Ibutilide

Ibutilide is an antiarrhythmic drug that was recently marketed for the rapid conversion of atrial fibrillation and atrial flutter. After intravenous administration, ibutilide is moderately effective in achieving prompt cardioversion to sinus rhythm, with greater efficacy in patients who have atrial flutter. Like other drugs that prolong ventricular repolarization, ibutilide administration carries a risk of excessive QT prolongation, or the acquired long-QT syndrome, with associated polymorphic ventricular tachycardia (torsade de pointes), necessitating careful patient selection and clinical monitoring during drug administration.

1. Zuventus Healthcare Ltd Ibutilide “T he Pure Class III Antiarrhythmic”

2. Ibutilide Ibutilide is the first 'pure' class III anti-arrhythmic drug to be available. [1] Approved by the USFDA in Dec.1995 June 2016 (Zuventus Health Care Ltd) received manufacturing & marketing approval from DCGI India. API as well as finished product developed through “in house R&D” Marketed as “ Fibricor” 1. Drugs.  1997 Aug;54(2):312-30.

3. “Pure Class III” Ibutilide: “cardiac electrophysiological actions” Only. Ibutilide: "Pure" action potential–prolonging drug  It has no “negative inotropic” effects Goodman & Gilman's The Pharmacological Basis of Therapeutics - 12th Ed Amiodarone Dronadarone and sotalol are mixed acting class-III drugs. Sotalol: Has class II and III activities Amiodarone: Has Class I, II, III and IV activities and has multiple cardiac (electrophysiologic characteristics of all 4 classes) & systemic side effects. Dronaderon : Similar to Amiodarone

4. Ibutilide Formula: C 22 H 38 N 2 O 5 S Chemical Name: Methanesulfonamide , N-{4-{4-( ethylheptylamino )-1- hydroxybutyl }phenyl}, (+) (-), (E)-2-butenedioate (1:0.5) ( hemifumarate salt) Chemistry

5. Unique mechanism of action Ibutilide, at nanomolar concentrations (10 -8 ), “prolongs repolarization by activation of a slow, inward current (predominantly sodium).” It blocks Potassium channels at 1000 times concentration i.e. (10 -5 ) Plasma levels achieved after 1mg infusion are in the range of (10 -8 ) This mechanism of action is “ unique among available class III drugs” Naccarelli GV. Am J Cardiol . 1996 Oct 17;78(8A):12-6. Ibutilide does not have a sodium-blocking, Antiadrenergic, and Calcium blocking activity

6. Unique Mechanism of Action among available class III drugs Activation of a late inward sodium current  Increased sodium influx Shah D. Eur Heart J. 2016 May 21;37(20):1622-5. Prolongation of the myocardial action potential duration. + - V Max plateau Slow Na  (Ibutilide) Ca Na N T QT APD Action Potential Duration K + (other class III) Repolarization

7. No Hemodynamic Effects No clinically significant Hemodynamic effect (at doses up to 0.03 mg/kg) demonstrated on Cardiac output, Mean pulmonary arterial pressure Capillary wedge pressure Katherine T. Murray. Ibutilide. Circulation 1998;97;493-497.

8. Ibutilide: Electrophysiological Effects No clinically significant effect on QRS ( at the recommended dosage) A dose related prolongation of the QT interval Prolongation of QT interval is similar in men & women Prolongs action potential duration and effective refractory periods in both atria and ventricles Nair M. J Am Board Fam Med. 2011 Jan-Feb;24(1):86-92.

9. Pharmacokinetics Ibutilide is intravenously (i.v.) administered Due to its high first-pass metabolism, its not given orally Katherine T. Murray. Ibutilide. Circulation 1998;97;493-497. .http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf The pharmacokinetics of Ibutilide is similar regardless of The type of atrial arrhythmia, Age, sex Left ventricular ejection fraction, Occurrence of polymorphic ventricular tachycardia The concomitant use of digoxin, CCBs, or β -blockers.

10. After IV infusion, Ibutilide plasma concentrations rapidly decrease in a multiexponential fashion. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf Pharmacokinetics

11. Indications http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf For the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm.

