FDA label e4412a6a-ed4d-410d-8abb-86e1d7b72a3c

WARNINGS Mortality: In the National Heart, Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two 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 1C 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 ten 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 1C antiarrhythmic to have a significant 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. 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 ER capsules 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. In a 474 patient U.S. uncontrolled, open label multicenter trial using the immediate release formulation in patients with symptomatic SVT, 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study. However, in four of the nine patients, the ventricular tachycardia was of atrial origin. Six of the nine 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 a change in the patients’ arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with propafenone HCl for atrial fibrillation/flutter have included increased PVCs, VT, VF, Torsade de Pointes, asystole, and death. In the RAFT study, there were five deaths, three in the pooled propafenone ER capsules group (0.8%) and two in the placebo group (1.6%). In the overall propafenone ER capsules and propafenone HCl immediate release database of eight studies, the mortality rate was 2.5% per year on propafenone HCl and 4% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied. 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 and is not recommended. Such drugs may include many antiarrhythmics, some phenothiazines, cisapride, bepridil, tricyclic antidepressants and oral macrolides. Class Ia and III antiarrhythmic agents should be withheld for at least five half-lives prior to dosing with propafenone ER capsules. The use of propafenone with Class Ia and III antiarrhythmic agents (including quinidine and amiodarone) is not recommended. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema) Patients with bronchospastic disease should not, in general, receive propafenone or other agents with beta-adrenergic-blocking activity. Congestive Heart Failure Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt congestive heart failure. In the U.S. trial (RAFT) in patients with symptomatic atrial fibrillation, congestive heart failure was reported in four (1%) patients receiving propafenone ER capsules (all doses), compared to one (0.8%) patient receiving placebo. Proarrhythmic effects are more likely to occur when propafenone is administered to patients with congestive heart failure (NYHA III and IV) or severe myocardial ischemia (see CONTRAINDICATIONS ). Conduction Disturbances: Propafenone causes dose-related first degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related. Propafenone should not be given to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker (see CONTRAINDICATIONS ). In a U.S. trial (RAFT) in 523 patients with a history of symptomatic atrial fibrillation treated with propafenone ER capsules, electrocardiograms obtained in response to symptoms were associated with no patients having sinus rhythm with Mobitz Type I (Wenckenbach) second degree AV block, sinus rhythm with Mobitz Type II second degree AV block, or third degree AV block. Sinus bradycardia (rate <50 beats/min) was reported with the same frequency with propafenone ER capsules and placebo. Effects on Pacemaker Threshold: Propafenone may alter both pacing and sensing thresholds of artificial pacemakers. Pacemakers should be monitored and programmed accordingly during therapy. Hematologic Disturbances: Agranulocytosis (fever, chills, weakness, and neutropenia) has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first two months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days. Unexplained fever and/or decrease in white cell count, particularly during the initial three months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Patients should be instructed to report promptly the development of any signs of infection such as fever, sore throat, or chills.

