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Safety evaluation of fospropofol for sedation during minor surgical procedures
Journal of Clinical Anesthesia (2010) 22, 260–267
Original contribution
Safety evaluation of fospropofol for sedation during minor surgical procedures☆ Tong J. Gan MD (Professor and Vice Chairman)a,⁎, Bradley D. Berry MD (Staff Physician)b , Evan F. Ekman MD (President and Medical Director)c , Richard C. Muckerman II MD (Staff Physician)d , Neal Shore MD (Medical Director)e , Robert Hardi MD (Staff Physician)f a
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA International Heart Institute of Montana, Missoula, MT 59802, USA c Southern Orthopedic Sports Medicine, Columbia, SC 29204, USA d St. Louis Women's Healthcare Group,Chesterfield, MO 63017, USA e Carolina Urologic Research Center, Myrtle Beach, SC 29572, USA f Metropolitan Gastroenterology Group, Chevy Chase, MD 20815, USA b
Received 10 December 2008; revised 20 July 2009; accepted 30 August 2009
Keywords: Fospropofol; Minor surgery; Moderate sedation; Patient safety
Abstract Study Objective: To evaluate the safety of intravenous (IV) fospropofol when used to provide minimal to moderate sedation in patients undergoing minor surgical procedures. Design: Phase 3, open-label, single-arm study. Setting: Multi-center. Patients: 123 ASA physical status I, II, III, and IV patients, aged ≥18 years. Interventions: Patients were pretreated with fentanyl 50 μg before receiving an initial dose of IV fospropofol 6.5 mg/kg. Patients could receive up to 5 supplemental doses of fospropofol 1.63 mg/kg to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score ≤ 4 to allow the start of the procedure and to maintain adequate sedation levels during the procedure. Measurements: Study endpoints included measures of sedation depth, requirement for supplemental sedative doses, use of alternative sedatives, and the frequency and nature of treatment-emergent and sedative-related adverse events. Main Results: A mean of 2.4 supplemental doses of fospropofol was administered, and in 60% of patients, two or fewer supplemental doses of fospropofol were sufficient to initiate and complete the procedure. Alternative sedative medication was administered in 6 of 123 patients (4.9%). Mean (SD) MOAA/S score during the procedure was 3.8 (0.5). Sixty-one percent (61%) of patients had a MOAA/S score of 5 (fully alert) within two minutes after the end of the procedure. Few patients (7 of 123; 5.7%) had MOAA/S scores of 0 to 1 (deep sedation) during the procedure, and all 7 were either ASA physical status I (n = 1) or II (n = 6). The most common treatment-related adverse events (TRAEs) were self-
☆ Supported by MGI Pharma, Inc., Bloomington, MN, USA. ⁎ Corresponding author. Tel.: +1 919 681 4660; fax: +1 919 681 7901. E-mail address: [email protected] (T.J. Gan).
0952-8180/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2009.08.007
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limited: paresthesias (62.6%) and pruritus (27.6%). Five patients experienced sedation-related adverse events, including hypotension (n = 4), bradycardia (concurrently with hypotension and managed with atropine; n = 1), or hypoxemia (less than one min and managed with chin lift and verbal stimulation; n = 1). Twenty patients with previous or existing hepatic disease (ranging from minimal to severe) and 5 patients with severe renal impairment had adverse events similar to the overall population. No deaths were reported, and no patient discontinued the study due to adverse events. Conclusion: An initial dose of IV fospropofol 6.5 mg/kg with supplemental doses was safe and welltolerated as moderate sedation for use in minor surgical procedures. © 2010 Elsevier Inc. All rights reserved.
1. Introduction The demand for procedural sedation continues to increase as more emphasis is placed on cancer screening and other outpatient procedures. Practice guidelines for sedation and analgesia by non-anesthesiologists indicate that sedation/ analgesia provides two benefits that result in optimal operating conditions and satisfaction for both the provider and patient [1]. First, it allows patients to tolerate unpleasant procedures by relieving anxiety, discomfort, and pain. Second, it optimizes the conduct of uncomfortable procedures that require no movement in children and uncooperative adults. Procedural sedation most often combines an opioid for analgesia with a benzodiazepine for sedation [2]. Midazolam is the most widely used benzodiazepine because of its amnestic, anxiolytic, and sedative properties, and its shorter elimination half-life when compared with other benzodiazepines [3]. However, a disadvantage of midazolam use is the prolonged time to cognitive recovery [4-6]. In addition, midazolam is a selective substrate of cytochrome (CYP) 3A4 and CYP3A5 P450 isoenzymes and, as a result, it has wide interpatient variability in metabolic activity when co-administered with drugs that are inhibitors of these enzymes [7,8]. As more procedures requiring sedation are performed in physician offices and outpatient surgery centers, specialists are becoming more involved with procedural sedation. Although most physicians are generally satisfied with their current sedation regimens, procedure-related discomfort, slow onset of action, and delayed patient recovery are common reasons for dissatisfaction with conventional sedation. The need exists for an effective sedative agent for use during minor surgical procedures that can safely, readily, and reliably be titrated to target a moderate level of sedation on an individual patient basis. Fospropofol disodium (Eisai, Inc., Woodcliff Lake, NJ, USA) injection is a water-soluble prodrug of propofol that has been evaluated for sedation during diagnostic and therapeutic procedures [9-11]. Fospropofol is rapidly hydrolyzed by alkaline phosphatases to release propofol, as well as phosphate and formaldehyde, which is rapidly converted to formate. Notably, these metabolites do not accumulate in excess of endogenous levels [9,12]. Following intravenous (IV) administration of fospropofol, there is a
characteristic smooth and predictable increase in the plasma concentration of fospropofol-derived propofol [12]. Fospropofol produces a lower peak plasma concentration (Cmax) than the conventional lipid-emulsion formulation of propofol, although the elimination kinetics of fospropofol-derived propofol are identical to those of conventional propofol [12]. The primary purpose of this study was to evaluate the overall safety of fospropofol as a sedative for patients undergoing minor surgical procedures.
2. Materials and methods 2.1. Study design The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. The study protocol was approved by either a central review board or the institutional review board at each participating site. All patients provided written, informed consent prior to participation in this study. This study was registered (NCT00327392) at clinicaltrials.gov. This phase 3, open-label, single-arm study evaluated the safety of IV fospropofol 6.5 mg/kg following analgesic pretreatment with fentanyl in patients undergoing minor surgical procedures that required sedation. The surgical procedures were performed by skilled physicians, and a nurse, respiratory therapist, or other clinician skilled in airway management and authorized by the study facility was immediately available during the procedure.