12. Ibutilide: Dosage & Administration Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in the event of sustained or nonsustained ventricular tachycardia, or marked prolongation of QT or QTc. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf

13. Dilution Solutions used for dilution → Ibutilide Injection 10 ml one Vial + 50 ml  of 5 % Dextrose Injection Ibutilide Injection 10 ml one Vial + 50 ml  of 0.9 % NaCl Injection Ibutilide Injection may be administered undiluted or diluted in 50 mL of diluent Admixtures of the product, with approved diluents, are chemically and physically stable for 24 hours at room temperature (15°to 30°C ) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf

14. Clinical settings for Ibutilide usage (cardioversion in AF and AFL) Recent onset atrial fibrillation or flutter Persistent atrial fibrillation or flutter As standalone therapy In patients already on oral amiodarone To facilitate electrical cardioversion To facilitate cardioversion of atrial flutter by overdrive atrial pacing Post-operative atrial fibrillation or flutter Pre-excited atrial fibrillation in patients with WPW syndrome Atrial fibrillation or flutter during an electrophysiological study or ablation procedure Children and those with congenital heart disease Elderly patients with atrial fibrillation or flutter Kartikeya Bhargava . Role of Ibutilide in Atrial Fibrillation Supplement Issue on Atrial Fibrillation . JAPI  • August 2016 • Vol. 64.

15. Contraindications http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf Patients with history of hypersensitivity to Ibutilide fumarate or excipients in the formulation. 

16. Warnings & Precautions Potential to prolong refractoriness When given with Class Ia and other class III antiarrhythmic , concomitantly or within 4 hours post infusion Class I and III agents may be withheld for at least 5 half-lives prior to ibutilide infusion Potential for Proarrhythmia when given with drugs that prolong the QT interval , such as Phenothiazines, Tricyclic or Tetracyclic antidepressants Antihistamines- terfenadine, Astemizole http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf Doses of more than two infusions are not recommended in a single setting due to the risk of QT prolongation Not recommended in Patients with QTc intervals > 440 msec. Patients with H/O polymorphic ventricular tachycardias (e.g., torsades de pointes). More rapid infusion is not recommended.

17. Side Effects Event Placebo (n=127) Ibutilide (n=586) n % n % CARDIOVASCULAR   Ventricular extrasystoles 1 0.8 30 5.1   Nonsustained monomorphic VT 1 0.8 29 4.9   Nonsustained polymorphic VT — — 16 2.7   Hypotension 2 1.6 12 2.0   Bundle branch block — — 11 1.9   Sustained polymorphic VT — — 10 1.7   AV block 1 0.8 9 1.5   Hypertension — — 7 1.2   QT segment prolonged — — 7 1.2   Bradycardia 1 0.8 7 1.2   Palpitation 1 0.8 6 1.0   Tachycardia 1 0.8 16 2.7 GASTROINTESTINAL   Nausea 1 0.8 11 1.9 CENTRAL NERVOUS SYSTEM   Headache 4 3.1 21 3.6

18. Common Non-arrhythmic Toxicity of most frequently used anti-arrhythmic agents in AF/AFL Ibutilide Nausea Amiodarone Tremor, peripheral neuropathy, pulmonary inflammation, hypothyroidism and hyperthyroidism, photosensitivity Dofetilide Nausea Propafenone Taste disturbance, dyspepsia, nausea, vomiting Flecainide Dizziness, nausea, headache, decreased myocardial contractility Sotalol Hypotension, bronchospasm Harrison's Principles of Internal Medicine, 18th Ed. Chapter 233. The Tachyarrhythmias  >

19. Pro-arrhythmic Manifestations Amiodarone Sinus bradycardia, AV block, increase in defibrillation threshold Rare: long QT and torsades des pointes, 1:1 ventricular conduction with atrial flutter Ibutilide Long QT and torsades de pointes Flecainide 1:1 Ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease; sinus bradycardia Dofetilide Long QT and torsades des pointes Propafenone 1:1 Ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease; sinus bradycardia Sotalol Long QT and torsades des pointes, sinus bradycardia Harrison's Principles of Internal Medicine, 18th Ed. Chapter 233. The Tachyarrhythmias  

20. How to reduce Torsades de pointes Pretreatment with Class IC drugs Class IC drugs: Flecainide and Propafenone. Ibutilide effect is mediated through the delay of slow Na(+) current inactivation. 1 Pretreatment with IC agents can reduce the increase in QTc seen with Ibutilide 2 There is lower risk of Proarrhythmia since the class IC drugs induced slow conduction by blocking sodium channels which exert somewhat protective effect against Ibutilide toxicity. Ibutilide has been safely used in patients who are already on class IC drugs. 1. Kartikeya Bhargava. Supplement Issue on Atrial Fibrillation . JAPI  • August 2016 • Vol. 64. 2. Reiffel JA. J Cardiovasc Pharmacol Ther . 2000 Jul;5(3):177-81.

