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Background: Standardized treatment of fetal tachyarrhythmia has not been established., Objectives: This study sought to evaluate the safety and efficacy of protocol-defined transplacental treatment for fetal supraventricular tachycardia (SVT) and atrial flutter (AFL)., Methods: In this multicenter, single-arm trial, protocol-defined transplacental treatment using digoxin, sotalol, and flecainide was performed for singleton pregnancies from 22 to <37 weeks of gestation with sustained fetal SVT or AFL ≥180 beats/min. The primary endpoint was resolution of fetal tachyarrhythmia. Secondary endpoints were fetal death, pre-term birth, and neonatal arrhythmia. Adverse events (AEs) were also assessed., Results: A total of 50 patients were enrolled at 15 institutions in Japan from 2010 to 2017; short ventriculoatrial (VA) SVT (n = 17), long VA SVT (n = 4), and AFL (n = 29). One patient with AFL was excluded because of withdrawal of consent. Fetal tachyarrhythmia resolved in 89.8% (44 of 49) of cases overall and in 75.0% (3 of 4) of cases of fetal hydrops. Pre-term births occurred in 20.4% (10 of 49) of patients. Maternal AEs were observed in 78.0% (39 of 50) of patients. Serious AEs occurred in 1 mother and 4 fetuses, thus resulting in discontinuation of protocol treatment in 4 patients. Two fetal deaths occurred, mainly caused by heart failure. Neonatal tachyarrhythmia was observed in 31.9% (15 of 47) of neonates within 2 weeks after birth., Conclusions: Protocol-defined transplacental treatment for fetal SVT and AFL was effective and tolerable in 90% of patients. However, it should be kept in mind that serious AEs may take place in fetuses and that tachyarrhythmias may recur within the first 2 weeks after birth., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We report a 48-day-old female infant, who developed cardiac conduction abnormalities and seizures secondary to supratherapeutic doses of oral flecainide. Flecainide was started in this infant for treatment of supraventricular tachycardia. The drug was withdrawn with successful normalization of the QRS complex and no further recurrence of seizures. The Naranjo probability score for adverse drug reaction was 8, making the causality "probable." The case restates an important message that physicians should be aware of the side effects of the drugs that they prescribe, especially of those drugs which have a narrow therapeutic window.

Background: The optimal treatment for fetal supraventricular tachycardia (SVT) with 1:1 atrioventricular relationship is unclear., Objective: We compared the effectiveness of transplacental treatment protocols used in 2 centers., Methods: Pharmacologic treatment was used in 84 fetuses. Maternal oral flecainide was the primary therapy in center 1 (n = 34) and intravenous maternal digoxin in center 2 (n = 50). SVT mechanism was classified by mechanical ventriculoatrial (VA) time intervals as short VA or long VA. Treatment success was defined as conversion to sinus rhythm (SR), or rate control, defined as >15% rate reduction., Results: Short VA interval occurred in 67 fetuses (80%) and long VA in 17 (20%). Hydrops was present 28 of 84 (33%). For short VA SVT, conversion to SR was 29 of 42 (69%) for digoxin and 24 of 25 (96%) for flecainide (P = .01). For long VA SVT, conversion to SR and rate control was 4 of 8 (50%) and 0 of 8, respectively, for digoxin, and 6 of 9 (67%) and 2 of 9 (cumulative 89%) for flecainide (P = .13). In nonhydropic fetuses, digoxin was successful in 23 of 29 (79%) and flecainide in 26 of 27 (96%) (P = .10). In hydrops, digoxin was successful in 8 of 21 (38%), flecainide alone in 6 of 7 (86%, P = .07 vs digoxin), and flecainide ± amiodarone in 7 of 7 (100%) (P = .01). Intrauterine or neonatal death occurred in 9 of 21 hydropic fetuses treated with digoxin (43%), compared to 0 of 7 (P = .06) treated with flecainide., Conclusions: Flecainide was more effective than digoxin, especially when hydrops was present. No adverse fetal outcomes were attributed to flecainide., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Objective: We examined the effect of gender-associated differences in pharmacokinetics on the anti-arrhythmic effects of flecainide in Japanese patients with supraventricular tachyarrhythmia and in healthy subjects., Methods: The study population comprised 72 outpatients (52 males and 20 females) treated with oral flecainide for supraventricular tachyarrhythmias. Serum flecainide concentrations were determined by use of high-performance liquid chromatography. The anti-arrhythmic efficacy of flecainide was assessed for at least 2 months through evaluation of symptomatology, electrocardiograms, and Holter monitoring. Pharmacokinetics of flecainide after a single 50-mg dose was examined in 14 healthy subjects (7 males and 7 females)., Results: The daily dose of flecainide did not differ between males and females (2.87 +/- 0.68 versus 2.92 +/- 0.90 mg/kg). The serum flecainide concentration was significantly lower in males than in females (315 +/- 151 versus 408 +/- 184 ng/mL, P < 0.05). Clinically relevant efficacy of flecainide was achieved significantly (P < 0.05) less often in male patients (31 of 52; 60%) than in female patients (19 of 20; 95%). We confirmed that nonrenal clearance of flecainide among healthy subjects was significantly higher in males than in females (0.77 +/- 0.16 versus 0.57 +/- 0.06 L h(-1) kg(-1), P < 0.05)., Conclusions: Our results suggest that the anti-arrhythmic efficacy of flecainide differed between males and females because of gender-associated differences in pharmacokinetics.