2.2. Study population The study population included male and female ASA physical status I, II, III, and IV patients ≥ 18 years of age, who were scheduled to undergo a minor surgical procedure with sedation. Eligible procedures included arthroscopy, arteriovenous (AV) shunt placement, bunionectomy, dilatation and curettage (D & C), esophagogastroduodenoscopy (EGD), lithotripsy, transesophageal echocardiography (TEE), and ureteroscopy. Female patients of childbearing potential were required to use a medically acceptable method of birth control for at least one month prior to drug
262 administration and to have a negative serum pregnancy test result at screening and prior to administration of fospropofol. Patients were excluded from the study if they had a history of allergy or hypersensitivity to any anesthetic agent, opioid, or benzodiazepine, or any contraindication to the use of fentanyl or midazolam. Patients also were excluded for the presence of a difficult airway as evidenced by a Mallampati Classification Score of 4, or a Mallampati Classification Score of 3 and a thyromental distance ≤ 4 cm; the presence of an abnormal, clinically significant 3-lead electrocardiogram (ECG) finding at baseline (predosing); and for participation in an investigational drug study within one month prior to the start of the study.
2.3. Sedation and maintenance phase All patients received supplemental oxygen via nasal cannula (4 L/min), and ECG, pulse oximeter, and blood pressure (BP) monitors were all attached before administration of the study drug. All patients received analgesic pretreatment with fentanyl 50 μg administered 5 minutes prior to the initial dose of fospropofol. It was recommended that patients receive only one additional dose of fentanyl 25 μg if the patient continued to experience pain during the procedure; however, additional doses of fentanyl (given at least 10 min from previous fentanyl dose) were permitted. Fospropofol disodium was supplied as a clear, colorless, sterile, aqueous solution containing 35 mg/mL of fospropofol disodium. An initial bolus dose of fospropofol 6.5 mg/kg and supplemental doses of 1.63 mg/kg were administered as needed to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score ≤ 4, allowing the physician to start the procedure. This dosing schedule was also used to maintain adequate sedation levels during the procedure if the patient had a MOAA/S score ≥ 4 and showed purposeful movement. In patients ≥ 65 years of age or those classified as ASA physical status IV (or III at the investigator's discretion), initial bolus and supplemental doses of fospropofol were reduced by 25% (4.875 mg/kg). Because deep levels of sedation (MOAA/S scores of 0 and 1) may be associated with an increased risk of respiratory compromise, additional doses of fospropofol were not administered to patients who had a MOAA/S score b 4 or who did not show purposeful movement during the sedation phase. A period of at least 4 minutes was required between each administration of fospropofol. Alternative sedative medication was allowed but was not considered until the initial bolus and at least 5 supplemental doses of fospropofol had been given. Propofol was prohibited for use as an alternative sedative medication because of its interference with the pharmacokinetic analysis.
2.4. Evaluation criteria The number and proportion of patients receiving alternative sedative medications and the number of
T.J. Gan et al. supplemental doses of fospropofol were recorded. Sedation level was assessed using the MOAA/S scale [ranging from 0 (nonresponsive) to 5 (alert)]. Assessments were made one minute before and after pretreatment with fentanyl and conducted every two minutes thereafter until the patient was Fully Alert (defined as 3 consecutive MOAA/S scores of 5, at or after the end of the procedure). The duration and percentage of time that patients were at each MOAA/S score was recorded from the first dose of the study drug until the patient was Fully Alert. Duration of the surgical procedure was measured from the start time of the first incision (or the treatment of nonsurgical condition) to the end of the procedure.
2.5. Safety evaluation Safety was assessed by continuous clinical monitoring of ECG, oxygen saturation via pulse oximetry (SpO2), and adverse events (AEs) at baseline (predosing), during the procedure, and during the recovery period. Adverse event data were also collected during a Day 1 post-procedure telephone interview for all patients and at follow-up visits on each of Days 2 through 5. At screening, baseline, recovery, and follow-up visits, a venous blood sample was obtained for measuring hematology, serum chemistry, and serum electrolytes. A urine sample was obtained for urinalysis at screening, recovery, and follow-up visits. Treatment-related AEs (TRAEs) included those AEs considered definitely, probably, or possibly related to the study drug. The frequency of sedation-related adverse events (SRAEs) was tabulated separately from all other AEs and included: apnea (lack of spontaneous breathing N 30 sec), hypoxemia (SpO2 b 90% for N 30 sec), bradycardia [heart rate (HR) b 50 bpm and requiring medical intervention], and hypotension [systolic blood pressure (SBP) b 90 mmHg and requiring medical intervention]. The need for airway assistance was also assessed.
2.6. Statistical analysis As this was a safety study, no formal statistical hypothesis testing was performed. The sample size for this study was determined by (1) overall patient exposure to fospropofol required for a New Drug Application (NDA), and (2) the feasibility of using fospropofol during a variety of minor surgical procedures. With 125 patients receiving fospropofol, the study had 85% power to detect a frequency of major airway assistance (eg, manual ventilation or mechanical intubation) or serious AE if the underlying frequency was at least 1.5%. Summary statistics were reported. For continuous or ordinal variables, data were summarized with mean, standard deviation (SD), median, minimum, and maximum values. For categorical variables, number and proportion were tabulated for each category. The safety population was used for all analyses and was
Fospropofol for minor surgical procedures defined as all enrolled patients who received at least one dose of fospropofol at any time.
3. Results 3.1. Demographics and baseline characteristics Of the 149 patients screened for the study, 26 failed screening, leaving 123 patients for analysis. Of the 26 screening failures, 8 patients withdrew consent, 4 did not meet the inclusion/exclusion criteria, 4 were not enrolled at the investigator's discretion, and three experienced pretreatment AEs which, in the opinion of the investigator, disqualified them from participation in the study. The 7 remaining patients failed screening due to patient cancellation (n = 2), non-visualized kidney calculus (n = 1), investigator discretion due to elevated blood glucose (n = 1), procedure cancellation (n = 1), surgeon's desire to use general anesthesia (n = 1), and patient's not meeting the special population criteria (n = 1). Demographic and baseline characteristics of enrolled patients are shown in Table 1.
Table 1 Demographic and baseline characteristics of the study population. Fospropofol (n = 123) Age (yrs) mean (SD) range (min, max) Age group, n (%) 18-64 yrs ≥ 65 yrs ≥ 75 yrs Gender, n (%) male female Mean (SD) weight (kg) range Weight group, n (%) b 60 kg 60 b 90 kg ≥ 90 kg ASA physical status, n (%) I II III IV Dose of study drug, n (%) standard dose a dose reduced by 25% a
51.3 (15.3) 18-87 99 (80.5) 24 (19.5) 11 (9.0) 56 (45.5) 67 (54.5) 80.1 (19.3) 44-132 18 (14.6) 69 (56.1) 36 (29.3) 33 67 22 1
(26.8) (54.5) (17.9) (0.8)
92 (74.8) 31 (25.2)
Patients ≥ 65 years of age or ASA physical status IV received initial and supplemental doses of study medication reduced by 25% from the standard dose. ASA physical status III patients received reduced initial and supplemental doses at the investigator's discretion. a Standard dose was 6.5 mg/kg.
263 The median procedure duration was 17.0 minutes (range: two to 110 min). The majority (n = 92; 75%) of procedures were completed in 26.0 minutes or less. The duration and types of surgical procedures performed are shown in Table 2.
