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Fospropofol, A New , and Its Utility in the Perioperative Period

Basem Abdelmalak1,*, Ashish Khanna2 and John Tetzlaff3

1Associate Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Staff, De- partments of General Anesthesiology and Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH; 2Resident Anesthesiologist, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH; 3Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Staff, Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH, USA

Abstract: Fospropofol is an intravenous sedative-anesthetic agent that is FDA-approved for monitored anesthesia care (MAC) sedation in adult patients undergoing diagnostic or therapeutic procedures. As a of , fospropofol’s pharmacologic activity results from its breakdown by and release of propofol, which is the active molecule. It exhibits a longer time to peak clini- cal effect and a more prolonged action compared to propofol. Thus patients may exhibit smoother hemodynamic and respiratory depres- sion compared to propofol lipid emulsion bolus. Another advantage over propofol is that it does not induce a burning sensation on IV administration. Side effects include perineal paresthesia and itching, respiratory depression, hypoxemia, hypotension, loss of conscious- ness, and apnea with higher IV boluses. Therefore, current recommendations call for it to be administered only by clinicians trained in general anesthesia, who are thus skilled in advanced airway management. Fospropofol has a unique dosing regimen, with a standard dose for adults 18-65 years of age, and a modified dose (75% of the standard dose) for patients > 65 years of age and for sicker adult patients whose American Society of Anesthesiologists physical status score is  3. Also, the minimum and maximun IV bolus doses are body-weight adjusted to 60 and 90 kg respectively. Available evidence demonstrates that fospropofol in MAC sedation is successful in patients undergoing esophagogastroscopy, colono- scopy and flexible bronchoscopy. The use of fospropofol is also now being explored in many other perioperative settings. In light of cur- rent shortages of many anesthetic drugs, whether forspropofol can take the place of propofol in ICUs and operating rooms remains to be determined. Keywords: Fospropofol, anesthetic management, perioperative care, side effects, anesthesia, conscious sedation, MAC anesthesia.

INTRODUCTION Introduction of propofol in the market was welcomed by the Fospropofol is a new IV sedative/anesthetic drug. It is a water- medical community. It shortened recovery time as well as time to soluble prodrug of propofol with pharmacokinetic attributes differ- discharge from the PACU, and it increased the satisfaction of pa- ent from those of propofol. We discuss its unique structural and tients and physicians alike [3]. pharmacologic properties and dosing schedule. We also discuss the Close to 30% of patients experience some pain on intravenous differences between propofol and fospropofol in chemical structure, injection of propofol [2,4,5,6]. Recently, the transient receptor po- pharmacodynamic and pharmacokinetic properties, clinical tential (TRP) receptors, TRPA1 and TRPV1 have been found to properties, and side effects. Moreover, we present an overview of play a role in this pain pathway via excitation of nociceptive neu- the available clinical trials data on the clinical utility of fospropofol rons during propofol injection [6]. In addition, with propofol the in sedation and anesthesia of adults undergoing diagnostic and/or transition from moderate sedation to general anesthesia may be therapeutic procedures. Finally, we provide an overview of future sudden owing to the steep dose response curve, more so in volume- directions for investigators interested in further exploring the depleted or cardiovascularly compromised patients; and it has a clinical utility of this unique sedative/anesthetic agent. “narrow therapeutic window” when used for sedation. Propofol also lacks a specific pharmacologic antagonist [6]. In addition, the FOSPROPOFOL VS PROPOFOL propofol lipid emulsion formula introduces another set ofconcerns, The decade 1996-2006 saw a substantial (~ 300%) increase in including the need for absolute sterility when handling the drug ,the ambulatory anesthesia services in freestanding ambulatory centers relatively short window of usage (6 h) when the vial is opened and [1]. This increase led to a greater need for varying degrees of the hypertriglyceridemia seen in patients receiving prolonged sedation (MAC ) as well as general anesthetics in such duration propofol infusion in the ICU setting [8-11] outpatient settings. The ideal pharmacologic agent for ambulatory Propofol injectable emulsion is available in a single-use vial surgery would have a quick onset and offset, the ability to maintain parenteral product which contains 0.005% disodium edetate to re- a steady state of anesthesia intraoperatively without adverse side tard the rate of growth of microorganisms in the event of accidental effects, stable hemodynamics, and preferably anti-emetic pro- extrinsic contamination. However, the lipid emulsion can still sup- perties. In 1977 Kay and Rolly introduced propofol or 2,6- port the growth of microorganisms such as Escherichia coli or diisopropylphenol [2]. Since its introduction into clinical practice in Candida albicans and is not an antimicrobially preserved product 1986 by AstraZeneca under the trade name Diprivan®, it gradually under USP standards. Propofol has been implicated in many infec- became the so-called “wonder drug” with many characteristics of tious processes in the clinical setting including sepsis and other life- the conceptually ideal drug for ambulatory anesthesia. threatening illnesses [12-18]. Another concern involves propofol infusion syndrome, a rare *Address correspondence to this author at the General Anesthesiology/ E31, condition that includes severe metabolic acidosis, rhabdomyolysis, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; renal failure, and hemodynamic instability. Impairment of the mito- Tel: 216/444-3746; Fax: 216/444-2294; E-mail: [email protected] chondrial enzyme carnitine palmi- toyl transferase I (CPT I) and

1873-4286/12 $58.00+.00 © 2012 Bentham Science Publishers 6242 Current Pharmaceutical Design, 2012, Vol. 18, No. 38 Abdelmalak et al. uncoupling of oxidation and respiratory chain is the putative Aquavan® (Guilford Pharmaceuticals, Baltimore, MD), initially mechanism of this injury at the cellular and subcellular level. Fatty referred to as GPI 15715 and now as fospropofol. acid transport across the mitochondrial membrane is dependent on GPI 15715, or fospropofol, is a N-phosphono-O-methyl prodrug these enzymes and their underutilization leads to cell death and of propofol. Chemically it is described as C13H19O5PNa2 and 2,6- resultant myonecrosis [8]. This condition is more commonly seen diisopropylphenol methoxyphosphonic acid (or 2,6-diisopropyl- with prolonged propofol infusion in critically ill patients, and the phenoxymethyl phosphate disodium salt). The comparative struc- concurrent administration of catecholamines andsteroids [8]. ture of propofol and fospropofol is illustrated in Fig. (1). Fospropo- The search for alternatives to serve as carriers for propofol was fol has a higher molecular weight (332.24 gram/mole) than propo- initiated through the use of solvents such as -cyclodextrins or mi- fol (178.27 gram/mole). croemulsion formulations [19-22]. Though investigators had dem- Fospropofol is metabolized in vivo and releases propofol, onstrated that addition of a large hydrophilic group, typically a phosphate, and formaldehyde by action of the enzyme alkaline phosphate monoester or a hemisuccinate, to a hydrophobic drug phosphatase [23,24]. In vivo, 1 mg of fospropofol releases 0.54 mg could convert it into a hydrophilic prodrug, such attempts at creat- of propofol. (See section under accumulation of metabolites.) Be- ing phosphoester from propofol were unsuccessful. cause the prodrug is converted to propofol, the time to peak of pro- It was determined that linking propofol with a methylphosphate pofol concentration after a bolus of fospropofol and the elimination group at C-1 (replacing a noncharged hydroxyl group with a of propofol after infusion are longer than for propofol lipid emul- charged phosphate group) increases electronegativity and lends sion. The released propofol increases activity of gamma- polarity to the molecule, which leads to water of this aminobutyric acid (GABA), the chief inhibitory neurotransmitter of propofol prodrug. This finding led to the development of the central nervous system (CNS), potentiating GABA-inhibitory

