American Society of Anesthesiologists Comments on Fospropofol (Aquavan) NDA 22-244 Open Public Hearing May 7, 2008, meeting of the Anesthetic and Life.

American Society of American Society of Anesthesiologists Comments on Anesthesiologists Comments on Fospropofol (Aquavan)Fospropofol (Aquavan)NDA 22-244NDA 22-244

Open Public HearingOpen Public HearingMay 7, 2008, meeting of theMay 7, 2008, meeting of theAnesthetic and Life Support Drugs Advisory Anesthetic and Life Support Drugs Advisory CommitteeCommittee

Thomas K. Henthorn, MDThomas K. Henthorn, MD

Professor and ChairProfessor and Chair

Department of AnesthesiologyDepartment of Anesthesiology

University of Colorado DenverUniversity of Colorado Denver

Chair, ASA Subcommittee on Anesthetic Action and Chair, ASA Subcommittee on Anesthetic Action and BiochemistryBiochemistry

Complexities posed by the Complexities posed by the Pharmacokinetics and Pharmacokinetics and Pharmacodynamics of Pharmacodynamics of FospropofolFospropofol More interindividual variability in the PKsMore interindividual variability in the PKs

– Incomplete hydrolysis (unlike similar prodrug Incomplete hydrolysis (unlike similar prodrug fosphenytoin which is complete)fosphenytoin which is complete)

– Nonlinear kineticsNonlinear kinetics Lipid-free propofol does not have the Lipid-free propofol does not have the

same PK/PD profile as the emulsion same PK/PD profile as the emulsion formulationformulation

Steep concentration response curveSteep concentration response curve Synergism with other sedative-hypnoticsSynergism with other sedative-hypnotics

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

Aquavan

Plasma Propofol Following 20 Plasma Propofol Following 20 minute infusions of Diprivan and minute infusions of Diprivan and AquavanAquavanGibiansky E, Struys MM, Gibiansky L, Vanluchene AL, Vornov J, Mortier EP, Burak Gibiansky E, Struys MM, Gibiansky L, Vanluchene AL, Vornov J, Mortier EP, Burak E, Van Bortel L E, Van Bortel L Anesthesiology 2005; 103: 718Anesthesiology 2005; 103: 718

Dose escalation 5 mg/kg – 30 mg/kg

Pharmacokinetic Models Pharmacokinetic Models for Fospropofol and for Fospropofol and PropofolPropofol

Fechner et al. Anesthesiology Anesthesiology 2004; 101: 6262004; 101: 626

Gibiansky E, et al., Gibiansky E, et al., Anesthesiology Anesthesiology 2005; 103: 7182005; 103: 718

AQUAVAN® Injection, a Water-soluble Prodrug AQUAVAN® Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN® Dose-escalation Comparison with DIPRIVAN® (Part 2):(Part 2): Pharmacodynamics and Safety Pharmacodynamics and SafetyStruys MM, Vanluchene AL, Gibiansky E, Gibiansky L, Vornov J, Mortier Struys MM, Vanluchene AL, Gibiansky E, Gibiansky L, Vornov J, Mortier EP, Van Bortel L EP, Van Bortel L Anesthesiology 2005; 103: 730Anesthesiology 2005; 103: 730

Equipotency on an equimolar basisEquipotency on an equimolar basis– Fospropofol:PropofolFospropofol:Propofol– 1.86:11.86:1

Actual equipotency to produce Actual equipotency to produce similar plasma propofol similar plasma propofol concentrationsconcentrations– Fospropofol:PropofolFospropofol:Propofol– 6.32:16.32:1

Fospropofol introduces Fospropofol introduces additional pharmacokinetic additional pharmacokinetic variabilityvariability Dose equivalency of fospropofol with propofol is Dose equivalency of fospropofol with propofol is

not on a equimolar basisnot on a equimolar basis– Propofol is being ‘lost’Propofol is being ‘lost’– Cannot discern whether this loss occurs before or after Cannot discern whether this loss occurs before or after

hydrolysis step from the studies to datehydrolysis step from the studies to date Apparent fraction hydrolyzed increases with doseApparent fraction hydrolyzed increases with dose

– Leads to an overestimation of the Cmax of propofol at Leads to an overestimation of the Cmax of propofol at low doses and underestimation at high doses of low doses and underestimation at high doses of approximately 43% and 36%, respectivelyapproximately 43% and 36%, respectively