3.2. Dose The mean total amount of fentanyl administered per patient was 58.5 μg (range: 25 to 100 μg). A majority of patients (n = 83, 67.5%) required only the initial 50 μg of fentanyl to manage procedural pain. The mean total dose of fospropofol administered during the procedure was 742.0 mg (range: 280.0 to 1,592.5 mg), equivalent to a mean of 9.3 mg/kg. Thirty-one (25.2%) patients received a dose of fospropofol reduced by 25% according to protocol. The number of supplemental doses of the study drug administered is shown in Fig. 1. A mean of 2.4 supplemental doses of fospropofol was administered, and in 60.2% (n = 74) of patients, two or fewer supplemental doses of fospropofol were sufficient to initiate and complete the procedure. The dosage requirements for fospropofol or supplemental medications were not affected by patient body weight. Alternative sedative medication was administered to 6 (4.9%) patients (midazolam, n = 3; sevoflurane, n = 2; and nalbuphine, n = 1) due to inadequate sedation. All were in the 18 to 64-year age group, and all received between 4 and 6 supplemental doses of fospropofol (total dose between 420 mg and 630 mg) before receiving alternative sedative medication. Although propofol was not recommended for use as an alternative sedative medication because of its interference with pharmacokinetic analyses, it was administered in two of the 6 (1.6%) patients. Both patients underwent lithotripsy and had received a total of 612.5 mg and 420 mg of fospropofol, respectively, before propofol was administered for inadequate sedation. No association was detected between the type of surgical procedure and the alternative sedative medication administered.
Table 2 Type and duration of surgical procedure in patients receiving fospropofol Type of procedure
Number (%) Median procedure of patients duration (min)
Esophagogastroduodenoscopy Arthroscopy Hysteroscopy Bunionectomy Transesophageal echocardiogram Ureteroscopy Lithotripsy Dilation and curettage Arteriovenous shunt placement
27 22 21 18 13
(22.0) (17.9) (17.1) (14.6) (10.6)
4.0 17.5 12.0 43.5 14.0
10 8 3 1
(8.1) (6.5) (2.4) (0.8)
12.0 29.5 8.0 45.0
264
T.J. Gan et al. Table 3
Treatment-related adverse events (TRAEs)
TRAEs in N 2% of patients
Fospropofol (n = 123)
Patients with ≥ one TRAE paresthesia a pruritus b nausea hypotension vomiting headache
101 (82.1) 77 (62.6) 34 (27.6) 5 (4.1) 4 (3.3) 4 (3.3) 3 (2.4)
Number (%) of patients
Fig. 1
Number of supplemental doses of fospropofol administered.
3.3. Depth of sedation Seven (5.7%) patients had a MOAA/S score of 0 or 1 at any time from the first dose of the study medication until Fully Alert. Median time spent at a MOAA/S score of 0 or 1 was 4 minutes (range: 2 to 14 min). One of the 7 patients received an alternative sedative for 12 minutes prior to reaching a MOAA/S score of 1. This ASA physical status II patient was a 41-year-old woman who weighed 95 kg. She received 2.0 mg of midazolam plus sevoflurane in addition to 1,137.5 mg of fospropofol and 75 μg of fentanyl. She did not experience any SRAEs; however, a chin lift and placement of an oral airway were required. One patient who spent 14 minutes at a MOAA/S score of 0 received 30 mL of mepivacaine hydrochloride to achieve a pain block for her hysteroscopy, followed by 50 μg fentanyl and the initial dose of 6.5 mg/kg fospropofol. Her MOAA/S score decreased 4 minutes later to 0, where it remained for 10 minutes before her hysteroscopy started, then increased from 0 to 3 within 4 minutes of the start of her procedure. Her MOAA/S score remained at 3 until her hysteroscopy was completed in 9 minutes. The patient received no supplemental fentanyl, study sedative, or airway assistance, and she experienced one AE of mild pruritis. Only one of the 7 patients whose MOAA/S score decreased to 0 to 1 experienced a SRAE. This patient was a 51-year-old, ASA physical status II woman who weighed 83 kg. During her hysteroscopy, she experienced mild hypoxemia, which required a chin lift and verbal stimulation. Her MOAA/S score remained at 1 for two minutes, and the hypoxemia resolved within one minute.
3.4. Safety
a Paresthesia included the following preferred terms: anal discomfort (reported as anal burning), burning sensation, genital burning sensation, nasal discomfort (reported as burning), pain (reported as stinging), paresthesia of genital male, perineal pain (reported as burning), skin burning sensation, and vaginal burning sensation. b Pruritus included the following preferred terms: genital pruritus female, nasal discomfort (reported as itching), anal pruritus, pruritus generalized, and pruritus genital.
septal defect (n = 2), apnea, and cardiac arrest (n = 1), and increased ammonia and hepatic encephalopathy (n = 1). None of these AEs was considered to be related to fospropofol. No patient was discontinued from the study due to an AE, and no deaths were reported. Five (4.1%) patients treated with fospropofol experienced at least one pre-defined SRAE [hypotension (n = 4), bradycardia (n = 1), or hypoxemia (n = 1)] on the day of the procedure (Table 4). 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
Table 4
Sedation-related adverse event
Fospropofol (n = 123) Number (%) of patients
a
Apnea Hypoxemia b Hypotension c Bradycardia d
0 1 (0.8) 4 (3.3) 1 (0.8)
Apnea was defined as a lack of spontaneous breathing N30 seconds. Hypoxemia was defined as oxygen saturation b 90% for N 30 seconds. c Hypotension was defined as systolic blood pressure b 90 mmHg and required medical intervention (such as intravenous fluids or concomitant medication). d Bradycardia was defined as heart rate b 50 beats per minute and required medical intervention (such as concomitant medication). a
b
Treatment-related AEs were experienced in 101 (82.1%) patients. The three most common TRAEs reported in patients were paresthesia (n = 77, 62.6%) and pruritus (n = 34, 27.6%), and the majority of TRAEs were mild to moderate (Table 3). Four patients experienced serious AEs: atrial
Sedation-related adverse events (SRAEs)
Fospropofol for minor surgical procedures
265
Table 5 Patients requiring airway assistance after fospropofol (n = 123)
3.5. Airway assistance
Airway assistance
Crying, dystonia, and urticaria (n = 1)
Seven of 123 patients (5.7%) required at least one type of airway assistance (Table 5). One of these patients (discussed above) who underwent a hysteroscopy required airway assistance (consisting of verbal stimulation and a chin lift) attributed to hypoxemia. No other patient required airway assistance that was associated with an SRAE, and no patient required manual or mechanical ventilation.
Hypoxemia (n = 1)
3.6. Hepatic or renal impairment
Crying, dystonia, and urticaria (n = 1)
Twenty of the 123 patients (16.3%) had previous or existing hepatic disease (ranging from minimal to severe). Five of the 123 patients (4.1%) had severe renal impairment (creatinine clearance ≤ 30 mL/min). Demographic characteristics for this subset of patients were similar to the overall patient population (Table 6). Adverse events were also similar to the overall patient population. Treatment-related AEs were similar to those observed in other patients in the study, with paresthesia (50%) and pruritus (30%) being the most common. No SRAEs were observed in this subset of patients.