21. Combined therapy of iv esmolol and Ibutilide vs. Ibutilide alone in patients with recent onset AF showed a higher rate of conversion to sinus rhythm (67% vs. 46%), reduced rate of immediate recurrence and a lower risk of proarrhythmia 1 The addition of Esmolol reduces QTc prolongation and diminishes the risk of ventricular tachycardia Magnesium prevents significant prolongation of QT interval and therefore reduces the risks of torsade de pointes 2 1. Fragakis N. Europace 2009; 11:70. 2. Wang A. Pharm Pract (Granada). 2012 Apr;10(2):65-71. 21 How to reduce Torsades de pointes Ibutilide in combination with Esmolol or MgSO4

22. Predictor of successful cardioversion with Ibutilide Recent onset of arrhythmia Atrial flutter rhythm Relatively high heart rate Lack of a H/O of CHF Lack of concomitant digoxin therapy Female gender and younger age Zaqqa M. Am J Cardiol . 2000 Jan 1;85(1):112-4, A9.

23. Geriatric Use Usually start at the low end of the dosing range, because of Decreased hepatic or renal function Decreased Cardiac function Concomitant disease or other drug therapy. http:// www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf Clinical experience shows no difference in responses between the elderly & younger patients.

24. Use in Patients with Hepatic or Renal Dysfunction The safety, effectiveness & pharmacokinetics of Ibutilide have not been established in patients with hepatic or renal dysfunction. It is unlikely that dosing adjustments would be necessary in patients with compromised renal or hepatic function Patients with abnormal liver function should be monitored for >4-hour period. http:// www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf

25. Recommendations

26. Recommendation from AHA/ACC/HRS Guidelines 2014 Anti-arrhythmic Drugs Class of Recommendation in following Indications Atrial Fibrillation/Flutter Wolff Parkinson White and Pre-excitation Syndrome Post operative Cardiac & Thoracic Surgery induced AF Ibutilide Class I Class I Class IIa Amiodarone Class IIa Not recommended Not recommended Flecainide Class I (in Hospital) Class IIa (outside hospital with β -blocker) Not recommended Not recommended Dofetilide Class I Not recommended Not recommended Propafenone Class I (in Hospital) Class IIa (outside hospital with β -blocker) Not recommended Not recommended Class-I Recommendation: Benefit >>> Risk   ;Procedure/treatment  SHOULD  be performed/administered Class-II Recommendation: CLASS II a  - Benefit >> Risk Additional studies with focused objectives needed  ; IT IS REASONABLE  to perform procedure/administer treatment; CLASS II b  - Benefit ≥ Risk ;Additional studies with broad objectives needed; additional registry data would be helpful  Procedure/treatment  MAY BE CONSIDERED Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.  J Am Coll Cardiol. 2014;64(21):2246-2280. 

27. 28 Ibutilide Use In Different Clinical Settings

28. IBUTILIDE Rescue for failed Amiodarone therapy SN Title N Drugs Primary Endpoint Results 1 Marcus G. Hennersdorf et al. Conversion of recent onset atrial fibrillation or flutter with ibutilide after amiodarone has failed . Intensive Care Med.  2002 Jul;28(7):925-9. 26 Ibutilide (1 mg or, 2 mg i.v. ) after Amiodarone (150 mg i.v. ) failed in Persistent arrhythmia Conversion of recent onset atrial fibrillation or flutter after amiodarone has failed. Ibutilide led “ Sinus Rhythm ” conversion in 81.5% of patients where Amiodarone had failed 29