ADVERSE REACTIONS 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 in a placebo-controlled trial (RAFT) conducted in the U.S. The most commonly reported adverse events in the trial included dizziness, chest pain, palpitations, taste disturbance, dyspnea, nausea, constipation, anxiety, fatigue, upper respiratory tract infection, influenza, first degree heart block and vomiting. The frequency of discontinuation due to adverse events was highest during the first 14 days of treatment. The majority of the patients with serious adverse events who withdrew or were discontinued recovered without sequelae. Adverse events occurring in 2% or more 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, are listed in Table 2. Table 2: Most common adverse events (≥2% in any RAFT propafenone ER treatment group and more common on propafenone than on placebo) Propafenone ER Capsules MeDRA Body System/Preferred Term 225 mg BID (N = 126) n (%) 325 mg BID (N = 135) n (%) 425 mg BID (N = 136) n (%) Placebo (N=126 n (%) Mean exposure (days) 124 149 141 91 Cardiac disorders Angina pectoris 0 (0) 0 (0) 3 (2) 0 (0) Atrial flutter 3 (2) 2 (1) 0 (0) 1 (1) AV block first degree 3 (2) 3 (2) 4 (3) 0 (0) Bradycardia 4 (3) 4 (3) 6 (4) 1 (1) Cardiac failure congestive 0 (0) 1 (1) 3 (2) 1 (1) Cardiac murmur 2 (2) 3 (2) 6 (4) 0 (0) Edema 6 (5) 18 (13) 10 (7) 8 (6) Eye disorders Vision blurred 1 (1) 1 (1) 5 (4) 0 (0) Gastrointestinal disorders Constipation 10 (8) 19 (14) 16 (12) 3 (2) Diarrhea 2 (2) 3 (2) 5 (4) 3 (2) Dry mouth 1 (1) 1 (1) 5 (4) 1 (1) Flatulence 3 (2) 3 (2) 1 (1) 0 (0) Nausea 11 (9) 15 (11) 23 (17) 11 (9) Vomiting 1 (1) 0 (0) 8 (6) 3 (2) General disorder and administration site Fatigue 14 (11) 17 (13) 17 (13) 7 (6) Weakness 4 (3) 6 (4) 6 (4) 3 (2) Infections and Infestations Upper respiratory tract infection 11 (9) 16 (12) 11 (8)) 7 (6) Investigations Blood alkaline phosphatase increased 0 (0) 0 (0) 4 (3) 0 (0) Cardioactive drug level above therapeutic 1 (1) 1 (1) 3 (2) 1 (1) Hematuria 2 (2) 2 (1) 4 (3) 3 (2) Musculoskeletal, connective tissue and bone Muscle weakness 1 (1) 5 (4) 1 (1) 0 (0) Nervous system disorders Dizziness (excluding vertigo) 29 (23) 28 (21) 29 (21) 18 (14) Headache 8 (6) 12 (9) 14 (10) 11 (9) Taste disturbance 7 (6) 18 (13) 30 (22) 1 (1) Tremor 2 (2) 0 (0) 3 (2) 1 (1) Somnolence 1 (1) 1 (1) 4 (3) 0 ( 0) Psychiatric disorders Anxiety 12 (10) 17 (13) 16 (12) 13 (10) Depression 1 (1) 4 (3) 0 (0) 2 (2) Respiratory, thoracic and mediastinal disorder Dyspnea 16 (13) 23 (17) 17 (13) 9 (7) Rales 2 (2) 1 (1) 3 (2) 0 (0) Wheezing 0 (0) 0 (0) 3 (2) 0 (0) Skin & subcutaneous tissue disorders Ecchymosis 2 (2) 3 (2) 5 (4) 0 (0) No clinically important differences in incidence of adverse reactions were noted by age, or gender. Too few non-White 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 propafenone ER treatment groups and not listed in Table 2 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 in Table 2 include the following adverse events by body and preferred term. Blood and lymphatic system disorders: anemia; lymphadenopathy; spleen disorder; thrombocytopenia; Cardiac disorders: angina unstable; arrhythmia; atrial hypertrophy; atrioventricular block; bundle branch block left; bundle branch block right; cardiac arrest; cardiac disorder; conduction disorder; coronary artery disease; extrasystoles; myocardial infarction; nodal arrhythmia; palpitations; pericarditis; sinoatrial block; sinus arrest; sinus arrhythmia; sinus bradycardia; supraventricular extrasystoles; supraventricular tachycardia; ventricular arrhythmia; 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; dry throat; 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 electrocardiogram; abnormal heart sounds; abnormal liver function tests; 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; electrocardiogram QT prolonged; glycosuria present; heart rate irregular; 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; pruritis; 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. Laboratory: Electrocardiograms 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. Table 3: Mean Change in 12-Lead Electrocardiogram Results (RAFT) *Calculated using Bazett’s correction factor. Propafenone ER Capsules BID 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±15 6±15 -2±12 QTc* (ms) 2±30 5±36 6±37 5±35 In RAFT, 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 BID, 325 mg BID, and 425 mg BID and placebo dose groups. Similar results were seen in the ERAFT study. Table 4: Number of patients according to the range of maximum QTc change compared to baseline over the study in each dose group (RAFT study) Range of maximum QTc change Propafenone ER Capsules Placebo 225 mg BID 325 mg BID 425 mg BID 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%) ≤10% 99 (83%) 95 (74%) 88 (72%) 91 (76%)

