FLECAINE LP

Flecainide acetate is an antiarrhythmic drug available in tablets of 50 mg, 100 mg, or 150 mg for oral administration.

Flecainide acetate is benzamide, N-(2-piperidinyl-methyl)-2,5-bis (2,2,2-trifluoroethoxy)-monoacetate.

The structural formula is given below.

Flecainide acetate

USP is a white to slightly off-white, crystalline powder with a pK a of 9.3.

It has an aqueous solubility of 48.4 mg/mL at 37°C. Flecainide acetate tablets, USP also contain: croscarmellose sodium, hydrogenated vegetable oil type 1, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

In patients without structural heart disease, flecainide acetate tablets, USP are indicated for the prevention of — paroxysmal supraventricular tachycardias (PSVT), including atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia and other supraventricular tachycardias of unspecified mechanism associated with disabling symptoms — paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms Flecainide acetate tablets, USP are also indicated for the prevention of — documented ventricular arrhythmias, such as sustained ventricular tachycardia ( sustained VT), that in the judgment of the physician are life-threatening.

Use of flecainide acetate tablets, USP for the treatment of sustained VT, like other antiarrhythmics, should be initiated in the hospital.

The use of flecainide acetate tablets, USP are not recommended in patients with less severe ventricular arrhythmias even if the patients are symptomatic.

Because of the proarrhythmic effects of flecainide acetate tablets, USP, its use should be reserved for patients in whom, in the opinion of the physician, the benefits of treatment outweigh the risks.

Flecainide acetate tablets, USP should not be used in patients with recent myocardial infarction.

Use of flecainide acetate tablets, USP in chronic atrial fibrillation has not been adequately studied and is not recommended.

As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of flecainide acetate tablets, USP favorably affects survival or the incidence of sudden death.

Lactation Structural cardiac anomaly History of heart failure Recent history of myocardial infarction Severe Bradycardia Children under 12 years of age Atrial flutter Pregnancy Hyperkalaemia Hypokalaemia Hypomagnesaemia Severe hypotension Severe hepatic impairment Renal impairment Left ventricular failure Interchangeability Cardiac surgery, history Newborn exposed in utero to the medicine Porting a pacemaker Elderly Subject at risk of heart failure Cardiac conduction disorder.

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.

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.

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 to 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.

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 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.

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 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 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. See DOSAGE 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 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 to 15) the plasma elimination half-life is approximately to 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 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 levels 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.

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 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.

PAF in patients receiving placebo was about to 3 days, whereas for those receiving flecainide the median time-before-recurrence was 15 days.

Mechanism of action

The antiarrhythmic properties of flecainide acetate are similar to those of class I antiarrhythmics of the Vaughan-Williams classification, subclass IC. flecainide acetate has a negative inotropic effect.

In humans, flecainide acetate prolongs intraauricular, nodal and intraventricular conduction times.

It slightly increases the effective refractory periods atrial and ventricular, the effective refractory period of the atrial node and the refractory period of the anterograde and retrograde accessory pathways.

It does not cause significant changes in heart frequency except in patients with sinus dysfunction.

• White Globules decreased (Uncommon)
• Platelet number decreased (Uncommon)
• Liver enzymes (increase) (Rare)
• Antinuclear body (increase) (Very rare)
• Alopecia (Uncommon)
• Rash (Uncommon)
• Allergic dermatitis (Uncommon)
• Urticaria (Rare)
• Photosensitivity (Very rare)
• Hyperhidrosis (Rare)
• Edema (Common)
• Fever (Common)
• Asthenia (Common)
• Fatigue (Common)
• Flushing (Rare)
• Inflammation Chest pain
• Erythropenia (Uncommon)
• Thrombocytopenia (Uncommon)
• Ictery (Rare)
• Hepatic impairment
• Appetite decreased (Uncommon)
• Vision disorder (Very common)
• Diplopia (Very common)
• Corneal deposit (Very rare)
• Blurty vision Feeling dizzy (Very common)
• Vertigo (Rare)
• Ear ringing (Rare)
• Mental confusion (Rare)
• Anxiety (Rare)
• Insomnia (Rare)
• Hallucination (Rare)
• Depression (Rare)
• Instability Atrial flutter (Uncommon)
• Arrhythmia (Common)
• Flutter (Uncommon)
• Congestive puff (Rare)
• Hot flash (Rare)
• Syncope (Rare)
• Arrhythmia (aggravation)
• Atrial tachysystolia
• Palpitation Branch block Myocardial infarction Tachycardia Brugada syndrome Ventricular tachycardia
• Severe heart failure Sinus break Cardiac conduction disorder Cardiogenic shock Electrocardiogram anomaly
• Complete atrial cell QRS (longening)
• Ventricular fibrillation 2nd degree atrial cell
• Hypotension Congestive heart failure Cardiac arrest Sinoatrial block Bradycardia
• Extension of PR space Heart conduction disorder (aggravation)
• Atrialculoventric block
• Heart failure Dyspepsia (Uncommon)
• Constipation (Uncommon)
• Nausea (Uncommon)
• Abdominal pain (Uncommon)
• Vomiting (Uncommon)
• Flatulence (Uncommon)
• Diarrhoea (Uncommon)
• Abnormal liver function
• Digestive disorder Muscle pain Joint pain Peripheral neuropathy (Rare)
• Amnesia (Rare)
• Ataxia (Rare)
• Convulsions (Rare)
• Sensory deficiency (Rare)
• Neurosensory disorder (Rare)
• Trembling (Rare)
• Somnolence (Rare)
• Dyskinesia (Rare)
• Headache (Rare)
• Dyspnoea (Common)
• Interstitial pneumopathy (Very rare)
• Pneumopathy (Rare)
• Pulmonary dysfunction (Very rare).