29. 70 pts on longterm oral amiodarone for cardioversion in “ Afib ” (57/70) or “ Afl ” (13/70) Patients administered 2 mg i.v. Ibutilide . 55 patients (79%) had structural heart disease. Patients on amiodarone:153 days Patients with arrhythmia for 196 days before cardioversion. Kathy Glatter. Circulation. 2001;103:253-257. Patients converted within 30 minutes of infusion. AFib - 22 of 57 (39%) and AFl -7 of 13 (54%) only 1 episode of torsade de pointes occurred Ibutilide Add-on to long term Oral Amiodarone 30

30. Ibutilide Vs. Amiodarone ( i.v. ) in AF & AFl N= 152 (Ibutilide n=79, Amiodarone n= 73) Duration of AF or Afl :  3-48 h Conversion to SR All patients Ibutilide: 63 of 79 pts (80%) Amiodarone: 42 of 73 pts (57%) In AFL Ibutilide: 20 of 23 pts ( 87%) Amiodarone: 6 of 21 pts ( 29%) In AF Ibutilide: 43 of 56 pts ( 77%) Amiodarone : 36 of 52 pts (69 %) 80% 57% 77% 69 % 87% 29% Ibutilide is more effective than amiodarone in converting recent-onset AF or AFl to Sinus Rhythm Kafkas NV. Int J Cardiol . 2007 Jun 12;118(3):321-5. 31

31. Ibutilide: Shorter Arrhythmia Termination Time Kafkas NV, Int J Cardiol . 2007 Jun 12;118(3):321-5. Atrial Fibrillation 53.4 min 492 min Atrial Flutter 28.4 min 762 min 32

32. Ibutilide vs. Propafenone SN Title N Drugs Primary Endpoint Results 1 Zhang HC et al. Immediate cardioversion of atrial fibrillation and atrial flutter lasting less than 90 days by ibutilide versus propafenone: a multicentre study. Zhonghua Yi Xue Za Zhi . 2005 Mar 30;85(12):798-801. 212 Ibutilide (1 mg) (n = 107), 75 AF & 32 AFL Propafenone (70 mg) (n = 105, 76 AF & 29 AFL IV over 10 mins Cardioversion AFL conversion rate Ibutilide = 78.1% Propafenone 48.3% 33

33.   Ibutilide vs. Propafenone Ibutilide 1 mg or Propafenone 70 mg [2 infusions, 10 min apart] N= 82 pts with AF Onset : 2 h to 90 days The treatment was considered successful if sinus rhythm occurred within 90 mins p = 0.043 Zhang N. Int J Clin Pract . 2005 Dec;59(12):1395-400. Ibutilide is more effective than intravenous propafenone for the cardioversion  34

34. Sun JL. Cardiovasc Drugs Ther . 2005 Jan;19(1):57-64. Ibutilide was superior to propafenone for treating atrial flutter (90% vs. 30%). n=40 Ibutilide-20 Propafenone-20 Bradycardia & hypotension were more common side effects with propafenone. Randomized to receive Ibutilide 1 mg Propafenone 70mg  Ibutilide vs. Propafenone 35

35. Ibutilide with Propafenone 3 John A. Chiladaki et al. Ibutilide added to propafenone for the conversion of atrial fibrillation and atrial flutter. J Am Coll Cardiol .  2004 Aug 18;44(4):859-63. 202  Oral propafenone N=202 With AF/AFL without left ventricular dysfunction. IV Ibutilide (1mg) N=104 (48 pts with paroxysmal arrhythmia, & 56 with chronic arrhythmia) Safety & efficacy of Ibutilide when added to propafenone Ibutilide offered an overall conversion efficacy of 66.3%. 70.8% for patients with paroxysmal AF/AFL 62.5% for patients with chronic AF/AFL. 36

36. Ibutilide 2mg Cardioversion of pts on Class IC Agents Total 71 pts. AF (n=48) & AFL (n= 23) Pts. on Propafenone 300 to 900 mg/day (n=46) or Flecainide 100 to 300 mg/day (n= 25) Conversion rates: AF - 23 of 48 pts (47.9%) AFL- 17 of 23 pts (73.9%) No pts needed to stop of Ibutilide infusion for ventricular dysrhythmia or excessive QT prolongation . Attenuation of Ibutilide-induced QTC prolongation: Class IC agents block slow inward I Na in addition to fast I Na In this study mean Ibutilide-induced QTC interval prolongation was 20 ms as compared to 47 to 90ms (reported in literature) This attenuation is without decrease in Ibutilide efficacy Hongo RH. J Am Coll Cardiol . 2004 Aug 18;44(4):864-8. 37

