Tambocor (Flecainide Acetate)

TAMBOCOR™

3M Pharmaceuticals

Flecainide Acetate

Antiarrhythmic Agent

Action And Clinical Pharmacology: Flecainide belongs to the membrane stabilizing group of antiarrhythmic agents; it has electrophysiologic effects characteristic of the 1C class of the modified Vaughan-Williams classification. It also possesses local anesthetic properties.

In single cell preparations from canine cardiac tissue (Purkinje fibres) flecainide decreased the rate of rise (Vmax, Phase O) of the action potential without greatly affecting its duration; the duration of the effective refractory period was lengthened and a small change was observed in the slope of Phase 4 depolarization. In ventricular muscle, some lengthening of the action potential duration has been observed.

Flecainide 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).

Decreases in ejection fraction, consistent with a negative inotropic effect, have been observed after single administration of 200 to 250 mg flecainide; both increases and decreases in ejection fraction have been encountered during multidose therapy in patients at usual therapeutic doses (see Warnings).

During long-term clinical studies, some patients have developed congestive heart failure (CHF) while taking flecainide (see Warnings and Adverse Effects).

Flecainide does not usually alter heart rate, although bradycardia and tachycardia have been reported. In clinical studies, systolic and diastolic blood pressures increased slightly during therapy. A few patients have required changes in antihypertensive medication.

Following oral administration, flecainide is nearly completely absorbed with bioavailability of 90 to 95%. Peak plasma levels are attained at about 3 hours in most individuals (range, 1 to 6 hours). Food and antacids do not affect absorption. Flecainide does not undergo any consequential presystemic biotransformation.

The plasma half-life averages about 20 hours (range, 12 to 27 hours) after multiple oral doses in patients with premature ventricular complexes and normal renal function; this is similar to that in patients with CHF (mean, 19 hours), but it is moderately longer than for healthy subjects (mean, 14 hours). In patients with renal impairment the plasma half-life of flecainide is often prolonged and ranges from about 14 to 190 hours. Flecainide elimination from plasma is somewhat slower in healthy elderly subjects (t 1/2=18 hours) than in young healthy subjects.

Steady state plasma levels are reached within 3 to 5 days; once steady state is attained, no additional drug accumulation in plasma occurs. Therapeutic plasma concentrations of flecainide range from 0.2 to 1.0 g/mL. The plasma levels are not directly proportional to dose. Within the usual therapeutic dose range, plasma levels deviate upwards from direct proportionality (average deviation about 10 to 15% per 100 mg).

The extent of flecainide binding to plasma proteins is about 40% and is independent of plasma drug level over the range of 0.015 to 3.4 g/mL.

In healthy subjects, about 30% of a single oral dose (range, 10% to 50%) is excreted in urine as unchanged flecainide. The two major 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 in urine. 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 2 major metabolites are very low (less than 0.05 g/mL).

With increasing renal impairment, the extent of unchanged drug excretion in urine is reduced. Since flecainide is also extensively metabolized, there is no simple relationship between creatinine clearance and the rate of flecainide elimination from plasma (see Dosage). When urine is very alkaline (pH 8 or higher), as may occur in rare conditions (e.g., renal tubular acidosis, strict vegetarian diet), flecainide elimination from plasma is much slower.

Hemodialysis removes only about 1% of an oral dose as unchanged flecainide.

Indications And Clinical Uses:

No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risks and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias.

In patients without structural heart disease and with disabling symptoms, flecainide is indicated for the prevention of: paroxysmal supraventricular tachycardias (PSVT), including AV nodal reentrant tachycardia, AV reentrant tachycardia and other supraventricular tachycardias of unspecified mechanism; paroxysmal atrial fibrillation/flutter (PAF).

Patients treated with flecainide for supraventricular arrhythmias having impaired left ventricular function (ejection fraction<40) and/or ischemic heart disease may be at increased risk for cardiac adverse reactions. Use of flecainide in chronic atrial fibrillation has not been adequately studied and is not recommended (see Warnings).

