New Drugs & Delivery Techniques

1. 2nd Annual Ellison Pierce Symposium Positioning Your ORs For The Future New Drugs & Delivery Techniques Keith B. Thomasset, PharmD, BCPS Clinical Manager – Pharmacy Services Boston University School of Medicine May 19, 2006 3:30- 4:00pm

2. QUESTION: Which of the following is not an approved indication for utilizing morphine sulfate extended release liposomal injection: • Elective cesarean section • Lobectomy • Total knee arthroplasty • Lower abdominal surgery Cross-Tab Label 0 / 10

3. QUESTION: Sugammadex (Org 25969) is a reversal agent for rocuronium and contains what type of carrier matrix? • Lipid emulsion • Propylene glycol • Cyclodextrin • Tween-80 Cross-Tab Label 0 / 10

4. QUESTION: When administering the first dose of cefazolin as an agent for surgical infection prophylaxis at 6:30AM for a case of 5 hours duration, assuming normal blood loss, the next dose should be administered: • At 9:00AM • At 10:30AM • At 2:30 PM • Another dose is not required Cross-Tab Label 0 / 10

5. Objectives • Describe the advantages of liposomal based morphine sulfate for anesthesia practice • Appraise the role of Sugammadex (Org 25969) in the reversal of rocuronium muscle relaxation • Outline the importance of proper antimicrobial timing prior to surgical incision

6. DepoDur®(Morphine sulfate extended release liposomal injection) • Liposomal formulation of morphine sulfate • Epidural administration – lumbar level • 48 hour pain relief • Studied in: • Hip arthroplasty • Knee arthroplasty • Lower abdominal surgery • Elective cesarean section

7. DepoDur® DepoFoam® SkyePharma. Data on File. Endo Pharmaceuticals Inc.: Chadds Ford, PA; April 21, 2004.

8. Difficult to provide prolonged pain relief Multiple injections Epidural continuous infusion High doses result Adverse effects Indwelling epidural catheter Infection risk Spinal hematoma Liposomal formulation Single injection No indwelling catheter Decreases post operative pain requirements PCA Decrease rescue opioid doses Decreased adverse effects No indwelling catheter Decrease infection risk Decrease spinal hemoatome risk Liposomal vs. Conventional Epidural Opioids

9. Advantages • Decreased post operative opioid use • Decreased utilization of rescue doses • Decreased time to rescue therapy • Potential to prevent rescue therapy requirements • Decrease adverse effects • Potential decreased post operative nausea and vomiting • Potential improvement in patient flow • Quicker movement through the system • Quicker movement through the system

10. Post-Op Opioid Use Lower Abdominal Surgery Anesth Anal 2005;100:1069.

11. Time to Rescue Therapy Hip Arthroplasty Anesthesiology 2005;102(5):1018.

12. Patients Requiring No Rescue Therapy Elective Cesarean Delivery Anesth Anal 2005;100:1155.

13. Greater than 10% incidence Decreased oxygen saturation Hypotension Urinary retention N/V/H Constipation Pruritis Pyrexia Dizziness Incidence between 5-10% Hypoxia Tachycardia Insomnia Incidence < 5% Paralytic ileus Abdominal distention Hypertension Bladder spasm Potential interaction with epidural anesthetics Reduced sustained release activity Under further investigation Adverse Effects & Precautions

14. DepoDur® • Administration • Lumbar epidural administration • prior to surgery • after clamping of umbilical cord during cesarean section • Dosing • Orthopedic surgery of lower extremity – 15mg • Lower abdominal or pelvic surgery – 10-15mg • Elective cesarean section – 10mg

15. Neuromuscular Blockade Reversal www.medlib.med.utah.edu/ kw/mg/mml/ms_illus002.gif

16. Common Agents Neostigmine 0.5-2mg IV Acetylcholinesterase inhibitor Edrophonium 10mg IV • Reversal • Atropine • 0.6-1.2mg IV • Antimuscarinic agent Glycopyrrolate0.2-0.4 mg IV

17. Limitations • Not agent specific • Nonselective acetylcholine neurotransmission • Bradycardia • Hypersalivation • Bronchoconstriction • Interpatient variability of effect • Lack of effect against profound neuromuscular block • Require recurrence of first twitch during train-of-four stimulation

