American Society of Anesthesiologists Comments on Fospropofol (Aquavan) NDA 22-244 Open Public Hearing May 7, 2008, meeting of the Anesthetic 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
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
Plasma Propofol Following 20 minute infusions of Diprivan and Aquavan Fechner J, Ihmsen H, Hatterscheid D, Jeleazcov C, Schiessl C, Vornov JJ, Schwilden H, Schuttler J Anesthesiology 2004; 101: 626
Plasma Propofol Following 20 minute infusions of Diprivan and Aquavan Gibiansky E, Struys MM, Gibiansky L, Vanluchene AL, Vornov J, Mortier EP, Burak E, Van Bortel L Anesthesiology 2005; 103: 718
Pharmacokinetic Models for Fospropofol and Propofol
AQUAVAN® Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN® (Part 2): Pharmacodynamics and Safety Struys 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
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
Lipid-free propofol (from fospropofol) has different pharmacokinetics than lipid emulsion propofol
Lipid-free propofol (from fospropofol) is more potent than lipid emulsion propofol
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
Dose titration
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
Sedative Combinations Produce Variable Synergism Triple anesthetic combination: propofol-midazolam-alfentanil. Vinik HR et al., Anesth Analg 1994; 78: 354
Practice Guidelines for Sedation and Analgesia by Non-Anesthesiologists Anesthesiology: 96(4):1004, 2002
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.
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.
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.
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.
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.
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.
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.”
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.
