INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Patients should be instructed to notify their health care providers of any change in over-the- counter, prescription and supplement use. The health care provider should assess the patients medication history including all over-the-counter, prescription and herbal/natural preparations for those that may affect the pharmacodynamics or kinetics of propafenone HCl extended release [see WARNINGS and PRECAUTIONS 5.2)]. Patients should also check with their health care providers prior to taking new over-the-counter medicine.o If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their health care provider.o Patients should be instructed NOT to double the next dose if dose is missed. The next dose should be taken at the usual time.PATIENT INFORMATIONPROPAFENONE HCl EXTENDED RELEASE CAPSULESRead this Patient Information Leaflet before you start taking propafenone HCl extended releaseand each time you get refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.What is propafenone HCl ER capsules Propafenone HCl ER capsules is prescription medicine that is used:in certain people who have heart rhythm disorder called atrial fibrillation (AF) to increase the amount of time between having symptoms of AF It is not known if propafenone HCl ER capsules is safe and effective in children.Who should not take propafenone HCl ER capsulesDo not take propafenone HCl ER capsules if you have:heart failure (weak heart) had recent heart attack heart rate that is too slow, and you do not have pacemaker very low blood pressure certain breathing problems that make you short of breath or wheeze certain abnormal body salt (electrolyte) levels in your blood Talk to your doctor before taking propafenone HCl ER capsules if you think you have any of the conditions listed above.What should tell my doctor before taking propafenone HCl ER capsulesBefore you take propafenone HCl ER capsules, tell your doctor if you:have liver or kidney problems have breathing problems have symptoms including diarrhea, sweating, vomiting, or loss of appetite or thirst that are severe. These symptoms may be sign of abnormal electrolyte levels in your blood. have myasthenia gravis have lupus erythematosis have been told you have or had an abnormal blood test called Antinuclear Antibody Test or ANA TEST are pregnant or plan to become pregnant. It is not known if propafenone HCl ER capsules will harm your unborn baby. are breastfeeding or plan to breastfeed. Propafenone HCl ER capsules can pass into your milk and may harm your baby. You and your doctor should decide if you will breastfeed or take propafenone HCl ER capsules. You should not do both. have any other medical conditions Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Propafenone HCl ER capsules and certain other medicines can affect each other and cause serious side effects. Propafenone HCl ER capsulese may affect the way other medicines work, and other medicines may affect how propafenone HCl ER capsules works. Especially tell your doctor if you take:amiodarone or other medicines for your abnormal heart beats an antidepressant medicine medicine to treat anxiety ritonavir (for example, KALETRA(R), NORVIR(R)) or saquinavir (for example, INVIRASE(R)) an antibiotic medicine ketoconazole (for example, NIZORAL(R)) digoxin (LANOXIN(R)) warfarin sodium (for example, COUMADIN(R), JANTOVEN(R)) Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should take propafenone HCl ER capsulesTake propafenone HCl ER capsules exactly as prescribed. Your doctor will tell you how many capsules to take and how often to take them. To help reduce the chance of certain side effects, your doctor may start you with low dose of propafenone HCl ER capsules, and then slowly increase the dose. Do not open or crush the capsule. You may take propafenone HCl ER capsulese with or without food. You should not drink grapefruit juice during treatment with propafenone HCl ER capsules. If you miss dose of propafenone HCl ER capsules, take your next dose at the usual time. Do not take doses at the same time. If you take too much propafenone HCl ER capsules, call your doctor or go to the nearest hospital emergency room right away. Call your doctor if your heart problems get worse. What are possible side effects of propafenone HCl ER capsulesPropafenone HCl ER capsulescan cause serious side effects including: New or worsened abnormal heart beats, that can cause sudden death or be life-threatening. Your doctor may do an electrocardiogram (ECG or EKG) before and during treatment to check your heart for these problems. any new or increased swelling in your arms or legs trouble breathing sudden weight gain Effects on pacemaker function. Propafenone HCl ER capsules may affect how an implanted pacemaker or defibrillator works. Your doctor should check how your pacemaker or defibrillator is working during and after treatment with propafenone HCl ER capsules. They may need to be re-programmed. fever sore throat chills Worsening of myasthenia gravis in people who already have this condition. Tell your doctor about any change in your symptoms. Propafenone HCl ER capsules may cause lower sperm counts in men. This could affect the ability to father child. Talk to your doctor if this is concern for you. dizziness fast or irregular heartbeats chest pain trouble breathing taste changes nausea tiredness feeling anxious constipation upper respiratory infection or flu swelling Tell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of propafenone HCl ER capsules. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store propafenone HCl ER capsulesoStore propafenone HCl ER capsules at room temperature between 59F to 86F (15C to 30C). oKeep the bottle tightly closed.Keep propafenone HCl ER capsules and all medicines out of the reach of children.General information about propafenone HCl ER capsulesMedicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use propafenone HCl extended release for condition for which it was not prescribed by your doctor. Do not give propafenone HCl extended release to other people, even if they have the same symptoms you have. It may harm them.This leaflet summarizes the most important information about propafenone HCl ER capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about propafenone HCl ER capsules that is written for healthcare professionals. For more information about propafenone HCl ER capsules, call AvKARE, Inc. at 1-855-361-3993.What are the ingredients in propafenone HCl ER capsules Active Ingredient: Propafenone hydrochlorideInactive Ingredients: ethylcellulose, lactose anhydrous, magnesium stearate and povidone. Each capsule contains Titanium dioxide and gelatin. In addition the 325 mg capsule also contains FD&C Blue No.1, D&C Yellow No. 10 and FD&C Red No. 40 and the 425 mg capsule contains FD&C Blue No.1, FD&C Red No. 40 and FD&C Yellow No. 6. The black ink consists of D&C Yellow No.10, iron oxide black, n-butyl alcohol, propylene