Fig. (1). Metabolism of fospropofol and accumulation of end-products. Reprinted with permission from Cleveland Clinic Center for Medical Art and Photog- raphy © 2011 all rights reserved. Fospropofol in the Perioperative Period Current Pharmaceutical Design, 2012, Vol. 18, No. 38 6243 synaptic currents and forming the basis for its sedative- intended, which in turn could result in cardiorespiratory com- action observed in vivo. promise. Fospropofol also has a distinct advantage over the traditional CONTRAINDICATIONS propofol preparation because it is less painful under IV injection, and lacks the lipid load when prolonged infusion is required. Allergy to the drug is the only absolute condraindication for fospropofol [24]. However, as we mention elsewhere in this review, INDICATIONS several clinical situations call for cautious use of the drug. As of the time of writing, the only FDA-approved indication for PREPARATION fospropofol injection is as an intravenous sedative-hypnotic agent for monitored anesthesia care (MAC) sedation in adult patients Fospropofol is formulated as a clear to slightly yellow aqueous undergoing diagnostic or therapeutic procedures [24]. solution. The commercially available formulation contains 3.5% of fospropofol per milliliter in water. Each 30 ml single use vial of DOSAGE AND ADMINISTRATION Lusedra contains 35 mg of fospropofol disodium per ml (a total Current usage guidelines for fospropofol recommend admini- of 1,050 mg of fospropofol disodium in a 30 ml vial), monothio- stration as a bolus injection [24]. Two dosing regimens are at glycerol (0.25% w/v), and tromethamine (0.12% w/v); and it has a present used for fospropofol, specifically the Standard Dosing pH of 8.2 – 9.0 [23]. Regimen and the Modified Dosing Regimen. As with all intravenous medications, sterile syringes should be used and strict aseptic techniques should be followed. Fospropofol A. STANDARD DOSING REGIMEN FOR SEDATION syringes should be prepared immediately after vials are opened. It is For adults aged 18 to 65 years who are healthy or who have also prudent to look for evidence of particulate matter or only mild systemic disease (American Society of Anesthesiologists discoloration immediately prior to use. physical status [ASA PS] 1 or 2), the standard dosing regimen of Fospropofol has been shown to be compatible with most of the fospropofol is an initial intravenous bolus of 6.5 mg/kg followed by commonly used perioperative intravenous (IV) fluids including supplemental doses of 1.6 mg/kg intravenously (25% of initial normal saline (NS), and lactated ringer’s solution. It is physically dosage), no more than every 4 min as needed to achieve the desired incompatible with or meperidine; there is insufficient level of sedation. data on its compatibility with other agents. It is therefore recommended that the IV line be flushed with saline before and B. MODIFIED DOSING REGIMEN after administration. The drug does not appear to be photosensitive Adults 65 years of age or those with severe systemic disease and does not require a filter for administration [24]. (ASA PS 3 ) should receive initial and supplemental intravenous dosages of 75% of the standard dosing regimen [24]. Supplemental CLINICAL PHARMACOLOGY doses and individualization of dosing regimens to the patient’s level The reader is to be reminded that as the topic of the pharma- of sedation may be needed depending on the type of procedure the cokinetics and pharmacodynamics of fospropofol is explored here, patient is undergoing. Assessment of the level of sedation will be we have addressed the issue of the retracted studies on the topic as contingent on the patient’s response to verbal or light tactile explained below. However in this section we relied on data from stimulation. In any event the recommendations for additional IV the US prescribing information, which was based on a crossover boluses (25% of the initial bolus) are that they should not be given study in healthy volunteers (n = 68) receiving a single intravenous more frequently than every 4 minutes. bolus dose of fospropofol 6 and 18 mg/kg (unpublished data)[24]. Dosing of fospropofol is limited by lower and upper weight This study used a newer assay method for the amount of propofol bounds of 60 kg and 90 kg. Adults who weigh >90 kg should be derived from fospropofol. Additional data are drawn from clinical dosed as if they weighed 90 kg. No initial dose should exceed 16.5 trials in patients undergoing therapeutic and diagnostic procedures ml (Lusedra is 35 mg/ml); no supplemental dose should exceed 4 and receiving fospropofol 6.5mg/kg (n=667 [fospropofol data] and ml. Adults who weigh <60 kg should be dosed as if they weighed N=400 [released propofol data]). These data have been supple- 60 kg. Dosages lower than those specified for the lower weight mented by an extensive review of published literature and abstracts limit may be used to achieve lighter levels of sedation [24]. from recent national meetings [24-29].

ONSET OF ACTION—CLINICAL CORRELATIONS MECHANISM OF ACTION Propofol is the “gold standard” for brief sedation because of Following intravenous injection, fospropofol is metabolized by rapid onset and rapid resolution. These features have made it a alkaline phosphatase to release propofol (the active molecule), suitable agent in outpatient procedural sedation/anesthesia. The phosphate, and formaldehyde. Since for every molecule of fospro- fast-on, fast-off action leads to rapid emergence and patient pofol administered one molecule of propofol is produced this means satisfaction because of a clearheaded awakening. that (based on their respective molecular weights) 1.86 mg of fos- Fospropofol has a slower onset of action than propofol because propofol will produce 1mg of propofol . It is important to remem- it is a prodrug which undergoes metabolism to break down into its ber in this regard that 1.86 mg of fospropofol is the molar equiva- active molecule. The onset of action is typically 4 to 13 min. lent of 1 mg propofol and thus for every millimole of fospropofol Aditionally the relatively slow breakdown process results in more administered, one millimole of propofol is produced [24]. or less sustained levels of propofol and hence the longer duration of AND PHARMACODYNAMICS action compared to propofol. Thus the use of fospropofol is characterized by fewer peaks and troughs in the released propofol Early studies of the pharmacokinetic and pharmacodynamic bloodstream levels and requires fewer frequent boluses compared to properties of fospropofol have now been retracted [30] in a series of propofol lipid emulsion [24]. These qualities make it an attractive six studies which were all either phase I or phase II FDA trials and option for very brief outpatient procedures where a single loading all of which were inaccurate in the analytical assay for the released dose may be enough for an entire procedure. It is important for the propofol [31-36]. This analytical assay error rendered the results of clinician who administers the drug to recognize that a time lag will these studies unreliable. The studies were sponsored by Guilford occur between drug injection and the onset of clinical effects; Pharma (Baltimore, MD), which was later acquired by MGI Pharma during this time, the clinician should therefore not give additional (Baltimore, MD). These were conducted by academic and industry boluses, because these could lead to a deeper level of sedation than 6244 Current Pharmaceutical Design, 2012, Vol. 18, No. 38 Abdelmalak et al. experts in two independent academic facilities in Europe (Ghent, Belgium and Erlangen, Germany) [30,37,38] Ownership of the drug was transferred in the middle of 2009 from MGI Pharma to Eisai Co. Ltd. (Woodcliff Lake, NJ). MGI Pharma promised that the fospropofol/propofol conversion analytical assays would be re-evaluated, and that the new results would be published within a 12- month period with a validation of the degree of error from the original erroneous study. However, after transfer of ownership to Eisai, the new team was unable to conduct new studies within the 12-month deadline and thus the studies were retracted because of the error and because of the pos- sibility that the conclusions reached in these studies were flawed [30,38,39]. The need for the breakdown of fospropofol to release the active ingredient propofol results in differences in the peak plasma levels and in the duration of the sustained therapeutic plasma levels, hence the different pharmacodynamic effects between the two forms of propofol (watersoluble prodrug, and lipid emulsion). In an attempt to correctly characterize the pharmacokinetic/pharmacodynamic profile of propofol derived from fospropofol a recent study (unpub- lished data from the fospropofol package insert) used a newer assay for propofol. This study involved 12 healthy subjects, each receiv- ing 10-mg/kg intravenous bolus dose of fospropofol, and the seda- tive effect was measured as a decrease in Modified Observer’s As- sessment of Alertness/Sedation (MOAA/S) score [24]. The MOAA/S scale ranges from a heavily sedated score of 0 (does not respond to painful trapezius squeeze) to an alert score of 5 (re- sponds readily to name spoken in normal voice) [40].

