Thomas K. Henthorn, MD Professor and Chair Department of Anesthesiology University of Colorado Denver

1. American Society of Anesthesiologists Comments on Fospropofol (Aquavan)NDA 22-244Open Public HearingMay 7, 2008, meeting of theAnesthetic and Life Support Drugs Advisory Committee Thomas K. Henthorn, MD Professor and Chair Department of Anesthesiology University of Colorado Denver Chair, ASA Subcommittee on Anesthetic Action and Biochemistry

2. Complexities posed by the Pharmacokinetics and Pharmacodynamics of Fospropofol • More interindividual variability in the PKs • Incomplete hydrolysis (unlike similar prodrug fosphenytoin which is complete) • Nonlinear kinetics • Lipid-free propofol does not have the same PK/PD profile as the emulsion formulation • Steep concentration response curve • Synergism with other sedative-hypnotics

3. Plasma Propofol Following 20 minute infusions of Diprivan and AquavanFechner J, Ihmsen H, Hatterscheid D, Jeleazcov C, Schiessl C, Vornov JJ, Schwilden H, Schuttler J Anesthesiology 2004; 101: 626 Aquavan

4. Plasma Propofol Following 20 minute infusions of Diprivan and AquavanGibiansky E, Struys MM, Gibiansky L, Vanluchene AL, Vornov J, Mortier EP, Burak E, Van Bortel L Anesthesiology 2005; 103: 718 Dose escalation 5 mg/kg – 30 mg/kg

5. Pharmacokinetic Models for Fospropofol and Propofol Fechner et al. Anesthesiology 2004; 101: 626 Gibiansky E, et al., Anesthesiology 2005; 103: 718

6. AQUAVAN® Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN® (Part 2): Pharmacodynamics and SafetyStruys MM, Vanluchene AL, Gibiansky E, Gibiansky L, Vornov J, Mortier EP, Van Bortel L Anesthesiology 2005; 103: 730 • Equipotency on an equimolar basis • Fospropofol:Propofol • 1.86:1 • Actual equipotency to produce similar plasma propofol concentrations • Fospropofol:Propofol • 6.32:1

7. Fospropofol introduces additional pharmacokinetic variability • Dose equivalency of fospropofol with propofol is not on a equimolar basis • Propofol is being ‘lost’ • Cannot discern whether this loss occurs before or after hydrolysis step from the studies to date • Apparent fraction hydrolyzed increases with dose • Leads to an overestimation of the Cmax of propofol at low doses and underestimation at high doses of approximately 43% and 36%, respectively • This nonlinearity creates a potentially ‘dangerous’ situation • These conditions strongly argue for the presence of personnel sufficiently educated and trained to deal with the full continuum of sedation and anesthesia

8. Lipid-free propofol (from fospropofol) has different pharmacokinetics than lipid emulsion propofol Fechner et al. Anesthesiology 2004; 101: 626

9. Lipid-free propofol (from fospropofol) is more potent than lipid emulsion propofol Fechner et al. Anesthesiology 2004; 101: 626

10. Dose titration • The concentration-response relationship for propofol is steep • The Hill coefficient (gamma) determines the slope or steepness of the sigmoid Emax curve • Midazolam gamma – approximately 0.8 • Propofol gamma – approximately 3.0 • This makes propofol dose titration seem unpredictable compared to midazolam

11. Dose titration

12. Dose titration • The solution for a steep concentration-response relationship • Administer small fractions of initial dose • Current Phase II/III studies for Aquavan do nicely follow this guideline • Fospropofol 6.5 mg/kg as initial dose followed by ¼ of this dose (1.6 mg/min) every 4 minutes up to a maximum of 3 repeat doses • ‘Sedation failure’ rate of approximately 20% • At least 15 minutes would be required to reach ‘sedation failure’ decision • Options at point of ‘sedation failure’ • Cancel procedure • Continue with procedure without adequate sedation • Go ‘off label’ with additional fospropofol • Change sedative drug (e.g., midazolam)

13. Fospropofol Sedation Success during ColonoscopyCohen LB. Alimentary Pharmacology & Therapeutics27 (7), 597-608. Figure 1. Sedation success. The primary end point of this study was sedation success, where a highly significant dose-dependent trend was observed across fospropofol dosing groups in the modified intent-to-treat population (P <0.001 by Cochran–Armitage trend test). The sedation success rates were 24%, 35%, 69% and 96% in the FP 2.0, FP 5.0, FP 6.5 and FP 8.0 groups respectively. *P <0.05 vs. FP 2.0 and FP 5.0.