glycol, FD&C Blue No. 2, FD&C Red No. 40, FD&C Blue No. and shellac glaze~45% (20% esterfied) in ethanol. The other brands listed are trademarks of their respective owners and are not trademarks of AvKARE, Inc. The makers of these brands are not affiliated with and do not endorse AvKARE, Inc. or its products.Manufactured for:AvKARE, Inc.Pulaski, TN 38478 Mfg. Rev. 03/15 AV 01/16 (P) in certain people who have heart rhythm disorder called atrial fibrillation (AF) to increase the amount of time between having symptoms of AF heart failure (weak heart) had recent heart attack a heart rate that is too slow, and you do not have pacemaker very low blood pressure certain breathing problems that make you short of breath or wheeze certain abnormal body salt (electrolyte) levels in your blood have liver or kidney problems have breathing problems have symptoms including diarrhea, sweating, vomiting, or loss of appetite or thirst that are severe. These symptoms may be sign of abnormal electrolyte levels in your blood. have myasthenia gravis have lupus erythematosis have been told you have or had an abnormal blood test called Antinuclear Antibody Test or ANA TEST are pregnant or plan to become pregnant. It is not known if propafenone HCl ER capsules will harm your unborn baby. are breastfeeding or plan to breastfeed. Propafenone HCl ER capsules can pass into your milk and may harm your baby. You and your doctor should decide if you will breastfeed or take propafenone HCl ER capsules. You should not do both. have any other medical conditions amiodarone or other medicines for your abnormal heart beats an antidepressant medicine a medicine to treat anxiety ritonavir (for example, KALETRA(R), NORVIR(R)) or saquinavir (for example, INVIRASE(R)) an antibiotic medicine ketoconazole (for example, NIZORAL(R)) digoxin (LANOXIN(R)) warfarin sodium (for example, COUMADIN(R), JANTOVEN(R)) Take propafenone HCl ER capsules exactly as prescribed. Your doctor will tell you how many capsules to take and how often to take them. To help reduce the chance of certain side effects, your doctor may start you with low dose of propafenone HCl ER capsules, and then slowly increase the dose. Do not open or crush the capsule. You may take propafenone HCl ER capsulese with or without food. You should not drink grapefruit juice during treatment with propafenone HCl ER capsules. If you miss dose of propafenone HCl ER capsules, take your next dose at the usual time. Do not take doses at the same time. If you take too much propafenone HCl ER capsules, call your doctor or go to the nearest hospital emergency room right away. Call your doctor if your heart problems get worse. New or worsened abnormal heart beats, that can cause sudden death or be life-threatening. Your doctor may do an electrocardiogram (ECG or EKG) before and during treatment to check your heart for these problems. any new or increased swelling in your arms or legs trouble breathing sudden weight gain any new or increased swelling in your arms or legs trouble breathing sudden weight gain Effects on pacemaker function. Propafenone HCl ER capsules may affect how an implanted pacemaker or defibrillator works. Your doctor should check how your pacemaker or defibrillator is working during and after treatment with propafenone HCl ER capsules. They may need to be re-programmed. fever sore throat chills fever sore throat chills Worsening of myasthenia gravis in people who already have this condition. Tell your doctor about any change in your symptoms. Propafenone HCl ER capsules may cause lower sperm counts in men. This could affect the ability to father child. Talk to your doctor if this is concern for you. dizziness fast or irregular heartbeats chest pain trouble breathing taste changes nausea tiredness feeling anxious constipation upper respiratory infection or flu swelling dizziness fast or irregular heartbeats chest pain trouble breathing taste changes nausea tiredness feeling anxious constipation upper respiratory infection or flu swelling.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most commonly reported adverse events with propafenone (>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 AvKARE, Inc. at 1-855-361-3993; email drugsafetyavkare.com; 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 drug cannot be directly compared to 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 ER capsules 225 mg BID in 126 patients, to propafenone ER capsules 325 mg BID in 135 patients, to propafenone ER capsules 425 mg BID in 136 patients, and to placebo in 126 patients for up to 39 weeks (mean 20 weeks) in placebo- controlled trial (RAFT) conducted in the U.S. The most commonly reported adverse events with propafenone (>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 >= 2% of the patients in any of the RAFT propafenone ER 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 >= 2% of the patients in any of the RAFT propafenone ER 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 CLINICALSTUDIES 14)] propafenone ER 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 and preferred term.Blood and lymphatic system disorders: Anemia, lymphadenopathy, spleen disorder, thrombocytopenia. Cardiac disorders: 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 disorders: Hearing impaired, tinnitus, vertigo. Eye disorders: Eye hemorrhage, eye inflammation, eyelid ptosis, miosis, retinal disorder, visual acuity reduced. Gastrointestinal disorders: 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. Hepato-biliary disorders: 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 disorders: Anorexia, dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalemia. Musculoskeletal, connective tissue and bone disorders: Arthritis, bursitis, collagen-vascular disease, costochondritis, joint disorder, muscle cramps, muscle spasms, myalgia, neck pain, pain in jaw, sciatica, tendonitis. Nervous system disorders: Amnesia, ataxia, balance impaired, brain damage, cerebrovascular accident, dementia, gait abnormal, hypertonia, hypothesia, insomnia, paralysis, paresthesia, peripheral neuropathy, speech disorder, syncope, tongue hypoesthesia. Psychiatric disorders: Decreased libido, emotional disturbance, mental disorder, neurosis, nightmare, sleep disorder. Renal and urinary disorders: Dysuria, nocturia, oliguria, pyuria, renal failure, urinary casts, urinary frequency, urinary incontinence, urinary retention, urine abnormal. Reproductive system and breast disorders: Breast pain, impotence, prostatism. Respiratory, thoracic and mediastinal disorders: 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 disorders: Alopecia, dermatitis, dry skin, erythema, nail abnormality, petechiae, pruritus, sweating increased, urticaria. Vascular disorders: Arterial embolism limb, deep limb venous thrombosis, flushing, hematoma, hypertension, hypertensive crisis, hypotension, labile blood pressure, pallor, peripheral coldness, peripheral vascular disease, thrombosis.

