Flecainide acetate slows cardiac conduction in most patients to produce dose-related increases in PR, QRS, and QT intervals. PR interval increases on average about 25% (0.04 seconds) and as much as 118% in some patients. Approximately one-third of patients may develop new first-degree AV heart block (PR interval ≥ 0.2 seconds). The QRS complex increases on average about 25% (0.02 seconds) and as much as 150% in some patients. Many patients develop QRS complexes with a duration of 0.12 seconds or more. In one study, 4% of patients developed new bundle branch block while on flecainide acetate. The degree of lengthening of PR and QRS intervals does not predict either efficacy or the development of cardiac adverse effects. In clinical trials, it was unusual for PR intervals to increase to 0.3 seconds or more, or for QRS intervals to increase to 0.18 seconds or more. Thus, caution should be used when such intervals occur, and dose reductions may be considered. The QT interval widens about 8%, but most of this widening (about 60% to 90%) is due to widening of the QRS duration. The JT interval (QT minus QRS) only widens about 4% on the average. Significant JT prolongation occurs in less than 2% of patients. There have been rare cases of Torsade de Pointes-type arrhythmia associated with flecainide acetate therapy.
Clinically significant conduction changes have been observed at these rates: sinus node dysfunction such as sinus pause, sinus arrest and symptomatic bradycardia (1.2%), second-degree AV block (0.5%) and third-degree AV block (0.4%). An attempt should be made to manage the patient on the lowest effective dose in an effort to minimize these effects. (See DOSAGE AND ADMINISTRATION.) 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.
Flecainide acetate should be used only with extreme caution in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pause, or sinus arrest.
Flecainide acetate is known to increase endocardial pacing thresholds and may suppress ventricular escape rhythms. These effects are reversible if flecainide is discontinued. It should be used with caution in patients with permanent pacemakers or temporary pacing electrodes and should not be administered to patients with existing poor thresholds or nonprogrammable pacemakers unless suitable pacing rescue is available.
The pacing threshold in patients with pacemakers should be determined prior to instituting therapy with flecainide acetate, again after one week of administration and at regular intervals thereafter. Generally threshold changes are within the range of multiprogrammable pacemakers and, when these occur, a doubling of either voltage or pulse width is usually sufficient to regain capture.
Hypokalemia or hyperkalemia may alter the effects of Class I antiarrhythmic drugs. Preexisting hypokalemia or hyperkalemia should be corrected before administration of flecainide acetate.
The safety and efficacy of flecainide acetate in the fetus, infant, or child have not been established in double-blind, randomized, placebo-controlled trials. The proarrhythmic effects of flecainide acetate, as described previously, apply also to children. In pediatric patients with structural heart disease, flecainide acetate has been associated with cardiac arrest and sudden death. Flecainide acetate should be started in the hospital with rhythm monitoring. Any use of flecainide acetate in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children.
Flecainide has been administered to patients receiving digitalis preparations or beta-adrenergic blocking agents without adverse effects. During administration of multiple oral doses of flecainide to healthy subjects stabilized on a maintenance dose of digoxin , a 13% to 19% increase in plasma digoxin levels occurred at six hours postdose.
In a study involving healthy subjects receiving flecainide and propranolol concurrently, plasma flecainide levels were increased about 20% and propranolol levels were increased about 30% compared to control values. In this formal interaction study, flecainide and propranolol were each found to have negative inotropic effects; when the drugs were administered together, the effects were additive. The effects of concomitant administration of flecainide and propranolol on the PR interval were less than additive. In flecainide clinical trials, patients who were receiving beta blockers concurrently did not experience an increased incidence of side effects. Nevertheless, the possibility of additive negative inotropic effects of beta blockers and flecainide should be recognized.
Flecainide is not extensively bound to plasma proteins. In vitro studies with several drugs which may be administered concomitantly showed that the extent of flecainide binding to human plasma proteins is either unchanged or only slightly less. Consequently, interactions with other drugs which are highly protein bound (e.g., anticoagulants) would not be expected. Flecainide has been used in a large number of patients receiving diuretics without apparent interaction. Limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination. In healthy subjects receiving cimetidine (1 gm daily) for one week, plasma flecainide levels increased by about 30% and half-life increased by about 10%.
When amiodarone is added to flecainide therapy, plasma flecainide levels may increase two-fold or more in some patients, if flecainide dosage is not reduced. (See DOSAGE AND ADMINISTRATION)
Drugs that inhibit cytochrome P450IID6, such as quinidine , might increase the plasma concentrations of flecainide in patients that are on chronic flecainide therapy; especially if these patients are extensive metabolizers.
There has been little experience with the coadministration of flecainide and either disopyramide or verapamil. Because both of these drugs have negative inotropic properties and the effects of coadministration with flecainide are unknown, neither disopyramide nor verapamil should be administered concurrently with flecainide unless, in the judgment of the physician, the benefits of this combination outweigh the risks. There has been too little experience with the coadministration of flecainide with nifedipine or diltiazem to recommend concomitant use.
Long-term studies with flecainide in rats and mice at doses up to 60 mg/kg/day have not revealed any compound-related carcinogenic effects. Mutagenicity studies (Ames test, mouse lymphoma and in vivo cytogenetics) did not reveal any mutagenic effects. A rat reproduction study at doses up to 50 mg/kg/day (seven times the usual human dose) did not reveal any adverse effect on male or female fertility.
Flecainide has been shown to have teratogenic effects (club paws, sternebrae and vertebrae abnormalities, pale hearts with contracted ventricular septum) and an embryotoxic effect (increased resorptions) in one breed of rabbit (New Zealand White) when given doses of 30 and 35 mg/kg/day, but not in another breed of rabbit (Dutch Belted) when given doses up to 30 mg/kg/day. No teratogenic effects were observed in rats and mice given doses up to 50 and 80 mg/kg/day, respectively; however, delayed sternebral and vertebral ossification was observed at the high dose in rats. Because there are no adequate and well-controlled studies in pregnant women, flecainide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether the use of flecainide during labor or delivery has immediate or delayed adverse effects on the mother or fetus, affects the duration of labor or delivery, or increases the possibility of forceps delivery or other obstetrical intervention.
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