1. Alex Y. Bekker, MD, PhD Associate Professor of Anesthesiology and Neurosurgery New York University Medical Center New York, New York Dexmedetomidine for Monitored Anesthesia Care (MAC)

2. “We have completed our review of this application, as amended, and it is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text.”

3. Monitored Anesthesia Care: Definition Monitored Anesthesia Care (MAC) may include varying levels of sedation, analgesia, and anxiolysis as necessary. The provider of MAC must be prepared and qualified to convert to general anesthesia when necessary. Position on Monitored Anesthesia Care, ASA 2005

4. Continuum of Depth of Sedation Minimal Sedation (Anxiolysis) Moderate Sedation/ Analgesia (Conscious Sedation) Deep Sedation/ Analgesia General Anesthesia ResponsivenessNormal Response to verbal Stimulation Purposeful response to verbal or tactile stimulation Purposeful response after repeated or painful stimulation Unarousable, even with painful stimulation AirwayUnaffectedNo intervention required Intervention may be required Intervention often required Spontaneous ventilation UnaffectedAdequateMay be inadequate Frequently inadequate Cardiovascular function UnaffectedUsually maintained May be impaired Practice Guidelines for Sedation and Analgesia by Non-Anesthesiologists, Anesthesiology 2002

5. Injury and Liability Associated with Monitored Anesthesia Care Bhananker and colleagues assessed the patterns of injury and liability associated with monitored anesthesia care (MAC; n = 121) as compared with general (n = 1519) and regional anesthesia (n = 312) Bhananker S, Anesthesiology 2006 * * * * * P<.025 MAC versus Regional % of claims in anesthesia group

6. Injury Associated with MAC N=121% Respiratory event 24 Cardiovascular event14 Equipment failure/malfunctioning21 Related to regional block 2 Inadequate anesthesia/patient movement11 Medication related 9 Other events20 Bhananker S, Anesthesiology 2006

7. Characteristics of an Ideal Sedative Cooperative sedation Minimal depression of ventilation Hemodynamic stability Analgesic effects Wide therapeutic window Minimal risks of side effects Favorable pharmacodynamic/ pharmacokinetic profile Amnesia (?)

8. Study Design: Monitored Anesthesia Care 325 Patients: 260 Dex; 65 Placebo receiving MAC for surgical procedures; 25 US sites 2 Precedex Arms: 0.5 mcg/kg/10 min load or 1.0 mcg/kg/10 min load; 0.6 mcg/kg/hr maintenance titrated 0.2 – 1.0 mcg/kg/hr. OAA/S Scale: Midazolam rescue for > 4. Primary Endpoint: % of pts not requiring MDZ based on OAA/S. Secondary Endpoints: total MDZ, fentanyl, sedation failures; pt satisfaction; anesthesiologist assessment; PONV Safety: respiratory depression; hemodynamic stability

9. MAC Primary Efficacy Requirement of Rescue Midazolam (MDZ) Rescue MDZ/ No Rescue MDZ DEX 0.5 mcg/kg N=134 n (%) DEX 1 mcg/kg N=129 n (%) PBO N=63 n (%) Did Not Require Rescue MDZ 54 (40.3)70 (54.3)2 (3.2) Required Rescue MDZ80 (59.7)59 (45.7)61 (96.8) p-value<0.001 –

10. MAC Secondary Efficacy Anesthesiologist Assessment

11. MAC Secondary Efficacy Subject Assessment

12. Overview of Awake Fiberoptic Intubation Trial Double-blind, randomized, placebo-controlled 100 patients: 50 Precedex; 50 Placebo; 18 US sites Precedex: 1.0 mcg/kg/10 min; 0.7 mcg/kg/hr maint Rescue is Midazolam(0.5 mg doses) based on Ramsay Sedation Scale of 1. Primary Endpoint: % of patients requiring Midazolam Secondary Endpoints: Total MDZ dose; other rescue meds; patient satisfaction; anesthesiologist assessment Safety Endpoints: hemodynamic stability; respiratory depression

13. AWAKE Primary Efficacy Requirement of Rescue Midazolam (MDZ) AWAKE Primary Efficacy Requirement of Rescue Midazolam (MDZ) Rescue MDZ/No Rescue MDZ DEX (N=55) n (%) PBO (N=50) n (%) p-value Required Rescue MDZ 26 (47.3%) 43 (86.0%) <0.001 Did Not Require Rescue MDZ 29 (52.7%)* 7 (14.0%) –