Propofol released from fospropofol reached peak plasma levels (2.2 ± 0.4 μg/ml) at 8 min (range 4-13 min) and minimum mean MOAA/S score of 1.2 (range 0-3) at 7 min (range 1-15 min). Com- plete recovery from sedative effects was seen between 21 and 45 min after fospropofol administration [24]. The pharmacokinetic and pharmacodynamic results are shown in Fig. (2). The metabolism of fospropofol to propofol has been typically described as a multi-compartmental model [41]. The pharmaco- kinetic and pharmacodynamic characteristics of propofol released from fospropofol differ from those of propofol emulsion MOAA/S =Modified Observer’s Assessment of Aware- administered intravenously; the former’s characteristics entail lower ness/Sedation Scale peak concentrations and more prolonged plasma concentrations [40,42]. Instrumental in the development of the five-compartment Fig. (2). Pharmacokinetic and pharmacodynamic profiles after a 10 pharmacokinetic model of fospropofol was a randomized double- mg/kg bolus dose of Lusedra™. Adopted with permission from blind phase III study of 18 colonoscopy patients pretreated with Lusedra ™ package insert, US prescribing information from Eisai randomized to 6.5 mg/kg or 2 mg/kg fospropofol with Co. Ltd. midazolam as a control [27]. The results of this study showed that maximum released propofol concentration (Cmax) was achieved at 8 the start of an injection (the time for one arm-brain circulation). As min; and about 85% of Cmax was achieved by 4 min. If a supple- with other rapidly acting intravenous anesthetic agents, propofol mental dose was administered at 4 min, a 25% higher Cmax would has a half-time of the blood-brain equilibration of approximately 1 be achieved at 9 min. The second supplemental dose at 8 min would to 3 min, and this accounts for the rapid induction of anesthesia increase Cmax by another 25% at 12 min. The results confirmed that [16,43]. With fospropofol the recommended maximum dose is 12.5 a 6.5 mg/kg fospropofol dose (with 60-90 kg weight range) pro- mg/kg, which should lead to loss of consciousness (general anes- vides optimal propofol for sedation in the majority of patients. The thesia) in about 4 min (the recommended effective sedation dose is pharmacokinetic profile also justified the dose-to-effect titration 6.5 mg/kg) [44]. with 4 min intervals between the doses. The 5-compartment model (Fig. 3) for fospropofol metabolism can be conveniently subdivided The pharmacokinetic and pharmacodynamic profile of fospro- into a 3-compartment model. This model comprises fospropofol pofol has been evaluated in randomized, blinded, dose-controlled compartments 1 and 2, propofol compartments 4 and 5, and com- studies for sedation in patients undergoing colonoscopy and flexible partment 3 describing complete metabolism of fospropofol to pro- bronchoscopy. Using the standard and modified dosing regimens, pofol with a time delay. Other investigators had previously also Cohen et al. studied fospropofol-induced sedation in patients un- postulated a six-compartment model for fosprophol based on the dergoing colonoscopy. Their results showed that the median (range) assumption that fospropofol exists as a dual peripheral compart- time to sedation (time from first dose of sedative to the first of 2 ment. Fig. (4) shows the 6-compartment model for fospropofol consecutive MOAA/S scores of  4) was 8.0 (2-28) minutes and the metabolism [41]. median time to a fully alert state (3 consecutive responses to their name spoken in a normal tone, measured every 2 min beginning at When propofol lipid emulsion is used for the induction of gen- or after the end of the procedure) was 5.0 (0-47) minutes [24,45]. eral anesthesia, it has a peak onset of action of about 40 sec from

Fospropofol in the Perioperative Period Current Pharmaceutical Design, 2012, Vol. 18, No. 38 6245

Fig. (3). The five-compartment model for fospropofol metabolism Adopted with permission from Pergolizzi JV Jr, Gan TJ. Plavin S, Labhsetwar S, Taylor R. Perspectives on the role of fospropofol in the monitored anesthesia care setting. Anesthesiol Res Pract 2011; 2011; 458920. Epub 2011, Apr 14. Copyright 2011 Joseph V.Pergolizzi Jr et al.; publisher and licensee Hindawi Publishing Corporation.

K= Time constant Keli =Elimination rate constant Kmet=Metabolism rate constant Fig. (4). The six-compartment model for Fospropofol metabolism Adopted with permission from Harris EA, Lubarsky DA, Candiotti KA. Monitored anesthesia care (MAC) sedation: clinical utility of fospropofol. Ther Clin Risk Manag 2009; 5: 949-59. Epub 2009, Dec 29. Copyright 2009 Harris et al.; publisher and licensee Dove Medical Press Ltd.