37. Ibutilide Vs. Procainamide ADVERSE EVENTS : More common with procainamide (46.2%) than with Ibutilide group -29.0% Ibutilide - Extrasystole occurred . Procainamide - Headache, hypotension, flushing, dizziness and hypesthesia Volgman AS. J Am Coll Cardiol . 1998 May;31(6):1414-9. Combined Conversion rates Ibutilide –58% Procainamide - 18% Atrial Flutter Ibutilide - 76% Procainamide - 14% Atrial Fibrillation Ibutilide - 51% Procainamide -21% Study Establishes The Superior Efficacy Of Ibutilide Over Procainamide Total N= 120 , Ibutilide n=60 procainamide n=60 38

38. Randomized, double-blinded comparative study- 136 patients treated : i.v. Ibutilide (n=73) placebo (n=22) iv procainamide (n=53) Bruce S. Stambler et al. Circulation. 1997;96:4298-4306 Ibutilide Vs. Procainamide In AFL Ibutilide converted 29 of 45 pts= 64% Procainamide & placebo converted 0% In AF Ibutilide converted 9 of 28 pts 32% Procainamide converted in 1 of 20 5% Placebo converted 0% 39

39. Ibutilide vs. Procainamide SN Title N Drugs Primary Endpoint Results 3 Stambler BS et al.; Comparative efficacy of iv Ibutilide versus procainamide for enhancing termination of atrial flutter by atrial overdrive pacing Am J Cardiol . 1996 May 1;77(11):960-6 . 54 Ibutilide n=15 or Procainamide n=33 or Placebo n =11 Termination of atrial flutter Pacing converted SR 18% placebo, 87% ibutilide, (88%) procainamide  40

40. Ibutilide vs. Sotalol Vos M. et al. Heart. 1998;79(6):568-575 .] Ibutilide (given in 1 or 2 mg doses over 10 mins Rapidly terminates persistent AF or AFL. Ibutilide (2 mg) was superior to Sotalol in both atrial flutter and fibrillation Ibutilide vs Sotalol in Atrial flutter (70% vs. 19%), Ibutilide vs Sotalol in Atrial Fibrillation (44%  v  11%) Double blind, randomised study . 308 patients with atrial fibrillation (n = 251) or atrial flutter (n = 57) (duration 3 hrs to 45 days) . three groups : 1 mg ibutilide (n = 99) 2 mg ibutilide (n = 106) 1.5 mg/kg DL-sotalol (n = 103) 41

41. Magnesium as an adjunct to Ibutilide, improves efficacy & minimize toxicity Magnesium have intrinsic antiarrhythmic properties Potential to increase the efficacy of class III antiarrhythmics Delays AV node conduction, without significant effect on the sinus node Efficacy of magnesium & Ibutilide combination is due to the additive potassium blockade effect Side effects of magnesium are usually mild : e.g. minor tingling, flushing & dizziness Wang A. Pharm Pract (Granada). 2012 Apr;10(2):65-71. 42

42. Magnesium as an adjunct for Ibutilide….. Therefore, magnesium with Ibutilide involves minimal risks with monitoring of vital signs & ECG. Magnesium prevents significant prolongation of QT interval and therefore reduces the risks of torsade de pointes The administration of magnesium makes Ibutilide a much safer agent, & magnesium increased the conversion efficacy of Ibutilide Wang A. Pharm Pract (Granada). 2012 Apr;10(2):65-71. 4 g of magnesium may be given within 2 hrs prior to initiation of Ibutilide for conversion of AF or typical flutter 43

