Cardiovascular Drugs That Prolong The QT Interval Ladies and gentlemen, members of the A.C., Dr. Taminga, as a member of the Division… The CardioRenal Division’s experience with drugs that prolong falls into two broad categories. First, our Division has been involved in the review of most, if not all, of the other drugs discussed this morning in a consultative role. In particular, the Divisional consult…. Dr. MaryAnn Gordon. While I’m happy to discuss any aspects of the Ziprasidone review, I will focus my remarks this morning instead on our Divisional experience reviewing drugs with clinical cardiovascular effects that are also found to prolong the QT. Douglas C. Throckmorton, M.D. U.S. Food & Drug Administration Division of Cardio-Renal Drug Products FDA 7.00

Issues Approval of anti-arrhythmic drugs that prolong the QT interval Sotalol and Dofetilide Approval of cardiac drugs that prolong the QT interval, excluding the anti-arrhythmics Bepridil Relationship between QT prolongation, Torsade de Pointes (TdP), and Clinical Events There are three issues that I’d like to address today related to the approval of drugs that prolong the QT in the CardioRenal Division FDA 7.00

I. Approval for Atrial Arrhythmias Sotalol and Dofetilide have a dose-dependent effect on QTc and cause TdP Effect on QT intrinsic to their effect as an anti-arrythmic Approval was based on Demonstration of symptomatic benefit Obtaining sufficient information to adequately describe the nature of the arrhythmic risk FDA 7.00

d, l,-Sotalol Class III anti-arrhythmic Mean effect on QTc Approved for Treatment of life-threatening ventricular arrhythmias Maintenance of Normal Sinus Rhythmn in patients with atrial arrhythmias Mean effect on QTc 10 to 40 msecs at doses from 160 to 640 mg/ day Dose-dependent effect on QTc prolongation and TdP FDA 7.00

Sotalol: Mean QTc Prolongatation and TdP X 4.0 4 X Mean QTc (msec) X 7/ 185 X TdP (%) 3 5 X 3.0 3 X X X 2 5 23/ 893 20/ 775 Change in Mean QTc (msec) Incidence of Torsades (%) 2.0 2 1 5 X X 21/ 2371 1.0 From the Sotalol database we have some of the most complete data available linking changes in QT to the occurrence of clinically significant cardiac events The first thing to note is that the database contains substantial numbers of patients who recieved sotalol doses that vary by an order of magnitude, between 80 and 800 mg per day. This allows us to examine the relationship between drug dose and clinical events over a meaningful dose-range. We can tell a lot about how steep the Looking at a database from a narrower range of drug doses, say between 80 and 160 mg per day, it would be much more difficult to establish that relationship. For Sotalol, then, there was a continuous relationship between drug dose and prolongation of the mean QTc, as well as the incidence of TdP. 1 X 5 1/ 350 X X 5/ 1802 7 1 7 D o s e S t a l ( m g w i c - d y ) N= 6736 Patients FDA 7.00

Sotalol: Effect on Mortality Post-Myocardial Infarction Trial (Julian Study); n=1,456 Early (<10 Days) Excess Mortality with Sotalol Mortality on Sotalol at one year 7.3% Mortality on Placebo at one year 8.9% FDA 7.00

Sotalol: Effect on Mortality Patients with Atrial Fibrillation and Atrial Flutter*; n=1191 Sotalol: 3/747 (0.44%) 2 sudden deaths Quinidine: 1/86 (0.12%) 0 sudden deaths Placebo: 2/358 (0.56%) 1 sudden death * Double-Blind portion of the trials only. FDA 7.00

Dofetilide Class III anti-arrhythmic Mean effect on QTc Approved for Maintenance of normal sinus rhythmn (NSR) Conversion of atrial fibrillation/flutter to NSR Mean effect on QTc 34 msec placebo-subtracted QTc prolongation in phase II/III trials (n=976) Dose-dependent effect on mean QTc 5 to 20 msecs QTc prolongation at doses of 125 to 500 mcg BID FDA 7.00

Dofetilide: Dose-Effect on TdP and VF* *NDA SVA Population N=1,346 FDA 7.00

Dofetilide: Mortality Effect in High-Risk Population DIAMOND CHF and MI Patients with structural heart disease and CHF Dofetilide: 541/1511 (36%) Placebo: 560/1517 (37%) FDA 7.00

Dofetilide: Mortality in Supraventricular Arrhythmia Trials FDA 7.00

Dofetilide: Dose-Adjustment to Minimize Cardiac Toxicity Measure baseline ECG, determine appropriateness of use Calculate creatinine clearance, choose appropriate starting dose Start Dofetilide under continuous ECG monitoring, dose-adjust as needed FDA 7.00

Dofetilide: Effect of Dose-Adjusting for Renal Fxn FDA 7.00

Dofetilide/ Sotalol Summary Dose-dependent effect on QT, QTc, TdP and Ventricular Fibrillation Effects on QTc and TdP rate expected Overall mortality in high-risk and target populations not adverse Characterization of factors affecting risk of TdP Exploration of broad dose-range Exploration of other risk factors (e.g., Dofetilide and Renal Fxn) FDA 7.00

II. Approval As Second-Line Therapy Bepridil prolongs QT and causes TdP Not seen with other anti-anginals Approval based on demonstration of symptomatic benefit in a population resistant to available therapy FDA 7.00

Bepridil Calcium Channel Blocker Mean Effect on QTc Approved for treatment of chronic stable angina in patients intolerant or resistant to other anti-anginals Mean Effect on QTc 30 to 70 msec 5% of patients on Bepridil >25% increase (appr. 100 msec) TdP: 7 cases in 840 angina patients in the U.S. population (0.8%), with 3 fatalities FDA 7.00

Bepridil Effective in Resistant Populations 86 patients with angina, refractory to Diltiazem, randomized to Diltizem or Bepridil Bepridil more effective anti-anginal in this population, measured by exercise stress testing: time to onset of angina time to 1 mm ST-segment depression total exercise time FDA 7.00

Bepridil: Summary Dose-dependent effect on QT, QTc and clear association with TdP Effective in resistant patient population FDA 7.00

Division of Cardio-Renal Drug Products Summary/Conclusions Use of cardiovascular drugs that prolong the mean QT in a dose-dependent fashion is associated with an increased risk for Torsade de Pointes and Sudden Death FDA 7.00

Division of Cardio-Renal Drug Products Summary/Conclusions Cardiac drugs treating symptoms (e.g., atrial arrhythmias) have been approved with the following Demonstration of symptomatic benefit Sufficient information to adequately describe the nature of the arrhythmic risk Description of the drug-effect over a broad dose-range Exploration of potential factors that modify the arrhythmic risk Point estimates of total mortality in high-risk population and in target population FDA 7.00

Division of Cardio-Renal Drug Products Summary/Conclusions Cardiac drugs that cause QT prolongation can also be approved as second-line therapy by demonstrating a symptomatic benefit in a resistant population FDA 7.00