Techniques in Gastrointestinal Endoscopy 18 (2016) 22–28

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Techniques in Gastrointestinal Endoscopy

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New horizons for sedation: The ultrashort acting remimazolam

Daniel J. Pambiancoa,1,2,n, Brooks D. Cashb,2 a Charlottesville Medical Research, 325 Winding River Lane, Suite 102, Charlottesville, Virginia 22911 b Digestive Health Center, University of South Alabama, Mobile, Alabama article info abstract

Article history: Procedural sedation is used in 98% of endoscopies performed in the United States. The predominant agents Received 17 November 2015 used are , opioids, and . The optimal sedation depends on the procedure being Accepted 11 February 2016 performed and its duration. An ideal sedative would allow for flexible, rapid onset and offset of sedation with predictable short duration of action with minimal cardiopulmonary risk factors. Remimazolam is a Keywords: novel “soft drug” with the characteristics of a benzodiazepine and organ-independent metabolism. Remimazolam Remimazolam binds selectively and with high affinity to the gamma-aminobutyric acid receptor, with Benzodiazepine no off-target activities. In animal studies, remimazolam has a short, initial phase half-life and high volume Procedural sedation of distribution, indicating extensive tissue distribution, minimal tissue accumulation, and rapid elimina- Pharmacokinetics tion. Remimazolam is hydroxylated to an inactive metabolite, and its effects can be reversed with Clinical trials flumazenil. In clinical studies for procedural sedation, remimazolam was well tolerated with no serious Gastrointestinal endoscopy adverse events. Times to onset or offset of sedation were shorter with remimazolam versus active control. All remimazolam-related adverse reactions are well known to clinicians and can be managed by trained staff. This article summarizes the preclinical and clinical data on the efficacy and safety or remimazolam for endoscopic sedation. Remimazolam is in clinical development for procedural sedation, general anesthesia, and sedation in the intensive care unit. Remimazolam is a promising new sedative or anesthetic agent with scientific support for continued clinical development. Phase III studies with remimazolam for procedural sedation are underway. & 2016 Elsevier Inc. All rights reserved.

1. Introduction also advanced endoscopic procedures such as endoscopic ultra- sound, double balloon enteroscopy, and endoscopic retrograde Since the advent of fiberoptic endoscopy, in the mid 1950s, the cholangiopancreatography. Simultaneously, there has been a log- diagnosis and treatment of gastrointestinal (GI) disorders has been arithmic growth in the use of and need for sedation, allowing for transmogrified by the use of this modality to become the primary greater patient comfort and safety in the evolution of these tool used in colon cancer screening and prevention, as well as the erstwhile nonsurgical procedures. As the number and complexity investigation of abdominal pain, anemia, altered bowel habits, GI of endoscopic procedures increase, the role of sedation has been blood loss, and abnormal imaging [1]. Currently our armamen- integral in patient and physician satisfaction. Presently, 98% of tarium includes the use of not only routine diagnostic and endoscopic procedures in the United States are performed with therapeutic esophagogastroduodenoscopy and colonoscopy but sedation administered by gastroenterologist or anesthesia profes- sionals [2]. However, unlike surgery that requires general anes- thesia, optimal sedation requirements for endoscopy need to be matched to patient comfort, comorbidity risks, the anticipated B.D.C. has served as a consultant and an advisory board member for PAION and procedural discomfort, and the length of the procedure in order to has received research funding from PAION. D.J.P. has served as a speaker, consultant and an advisory board member for PAION, and has received research funding minimize the unnecessary risk of deeper sedation or general from PAION. anesthesia [3]. Most of the patients require moderate sedation n Corresponding author. for relatively short procedures for which the ideal agent or admin- E-mail address: [email protected] (D.J. Pambianco). istration model is still being sought. 1 Guarantor of article. This article focuses on the unmet needs of our current sedation 2 Contributed equally to the concept for the review article, provided substantial feedback on previous drafts and approved the final, submitted version of the practices and the evolution and potential of the novel compound, manuscript. remimazolam, an ultrashort acting benzodiazepine. http://dx.doi.org/10.1016/j.tgie.2016.02.004 0049-0172/& 2016 Elsevier Inc. All rights reserved. D.J. Pambianco, B.D. Cash / Techniques in Gastrointestinal Endoscopy 18 (2016) 22–28 23

