This study was funded by Hospira Inc.

1. Monitored Anesthesia Care with Dexmedetomidine: A Prospective, Randomized, Double-Blind, Multicenter Trial Dr. Keith Candiotti Department of Anesthesiology University of Miami This study was funded by Hospira Inc.

2. Martin W. Allard Alex Y. Bekker Sergio D. Bergese Keith A. Candiotti Eric L. Diamond Dennis D. Doblar Thomas J. Ebert Marc Feldmam Robert B. Fisher Tong J. Gan Steven Gayer Ira J. Gottlieb Craig T. Hartrick Gary R. Haynes Fima Lenkovsky Terri Monk Paul A. Moore Thomas N. Pajewski Beverly K. Philip Michael A.E. Ramsay Ruben Ricardo Bernhard Riedel Charles R. Roberson Fred E. Shapiro Jeffrey H. Silverstein Tracey L. Stierer. MAC Investigators

3. MAC • A 2006 review of closed claims in the ASA Closed Claims Database reveals that oversedation leading to respiratory depression played a major role in patient injuries during MAC. • MAC claims were fewer than GA overall • Claims for death or permanent brain damage were 40%, similar to GA1 1Bhananker SM et al. Anesthesiology 2006;104:228-34.

4. MAC • Most commonly used drugs are midazolam, propofol and fentanyl. • All 3 of these drugs is known to cause respiratory depression-especially in combination. 1Bhananker SM et al. Anesthesiology 2006;104:228-34.

5. Dexmedetomidine • DEX is a centrally acting alpha-2 receptor antagonist that does not produce significant respiratory depression.1-3 • Dex has an analgesic-sparing effect, reducing opioid requirements both during and after surgery.3 • The agent also possess a sympatholytic effect that can mitigate tachycardia and HTN.3 1Ebert TJ et al. Anesthesiology 2000;93:382-94. 2 Venn RM et al. Crit Care 2000;4:302-8. 3Arain SR et al. AA 2002;95:461-6

6. Dexmedetomidine • DEX is currently approved for use in initially intubated patients in an intensive care setting. • This trial was designed to evaluate the safety and efficacy of DEX in non-intubated patients in a large multicenter trial (26 sites) using it as the primary sedative agent. • FDA trial designed to compare against a placebo group using midazolam and fentanyl for rescue.

7. Study Design • Randomized 2:2:1 • LOAD • DEX 0.5 mcg/kg load • DEX 1 mcg/kg load • Saline Placebo • MAINTENANCE • Both DEX groups 0.6 mcg/kg/hr (titrated) • Placebo had saline infusion

8. Study Design PBO 65 DEX 130 DEX 130 DEX 0.5 mg/kg 10 min DEX 1 mcg/kg 10 min PBO 10 min Load Maintenance 0.6 mcg/kg/hr titrate PBO Infusion 0.6 mcg/kg/hr titrate Midazolam/Fentanyl Rescue

9. Study Design • Observer’s Assessment of Alertness/Sedation Scale used (OAA/S) • 5=responds to name spoken in normal tone • 4=responds only after mild prodding or shaking • 3=responds only after name loudly and/or repeatedly • 2=lethargic response to name spoken in normal tone • 1=does not respond to mild prodding or shaking

10. Study Design • Study drug started at least 15 min prior to block or local anesthetic • Midazolam 0.5 mg doses given for OAA/S>4 • Fentanyl was given for pain

11. Study Design • Primary endpoint • % patients not requiring midazolam for rescue based on an OAA/S of ≤ 4. • Secondary endpoint • Total rescue midazolam and/or fentanyl • Time to rescue • Patients who converted to alternative therapy • Readiness for D/C • Hemodynamic stability • Patient and Anesthesiologist Satisfaction • Safety endpoints • Cardiac and pulmonary etc.

12. Results-Endpoints • 326 in intent-to-treat • Randomization was good • Fewer patients in both DEX groups required midazolam and used less (p< 0.001) • Both DEX groups required less fentanyl (p< 0.01)

13. Midazolam Mean 1.4 mg Mean 0.9 mg Mean 4.1 mg Groups vs. PBO (p< 0.001)

14. Fentanyl(p < 0.001)

15. Results-Endpoints • Anesthesiologists indicated that DEX was easier to control than PBO + midazolam (p<0.009) • PBO required more fentanyl in PACU than DEX 1 mcg load group (p≤0.068) • Patient satisfaction was higher with DEX (p<0.009)

16. Results-Safety • Most common AE with DEX were protocol defined bradycardia and hypotension which were predominately mild to moderate in severity and did not require intervention. • Mean decrease in SBP (p≤0.043) and DBP (p<0.001) was greater in DEX than PBO group.

17. Results-Safety • HR decrease in both DEX groups was significant from baseline and vs. PBO group (p<0.001) • Incidence of significant respiratory depression (RR < 8 or O2 Sat% < 90%) was lower in DEX treated patients (p=0.018)

18. Respiratory Depression(O2 Sat < 90%, CV RR < 8)

19. PACU D/C(p = 0.068)

20. Results-Safety • Coadministration of midazolam or fentanyl with DEX was not associated with an increase in hypotension, bradycardia or respiratory depression. • In PBO group midazolam and fentanyl were associated with a respective 13.1 and 16.1% rate absolute respiratory depression or need for intervention.

21. Conclusions • DEX is an effective baseline sedative for patients undergoing MAC for a variety of procedures. • Less opioids are required and less respiratory depression is seen with DEX.

22. Conclusions • FDA decision based on this trial: “This supplemental new drug application provides for the use of Precedex Injection for sedation of nonintubated patients prior to and/or during surgical and other procedures”.