Flecainide is also indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia (sustained VT), that in the judgment of the physician, are life-threatening.

Because of the proarrhythmic effects of flecainide, its use should be reserved for patients in whom, in the opinion of the physician, the benefits of treatment outweigh the risks. The use of flecainide is not recommended in patients with less severe ventricular arrhythmias, even if the patients are symptomatic (see Warnings). Use of flecainide for treatment of sustained ventricular tachycardia should be initiated in the hospital.

Tambocor should not be used in patients with recent myocardial infarction (see Warnings).

Contra-Indications: In patients with: second or third degree AV block, unless a pacemaker is present to sustain rhythm; bifascicular or trifascicular bundle branch block unless a pacemaker is present to sustain rhythm; cardiogenic shock; and hypersensitivity to the drug.

Manufacturers’ Warnings In Clinical States:

Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in post-myocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in non-fatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. This rate was 19/323 (5.8%) for flecainide and 7/318 (2.2%) for its matched placebo. The average duration of treatment with flecainide was 10 months. CAST was continued using a revised protocol with the moricizine and placebo arms only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine treated group.

The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present it is prudent to consider these results when using any antiarrhythmic agent.

Ventricular Proarrhythmic Effects in Patients with Atrial Fibrillation/Flutter: A review of the world literature revealed reports of 568 patients treated with flecainide for paroxysmal atrial fibrillation/flutter (PAF). Ventricular tachycardia was experienced in 0.4% (2/568) of these patients. Of 19 patients in the literature with chronic atrial fibrillation, 10.5% (2/19) experienced ventricular tachycardia or ventricular fibrillation. Flecainide is not recommended for use in patients with chronic atrial fibrillation. Case reports of ventricular proarrhythmic effects in patients treated with flecainide for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), ventricular tachycardia (VT), ventricular fibrillation (VF), and death.

As with other class I agents, patients treated with flecainide atrial flutter have been reported with 1:1 AV conduction due to slowing of the atrial rate. A paradoxical increase in the ventricular rate also may occur in patients with atrial fibrillation who receive flecainide. Concomitant negative chronotropic therapy such as digoxin or beta-blockers may lower the risk of this complication.

Proarrhythmic Effects: Flecainide, like other antiarrhythmic agents, can cause new or worsened arrhythmias. Such proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, e.g., tachycardia that is more sustained or more resistant to conversion to sinus rhythm, with potentially fatal consequences. In studies of 225 patients with supraventricular arrhythmia (108 with paroxysmal supraventricular tachycardia and 117 with paroxysmal atrial fibrillation), there were nine (4%) proarrhythmic events, eight of them in patients with paroxysmal atrial fibrillation. Of the nine, seven (including the one in a PSVT patient) were exacerbations of supraventricular arrhythmias (longer duration, more rapid rate, harder to reverse). Two were ventricular arrhythmias, including one fatal case of VT/VF and one wide complex VT (the patient showed inducible VT, however, after withdrawal of flecainide), both in patients with paroxysmal atrial fibrillation and known coronary artery disease.

In studies of patients with ventricular arrhythmias, flecainide proarrhythmic effects were reported in 6.8% of patients. Three fourths of the proarrhythmic events were new or worsened ventricular tachyarrhythmias, the remainder being increased frequency of PVCs or new supraventricular arrhythmias.

In patients with complex ventricular arrhythmias, it is often difficult to distinguish a spontaneous variation in the patient’s underlying rhythm disorder from drug-induced worsening, so that the following occurrence rates must be considered approximations. Their frequency appears to be related to dose and to the underlying cardiac disease. Among patients treated for sustained VT (who frequently also had heart failure, a low ejection fraction, a history of myocardial infarction and/or an episode of cardiac arrest), the incidence of proarrhythmic events was 13% when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In early studies in patients with sustained VT utilizing a higher initial dose (400 mg/day) the incidence of proarrhythmic events was 26%; moreover, in about 10% of the patients treated, proarrhythmic events resulted in death, despite prompt medical attention. With lower initial doses, the incidence of proarrhythmic events resulting in death decreased to 0.5% of these patients. Accordingly, it is extremely important to follow the recommended dosage schedule (see Dosage).