14. Characteristics of Cooperative Sedation  In cooperative sedation, patients easily transition from sleep to wakefulness and task performance when aroused  Patients are able to resume rest when not stimulated  Cooperative sedation is most useful during procedures in which communication with the patient must be maintained  Facilitates participation in therapeutic maneuvers  Allows for patient interaction in care decisions  May contribute to shorter recovery room convalescence  Reduces risk of developing drug-induced complications

15. “The brain is not a sausage, it’s more like a well tuned musical instrument” Rudolfo Llinas Endogenous sleep Loss of response to external stimuli Sedative component of anesthesia

16. Arousability From Sedation During Dexmedetomidine Infusion BIS indicates Bispectral Index System During cognitive and cold pressor testing Just prior to cognitive and cold pressor testing Dexmedetomidine Infusion (mcg/kg/h) Hall JE, Anesth Analg 2000 Patients were infused with placebo or 1 of 2 doses of dexmedetomidine and monitored with the Bispectral Index System (BIS) before stimulation and immediately after being asked to perform cognitive and cold pressor testsPatients were infused with placebo or 1 of 2 doses of dexmedetomidine and monitored with the Bispectral Index System (BIS) before stimulation and immediately after being asked to perform cognitive and cold pressor tests Patients receiving either infusion of dexmedetomidine could be completely aroused by a mild stimulus 1Patients receiving either infusion of dexmedetomidine could be completely aroused by a mild stimulus 1

17.  Avoid oversedation  Reduce anxiety  Maintain communication  Minimize respiratory depression  Avoid oversedation  Reduce anxiety  Maintain communication  Minimize respiratory depression Dexmedetomidine in Carotid Endarterectomy

18. Intraoperative Assessment of Sedation Level by the Blinded Observer Bekker A, J Neurosurg Anesth 2004

19. The Safety of Dexmedetomidine as Primary Sedative for Awake CEA Total number of patients N=151 General Anesthesia N=10Regional/DexN=123 Regional/No Dex N=18 No Shunt N=0ShuntN=10 N=111ShuntN=12 N=12ShuntN=6 ElectiveN=10ObligatoryN=0ElectiveN=7ObligatoryN=5ObligatoryN=2ElectiveN=4 Bekker A, Anesth Analg 2006

20. Clinical Experience with Dexmedetomidine for DBS Implantation Dex (0.3-0.6 mcg/kg/hr) did not impair intensity of movement disorder or interfere with MER in PD patientsDex (0.3-0.6 mcg/kg/hr) did not impair intensity of movement disorder or interfere with MER in PD patients Titration of Dex provided satisfactory sedation for DBS implantationTitration of Dex provided satisfactory sedation for DBS implantation Dex provided HD stability and decreased the use of antihypertensives 1Dex provided HD stability and decreased the use of antihypertensives 1 Propofol induced dyskinesia was controlled with DEX during DBS placement 2Propofol induced dyskinesia was controlled with DEX during DBS placement 2 1 Rozet I, Anesth Analg 2006. 2 Deogaonkar A, Anesthesiology 2006.

21. Dexmedetomidine and Respiratory Depression 1Minimal effects on ventilation is well documented in human volunteers 1 2Lack of respiratory depression was demonstrated in ICU patients 2 12 1 Belleville JP, Anesthesiology, 1992; Ebert TJ, Anesthesiology, 2000. 2 Venn RM, Crit Care, 2000; Martin E, J Intensive Care Med 2004.

22. Hospira MAC Trial: Respiratory Depression Definition of Respiratory Depression: Respiratory rate < 8 bpm or oxygen saturation < 90% Dex 0.5 Dex 1.0 Pcb 5 (3.7%) 3 (2.3%) 8 (12.7  P<0.018 Both Dex groups: neither respiratory depression nor intervention Plb group: respiratory depression or a need for intervention 13.1% and 16.1% respectively

23. Dexmedetomidine and Hemodynamic Stability Arain SR, Anesth Analg 2002Bekker A, J Neurosurg Anesth 2004

24. MAC Trial: Mean Changes in Systolic and Diastolic Blood Pressure and Heart Rate

25. *P<.05 difference over time compared with baseline † P<.05 difference between groups 0 10 20 30 40 100 VAS Pain 0 40 60 80 100 VAS Sedation Propofol Dexmedetomidine 5 20 355065 Surg End Pre- surg Time After Surgery, minutes * † Arain SR, Anesth Analg, 2002 Improved postoperative pain and greater sedation with dexmedetomidine compared with propofol Postoperative Effects of Dexmedetomidine Less Alert More Alert Less Pain More Pain