Silvestri et al. studied fospropofol-induced sedation in patients [24]. These results are similar to those reported by Shah et al. undergoing flexible bronchoscopy. They found that patients who which showed that maximum released propofol concentration received the standard and modified fospropofol dosing regimens, (Cmax) was achieved at 8 min with about 85% of Cmax being had a median time to sedation of 4 (2-22) min and a median time to achieved by 4 min [27]. Concentration-time profiles in all these a fully alert state of 5.5 (0- 61) min [24,47]. cases showed a bi-exponential decline. Pharmacokinetic parameters from a crossover study of 68 DISTRIBUTION healthy subjects, 18 to 45 years of age, who received 6- and 18- mg/kg intravenous bolus doses of fospropofol showed that the Fospropofol has a much smaller volume of distribution (5.8 maximum concentration (Cmax) and area under curve(AUC)0- L/kg) as compared to the propofol released by fospropofol break- values of fospropofol and the released propofol were dose- down (0.33±0.069 L/kg). An important clinical implication for the proportional, and inter-individual variability was low. Propofol was perioperative physician to keep in mind is that both fospropofol and rapidly released, reaching plasma Cmax at a median Tmax of 12 its active metabolite propofol are highly protein-bound (approxi- min for fospropofol 6 mg/kg and 8 min for fospropofol 18 mg/kg mately 98%), primarily to albumin [24]. Therefore, free drug levels could be altered in malnourished or hypoprotenemic patients. 6246 Current Pharmaceutical Design, 2012, Vol. 18, No. 38 Abdelmalak et al.

Table 1. Differences in the Chemical Structure and Clinical Pharmacology between Propofol and Fospropofol

Propofol Fospropofol

Chemical structure 2,6-diisopropylphenol 2,6-diisopropylphenoxymethyl phosphate, disodium salt

Molecular formula C12H18O C13H19O5PNa2

Molecular weight 178.27 gram/mole 332.24 gram/mole

Solubility Lipid soluble Water soluble

Solution color White Clear

FDA-approved indications MAC sedation, general anesthesia, ICU seda- MAC sedation

Dosing - For MAC and ICU sedation: 25- Standard dose: 100ug/kg/min - For induction of sedation 6.5 mg/kg bolus - For maintenance of TIVA: 100-300ug/kg/min - Minimal and maximal dose is body weight adjusted to - For induction of general anesthesia: 2.0-3.0 60 and 90 kg respectively mg/kg Modified Dose: 75% of the standard dose, for patients>65 years old and ASA PS >3

Sedation Therapeutic Window Very narrow Relatively wider

Following an IV bolus administration:

Time to onset clinical effect <40 sec 4-13 min

Peak effect 1-3 min 8 min

Duration of action 3-5 min Longer

Side Effects:

Pain on injection Yes No

Perineal itching and paraesthesia No Yes

Propofol infusion syndrome Yes No

Formate accumulation No Yes

MAC: Monitored anesthesia care TIVA: Total intravenous anesthesia ASA PS: American Society of Anesthesiologists Physical Status

0.280±0.053 L/h/kg. The terminal phase elimination half-life (t1/2) METABOLISM of fospropofol in healthy subjects was comparable to that in pa- Fospropofol is completely metabolized by the enzyme alkaline tients in whom it was used for MAC sedation and/or minor surgical phosphatase to propofol, formaldehyde, and phosphate. Formalde- procedures. After labeled drug administration, 70% of radioactivity hyde is further metabolized to formate by several enzyme systems, was recovered in the urine within 8 days and the total body clear- most importantly formaldehyde dehydrogenase, present in various ance had only a minor component of renal elimination (<0.02% of tissues, particularly the red blood cells. The formate produced is dose). An important clinical correlate that may be derived from rapidly eliminated by oxidation to carbon dioxide [24]. (See section these data is that fospropofol can be used in patients who have under accumulation of metabolites.) varying degrees of kidney failure since its clearance is not signifi- Propofol released from fospropofol is further metabolized (ap- cantly renal dependent [24]. proximately 60%) in the to major metabolites propofol glucu- ronide (34.8%), quinol-4-sulfate (4.6%), quinol-1- glucuronide SIDE EFFECTS’ PROFILE (11.1%), and quinol-4-glucuronide (5.1%). The rest of metabolism The side effect profile of fospropofol is very different from (approximately 40%) entails largely extra-hepatic clearance by the propofol. Table 2 shows pooled data of adverse reactions from kidney, intestine and lungs (minor role). Fospropofol is not a sub- various studies examining the use of fospropofol during colono- strate of CYP450 enzymes; therefore no interaction is expected scopy, bronchoscopy and minor surgical procedures. Although with drugs that are enzyme-inducers or enzyme-inhibitors [24, 48]. fospropofol does not cause pain on intravenous injection, clinicians should be aware of the following reported side effects: ELIMINATION Paresthesia (incidence 52–73%), including perineal discomfort After a single 400-mg IV dose of labeled fospropofol disodium or burning sensation [24]. in humans, total body clearance (CLp) was determined to be Fospropofol in the Perioperative Period Current Pharmaceutical Design, 2012, Vol. 18, No. 38 6247

Table 2. Pooled data of adverse reactions from a phase II dose response study and a phase III randomized control trial in pa- tients undergoing colonoscopy (n=183) compared with an open- label trial in patients undergoing minor procedures (n=123) and a randomized, double-blind, controlled phase III study in patients undergoing flexible bronchoscopy (n=149) [44,45,48,52]. (Adopted from Eisai Inc. Package Insert Lusedra™ US prescribing information).

Colonoscopy Minor Procedure Bronchoscopy Reaction Term (N=183) n (% ) (N=123) n (%) (N=149) n (%)

Gastrointestinal disorders Nausea Vomiting 0 5 (4) 2 (1)

Injury, poisoning, and procedural complications Procedural Pain 0 0 3 (2)

Nervous system disorders Paresthesiaa Headache 135 (74) 77 (63) 78 (52) 1 (1) 3 (2) 1 (1)

Respiratory, thoracic, and mediastinal disorders Hypoxemia 3 (2) 1 (1) 16 (11)

Skin and subcutaneous tissue disorders Pruritusb 30 (16) 34 (28) 24 (16)

Vascular disorders Hypotension 4 (2) 4 (3) 10 (7) aParesthesia includes the following terms: Paresthesia genital male; Burning sensation; Genital burning Jurning sensation; Vaginal burning sensation; Skin burning sensation; Geni- tal pain (reported as burning); Perineal pain (reported as burning); Anal discomfort (reported as burning); Chest pain (reported as burning); Ear discomfort (reported as burning); Nasal discomfort (reported as burning); Buttock pain (reported as stinging); Groin pain (reported as stinging); Pain (reported as stinging); Sensory disturbance (reported as non-specific sensation in pubic area). bPruritus includes the following terms: Genital pruritus female; Genital pruritus male; Pruritus genital; Pruritus ani; Pruritus generalized.