The relatively high frequency of proarrhythmic events in patients with sustained ventricular tachycardia and serious underlying heart disease, and the need for careful titration and monitoring, requires that flecainide therapy be started in the hospital (see Dosage).

Heart Failure: Because flecainide has a negative inotropic effect, it may cause or worsen congestive heart failure, particularly in patients with cardiomyopathy, pre-existing severe heart failure (NYHA functional class III or IV) or low ejection fractions (less than 40%). In patients with supraventricular arrhythmias new or worsened CHF developed in 0.4% (1/225) of patients. New or worsened CHF which might be attributed to flecainide treatment occurred in approximately 5% of patients studied in various trials. CHF developed rarely (1%) in patients who had no previous history of CHF. Flecainide should be used cautiously in patients who are known to have a history of CHF or myocardial dysfunction. The initial dose should be no more than 100 mg twice daily in such patients (see Dosage) and they should be carefully monitored. Careful attention must be given to maintenance of cardiac function, including optimization of digitalis, diuretic or other therapy. In the cases where CHF has occurred or worsened during flecainide therapy, the onset has ranged from a few hours to several months after starting therapy. Patients who develop evidence of reduced myocardial function while on flecainide should have their dose reduced or discontinued. It is recommended that plasma flecainide levels be monitored. Attempts should be made to keep trough plasma levels below 0.7 to 1 g/mL.

Effects on Cardiac Conduction: In most patients flecainide slows cardiac conduction sufficiently to produce dose-related increases in the duration of the PR, QRS and QT intervals on the ECG.

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 0.20 seconds). The QRS complex increases on average about 25% (0.2 seconds) and as much as 150% in some patients. Many patient 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. 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 0.30 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 a few cases of Torsades de Pointes-type arrhythmia associated with flecainide-induced QT prolongation and bradycardia.

Clinically significant conduction changes have been observed with these incidences: 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). If second or third degree AV block, or right bundle branch block associated with a left hemiblock occurs, therapy should be discontinued unless a temporary or implanted ventricular pacemaker is in place to ensure an adequate ventricular rate.

Sinus Node Dysfunction: In patients with sinus node dysfunction (eg, sick sinus syndrome), flecainide should be used with extreme caution because it may cause sinus bradycardia, sinus pause or sinus arrest.

Digitalis Intoxication: Flecainide has not been evaluated in the treatment of arrhythmias secondary to digitalis intoxication, and it increases the plasma level of digoxin. Therefore, it is not recommended for such use.

Electrolyte Disturbances: The presence of potassium excess or deficit may alter the effects of antiarrhythmic drugs. Any pre-existing hypokalemia or hyperkalemia should be corrected before drug administration.

Effects of Pacemaker Thresholds: Flecainide 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, again after 1 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.

Concomitant Antiarrhythmic Therapy: Due to limited experience, the concomitant use of flecainide and other antiarrhythmic agents is not recommended.

Both disopyramide and verapamil have negative inotropic properties and the effects of giving them with flecainide are unknown. Therefore, neither disopyramide or verapamil should be administered concurrently with flecainide unless, in the judgment of the physician, the possible benefit of this combination therapy clearly outweighs the risks.

When flecainide and amiodarone are coadministered, plasma flecainide levels may increase two-fold or more. If the combination therapy is required, the dose should be reduced (see Dosage).

Lidocaine has been used occasionally with flecainide while awaiting the therapeutic effect of flecainide. No adverse drug interactions were apparent. However, no studies have been performed to demonstrate the usefulness of this regimen.

Pregnancy: 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) but not in another breed of rabbit (Dutch Belted) when given in doses about 4 times (but not 3 times) the usual human dose (assuming a patient weight of 50 kg). No teratogenic effects were observed in rats and mice given doses up to 50 to 80 mg/kg/day, respectively; however, delayed sternebral and vertebral ossification was observed at the high dose in rats. There is no information about the effect on human fetus. Flecainide should not be used during pregnancy unless as a drug of last resort in life-threatening arrhythmias.