<table border="1" ID="id_58e054be-f160-410e-8f46-f1f45f9849b5"> <caption ID="id_46d7e9e4-c7ab-4bde-88cc-36d7550d77a9">Table 2: Most common adverse events (&#x2265;2% in any RAFT propafenone ER treatment group and more common on propafenone than on placebo) </caption> <col width="114px"/> <col width="77px"/> <col width="81px"/> <col width="76px"/> <col width="69px"/> <col width="61px"/> <tbody> <tr ID="id_4a14d5ba-f64b-46b9-9810-5c1d8b646d6b"> <td align="center" valign="top" colspan="6" styleCode="Lrule Botrule Rrule">Propafenone ER Capsules</td> </tr> <tr ID="id_b2820a4e-d19b-4bdb-aa36-2ad89e0ca11d"> <td align="center" valign="top" styleCode="Lrule Botrule Rrule">MeDRA Body System/Preferred Term</td> <td align="center" valign="top" styleCode="Botrule Rrule">225 mg BID (N = 126) n (%)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">325 mg BID (N = 135) n (%)</td> <td align="center" valign="top" styleCode="Botrule Rrule">425 mg BID (N = 136) n (%)</td> <td align="center" valign="top" styleCode="Botrule Rrule">Placebo (N=126 n (%)</td> </tr> <tr ID="id_96e6bd1f-e22b-4c74-90ec-8666436e5174"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Mean exposure (days) </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule">124 </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">149 </td> <td align="center" valign="top" styleCode="Botrule Rrule">141 </td> <td align="center" valign="top" styleCode="Botrule Rrule">91 </td> </tr> <tr ID="id_88bab802-1175-4281-9481-5c666b71d208"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Cardiac disorders</content> </td> </tr> <tr ID="id_5a71e3b5-f89c-4c18-b6ea-fd87a6240156"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Angina pectoris </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">0 (0) </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> </tr> <tr ID="id_1c0283ef-02d0-4f06-839b-42d4c90ee80d"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Atrial flutter </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">2 (1) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> </tr> <tr ID="id_78ce515b-6a04-47a6-8bf3-183e39892bcd"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">AV block first degree </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 (3) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> </tr> <tr ID="id_b601b3aa-ea71-4fe1-895a-2ebb157b53ff"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Bradycardia </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 (3) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">4 (3) </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 (4) </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> </tr> <tr ID="id_2018cecc-df3f-42c5-807f-e7ec9f9f44a8"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Cardiac failure congestive </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> </tr> <tr ID="id_34916d1a-cf33-4572-a854-f1be6ee8f02e"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Cardiac murmur </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 (2) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 (4) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> </tr> <tr ID="id_50553f2c-29f1-428d-80e0-aae09c4ae01a"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Edema </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 (5) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">18 (13) </td> <td align="center" valign="top" styleCode="Botrule Rrule">10 (7) </td> <td align="center" valign="top" styleCode="Botrule Rrule">8 (6) </td> </tr> <tr ID="id_f475e38a-d222-4389-ac2f-ee6adb83501f"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Eye disorders</content> </td> </tr> <tr ID="id_51a028ef-c631-41e8-99d6-cd838b1f29bd"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Vision blurred </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 (4) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> </tr> <tr ID="id_d44d12f1-8e24-4ea3-a854-76fdfaf3d54b"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> </tr> <tr ID="id_bd6121c6-94e4-4874-b4b7-d0b42e3ccdcd"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Constipation </td> <td align="center" valign="top" styleCode="Botrule Rrule">10 (8) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">19 (14)</td> <td align="center" valign="top" styleCode="Botrule Rrule">16 (12)</td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2) </td> </tr> <tr ID="id_45b91b8d-56e5-4a60-ab0f-106cd5f5a188"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Diarrhea </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 (2) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">3 (2)</td> <td align="center" valign="top" styleCode="Botrule Rrule">5 (4)</td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2) </td> </tr> <tr ID="id_dea5c2a4-7537-47e9-ac40-969c6a73f705"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Dry mouth </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">1 (1)</td> <td align="center" valign="top" styleCode="Botrule Rrule">5 (4)</td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> </tr> <tr ID="id_0464a0d3-edb8-4633-87e6-48bea03ddbb2"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Flatulence </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">3 (2)</td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1)</td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> </tr> <tr