Pruritis (incidence 16-21%), including genital, perineal, and dose). This complication highlights the importance of continual generalized pruritis [24]. assessment of adequate ventilation during sedation [24]. Both pruritis and paresthesias are self-limiting, start within 5 Due consideration should also be given to co-administration of min after drug administration, last about 1-2 min and are of a mild narcotics and other sedative hyponotic drugs due to the potential for degree [46]. Premedication with other agents does not prevent them synergistic effects. and at present there is no treatment for them. They were reported most frequently in the perineal region, and are not dose-dependent ACCUMULATION OF METABOLITES side effects [45]. The reason for these neural phenomena remains Fospropofol’s metabolism creates propofol, phosphate and unknown [24]. formaldehyde. Alkaline dehydrogenase and formaldehyde dehydro- Hypoxemia (4% incidence with standard or modified dosing genase (glutathione-dependent reaction) break down the formalde- regimen; 27% with greater than recommended dose). It may be hyde to formate, which further liberates carbon dioxide and water . present also in patients who retain purposeful responsiveness, and This latter reaction is catalyzed by 10-formyltetrahydrofolate dehy- may go unrecognized. Hypoxia occurred more often during bron- drogenase with tetrahydrofolate as coenzyme. choscopy (10% of patients), whereas in minor surgery or colono- Formate is an end-metabolite of fospropofol and is also pro- scopy it was rare (0.8 – 1.6%) [24]. While such risk was dose- duced by endogenous metabolism of mammalian and human cells. dependent, it was not associated with preoperative variables such as However, in higher than normal concentrations (13 ± 7 μg/ml), as age, weight, and ASA status [47]. seen in cases of intoxication (7 – 11 mg/ml), formate can Unresponsiveness to vigorous tactile or painful stimulation have deleterious effects, including metabolic acidosis and retinal (a state of general anesthesia) following doses intended for induc- toxicity leading to blindness. These toxic concentrations are about tion of sedation (4% during colonoscopy; 16% during broncho- 350 times higher than those that are reached with usual metabolism scopy) [24]. during standard or modified fospropofol dosing regimens. As long as tetrahydrofolate (the co-enzyme, catalyzing the breakdown of Hypotension (4% incidence with standard or modified dosing formate to CO and H O) concentrations are normal and maximum regimen; 6% with greater than recommended dose) [24]. It is sug- 2 2 dosing rates are not exceeded, there is a negligible chance of toxic- gested that maintaining adequate intravascular volume, cautious use ity related to formaldehyde liberation via fospropofol [49-52]. Fig. in patients who are volume-depleted or who have a perioperative (1) shows the breakdown of fospropofol into its constituent com- myocardial dysfunction may ameliorate this complication. pounds after metabolism and the effect of the accumulation of Respiratory depression (<1% incidence with standard or breakdown products. modified dosing regimen; 3% with greater than recommended 6248 Current Pharmaceutical Design, 2012, Vol. 18, No. 38 Abdelmalak et al.