Moderate Minimal sedaon sedaon/analgesia “anxiolysis” “conscious sedaon” Deep sedaon/analgesia General Anesthesia Normal response Purposeful response to Purposeful response Unarousable even Responsiveness to verbal verbal or tacle following repeated or with painful smulus communicaon smulaon painful smulaon Intervenon may Intervenon Airway Unaffected No intervenon required be required o en required Spontaneous Unaffected Adequate May be inadequate Frequently inadequate Venlaon Cardiovascular Unaffected Usually maintained Usually maintained May be impaired funcon Remimazolam Propofol

Colonoscopy Upper GI endoscopy Bronchoscopy Major surgery Trauma (limb reseng, wound dressing) Biopsies Minor procedures ICU sedaon MRI/Scanning procedures

Fig. 1. Continuum of sedation: definition of general anesthesia and levels of sedation/analgesia (ASA, 1999—modified) [19] and intended use of remimazolam. (Color version of figure is available online.)

2. Sedation background patient and manage the level of sedation for the endoscopic procedure [6,7]. The goals of sedation are to balance patient comfort and Benzodiazepines were discovered in the 1950s with the van- tolerability with the risks of drug-related side effects and guard of and later , the latter of which over sedation. It is intended to reduce patient anxiety and was widely used for endoscopic sedation until the advent of discomfort for procedures that may need to be repetitive while midazolam in the 1980s. Owing to midazolam's water solubility, allowing the endoscopist patient stability to perform a thorough which eliminated pain on injection and its shorter half-life, it examination [4]. usurped the use of diazepam [8]. Sedation has been defined as a drug-induced suppression of Midazolam is considered a safe and effective sedation agent. consciousness that is a continuum from anxiolysis (minimal) to The mean elimination half-life of midazolam is about 3 hours conscious sedation (moderate) to unconsciousness (general anes- (range: 1.8-6.4 hour), and it is metabolized by cytochrome P450- thesia). The American Society of Anesthesiologists (ASA) has 3A4. It is well established that individual variability in P450 developed and defined the continuum of sedation for medical activity and interactions with drugs that inhibit or activate the procedures of varying invasiveness (Figure 1). The ability to 3A4 system can contribute to the unpredictability in onset or achieve and maintain the balance of appropriate necessary depth duration of midazolam's sedative effects. As such and similar to of individualized sedation with minimal adversity is a combination propofol, plasma effect-site concentration after an IV dose and its of expertise and pharmacology. relationship to pharmacodynamic measures (ie, reaction time, eye Currently, midazolam and propofol are the most commonly used movement, sedation depth) have shown extensive intersubject intravenous (IV) sedatives used for procedural sedation often in variability [9]. conjunction with IV opioids [5], however each agent has disadvantages. Moreover, midazolam is hydroxylated into active and inactive Propofol, an anesthetic alkylphenol, is an IV sedative or metabolites, which can increase the risk of excessive sedation by hypnotic that is used for sedation and general anesthesia in higher drug interactions. About 60%-70% of the biotransformation prod- doses. Among its major advantages for brief procedural sedation uct is 1-hydroxy-midazolam (alpha-hydroxy-midazolam), which such as endoscopy are its exceptional sedative properties with fast is at least as potent as the parent compound and may contribute induction and extremely short half-life, allowing for rapid recovery to the net pharmacologic activity of midazolam [9]. Midazolam from sedation and rapid discharge from the endoscopy suite. accumulates with renal impairment, prolonged infusion, and after However, there are some safety and tolerability concerns, includ- repeated single dose infusions—a common dosing schedule dur- ing injection site pain, susceptibility to bacterial contamination, ing short, conscious sedation administration. Owing to these and cardiovascular and respiratory depression. The induction or variable pharmacokinetic and pharmacodynamic effects, midazo- maintenance dosing to effect-site concentration is not linear owing lam can be difficult to titrate and may produce prolonged to tissue compartment variability, and repeated or prolonged sedation, thus delaying recovery. These characteristics make administration can lead to unpredictable clinical consequences, midazolam a suboptimal candidate as a sedative or anesthetic predominantly apnea, and . As a result of this potential agent. narrow therapeutic window, rapid progression to respiratory The development of new sedative and anesthetic drugs over depression and hypoxia can cause the potential need for respira- the last decade has been driven by the changing demands of tory rescue with endotracheal intubation. Consequently, the clinical practice, where procedures once performed in the hospital presence of an anesthesia professional is required to monitor the are now performed in ambulatory settings, on an increasingly 24 D.J. Pambianco, B.D. Cash / Techniques in Gastrointestinal Endoscopy 18 (2016) 22–28

