54% (P = .001), respectively, compared to no-drug baseline. There was a strong inverse correlation (r2 = 0.87; P = .03) between the duration of AF and the change in atrial depolarization duration in response to intratracheal flecainide. Induction of AF resulted in a marked increase in ventricular rate and corresponding reduction in mean arterial pressure, which returned to baseline levels within 5 minutes after conversion. Conclusion Intratracheal flecainide instillation is effective in rapidly converting AF to normal sinus rhythm and restoring mean arterial pressure and heart rate to baseline values. The basis for this efficacy is likely rapid absorption of the drug through the lungs and delivery as a first-pass bolus to the left atrial and ventricular chambers and then to the coronary arterial circulation. The anti-AF effect of flecainide is inversely correlated with the drug’s prolongation of atrial depolarization, implicating slowing of intra-atrial conduction as an important mechanism underlying conversion of AF to normal sinus rhythm.

Background: Different cardiac troponin I (cTnI) assays give different results. Only 1 manufacturer has marketed troponin T (cTnT) assays. Therefore, cTnT often is preferred for detection of myocardial infarction in human patients. Studies of cTnT in horses are limited. Objectives: To compare a cTnI and a high-sensitive cTnT assay (hs-cTnT) in horses. Animals: Cardiac troponin I and cTnT were determined in 35 healthy horses (group 1), 23 horses suspected to have primary myocardial damage (group 2a), and 41 horses with secondary myocardial damage caused by structural heart disease (group 2b). Methods: All cTnI samples were analyzed at laboratory A (limit of detection [LOD]: 0.03 ng/mL), whereas cTnT samples were analyzed at 2 laboratories with the same hs-cTnT assay (laboratory B, LOD: 10.0 pg/mL; laboratory C, LOD: 4.0 pg/mL). Results: The median cTnI concentration in group 2a (0.90 ng/mL; range, 0.03–58.27 ng/mL) was significantly higher (P < .001) than in group 1 (0.03 ng/mL; range, 0.03–0.09 ng/mL) or group 2b (0.05 ng/mL; range, 0.03–30.92 ng/mL), and the optimal cut-off for detection of primary myocardial damage was 0.095 ng/mL (sensitivity: 90.5%, specificity: 100%). Using an LOD of 10.0 pg/mL for all cTnT samples, a cut-off value of 10.5 pg/mL was found, but sensitivity was low (42.9%). When only samples analyzed at laboratory C (n = 58) were included, a cut-off of 6.6 pg/mL was found (sensitivity: 81%, specificity: 100%). Conclusions and Clinical Importance: Despite large quantitative differences, cTnI and cTnT are both useful for detection of myocardial damage in horses.

Background: Flecainide acetate is a drug used primarily for cardiac arrhythmia. Some studies also imply that flecainide acetate has the potential to regulate inflammatory-immune responses; however, its mechanism of action is contended. We determined the effects of flecainide acetate on lipopolysaccharide (LPS)-stimulated human neutrophils in vitro and on mortality in a septic rat model. Methods: Neutrophils from human blood were cultured with varying concentrations of flecainide acetate (1 μM, 10 μM, or 100 μM) with or without LPS (100 ng/ml). To assess neutrophil activation, the protein levels of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and IL-8 were measured after a 4-hour culture period. To assess the intracellular signaling pathways, the levels of phosphorylation of p38 mitogen-activated protein kinase (p38), extracellular signal-regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) were measured after a 30-minute culture period, and the nuclear translocation of nuclear factor (NF)-κB was measured after a 1-hour culture period. Additionally, the survival rate was investigated in a rat sepsis model. Results: Flecainide acetate down-regulated the activation of proinflammatory cytokines, including TNF-α and IL-6 and IL-8, and intracellular signaling pathways including ERK 1/2 and NF-κB. Flecainide acetate also improved the survival rate in the rat sepsis model. Conclusions: Collectively, these findings indicate that flecainide acetate can improve survival in a rat sepsis model by attenuating LPS-induced neutrophil responses. We therefore suggest that flecainide acetate plays an important role in modulating inflammatory-immune responses.