BOXED WARNING SECTION.

WARNING: MORTALITY. In the National Heart, Lung and Blood Institutes Cardiac Arrhythmia Suppression Trial (CAST), long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had myocardial infarction more than days but less than years previously, an increased rate of death or reversed cardiac arrest rate (7.7%;56/730) was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in patients assigned to placebo (3.0%; 22/725). The average duration of treatment with encainide or flecainide in this study was 10 months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any IC antiarrhythmic to have significant proarrhythmic risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs. In the National Heart, Lung and Blood Institutes Cardiac Arrhythmia Suppression Trial (CAST), long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had myocardial infarction more than days but less than years previously, an increased rate of death or reversed cardiac arrest rate (7.7%;56/730) was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in patients assigned to placebo (3.0%; 22/725). The average duration of treatment with encainide or flecainide in this study was 10 months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any IC antiarrhythmic to have significant proarrhythmic risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs. See full prescribing information for complete boxed warning.o An increased rate of death or reversed cardiac arrest rate was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in patients assigned to placebo. At present it is prudent to consider any IC antiarrhythmic to have significant risk of provoking proarrhythmic events in patients with structural heart disease.o Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Propafenone is Class 1C antiarrhythmic drug with local anesthetic effects, and direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to 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 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 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 to 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). 12.2 Pharmacodynamics. Electrophysiology: Electrophysiology studies in patients with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His- Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolff-Parkinson-White syndrome, propafenone hydrochloride reduce conduction and increase the effective refractory period of the accessory pathway in both directions. Electrocardiograms: Propafenone prolongs the PR and QRS intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval. Table 1. Mean Change +- SD in 12-Lead Electrocardiogram Results (RAFT) Propafenone HCl ER CapsulesTwice-Daily Dosing 225 mg 325 mg 425 mg Placebo (n 126)(n 135) (n 136) (n 126) PR (ms) 9+-22 12+-23 21+-24 1+-16 QRS (ms) 4+-14 6+-156+-15-2+-12Heart rate5+-24 7+-23 2+-22 8+-27 QTc ms) 2+-30 5+-36 6+-37 5+-35Calculated using Bazetts correction factorIn RAFT see CLINICAL STUDIES 14 )], the distribution of the maximum changes in QTc compared to baseline over the study in each patient was similar in the propafenone ER capsules 225 mg twice daily, 325 mg twice daily, and 425 mg twice daily and placebo dose groups. Similar results were seen in the ERAFT study. Table 2. Number of Patients According to the Range of Maximum QTc change compared to baseline over the study in each dose group (RAFT study). Range maximum QTc changePropafenone HCl ER CapsulesPlacebo 225 mg twice daily325 mg twice daily425 mg twice daily (n= 119)(n 129) (n= 123) (n 100) n(%)n(%)n(%)n(%)>20%1(1) 6(5) 3(2) 5(4) 10 20% 19(16) 28(22)32(26)24(20)0<=10%99(83)95(74) 88(72) 91(76) Hemodynamics: Studies in humans have shown that propafenone exerts negative inotropic effect on the myocardium. Cardiac catheterization studies in patients with moderately impaired ventricular function (mean C.I.=2.61 L/min/m 2), utilizing intravenous propafenone infusions (loading dose of mg/kg over 10 min+ followed by mg/min for 30 min) that gave mean plasma concentrations of 3.0 mcg/mL (a dose that produces plasma levels of propafenone greater than does recommended oral dosing), showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances and depression of cardiac output and cardiac index. 12.3 Pharmacokinetics. Absorption/Bioavailability: Maximal plasma levels of propafenone are reached between to hours following the administration of propafenone ER capsules. Propafenone is known to undergo extensive and saturable presystemic biotransformation which results in dose and dosage form dependent absolute bioavailability; e.g., 150 mg immediate release tablet had an absolute bioavailability of 3.4%, while 300 mg immediate release tablet had an absolute bioavailability of 10.6%. Absorption from 300 mg solution dose was rapid, with an absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability of propafenone from immediate release tablets increased still further. Relative bioavailability assessments have been performed between propafenone ER capsules and propafenone immediate release tablets. In extensive metabolizers, the bioavailability of propafenone from the ER formulation was less than that of the immediate release formulation as the more gradual release of propafenone from the prolonged-release preparations resulted in an increase of overall first pass metabolism see Metabolism]. As result of the increased first pass effect, higher daily doses of propafenone were required from the ER formulation relative to the immediate release formulation, to obtain similar exposure to propafenone. The relative bioavailability of propafenone from the 325 twice daily regimens of propafenone ER capsules approximates that of propafenone immediate release 150 mg three times daily regimen. Mean exposure to 5-hydroxypropafenone was about 20 to 25% higher after ER capsule administration than after immediate release tablet administration. Food increased the exposure to propafenone 4-fold after single dose administration of 425 mg of propafenone ER capsules. However, in the multiple dose study (425 mg dose BID), the difference between the fed and fasted state was not significant.Distribution: Following intravenous administration of propafenone, plasma levels decline in bi-phasic manner consistent with 2 compartment pharmacokinetic