Labor and Delivery: 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.

Precautions: Hepatic Impairment: Since flecainide elimination from plasma can be markedly slower in patients with significant hepatic impairment, it should not be used in such patients unless the potential benefits clearly outweigh the risks. If used, frequent and early plasma level monitoring is required to guide dosage (see Dosage); dosage increases should be made very cautiously when plasma levels have plateaued (after more than 4 days).

Abnormalities of liver function have rarely occurred in patients treated with flecainide (see Adverse Effects). In foreign post-marketing surveillance studies, there have been rare reports of hepatic dysfunction including reports of cholestasis and hepatic failure. Although no causal relationship has been established, periodic monitoring of liver function tests should be carried out during flecainide therapy. In patients who develop unexplained jaundice or signs of hepatic dysfunction, it is advisable to discontinue flecainide in order to eliminate the drug as the possible causative agent.

Renal Impairment: The elimination of flecainide from the body depends on renal function (ie, 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. Different dosage regimens are recommended for patients with various degrees of renal insufficiency (see Pharmacology and Dosage).

Blood Dyscrasias: There have been extremely rare reports of blood dyscrasias (pancytopenia, anemia, thrombocytopenia, leukopenia, granulocytopenia). Although no causal relationship has been established, it is advisable to discontinue flecainide in patients who develop blood dyscrasia in order to eliminate it as the possible causative agent.

Occupational Hazards: Since flecainide can cause dizziness, light headedness, faintness and visual disturbance, patients should be cautioned about engaging in activities requiring judgment and physical co-ordination (such as driving an automobile or operating dangerous machinery) when these effects occur.

Geriatrics: Flecainide elimination from plasma is somewhat slower in this age group (see Dosage).

Lactation: Flecainide is excreted in human milk. Because of the drug’s potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Children: The safety and effectiveness in children below the age of 18 years have not been established.

Drug Interactions: Flecainide has been administered to patients receiving digitalis preparations or beta-adrenergic blocking agents without adverse effects. During multiple oral doses to healthy subjects stabilized on a maintenance dose of digoxin, a 13 to 19% increase in plasma digoxin levels occurred at 6 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 with control values. In this 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 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 has been used in a large number of patients receiving diuretics without apparent interaction.

Interactions with antiarrhythmics, see Warnings.

Limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate a 30% increase in the rate of flecainide elimination.

In healthy subjects receiving cimetidine (1 g daily) for 1 week, plasma flecainide levels increased by about 30% and half-life increased by about 10%.

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.

Adverse Reactions: In postmyocardial infarction patients, flecainide was found to be associated with a 5.8% rate of mortality and nonfatal cardiac arrest (see Warnings).

Flecainide has been evaluated in 225 patients with supraventricular arrhythmias. The most serious adverse reaction reported for flecainide patients with supraventricular arrhythmias were new or worsened supraventricular or ventricular arrhythmias which were reported in 4% of patients (see Warnings), conduction disturbance which occurred in 2% of patients, and new or worsened CHF occurred in 0.4% of patients.

The most commonly reported non-cardiac adverse reactions for supraventricular patients remain consistent with those known for patients treated with flecainide for ventricular arrhythmias: vision disturbance 38%, dizziness 37%, headache 18%, nausea 18%, dyspnea 13%, fatigue 13%, chest pain 12%, palpitations 11%. Although these incidences are higher than those reported in ventricular patients it is difficult to compare supraventricular and ventricular data bases because many of the supraventricular patients were dosed to tolerance in the clinical trials.

Flecainide has been evaluated in 1 224 patients which included both life threatening and non life threatening ventricular arrhythmias. The separate figures for these 2 groups of patients are not available at this time. The possibility exist that the incidences of adverse reactions in patients with life threatening ventricular arrhythmias for which this drug is indicated, might be different than that listed below. The most serious adverse reactions reported were new or exacerbated ventricular arrhythmias which occurred in 6.8% of patients, and new or worsened congestive heart failure which occurred in 3.9% of patients (or 5% of 717 patients in controlled clinical studies).