Refractory neonatal supra-ventricular tachycardia may require the use of flecainide as anti-arrhythmic. Close control of plasma levels is mandatory due to pro-arrhythmic complications. However, inadvertent hemolysis during blood sampling may cause an increase in measured plasma flecainide concentrations. We conclude, therefore, that dosing of the drug should be always done with caution, and in case of suspected haemolysis plasma levels should be repeated with a new blood sample.

Objective: To examine the effect of CYP2D6 genotype on the pharmacokinetics of flecainide, we conducted a population pharmacokinetic analysis of the data collected during routine therapeutic drug monitoring of Japanese patients with supraventricular tachyarrhythmia., Methods: Population analysis was performed on retrospective data from 58 patients with normal kidney and liver function treated with oral flecainide for supraventricular tachyarrhythmia. Serum concentrations of flecainide were determined by high-performance liquid chromatography. CYP2D6 genotyping for extensive metabolizer (EM), intermediate metabolizer (IM) and poor metabolizer (PM) alleles was conducted by allele-specific polymerase chain reaction (PCR) and stepdown PCR. WinNonMix was used to estimate oral clearance (CL/F) of flecainide with a one-compartment model for first-order absorption., Results: Body weight, age, sex, serum creatinine concentration (Scr), and CYP2D6 genotype influenced flecainide pharmacokinetics. The CL/F was affected by age (30% reduction in > or =70 years old) and sex (24% reduction in females). The ratios of CL/F for the five CYP2D6 genotypes were: 1.00 (EM/EM), 0.89 (EM/IM), 0.84 (EM/PM), 0.79 (IM/IM), 0.73 (IM/PM). A model including these five covariates reduced the interpatient variability of CL/F from 32.9% (base model) to 17.8%. Using a Bayesian method we estimated that the CL/F in IMs was significantly lower than in homozygous EMs (0.25+/-0.05 l h(-1) kg(-1) vs. 0.37+/-0.08 l h(-1) kg(-1), P<0.05) among male patients under 70 years old., Conclusions: CYP2D6 genotype, even in IMs, as well as body weight, age, sex, and Scr influence flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia.

Background: Efficacy of flecainide acetate for the treatment of fetal supraventricular tachycardia with cardiac failure was reported., Case: For a case in which maternal digoxin therapy failed, flecainide acetate (400 mg/day) is used from 27 weeks. Cardioversion with improved cardiac function occurred 6 days after treatment. Fetal serum flecainide acetate level was 292 ng/ml which was 64% of the maternal level (453 ng/ml). No adverse maternal side effects were noted with 11 weeks of therapy. A vigorous male baby, weighing 3,610 g, Apgar 8/9, Ua-pH 7.24, was born. He is now 1 year of age and in good condition with medication of 5 mg/kg flecainide acetate., Conclusion: Flecainide acetate seemed to be safe for both mother and fetus, and effective for the treatment of fetal supraventricular tachycardia which is refractory to transplacental digoxin therapy.