The most common reasons for discontinuation of fospropofol 186 ug/kg/min of fospropofol is equal to 100 ug/kg/min of propo- use were paresthesias and cough. The incidence of reported discon- fol. Based on the fact that fospropofol is formulated as 35mg/ml tinuation has been low (<1%) in various studies [45,46]. compared to 10mg/ml of propofol and the molar equivalents, a flow Although QT prolongation is a concern with many of the cur- rate of fospropofol can be derived. However, whether these cited rently used and anesthetics, fospropofol did not prolong advantages hold true remains to be seen when such a regimen is corrected QT intervals. The effect of fospropofol on the corrected tried in actual clinical scenarios. It is worth remembering that fos- QT interval was measured in a crossover study in healthy volun- propofol was never designed as an infusion drug. It was meant to be teers (n = 68). In this study the subjects received the following a single bolus dose that would serve as a possible “sustained release treatments: 6 mg/kg intravenous fospropofol; 18 mg/kg intravenous propofol” delivery agent and allow short procedures such as bron- fospropofol; moxifloxacin 400 mg orally (positive control); and choscopy, colonoscopy, and some other outpatient invasive proce- normal saline IV. When given in doses of 6 or 18mg/kg the re- dures. It is obvious that this is a mathematical derivation and more sponses of the corrected QT interval did not differ significantly research is required before the potential infusion of fospropofol, from those reported for placebo recipients [24,26]. targeting propofol dosage rates, could be confidently applied to clinical use. . FOSPROPOFOL INFUSION Side Effects' Profile During Prolonged Exposure in Adult Pa- Few studies have examined the efficacy and safety of a poten- tients tial fospropofol infusion regimen and its clinical applicability. A study to characterize pharmacokinetics and pharmacodynamics of Few reports have been published on the use of this agent for fospropofol administered as continuous infusion or bolus compared prolonged sedation, as in the intensive care unit in intubated and with continuous infusion of propofol injectable emulsion is pres- mechanically ventilated patients [54,57]. As of this writing, FDA ently recruiting (Clinicaltrials.gov identifier NCT01308541). approval has not been granted for the use of fospropofol to maintain Meanwhile, Candiotti et al. conducted a single-center, randomized, sedation during prolonged mechanical ventilation in the intensive open-label pilot study of the safety and tolerability of fopropofol for care unit. patients needing intubation and mechanical ventilation in the ICU Candiotti et al. in their study on intubated and mechanically [54]. In this study, 60 patients were randomized to receive 1 of 3 ventilated patients observed a single episode of nonsustained ven- regimens with the goal of maintaining a Ramsay Sedation Score of tricular tachycardia lasting 5-10 seconds. The patient in question 2 to 5: (1) fospropofol IV infusion at 25ug/kg/min with a 100mg had low-normal potassium and magnesium levels and the episode bolus and increased infusion rate (25ug/kg/min every 5 min) for did not recur after adequate replacement of the deficiencies. An- agitation events (infusion/bolus); (2) fospropofol IV infusion at 25 other patient in this study showed a significant increase in blood ug/kg/min with an increased infusion rate (25ug/kg/min every 5 formate level on fospropofol infusion. However, this was attribut- min) for agitation events (infusion only); or (3) propofol IV infu- able to co-existing renal and hepatic failure with ongoing acute sion at 25ug/kg/min with an increased infusion rate(5-10 ug/kg/min myeloid leukemia and lack of dialysis. Importantly, there were no every 5 min) for agitation events. Incidence rates for adverse events adverse effects seen in this case related to the elevated formate. were similar between fospropofol groups. In the fospropofol [24,54]. In an open-label, single-center, randomized study (unpub- groups, 28 of 38 patients (74%) experienced adverse events com- lished data- Clinicaltrials.gov identifier NCT00209521) investiga- pared to 14 of 22 patients (64%) in the propofol group. The fre- tors compared fospropofol to propofol infusion in patients undergo- quency of adverse events was similar between the two fospropofol ing coronary artery surgery This study examined the safety and dosing groups, with the exception of procedural pain (33.3% vs tolerability of fospropofol when used perioperatively to sedate, 5.0%; infusion/bolus and infusion only respectively). In the two induce, and maintain general anesthesia and to postoperatively se- fospropofol dosing groups, the most common adverse events with date in the intensive care unit. Propofol and fospropofol infusions fospropofol were procedural pain (21.1%) and nausea (13.2%). were run via a target-controlled infusion (TCI) system to target Two patients (1 each in the fospropofol infusion/bolus group and desired plasma concentrations. Infusions were started immediately the propofol group) experienced hypotension during the study as a preoperatively and continued into the post-operative period in the potential sedation-related adverse event. Mean plasma formate ICU. A given infusion was titrated to specific desired ranges of levels were not significantly different among groups. Patients in all bispectral index (BIS) (Covidien, Berlin, Ireland) scores during three treatment groups maintained Ramsay Sedation Scores of 2 to induction, maintenance and emergence from general anesthesia. In 5 for >90% of the time they were sedated. This pilot study suggests addition, an infusion was run with the TCI technique. that fospropofol, administered in either an infusion/bolus or infu- Patients studied were between the ages of 20 and 70, and were sion-only regimen, is well tolerated and effective for short-term scheduled for first-time elective coronary artery bypass graft induction and maintenance of sedation in mechanically ventilated (CABG) surgery, with 1 to 4 grafts. The patients had ASA PS 2 or intensive care unit patients [54]. Additional details are available at 3 and good left ventricular function (LVEF 50%); if females, they the US National Institutes of Health website clinicaltrials.gov under were either surgically sterile or post-menopausal. Efficacy end- the identifier NCT00125398. points included adequate sedation/hypnotic events (as measured by A recent editorial has proposed a mathematical model for a the BIS index), hemodynamic instability, anesthesiologist’s as- possible fospropofol infusion regimen [55]. The authors have high- sessment of overall quality of induction, maintenance and ease of lighted the possible advantages of such an infusion technique, in control of anesthesia, and sedation. The results showed no signifi- terms of more stable propofol levels that would result in a steady cant difference between fospropofol and propofol treatment groups plain of sedation, avoidance of the possibility of excessive fospro- in mean MAP, heart rate, and BIS index; and adequate sedation was pofol administration and the convenience of use with syringe maintained in all patients. pumps eliminating the inconvenience of repetitive boluses. They Adverse events related to the CABG (reactionary pleural effu- proposed the need for derivation of a “propofol equivalent” regimen sion and post-procedural pain) were similar (75% vs 50%) in type of fospropofol dosing [24,56]. To calculate the target fospropofol and frequency in both groups, with the exception of burning and infusion, the first step would be to determine the propofol infusion pruritis, experienced only by the fospropofol group. Serious adverse rate needed for a particular infusion dosage in ug/kg/min of propo- events were experienced by one patient in each group and were not fol. The second step would be to use that in the chemical equiva- considered a consequence of drug administration. There were no lence that states that 1.86 mg of fospropofol disodium is the molar visible patterns of increase in plasma formate concentrations above equivalent of 1 mg propofol. Mathematically this would mean that baseline levels and comparable formate levels; 52% vs 64% con- Fospropofol in the Perioperative Period Current Pharmaceutical Design, 2012, Vol. 18, No. 38 6249 centrations were below the limit of quantification after fospropofol FOSPROPOFOL USE IN PATIENTS WITH HEPATIC AND and propofol administration, respectively. There were no deaths or RENAL IMPAIRMENT treatment withdrawals during the study period. These results, yet There is also insufficient evidence to support its use in patients unpublished, suggest that fospropofol infusion used for induction with liver impairment. Similarly, in patients with renal disease, and maintenance of general anesthesia and postoperative sedation though safety has been demonstrated in patients with creatinine was well tolerated and was as effective as propofol infusion, both clearance of >30ml/min (mild to moderate renal impairment), there delivered via a TCI system. are few data on the behavior of this drug at a creatinine clearance of <30ml/min (severe renal impairment and end-stage renal disease) DRUG INTERACTIONS [24]. Co-administration of other and/or sedative hypnotic drugs may produce additive cardiovascular and respiratory depres- CLINICAL INDICATIONS IN THE PERIOPERATIVE PE- sion. However, the plasma pharmacokinetics of fospropofol are not RIOD affected by analgesic premedication