Fospropofol for sedation Chris More, SRNA Jeff Varga, SRNA

Properties Water soluble prodrug of propofol Sedative/hypnotic agent Indications: MAC/sedation in adults undergoing diagnostic or therapeutic procedures

Pharmacology Pharmacologically inactive Hydrolyzed to propofol GABA-ergic Fospropofol 1.86mg = Propofol 1mg Sedation-hypnotic effects indistinguishable from propofol except: More gradual onset Longer duration Pharmacologically inactive phosphate prodrug of propofol, hydrolyzed by alkaline phosphatases to liberate propofol. Exerts its effect through the potentiation of the GABA receptor Fospropofol disodium 1.86mg is the molar equivalent of propofol 1mg In comparison to the rapid rise and fall in plasma propofol concentrations observed after administration of propofol lipid emulsion, fospropofol disodium produces a smooth and gradual increase and decrease in therapeutic plasma propofol concentrations

Dosing Initial dose: 6.5mg/kg Supplemental dose: 1.5mg/kg Onset: 40 seconds Peak effect: 3-15 minutes Duration: 20-45 minutes Supplemental dose: 1.5mg/kg Frequency: 4 minutes Modified Dosing (>65yo or ASA 3-4): Initial: 5mg/kg Supplemental: 1mg/kg every 4 minutes Because of the high variability between patients in the rate of conversion of fospropofol into propofol, its difficult to anticipate the peak effect and duration of this drug This can cause providers to stack doses and get an over anesthetized patient, requiring airway or hemodynamic intervention Studies show re-dosing should occur no sooner than every 4 minutes Modified dosing for patients over 65 years old, or those with severe systemic disease ASA 3-4

Advantages Less pain at injection site Less hyperlipidemia with long term administration Reduced risk of bacteremia

Disadvantages Paresthesia in perianal and perineal areas Pruritis Hypoxemia and hypotension Currently no research on cost analysis comparing fospropofol, propofol, versed Paresthesias (burning, stinging, or tingling sensations) generally occurred in the perianal and perineal regions and were usually described as mild to moderate in intensity, were transient and self-limited, generally occurred within 5 minutes after administration of the initial dose, and typically lasted 1 to 2 minutes

Research Sedation for Colonoscopy (Cohen et al.) 314 patients >18 years (ASA I-III) were randomized to receive fospropofol 2 mg/kg, fospropofol 6.5- mg/kg, or midazolam 0.02 mg/kg, after pretreatment with intravenous fentanyl 50 mcg Results Sedation success was higher in the fospropofol 6.5 mg/kg versus 2 mg/kg group (87% vs. 26%; P<0.001) and was 69% in the midazolam group Patients in the 6.5-mg/kg group were significantly less likely to remember being awake during the procedure (51% vs. 100% in the 2-mg/kg group, P<0.001; 60% for the midazolam group)

Research Sedation for Bronchoscopy (Silvestri et al.) 252 patients, 150 were randomized to receive 6.5 mg/kg fospropofol; 102 were randomized to receive 2 mg/kg fospropofol Results Sedation success rates were 88.7% and 27.5%, respectively (p < 0.0001). Treatment success (91.3% vs 41.2%, respectively; p < 0.001), willingness to be treated again (94.6% vs 78.2%, respectively; p < 0.001), and absence of procedural recall (83.3% vs 55.4%, respectively; p < 0.001) were significantly better with the administration of 6.5 mg/kg fospropofol median time to full alertness was slightly longer for the 6.5 mg/kg dose (5.5 vs 3.0 min, respectively).

Research – Safety Evaluation Sedation for minor surgical procedures (Gan et al.) 123 patients ≥18 years (ASA I-IV) Arthroscopy, AV shunt placement, bunionectomy, D & C, EGD, lithotripsy, TEE, and ureteroscopy. Pretreatment with fentanyl 50 μg Initial bolus dose of fospropofol 6.5 mg/kg Supplemental doses of 1.63 mg/kg Procedural duration 4 mins – 45 mins Results Need for alternative sedative medications during the procedure low (4.9% of pts) Adverse events: Paresthesia (n = 77, 62.6%) Pruritus (n = 34, 27.6%) Hypotension (n = 4, 3.25%) Bradycardia (n = 1, 0.8%) Hypoxemia (n = 1, 0.8%) Fospropofol at an initial dose of 6.5 mg/kg is easily titrated to a target level of sedation for brief diagnostic and therapeutic procedures, and is associated with an acceptable safety and tolerability profile Hypotension occurred during the dosing and recovery periods of the procedure but was considered to be related to fospropofol in only three of these patients. The hypotension resolved with treatment of atropine (n = 1), ephedrine (n = 1), and normal saline (n = 1). One case of hypotension occurred after administration of propofol in a patient not adequately sedated with fospropofol. Concurrently with hypotension, one patient experienced bradycardia, which resolved with atropine. Hypoxemia (less than one min) was reported in one patient (the hysteroscopy patient described above) and was managed with airway assistance (chin lift and verbal stimulation). No patient experienced apnea on the day of the procedure. The need for alternative sedative medications during the procedure was also low (4.9% of pts)

Summary Safe Effective for minor surgical procedures Requires patience! Further research needed Experiences?

References Cohen, L.B., Cattau, E., Goetsch, A., et al. A random, double-blind, phase 3 study of fospropofol disodium for sedation during colonoscopy. Journal of Clinical Gastroenterology, 2010;44:345–353 Gan, T.J., Berry, B.D., Ekman, E.F., et al. Safety evaluation of fospropofol for sedation during minor surgical procedures. Journal of clinical anesthesia, 2010;22:260-270 Garnock-Jones, K. P., & Scott, L. J. (2010). Fospropofol. Drugs , 70 (4), 469-477 Leslie, J. B. (2010). Fospropofol (lusedra) may be an alternative to propofol for monitored anesthesia. Anesthesia patient safety foundation newsletter , 25 (2), 21-44. Silvestri GA, Vincent BD, Wahidi MM, et al. A phase 3, randomized, double-blind study to assess the efficacy and safety of fospropofol disodium injection for moderate sedation in patients undergoing flexible bronchoscopy. Chest 2009 Jan; 135 (1): 41-7 US FDA. Center for drug evaluation and research summary review for application number 22-244, (fospropofol) [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022244s000_SumR.pdf