Number Indication for (%) of airway assistance patients
Patients with ≥ one type 7 (5.7) of airway assistance Increased oxygen flow 2 (1.6) Patient repositioning Verbal stimulation Tactile stimulation Face mask (100% oxygen) Jaw thrust Chin lift
0 1 (0.8) 0 1 (0.8)
Nasal trumpet Oral airway Suction a
0 1 (0.8) 3 (2.4)
0 2 (1.6)
Hypoxemia (n = 1) and inadequate sedation (n = 1) Inadequate sedation (n = 1) Investigator discretion during EGD (n = 3)
EGD = esophagogastroduodenoscopy. a Same center; no patients experienced airway complications requiring manual ventilation (bag-valve-mask) or mechanical ventilation (intubation).
4. Discussion managed with airway assistance (chin lift and verbal stimulation). No patient experienced apnea on the day of the procedure. Table 6
Demographics and safety in patients with hepatic and renal impairment
Median age, yrs (range) Creatinine clearance (mL/min) median (range) ASA physical status I/II III Treatment-related adverse events paresthesia pruritus nausea vomiting restless legs syndrome Sedation-related adverse events airway assistance increased oxygen flow suction Serious adverse events ammonia increased a apnea b cardiac arrest b hepatic encephalopathy a a b
The findings of this study show the safety of the 6.5 mg/kg dosing regimen of fospropofol injection in
Patients with hepatic impairment (n = 20)
Patients with renal impairment (n = 5)
57 (39-73)
64 (57-82)
— Number (%) of patients
21 (11-30)
12 (60.0) 8 (40.0) 14 (70.0) 10 (50.0) 6 (30.0) 2 (10.0) 1 (5.0) 0 0 4 (20.0) 1 (5.0) 3 (15.0) 1 (5.0) 1 (5.0) 0 0 1 (5.0)
Events were in the same patient and were deemed secondary to cirrhosis. Events were in the same patient and were attributed to underlying disease and concomitant medication.
0 5 (100.0) 2 (40.0) 1 (20.0) 0 0 0 1 (20.0) 0 0 0 0 1 (20.0) 0 1 (20.0) 1 (20.0) 0
266 patients undergoing minor surgical procedures. The majority of patients were moderately sedated with fospropofol, as shown by the low frequency of deep sedation observed in this study (5.7% of pts reached MOAAS scores of 0 or 1). The need for alternative sedative medications during the procedure was also low (4.9% of pts). The majority of TRAEs were categorized as either mild or moderate. Paresthesia and pruritus were the most common AEs observed and were transient and self-limited, requiring no treatment in this study. Paresthesia and pruritus usually occurred within 5 minutes of the initial administration of fospropofol. Five (4.1%) patients experienced SRAEs with fospropofol, although all resolved with minimal intervention. Of the patients who experienced SRAEs, one patient had received supplemental propofol before the onset of the SRAE (hypotension). The results of this study confirm the tolerability profile observed in phase 3 studies [13,14] and support the use of fospropofol as an alternative to the agents currently in use for procedural sedation. Compared with propofol, fospropofol disodium has a different pharmacokinetic and pharmacodynamic profile that is characterized by an extended elimination half-life, a longer residence time, and a delayed onset of action, which may provide an improved safety and efficacy profile [15]. Furthermore, administration of fospropofol in an aqueous solution rather than the lipid emulsion required for propofol may reduce the risks associated with bacterial contamination and lipid-related side effects [15]. Fospropofol is metabolized by alkaline phosphatase into propofol, formaldehyde, and phosphate following IV administration [12]. Following fospropofol administration, plasma concentrations of propofol peak at approximately 8 minutes, followed by an elimination half-life of about two hours [12]. Analysis of fospropofol and propofol pharmacokinetics indicates that clearance of fospropofol is dependent on total body weight, which supports bodyweight-based dosing [12]. Compared with propfol, fospropofol's slower onset should impact patient hemodynamics less, though potentially slowing patient recovery. In clinical conditions where a more prolonged effect is desired and immediate onset of action is less important, fospropofol may have advantages over propofol. Fospropofol has demonstrated efficacy in patients undergoing bronchoscopy and colonoscopy, in addition to the minor procedures described here [13,14]. Results of a phase 2 study evaluating fospropofol in 127 patients undergoing colonoscopy showed that an initial dose of 6.5 mg/kg was optimal to achieve efficacy and tolerability in a majority of patients [13]. A phase 3 study of 252 patients undergoing flexible bronchoscopy, found that fospropofol provided safe and effective sedation [14]. Results from a phase 3 trial of fospropofol in patients undergoing colonoscopy showed that optimal sedation success was achieved in most patients at a dose of 6.5 mg/ kg [16,17]. While the most common AEs with fospropofol are paresthesias and pruritus, the most common AE with propofol is pain on injection.
T.J. Gan et al. Interpretation of these study results is limited by the study design. Because this was an open-label study of safety, no control group was available for comparison, and data collection was not blinded. The most common AEs with fospropofol 6.5 mg/kg in this study were consistent with the AEs reported in controlled trials and included mild, selflimited paresthesias and pruritus [13], although SRAEs occurred in 20% of patients with fospropofol in the bronchoscopy study [14]. However, consistent with the results reported here, no SAEs or deaths were reported, and no patient required either manual or mechanical ventilation in phase 3 trials [13,14]. This study also includes the first report of safety among patients with underlying renal or hepatic disease, which was not different from the overall study population. In summary, the results of this trial show that 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. Fospropofol produces a predictable pharmacokinetic and pharmacodynamic profile, delivering controlled sedation in an outpatient setting. Fospropofol is pending approval as an IV sedativehypnotic agent indicated for monitored anesthesia care sedation in adult patients undergoing diagnostic or therapeutic procedures. The standard dosing regimen should be an initial dose of 6.5 mg/kg followed by supplemental doses of 1.6 mg/kg, with a dosage reduction by 25% in those who are ASA physical status III or IV or at least 65 years of age.
Acknowledgments The authors would like to acknowledge the contributions of the prinicipal investigators at each study site: Vasanth K. Bethala, MD, Slidell, LA; Paul Diehl, MD, Sandy, UT; Maciej L. Dryjski, MD, Buffalo, NY; Kyle Etzkom, MD, Jacksonville, FL; Evan R. Goldfischer, MD, Poughkeepsie, NY; Ira J. Gottlieb, DPM, Pasadena, MD; Anthony E. Martin, MD, Louisville, KY; Dasarathy Srinivas, MD, Slidell, LA; Vadim David Vornik, MD, Dallas, TX; and Steven Wininger, MD, Phoenix, AZ. The authors also would like to acknowledge the editorial assistance of Richard S. Perry, PharmD, in the preparation of this manuscript.
