Propafenone

INDICATIONS AND USAGE Propafenone Hydrochloride Tablets are indicated to: • prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease. • prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients without structural heart disease. • treat documented ventricular arrhythmias, such as sustained ventricular tachycardia that, in the judgment of the physician, are life-threatening. Initiate treatment in the hospital. Usage Considerations: • The use of Propafenone Hydrochloride Tablets in patients with permanent atrial fibrillation (AF) or in patients exclusively with atrial flutter or PSVT has not been evaluated. Do not use Propafenone Hydrochloride Tablets to control ventricular rate during AF. • Some patients with atrial flutter treated with propafenone have developed 1:1 conduction, producing an increase in ventricular rate. Concomitant treatment with drugs that increase the functional atrioventricular (AV) nodal refractory period is recommended. • The use of Propafenone Hydrochloride Tablets in patients with chronic atrial fibrillation has not been evaluated. • Because of the proarrhythmic effects of Propafenone Hydrochloride Tablets, its use with lesser ventricular arrhythmias is not recommended, even if patients are symptomatic, and any use of the drug should be reserved for patients in whom, in the opinion of the physician, the potential benefits outweigh the risks. • The effect of propafenone on mortality has not been determined [see Boxed Warning ] . Propafenone Hydrochloride Tablets are an antiarrhythmic indicated to: • prolong the time to recurrence of symptomatic atrial fibrillation (AF) in patients with episodic (most likely paroxysmal or persistent) AF who do not have structural heart disease. ( 1 ) • prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients who do not have structural heart disease. ( 1 ) • treat documented life-threatening ventricular arrhythmias. ( 1 ) Usage Considerations: • Use in patients with permanent atrial fibrillation or with atrial flutter or PSVT has not been evaluated. Do not use to control ventricular rate during atrial fibrillation. ( 1 ) • In patients with atrial fibrillation and atrial flutter, use Propafenone Hydrochloride Tablets with drugs that increase the atrioventricular nodal refractory period. ( 1 ) • Because of proarrhythmic effects, use with lesser ventricular arrhythmias is not recommended, even if patients are symptomatic. ( 1 ) • The effect of propafenone on mortality has not been determined. ( 1 )

DOSAGE AND ADMINISTRATION The dose of Propafenone Hydrochloride Tablets must be individually titrated on the basis of response and tolerance. Initiate therapy with Propafenone Hydrochloride Tablets 150 mg given every 8 hours (450 mg per day). Dosage may be increased at a minimum of 3- to 4- day intervals to 225 mg every 8 hours (675 mg per day). If additional therapeutic effect is needed, the dose of Propafenone Hydrochloride Tablets may be increased to 300 mg every 8 hours (900 mg per day). The usefulness and safety of dosages exceeding 900 mg per day have not been established. In patients with hepatic impairment or those with significant widening of the QRS complex or second- or third-degree AV block, consider reducing the dose. As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of Propafenone Hydrochloride Tablets should be increased more gradually during the initial phase of treatment. The combination of cytochrome P450 3A4 (CYP3A4) inhibition and either cytochrome P450 2D6 (CYP2D6) deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proarrhythmia and other adverse events. Therefore, avoid simultaneous use of Propafenone Hydrochloride Tablets with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.1 )] . • Initiate therapy with 150 mg given every 8 hours. ( 2 ) • As needed, uptitrate in 3 to 4 days to 225 to 300 mg every 8 hours. ( 2 ) • Consider reducing the dose in patients with hepatic impairment, significant widening of the QRS complex, or second- or third-degree AV block. ( 2 )