ID="id_7611e746-73cf-47a1-9769-219c92082758"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Nausea </td> <td align="center" valign="top" styleCode="Botrule Rrule">11 (9) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">15 (11)</td> <td align="center" valign="top" styleCode="Botrule Rrule">23 (17)</td> <td align="center" valign="top" styleCode="Botrule Rrule">11 (9) </td> </tr> <tr ID="id_8cf98358-bba2-49b0-a3bf-9ee8d7768971"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Vomiting </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">0 (0)</td> <td align="center" valign="top" styleCode="Botrule Rrule">8 (6)</td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2) </td> </tr> <tr ID="id_9224fcbf-f065-497a-9a99-ecd3c9f9aadb"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">General disorder and administration site</content> </td> </tr> <tr ID="id_cd0f815f-15d7-4752-80db-e719f20c13b1"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Fatigue </td> <td align="center" valign="top" styleCode="Botrule Rrule">14 (11) </td> <td align="center" valign="top" styleCode="Botrule Rrule">17 (13) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">17 (13) </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 (6)</td> </tr> <tr ID="id_b1a5992e-0bac-4474-801c-86bc43bf127e"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Weakness </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 (3) </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 (4) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">6 (4) </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2)</td> </tr> <tr ID="id_1db92760-8c1f-44ff-8986-dd9b548ddfd5"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Infections and Infestations</content> </td> </tr> <tr ID="id_af5ee4be-b25f-483e-a6b7-fbd072b5a1ca"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Upper respiratory tract infection </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 11 (9)</td> <td align="center" valign="top" styleCode="Botrule Rrule"> 16 (12)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule"> 11 (8))</td> <td align="center" valign="top" styleCode="Botrule Rrule"> 7 (6)</td> </tr> <tr ID="id_836b3250-1081-4be5-b6e4-e8abfc3f5080"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Investigations</content> </td> </tr> <tr ID="id_0918c53f-d8b8-47b6-aca0-305cb0abfcbc"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Blood alkaline phosphatase increased</td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0)</td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">4 (3)</td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0)</td> </tr> <tr ID="id_f75d9510-4fa8-4036-8968-a229b89e3d75"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Cardioactive drug level above therapeutic</td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> </tr> <tr ID="id_cf3fd170-9bab-4a19-8abf-98c47a74d5ec"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Hematuria</td> <td align="center" valign="top" styleCode="Botrule Rrule">2 (2)</td> <td align="center" valign="top" styleCode="Botrule Rrule">2 (1)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">4 (3)</td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2)</td> </tr> <tr ID="id_60213d13-1d42-420c-9543-818b65d5b248"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Musculoskeletal, connective tissue and bone</content> </td> </tr> <tr ID="id_48c09e69-5fe6-4383-955b-490979a389cb"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Muscle weakness</td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1)</td> <td align="center" valign="top" styleCode="Botrule Rrule">5 (4)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">1 (1)</td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0)</td> </tr> <tr ID="id_fbe317c4-d0ae-45ff-99ca-01802f30c7a3"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Nervous system disorders</content> </td> </tr> <tr ID="id_60caaa1b-ad99-4c3d-9de2-dfcf81da50f2"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Dizziness (excluding vertigo)</td> <td align="center" valign="top" styleCode="Botrule Rrule"> 29 (23)</td> <td align="center" valign="top" styleCode="Botrule Rrule"> 28 (21)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule"> 29 (21)</td> <td align="center" valign="top" styleCode="Botrule Rrule"> 18 (14)</td> </tr> <tr ID="id_d6a88270-8cfa-41e3-a539-8cfb1847db55"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Headache </td> <td align="center" valign="top" styleCode="Botrule Rrule">8 (6) </td> <td align="center" valign="top" styleCode="Botrule Rrule">12 (9) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">14 (10) </td> <td align="center" valign="top" styleCode="Botrule