– This nonlinearity creates a potentially ‘dangerous’ This nonlinearity creates a potentially ‘dangerous’ situationsituation

These conditions strongly argue for the presence These conditions strongly argue for the presence of personnel sufficiently educated and trained to of personnel sufficiently educated and trained to deal with the full continuum of sedation and deal with the full continuum of sedation and anesthesiaanesthesia

Lipid-free propofol (from Lipid-free propofol (from fospropofol) has different fospropofol) has different pharmacokinetics than lipid pharmacokinetics than lipid emulsion propofolemulsion propofol

Fechner et al. Anesthesiology 2004; 101: 626Anesthesiology 2004; 101: 626

Lipid-free propofol (from Lipid-free propofol (from fospropofol) is more potent fospropofol) is more potent than lipid emulsion propofolthan lipid emulsion propofol

Fechner et al. Anesthesiology Anesthesiology 2004; 101: 6262004; 101: 626

Dose titrationDose titration

The concentration-response relationship The concentration-response relationship for propofol is steepfor propofol is steep– The Hill coefficient (gamma) determines the The Hill coefficient (gamma) determines the

slope or steepness of the sigmoid Emax slope or steepness of the sigmoid Emax curvecurve

– Midazolam gamma – approximately 0.8Midazolam gamma – approximately 0.8– Propofol gamma – approximately 3.0Propofol gamma – approximately 3.0

This makes propofol dose titration seem This makes propofol dose titration seem unpredictableunpredictable compared to midazolam compared to midazolam

Dose titrationDose titration

Comparison of gammas

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Dose titrationDose titration

The solution for a steep concentration-The solution for a steep concentration-response relationshipresponse relationship– Administer small fractions of initial doseAdminister small fractions of initial dose

Current Phase II/III studies for Aquavan do Current Phase II/III studies for Aquavan do nicely follow this guidelinenicely follow this guideline– Fospropofol 6.5 mg/kg as initial dose followed by ¼ Fospropofol 6.5 mg/kg as initial dose followed by ¼

of this dose (1.6 mg/min) every 4 minutes up to a of this dose (1.6 mg/min) every 4 minutes up to a maximum of 3 repeat dosesmaximum of 3 repeat doses

– ‘‘Sedation failure’ rate of approximately 20%Sedation failure’ rate of approximately 20%– At least 15 minutes would be required to reach At least 15 minutes would be required to reach

‘sedation failure’ decision‘sedation failure’ decision Options at point of ‘sedation failure’Options at point of ‘sedation failure’

– Cancel procedureCancel procedure– Continue with procedure without adequate sedationContinue with procedure without adequate sedation– Go ‘off label’ with additional fospropofolGo ‘off label’ with additional fospropofol– Change sedative drug (e.g., midazolam)Change sedative drug (e.g., midazolam)

Fospropofol Sedation Success during ColonoscopyCohen LB. Alimentary Pharmacology & Therapeutics 27 (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.

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

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

Propofol derived from Propofol derived from fospropofol is an anesthetic fospropofol is an anesthetic drugdrug Aquavan has high variability in its conversion Aquavan has high variability in its conversion

to propofolto propofol The fraction converted is nonlinear with a The fraction converted is nonlinear with a

higher fraction being converted as dose higher fraction being converted as dose increasesincreases

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 Propofol derived from fospropofol is an anesthetic fospropofol is an anesthetic drugdrug 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.

ConclusionsConclusions

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

ConclusionsConclusions

Propofol is efficacious and safe when administered by Propofol is efficacious and safe when administered by physicians with the appropriate training and appropriate physicians with the appropriate training and appropriate monitoring technology.monitoring technology.

Because sedation is a continuum and the propofol Because sedation is a continuum and the propofol plasma (or effect site) concentration-response plasma (or effect site) concentration-response relationship is steep, it is not always possible to predict relationship is steep, it is not always possible to predict how an individual patient will respond.how an individual patient will respond.

Delayed time to peak effect (as seen with Aquavan) can Delayed time to peak effect (as seen with Aquavan) can increase the difficulty of titrating a drug with a steep increase the difficulty of titrating a drug with a steep response curve and narrow margin of safety.response curve and narrow margin of safety.