No specific antidote has been identified for the treatment of flecainide acetate overdosage.

Overdoses ranging up to 8000 mg have been survived, with peak plasma flecainide concentrations as high as 5.3 mcg/mL.

Untoward effects in these cases included nausea and vomiting, convulsions, hypotension, bradycardia, syncope, extreme widening of the QRS complex, widening of the QT interval, widening of the PR interval, ventricular tachycardia, AV nodal block, asystole, bundle branch block, cardiac failure, and cardiac arrest.

The spectrum of events observed in fatal cases was much the same as that seen in the non-fatal cases.

Death has resulted following ingestion of as little as 1000 mg; concomitant overdose of other drugs and/or alcohol in many instances undoubtedly contributed to the fatal outcome.

Treatment of overdosage should be supportive and may include the following: removal of unabsorbed drug from the gastrointestinal tract, administration of inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol; mechanically assisted respiration; circulatory assists such as intra-aortic balloon pumping; and transvenous pacing in the event of conduction block.

Because of the long plasma half-life of flecainide (12 to 27 hours in patients receiving usual doses), and the possibility of markedly non-linear elimination kinetics at very high doses, these supportive treatments may need to be continued for extended periods of time.

Hemodialysis is not an effective means of removing flecainide from the body.

Since flecainide elimination is much slower when urine is very alkaline (pH 8 or higher), theoretically, acidification of urine to promote drug excretion may be beneficial in overdose cases with very alkaline urine.

There is no evidence that acidification from normal urinary pH increases excretion.

Flecainide acetate tablets are contraindicated in patients with preexisting second.

• or third-degree AV block, or with right bundle branch block when associated with a left hemiblock (bifascicular block), unless a pacemaker is present to sustain the cardiac rhythm should complete heart block occur.

Flecainide acetate tablets are also contraindicated in the presence of cardiogenic shock or known hypersensitivity to the drug.

For patients with sustained

VT, no matter what their cardiac status, flecainide acetate tablets, like other antiarrhythmics, should be initiated in-hospital with rhythm monitoring.

Flecainide has a long half-life (12 to 27 hours in patients).

Steady-state plasma levels, in patients with normal renal and hepatic function, may not be achieved until the patient has received to 5 days of therapy at a given dose.

Therefore, increases in dosage should be made no more frequently than once every four days, since during the first to 3 days of therapy the optimal effect of a given dose may not be achieved.

For patients with PSVT and patients with PAF the recommended starting dose is 50 mg every 12 hours.

Flecainide acetate tablets doses may be increased in increments of 50 mg bid every four days until efficacy is achieved.

PAF patients, a substantial increase in efficacy without a substantial increase in discontinuations for adverse experiences may be achieved by increasing the flecainide acetate tablets dose from to 100 mg bid.

The maximum recommended dose for patients with paroxysmal supraventricular arrhythmias is 300 mg/day. For sustained VT the recommended starting dose is 100 mg every 12 hours.

This dose may be increased in increments of 50 mg bid every four days until efficacy is achieved.

Most patients with sustained

VT do not require more than 150 mg every 12 hours (300 mg/day) and the maximum dose recommended is 400 mg/day. In patients with sustained VT, use of higher initial doses and more rapid dosage adjustments have resulted in an increased incidence of proarrhythmic events and CHF, particularly during the first few days of dosing.

Therefore, a loading dose is not recommended.

Intravenous lidocaine has been used occasionally with flecainide acetate tablets while awaiting the therapeutic effect of flecainide acetate tablets.

No adverse drug interactions were apparent.

However, no formal studies have been performed to demonstrate the usefulness of this regimen.

An occasional patient not adequately controlled by (or intolerant to) a dose given at 12-hour intervals may be dosed at eight-hour intervals.