model. The average distribution half-life corresponding to the first phase was about minutes. The volume of the central compartment was about 88 liters (1.1 L/kg) and the total volume of distribution about 252 liters. In serum, propafenone is greater than 95% bound to proteins within the concentration range of 0.5 to mcg/mL.Metabolism: There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half -life from to 10 hours. These patients metabolize propafenone into two active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2. In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed. In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with diminished ability to metabolize debrisoquine and variety of other drugs such as encainide, metoprolol, and dextromethorphan whose metabolism is mediated by the CYP2D6 isozyme. In these patients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers. As consequence of the observed differences in metabolism, administration of propafenone ER capsules to slow and extensive metabolizers results in significant differences in plasma concentrations of propafenone, with slow metabolizers achieving concentrations about twice those of the extensive metabolizers at daily doses of 850 mg/day. At low doses the differences are greater, with slow metabolizers attaining concentrations about to times higher than extensive metabolizers. In extensive metabolizers, saturation of the hydroxylation pathway (CYP2D6) results in greater-than-linear increases in plasma levels following administration of propafenone ER capsules. In slow metabolizers, propafenone pharmacokinetics is linear. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxymetabolite in the slow metabolizers, and because steady state conditions are achieved after to days of dosing in all patients, the recommended dosing regimen of propafenone ER capsules is the same for all patients. The larger inter-subject variability in blood levels require that the dose of the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity [see DOSAGE AND ADMINISTRATION 2)]. The 5-hydroxypropafenone and norpropafenone metabolites have electrophysiologic properties similar to propafenone in vitro. In man after administration of propafenone ER capsules, the 5-hydroxypropafenone metabolite is usually present in concentrations less than 40% of propafenone. The norpropafenone metabolite is usually present in concentrations less than 10% of propafenone. Inter-Subject Variability: With propafenone, there is considerable degree of inter- subject variability in pharmacokinetics which is due in large part to the first pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. higher degree of inter-subject variability in pharmacokinetic parameters of propafenone was observed following both single and multiple dose administration of propafenone ER capsules. Inter-subject variability appears to be substantially less in the poor metabolizer group than in the extensive metabolizer group, suggesting that large portion of the variability is intrinsic to CYP2D6 polymorphism rather than to the formulation. Stereochemistry: Propafenone ER capsule is racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5--hydroxylation pathway (CYP2D6). This results in higher ratio of S-propafenone to R--propafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is more potent -antagonist than the R-enantiomer. Following administration of proprafenone HCl immediate release tablets or propafenone ER capsules, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. The S/R ratios of propafenone obtained after administration of 225 mg, 325 mg and 425 mg propafenone ER capsules are independent of dose. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time. Special Populations: Hepatic Impairment: Decreased liver function increases the bioavailability of propafenone. Absolute bioavailability assessments have not been determined for the propafenone ER capsule formulation. Absolute bioavailability of propafenone HCl immediate release tablets is inversely related to indocyanine green clearance, reaching 60 to 70% at clearances of mL/min and below. Protein binding decreases to about 88% in patients with severe hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction see WARNINGS ANDPRECAUTIONS 5.8)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Propafenone ER capsules has been evaluated in patients with history of electrocardiographically documented recurrent episodes of symptomatic AF in randomized, double-blind, placebo controlled trials.RAFT: In one U.S. multicenter study (propafenone ER capsules Atrial Fibrillation Trial, RAFT), doses of propafenone ER capsules (225 mg twice daily, 325 mg twice daily and 425 mg twice daily) and placebo were compared in 523 patients with symptomatic, episodic AF. The patient population in this trial was 59% male with mean age of 63 years; 91% White and 6% Black. The patients had median history of AF of 13 months, and documented symptomatic AF within 12 months of study entry. Over 90% were NYHA Class I, and 21% had prior electrical cardioversion. At baseline, 24% were treated with calcium channel blockers, 37% with beta blockers, and 38% with digoxin. Symptomatic arrhythmias after randomization were documented by transtelephonic electrocardiogram and centrally read and adjudicated by blinded adverse event committee. Propafenone ER capsules administered for up to 39 weeks was shown to prolong significantly the time to the first recurrence of symptomatic atrial arrhythmia, predominantly AF, from Day of randomization (primary efficacy variable) compared to placebo, as shown in Table 4.Table 3: Analysis of Tachycardia-Free Period (Days) from Day of Randomization Propafenone HCl ER CapsulesTwice Daily Dose Parameter 225 mg (N 126) n(%)325 mg (N 135) n(%)425 mg (N 136) n(%)Placebo(N=126) n(%)Patients completing with terminating event66(52)56(41)41(30)87(69)Comparison of tachycardia-free periods Kaplan-Meier Media112291NA+41 Range 0-285 0-2930-3000-289p-Value (Log-rank test)0.014<0.0001<0.0001--- Hazard Ratio compared to placebo0.670.430.35---95% CI for Hazard Ratio(0.49,0.93)(0.31,0.61)(0.24,0.51)--- Terminating events comprised 91% AF, 5% atrial flutter, and 4% PSVT.