Objective To describe a case of supraventricular tachycardia and sudden death in a horse following administration of flecainide acetate. Case Summary An 8-year-old Hanoverian warmblood gelding was treated for chronic, naturally occurring, supraventricular tachycardia with digoxin, procainamide hydrochloride, quinidine sulfate, and flecainide acetate. After oral administration of flecainide, polymorphic ventricular tachycardia (torsades de pointes) and ventricular fibrillation developed, leading to cardiovascular collapse and death. New or Unique Information Provided Atrial fibrillation is the most commonly diagnosed dysrhythmia associated with poor performance in horses, while atrial tachycardia is rarely documented. Here, we describe a case of sudden death in a horse with atrial tachycardia following the oral administration of flecainide acetate, after the lack of response to other antiarrhythmic drugs. Information provided in this case report is new and will make clinicians aware of the potential complications of flecainide alone or in combination with other drugs, in horses with cardiac dysrhythmias.

Flecainide base is pharmaceutically active substance used for production of flecainide acetate which is known in market as Tambacor, Almarytm, Apocard, Ecrinal or Flecaine. It is determined that flecainide base forms four polymorphic forms abbreviated as Ib, IIb, IIIb and IVb. Flecainide base form Ib is thermodynamically stable form at laboratory temperature while form IIIb is stable at higher temperatures. Flecainide form Ib absorbs water in its structure between layers and forms non-stoichiometric hydrate. Flecainide base binds with organic solvents and form monosolvates. Flecainide base form Ib crystallizes in orthorhombic crystals with lattice parameters a = 27.88 Å, b = 13.78 Å, c = 9.98 Å and two independent molecules in unit cell (Z' = 2; Z = 8). Molecule arrangement in flecainide base form Ib structure is not dense and it forms a channel-type structure, where molecules of water and alcohols are placed.

Flecainide acetate is an antiarrhythmic drug used in the treatment of supraventricular arrhythmias. Flecainide causes very rare but often serious intoxications. These intoxications happen either due to a non-accidental overdose or because of a narrow therapeutic index in a patient who suffers from cardiomyopathy or has electrolyte abnormalities. We report an original case of a patient who had taken a high dose of flecainide with the aim of suicide. The patient suffered a cardiogenic shock with complications of lactic metabolic acidosis. Fast diagnosis is essential to reduce the high morbidity and mortality of this intoxication. The treatment plan is symptomatic. It aims at eliminating the poison and compensating cardiac function by treating the shock and the electrolyte imbalances. This allowed us to swiftly regain normal electrical and mechanical cardiac function in our patient. 3 weeks after the psychiatric consultation no sequelae were found. This case highlights that thorough history is essential in order to determine the diagnosis of a drug intoxication since the range of used products is wide. On the other hand, in case of any intoxication, while we apply a specific treatment, a well-managed, systematic, symptomatic treatment is essential to reduce morbidity and mortality.

Flecainide acetate is a sodium channel blocker and a class Ic antiarrhythmic agent with potential life-threatening proarrhythmic and cardioinhibitory properties when taken in overdose. Quinapril is an angiotensin-converting enzyme inhibitor (ACE-inhibitor) and overdose can lead to prolonged hypotension and, less frequently, transient renal impairment. We describe the first published case of intoxication with both drugs. The patient developed a broad-QRS-tachycardia and severe hypotension. Treatment with volume expansion, hypertonic sodium bicarbonate, inotropic support with norepinephrine and insertion of an intra-aortic balloon pump led to complete recovery after 72 hours. We assume that the clinical picture was mainly dictated by flecainide intoxication. Relevant literature data are discussed.

神経因性疼痛の治療薬として, しばしばNaチャネル遮断作用のある抗不整脈薬が試みられる. これまで, リドカイン (キシロカイン®) , メキシレチン (メキシチール®) がおもに使用されていたが, ペインクリニック領域では近年, Ic群の抗不整脈薬であるフレカイニド (タンボコール®) の有効性についての報告が認められる. フレカイニドには同一の注射薬と内服薬があり, かつ作用時間が長いという利点がある. 今回の検討 (24症例) でもリドカイン, メキシレチンで効果不十分であっても, フレカイニドでそれ以上の効果を認めた症例が13例あった. 難治性疼痛の治療においては各種の薬剤の併用を必要とする場合があるが, 今回の症例群からも, 改めてフレカイニドの鎮痛薬としての臨床使用の有効性が示唆された.