WARNINGS AND PRECAUTIONS May cause new or worsened arrhythmias. Evaluate patients via ECG prior to and during therapy. (5.1) Propafenone hydrochloride may unmask Brugada or Brugada-like Syndrome. (4 , 5.2) Avoid use with other drugs that prolong the QT interval. (5.3) Avoid simultaneous use of propafenone with both a cytochrome P450 2D6 (CYP2D6) inhibitor and a 3A4 inhibitor (CYP3A4). (5.4) May provoke overt heart failure. (5.5) May cause dose-related first-degree AV block or other conduction disturbances. Only use in patients with conduction disorders who have pacemakers. (5.6) May affect artificial pacemakers. Monitor pacemaker function. (5.7) Agranulocytosis: Patients should report signs of infection. (5.8) May exacerbate myasthenia gravis. (5.11) 5.1 Proarrhythmic Effects Propafenone has caused new or worsened arrhythmias. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole, and torsade de pointes. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. It is therefore essential that each patient given propafenone hydrochloride be evaluated electrocardiographically prior to and during therapy to determine whether the response to propafenone hydrochloride supports continued treatment. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret [see Clinical Pharmacology (12.2) ]. In a U.S. uncontrolled, open-label, multicenter trial in subjects with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these subjects experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial. However, in 4 of the 9 subjects, the ventricular tachycardia was of atrial origin. Six of the 9 subjects that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all subjects had a recurrence of SVT during the trial which could have been a change in the subjects’ arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death. Overall in clinical trials with propafenone hydrochloride (which included subjects treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all subjects had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening or new appearance of VT or VF). Of the subjects who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proarrhythmia in subjects with less serious or benign arrhythmias, which include subjects with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST trial [see Boxed Warning: Mortality ] suggests that an increased risk of proarrythmia is present throughout treatment. In a trial of sustained-release propafenone, there were too few deaths to assess the long-term risk to patients. There were 5 deaths; 3 in the pooled group for sustained-release propafenone (0.8%), and 2 in the placebo group (1.6%). In the overall database of 8 trials of sustained-release propafenone and immediate-release propafenone hydrochloride, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied. 5.2 Unmasking Brugada Syndrome Brugada Syndrome may be unmasked after exposure to propafenone hydrochloride. Perform an ECG after initiation of propafenone hydrochloride, and discontinue the drug if changes are suggestive of Brugada Syndrome [see Contraindications (4) ] . 5.3 Use with Drugs that Prolong the QT Interval and Antiarrhythmic Agents The use of propafenone hydrochloride in conjunction with other drugs that prolong the QT interval has not been extensively studied. Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides. Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with propafenone hydrochloride. Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics. 5.4 Drug Interactions: Simultaneous Use with Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4 Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the U.S. population are naturally deficient in CYP2D6 activity and other demographic groups are deficient to a somewhat lesser extent. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of propafenone hydrochloride with both a CYP2D6 inhibitor and a CYP3A4 inhibitor. 5.5 Use in Patients with a History of Heart Failure Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt heart failure. In clinical trial experience with propafenone hydrochloride, new or worsened congestive heart failure (CHF) has been reported in 3.7% of subjects with ventricular arrhythmia; of those 0.9% were considered probably or definitely related to propafenone hydrochloride. Of the subjects with CHF probably related to propafenone, 80% had pre-existing heart failure and 85% had coronary artery disease. CHF attributable to propafenone hydrochloride developed rarely (less than 0.2%) in subjects with ventricular arrhythmia who had no previous history of CHF. CHF occurred in 1.9% of subjects studied with PAF or PSVT. In a U.S. trial of sustained-release propafenone in subjects with symptomatic AF, heart failure was reported in 4 (1.0%) subjects receiving sustained-release propafenone (all doses) compared with 1 (0.8%) subject receiving placebo. 5.6 Conduction Disturbances Propafenone slows atrioventricular conduction and may also cause dose-related first-degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related. Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker [see Contraindications (4) , Clinical Pharmacology (12.2) ] . The incidence of first-degree, second-degree, and third-degree AV block observed in 2,127 subjects with ventricular arrhythmia was 2.5%, 0.6%, and 0.2%, respectively. Development of second- or third-degree AV block requires a reduction in dosage or discontinuation of propafenone hydrochloride. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in subjects receiving propafenone. Bradycardia has also been reported (1.5%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone. In a U.S. trial in 523 subjects with a history of symptomatic AF treated with sustained-release propafenone, sinus bradycardia (rate less than 50 beats/min) was reported with the same frequency with sustained-release propafenone and placebo. 5.7 Effec

CONTRAINDICATIONS Propafenone hydrochloride extended-release capsules are contraindicated in the following circumstances: • Heart failure • Cardiogenic shock • Sinoatrial, atrioventricular and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, AV block) in the absence of an artificial pacemaker • Known Brugada Syndrome • Bradycardia • Marked hypotension • Bronchospastic disorders or severe obstructive pulmonary disease • Marked electrolyte imbalance • Heart failure ( 4 ) • Cardiogenic shock ( 4 ) • Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation and/or conduction in the absence of pacemaker ( 4 ) • Known Brugada Syndrome ( 4 ) • Bradycardia ( 4 ) • Marked hypotension ( 4 ) • Bronchospastic disorders and severe obstructive pulmonary disease ( 4 ) • Marked electrolyte imbalance ( 4 )