In some patients, treatment has been associated with episodes of unresuscitatable ventricular tachycardia or ventricular fibrillation. There have also been instances of second (0.5%) or third degree (0.4%) AV block. A total of 1.2% of patients developed sinus bradycardia, sinus pause, or sinus arrest (see Warnings). The frequency of most of these serious adverse reactions probably increases with higher trough plasma levels, especially when these trough levels exceed 0.7 mg/mL.

The most commonly reported non-cardiac adverse reactions experienced by patients with ventricular arrhythmias participating in clinical trials were dizziness 26.6%, visual disturbance 25.9% (includes blurred vision, doplopia, visual field effects, photophobia), headache 10.4%, nausea 10.1%, and dyspnea 8.6%. Other adverse reactions occurring in over 3% of the patients in clinical trials:

Body as a Whole: fatigue 7.4%, asthenia 4.7%.

Cardiovascular: palpitations 6.0%, chest pain 6.0%.

Gastrointestinal: constipation 4.2%, abdominal pain 3.3%.

Nervous System: tremor 5.6%, nervousness 3.1%, paresthesia 3.1%.

Skin: rash 4.1%.

The following additional adverse reactions, possibly related to flecainide therapy and occurring in 1 to less than 3% of patients have been reported in clinical trials:

Body as a Whole: pain, increased sweating, flushing, dry mouth, arthralgia, fever, myalgia.

Cardiovascular: edema, syncope, tachycardia, angina pectoris, conduction disturbance.

Gastrointestinal: vomiting, diarrhea, anorexia.

Nervous System: hypoesthesia, somnolence, insomnia, ataxia.

Respiratory: coughing.

Skin: pruritus.

Special Senses: tinnitus.

Urinary System: micturition disorder (includes urinary retention, frequency, polyuria, dysuria).

The following additional adverse experiences, possibly related to flecainide, have been reported in less than 1% of patients:

Body as a Whole: impotence, decreased libido, gynecomastia, malaise.

Cardiovascular: bradycardia, EC abnormality, hypertension, hypotension, heart disorder, myocardial infarction, peripheral ischemia, pulmonary edema.

Gastrointestinal: dyspepsia, flatulence, gastrointestinal hemorrhage.

Nervous System: anxiety, twitching, convulsions, nystagmus, stupor, dysphonia, speech disorder, coma, amnesia, confusion, depersonalization, hallucination, paranoid reaction, euphoria, apathy.

Respiratory: bronchospasm, laryngismus.

Skin: dermatitis, hypertrichosis, photosensitivity reaction, skin discoloration.

Special Senses: deafness, parosmia, loss of taste, taste perversion.

Urinary System: renal failure, hematuria.

Laboratory Abnormalities: hyperglycemia, increased nonprotein in nitrogen, increased serum alkaline phosphatase, increased serum ALT and AST. Patients with elevations of liver function tests have been asymptomatic and no cause and effect relationship with flecainide has been established.

Adverse reactions leading to discontinuation of therapy occurred in 18.5% of the patients. The two most common were non-cardiac adverse reactions 9.0% and new or worsened arrhythmias 6.8%.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No specific antidote has been identified for the treatment of flecainide overdosage. Animal studies suggest the following events might occur with overdosage: lengthening of the PR interval; increase in the QRS duration, QT interval and amplitude of the T-wave; a reduction in myocardial rate and contractility; conduction disturbances; hypotension; and death from respiratory failure or asystole. 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 (range from 12 to 27 hours in patients), 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), acidification of urine to promote drug excretion may, theoretically, be beneficial in overdose cases with very alkaline urine. There is no evidence that acidification from normal urinary pH increases excretion.

Dosage And Administration: Supraventricular Arrhythmias: The recommended starting dose for patients with paraoxysmal supraventricular tachycardias or patients with paroxysmal atrial fibrillation/flutter is 50 mg every 12 hrs. Flecainide may be increased in increments of 50 mg b.i.d. every 4 days until efficacy is achieved. The maximum recommended dose is 300 mg/day.