14. Sedative Combinations Produce Variable SynergismTriple anesthetic combination: propofol-midazolam-alfentanil. Vinik HR et al.,Anesth Analg 1994; 78: 354

15. Practice Guidelines for Sedation and Analgesia by Non-AnesthesiologistsAnesthesiology: 96(4):1004, 2002

16. Propofol derived from fospropofol is an anesthetic drug • Aquavan has high variability in its conversion to propofol • The fraction converted is nonlinear with a higher fraction being converted as dose increases • Propofol from Aquavan is more potent (when comparing plasma propofol concentrations) • Compared to the standard drug used for sedation (midazolam), propofol concentration-response curve is much steeper • Making Aquavan more ‘unpredictable’ • Requiring a very (or impossibly) large educational effort if Aquavan is introduced into the ‘proceduralist’ environment without the presence of personnel trained in the continuum of sedation.

17. Propofol derived from fospropofol is an anesthetic drug • Small initial doses with well-spaced and even smaller repeat doses appeared to be safe in Phase II/III trials • But these dosing limitations led to a high ‘sedation failure’ rate. • Necessitating the addition of midazolam to the fentanyl-propofol regimen • Adding midazolam to this combination appears to double the synergistic sedative-anesthesia interaction and led to the cases of deep sedation/anesthesia seen during the trials.

18. Conclusions • Propofol, whether administered in a lipid emulsion formulation or as fospropofol (Aquavan) is a powerful anesthetic agent that can produce unpredictable levels of sedation along the continuum from sedation to general anesthesia.

19. Conclusions • Propofol is efficacious and safe when administered by physicians with the appropriate training and appropriate monitoring technology. • Because sedation is a continuum and the propofol plasma (or effect site) concentration-response relationship is steep, it is not always possible to predict how an individual patient will respond. • Delayed time to peak effect (as seen with Aquavan) can increase the difficulty of titrating a drug with a steep response curve and narrow margin of safety. • Patients appear to differ in their individual reactions to a standard dose. • Besides the known approximately 20-fold variation in the rate of metabolism of propofol, there appears to be additional variability in the production of propofol from fospropofol and nonlinear conversion as larger cumulative doses are administered.

20. Conclusions • There are no antagonist or reversal medications for propofol. • Lack of a specific antagonist is an important factor that distinguishes propofol from other sedatives, such as benzodiazepines and narcotics, currently used by non-anesthesiologist physicians. • Due to the potential for rapid, profound changes in sedative/anesthetic depth and the lack of antagonist medications, agents such as propofol require special attention. • Even if moderate sedation is intended, patients receiving propofol should receive care consistent with that required for deep sedation. • This means that the clinician administering propofol must be competent to recognize a state of general anesthesia and rescue a patient experiencing any of the complications of general anesthesia.

21. Conclusions • The July 2003 issue of Outpatient Surgery magazine reported 74.8% felt that propofol administration by RNs was a patient-safety risk and 71.2% believed administering anesthesia with propofol to be outside of an RN’s scope of practice. • According to the article, many RNs are uncomfortable using propofol, feeling that unpredictable and instantaneous patient reactions such as loss of an airway render administration and monitoring of the drug beyond their competence. • The American Association for the Accreditation of Ambulatory Surgical Facilities (AAAASF) has explicitly taken the position that propofol, unlike other intravenous sedation, may not be administered by a registered nurse.

22. Conclusions • The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires that clinicians intending to administer deep sedation be qualified to rescue patients from general anesthesia and be competent to manage an unstable cardiovascular system as well as a compromised airway and inadequate oxygenation and ventilation. • The joint ASA/ AANA statement on propofol use indicates that, “personnel who administer propofol should be qualified to rescue patients whose level of sedation becomes deeper than initially intended and who enter, if briefly, a state of general anesthesia.”

23. Conclusions • The current labeling for Propofol includes the precaution that the individual who administers the drug should “not [be] involved in the conduct of the surgical/diagnostic procedure.” • Logic and the clinical pharmacology of fospropofol dictated that similar language should be on the label of Aquavan.