43. Ibutilide and Magnesium Combination Therapy Article Study Design Groups Doses of magnesium used Rates of Successful Cardioversion Kalus JS. Am J Health Syst Pharm. 2003 Nov 15;60(22):2308-12. Retrospective, cohort N = 321 Control: Ibutilide alone N = 214 Treatment: Ibutilide & MgSO4 N = 107 Mean total dose: 2.2 + 1 grams Magnesium was given within 2 hours before or during ibutilide therapy Treatment group: 72% Control group: 60.3% p = 0.04 Patsilinakos S. Am J Cardiol .  2010 Sep 1;106(5):673-6. Prospective N = 476 Ibutilide alone N = 229 2] Ibutilide & MgSO4 N = 247 5 grams given 1 hour prior to first dose of Ibutilide, followed by another 5 grams given over 2 hours Treatment group: 76.5% Control group: 67.3% p = 0.033 Steinwender C. Int J Cardiol .  2010 Jun 11;141(3):260-5. Randomized, placebo controlled N = 117 Ibutilide and placebo N = 59 2. Ibutilide & MgSO4 N = 58 Magnesium 4 grams or placebo given 20 minutes prior to first dose of ibutilide Treatment group (typical AF): 85% Control group (typical AF): 59% p = 0.017 Tercius AJ. Pacing Clin Electrophysiol  2007 Nov;30(11):1331-5. Retrospective cohort N = 229 Ibutilide only N = 88 2. Ibutilide & MgSO4 N = 141 Magnesium 1-4 grams within 2 hours prior to ibutilide 78% more chances of conversion with combination versus 59.8% without MgSO4 44

44. 1 Stavros E. Et al. Ibutilide to expedite ED therapy for recent-onset atrial fibrillation flutter Am J Emerg Med.2006 Jul;24(4):407-12. Total = 36 (AFib = 26) & (AFl = 10) Ibutilide 1 mg Successful conversion within 1 hour 90% patients with AFl and 61.5% patients with AFib converted to sinus rhythm No significant complications occurred. 2 Amy Eversole.et al . Ibutilide: Efficacy and Safety in Atrial Fibrillation and Atrial Flutter in a General Cardiology Practice . Clin . Cardiol . 2001;24,521-525 Total = 54 Afib (n=34) Afl (n= 20) Ibutilide 1 mg for pts ≥ 60 kg & 0.1 mg/kg for pts < 60 kg Successful cardioversion 70.6% pts with AFib & 75% with AFl converted to SR. Conversion of AFib to SR more likely if duration of AFib = 96 h versus >96 h (81 % vs. 17%). 3 Gowda RM.et al. Use of  ibutilide  for cardioversion of recent-onset atrial fibrillation and flutter in elderly. Am J Ther . 2004 Mar-Apr;11(2):95-7. Total = 32 AFib n=19 AFl n =13 Ibutilide 1 mg Cardioversion Successful Arrhythmia Termination = 59%. 63% in patients with AFib & 54% in AFl The mean conversion time was 33 +/- 45 minutes. Efficacy of Ibutilide 45

45. 44 patients (75%) converted to SR after Ibutilide 31 on single dose (53%) & 13 on double dose (22%) Ibutilide in AFL- Single vs Double Dose Andò G . Minerva Cardioangiol .  2004 Feb;52(1):37-42. The mean time to the 2nd dose was 34 min in responders 46 N= 59 patients dose- 1 mg Ibutilide.

46. 266 pts with AF (n = 133) or flutter (n = 133), Arrhythmia duration - 3 hrs to 45 days Randomized to receive up to two 10-min infusions of Ibutilide (1.0 and 0.5 mg) or Ibutilide (1.0 and 1.0 mg) Placebo The conversion rate 47% after Ibutilide & 2% after placebo Efficacy was higher in AFl than fibrillation (63% versus 31%) Arrhythmia termination - 27 min after start of the infusion Of 180 Ibutilide-treated patients, 15 (8.3%) developed polymorphic ventricular tachycardia during or soon after the infusion Efficacy and safety of Repeated I.V. doses of Ibutilide Ibutilide given in repeated doses is effective in rapidly terminating AF & AFl Stambler B et al. Circulation 1996;94:1613-1621. 47