Rrule">11 (9) </td> </tr> <tr ID="id_408cc8e1-ab1d-4925-8394-dac97758311a"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Taste disturbance </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 (6) </td> <td align="center" valign="top" styleCode="Botrule Rrule">18 (13) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">30 (22) </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> </tr> <tr ID="id_c933897a-f4f7-4a11-a783-542fa2d8eee3"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Tremor </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 (2) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> </tr> <tr ID="id_0bd7d2c3-1bdf-44d4-9f4c-cdf906462b18"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Somnolence </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">4 (3) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 ( 0) </td> </tr> <tr ID="id_08de5f5c-01a2-4918-8420-f30b999ba97e"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Psychiatric disorders</content> </td> </tr> <tr ID="id_2cd4982c-dab1-4043-b742-49a0059d9596"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Anxiety</td> <td align="center" valign="top" styleCode="Botrule Rrule">12 (10)</td> <td align="center" valign="top" styleCode="Botrule Rrule">17 (13)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">16 (12)</td> <td align="center" valign="top" styleCode="Botrule Rrule">13 (10)</td> </tr> <tr ID="id_26c00b4b-9f33-43f3-8912-03643f0f5155"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Depression</td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1)</td> <td align="center" valign="top" styleCode="Botrule Rrule">4 (3)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">0 (0)</td> <td align="center" valign="top" styleCode="Botrule Rrule">2 (2)</td> </tr> <tr ID="id_ecb4af85-5eab-41d3-8fd5-4a3c7b3c3ad9"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Respiratory, thoracic and mediastinal disorder</content> </td> </tr> <tr ID="id_d7f71ab0-6638-4f35-8ed7-0f138c1aee32"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Dyspnea</td> <td align="center" valign="top" styleCode="Botrule Rrule">16 (13)</td> <td align="center" valign="top" styleCode="Botrule Rrule">23 (17)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">17 (13)</td> <td align="center" valign="top" styleCode="Botrule Rrule">9 (7)</td> </tr> <tr ID="id_12c23f03-c979-4266-a04a-b4be96c2a977"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Rales</td> <td align="center" valign="top" styleCode="Botrule Rrule">2 (2)</td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1)</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">3 (2)</td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0)</td> </tr> <tr ID="id_185b4ac0-af09-4b3a-992a-1f32a6d82b57"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Wheezing</td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">3 (2) </td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0) </td> </tr> <tr ID="id_01d5608b-3072-4204-bdfc-1bba4c9361a0"> <td align="left" valign="top" colspan="6" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">Skin &amp; subcutaneous tissue disorders</content> </td> </tr> <tr ID="id_3a03e9bd-eb63-4fbf-a1ad-bd7b5d97fd2f"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Ecchymosis</td> <td align="center" valign="top" styleCode="Rrule">2 (2)</td> <td align="center" valign="top" styleCode="Rrule">3 (2)</td> <td align="center" valign="top" colspan="2" styleCode="Rrule">5 (4)</td> <td align="center" valign="top" styleCode="Botrule Rrule">0 (0)</td> </tr> </tbody> </table>

<table border="1" ID="id_12aa0629-08fa-4eb9-8905-242d2fe177e1"> <caption ID="id_3920d7ce-abcb-4389-b0d5-c92f3b13d787">Table 3: Mean Change in 12-Lead Electrocardiogram Results (RAFT) </caption> <col width="80px"/> <col width="64px"/> <col width="60px"/> <col width="76px"/> <col width="61px"/> <tfoot ID="id_5d105176-15d6-4eff-b30d-d2179d8d9f1b"> <tr> <td align="left" valign="top" colspan="5" styleCode="Lrule Botrule Rrule"> <paragraph>*Calculated using Bazett&#x2019;s correction factor. </paragraph> </td> </tr> </tfoot> <tbody> <tr ID="id_cf6ac3b1-d6d5-4db6-8f24-e49878233579"> <td align="left" valign="top" rowspan="2" styleCode="Botrule Toprule Rrule Lrule"/> <td align="center" valign="top" colspan="3" styleCode="Botrule Rrule"> <content styleCode="bold">Propafenone ER Capsules BID dosing </content> </td> <td align="right" valign="top" styleCode="Botrule Rrule"/> </tr> <tr ID="id_ee0f67c0-2d29-4e9e-aa70-c7e49fd9b18c"> <td align="right" valign="top" styleCode="Lrule Botrule Rrule">225 mg </td> <td align="right" valign="top" styleCode="Botrule Rrule">325 mg </td> <td align="center" valign="top" styleCode="Botrule Rrule">425 mg </td> <td align="center" valign="top" styleCode="Botrule