Benzodiazepine Safety Ester Technology

Diazepam Fentanyl (1960s) (1960s) (1970s) Midazolam (1980s) Remifentanil • Aqueous solubility (1990s) • Availability of antagonist • No injection pain Remimazolam • Respiratory depression • Risk for CV effects N • Short duration of action • Anxiolysis N • Predictable response • Amnesia • Inactive metabolite O • No psychomimetic effects Br N • Rapid onset • Control of major inhibitory NT O • Rapid offset CH3 N • Predictable response

Dexmedetomidine Propofol (1990s) (1980s)

Etomidate Ketamine (1960s) (1960s)

GABAA Mechanism Rapid Onset/Offset

Fig. 2. Pharmacological milestones leading to the development of remimazolam. elderly population with multiple comorbidities [5]. As per the safer with an increased therapeutic index and a rapid predictable American Gastroenterological Association— metabolism to inactive metabolites [11].

The ideal agent for endoscopic sedation should possess seda- 3. Remimazolam tive, analgesic, and amnestic properties and a pharmacokinetic profile compatible with rapid onset (1-2 min), brief duration 3.1. Historical overview (5-10 min), and fast recovery (15-20 min). It also should pro- vide a predictable pharmacodynamic response within the range Midazolam is the parent compound of remimazolam; therefore, of moderate sedation, exert minimal depressant effects on the remimazolam has the characteristic safety profile of a benzodia- cardiopulmonary system, and possess a pharmacologic antag- zepine and a gamma-aminobutyric acid (GABA ) neurotransmitter onist. Finally, its use by an endoscopist and/or nurse should A receptor mechanism of action. Remimazolam was created as a new comply with state and federal regulations, and it should be cost candidate compound after a confluence of historical milestones in effective compared with current methods of sedation [10]. pharmacology [12] (Figure 2). The critical step in the creation of remimazolam was the addition of a carboxylic ester linkage to the These demands and recent advances in clinical pharmacology molecule, as was also done with an analgesic compound in have led to the concept of “soft” drugs, which are designed to be widespread use, remifentanil. This technology creates a “soft drug”

Fig. 3. Pharmacokinetics of remimazolam and its inactive metabolite. (Color version of figure is available online.) D.J. Pambianco, B.D. Cash / Techniques in Gastrointestinal Endoscopy 18 (2016) 22–28 25

Distribution studies showed minimal accumulation in any tissue. N N N N The main route of metabolism of remimazolam is via the inactive O Carboxylesterases O metabolite CNS7054, which is subject to hydroxylation and Br N Br N glucuronidation (Figure 4). The hydrolyzation of CNS7056 to OMe OH CNS7054 is catalyzed by tissue carboxylesterases, without invol- N N vement of cytochrome P450 isoenzymes [14]. Moreover, remi- mazolam causes no relevant inhibition of the studied cytochrome

CNS 7054 P450 isoenzymes, nor are there inducing effects on CYP iso- Remimazolam enzymes when studied in vitro [14]. (CNS 7056) (inacve metabolite) Results from preclinical studies showed remimazolam to have Fig. 4. Metabolism of remimazolam. predictable PD and PK profiles, with rapid onset and offset of action [14]. Remimazolam-induced sedation can be effectively that allows for organ-independent metabolism of remimazolam by reversed with flumazenil, and hypotension is not observed with nonspecific and widespread tissue esterases, for which there are physiologically relevant doses of remimazolam. Importantly, there no known deficiency conditions. Importantly, it allows for rapid is a wide therapeutic window between therapeutic doses and toxic onset of sedation and a rapid offset with a predictable short doses (Figure 5). duration of action and a favorable cardiostability profile [11]. With the unique characteristics of a benzodiazepine, remimazolam has potential for 3 main indications: procedural sedation, general anesthesia, and sedation in the intensive care unit. 3.3. Clinical trials