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injection: a phase I dose-escalation comparison with DIPRIVAN (part 2): pharmacodynamics and safety. Anesthesiology 2005;103: 730-43. Shah A, Fechner J, Struys M, Mistry B. Differential PK/PD of propofol after intravenous fospropofol and Diprivan® in healthy subjects [Abstract]. Anesthesiology 2007;107:A46. Cohen LB. Clinical trial: a dose-response study of fospropofol disodium for moderate sedation during colonoscopy. Aliment Pharmacol Ther 2008;27:597-608. Silvestri GA, Vincent BD, Wahidi MM, Robinette E, Hansbrough JR, Downie GH. 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; 135:41-7. Levitzky BE, Vargo JJ. Fospropofol disodium injection for the sedation of patients undergoing colonoscopy. Ther Clin Risk Manag 2008;4:733-8. Cohen LB, Rex DK, Kline J, Wang C. Patient and physician satisfaction with fospropofol disodium: results of a phase 3, randomized, double-blind trial evaluating fospropofol disodium for moderate sedation in patients undergoing colonoscopy. [Abstract] Gastrointest Endosc 2007;65:AB367. Rex DK, Cohen LB, Kline JK, Wang C. Fospropofol disodium is effective and safe for sedation in patients undergoing colonoscopy: results of a phase 3, randomized double-blind trial. [Abstract] Gastrointest Endosc 2007;65:A369.
Original contribution
Safety evaluation of fospropofol for sedation during minor surgical procedures☆ Tong J. Gan MD (Professor and Vice Chairman)a,⁎, Bradley D. Berry MD (Staff Physician)b , Evan F. Ekman MD (President and Medical Director)c , Richard C. Muckerman II MD (Staff Physician)d , Neal Shore MD (Medical Director)e , Robert Hardi MD (Staff Physician)f a
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA International Heart Institute of Montana, Missoula, MT 59802, USA c Southern Orthopedic Sports Medicine, Columbia, SC 29204, USA d St. Louis Women's Healthcare Group,Chesterfield, MO 63017, USA e Carolina Urologic Research Center, Myrtle Beach, SC 29572, USA f Metropolitan Gastroenterology Group, Chevy Chase, MD 20815, USA b
Received 10 December 2008; revised 20 July 2009; accepted 30 August 2009
Keywords: Fospropofol; Minor surgery; Moderate sedation; Patient safety
Abstract Study Objective: To evaluate the safety of intravenous (IV) fospropofol when used to provide minimal to moderate sedation in patients undergoing minor surgical procedures. Design: Phase 3, open-label, single-arm study. Setting: Multi-center. Patients: 123 ASA physical status I, II, III, and IV patients, aged ≥18 years. Interventions: Patients were pretreated with fentanyl 50 μg before receiving an initial dose of IV fospropofol 6.5 mg/kg. Patients could receive up to 5 supplemental doses of fospropofol 1.63 mg/kg to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score ≤ 4 to allow the start of the procedure and to maintain adequate sedation levels during the procedure. Measurements: Study endpoints included measures of sedation depth, requirement for supplemental sedative doses, use of alternative sedatives, and the frequency and nature of treatment-emergent and sedative-related adverse events. Main Results: A mean of 2.4 supplemental doses of fospropofol was administered, and in 60% of patients, two or fewer supplemental doses of fospropofol were sufficient to initiate and complete the procedure. Alternative sedative medication was administered in 6 of 123 patients (4.9%). Mean (SD) MOAA/S score during the procedure was 3.8 (0.5). Sixty-one percent (61%) of patients had a MOAA/S score of 5 (fully alert) within two minutes after the end of the procedure. Few patients (7 of 123; 5.7%) had MOAA/S scores of 0 to 1 (deep sedation) during the procedure, and all 7 were either ASA physical status I (n = 1) or II (n = 6). The most common treatment-related adverse events (TRAEs) were self-
☆ Supported by MGI Pharma, Inc., Bloomington, MN, USA. ⁎ Corresponding author. Tel.: +1 919 681 4660; fax: +1 919 681 7901. E-mail address: [email protected] (T.J. Gan).
0952-8180/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2009.08.007
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limited: paresthesias (62.6%) and pruritus (27.6%). Five patients experienced sedation-related adverse events, including hypotension (n = 4), bradycardia (concurrently with hypotension and managed with atropine; n = 1), or hypoxemia (less than one min and managed with chin lift and verbal stimulation; n = 1). Twenty patients with previous or existing hepatic disease (ranging from minimal to severe) and 5 patients with severe renal impairment had adverse events similar to the overall population. No deaths were reported, and no patient discontinued the study due to adverse events. Conclusion: An initial dose of IV fospropofol 6.5 mg/kg with supplemental doses was safe and welltolerated as moderate sedation for use in minor surgical procedures. © 2010 Elsevier Inc. All rights reserved.
1. Introduction The demand for procedural sedation continues to increase as more emphasis is placed on cancer screening and other outpatient procedures. Practice guidelines for sedation and analgesia by non-anesthesiologists indicate that sedation/ analgesia provides two benefits that result in optimal operating conditions and satisfaction for both the provider and patient [1]. First, it allows patients to tolerate unpleasant procedures by relieving anxiety, discomfort, and pain. Second, it optimizes the conduct of uncomfortable procedures that require no movement in children and uncooperative adults. Procedural sedation most often combines an opioid for analgesia with a benzodiazepine for sedation [2]. Midazolam is the most widely used benzodiazepine because of its amnestic, anxiolytic, and sedative properties, and its shorter elimination half-life when compared with other benzodiazepines [3]. However, a disadvantage of midazolam use is the prolonged time to cognitive recovery [4-6]. In addition, midazolam is a selective substrate of cytochrome (CYP) 3A4 and CYP3A5 P450 isoenzymes and, as a result, it has wide interpatient variability in metabolic activity when co-administered with drugs that are inhibitors of these enzymes [7,8]. As more procedures requiring sedation are performed in physician offices and outpatient surgery centers, specialists are becoming more involved with procedural sedation. Although most physicians are generally satisfied with their current sedation regimens, procedure-related discomfort, slow onset of action, and delayed patient recovery are common reasons for dissatisfaction with conventional sedation. The need exists for an effective sedative agent for use during minor surgical procedures that can safely, readily, and reliably be titrated to target a moderate level of sedation on an individual patient basis. Fospropofol disodium (Eisai, Inc., Woodcliff Lake, NJ, USA) injection is a water-soluble prodrug of propofol that has been evaluated for sedation during diagnostic and therapeutic procedures [9-11]. Fospropofol is rapidly hydrolyzed by alkaline phosphatases to release propofol, as well as phosphate and formaldehyde, which is rapidly converted to formate. Notably, these metabolites do not accumulate in excess of endogenous levels [9,12]. Following intravenous (IV) administration of fospropofol, there is a
characteristic smooth and predictable increase in the plasma concentration of fospropofol-derived propofol [12]. Fospropofol produces a lower peak plasma concentration (Cmax) than the conventional lipid-emulsion formulation of propofol, although the elimination kinetics of fospropofol-derived propofol are identical to those of conventional propofol [12]. The primary purpose of this study was to evaluate the overall safety of fospropofol as a sedative for patients undergoing minor surgical procedures.
2. Materials and methods 2.1. Study design The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. The study protocol was approved by either a central review board or the institutional review board at each participating site. All patients provided written, informed consent prior to participation in this study. This study was registered (NCT00327392) at clinicaltrials.gov. This phase 3, open-label, single-arm study evaluated the safety of IV fospropofol 6.5 mg/kg following analgesic pretreatment with fentanyl in patients undergoing minor surgical procedures that required sedation. The surgical procedures were performed by skilled physicians, and a nurse, respiratory therapist, or other clinician skilled in airway management and authorized by the study facility was immediately available during the procedure.