Rrule">Placebo</td> </tr> <tr ID="id_77c3f048-1add-45f2-9228-3b09029acd9a"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"/> <td align="right" valign="top" styleCode="Botrule Rrule">n=126 </td> <td align="center" valign="top" styleCode="Botrule Rrule">n=135 </td> <td align="center" valign="top" styleCode="Botrule Rrule">n=136 </td> <td align="center" valign="top" styleCode="Botrule Rrule">n=126 </td> </tr> <tr ID="id_391595b8-74ee-456d-8be4-f2ab6aabe553"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">PR (ms) </td> <td align="right" valign="top" styleCode="Botrule Rrule">9&#xB1;22 </td> <td align="center" valign="top" styleCode="Botrule Rrule">12&#xB1;23 </td> <td align="center" valign="top" styleCode="Botrule Rrule">21&#xB1;24 </td> <td align="center" valign="top" styleCode="Botrule Rrule">1&#xB1;16 </td> </tr> <tr ID="id_19a8801a-2d87-42fe-a90b-2a32a2d24dda"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">QRS (ms) </td> <td align="right" valign="top" styleCode="Botrule Rrule">4&#xB1;14 </td> <td align="center" valign="top" styleCode="Botrule Rrule">6&#xB1;15 </td> <td align="center" valign="top" styleCode="Botrule Rrule">6&#xB1;15 </td> <td align="center" valign="top" styleCode="Botrule Rrule">-2&#xB1;12 </td> </tr> <tr ID="id_b1783efb-6ef9-48ac-a1ff-82f20d730cd9"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">QTc* (ms) </td> <td align="right" valign="top" styleCode="Botrule Rrule">2&#xB1;30 </td> <td align="center" valign="top" styleCode="Botrule Rrule">5&#xB1;36 </td> <td align="center" valign="top" styleCode="Botrule Rrule">6&#xB1;37 </td> <td align="center" valign="top" styleCode="Botrule Rrule">5&#xB1;35 </td> </tr> </tbody> </table>

<table ID="id_25a69ab1-5c0d-45db-bea8-f022d139ca10"> <caption ID="id_a626fc5d-2798-4bbd-b3f6-8e5258a65d28">Table 4: Number of patients according to the range of maximum QTc change compared to baseline over the study in each dose group (RAFT study)</caption> <col width="104px"/> <col width="76px"/> <col width="76px"/> <col width="76px"/> <col width="80px"/> <tbody> <tr ID="id_cda54758-5321-434a-ad5a-ff72094785a8" styleCode="Toprule"> <td align="left" valign="top" styleCode="Botrule Toprule Rrule"> <content styleCode="bold">Range of maximum </content> QTc change </td> <td align="center" valign="top" colspan="3" styleCode="Botrule Rrule"> <content styleCode="bold">Propafenone ER Capsules</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">Placebo </content> </td> </tr> <tr ID="id_6d064b56-1421-4642-acb1-2b2f30273026"> <td align="left" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule">225 mg BID </td> <td align="left" valign="top" styleCode="Botrule Rrule">325 mg BID </td> <td align="left" valign="top" styleCode="Botrule Rrule">425 mg BID </td> <td align="left" valign="top" styleCode="Botrule"/> </tr> <tr ID="id_b5440a35-7be0-4935-a2ac-bc40fa206071"> <td align="left" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule">N=119 </td> <td align="center" valign="top" styleCode="Botrule Rrule">N=129 </td> <td align="center" valign="top" styleCode="Botrule Rrule">N=123 </td> <td align="center" valign="top" styleCode="Botrule">N=100 </td> </tr> <tr ID="id_7b389132-a31a-4387-8740-ce2da667b352"> <td align="left" valign="top" styleCode="Botrule Rrule"/> <td align="center" valign="top" styleCode="Botrule Rrule">n (%) </td> <td align="center" valign="top" styleCode="Botrule Rrule">n (%) </td> <td align="center" valign="top" styleCode="Botrule Rrule">n (%) </td> <td align="center" valign="top" styleCode="Botrule">n (%) </td> </tr> <tr ID="id_2102a8a6-3be8-4e21-95e3-b6b41ace58da"> <td align="center" valign="top" styleCode="Botrule Rrule">&gt;20% </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 (1%) </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 (5%) </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 (2%) </td> <td align="center" valign="top" styleCode="Botrule">5 (4%) </td> </tr> <tr ID="id_08c0b90e-336e-4da4-b355-87ea48f1ebf6"> <td align="center" valign="top" styleCode="Botrule Rrule">10-20% </td> <td align="center" valign="top" styleCode="Botrule Rrule">19 (16%) </td> <td align="center" valign="top" styleCode="Botrule Rrule">28 (22%) </td> <td align="center" valign="top" styleCode="Botrule Rrule">32 (26%) </td> <td align="left" valign="top" styleCode="Botrule">24 (20%) </td> </tr> <tr ID="id_9b43be83-eb7a-4888-93ed-4a7b5eded9d3" styleCode="Botrule"> <td align="center" valign="top" styleCode="Rrule">&#x2264;10% </td> <td align="center" valign="top" styleCode="Rrule">99 (83%) </td> <td align="center" valign="top" styleCode="Rrule">95 (74%) </td> <td align="center" valign="top" styleCode="Rrule">88 (72%) </td> <td align="left" valign="top">91 (76%) </td> </tr> </tbody> </table>