Flecainide has been shown to be effective in short-term, controlled studies for prevention of paroxysmal supraventricular tachycardia (SVT) and paroxysmal atrial fibrillation (AF). However, it is unknown whether this beneficial response is maintained during long-term chronic therapy. Forty-nine patients were studied who enrolled in double-blind, placebo-controlled, short-term studies of safety and efficacy and subsequently received long-term, open-label therapy for > or = 6 months (mean duration of therapy, 17 months). To evaluate chronic efficacy, events during long-term therapy were documented by a transtelephonic monitor for either 4 or 8 weeks, comparable to the corresponding 4- or 8-week placebo-baseline periods in the same patients. Results during chronic therapy were compared with those at baseline and after the initial (short-term) treatment period. Compared with placebo-baseline results, the number of patients free of arrhythmic attacks increased significantly for both patients with SVT (from 24% to 82%, p = 0.013, n = 17) and patients with AF (from 12% to 68%, p < 0.001, n = 25). Mean time to first attack and mean number of days between attacks also showed significant and parallel increases during the chronic efficacy period. In patients with paired short- and long-term efficacy evaluations with the same dose of flecainide, end points were maintained at equivalent levels or showed further improvement (i.e., mean rate of AF attacks decreased further with chronic therapy, p = 0.036). No proarrhythmic events, death, or myocardial infarction occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Four neonates with Wolff-Parkinson-White syndrome developed supraventricular tachycardia and received flecainide orally after reduction of the arrhythmia. The initial doses were 5 mg/kg/day. They are increased according to clinical response and flecainide concentrations, with 5 and 10 mg/kg/24 h respectively, were in the therapeutic range of 200 to 1000 micrograms/l. Flecainide was effective and well tolerated in the 4 cases. Therefore, this drug may be an alternative to digoxine to prevent supraventricular tachycardias in the neonatal period.

Thirty-five patients aged 6 days to 18 years (average 7.5 +/- 5.2 years) were treated for an average period of 16 months (range 8 days to 50 months) with flecainide acetate at an average dose of 4.8 +/- 1.4 mg/kg (2.9 to 10 mg/kg) or 130 +/- 30.5 mg/m2 administered twice daily. The cardiac arrhythmia was a resistant paroxysmal junctional tachycardia due to a Wolff-Parkinson-White syndrome in 27 cases, intranodal reentry in 6 cases and a chronic reciprocating rhythm in 2 cases. Treatment was successful with complete suppression of the tachycardia in 24 cases. Partial success with a good clinical result was obtained in 4 cases and there were 7 failures, 6 due to inefficacy of the drug, and 1 because of an extracardiac secondary effect. One case of incessant junctional tachycardia was observed in a 9 month old child in whom the preexcitation disappeared. Atrioventricular preexcitation persisted in 20 out of 24 cases. The duration of the non-preexcited QRS complexes increased significantly from 73.6 +/- 13.8 to 82.2 +/- 15.2 ms; n = 14, p less than 0.01. The minimal effective plasma concentration was 347 +/- 147 ng/ml. The plasma concentration/dose ratio of children over 4 years of age was the same as in adults. It was significantly higher in babies and infants suggesting a progressive acquisition of the capacity to metabolise flecainide during the first year of life. In conclusion, flecainide acetate was easy to use with respect to administration and follow-up, and seems to be a drug of choice for the treatment of junctional tachycardia in children.

The antiarrhythmic effects of flecainide acetate were evaluated in 9 patients with paroxysmal atrioventricular (AV) nodal tachycardia and 17 patients with AV tachycardia. An electrophysiologic study was performed before and after intravenous flecainide acetate, 2 mg/kg body weight, was infused over 15 minutes and was followed by a maintenance infusion of 1.6 mg/kg given over 1 hour to 26 patients and during oral treatment to 15. Treatment with oral flecainide acetate was continued for 14 +/- 5 months. Intravenous flecainide acetate terminated AV nodal tachycardia by blocking the retrograde fast pathway conduction in 7 of 7 patients and AV tachycardia by blocking retrograde conduction in the extranodal pathway in 10 of 10 patients. AV nodal tachycardia and AV tachycardia were noninducible in 8 of 9 patients (90%, p less than 0.001) and 11 of 17 patients (65%, p less than 0.001), respectively. Long-term treatment with oral flecainide acetate suppressed AV nodal tachycardia and AV tachycardia in 8 of 9 patients (90%, p less than 0.001) and 11 of 17 patients (65%, p less than 0.001), respectively. A favorable outcome was associated with block in the accessory pathway after intravenous flecainide acetate and noninducibility during oral treatment. Recurrences preferentially occurred in the younger patients. Flecainide acetate is effective in the acute and long-term management of paroxysmal supraventricular reentry tachycardia by suppressing conduction through the retrograde fast limb of the tachycardia circuit. The clinical effect can be predicted by electrophysiologic testing.