1. Prospective controlled study of QTc prolongation by droperidol in healthy volunteers Anesthetic & Life Support Drugs Advisory Committee Meeting November 18, 2003 Mehul Desai, M.D. Medical Officer Division of Cardiovascular and Renal Drugs Anesthetic & Life Support Drugs Advisory Committee Meeting November 18, 2003 Mehul Desai, M.D. Medical Officer Division of Cardiovascular and Renal Drugs Center for Drug Evaluation and Research

2. Study Objective To determine the effect of 0.625, 2.5, 5 mg bolus doses of intravenous droperidol, relative to placebo, on the heart rate corrected QT interval in young, healthy volunteers. Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

3. Study Design 4 period, placebo controlled, blinded, randomized, crossover study of 20 healthy volunteers 0.625 mg, 2.5 mg, 5 mg, and placebo (IV bolus over 30 seconds) Healthy subjects between ages 19-40 years on no prescription or over the counter medications; Normal baseline electrocardiograms. Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

4. Study Methods ECG’s: Baseline, 1, 2, 3, 4, 5, 8, 10, 15, 20, 40, 60, 120, 240, 480, and 720 minutes post dose. Read blinded to time, treatment, and subject identity. Originally the QT and RR intervals were measured manually in conjunction with a digitizer board. Heart rate was corrected using Fridericia’s method. Subsequently, the ECG’s were re-analyzed using digital technology and a subject specific heart rate correction. In addition, the impact of heart rate trending was also considered. (Dr. Malik) Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

5. Results: Subject characteristics Age (years) GenderEthnicityPlacebo0.625 mg2.5 mg5 mg 130MAAXXXX 239FAXXXX 333MCXX 435FCX 519FAAXXX 623MCXXX 725FCXX 8 FAAXX A = Asian, AA = African American, C = Caucasian, F = Female, M = Male Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

6. Results (Adverse Events) Neuropsychiatric adverse events lead to early study termination Restlessness, anxiety, difficulty concentrating, claustrophobia, etc. One subject was unable to work the day following the study due to persistent symptoms Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

7. Results: Heart rate -10 -5 0 5 10 15 20 25 1101001000 Time point of the study [min] Change from pre-dose baseline [bpm] (mean ± SEM) Placebo Dose 0.625 mg Dose 2.500 mg Dose 5.000 mg Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

8. Results: Individually corrected QTc Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

9. Results: Average changes in individual QTc 10 – 60 minutes post dose Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

10. Results: Maximal changes in individual QTc Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

11. Conclusions This study was underpowered secondary to early termination There is a strong suggestion that relatively low doses of droperidol prolong the QTc interval. Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003

12. Acknowledgements Indiana University: Adegboyega A, Gorski JC, Hall SD, Hilligoss J, Pinto A FDA: Collins JM, Jenkins JK, Honig PK, Haidar S, Huang SM, Hung HMJ, Kweder SL, Lee IP, Lesko LJ, Machado SG, Malinowski H, McCormick C, Pollock M, Sevka M, Temple R, Throckmorton DC St. Georges Hospital Medical School, London, UK: Malik M Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003