Flecainide clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
Clinical Pharmacology
Flecainide acetate has local anesthetic activity and belongs to the membrane stabilizing (Class 1) group of antiarrhythmic agents; it has electrophysiologic effects characteristic of the IC class of antiarrhythmics.
Electrophysiology. In man, flecainide acetate produces a dose-related decrease in intracardiac conduction in all parts of the heart with the greatest effect on the His-Purkinje system (H-V conduction). Effects upon atrioventricular (AV) nodal conduction time and intra-atrial conduction times, although present, are less pronounced than those on ventricular conduction velocity. Significant effects on refractory periods were observed only in the ventricle.
Sinus node recovery times (corrected) following pacing and spontaneous cycle lengths are somewhat increased. This latter effect may become significant in patients with sinus node dysfunction. (See WARNINGS.)
Flecainide acetate causes a dose-related and plasma-level related decrease in single and multiple PVCs and can suppress recurrence of ventricular tachycardia. In limited studies of patients with a history of ventricular tachycardia, flecainide acetate has been successful 30-40% of the time in fully suppressing the inducibility of arrhythmias by programmed electrical stimulation. Based on PVC suppression, it appears that plasma levels of 0.2 to 1 mcg/mL may be needed to obtain the maximal therapeutic effect. It is more difficult to assess the dose needed to suppress serious arrhythmias but trough plasma levels in patients successfully treated for recurrent ventricular tachycardia were between 0.2 and 1 mcg/mL. Plasma levels above 0.7 to 1 mcg/mL are associated with a higher rate of cardiac adverse experiences such as conduction defects or bradycardia. The relation of plasma levels to proarrhythmic events is not established, but dose reduction in clinical trials of patients with ventricular tachycardia appears to have led to a reduced frequency and severity of such events.
Hemodynamics. Flecainide acetate does not usually alter heart rate, although bradycardia and tachycardia have been reported occasionally.
In animals and isolated myocardium, a negative inotropic effect of flecainide has been demonstrated. Decreases in ejection fraction, consistent with a negative inotropic effect, have been observed after single administration of 200 to 250 mg of the drug in man; both increases and decreases in ejection fraction have been encountered during multidose therapy in patients at usual therapeutic doses. (See WARNINGS.)
Metabolism in Humans. Following oral administration, the absorption of flecainide acetate is nearly complete. Peak plasma levels are attained at about three hours in most individuals (range, 1 to 6 hours). Flecainide does not undergo any consequential presystemic biotransformation (first-pass effect). Food or antacid do not affect absorption. Milk, however, may inhibit absorption in infants. A reduction in flecainide acetate dosage should be considered when milk is removed from the diet of infants.
The apparent plasma half-life averages about 20 hours and is quite variable (range, 12 to 27 hours) after multiple oral doses in patients with premature ventricular contractions (PVCs). With multiple dosing, plasma levels increase because of its long half-life with steady-state levels approached in 3 to 5 days; once at steady-state, no additional (or unexpected) accumulation of drug in plasma occurs during chronic therapy. Over the usual therapeutic range, data suggest that plasma levels in an individual are approximately proportional to dose, deviating upwards from linearity only slightly (about 10 to 15% per 100 mg on average).
In healthy subjects, about 30% of a single oral dose (range, 10 to 50%) is excreted in urine as unchanged drug. The two major urinary metabolites are meta-O-dealkylated flecainide (active, but about one-fifth as potent) and the meta-O-dealkylated lactam of flecainide (non-active metabolite). These two metabolites (primarily conjugated) account for most of the remaining portion of the dose. Several minor metabolites (3% of the dose or less) are also found in urine; only 5% of an oral dose is excreted in feces. In patients, free (unconjugated) plasma levels of the two major metabolites are very low (less than 0.05 mcg/mL).
In vitro metabolic studies have confirmed that cytochrome P450IID6 is involved in the metabolism of flecainide.
When urinary pH is very alkaline (8 or higher), as may occur in rare conditions (e.g., renal tubular acidosis, strict vegetarian diet), flecainide elimination from plasma is much slower.
The elimination of flecainide from the body depends on renal function (i.e., 10 to 50% appears in urine as unchanged drug). With increasing renal impairment, the extent of unchanged drug excretion in urine is reduced and the plasma half-life of flecainide is prolonged. Since flecainide is also extensively metabolized, there is no simple relationship between creatinine clearance and the rate of flecainide elimination from plasma. (See DOSAGE AND ADMINISTRATION.)
In patients with NYHA class III congestive heart failure (CHF), the rate of flecainide elimination from plasma (mean half-life, 19 hours) is moderately slower than for healthy subjects (mean half-life, 14 hours), but similar to the rate for patients with PVCs without CHF. The extent of excretion of unchanged drug in urine is also similar. (SeeDOSAGE AND ADMINISTRATION.)
Under one year of age, currently available data are limited but suggest that the half-life at birth may be as long as 29 hours, decreasing to 11 to 12 hours by three months of age and 6 hours by one year of age. The pharmacokinetics in hydropic infants have not been studied, but case reports suggest prolonged elimination. In children aged 1 year to 12 years the half-life is approximately 8 hours. In adolescents (age 12 to 15) the plasma elimination half-life is approximately 11-12 hours. Since milk may inhibit absorption in infants, a reduction in flecainide acetate dosage should be considered when milk is removed from the diet (e.g., gastroenteritis, weaning . Plasma trough flecainide levels should be monitored during major changes in dietary milk intake.
From age 20 to 80, plasma levels are only slightly higher with advancing age; flecainide elimination from plasma is somewhat slower in elderly subjects than in younger subjects. Patients up to age 80+ have been safely treated with usual dosages.
The extent of flecainide binding to human plasma proteins is about 40% and is independent of plasma drug level over the range of 0.015 to about 3.4 mcg/mL. Thus, clinically significant drug interactions based on protein binding effects would not be expected.
Hemodialysis removes only about 1% of an oral dose as unchanged flecainide.
Small increases in plasma digoxin evels are seen during coadministration of flecainide acetate with digoxin Small increases in both flecainide and propranolol plasma levels are seen during coadministration of these two drugs. (See PRECAUTIONS, DRUG INTERACTIONS.)
Clinical Trials. In two randomized, crossover, placebo-controlled clinical trials of 16 weeks double-blind duration, 79% of patients with paroxysmal supraventricular tachycardia (PSVT) receiving flecainide were attack free, whereas 15% of patients receiving placebo remained attack free. The median time-before-recurrence of PSVT in patients receiving placebo was 11 to 12 days, whereas over 85% of patients receiving flecainide had no recurrence at 60 days.
In two randomized, crossover, placebo-controlled clinical trials of 16 weeks double-blind duration, 31% of patients with paroxysmal atrial fibrillation/flutter (PAF) receiving flecainide were attack free, whereas 8% receiving placebo remained attack free. The median time-before-recurrence of PAF in patients receiving placebo was about 2 to 3 days, whereas for those receiving flecainide the median time-before-recurrence was 15 days.[1]
References
- ↑ "FLECAINIDE ACETATE TABLET [APOTEX CORP.]". Retrieved 11 March 2014.