2.2. Study population The study population included male and female ASA physical status I, II, III, and IV patients ≥ 18 years of age, who were scheduled to undergo a minor surgical procedure with sedation. Eligible procedures included arthroscopy, arteriovenous (AV) shunt placement, bunionectomy, dilatation and curettage (D & C), esophagogastroduodenoscopy (EGD), lithotripsy, transesophageal echocardiography (TEE), and ureteroscopy. Female patients of childbearing potential were required to use a medically acceptable method of birth control for at least one month prior to drug
262 administration and to have a negative serum pregnancy test result at screening and prior to administration of fospropofol. Patients were excluded from the study if they had a history of allergy or hypersensitivity to any anesthetic agent, opioid, or benzodiazepine, or any contraindication to the use of fentanyl or midazolam. Patients also were excluded for the presence of a difficult airway as evidenced by a Mallampati Classification Score of 4, or a Mallampati Classification Score of 3 and a thyromental distance ≤ 4 cm; the presence of an abnormal, clinically significant 3-lead electrocardiogram (ECG) finding at baseline (predosing); and for participation in an investigational drug study within one month prior to the start of the study.
2.3. Sedation and maintenance phase All patients received supplemental oxygen via nasal cannula (4 L/min), and ECG, pulse oximeter, and blood pressure (BP) monitors were all attached before administration of the study drug. All patients received analgesic pretreatment with fentanyl 50 μg administered 5 minutes prior to the initial dose of fospropofol. It was recommended that patients receive only one additional dose of fentanyl 25 μg if the patient continued to experience pain during the procedure; however, additional doses of fentanyl (given at least 10 min from previous fentanyl dose) were permitted. Fospropofol disodium was supplied as a clear, colorless, sterile, aqueous solution containing 35 mg/mL of fospropofol disodium. An initial bolus dose of fospropofol 6.5 mg/kg and supplemental doses of 1.63 mg/kg were administered as needed to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score ≤ 4, allowing the physician to start the procedure. This dosing schedule was also used to maintain adequate sedation levels during the procedure if the patient had a MOAA/S score ≥ 4 and showed purposeful movement. In patients ≥ 65 years of age or those classified as ASA physical status IV (or III at the investigator's discretion), initial bolus and supplemental doses of fospropofol were reduced by 25% (4.875 mg/kg). Because deep levels of sedation (MOAA/S scores of 0 and 1) may be associated with an increased risk of respiratory compromise, additional doses of fospropofol were not administered to patients who had a MOAA/S score b 4 or who did not show purposeful movement during the sedation phase. A period of at least 4 minutes was required between each administration of fospropofol. Alternative sedative medication was allowed but was not considered until the initial bolus and at least 5 supplemental doses of fospropofol had been given. Propofol was prohibited for use as an alternative sedative medication because of its interference with the pharmacokinetic analysis.
2.4. Evaluation criteria The number and proportion of patients receiving alternative sedative medications and the number of
T.J. Gan et al. supplemental doses of fospropofol were recorded. Sedation level was assessed using the MOAA/S scale [ranging from 0 (nonresponsive) to 5 (alert)]. Assessments were made one minute before and after pretreatment with fentanyl and conducted every two minutes thereafter until the patient was Fully Alert (defined as 3 consecutive MOAA/S scores of 5, at or after the end of the procedure). The duration and percentage of time that patients were at each MOAA/S score was recorded from the first dose of the study drug until the patient was Fully Alert. Duration of the surgical procedure was measured from the start time of the first incision (or the treatment of nonsurgical condition) to the end of the procedure.
2.5. Safety evaluation Safety was assessed by continuous clinical monitoring of ECG, oxygen saturation via pulse oximetry (SpO2), and adverse events (AEs) at baseline (predosing), during the procedure, and during the recovery period. Adverse event data were also collected during a Day 1 post-procedure telephone interview for all patients and at follow-up visits on each of Days 2 through 5. At screening, baseline, recovery, and follow-up visits, a venous blood sample was obtained for measuring hematology, serum chemistry, and serum electrolytes. A urine sample was obtained for urinalysis at screening, recovery, and follow-up visits. Treatment-related AEs (TRAEs) included those AEs considered definitely, probably, or possibly related to the study drug. The frequency of sedation-related adverse events (SRAEs) was tabulated separately from all other AEs and included: apnea (lack of spontaneous breathing N 30 sec), hypoxemia (SpO2 b 90% for N 30 sec), bradycardia [heart rate (HR) b 50 bpm and requiring medical intervention], and hypotension [systolic blood pressure (SBP) b 90 mmHg and requiring medical intervention]. The need for airway assistance was also assessed.
2.6. Statistical analysis As this was a safety study, no formal statistical hypothesis testing was performed. The sample size for this study was determined by (1) overall patient exposure to fospropofol required for a New Drug Application (NDA), and (2) the feasibility of using fospropofol during a variety of minor surgical procedures. With 125 patients receiving fospropofol, the study had 85% power to detect a frequency of major airway assistance (eg, manual ventilation or mechanical intubation) or serious AE if the underlying frequency was at least 1.5%. Summary statistics were reported. For continuous or ordinal variables, data were summarized with mean, standard deviation (SD), median, minimum, and maximum values. For categorical variables, number and proportion were tabulated for each category. The safety population was used for all analyses and was
Fospropofol for minor surgical procedures defined as all enrolled patients who received at least one dose of fospropofol at any time.
3. Results 3.1. Demographics and baseline characteristics Of the 149 patients screened for the study, 26 failed screening, leaving 123 patients for analysis. Of the 26 screening failures, 8 patients withdrew consent, 4 did not meet the inclusion/exclusion criteria, 4 were not enrolled at the investigator's discretion, and three experienced pretreatment AEs which, in the opinion of the investigator, disqualified them from participation in the study. The 7 remaining patients failed screening due to patient cancellation (n = 2), non-visualized kidney calculus (n = 1), investigator discretion due to elevated blood glucose (n = 1), procedure cancellation (n = 1), surgeon's desire to use general anesthesia (n = 1), and patient's not meeting the special population criteria (n = 1). Demographic and baseline characteristics of enrolled patients are shown in Table 1.
Table 1 Demographic and baseline characteristics of the study population. Fospropofol (n = 123) Age (yrs) mean (SD) range (min, max) Age group, n (%) 18-64 yrs ≥ 65 yrs ≥ 75 yrs Gender, n (%) male female Mean (SD) weight (kg) range Weight group, n (%) b 60 kg 60 b 90 kg ≥ 90 kg ASA physical status, n (%) I II III IV Dose of study drug, n (%) standard dose a dose reduced by 25% a
51.3 (15.3) 18-87 99 (80.5) 24 (19.5) 11 (9.0) 56 (45.5) 67 (54.5) 80.1 (19.3) 44-132 18 (14.6) 69 (56.1) 36 (29.3) 33 67 22 1
(26.8) (54.5) (17.9) (0.8)
92 (74.8) 31 (25.2)
Patients ≥ 65 years of age or ASA physical status IV received initial and supplemental doses of study medication reduced by 25% from the standard dose. ASA physical status III patients received reduced initial and supplemental doses at the investigator's discretion. a Standard dose was 6.5 mg/kg.
