Critical Aspects in the Preparation of Extemporaneous Flecainide Acetate Oral Solution for Paediatrics

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.

An Improved Commercially Feasible Process for Flecainide Acetate

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.

Lixarit — clinical and pharmaceutical aspects of efficacy and safety of flecainide acetate generic drug

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.

Development and optimization of an in vivo electrocardiogram recording method and analysis program for adult zebrafish

Clinically pertinent electrocardiogram (ECG) data from model systems, such as zebrafish, are crucial for illuminating factors contributing to human cardiac electrophysiology abnormalities and disease. Current zebrafish ECG collection strategies have not adequately addressed the consistent acquisition of high-quality traces or sources of phenotypic variation that could obscure data interpretation. Thus, we developed a novel platform to ensure high-quality recording of in vivo subdermal adult zebrafish ECGs and zERG (Zebrafish ECG Reading GUI), a program to acquire measurements from traces commercial software cannot examine due to erroneous peak calling. We evaluate normal ECG trait variation, revealing the intervals are highly reproducible while wave amplitude variation appears largely driven by recording artifacts, and identify sex and body size as potential confounders to PR, QRS, and QT intervals. With this framework, we characterize the effect of the class I anti-arrhythmic drug flecainide acetate on adults, provide support for the impact of a Long QT syndrome model, and establish power calculations for this and other studies. These results highlight our pipeline as a robust approach to evaluate zebrafish models of human cardiac electrophysiologic phenotypes.

Abstract 15742: An Open-label, Multicenter Study of Flecainide Acetate Oral Inhalation Solution Shows Acute Conversion of Recent-onset, Symptomatic Atrial Fibrillation to Sinus Rhythm in a Dose- and Concentration-dependent Manner

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.