The pharmacodynamic equivalence of flecainide acetate immediate-release (IR) and controlled-release (CR) formulations was assessed from QRS duration in patients currently treated with the IR formulation. Patients were blindly assigned randomly to the IR (100 mg BID, n = 25) or to the CR group (200 mg OD, n = 23). Electrocardiographic parameters were measured at baseline and at week 8 from 24-h Holter monitoring. Mean (SD) normalized flecainide trough plasma concentration (measured 12 h after last intake) at week 8 was 381.3 ng/ml (104.8) with the IR and 381.4 ng/ml (123.8) with the CR formulation. Hodges-Lehmann estimate (95% CI) of the difference between IR and CR for change in QRS duration between baseline and week 8 was 1.6% (-0.1; 3.7), indicating that the formulations were pharmacodynamically equivalent. Median QRS values (102 vs 100.1 ms at baseline; 103.15 vs 99 ms at week 8) as well as first and third quartiles were very similar in both groups. The correlation between QRS duration and RR classes at baseline was highly significant (P0.0001). Correlation coefficient at week 8 was statistically significant for50% of the patients and was significant in a greater proportion of patients under the IR compared with the CR formulation. Circadian hourly variations of QRS duration as determined by harmonic analysis showed the occurrence of a peak of QRS widening following each intake of the IR, whereas this pattern was not observed with the CR formulation. The latter results are consistent with a greater occurrence of frequency-dependent QRS variations over the 24-h period with the IR compared with the CR formulation.

Background: The efficacy of flecainide acetate for the treatment of fetal supraventricular tachycardia with hydrops fetalis and changes in venous blood flow patterns in the fetus during treatment are reported. Case: Oral flecainide administration was started at 30 weeks of gestation. Cardioversion was achieved 6 days after treatment. Sustained abnormal venous Doppler indices were shown and complete normalization of venous returns was observed 6 days after cardioversion. A vigorous male baby was born, and he is now 1 year of age and in good condition with no medication. Conclusion: Reversible cardiac dysfunction was observed even after cardioversion in the fetus with supraventricular tachycardia, which could be assessed precisely by venous Doppler analysis.

Objectives Our objectives were study the single- and repeated-dose pharmacokinetics and electrocardiographic effects (QRS duration) of a new controlled-release form offlecainide acetate compared with the immediate-release form and to examine the influence of CYP2D6 activity. Methods Twenty-four healthy subjects (6 men and 6 women at both dosages) received single and repeated doses of 100 or 200 mg immediate-release and controlled-release flecainide in a randomized crossover design. Electrocardiograms were recorded and flecainide plasma concentrations were measured before administration and up to 96 hours after administration. Results The controlled-release formulation had sustained-release properties, with a significantly lower maximum concentration (Cmax) and delayed time to reach Cmax. Compared with the immediate-release formulation, the relative bioavailability of the controlled-release formulation at steady state was 0.85 ± 0.17 and0.89 ± 0.17 for the 100-mg/day and 200-mg/day doses, respectively. Trough flecainide plasma concentration at steady state was bioequivalent for both formulations. Maximumand minimum QRS increases were not significantly different for either the immediate-release or the controlled-release form of flecainide after administration of both single and repeated doses. Mean QRS duration during a dosing interval at steady state correlated withmean plasma concentration for both forms (pooled data; P < .001). The 95% confidence interval for this regression was 26% narrower for the controlled-release form thanfor the immediate-release form. Flecainide-induced QRS prolongation and pharmacokinetics were not significantly influenced by CYP2D6 activity. Conclusions Flecainide-induced QRS prolongation did not differ between the newcontrolled-release form and the immediate-release form. Flecainide plasma concentrations associated with the new controlled-release form predicted QRS prolongation with less variability compared with the immediate-release form. The CYP2D6 polymorphism did not appear to influence flecainide disposition kinetics or electrocardiographic effects at steady state. Clinical Pharmacology & Therapeutics (2002) 72, 112–122; doi: 10.1067/mcp.2002.125946

Flecainide acetate is a Vaughn-Williams class IC antiarrhythmic. It is used mainly for treatment of supraventricular arrhythmias due to reentry and is highly effective in suppressing frequent premature ventricular depolarization and nonsustained ventricular tachycardia (VT). Although less than 1% of drug overdoses are fatal, severe intoxication with Vaughn-Williams class IC antiarrhythmics is associated with average mortality of 22.5% and the rate of mortality after flecainide overdose is approximately 10%. Severe flecainide overdose is frequently fatal because of the rapid onset of hypotension and ventricular arrhythmias. Its cardiotoxicity is mainly due to its sodium and potassium channels blocking effects. Commonly recommended therapies like haemolysis or haemoperfusion is not helpful because of its large volume of distribution. As a result, the treatment goals are to decrease the amount of blockade; correct aggravating conditions for arrhythmias, such as electrolytes disturbances or hypoxia; avoid drugs with sodium channels blocking effects. Recently, there are some successful data on using peripheral cardiopulmonary bypass technique in the treatment of severe flecainide intoxication. This may be a promising treatment option in this type of drug overdose.