Patients appear to differ in their individual reactions to a Patients appear to differ in their individual reactions to a standard dose.standard dose.

Besides the known approximately 20-fold variation in Besides the known approximately 20-fold variation in the rate of metabolism of propofol, there appears to be the rate of metabolism of propofol, there appears to be additional variability in the production of propofol from additional variability in the production of propofol from fospropofol and nonlinear conversion as larger fospropofol and nonlinear conversion as larger cumulative doses are administered. cumulative doses are administered.

ConclusionsConclusions

There are no antagonist or reversal medications for There are no antagonist or reversal medications for propofol.propofol.

Lack of a specific antagonist is an important factor Lack of a specific antagonist is an important factor that distinguishes propofol from other sedatives, such that distinguishes propofol from other sedatives, such as benzodiazepines and narcotics, currently used by as benzodiazepines and narcotics, currently used by non-anesthesiologist physicians.non-anesthesiologist physicians.

Due to the potential for rapid, profound changes in Due to the potential for rapid, profound changes in sedative/anesthetic depth and the lack of antagonist sedative/anesthetic depth and the lack of antagonist medications, agents such as propofol require special medications, agents such as propofol require special attention.attention.

Even if moderate sedation is intended, patients Even if moderate sedation is intended, patients receiving propofol should receive care consistent with receiving propofol should receive care consistent with that required for deep sedation.that required for deep sedation.

This means that the clinician administering propofol This means that the clinician administering propofol must be competent to recognize a state of general must be competent to recognize a state of general anesthesia and rescue a patient experiencing any of anesthesia and rescue a patient experiencing any of the complications of general anesthesia. the complications of general anesthesia.

ConclusionsConclusions

The July 2003 issue of The July 2003 issue of Outpatient SurgeryOutpatient Surgery magazine reported 74.8% felt that propofol magazine reported 74.8% felt that propofol administration by RNs was a patient-safety risk administration by RNs was a patient-safety risk and 71.2% believed administering anesthesia and 71.2% believed administering anesthesia with propofol to be outside of an RN’s scope of with propofol to be outside of an RN’s scope of practice.practice.

According to the article, many RNs are According to the article, many RNs are uncomfortable using propofol, feeling that uncomfortable using propofol, feeling that unpredictable and instantaneous patient unpredictable and instantaneous patient reactions such as loss of an airway render reactions such as loss of an airway render administration and monitoring of the drug administration and monitoring of the drug beyond their competence.beyond their competence.

The American Association for the Accreditation The American Association for the Accreditation of Ambulatory Surgical Facilities (AAAASF) has of Ambulatory Surgical Facilities (AAAASF) has explicitly taken the position that propofol, explicitly taken the position that propofol, unlike other intravenous sedation, may not be unlike other intravenous sedation, may not be administered by a registered nurse.administered by a registered nurse.

ConclusionsConclusions

The Joint Commission on Accreditation of The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires that Healthcare Organizations (JCAHO) requires that clinicians intending to administer deep sedation clinicians intending to administer deep sedation be qualified to rescue patients from general be qualified to rescue patients from general anesthesia and be competent to manage an anesthesia and be competent to manage an unstable cardiovascular system as well as a unstable cardiovascular system as well as a compromised airway and inadequate compromised airway and inadequate oxygenation and ventilation.oxygenation and ventilation.

The joint ASA/ AANA statement on propofol use The joint ASA/ AANA statement on propofol use indicates that, “personnel who administer indicates that, “personnel who administer propofol should be qualified to rescue patients propofol should be qualified to rescue patients whose level of sedation becomes deeper than whose level of sedation becomes deeper than initially intended and who enter, if briefly, a initially intended and who enter, if briefly, a state of general anesthesia.”state of general anesthesia.”

ConclusionsConclusions

The current labeling for Propofol The current labeling for Propofol includes the precaution that the includes the precaution that the individual who administers the drug individual who administers the drug should “not [be] involved in the conduct should “not [be] involved in the conduct of the surgical/diagnostic procedure.” of the surgical/diagnostic procedure.”

Logic and the clinical pharmacology of Logic and the clinical pharmacology of fospropofol dictated that similar fospropofol dictated that similar language should be on the label of language should be on the label of Aquavan. Aquavan.