such as fentanyl (1 mcg/kg); Fospropofol has great potentials as a useful agent for sedation. meperidine (0.75 mg/kg); midazolam (0.01 mg/kg) or Since it is a prodrug, the blood levels of propofol after a single IV (0.1 mg/kg) [24]. bolus of fospropofol reach lower peak levels and are more sustained Interestingly, an in-vitro protein-binding study has shown no than after administration of intravenous bolus of propofol as a sole significant interaction between fospropofol and propofol at concen- induction agent. Such unique properties would eliminate the need to trations up to 200 mcg/ml and 5 mcg/ml, respectively. Though both deliver the drug by infusion as well as the need for frequent bolus- fospropofol and its metabolite, propofol, are highly protein bound ing in short procedures. their interaction with other highly protein-bound drugs given con- comitantly has not been studied [24]. The potential of fospropofol A. Use in Colonoscopy or its major metabolite, propofol, to inhibit or induce major cyto- Use of fospropofol as a sedative for colonoscopy was one of the chrome P450 enzymes, are not known. earliest investigated uses of the drug [23]. In 2008 Cohen et al. published the results of their randomized, double-blinded, multi- DRUG ABUSE AND DEPENDENCE POTENTIAL center trial in 127 ASA 1 adults undergoing colonoscopy [46]. While fospropofol is labeled as a schedule IV controlled drug Patients in this trial were randomized to receive one of the substance, to date there is no adequate data on its abuse or potential following regimens: fospropofol 2, 5, 6.5, or 8 mg ⁄ kg or for dependence. midazolam 0.02 mg⁄ kg following pre-treatment with fentanyl 50 ug [46]. Fospropofol produced a significant dose-dependent increase in OVERDOSAGE AND TOXICITY sedation success from 24% (2 mg⁄ kg), 35% (5 mg⁄ kg), and 69% Fospropofol overdosage will usually manifest as hemodynamic (6.5 mg⁄ kg) to 96% (8 mg⁄ kg; P < 0.001). In the 6.5 mg/kg group, deterioration along with respiratory depression and apnea[24]. there were no recorded episodes of deep sedation, whereas 25% of Management would entail IV fluids and/or pharmacologic patients experienced deep sedation in the 8mg/kg group, which was vasopressor support. Depression of respiration may require elective not a statistically significant difference, however, one can make the intubation and mechanical ventilation until the drug is metabolized. case for its clinical significance. Time to sedation, requirements for Formate and phosphate are metabolites of fospropofol and may alternative sedative medication, supplemental doses of sedative and contribute to signs of toxicity following overdosage. This may be fentanyl, time to readiness for discharge and endoscopist-rated especially true in patients with altered metabolic pathways for satisfaction scores were shown to be dose-dependent as well. The 8 metabolizing formaldehyde and formate. As mentioned previously mg/kg fospropofol group had the highest physician satisfaction under side effects, formate toxicity is a possibility but has not been ratings. Though the 8mg/kg dose had the maximum sedation reported with usual clinical doses in patients with normal metabolic success rates of 96%, time to readiness for discharge was also the pathways. Signs of formate toxicity are similar to those of methanol longest with this dose. Overall, 6.5mg/kg was judged to be the best toxicity and are associated with anion-gap metabolic acidosis. tolerated dose . While few patients receiving fospropofol Intravenous exposure to a large amount of phosphate could experienced mild to moderate adverse events (including potentially cause hypocalcemia with paresthesia, muscle spasms, hypotension and paresthesia), there were no serious adverse events and seizures. or deaths. An important limitation of this study is that it was not designed to compare the efficacy of fospropofol to midazolam. FOSPROPOFOL USE IN EXTREMES OF AGE AND IN However, both the fospro-pofol (6.5 mg group) and midazolam PREGNANCY treatment arms achieved high sedation success rates and overall There are no studies on pregnant human females to describe the patient satisfaction. The investigators concluded that the 6.5 mg/kg safety and efficacy of fospropofol during labor, delivery, cesarean dose produced an optimal balance of safety and efficacy in this section, or its teratogenic effects on a human fetus in development patient population. Such dose was then selected to be used in the and its use in nursing mothers. Animal studies (in pregnant rats and subsequent phase III trial as described below. rabbits) have shown neither significant teratogenic nor non- The phase III trial by the same group of investigators was pub- teratogenic effects. Though propofol has been reported to be ex- lished in 2010. It was a multicenter, double-blind, randomized trial creted in breast milk and transported across the placenta, there is no aiming to evaluate the safety and efficacy of two intravenous fos- data on fopropofol in this regard. Hence, there are no recommenda- propofol bolus doses for moderate sedation in patients undergoing tions supporting use of fospropofol in pregnant females and nursing colonoscopy [45]. They compared fospropofol 6.5 mg/kg with a mothers [24]. subtherapeutic dose of fospropofol (2 mg/kg) for patients under- As for fospropofol use at both ends of the age spectrum, there is going colonoscopy. A third treatment group, serving as a control insufficient evidence to demonstrate its safe use in pediatric pa- group, received 0.02 mg/kg of midazolam.The drugs were given in tients. However, it has been used effectively in patients > 65 years a 2:3:1 ratio, respectively. Supplemental doses of study medication of age, although they received the modified dosing regimen as (maximum of 3 doses > 4 min apart, 25% of initial dose) or 1 mg detailed above. It should be noted, however, that there was an midazolam, were permitted to achieve a Modified Observer's As- increase in the incidence of hypoxemic events with increasing age sessment of Alertness/Sedation scale score 4 to enable the proce- comparing patients younger and older than 65 yrs of age [58]. duralist to begin the scheduled procedure. The investigators showed that sedation success was higher in the fospropofol group (6.5 6250 Current Pharmaceutical Design, 2012, Vol. 18, No. 38 Abdelmalak et al. mg/kg) than in the 2 mg/kg group (87% vs. 26%; P<0.001) and was not required. Airway assistance was required in 16 patients in each 69% in the midazolam group. Patients in the 6.5-mg/kg group were subgroup. In the elderly patients subgroup, airway assistance con- significantly less likely to remember being awake during the sisted of administering oxygen to all 16 patients; 4 of the 16 procedure (51% vs. 100% in the 2-mg/kg group, P<0.001; 60% for patients in the younger subgroup also required additional the midazolam group). Mean physician satisfac-tion scores were maneuvers including suction, chin lift, bag-mask ventiilation, or higher in the fospropofol group (6.5-mg/kg) (7.7) than the 2-mg/kg tactile and verbal stimulation. Considering comorbidities and a high group (4.5), P<0.001. Most adverse events were mild to moderate; incidence of underlying chronic lung disease in this subgroup of the most common treatment-related adverse events were paresthe- patients, these adverse events were expected. It is noteworthy that sias (68% vs. 60%) and pruritus (16% vs. 26%) in the fospropofol the impact of age on the outcomes of flexible bronchoscopy is con- 6.5 and 2 mg/kg groups, respectively. Sedation-related adverse troversial: While some claim that adverse events are increased in events were comparable in the three groups. The investigators elderly patients, others claim that outcomes after bronchoscopy are concluded that the fospropofol 6.5-mg/kg dosing regimen for seda- not attributable to age alone [60-65]. Thus, the reports of fospro- tion during colonscopy, was well tolerated, and associated with pofol being able to provide adequate sedation for bronchoscopy higher rates of sedation success and higher rates of physician satis- mixed with the reported adverse events that can be serious,sparked faction than with the fospropofol 2-mg/kg dose. The main limi- the debate regarding the FDA recommendation concerning the tations of this study included the lack of a formal comparison with training and skills of the clinicians adminstering fospropofol that the midazolam group (as in the previous study) and the confound- were obviously patients’ safety motivated [59] ing effect of premedication with an (in this case, fentanyl 50 mcg). Cumulatively, these results suggest that sedation success and MONITORED ANESTHESIA CARE (MAC) IN MINOR physician satisfaction were dose-dependent. SURGICAL PROCEDURES Gan et al. in an open label, multi-center, uncontrolled-single B. Use in Bronchoscopy arm trial looked at 123 patients undergoing minor surgical proce- Fospropofol was also investigated in several studies for seda- dures using fospropofol for MAC sedation. They included patients tion during flexible bronchoscopy [47,58]. Silversti et al., in a ran- of ASA physical status I-IV and  18 years of age scheduled to domized, double-blinded, multicenter study, evaluated the use of undergo various minor surgical procedures which included arthro- fospropofol in patients > 18 years of age and undergoing flexible scopy, arteriovenous shunt placement, bunionectomy, dilatation and bronchoscopy [47]. Patients were randomized to either fospropofol curettage (D & C), esophagogastroduodenoscopy (EGD), 6.5mg/kg ( N=150) or 2.0mg/kg ( N=102) [47]. lithotripsy and transesophageal echocardiography (TEE) [53].All Of the 150 patients who were randomized to fospropofol 6.5 patients received IV fospropofol 6.5 mg/kg followed by up to 5 mg/kg, 61 were at least 65 years of age and comprised the subgroup supplemental doses of 1.63 mg/kg if needed. The initial dose of of elderly patients, who were used for post-hoc subgroup analysis, fospropofol was preceeded by a prior dose of 50 mcg of fentanyl. as discussed below. Alternative sedative was administered to 4.9% of patients due to inadequate sedation; 5.7% of patients had a MOAA/S score of 0 or All patients were pretreated with fentanyl, 50 mcg. Supplemen- 1 and these patients required at least one type of airway assistance. tal doses of fospropofol were given per protocol. Sedation success Treatment-related adverse events were reported in 82.1% of pa- rates were significantly greater in the 6.5 vs. 2.5 mg/kg groups tients. As might be expected, paresthesia (62.6%) and pruritus (88.7% and 27.5%, respectively [p < 0.0001]).. In addition, treat- (27.6%) were the two most common adverse events and were mild ment success (91.3% vs 41.2%) respectively; ( p < 0.001), willing- to moderate. Other adverse events included hypoxemia (0.8%), ness to be treated again (94.6% vs 78.2%, respectively; p < 0.001), hypotension (3.3%), and bradycardia (0.8%). This study, however, and absence of procedural recall (83.3% vs 55.4%, respectively; p < included only the use of one dose of fospropofol . The investigators 0.001) were significantly better with the administration of 6.5 concluded that an initial dose of IV fospropofol 6.5 mg/kg with mg/kg fospropofol. The proportion of patients requiring supplemen- supplemental doses was safe and well tolerated for the purpose of tal therapy with analgesics (16.7% vs 37.3%, respectively) and the moderate sedation for use in minor surgical procedures [53]. use of alternative sedative medications (8.0% vs 58.8%, respec- tively) was lower for patients in the 6.5 mg/kg dose group (all com- FOSPROPOFOL: UNEXPLORED AVENUES AND AREAS parisons, p < 0.001). The most frequent adverse events were tran- OF INTEREST sient and self-limited paresthesias and pruritus of mild-to-moderate Future studies are needed in a larger number of patients to fur- severity. Hypoxemia (predominantly mild-to-moderate) was the ther quantify its safety and efficacy not only in the most commonly most common sedation-related adverse event, and was comparable studied applications like colonoscopy and bronchoscopy, but also in in both groups.The investigators therefore concluded that fospropo- procedures performed at electrophysiology laboratories, interven- fol at 6.5mg/kg provided safe and effective sedation for patients tional radiology, MRI, and awake intubation, to name a few. More undergoing flexible bronchoscopy. importantly it should be compared with other commonly used seda- In a recent subset analysis by Silvestri et al., elderly patients tion regimens (midazolam with or without narcotics) as well as aged > 65 years were compared with those <65 years enrolled in a other emerging sedatives like in a randomized phase III, randomized, double-blind, dose-controlled study, and controlled trial [66,67]. undergoing flexible bronchoscopy [58]. Patients >65 years of age As an agent for induction and maintenance of general anesthe- received the modified dosing regimen initially as well as the sia, fospropofol has yet to be explored. The impact of its pharma- supplemntal doses (reduced by 25%). Results of this analysis cokinetic profile on patient flow and operating room efficiency and showed that sedation success and treatment success rates exceeded economics should also be determined. 85% in all groups and were higher in the elderly patients subgroup (92%). More patients in the younger group than in the elderly group ICU sedation in mechanically ventilated and intubated patients required at least one alternative sedative medication during the is another important area that deserves more attention. Fospropofol procedure (10 [11.2%] vs 2 [3.3%]). Physician and patient satisfac- has in theory eliminated or at least lessened some of the issues with tion scores were comparable in both groups. The most common prolonged usage of propofol in the ICU; for example, bacterial treatment-related adverse events were paresthesia, pruritus, hypo- contamination and lipid load. Prolonged administration of fospro- tension, and hypoxia, but hypoxia was not significantly different pofol could theoretically result in increased concentrations of for- between the two groups. Hypoxemia occurred in 26% of the elderly mate and phosphate. However, as the available data suggest, much and 18% of the younger patients group, but escalation of care was work remains to be done to determine its safety and efficacy when Fospropofol in the Perioperative Period Current Pharmaceutical Design, 2012, Vol. 18, No. 38 6251 used for short-term and long-term infusions, in patients with clini- [8] Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology cal indications for the same [54].Moreover, specific populations of propofol infusion syndrome: a simple name for a complex such as pediatric and obstetric patients and patients with end-stage syndrome. Intensive Care Med 2003; 29 : 1417-25. liver disease deserve further study to determine its usefulness in [9] Albrecht S, Ihmsen H, Suchodolski K, Frenkel C, Schüttler J. [Analgo-sedation in intensive care: a quantitative, EEG-based trial such populations. Finally, because of the recent shortages of various with propofol 1% and 2%]. Anaesthesist 1999; 48: 794-801. In anesthetic induction agents including propofol, an alternative agent German. (if fospropofol is indeed shown to be one) is certainly a desirable [10] Lindholm M. Critically ill patients and fat emulsions. Minerva aim [68]. anestesiologica 1992; 58: 875-9 [11] McLeod G, Dick J, Wallis C, Patterson A, Cox C, Colvin J. SUMMARY Propofol 2% in critically ill patients: effect on lipids. Crit Care Med Fospropofol is an intravenous sedative-hypnotic agent that is 1997; 25: 1976-81 FDA-approved for monitored anesthesia care (MAC) sedation in [12] Veber B, Gachot B, Bedos J, Wolff M. Severe sepsis after adult patients undergoing diagnostic or therapeutic procedures. As a intravenous injection of contaminated propofol. Anesthesiology 1994; 80: 712-3. prodrug of propofol, its pharmacologic activity results from break- [13] McNeil MM, Lasker BA, Lott TJ, Jarvis WR. Postsurgical Candida down by alkaline phosphatases and liberation of propofol, which is albicans infections associated with an extrinsically contaminated the active agent. It exhibits a longer time to peak effect than propo- intravenous anesthetic agent. J Clin Microbiol 1999; 37: 1398-403. fol and a more prolonged action. Providers must be informed of this [14] Sakuragi T, Yanagisawa K, Shirai Y, Dan K. Growth of more gradual onset of sedative effect, in order to avoid unnecessary Escherichia coli in propofol, lidocaine, and mixtures of propofol supplemental doses of fospropofol. and lidocaine. Acta Anaesthesiol Scand 1999; 43: 476-9. [15] Abdelmalak BB, Bashour CA, Yared JP. Skin infection and The standard dosing regimen consists of administration of an necrosis after subcutaneous infiltration of propofol in the intensive initial IV bolus dose of 6.5 mg/kg followed by supplemental doses care unit. Can J Anaesth 2008; 55: 471-3. of 1.6 mg/kg IV provided as needed, but no more frequent than at 4 [16] Propofol Package Insert. Available from: http: min intervals, to achieve and maintain mild to moderate sedation. //www1.astrazeneca-us.com/pi/diprivan.pdf. Patients 65 years of age or who have severe systemic disease [17] Fukada T, Ozaki M. Microbial growth in propofol formulations (ASA P3/P4) should follow a modified dosing regimen of 75% of with disodium edetate and the influence of venous access system the standard dosing regimen. dead space. Anaesthesia 2007; 62 : 575-80. [18] Seeberger MD, Staender S, Oertli D, Kindler CH, Marti W. The FDA-approved package insert of fospropofol states that Efficacy of specific aseptic precautions for preventing propofol- this drug should be administered only by persons who are trained in related infections: analysis by a quality-assurance programme using administering general anesthesia and who are not conducting the the explicit outcome method. J Hosp Infect 1998; 39: 67-70. diagnostic or therapeutic procedure. Patients who receive fospropo- [19] Ravenelle F, Vachon P, Rigby-Jones A, et al. Anaesthetic effects of fol should be monitored for potential loss of spontaneous respira- propofol polymeric micelle: a novel water soluble propofol tion, as well as for hypoxemia, unresponsiveness or minimal re- formulation. Br J Anaesth 2008; 101: 186-93. sponsiveness to vigorous tactile or painful stimulation, and hy- [20] Egan TD, Kern SE, Johnson KB, Pace NL. The pharmacokinetics potension. and pharmacodynamics of propofol in a modified cyclodextrin formulation (Captisol®) versus propofol in a lipid formulation Recent studies have shown the safety of fospropofol as an agent (Diprivan®): an electroencephalographic and hemodynamic study for MAC sedation in patients undergoing colonoscopy and flexible in a porcine model. Anesth Analg 2003; 97: 72-9. bronchoscopy. However, whether it can be considered another [21] Kim KM, Choi BM, Park SW, et al. 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Received: March 20, 2012 Accepted: June 28, 2012