Importance Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with β-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release—the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT—but has never been assessed prospectively. Objective To determine whether flecainide dosed to therapeutic levels and added to β-blocker therapy is superior to β-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT. Design, Setting, and Participants This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated β-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing. Interventions Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels. Main Outcomes and Measures The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia). Results Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P Conclusions and Relevance In this randomized clinical trial of patients with CPVT, flecainide plus β-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus β-blocker and β-blocker alone. Trial Registration clinicaltrials.gov Identifier:NCT01117454

Flecainide acetate is a classic Ic antiarrhythmic agent used to treat a variety of cardiac arrhythmias. Non-cardiac side effects usually affect the central nervous system. Few case reports of possible flecainide-induced peripheral neuropathy have been reported. We report this unique case in that flecainide-induced sensory neuropathy was confirmed with skin biopsy, and subsequent improvement of neuropathy was documented with assessment of intraepidermal nerve fiber density in a repeat nerve biopsy.

Digoxin has been an effective treatment for fetal supraventricular tachycardia (SVT), but second-line therapy remains more controversial. Thirty-seven cases of fetal SVT were identified that received digoxin as first-line therapy. Seventeen fetuses (46%) converted to and maintained normal sinus rhythm. Flecainide was used in 13/15 patients requiring second-line therapy; 12/13 (92%) converted to sinus rhythm. Of seven hydropic fetuses, five required second-line therapy and were then successfully converted with flecainide. The improved efficacy of flecainide was statistically significant with a p value

To determine oral dosage and to evaluate the pharmacokinetics in horses of orally administered flecainide, an antiarrhythmic drug, the correlations between its plasma concentration and PR, QRS and QT intervals in equine electrocardiograms (ECG) were investigated. Six healthy horses were administered a randomly ordered dose of 4 or 6 mg/kg of flecainide acetate. The ECG was monitored (heart rate (HR), PR, QRS, and QT intervals) and blood was taken at timed intervals to measure the plasma flecainide concentrations pre- and post-administration. The maximum plasma concentration reached 1014 ± 285 (SD) ng/ml in 45 ± 13 min and 1301 ± 400 ng/m l in 60 ± 37 min for doses of 4 and 6 mg/kg flecainide, respectively. From the pharmacokinetic analysis, clearance rates were 14.6 ± 6.4 and 11.7 ± 5.2 ml/kg/min and terminal elimination half-lives were 228 ± 53 and 304 ± 87 min. The QRS and QT intervals increased significantly for both doses following administration, though HR and PR intervals did not change. Plasma flecainide concentrations were significantly correlated with QRS (r=0.935, P

High-performance liquid chromatography with electrospray mass spectrometry (LC-MS) was used for analysis of the drug flecainide in serum. The clean-up was performed by solid-phase extraction, and an aromatic ring positional isomer was used as internal standard. Results from method validation on spiked serum samples showed excellent reproducibility; intra- and inter-assay variations (C.V.% and %Bias) were less than 6% within the therapeutic concentration range of the drug (0.2-1.0 microg/ml). Linearity was demonstrated from 0.05 to 2.0 microg/ml. The limit of detection and quantification was 0.025 and 0.05 microg/ml, respectively. Due to the high selectivity of the mass spectrometric detection, no interferences were observed. Results from clinical samples (n=18) from patients in treatment with Tambocor (flecainide acetate) showed excellent correlation with parallel data obtained from a method based on high-performance liquid chromatography (HPLC) with fluorescence detection after liquid/liquid extraction. The chromatographic separation of flecainide and internal standard was improved compared to earlier HPLC methods. The methodology is simple, accurate and requires only 0.25 ml of sample. It is a well suited method for routine therapeutic drug monitoring in a hospital or clinical chemistry laboratory.