26. Morphine-Sparing Effects in Inpatient Surgery 34 patients scheduled for inpatient surgery34 patients scheduled for inpatient surgery Randomized to either dexmedetomidine or morphineRandomized to either dexmedetomidine or morphine Agents were started 30 minutes before the end of surgeryAgents were started 30 minutes before the end of surgery Dexmedetomidine reduced the early postoperative need for morphine by 66%Dexmedetomidine reduced the early postoperative need for morphine by 66% P<.01 Morphine Dexmedetomidine P<.01 Arain SR, Anesth Analg 2004

27. MAC Trial: Fentanyl Use Time Period DEX 0.5 mcg/kg N=134 n (%) p – value DEX 1 mcg/kg N=129 n (%) p – value PBO N=63 n (%) Infusion Period Required Fentanyl 79 (59.0)<0.00155 (42.6)<0.00156(88.9) PACU Period Required Fentanyl 5 (3.7)0.1045 (3.9)0.1056 (9.5) Overall Required Fentanyl 81 (60.4)<0.00156 (43.4)<0.00156(88.9)

28. Pharmacokinetics of IV agents DexPropofolFentanylAlfenta Vdcc, l 16163010 Vdss, l 20035033030 Cl, l/min 0.61.80.80.3 T 1/2 , min 6464 T 1/2   hr 21.52.51

29. Dexmedetomodine Was Tried as a Primary Sedative for: Sedation in CT and MRI imaging studiesSedation in CT and MRI imaging studies Mason K, Ped Anesth 2008 Koroglu A, Anesth Analg 2006 Outpatient third molar surgeryOutpatient third molar surgery Ustin Y, J Oral Maxilfac Surg 2006 Cheung C, Anaesthesia 2007 Cataract surgeryCataract surgery Alhashemi J, Br J Anaest 2006 Cardiac catheterizationCardiac catheterization Tosun Z, J Card Vasc Anesth 2006 Mester R, Am J Therap 2008

30. Use of Dexmedetomidine in MRI 80 children aged 1-7 years80 children aged 1-7 years Randomly assigned to either dexmedetomidine or midazolamRandomly assigned to either dexmedetomidine or midazolam –10-minute loading doses: 1 mcg/kg dexmedetomidine, 0.2 mg/kg midazolam –Infusions: 0.5 mcg/kg/h dexmedetomidine, 6 mcg/kg/h midazolam 1 The quality of MRI was significantly better (P<.001) and the rate of adequate sedation was significantly higher (P<.001) with dexmedetomidineThe quality of MRI was significantly better (P<.001) and the rate of adequate sedation was significantly higher (P<.001) with dexmedetomidine 1 = no motion 2 = minor movement 3 = major movement necessitating another scan Quality of MRI *P<.001 compared with midazolam * * Koroglu A, Br J Anaesth 2005

31. Dexmedetomidine for GI Procedures Jalowiecki P, Anesthesiology 2005 Use of Dex was associated with bradycardia, hypotension, vertigo, nausea/vomiting, prolonged recovery Muller R, Gastroint Endosc 2008 Clinical efficacy of Dex alone is less than propofol during ERCP Demiraran Y, Can J Gastroenter 2007 Dex may be a good alternative to midazolam for upper endoscopy

32. Dexmedetomidine: Safety Propofol TI = 3.5 Harrison N, Anesthetic Pharmacology, 2004 Dexmedetomidine: Jorden V, Ann Pharmacoth, 2004 Pt 1 - 60 times the prescribed dose Pt 2 - 10 times the prescribed dose Pt 3 - 60 times the prescribed dose Ramsay M, Anesthesiology, 2004 Pt 1 - Infusion rate 10 mcg/kg/h Pt 2 - Infusion rate 5 mcg/kg/h Pt 3 – Infision rate 5 mcg/kg/h Therapeutic Index = (median lethal dose [LD50] / (mean effective dose [ED50]

33. Benzo- diazepines PropofolOpioids  2 Agonists SedationXXXX Alleviate anxiety XX Analgesic properties XX Promote arousability during sedation X No respiratory depression X Control delirium X Comparison of Clinical Effects

34. Benzo- diazepines PropofolOpioids  2 Agonists Prolonged weaning XX X*X*X*X* Respiratory depression XXX HypotensionXXXX ConstipationX DeliriogenicXXX TachycardiaMorphine BradycardiaFentanylX Comparison of Adverse Effects

35. All progress is based upon a universal innate desire on the part of every organism to live beyond its income