263 The median procedure duration was 17.0 minutes (range: two to 110 min). The majority (n = 92; 75%) of procedures were completed in 26.0 minutes or less. The duration and types of surgical procedures performed are shown in Table 2.
3.2. Dose The mean total amount of fentanyl administered per patient was 58.5 μg (range: 25 to 100 μg). A majority of patients (n = 83, 67.5%) required only the initial 50 μg of fentanyl to manage procedural pain. The mean total dose of fospropofol administered during the procedure was 742.0 mg (range: 280.0 to 1,592.5 mg), equivalent to a mean of 9.3 mg/kg. Thirty-one (25.2%) patients received a dose of fospropofol reduced by 25% according to protocol. The number of supplemental doses of the study drug administered is shown in Fig. 1. A mean of 2.4 supplemental doses of fospropofol was administered, and in 60.2% (n = 74) of patients, two or fewer supplemental doses of fospropofol were sufficient to initiate and complete the procedure. The dosage requirements for fospropofol or supplemental medications were not affected by patient body weight. Alternative sedative medication was administered to 6 (4.9%) patients (midazolam, n = 3; sevoflurane, n = 2; and nalbuphine, n = 1) due to inadequate sedation. All were in the 18 to 64-year age group, and all received between 4 and 6 supplemental doses of fospropofol (total dose between 420 mg and 630 mg) before receiving alternative sedative medication. Although propofol was not recommended for use as an alternative sedative medication because of its interference with pharmacokinetic analyses, it was administered in two of the 6 (1.6%) patients. Both patients underwent lithotripsy and had received a total of 612.5 mg and 420 mg of fospropofol, respectively, before propofol was administered for inadequate sedation. No association was detected between the type of surgical procedure and the alternative sedative medication administered.
Table 2 Type and duration of surgical procedure in patients receiving fospropofol Type of procedure
Number (%) Median procedure of patients duration (min)
Esophagogastroduodenoscopy Arthroscopy Hysteroscopy Bunionectomy Transesophageal echocardiogram Ureteroscopy Lithotripsy Dilation and curettage Arteriovenous shunt placement
27 22 21 18 13
(22.0) (17.9) (17.1) (14.6) (10.6)
4.0 17.5 12.0 43.5 14.0
10 8 3 1
(8.1) (6.5) (2.4) (0.8)
12.0 29.5 8.0 45.0
264
T.J. Gan et al. Table 3
Treatment-related adverse events (TRAEs)
TRAEs in N 2% of patients
Fospropofol (n = 123)
Patients with ≥ one TRAE paresthesia a pruritus b nausea hypotension vomiting headache
101 (82.1) 77 (62.6) 34 (27.6) 5 (4.1) 4 (3.3) 4 (3.3) 3 (2.4)
Number (%) of patients
Fig. 1
Number of supplemental doses of fospropofol administered.
3.3. Depth of sedation Seven (5.7%) patients had a MOAA/S score of 0 or 1 at any time from the first dose of the study medication until Fully Alert. Median time spent at a MOAA/S score of 0 or 1 was 4 minutes (range: 2 to 14 min). One of the 7 patients received an alternative sedative for 12 minutes prior to reaching a MOAA/S score of 1. This ASA physical status II patient was a 41-year-old woman who weighed 95 kg. She received 2.0 mg of midazolam plus sevoflurane in addition to 1,137.5 mg of fospropofol and 75 μg of fentanyl. She did not experience any SRAEs; however, a chin lift and placement of an oral airway were required. One patient who spent 14 minutes at a MOAA/S score of 0 received 30 mL of mepivacaine hydrochloride to achieve a pain block for her hysteroscopy, followed by 50 μg fentanyl and the initial dose of 6.5 mg/kg fospropofol. Her MOAA/S score decreased 4 minutes later to 0, where it remained for 10 minutes before her hysteroscopy started, then increased from 0 to 3 within 4 minutes of the start of her procedure. Her MOAA/S score remained at 3 until her hysteroscopy was completed in 9 minutes. The patient received no supplemental fentanyl, study sedative, or airway assistance, and she experienced one AE of mild pruritis. Only one of the 7 patients whose MOAA/S score decreased to 0 to 1 experienced a SRAE. This patient was a 51-year-old, ASA physical status II woman who weighed 83 kg. During her hysteroscopy, she experienced mild hypoxemia, which required a chin lift and verbal stimulation. Her MOAA/S score remained at 1 for two minutes, and the hypoxemia resolved within one minute.
3.4. Safety
a Paresthesia included the following preferred terms: anal discomfort (reported as anal burning), burning sensation, genital burning sensation, nasal discomfort (reported as burning), pain (reported as stinging), paresthesia of genital male, perineal pain (reported as burning), skin burning sensation, and vaginal burning sensation. b Pruritus included the following preferred terms: genital pruritus female, nasal discomfort (reported as itching), anal pruritus, pruritus generalized, and pruritus genital.
septal defect (n = 2), apnea, and cardiac arrest (n = 1), and increased ammonia and hepatic encephalopathy (n = 1). None of these AEs was considered to be related to fospropofol. No patient was discontinued from the study due to an AE, and no deaths were reported. Five (4.1%) patients treated with fospropofol experienced at least one pre-defined SRAE [hypotension (n = 4), bradycardia (n = 1), or hypoxemia (n = 1)] on the day of the procedure (Table 4). 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
Table 4
Sedation-related adverse event
Fospropofol (n = 123) Number (%) of patients
a
Apnea Hypoxemia b Hypotension c Bradycardia d
0 1 (0.8) 4 (3.3) 1 (0.8)
Apnea was defined as a lack of spontaneous breathing N30 seconds. Hypoxemia was defined as oxygen saturation b 90% for N 30 seconds. c Hypotension was defined as systolic blood pressure b 90 mmHg and required medical intervention (such as intravenous fluids or concomitant medication). d Bradycardia was defined as heart rate b 50 beats per minute and required medical intervention (such as concomitant medication). a
b
Treatment-related AEs were experienced in 101 (82.1%) patients. The three most common TRAEs reported in patients were paresthesia (n = 77, 62.6%) and pruritus (n = 34, 27.6%), and the majority of TRAEs were mild to moderate (Table 3). Four patients experienced serious AEs: atrial
Sedation-related adverse events (SRAEs)
Fospropofol for minor surgical procedures
265
Table 5 Patients requiring airway assistance after fospropofol (n = 123)
3.5. Airway assistance
Airway assistance
Crying, dystonia, and urticaria (n = 1)
Seven of 123 patients (5.7%) required at least one type of airway assistance (Table 5). One of these patients (discussed above) who underwent a hysteroscopy required airway assistance (consisting of verbal stimulation and a chin lift) attributed to hypoxemia. No other patient required airway assistance that was associated with an SRAE, and no patient required manual or mechanical ventilation.