+ Not Applicable: Fewer than 50% of the patients had events. The median time is not calculable.There was dose response for propafenone ER capsules for the tachycardia-free period as shown in the proportional hazard analysis and the Kaplan-Meier curves presented in Figure 1. Figure 1: RAFT Kaplan-Meier Analysis for the Tachycardia-free period from Day of randomization: In additional analyses, propafenone ER capsules (225 mg twice daily, 325 mg twice daily, and 425 mg twice daily) was also shown to prolong time to the first recurrence of symptomatic AF from Day (steady state pharmacokinetics were attained). The antiarrhythmic effect of propafenone HCl extended release was not influenced by age, gender, history of cardioversion, duration of AF, frequency of AF or use of medication that lowers heart rate. Similarly, the antiarrhythmic effect of propafenone ER capsules was not influenced by the individual use of calcium channel blockers, beta-blockers or digoxin. Too few non-White patients were enrolled to assess the influence of race on effects of propafenone ER capsules (propafenone hydrochloride).No difference in the average heart rate during the first recurrence of symptomatic arrhythmia between proprafenone ER capsules and placebo was observed.ERAFT: In European multicenter trial [(European Rythmonorm SR Atrial Fibrillation Trial (ERAFT)], doses of propafenone ER capsules (325 mg twice daily and 425 mg twice daily) and placebo were compared in 293 patients with documented electrocardiographic evidence of symptomatic paroxysmal AF. The patient population in this trial was 61% male, 100% White with mean age of 61 years. Patients had median duration of AF of 3.3 years, and 61% were taking medications that lowered heart rate. At baseline, 15% of the patients were treated with calcium channel blockers (verapamil and diltiazem), 42% with beta-blockers and 8% with digoxin. During qualifying period of up to 28 days, patients had to have ECG-documented incident of symptomatic AF. The double-blind treatment phase consisted of 4 day loading period followed by 91-day efficacy period. Symptomatic arrhythmias were documented by electrocardiogram monitoring. In ERAFT, Propafenone ER capsules was shown to prolong the time to the first recurrence of symptomatic atrial arrhythmia from Day of randomization (primary efficacy analysis). The proportional hazard analysis revealed that both propafenone ER capsules doses were superior to placebo. The antiarrhythmic effect of propafenone ER was not influenced by age, gender, duration of AF, frequency of AF or use of medication that lowers heart rate. It was also not influenced by the individual use of calcium channel blockers, beta-blockers or digoxin. Too few non-White patients were enrolled to assess the influence of race on the effects of propafenone ER capsules. There was slight increase in the incidence of centrally diagnosed asymptomatic AF or atrial flutter in each of the Propafenone ER capsules treatment groups compared to placebo.. this is the figure.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Inhibitors of CYP2D6, 1A2, and 3A4 may increase propafenone levels which may lead to cardiac arrhythmias. Simultaneous use with both CYP3A4 and CYP2D6 inhibitor (or in patient with CYP2D6 deficiency) should be avoided. 7.1) Propafenone may increase warfarin or digoxin levels. 7.2, 7.3) Concomitant use of lidocaine may increase central nervous system side effects. 7.3) Orlistat may reduce propafenone concentrations. Abrupt cessation of orlistat in patients stable on propafenone has resulted in convulsions, atrioventricular block, and circulatory failure. 7.5) 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 ER capsules with both CYP2D6 inhibitor and CYP3A4 inhibitor should be avoided [see WARNINGS and PRECAUTIONS 5.2) 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 20% increase in steady state plasma concentrations of propafenone. Fluoxetine: Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the propafenone max and AUC by 39 and 50% and the propafenone max and AUC by 71 and 50%. Quinidine: Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers [see CLINICAL PHARMACOLOGY 12)]. Concomitant administration of quinidine (50 mg three times daily) with 150 mg immediate release propafenone three times daily decreased the clearance of propafenone by 60% in EM, making them PM. Steady state plasma concentrations increased by more than 2-fold for propafenone, and decreased 50% for 5-OH-propafenone 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 corresponding decrease of 5OH-propafenone by 65%. The concentration of norpropafenone increased by 30%. In poor metabolizers, there was 50% decrease in propafenone plasma concentrations and increased the AUC and 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 max propafenone decreased by 84%, with corresponding decrease in AUC and max of 5OH-propafenone by 69 and 57%. 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility Section. Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose [MRHD] on mg/m basis) and rats (up to 270 mg/kg/day, about times the MRHD on mg/m basis) provided no evidence of carcinogenic potential for propafenone HCl. Propafenone HCl tested negative for mutagenicity in the Ames (salmonella) test and in the in vivo mouse dominant lethal test. It tested negative for clastogenicity in the human lymphocyte chromosome aberration assay in vitro and in rat and Chinese hamster micronucleus tests, and other in vivo tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia. Propafenone HCl, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone HCl, were seen at lethal or near lethal dose levels and were not seen in rats treated either orally or intravenously see WARNINGS AND PRECAUTIONS 5.11 )]. Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on mg/m basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone HCl was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about times the MRHD on mg/m basis). 13.2 Animal Pharmacology and/or Toxicology Section. Renal and Hepatic Toxicity in Animals: Renal changes have been observed in the rat following months of oral administration of propafenone HCl at doses of 180 and 360 mg/kg/day (about and times, respectively, the maximum recommended human daily dose [MRHD] on mg/m basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HCl at dose of 270 mg/kg/day (about times the MRHD on mg/m basis). There were no renal or hepatic changes at 90 mg/kg/day equivalent to the MRHD on mg/m basis).