Once adequate control of the arrhythmia has been achieved, it may be possible in some patients to reduce the dose as necessary to minimize side effects or effects on conduction.

In such patients, efficacy at the lower dose should be evaluated.

Flecainide acetate tablets should be used cautiously in patients with a history of CHF or myocardial dysfunction.

Any use of flecainide acetate tablets in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children.

Because of the evolving nature of information in this area, specialized literature should be consulted.

Under six months of age, the initial starting dose of flecainide acetate tablets in children is approximately 50 mg/m 2 body surface area daily, divided into two or three equally spaced doses.

Over six months of age, the initial starting dose may be increased to 100 mg/m 2 per day. The maximum recommended dose is 200 mg/m 2 per day. This dose should not be exceeded.

In some children on higher doses, despite previously low plasma levels, the level has increased rapidly to far above therapeutic values while taking the same dose.

Small changes in dose may also lead to disproportionate increases in plasma levels.

Plasma trough (less than one hour pre-dose) flecainide levels and electrocardiograms should be obtained at presumed steady state (after at least five doses) either after initiation or change in flecainide acetate tablets dose, whether the dose was increased for lack of effectiveness, or increased growth of the patient.

For the first year on therapy, whenever the patient is seen for reasons of clinical follow-up, it is suggested that a 12-lead electrocardiogram and plasma trough flecainide level are obtained.

The usual therapeutic level of flecainide in children is to 500 ng/mL.

In some cases, levels as high as 800 ng/mL may be required for control.

In patients with severe renal impairment (creatinine clearance of 35 mL/min/1.73 square meters or less), the initial dosage should be 100 mg once daily (or 50 mg bid); when used in such patients, frequent plasma level monitoring is required to guide dosage adjustments.

In patients with less severe renal disease, the initial dosage should be 100 mg every 12 hours; plasma level monitoring may also be useful in these patients during dosage adjustment.

In both groups of patients, dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days), observing the patient closely for signs of adverse cardiac effects or other toxicity.

It should be borne in mind that in these patients it may take longer than four days before a new steady-state plasma level is reached following a dosage change.

Based on theoretical considerations, rather than experimental data, the following suggestion is made: when transferring patients from another antiarrhythmic drug to flecainide acetate tablets allow at least two to four plasma half-lives to elapse for the drug being discontinued before starting flecainide acetate tablets at the usual dosage.

In patients where withdrawal of a previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, the physician should consider hospitalizing the patient.

When flecainide is given in the presence of amiodarone, reduce the usual flecainide dose by 50% and monitor the patient closely for adverse effects.

Plasma level monitoring is strongly recommended to guide dosage with such combination therapy.

The large majority of patients successfully treated with flecainide acetate tablets were found to have trough plasma levels between 0.2 and 1 mcg/mL.

The probability of adverse experiences, especially cardiac, may increase with higher trough plasma levels, especially when these exceed 1 mcg/mL.

Periodic monitoring of trough plasma levels may be useful in patient management.

Plasma level monitoring is required in patients with severe renal failure or severe hepatic disease, since elimination of flecainide from plasma may be markedly slower.

Monitoring of plasma levels is strongly recommended in patients on concurrent amiodarone therapy and may also be helpful in patients with CHF and in patients with moderate renal disease.

USP, 50 mg are white to off-white, round, biconvex tablets debossed with “CC” on one side and “11” on other side.

Bottles of 30 NDC 65862-621-30 Bottles of 100 NDC 65862-621-01 Bottles of 1,000 NDC 65862-621-99 Flecainide Acetate Tablets USP, 100 mg are white to off-white, round, biconvex tablets debossed with ‘1’ and ‘2’ separated by deep score line on one side and “CC” on other side.

Bottles of 30 NDC 65862-622-30 Bottles of 100 NDC 65862-622-01 Bottles of 1,000 NDC 65862-622-99 Flecainide Acetate Tablets USP, 150 mg are white to off-white, oval, biconvex tablets debossed with ‘1’ and ‘3’ separated by deep score line on one side and “CC” on other side.

Bottles of 30 NDC 65862-623-30 Bottles of 100 NDC 65862-623-01 Bottles of 1,000 NDC 65862-623-99 Store at 20º to 25ºC (68º to 77ºF) in a tight, light-resistant container.

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Windsor, NJ 08520.

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 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 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 acetate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Results from a multiple dose study conducted in mothers soon after delivery indicates that flecainide is excreted in human breast milk in concentrations as high as 4 times (with average levels about 2.5 times) corresponding plasma levels; assuming a maternal plasma level at the top of the therapeutic range (1 mcg/mL), the calculated daily dose to a nursing infant (assuming about 700 mL breast milk over 24 hours) would be less than 3 mg.

The safety and efficacy of flecainide acetate in the fetus, infant, or child have not been established in double-blind, randomized, placebo-controlled trials.