DRUG INTERACTIONS • Inhibitors of CYP2D6, 1A2, and 3A4 may increase propafenone levels which may lead to cardiac arrhythmias. Simultaneous use with both a CYP3A4 and CYP2D6 inhibitor (or in patients with CYP2D6 deficiency) should be avoided. ( 7.1 ) • Propafenone may increase digoxin or warfarin levels. ( 7.2 , 7.3 ) • Orlistat may reduce propafenone concentrations. Abrupt cessation of orlistat in patients stable on propafenone hydrochloride extended-release capsules has resulted in convulsions, atrioventricular block, and circulatory failure. ( 7.4 ) • Concomitant use of lidocaine may increase central nervous system side effects. ( 7.6 ) 7.1 CYP2D6 and CYP3A4 Inhibitors Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, and grapefruit juice) can be expected to cause increased plasma levels of propafenone. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with administration of propafenone may increase the risk of adverse reactions, including proarrhythmia. Therefore, simultaneous use of propafenone hydrochloride extended-release capsules with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see Warnings and Precautions ( 5.4 ) and Dosage and Administration ( 2 )]. Amiodarone Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended. Cimetidine Concomitant administration of propafenone immediate-release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone. Fluoxetine Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S-propafenone C max and AUC by 39% and 50% respectively and the R-propafenone C max and AUC by 71% and 50%, respectively. Quinidine Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers [see Clinical Pharmacology ( 12.3 )]. Concomitant administration of quinidine (50 mg 3 times daily) with 150 mg immediate-release propafenone 3 times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them poor metabolizers. Steady-state plasma concentrations increased by more than 2-fold for propafenone, and decreased 50% for 5-OH-propafenone. A 100 mg dose of quinidine increased steady state concentrations of propafenone 3-fold. Avoid concomitant use of propafenone and quinidine. Rifampin Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%. The concentration of norpropafenone increased by 30%. In poor metabolizers, there was a 50% decrease in propafenone plasma concentrations and increase in the AUC and C max of norpropafenone by 74% and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients: Both the AUC and C max of propafenone decreased by 84%, with a corresponding decrease in AUC and C max of 5-OH-propafenone by 69% and 57% respectively. 7.2 Digoxin Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60% to 270%, and decreased the clearance of digoxin by 31% to 67%. Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed. 7.3 Warfarin The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin. Adjust the warfarin dose as needed by monitoring INR (international normalized ratio). 7.4 Orlistat Orlistat may limit the fraction of propafenone available for absorption. In post marketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block and acute circulatory failure. 7.5 Beta-Antagonists Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%. The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol. In clinical trials using propafenone immediate-release tablets, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects. 7.6 Lidocaine No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine.