To determine a safe and efficacious dose of flecainide acetate for treating equine atrial fibrillation (Af), the safe dosage level was determined by injecting 1, 2, or 3 mg/kg i.v. of 1% flecainide acetate solution at a rate of 0.2 mg/kg/min to five clinically healthy horses. Clinical signs and the ECG were monitored (HR, PR, QRS, and QT intervals) and blood was taken to measure the plasma flecainide concentration pre- and post-administration. No abnormal signs were observed in the 1- or 2-mg/kg groups, while agitation was observed in three of five horses in the 3-mg/kg group. The QRS, and QT intervals for the 3-mg/kg group increased significantly. The peak plasma flecainide concentrations were 1.316 +/- 358 (SD) ng/ml, 1,904 +/- 314 ng/ml, and 2,251 +/- 387 ng/ml for the 1-, 2-, and 3-mg/kg groups, respectively. To evaluate the efficacy of flecainide, Af was induced by right atrial pacing in six clinically healthy horses, and 1% flecainide acetate solution was then administered until they converted to sinus rhythm. All horses with induced Af converted. For the conversion, a total dose of 1.40 +/- 0.63 mg/kg flecainide was required, the duration of administration was 7.00 +/- 3.15 min and plasma flecainide concentration at conversion was 1,303 +/- 566 ng/ml. In conclusion, flecainide acetate is a safe and effective antiarrhythmic agent for equine Af, and the clinically effective dosage is 1 to 2 mg/kg.

Blood and plasma concentration-time profile, distribution, metabolism, excretion of radioactivity after a single intravenous administration of 14C-Flecainide acetate at a dose of 2 mg/kg to dogs, and in vitro and in vivo plasma protein binding were studied. 1. Plasma levels of radioactivity reached a maximal concentration at 0.5 hr after the dose, followed by a decrease with a half-life of 1.9 hr. The AUC(0-24hr) was 4.82μg eq.·hr/ml and the plasma level decreased to below the detection limit at 48 hr post dose. A maximal concentration of the unchanged flecainide was attained at 5 min, followed by a rapid decrease and by an increase of polar metabolites, including conjugates of meta-O-dealkylated flecainide and meta-O-dealkylated lactam of flecainide, which were found to be dominant in plasma. 2. Plasma protein binding (in vitro) of rat and dog was about 55% and 70%, respectively. The binding (in vivo) of radioactivity to dog plasma ranged from 30.7 to 47.7% during 0.5 to 4 hr after the dosing. 3. Radioactivity was distributed to many tissues and decreased to low level at 168 hr post dose, except for pigment ocular tissues in which radioactivity was distributed at a high level and was retained. In the heart, liver and kidney at 0.5 hr post dose, the unchanged flecainide, polar metabolites and meta-Odealkylated flecainide and meta-O-dealkylated lactam of flecainide were the main constituents of radioactivity and several other minor metabolites were also observed. 4. The excretion ratios of radioactivity into urine and feces were estimated to be 56.2 and 42.1% of the dose after 168 hr post dose, respectively. In urine, radioactivity was constituted mainly of polar metabolites which included conjugate metabolites of meta-O-dealkylated flecainide and meta-O-dealkylated lactam of flecainide.

Over the past decade, various studies have demonstrated that class I antiarrhythmic drugs should be avoided in patients with heart failure, cardiac ischaemia or a previous myocardial infarction. In contrast, class II drugs (P-blockers) reduce morbidity and may even lower mortality in patients suffering from moderate to severe heart failure. In these patients, careful titration of the drug dosage, frequently during hospital admission, may be necessary.If in the setting of heart failure ventricular arrhythmias are symptomatic and/or sustained, patients can be treated effectively, after appropriate treatment of the underlying disease, with the class III drug amiodarone. Unfortunately, this drug does not lower overall mortality, implying that prophylactic institution of amiodarone is not indicated. Pure class III antiarrhythmic drugs like d-sotalol, ibutilide and dofetilide show a high rate of torsade de pointes, Currently, only ibutilide has been approved for clinically monitored intravenous administration. Class IV drugs, the calcium channel blockers, are still very useful for rate control of atrial fibrillation and conversion or prevention of atrioventricular nodal re-entrant tachycardias and circus movement tachycardias using a (concealed) bypass tract.Finally. an implantable cardioverter defibrillator seems to improve overall survival in patients with life-threatening ventricular arrhythmias. This may imply that an increasing number of patients will be candidates for such a device. However. it will be necessary to await publication of data involving these devices from current ongoing studies.