ASA Candiotti 11.1224558439115_46

Efficacy and Safety of3 Different IV Doses of Palonosetron for the Prevention of PONV in the Outpatient (Study 1) and Inpatient (Study 2) Settings : 

1 Efficacy and Safety of3 Different IV Doses of Palonosetron for the Prevention of PONV in the Outpatient (Study 1) and Inpatient (Study 2) Settings Study 1 (Outpatients—US): Candiotti KA, et al. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo for preventing postoperative nausea and vomiting. Anesth Analg. 2008;107:445-451. Study 2 (Inpatients—Europe): Kovac A, et al. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg. 2008;107:439-444. Keith Candiotti, MD Departments of Anesthesiology, Perioperative Medicine and Pain Management University of MiamiMiami, Florida American Society of Anesthesiologists Annual Meeting October 20, 2008

Palonosetron PONV Trials : 

Palonosetron PONV Trials Study funded by MGI/Eisai Study presented on behalf of all investigators involved in both trials. 2

Phase 3 Study Designs : 

Phase 3 Study Designs Study 1: Outpatients (US) Study 2: Inpatients (Europe) Patients Randomization Stratification Placebo vs PALO dosage Interactive voice response system M/F pts undergoing elective laparoscopic abdominal or gynecological surgery Female pts undergoing elective gynecological or breast surgery Hx of PONV/motion sickness Non-smoking status Gender Hx of PONV/motion sickness Non-smoking status Type of surgery Two Randomized, Stratified, Double-blind, Parallel-group, Balanced, Placebo-controlled Multicenter Studies

Patient Demographics : 

4 Patient Demographics

Stratification: PONV Risk Factors : 

5 Stratification: PONV Risk Factors

Anesthesia : 

6 Anesthesia Premeds Midazolam 1-2 mg IV or fentanyl 50-100 ?g IV as needed Induction Propofol 2.0-2.5 mg/kg IV or thiopental 2.5-5.0 mg/kg IV; methohexital 1.5-3.0 mg/kg IV Succinylcholine 1-1.5 mg/kg IV; rocuronium 0.4-0.6 mg/kg IV, cisatracuronium 0.15-0.3 mg/kg IV, vecuronium 0.05-0.1 mg/kg IV, or mivacurium 0.015-0.25 mg/kg Maintenance N2O 50-70% end tidal concentration, O2 30-50% end tidal concentration Rocuronium, cisatracuronium or vecuronium titrated as needed for muscle relaxation Inhalation agent Isoflurane 0.4-3%, desflurane 2-6% or sevoflurane 1-3% end tidal concentration, titrated as needed Intraoperative opioid Fentanyl 2-10 ?g/kg IV or sufentanil 0.2-0.6 ?g/kg, titrated as needed Muscle relaxant reversal Neostigmine <or= 2.5 mg IV and glycopyrrolate 0.4-0.8 mg IV as per usual clinical practice

Study Endpoints : 

7 Study Endpoints Primary endpoint for both studies Complete response* (CR) at 0-24 h and 24-72 h (no emetic episodes and no rescue medication) Secondary endpoints for both studies† CR at additional time intervals Complete control (CR plus no more than mild nausea) Percentage of pts experiencing emesis Number of emetic episodes Severity of nausea Time to treatment failure Patient functional interference (Study 1 only) * P value adjusted for 3-dose comparison vs placebo [P=0.05/3=0.0166] † Measured at 2, 6, 24, 48, and 72 h (all tested at P<0.05)

Slide 8: 

8 Complete Response(No Emesis, No Use of Rescue Medication) * Statistically significant at P <0.0166 (for primary analyses); analysis by logistic regression. †Statistically significant at P <0.05 (for secondary analyses); analysis by logistic regression. * † † Primary endpoints Primary endpoints % of Patients † * * * Study 1 Study 2

Percentage of Patients With No Treatment Failure : 

9 Percentage of Patients With No Treatment Failure P = 0.0185 for palonosetron 0.075 mg vs placebo. Time to treatment failure: time to first emetic episode and/or to first use of rescue meds. Patients who did not have treatment failure were censored at 72 hours. % of Patients With No Treatment Failure P = 0.0035 for palonosetron 0.075 mg vs placebo. Study 1: Outpatients (US) Study 2: Inpatients (Europe) 0 20 40 60 80 100 PALO 0.075 mg Placebo 20 40 60 80 100 0 20 40 60 80 Hours 0 PALO 0.075 mg Placebo

Nausea Severity : 

10 Nausea Severity * Statistically significant vs placebo at P<0.05 (Cochran-Mantel-Haenszel). 0-24 h 0-72 h 0 20 40 60 80 100 Placebo PALO 0.075 mg Placebo PALO 0.075 mg % of Patients Evaluable for Nausea Severe Moderate Mild None * * Placebo PALO 0.075 mg 0-24 h Placebo PALO 0.075 mg 0-72 h Study 1 Study 2 * *

Slide 11: 

11 Percentage of Patients Without Functional Interference* (Study 1 Only) * Functional interference due to nausea and vomiting was measured utilizing a Modified Osoba Nausea and Emesis Module. Measurements were based on a 4-point Likert scale: 1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much. The percentages provided above represent those patients with a score of 1 on any individual subscale. † P<0.05 (Mann-Whitney test for pair-wise comparisons of palonosetron vs placebo). 64 59 62 57 57 73 65 73 66 44 0 20 40 60 80 100 Appetite Sleep Physical activities Social life Enjoyment of life % of Patients Without Interference 0-24 h Placebo PALO 0.075 mg † † †

Most Frequent Treatment-related Adverse Events : 

12 Most Frequent Treatment-related Adverse Events

Changes in QTc : 

13 Changes in QTc ECGs: In triplicate at baseline (screening) and as a single recording at 15 minutes and at 3-6 hours (Study 1) and 6 hours (Study 2) post-study drug administration. Independent blinded cardiologist reading with manual QT interval measurement. Results: At 15 minutes post-dose, QT prolongation was consistent across all treatment groups. At 3 to 6 hours post-dose (Study 1) and at 6 hours post-dose (Study 2), QTc intervals remained slightly increased from baseline values; however, they tended to normalize compared with the 15-minute results.

Slide 14: 

14 Overall Summary Dose-response trend observed with increasing doses of PALO A single IV dose of PALO (0.075 mg) : was effective in reducing PONV in both the inpatient and outpatient settings was superior to placebo (0-24 hours) for the primary endpoint (CR) reduced the severity of nausea compared with placebo Adverse events: no dose relationship, no differences vs placebo, consistent with those expected for the 5-HT3 receptor antagonist class These benefits may: distinguish PALO as unique among the 5-HT3 receptor antagonists address important unmet needs, including nausea control