3.3.1. Phase I: First-in-man study 3.2. Preclinical trials The first-in-man trial of remimazolam (CNS7056-001) was a double-blind, single dose, phase I trial enrolling healthy volunteers Remimazolam binds selectively and with high affinity to brain in the United States (N ¼ 81) [15]. Subjects were randomized to benzodiazepine sites (GABAA receptor), with no evidence of off- receive remimazolam, placebo, or midazolam (6:1:3); 9 cohorts of target activities. The same properties were demonstrated for its subjects received escalating doses of remimazolam (0.01-0.30 mg/kg) principal metabolite, CNS7054, which displayed a 417-fold lower via IV infusion for 1 minute. The stopping rule was loss of conscious- affinity than its parent compound in homogenates of human brain ness (LoC); Modified Observer's Assessment of Alertness/Sedation tissue [13]. Scale (MOAA/S) o2forZ5minutesin450% of subjects in any In all animal species studied, remimazolam showed sedative single dose cohort [15] (Table 1). activity with a rapid onset, short duration, and reversal with Remimazolam was well tolerated at all doses administered and flumazenil. Remimazolam showed inhibition of human ether-a- no SAEs (serious adverse events) were reported. Airway patency go-go-related gene (hERG) tail currents at concentrations well and spontaneous respiration were maintained throughout the trial above those required to activate GABAA receptors in vitro, and with no requirement for mechanical ventilation in any patient. considerably higher than free plasma levels reached in any Remimazolam safely and rapidly induced sedation at doses toxicology or human study. Deep sedation was observed without Z0.05 mg/kg. The depth and duration of sedation appeared to excessive respiratory or cardiovascular depression in pigs, sheep, be sufficient to allow a short procedure requiring procedural and monkeys [14]. sedation at doses of Z0.075 mg/kg. Offset of sedation was rapid In various animal species, a very short initial phase half-life (10 minutes at doses of 0.075-0.20 mg/kg) compared with and high volume of distribution were observed, indicating midazolam (40 minutes at 0.075 mg/kg). Other results are rapid elimination after extensive tissue distribution (Figure 3). summarized in Table 2.

Fig. 5. Therapeutic window in animals and humans. (Color version of figure is available online.) 26 D.J. Pambianco, B.D. Cash / Techniques in Gastrointestinal Endoscopy 18 (2016) 22–28

3.3.2. Phase Ib: Multiple dose colonoscopy study The phase Ib study (CNS7056-002) was comprised of 2 parts part A was a double-blind, placebo-controlled, crossover trial fi fl ontrolled; PD, evaluating the ef cacy of umazenil as a reversal agent for remimazolam in healthy volunteers (N ¼ 6). Subjects received a 1-minute IV infusion of 0.25 mg/kg remimazolam and 3 minutes r April-September, 2009 May-September, 2010 Planned for 2014/2015 July-November, 2008 Planned for 2014/2015 2015 after successful sedation (MOAA/S score 3) subjects received 0.5 mg flumazenil or placebo. Alternate treatment was adminis- tered on the following day. In the flumazenil and placebo groups, the median times to fully alert (first of 3 consecutive MOAA/S scores ¼ 5) were 1.0 and 10.5 minutes, respectively [16]. Part B was an open-label, dose-escalation study investigating the efficacy of remimazolam in combination with fentanyl in

cacy, MOAA/Scacy, MOAA/S, April-September, 2009 ¼ fi fi subjects undergoing colonoscopy (N 45). The initial dose of remimazolam was 0.04-0.10 mg/kg, followed by up to 6 top-up colonoscopy Aldrete score start/peak sedation ECG, BIS, MOAA/S start/peak sedation PK doses of 0.04 mg/kg as necessary to induce and maintain sedation Safety, PK, and PD Safety, ef Procedure success, times to Procedure success, times to Safety, procedure success Planned for 2015 during the procedure. Remimazolam was well tolerated at all doses administered and no SAEs were reported. Remimazolam had a rapid time to onset of sedation (0.18-0.40 minute) and time to recovery, with the mean time to becoming fully alert ranging from 6.9-9.8 minutes. Overall, the depth and duration of sedation was sufficient to achieve successful procedures for 64%-100% of subjects in each dose cohort [16].