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Electrophysiology: Electrophysiology studies in patients with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His- Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolff-Parkinson-White syndrome, propafenone hydrochloride reduce conduction and increase the effective refractory period of the accessory pathway in both directions. Electrocardiograms: Propafenone prolongs the PR and QRS intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval. Table 1. Mean Change +- SD in 12-Lead Electrocardiogram Results (RAFT) Propafenone HCl ER CapsulesTwice-Daily Dosing 225 mg 325 mg 425 mg Placebo (n 126)(n 135) (n 136) (n 126) PR (ms) 9+-22 12+-23 21+-24 1+-16 QRS (ms) 4+-14 6+-156+-15-2+-12Heart rate5+-24 7+-23 2+-22 8+-27 QTc ms) 2+-30 5+-36 6+-37 5+-35Calculated using Bazetts correction factorIn RAFT see CLINICAL STUDIES 14 )], the distribution of the maximum changes in QTc compared to baseline over the study in each patient was similar in the propafenone ER capsules 225 mg twice daily, 325 mg twice daily, and 425 mg twice daily and placebo dose groups. Similar results were seen in the ERAFT study. Table 2. Number of Patients According to the Range of Maximum QTc change compared to baseline over the study in each dose group (RAFT study). Range maximum QTc changePropafenone HCl ER CapsulesPlacebo 225 mg twice daily325 mg twice daily425 mg twice daily (n= 119)(n 129) (n= 123) (n 100) n(%)n(%)n(%)n(%)>20%1(1) 6(5) 3(2) 5(4) 10 20% 19(16) 28(22)32(26)24(20)0<=10%99(83)95(74) 88(72) 91(76) Hemodynamics: Studies in humans have shown that propafenone exerts negative inotropic effect on the myocardium. Cardiac catheterization studies in patients with moderately impaired ventricular function (mean C.I.=2.61 L/min/m 2), utilizing intravenous propafenone infusions (loading dose of mg/kg over 10 min+ followed by mg/min for 30 min) that gave mean plasma concentrations of 3.0 mcg/mL (a dose that produces plasma levels of propafenone greater than does recommended oral dosing), showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances and depression of cardiac output and cardiac index.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption/Bioavailability: Maximal plasma levels of propafenone are reached between to hours following the administration of propafenone ER capsules. Propafenone is known to undergo extensive and saturable presystemic biotransformation which results in dose and dosage form dependent absolute bioavailability; e.g., 150 mg immediate release tablet had an absolute bioavailability of 3.4%, while 300 mg immediate release tablet had an absolute bioavailability of 10.6%. Absorption from 300 mg solution dose was rapid, with an absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability of propafenone from immediate release tablets increased still further. Relative bioavailability assessments have been performed between propafenone ER capsules and propafenone immediate release tablets. In extensive metabolizers, the bioavailability of propafenone from the ER formulation was less than that of the immediate release formulation as the more gradual release of propafenone from the prolonged-release preparations resulted in an increase of overall first pass metabolism see Metabolism]. As result of the increased first pass effect, higher daily doses of propafenone were required from the ER formulation relative to the immediate release formulation, to obtain similar exposure to propafenone. The relative bioavailability of propafenone from the 325 twice daily regimens of propafenone ER capsules approximates that of propafenone immediate release 150 mg three times daily regimen. Mean exposure to 5-hydroxypropafenone was about 20 to 25% higher after ER capsule administration than after immediate release tablet administration. Food increased the exposure to propafenone 4-fold after single dose administration of 425 mg of propafenone ER capsules. However, in the multiple dose study (425 mg dose BID), the difference between the fed and fasted state was not significant.Distribution: Following intravenous administration of propafenone, plasma levels decline in bi-phasic manner consistent with 2 compartment pharmacokinetic model. The average distribution half-life corresponding to the first phase was about minutes. The volume of the central compartment was about 88 liters (1.1 L/kg) and the total volume of distribution about 252 liters. In serum, propafenone is greater than 95% bound to proteins within the concentration range of 0.5 to mcg/mL.Metabolism: There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half -life from to 10 hours. These patients metabolize propafenone into two active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2. In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed. In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with diminished ability to metabolize debrisoquine and variety of other drugs such as encainide, metoprolol, and dextromethorphan whose metabolism is mediated by the CYP2D6 isozyme. In these patients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers. As consequence of the observed differences in metabolism, administration of propafenone ER capsules to slow and extensive metabolizers results in significant differences in plasma concentrations of propafenone, with slow metabolizers achieving concentrations about twice those of the extensive metabolizers at daily doses of 850 mg/day. At low doses the differences are greater, with slow metabolizers attaining concentrations about to times higher than extensive metabolizers. In extensive metabolizers, saturation of the hydroxylation pathway (CYP2D6) results in greater-than-linear increases in plasma levels following administration of propafenone ER capsules. In slow metabolizers, propafenone pharmacokinetics is linear. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxymetabolite in the slow metabolizers, and because steady state conditions are achieved after to days of dosing in all patients, the recommended dosing regimen of propafenone ER capsules is the same for all patients. The larger inter-subject variability in blood levels require that the dose of the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity [see DOSAGE AND ADMINISTRATION 2)]. The 5-hydroxypropafenone and norpropafenone metabolites have electrophysiologic properties similar to propafenone in vitro. In man after administration of propafenone ER capsules, the 5-hydroxypropafenone metabolite is usually present in concentrations less than 40% of propafenone. The norpropafenone metabolite is usually present in concentrations less than 10% of propafenone. Inter-Subject Variability: With propafenone, there is considerable degree of inter- subject variability in pharmacokinetics which is due in large part to the first pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. higher degree of inter-subject variability in pharmacokinetic parameters of propafenone was observed following both single and multiple dose administration of propafenone ER capsules. Inter-subject variability appears to be substantially less in the poor metabolizer group than in the extensive metabolizer group, suggesting that large portion of the variability is intrinsic to CYP2D6 polymorphism rather than to the formulation. Stereochemistry: Propafenone ER capsule is racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5--hydroxylation pathway (CYP2D6). This results in higher ratio of S-propafenone to R--propafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is more potent -antagonist than the R-enantiomer. Following administration of proprafenone HCl immediate release tablets or propafenone ER capsules, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. The S/R ratios of propafenone obtained after administration of 225 mg, 325 mg and 425 mg propafenone ER capsules are independent of dose. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time. Special Populations: Hepatic Impairment: Decreased liver function increases the bioavailability of propafenone. Absolute bioavailability assessments have not been determined for the propafenone ER capsule formulation. Absolute bioavailability of propafenone HCl immediate release tablets is inversely related to indocyanine green clearance, reaching 60 to 70% at clearances of mL/min and below. Protein binding decreases to about 88% in patients with severe hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction see WARNINGS ANDPRECAUTIONS 5.8)].

SPL UNCLASSIFIED SECTION.

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 be evaluated electrocardiographically prior to and during therapy, to determine whether the response to propafenone ER capsules 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 the RAFT study [see CLINICAL STUDIES 14) there were too few deaths to assess the long term risk to patients. There were deaths, in the pooled propafenone ER capsules group (0.8%) and in the placebo group (1.6%). In the overall propafenone ER capsules and propafenone immediate release database of studies, 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. In U.S. uncontrolled, open label multicenter trial using the immediate release formulation in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study. However, in of the patients, the ventricular tachycardia was of atrial origin. Six of the patients that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all patients had recurrence of SVT during the study which could have been change in the patients arrhythmia behavior or could represent 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 immediate release (which included patients treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing proarrhythmic event (0.7% was an increase in PVCs; 4.0% worsening, or new appearance, of VT or VF). Of the patients who had worsening of VT (4%), 92% had history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had prior myocardial infarction. The incidence of pro-arrhythmia in patients with less serious or benign arrhythmias, which include patients 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 study [see BOXED WARNING: MORTALITY] suggests that an increased risk of proarrhythmia is present throughout treatment.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Propafenone ER capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Animal Data: Teratogenic Effects: Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg/day (about times the maximum recommended human dose [MRHD] on mg/m 2basis) and 600 mg/kg/day (about times the MRHD on mg/m basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about three times the MRHD on mg/m basis) produced no evidence of embryotoxicity in rats, post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on mg/m basis). Non-teratogenic Effects: In study in which female rats received daily oral doses of propafenone from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on mg/m basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (four or more times the MRHD on mg/m basis) resulted in reductions in neonatal survival, body weight gain and physiological development. 8.2 Labor And Delivery. It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetrical intervention.. 8.3 Nursing Mothers. Propafenone is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from propafenone, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. The safety and effectiveness of propafenone in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of subjects in Phase clinical studies of propafenone ER capsules (propafenone hydrochloride) 46% were 65 and over, while 16% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals at higher doses cannot be ruled out. The effect of age on the pharmacokinetics and pharmacodynamics of propafenone has not been studied.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. May cause new or worsened arrhythmias. Evaluate patients via ECG prior to and during therapy. 5.1) Propafenone HCl Extended Release may unmask Brugada or Brugada-like Syndrome. Evaluate patients via ECG after initiation of therapy. (4, 5.2). Avoid use with other antiarrhythmic agents or other drugs that prolong the QT interval. 5.3) Avoid simultaneous use of propafenone with both cytochrome P450 2D6 inhibitor and 3A4 inhibitor. 5.2) May provoke overt heart failure. 5.5) May cause dose-related first degree AV block or other conduction disturbances. Should not be given to patients with conduction defects in absence of pacemaker. 