47. Ibutilide Vs. Placebo SN Title N Drugs Primary Endpoints Results & conclusion 1 Abi-Mansour P.et al . Am Heart J. 1998 Oct;136(4 Pt 1):632-42. n=250 Ibutilide 1 mg (n=209) or Placebo (n=41) Termination of atrial fibrillation or flutter 34.9% of ibutilide Pts had cardioversion within 1.5 hrs 0% of placebo Pts At 24 Hrs, 86.3% of Ibutilide recipients remained in SR 2 James T. VanderLugt.et al. Efficacy and Safety of Ibutilide Fumarate for the Conversion of Atrial Arrhythmias After Cardiac Surgery. Circulation. 1999;100: 369-375 . n = 302 AFib=201 AFl=101 Ibutilide (n= 218) (0.25, 0.5, or 1.0 mg) or Placebo (n=84) Conversion within 90 mins Conversion rates = Placebo 15%; Ibutilide 0.25 mg 40%, 0.5 mg 47%, and 1.0 mg 57% Mean time to conversion decreased as the Ibutilide dose was increased 48

48. Ibutilide in different conditions & procedures

49. Pretreatment with Ibutilide facilitate Electrical cardioversion It increases the conversion rate 1 Reduces the energy required to cardiovert 2 Reduces the number of attempts at cardioversion 1 Successful cardioversion in patients who failed initial shock without Ibutilide pretreatment 1   100% with Ibutilide versus 72 % without Ibutilide Oral H. N Engl J Med 1999; 340:1849–54. Mazzocca G. J Cardiovasc Med 2006; 7:124–8.

50. Ibutilide 1 mg with electrical cardioversion 51 n =100 Transthoracic cardioversion with or without pre-treatment Pretreatment reduced mean energy required for defibrillation (166 J vs. 228 J without pretreatment) Oral H. N Engl J Med.  1999 Jun 17;340(24):1849-54.

51. Ibutilide for conversion after Cardiac Surgery Ibutilide: Higher conversion rates than placebo, efficacy was dose related Polymorphic ventricular tachycardia - in Ibutilide group 1.8% vs. 1.2% in placebo group N= 302, Fibrillation- 201, flutter- 101 Ibutilide is a safe treatment alternative for Post cardiac surgery A trial Arrhythmias VanderLugt JT. Circulation. 1999 Jul 27;100(4):369-75. 52

52. Ibutilide in children & patients with Congenital Heart Disease RESULTS: 74 episodes of AFl and 4 episodes of AF (median episodes / patient was 1, range 1-31). Ibutilide converted 55 of all the episodes (71%). Success during its first-ever administration in 12 of 19 patients: 63%. One patient went into torsade de pointes. Hoyer AW. Pacing Clin Electrophysiol . 2007 Aug;30(8):1003-8. 19 patients (age 6 mths to 34 years) who received Ibutilide between 1996-2005 15 patients with CHD (14 had prior heart surgery); 4 children had normal heart structure. Ibutilide - effective in selected paedo pts for cardioversion of AFL 53

53. Ibutilide successfully terminated AF in 95% of patients (including children) during electrophysiology study of accessory pathways that were subsequently ablated. 1 Ibutilide an alternative to Procainamide for cardioversion in stable pts with preexcited AF. 2 Ibutilide in Preexcited AF in WPW Syndrome Glatter KA. Circulation. 2001 Oct 16;104(16):1933-9. 2. Varriale P. Pacing Clin Electrophysiol . 1999 Aug;22(8):1267-9. 54

54. Ibutilide Enhances Termination of AFl by Burst Atrial Overdrive Pacing 26 patients for “pacing termination” with standard protocol of “Burst Atrial Overdrive Pacing” Ibutilide enhanced pacing-induced termination of AFl compared to placebo (p <0.001) . PACING CONVERSION: 2 of 11 patients (18%) on placebo 13 of 15 patients (87%) on Ibutilide. Stambler BS. Am J Cardiol . 1996 May 1;77(11):960-6. 55

55. n=87 (AFL duration 2 hr to 30 days) randomized : Group 1 —i.v. Ibutilide treatment, up to 2 mg Group 2 —ATP with “burst” and “ramp” pacing protocols Andrea Mazza et al. Europace 2004;6:301-306 56 Ibutilide vs. Transoesophageal Atrial Pacing 

56. Andrea Mazza et al. Europace 2004;6:301-306 Group 1: i.v. ibutilide Group 2: Transoesophageal atrial pacing Rate of sinus rhythm restoration Ibutilide appears to be the best choice in AFL Ibutilide vs. Transoesophageal Atrial Pacing 