3.3.3. Phase IIa: Single dose endoscopy study 7.0 mg (2.0 mg top-ups) 0.04-0.10 mg/kg 2.5 mg 2.5 mg 2.5 mg A randomized, double-blind, dose finding, phase IIa trial (CNS7056-003) evaluated the safety and efficacy of 3, single doses (ie, no top-ups) of remimazolam (0.10, 0.15, or 0.20 mg/kg) vs a (REM) REM doses Endpoints Study dates single dose of midazolam (0.075 mg/kg) in patients undergoing a N diagnostic upper GI endoscopy (N ¼ 100) [17]. All 3 doses of remimazolam were well tolerated and no SAEs were reported. (total) Remimazolam had a rapid onset and offset of sedation and the 100 75 0.10-0.20 mg/kg Safety, ef 160 120 5.0 or 8.0 mg (3.0 mg top-ups), N 460 300 Induction: 5 mg maintenance: 460 300 Induction: 5 mg maintenance: 75 30 Induction: 5 mg maintenance: depth and duration of sedation were sufficient to achieve success- ful procedures for 32%-64% of patients who received remimazolam in the lowest and highest dose groups, respectively. The success rate was 44% with midazolam [17].

3.3.4. Phase IIb: Multiple dose colonoscopy study ciency 16 16 1.5 mg PK, safety 2015 18 y) with ASA III/IV 18 y) undergoing 18 y) undergoing fi The safety and efficacy of multiple doses of remimazolam Z Z Z were evaluated in a phase IIb study versus midazolam in patients undergoing colonoscopy (CNS7056-004) [18]. This is the first undergoing EGD colonoscopy colonoscopy bronchoscopy undergoing colonoscopy study to use fixed doses of remimazolam and patients were US patients (18-65 y) US Patients (18-70 y) undergoing US volunteers (18-75 y) 51 51 Pt A: 0.25 mg/kg Pt B: Thorough QT 54 54 10 or 20 mg QTc intervals, ECG parameters, randomized to the following 3 loading/top-up combinations: 8.0 mg/3.0 mg, 7.0 mg/2.0 mg, and 5.0 mg/3.0 mg. Patients randomized to midazolam received 2.5 mg/1.0 mg. A total of 160 patients entered the study. All doses of remimazolam were

C, positive controlled; CO, crossover; DB, double blind; ECG, electrocardiogram; LoC, loss of consciousness; OL, open label; P, phase;well PC, placebo c tolerated and no SAEs were reported. In the remimazolam þ oxacin),

fl groups, mean times to peak sedation ranged from 2.7-4.4 umazenil reversal);

fl minutes; the mean time in the midazolam group was 6.4 minutes. Mean times to fully alert ranged from 11.3-13.6 minutes in the C (moxi

þ remimazolam groups and 15.2 minutes in the midazolam group. The depth and duration of sedation were sufficient to achieve nding

fi successful procedures in Z92% of all patients who received remimazolam and in 75% of patients who received midazolam dose dose response OL (dose escalation) AC (midazolam), CO PI, R, DB, PC, AC (midazolam), SAD US volunteers (18-55 y) 81 54 0.01-0.30 mg/kg Safety and PK; blood, vitals, PIIa, R, DB, AC (midazolam), PIIb, R, DB, AC (midazolam), PIb, 2 parts: DB, PC ( (P r 0.007) [18].

3.4. Safety profile of remimazolam

[16] For the procedural sedation, remimazolam has shown a safety profile similar to that of midazolam. In studies for this indication, [15] [17] 240 patients received remimazolam (0.1, 0.15, and 0.2 mg/kg; 5 mg/3 mg, 7 mg/2 mg, and 8 mg/3 mg), and 66 patients received midazolam (0.075 mg/kg and 2.5 mg/1 mg). There were no appa-