5.6) May affect artificial pacemakers. Pacemakers should be monitored during therapy. 5.7) Agranulocytosis: Patients should report signs of infection. 5.8) Administer cautiously to patients with impaired hepatic and renal function. 5.9, 5.10) Exacerbation of myasthenia gravis has been reported. 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 be evaluated electrocardiographically prior to and during therapy, to determine whether the response to propafenone ER capsules 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 the RAFT study [see CLINICAL STUDIES 14) there were too few deaths to assess the long term risk to patients. There were deaths, in the pooled propafenone ER capsules group (0.8%) and in the placebo group (1.6%). In the overall propafenone ER capsules and propafenone immediate release database of studies, 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. In U.S. uncontrolled, open label multicenter trial using the immediate release formulation in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study. However, in of the patients, the ventricular tachycardia was of atrial origin. Six of the patients that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all patients had recurrence of SVT during the study which could have been change in the patients arrhythmia behavior or could represent 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 immediate release (which included patients treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing proarrhythmic event (0.7% was an increase in PVCs; 4.0% worsening, or new appearance, of VT or VF). Of the patients who had worsening of VT (4%), 92% had history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had prior myocardial infarction. The incidence of pro-arrhythmia in patients with less serious or benign arrhythmias, which include patients 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 study [see BOXED WARNING: MORTALITY] suggests that an increased risk of proarrhythmia is present throughout treatment. 5.2 Unmasking Brugada Syndrome Brugada Syndrome may be unmasked after exposure to propafenone ER capsules. Perform an ECG after initiation of propafenone 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 ER capsules (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 half-lives prior to dosing with propafenone ER capsules. 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 se 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 to somewhat lesser extent in other demographic groups. 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 ER capsules with both CYP2D6 inhibitor and CYP3A4 inhibitor.. 5.5 Use in Patients with History of Heart Failure. Propafenone exerts negative inotropic activity on the myocardium as well as beta blockade effects and may provoke overt heart failure. In the U.S. trial (RAFT) in patients with symptomatic AF, heart failure was reported in (1.0%) patients receiving propafenone ER capsules (all doses), compared to (0.8%) patient receiving placebo. Proarrhythmic effects more likely occur when propafenone is administered to patients with heart failure (NYHA III and IV) or severe myocardial ischemia [see CONTRAINDICATIONS (4)]. In clinical trial experience with propafenone immediate release, new or worsened heart failure has been reported in 3.7% of patients with ventricular arrhythmia. These events were more likely in subjects with preexisting heart failure and coronary artery disease. New onset of heart failure attributable to propafenone developed in <0.2% of patients with ventricular arrhythmia and in 1.9% of patients with paroxysmal AF or PSVT.. 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 pacemaker [see CONTRAINDICATIONS 4) and CLINICAL PHARMACOLOGY 12.2)]. In U.S. trial (RAFT) in 523 patients with history of symptomatic AF treated with propafenone ER capsules, sinus bradycardia (rate <50 beats/min) was reported with the same frequency with propafenone ER capsules and placebo.. 5.7 Effects on Pacemaker Threshold Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.. 5.8 Agranulocytosis. Agranulocytosis has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days. Unexplained fever or decrease in white cell count, particularly during the initial months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.. 5.9 Use in Patients with Hepatic Dysfunction. Propafenone is highly metabolized by the liver. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to to 40% in patients with normal liver function when given propafenone immediate release tablets. In patients with moderate to severe liver disease administered propafenone immediate release tablets, the mean half-life was approximately hours. No studies have compared bioavailability of propafenone from propafenone ER capsules in patients with normal and impaired hepatic function. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects [see OVERDOSAGE 10)] 5.10 Use in Patients with Renal Dysfunction Approximately 50% of propafenone metabolites are excreted in the urine following administration of propafenone immediate release tablets. No studies have been performed to assess the percentage of metabolites eliminated in the urine following the administration of propafenone ER capsules.In patients with impaired renal function, monitor for signs of overdosage see OVERDOSAGE( 10) ]. 5.11 Use in Patients with Myasthenia Gravis Exacerbation of myasthenia gravis has been reported during propafenone therapy.. 5.12 Elevated ANA Titers. Positive ANA titers have been reported in patients receiving propafenone. They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy. These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy. Carefully evaluate patients who develop an abnormal ANA test and if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone. Evaluation of the effects of short-term propafenone HCl administration on spermatogenesis in 11 normal subjects suggested that propafenone HCl produced reversible, short-term drop (within normal range) in sperm count.. 5.13 Impaired Spermatogenesis. Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone. Evaluation of the effects of short-term propafenone HCl administration on spermatogenesis in 11 normal subjects suggested that propafenone HCl produced reversible, short-term drop (within normal range) in sperm count.