57. Ibutilide after Radiofrequency Ablation 58

58. Ibutilide after Radiofrequency Ablation SN Title N Drugs Primary Endpoints Results & conclusion 1 Tian XC.et al . Efficacy of ibutilide for cardioversion of persistent Afib during radiofrequency ablation. Zhonghua Xin Xue Guan Bing Za Zhi . 2011 Nov; 39(11):1029-32. AFib (n = 18) Pts treated with 1 mg Ibutilide within 10 minutes after unsuccessful ablation Cardioversion Ibutilide   is highly effective and safe for cardioversion in pts where ablation failed. After Ibutilide administration 61.11% converted to SR. The average conversion time was 13.80 min. 2 Hou Yu.et al. Single dose of  ibutilide  for conversion of persistent Atrial fibrillation after radiofrequency ablation. Chin Med J ( Engl ). 2011 Mar;124(5):710-713 AFib (n = 40) Pts whose AFib was not converted to sinus rhythm after radiofrequency ablation were given 1mg Ibutilide. Rate of conversion  Ibutilide converted 72.5% patients to sinus rhythm. Mean conversion time = 13 mins . No cases of serious arrhythmias or other adverse reactions were found. 59

59. The Modified Ablation Guided by Ibutilide Use in Chronic Atrial Fibrillation (MAGIC-AF) Study  International multicenter RCT Assessed the utility of the intraprocedural administration of 0.25 mg of iv Ibutilide  before performing Complex fractionated atrial electrograms (CFAE) ablation Singh SM. Eur Heart J. 2016 May 21;37(20):1614-21. 200 pts undergoing a first-ever persistent AF catheter ablation procedure were randomly assigned to receive either 0.25 mg of iv Ibutilide or saline placebo CFAE sites were then targeted with ablation. 60

60. MAGIC-AF Study continued…… When CFAE ablation was guided by Ibutilide administration it results into Reduction in CFAE area and Greater AF termination   (75 vs. 57%) Singh SM. Eur Heart J. 2016 May 21;37(20):1614-21. 61

61. Ibutilide for AF and flutter in cancer pts. RESULTS: Successful cardioversion in 75% of patients 68 patients (84%) were on at least 1 medication that prolonged the QT interval at the time of Ibutilide administration No significant changes in the corrected QT interval post Ibutilide cardioversion Bickford CL . Am J Med Sci. 2014 Apr;347(4):277-81. Centre: University of Texas MD Anderson Cancer Center 81 patients received Ibutilide for AF/AFL from January 2002 to May 2006 Ibutilide is safe and effective in cancer pts. Despite the use of multiple drugs that can potentially prolong the QT interval , no patient experienced serious rhythm disturbances or significant QT prolongation during Ibutilide administration 62

62. Ibutilide in CAD (Coronary Artery Disease) MVD (Mitral Valve Disease) and LAH (Left Atrial Hypertrophy) The response rate in patients with CAD was higher than in patients without CAD (23/30= 77%, vs. 33/71= 46%) Das MK. Clin Cardiol . 2002 Sep;25(9):411-5. n=101 63

63. Continued…….. Ibutilide success rate: Presence of MVD- 37.7% (23/61 pts) Absence of MVD- 82.5% (33/40 pts) (p <0.01) Ibutilide Response rate: 85% (29 of 34 ) in pts without MVD & without markedly enlarged LA Ibutilide is most effective in patients with CAD or in patients without MVD and/or without markedly enlarged LA Das MK. Clin Cardiol . 2002 Sep;25(9):411-5. 64

64. Fibricor Summary Ibutilide is Pure class III antiarrhythmic drug for AFL and AF Quick onset of action (with in minutes) Best in class III antiarrythmics Easy and rapid administration Low incidence of adverse effects A good alternative to electrical cardioversion Ibutilide Pretreatment increases electrical conversion from 72% to 100% Can be used safely in AF/ AFL patients receiving oral amiodarone Accessory pathway-mediated AF - the conversion rate of Ibutilide is 95%. Safe and effective in post-cardiac surgery AF patients Risk of torsades de pointes (TDP)- up to 4% Proarrhythmia prevented by Class IC drugs (Flecainide & Propafenone) or IV Esmolol or Mg SO4 Monitor at least for 4 hrs or until QTc has returned to baseline The anticoagulation strategy is the same as for any other mode of cardioversion  65

65. Thank you !