[18] rent differences in oxygen saturation between remimazolam and Antonik et al Borkett et al Pambianco et al NCT02290873 (CNS 7056-006) PIII, R, DB, PC, AC (midazolam) Patients ( Article or NCT/(study #) Study design Population (CNS 7056-014)(CNS 7056-015) PI, R, DB, SD, PIII, AC R, (midazolam), DB, CO PC, AC (midazolam) Abuse liability Patients ( 40 40 5 or 10 mg Abuse potential, PD/PK 2015 NCT02296892 (CNS 7056-008) PIII, R, DB, PC, AC (midazolam) Patients ( Worthington et al (CNS 7056-005)(CNS 7056-012) PI, R, DB, SD, PI, OL, SD Renal insuf pharmacodynamics; PK, pharmacokinetics; R, randomized; REM, remimazolam; SAD, single, ascending dose; SD, single dose; US, United States. Table 1 Description of completed and planned clinical trials of remimazolam for procedural sedation. Abbreviations: AC, active controlled; BIS, bispectral index; midazolam groups, and the number of respiratory events and D.J. Pambianco, B.D. Cash / Techniques in Gastrointestinal Endoscopy 18 (2016) 22–28 27

Table 2 Summary of results from completed clinical trials of remimazolam for procedural sedation.

Article Dose groups End points

Antonik et al [15] Onset of sedation, m Offset of sedation, m Sedation level (MOAS/S) 0.01-0.05 n/a n/a None—Limited (4-5) 0.075-0.20 o1 710 710 m: medium (↓ to 1.5) 0.25-0.30 o1 730 730 m: LoC (↓ to 0)

Worthington et al [16] Time to LoC, m Time to awake, m Success rate (%) Time to discharge, m 0.04 0.33 9.8 66.7 23.8 0.075 0.40 9.6 100 24.1 0.10 0.18 6.9 64.3 19.3

Borkett et al [17] Time to LoC, m Time to awake, m Success rate (%) Time to discharge, m 0.10 90 11.0 32 14.0 0.15 NR 13.4 56 12.8 0.20 150 12.1 64 11.8

Pambianco et al [18] Time to peak sedation, m Time to awake, m Success rate (%) Time to discharge, m 5.0/3.0 4.4 13.3 97.5 11.3 7.0/2.0 4.0 11.3 95.0 12.4 8.0/3.0 2.7 13.6 92.5 14.6