Hypoxemia (n = 1)
3.6. Hepatic or renal impairment
Crying, dystonia, and urticaria (n = 1)
Twenty of the 123 patients (16.3%) had previous or existing hepatic disease (ranging from minimal to severe). Five of the 123 patients (4.1%) had severe renal impairment (creatinine clearance ≤ 30 mL/min). Demographic characteristics for this subset of patients were similar to the overall patient population (Table 6). Adverse events were also similar to the overall patient population. Treatment-related AEs were similar to those observed in other patients in the study, with paresthesia (50%) and pruritus (30%) being the most common. No SRAEs were observed in this subset of patients.
Number Indication for (%) of airway assistance patients
Patients with ≥ one type 7 (5.7) of airway assistance Increased oxygen flow 2 (1.6) Patient repositioning Verbal stimulation Tactile stimulation Face mask (100% oxygen) Jaw thrust Chin lift
0 1 (0.8) 0 1 (0.8)
Nasal trumpet Oral airway Suction a
0 1 (0.8) 3 (2.4)
0 2 (1.6)
Hypoxemia (n = 1) and inadequate sedation (n = 1) Inadequate sedation (n = 1) Investigator discretion during EGD (n = 3)
EGD = esophagogastroduodenoscopy. a Same center; no patients experienced airway complications requiring manual ventilation (bag-valve-mask) or mechanical ventilation (intubation).
4. Discussion managed with airway assistance (chin lift and verbal stimulation). No patient experienced apnea on the day of the procedure. Table 6
Demographics and safety in patients with hepatic and renal impairment
Median age, yrs (range) Creatinine clearance (mL/min) median (range) ASA physical status I/II III Treatment-related adverse events paresthesia pruritus nausea vomiting restless legs syndrome Sedation-related adverse events airway assistance increased oxygen flow suction Serious adverse events ammonia increased a apnea b cardiac arrest b hepatic encephalopathy a a b
The findings of this study show the safety of the 6.5 mg/kg dosing regimen of fospropofol injection in
Patients with hepatic impairment (n = 20)
Patients with renal impairment (n = 5)
57 (39-73)
64 (57-82)
— Number (%) of patients
21 (11-30)
12 (60.0) 8 (40.0) 14 (70.0) 10 (50.0) 6 (30.0) 2 (10.0) 1 (5.0) 0 0 4 (20.0) 1 (5.0) 3 (15.0) 1 (5.0) 1 (5.0) 0 0 1 (5.0)
Events were in the same patient and were deemed secondary to cirrhosis. Events were in the same patient and were attributed to underlying disease and concomitant medication.
0 5 (100.0) 2 (40.0) 1 (20.0) 0 0 0 1 (20.0) 0 0 0 0 1 (20.0) 0 1 (20.0) 1 (20.0) 0
266 patients undergoing minor surgical procedures. The majority of patients were moderately sedated with fospropofol, as shown by the low frequency of deep sedation observed in this study (5.7% of pts reached MOAAS scores of 0 or 1). The need for alternative sedative medications during the procedure was also low (4.9% of pts). The majority of TRAEs were categorized as either mild or moderate. Paresthesia and pruritus were the most common AEs observed and were transient and self-limited, requiring no treatment in this study. Paresthesia and pruritus usually occurred within 5 minutes of the initial administration of fospropofol. Five (4.1%) patients experienced SRAEs with fospropofol, although all resolved with minimal intervention. Of the patients who experienced SRAEs, one patient had received supplemental propofol before the onset of the SRAE (hypotension). The results of this study confirm the tolerability profile observed in phase 3 studies [13,14] and support the use of fospropofol as an alternative to the agents currently in use for procedural sedation. Compared with propofol, fospropofol disodium has a different pharmacokinetic and pharmacodynamic profile that is characterized by an extended elimination half-life, a longer residence time, and a delayed onset of action, which may provide an improved safety and efficacy profile [15]. Furthermore, administration of fospropofol in an aqueous solution rather than the lipid emulsion required for propofol may reduce the risks associated with bacterial contamination and lipid-related side effects [15]. Fospropofol is metabolized by alkaline phosphatase into propofol, formaldehyde, and phosphate following IV administration [12]. Following fospropofol administration, plasma concentrations of propofol peak at approximately 8 minutes, followed by an elimination half-life of about two hours [12]. Analysis of fospropofol and propofol pharmacokinetics indicates that clearance of fospropofol is dependent on total body weight, which supports bodyweight-based dosing [12]. Compared with propfol, fospropofol's slower onset should impact patient hemodynamics less, though potentially slowing patient recovery. In clinical conditions where a more prolonged effect is desired and immediate onset of action is less important, fospropofol may have advantages over propofol. Fospropofol has demonstrated efficacy in patients undergoing bronchoscopy and colonoscopy, in addition to the minor procedures described here [13,14]. Results of a phase 2 study evaluating fospropofol in 127 patients undergoing colonoscopy showed that an initial dose of 6.5 mg/kg was optimal to achieve efficacy and tolerability in a majority of patients [13]. A phase 3 study of 252 patients undergoing flexible bronchoscopy, found that fospropofol provided safe and effective sedation [14]. Results from a phase 3 trial of fospropofol in patients undergoing colonoscopy showed that optimal sedation success was achieved in most patients at a dose of 6.5 mg/ kg [16,17]. While the most common AEs with fospropofol are paresthesias and pruritus, the most common AE with propofol is pain on injection.
T.J. Gan et al. Interpretation of these study results is limited by the study design. Because this was an open-label study of safety, no control group was available for comparison, and data collection was not blinded. The most common AEs with fospropofol 6.5 mg/kg in this study were consistent with the AEs reported in controlled trials and included mild, selflimited paresthesias and pruritus [13], although SRAEs occurred in 20% of patients with fospropofol in the bronchoscopy study [14]. However, consistent with the results reported here, no SAEs or deaths were reported, and no patient required either manual or mechanical ventilation in phase 3 trials [13,14]. This study also includes the first report of safety among patients with underlying renal or hepatic disease, which was not different from the overall study population. In summary, the results of this trial show that 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. Fospropofol produces a predictable pharmacokinetic and pharmacodynamic profile, delivering controlled sedation in an outpatient setting. Fospropofol is pending approval as an IV sedativehypnotic agent indicated for monitored anesthesia care sedation in adult patients undergoing diagnostic or therapeutic procedures. The standard dosing regimen should be an initial dose of 6.5 mg/kg followed by supplemental doses of 1.6 mg/kg, with a dosage reduction by 25% in those who are ASA physical status III or IV or at least 65 years of age.
Acknowledgments The authors would like to acknowledge the contributions of the prinicipal investigators at each study site: Vasanth K. Bethala, MD, Slidell, LA; Paul Diehl, MD, Sandy, UT; Maciej L. Dryjski, MD, Buffalo, NY; Kyle Etzkom, MD, Jacksonville, FL; Evan R. Goldfischer, MD, Poughkeepsie, NY; Ira J. Gottlieb, DPM, Pasadena, MD; Anthony E. Martin, MD, Louisville, KY; Dasarathy Srinivas, MD, Slidell, LA; Vadim David Vornik, MD, Dallas, TX; and Steven Wininger, MD, Phoenix, AZ. The authors also would like to acknowledge the editorial assistance of Richard S. Perry, PharmD, in the preparation of this manuscript.
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