Ventricular Arrhythmias: For patients with sustained ventricular tachycardia, flecainide should be started in the hospital with rhythm monitoring. The recommended starting dose for patients with ventricular arrhythmias is 100 mg every 12 hours. Flecainide may be increased in increments of 50 g b.i.d. every 4 days until efficacy is achieved. Most patients do not require more than 150 mg every 12 hours (300 mg/day). The maximum dose is 400 g/day.

Use of higher initial doses and more rapid dosage adjustments has resulted in an increased incidence of proarrhythmic events and congestive heart failure, particularly during the first few days of dosing (see Warnings). Therefore, a loading dose is not recommended.

An occasional patient not adequately controlled by (or intolerant to) a dose given at 12-hour intervals may be given flecainide at 8 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.

In patients with a history of CHF or myocardial dysfunction, the initial dose should be no more than 100 mg every 12 hours. If needed to achieve efficacy, the dosage may be increased cautiously in increments of 50 mg twice a day every 4 days, and the maximum dosage should not exceed 200 mg every 12 hours (400 mg/day), because higher doses are associated with a greater incidence of worsened CHF (see Warnings).

In patients with severe renal impairment (creatinine clearance of 35 mL/min/1.73 mor less), the initial dosage should be 50 mg to 100 mg once daily; when used in such patients, daily plasma level monitoring is required to guide dosage adjustments (see Plasma Level Monitoring). In patients with less severe renal disease, the initial dosage should be 100 mg every 12 hours; plasma level monitoring is also recommended in these patients during dosage adjustment. In both groups of patients, dosage increases should be made very cautiously when plasma levels have plateaued, observing the patient closely for signs of adverse cardiac effects or other toxicity. It should be borne in mind that in these patients it is likely to take longer than 4 days before a new steady state plasma level is reached following a dosage change. Therefore the interval between dose increases should be longer than the 4 days recommended for patients with normal renal function.

In elderly patients flecainide elimination from plasma is somewhat slower. The initial dosage need not be adjusted, however, daily trough plasma flecainide level monitoring is recommended during dosage adjustment.

Plasma Level Monitoring: Therapeutic trough plasma flecainide levels were found to range between 0.2 and 1.0 g/mL. The probability of adverse experiences, especially cardiac, may increase with higher trough plasma levels, especially when these exceed 0.7 g/mL. Periodic monitoring of trough plasma levels may be useful in patient management. Because elimination of flecainide from plasma may be markedly slower in patients with severe chronic renal failure or severe hepatic disease, plasma level monitoring is required in these patients. Plasma level monitoring is recommended in patients with congestive heart failure, moderate renal disease, and the elderly.

Based on theoretical considerations, rather than experimental data, the following suggestion is made: when transferring patients from another antiarrhythmic drug to flecainide or from flecainide to another antiarrhythmic, allow at least 2 to 4 plasma half-lives to elapse for the drug being discontinued before starting the alternative 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.

If flecainide is given in the presence of amiodarone (see Warnings) the usual dose of flecainide should be reduced by 50% and the patient should be monitored closely for adverse reactions. Plasma level monitoring is strongly recommended to guide dosage with such combination therapy.

Availability And Storage: 50 mg: Each white, round, unscored tablet, imprinted with 3M on one side and TR 50 on the other side, contains: flecainide acetate 50 mg. Nonmedicinal ingredients: croscarmellose sodium, hydrogenated vegetable oil, magnesium stearate, microcrystalline cellulose and starch. Tartrazine-free. Bottles of 100.

100 mg: Each white, round, scored tablet, embossed with 3M on one side and TR 100 on the other side, contains: flecainide acetate 100 mg. Nonmedicinal ingredients: croscarmellose sodium, hydrogenated vegetable oil, magnesium stearate, microcrystalline cellulose and starch. Tartrazine-free. Bottles of 100.

Store between 15 to 30°C. Protect from light.

TAMBOCOR™ 3M Pharmaceuticals Flecainide Acetate Antiarrhythmic Agent

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