ADVERSE REACTIONS The most commonly reported adverse events with propafenone (greater than 5% and greater than placebo) excluding those not reasonably associated with the use of the drug included the following: dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, constipation, upper respiratory tract infection, edema, and influenza. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to propafenone hydrochloride extended-release capsules 225 mg twice daily in 126 patients, to propafenone hydrochloride extended-release capsules 325 mg twice daily in 135 patients, to propafenone hydrochloride extended-release capsules 425 mg twice daily in 136 patients, and to placebo in 126 patients for up to 39 weeks (mean: 20 weeks) in a placebo- controlled trial (RAFT) conducted in the U.S. The most commonly reported adverse events with propafenone (greater than 5% and greater than placebo) excluding those not reasonably associated with the use of the drug or because they were associated with the condition being treated, were dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, constipation, upper respiratory tract infection, edema, and influenza. The frequency of discontinuation due to adverse events was 17%, and the rate was highest during the first 14 days of treatment. Cardiac-related adverse events occurring in greater than or equal to 2% of the patients in any of the RAFT propafenone extended-release capsules treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, included the following: angina pectoris, atrial flutter, AV block first-degree, bradycardia, congestive cardiac failure, cardiac murmur, edema, dyspnea, rales, wheezing, and cardioactive drug level above therapeutic. Propafenone prolongs the PR and QRS intervals in patients with atrial and ventricular arrhythmias. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval [see Clinical Pharmacology (12.2) ]. Non-cardiac related adverse events occurring in greater than or equal to 2% of the patients in any of the RAFT propafenone extended-release capsules treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, included the following: blurred vision, constipation, diarrhea, dry mouth, flatulence, nausea, vomiting, fatigue, weakness, upper respiratory tract infection, blood alkaline phosphatase increased, hematuria, muscle weakness, dizziness (excluding vertigo), headache, taste disturbance, tremor, somnolence, anxiety, depression, ecchymosis. No clinically important differences in incidence of adverse reactions were noted by age or gender. Too few non-Caucasian patients were enrolled to assess adverse events according to race. Adverse events occurring in 2% or more of the patients in any of the ERAFT [see Clinical Studies (14) ] propafenone hydrochloride extended-release capsules treatment groups and not listed above include the following: bundle branch block left, bundle branch block right, conduction disorders, sinus bradycardia, and hypotension. Other adverse events reported with propafenone clinical trials not already listed elsewhere in the prescribing information include the following adverse events by body system and preferred term. Blood and Lymphatic System Anemia, lymphadenopathy, spleen disorder, thrombocytopenia. Cardiac Unstable angina, atrial hypertrophy, cardiac arrest, coronary artery disease, extrasystoles, myocardial infarction, nodal arrhythmia, palpitations, pericarditis, sinoatrial block, sinus arrest, sinus arrhythmia, supraventricular extrasystoles, ventricular extrasystoles, ventricular hypertrophy. Ear and Labyrinth Hearing impaired, tinnitus, vertigo. Eye Eye hemorrhage, eye inflammation, eyelid ptosis, miosis, retinal disorder, visual acuity reduced. Gastrointestinal Abdominal distension, abdominal pain, duodenitis, dyspepsia, dysphagia, eructation, gastritis, gastroesophageal reflux disease, gingival bleeding, glossitis, glossodynia, gum pain, halitosis, intestinal obstruction, melena, mouth ulceration, pancreatitis, peptic ulcer, rectal bleeding, sore throat. General Disorders and Administration Site Conditions Chest pain, feeling hot, hemorrhage, malaise, pain, pyrexia. Hepatobiliary Hepatomegaly. Investigations Abnormal heart sounds, abnormal pulse, carotid bruit, decreased blood chloride, decreased blood pressure, decreased blood sodium, decreased hemoglobin, decreased neutrophil count, decreased platelet count, decreased prothrombin level, decreased red blood cell count, decreased weight, glycosuria present, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, increased blood cholesterol, increased blood creatinine, increased blood glucose, increased blood lactate dehydrogenase, increased blood pressure, increased blood prolactin, increased blood triglycerides, increased blood urea, increased blood uric acid, increased eosinophil count, increased gamma-glutamyltransferase, increased monocyte count, increased prostatic specific antigen, increased prothrombin level, increased weight, increased white blood cell count, ketonuria present, proteinuria present. Metabolism and Nutrition Anorexia, dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalemia. Musculoskeletal, Connective Tissue, and Bone Arthritis, bursitis, collagen-vascular disease, costochondritis, joint disorder, muscle cramps, muscle spasms, myalgia, neck pain, pain in jaw, sciatica, tendonitis. Nervous System Amnesia, ataxia, balance impaired, brain damage, cerebrovascular accident, dementia, gait abnormal, hypertonia, hypothesia, insomnia, paralysis, paresthesia, peripheral neuropathy, speech disorder, syncope, tongue hypoesthesia. Psychiatric Decreased libido, emotional disturbance, mental disorder, neurosis, nightmare, sleep disorder. Renal and Urinary Dysuria, nocturia, oliguria, pyuria, renal failure, urinary casts, urinary frequency, urinary incontinence, urinary retention, urine abnormal. Reproductive System and Breast Breast pain, impotence, prostatism. Respiratory, Thoracic, and Mediastinal Atelectasis, breath sounds decreased, chronic obstructive airways disease, cough, epistaxis, hemoptysis, lung disorder, pleural effusion, pulmonary congestion, rales, respiratory failure, rhinitis, throat tightness. Skin and Subcutaneous Tissue Alopecia, dermatitis, dry skin, erythema, nail abnormality, petechiae, pruritus, sweating increased, urticaria. Vascular Arterial embolism limb, deep limb venous thrombosis, flushing, hematoma, hypertension, hypertensive crisis, hypotension, labile blood pressure, pallor, peripheral coldness, peripheral vascular disease, thrombosis.

Mechanism of Action Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects and a direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and, to a lesser extent, myocardial fibers, propafenone reduces the fast-inward current carried by sodium ions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1 / 50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta-adrenergic blocking potency (per mg) about 1 / 40 that of propranolol in man. In clinical trials with the immediate-release formulation, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. At very high concentrations in vitro , propafenone can inhibit the slow inward current carried by calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e., the transient outward, the delayed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared with propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity (N-depropylpropafenone has weaker sodium channel activity but equivalent affinity for beta-receptors).