Abbreviation: LoC, loss of consciousness. airway interventions (chin lifts and jaw thrusts) were low and be conducted. These trials would be placebo and active controlled similar among all groups. No ventilator support was necessary in (ie, midazolam) focusing on the evaluation of the safety of any patient and there were no SAEs. remimazolam in patients with poorer health status. If these findings are confirmed in the phase III studies, it is 3.5. Discussion expected that remimazolam can be used like midazolam in the setting of procedural sedation but with a faster and more predict- As with other benzodiazepines, there is likely to be an increased able clinical onset and offset. A sedation profile with a rapid reach risk of apnea, airway obstruction, desaturation, or hypoventilation of peak sedation within 1-2 minutes and rapid offset is comparable in the presence of or other CNS depressants. Similarly, there to propofol but with a broader therapeutic window, which may is the likelihood of an increase in any hypnotic effects of remima- lead to more timely starts of procedures and should be expected to zolam if opioids are used as concomitant . These lead to increased patient satisfaction. risks are managed by omitting or reducing the doses of concom- itant narcotics for esophagogastroduodenoscopy and colonoscopy, respectively, similar to the risk mitigation strategies of other References benzodiazepines. All of the above mentioned adverse reactions are well known to clinicians and can be appropriately managed [1] Wilcox CM. Fifty years of gastroenterology at the University of Alabama at Birmingham: a festschrift for Dr. Basil I. Hirschowitz. Am J Med Sci 2009;338: by adequately trained staff. Finally, as with all benzodiazepines, the 84–8. reversal agent, flumazenil could be used as a rescue [2] Cohen LB, Wecsler JS, Gaetano JN, Benson AA, Miller KM, Durkalski V, et al. from deeper than intended levels of sedation, in addition to other Endoscopic sedation in the United States: results from a nationwide survey. – routine airway management practices [16]. Am J Gastroenterol 2006;101:967 74. [3] Green SM. Research advances in procedural sedation and analgesia. Ann Emerg Med 2007;49:31–6. [4] American Association for Study of Liver D, American College of G, American 4. Conclusions Gastroenterological Association I, American Society for Gastrointestinal E, Society for Gastroenterology N, Associates, et al. Multisociety sedation “ ” curriculum for multisociety gastrointestinal endoscopy. Gastrointest Endosc Remimazolam, a new soft drug for sedation and anesthesia, 2012, 76: e1–e25. has the characteristic safety profile of a benzodiazepine and a [5] Inadomi JM, Gunnarsson CL, Rizzo JA, Fang H. Projected increased growth rate of anesthesia professional-delivered sedation for colonoscopy and EGD in the GABAA receptor mechanism of action, with a rapid onset, predict- United States: 2009 to 2015. Gastrointest Endosc 2010;72:580–6. able course, and rapid offset of action. For procedural sedation, [6] Hemmings HJ. The pharmacology of intravenous anesthetic induction agents: results from 2 phase I studies suggest that remimazolam shows a primer. Anesthesiology News. New York: McMahon Publishing; 2010, 9–16. linear PK, was well tolerated at all doses tested, and fully reversible [7] Perouansky M, Hemmings HJ. Intravenous anesthetic agents. In: Hemmings fl HJ, Hopkins P, editors. Foundatons of Anesthsia: Basic Science and Clinical with umazenil. In 2 phase II trials, remimazolam demonstrated Practice. 2nd ed. London: Mosby Elsevier; 2005. p. 295–310. efficacy during GI endoscopy and colonoscopy. Phase III studies are [8] Olkkola KT, Ahonen J. Midazolam and other benzodiazepines. Handbook of planned or are underway to confirm the phase II findings for Experimental Pharmacology 2008;182:335–60. fi [9] Roche Pharmaceuticals. Versed (midazolam HCL injection): Full Prescribing endoscopy/colonoscopy and to evaluate the ef cacy of remimazo- Information. Nutley, NJ; 1999. lam in more seriously ill patients (ASA III/IV) undergoing colono- [10] Cohen LB, Delegge MH, Aisenberg J, Brill JV, Inadomi JM, Kochman ML, et al. scopy. Additional phase III trials with remimazolam for the AGA institute review of endoscopic sedation. Gastroenterology 2007;133: – indications of sedation, general anesthesia and intensive care unit 675 701. [11] Egan TD. Is anesthesiology going soft?: Trends in fragile pharmacology. sedation are underway or planned. Anesthesiology 2009;111:229–30. The phase III program currently underway for the procedural [12] Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, et al. sedation indication consists of 2 confirmatory trials using 2 Design, synthesis, and pharmacological evaluation of ultrashort- to long- acting opioid analgetics. J Med Chem 1991;34:2202–8. procedure models: bronchoscopy and colonoscopy. Both trials [13] Kilpatrick GJ, McIntyre MS, Cox RF, Stafford JA, Pacofsky GJ, Lovell GG, et al. would be placebo and active controlled (ie, midazolam) to provide CNS 7056: a novel ultra-short-acting benzodiazepine. Anesthesiology 2007; confirmatory evidence of the safety and efficacy of remimazolam 107:60–6. fi fi [14] Ono Pharmaceutical Co. Ltd. Data on le. Osaka, Japan. for procedural sedation. In parallel to the 2 con rmatory trials, a [15] Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- separate trial in ASA III/IV patients undergoing colonoscopy would and midazolam-controlled phase I single ascending-dose study evaluating the 28 D.J. Pambianco, B.D. Cash / Techniques in Gastrointestinal Endoscopy 18 (2016) 22–28

safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS midazolam for sedation in upper gastrointestinal endoscopy. Anesth Analg 7056): part I. safety, efficacy, and basic pharmacokinetics. Anesth Analg 2012; 2015;120:771–80. 115:274–83. [18] Pambianco DJ, Borkett KM, Riff DS, Winkle PJ, Schwartz HI, Melson TI, et al. [16] Worthington MT, Antonik LJ, Goldwater DR, Lees JP, Wilhelm-Ogunbiyi K, A phase IIb study comparing the safety and efficacy of remimazolam Borkett KM, et al. A phase Ib, dose-finding study of multiple doses of and midazolam in patients undergoing colonoscopy. Gastrointest Endosc remimazolam (CNS 7056) in volunteers undergoing colonoscopy. Anesth 2015. http://dx.doi.org/10.1016/j.gie.2015.08.062 [Epub ahead of print]. Analg 2013;117:1093–100. [19] American Society of Anesthesiologists. Standard of Care Continuum of [17] Borkett KM, Riff DS, Schwartz HI, Winkle PJ, Pambianco DJ, Lees JP, et al. A Depth Sedation. Sample Policy and Procedure Statements. Schaumburg, IL: Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus ASA; 1999.