1. 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
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2. 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
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3. 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
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4. 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
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5. Sotalol: Mean QTc Prolongatation and TdPX
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
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6. 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%
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7. 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.
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8. 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
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9. Dofetilide: Dose-Effect on TdP and VF*
*NDA SVA Population
N=1,346
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10. 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%)
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11. Dofetilide: Mortality in Supraventricular Arrhythmia Trials
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12. 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
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13. Dofetilide: Effect of Dose-Adjusting for Renal Fxn
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14. 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)
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15. 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
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16. 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
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17. 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
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18. Bepridil: Summary
Dose-dependent effect on QT, QTc and clear association with TdP
Effective in resistant patient population
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19. 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
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20. 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
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21. 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
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