18. Agent Specific Reversal Sugammadex (Org 25969) • Cyclodextrin compound • Encapsulate lipophilic molecules • Highly water soluble • No endogenous targets • Biological tolerance Anesthesiology 99(3) p. 633 J Med Chem 45(9) p. 1807

19. Agent Specific Reversal • Mechanism of Action • Hydrophillic exterior and hydrophobic interior • Encapsulation of rocuronium molecule • Prevention of interactions with nicotinic receptors • Increased excretion of complex • 1:1 complex Anesthesiology 103(4), p. 696

20. Other Potential Exogenous Targets • Affinity highest with aminosteroid NMBAs • Others • Atropine • Verapamil • Non-NMBA Steroid Compounds • Hydrocortisone • Prednisone • Methylprednisone Anesthesiology 2006; 104(4)

21. Limitations • Not agent specific • Non-selective acetylcholine neurotransmission • Bradycardia • Hypersalivation • Bronchoconstriction • Interpatient variability of effect • Lack of effect against profound neuromuscular block • Only effective once partial spontaneous recovery has occurred

22. Sugammadex® (Org 25969) • Not agent specific – specific to amniosteroid NMBAs • Adverse effects • Bradycardia – not identified to date • Hypersalivation – not identified to date • Bronchoconstriction – not identified to date • Interpatient variability of effect – scant data • Lack of effect against profound neuromuscular block – scant human data

23. Dosing Anesthesiology 103(4), p. 701

24. Time to Reversal Anesthesiology 2005; 103(4) Anesthesiology 2006;104(4) Br J of Anesthesia 2006;96(1)

25. Dosing and Data Dilemma • Mostly dose finding studies • 0.1mg/kg - 8mg/kg • Single vs. multiple dose per patient • All human studies with rocuronium • Intermittent/single bolus or continuous infusion • All placebo controlled Anesthesiology 2005; 103(4) Anesthesiology 2006;104(4) Br J of Anesthesia 2006;96(1)

26. Conclusion • Elimination half life is ~ 100 min • Totally agent removal at 400 min (6.5 hours) • Renal failure??? • Data suggests no recurarization for 90 minutes • Any for time period > 90 minutes? • More safety and efficacy data needed • Ideal dose yet to be determined • Impact on daily practice • Cost effectiveness STAY TUNED

27. Decreasing the Risk of Surgical Site Infections • Maintain high levels of inspired oxygen • Maintain peri-operative normothermia • Avoid shaving operative site • Maintain adequate glucose control • Appropriate use of peri-operative antibiotics

28. Goal OutcomesAntimicrobial Specific • Evidence-based recommendations • Correct drug • Correct dose • Correct duration • Including intra-operative dosing

29. It’s All About Timing Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

30. Timing of Doses Incision should occur within 60 minutes of antimicrobial administration • Initial Dosing • Cefazolin, Cefoxitin, Cefotetan, Clindamycin • Administer over 10-15 minutes • Vancomycin, Gentamicin, Metronidazole • Administer over at least 1 hour (1 gm/hr for vancomycin)

31. Timing of Doses • Intra-operative Dosing • Redose • Large amount of intra-operative blood loss (~1500mL) • Approximately 2X half life of antimicrobial • Cefazolin, Cefoxitin, Clindamycin • Q4 hours intra-op • Vancomycin • Q6 hours intra-op • Cefotetan, Levofloxacin, Gentamicin • Not needed intra-op due to prolonged duration

32. Antimicrobial Choice Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

33. When to Stop Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

34. Develop agreement Choice Dosing Administration Redosing Intergroup Surgery Anesthesia ID Pharmacy ITS Implementation Adminstration time Intraop reminders Stickers Pagers Standard Orders Physician order entry Orders per guidelines Auto stops BMC Antimicrobial Prophylaxis Plan

35. Boston Medical Center Scorecard Figure based on compliance of the following combined points: antibiotics (correct agent, correct timing, correct discontinuation)

36. Boston Medical Center Scorecard

37. Boston Medical Center Scorecard