Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: PAION Deutschland GmbH, Heussstraße 25, 52078 Aachen, Germany Tel: +800 4453 4453 e-mail: info@paion.com
Pharmacotherapeutic group: Psycholeptics, hypnotics and sedatives
ATC code: N05CD14
Remimazolam is an ultra-short acting benzodiazepine sedative. The effects of remimazolam on the CNS are dependent on the dose administered intravenously and presence or absence of other medicinal products. Remimazolam binds to benzodiazepine sites of gamma amino butyric acid type A [GABAA] receptors with high affinity, while its carboxylic acid metabolite (CNS7054) has approximately 300 times lower affinity for these receptors. Remimazolam does not show clear selectivity between subtypes of the GABAA receptor.
The primary pharmacodynamic effect of remimazolam is sedation. Sedation is observed starting at single bolus doses of 0.05 to 0.075 mg/kg in healthy young adults, with an onset of 1 to 2 min following dosing. Induction of mild to moderate sedation is associated with plasma levels of around 0.2 µg/mL. Loss of consciousness is seen at doses of 0.1 mg/kg (elderly) or 0.2 mg/kg (healthy young adults) and associated with plasma concentrations of around 0.65 µg/mL. Depth, duration and recovery from sedation is dose-dependent. Time to fully alert was 10 min for 0.075 mg/kg of remimazolam.
Remimazolam can cause anterograde amnesia after administration, which prevents patients from remembering events occurring during the procedure. Brice questionnaire data from 743 remimazolamtreated patients, assessed 10 minutes after the patient became fully alert and one day after the procedure, show that 76% of patients had no recollection of the procedure.
The efficacy of remimazolam was based on two pivotal studies CNS7056-006 and CNS7056-008 in adult patients (aged 18 to 95 years) with ASA-PS I-III who were scheduled for colonoscopy or bronchoscopy, respectively. The safety database for remimazolam additionally comprised a dedicated safety and efficacy trial in ASA-PS III/IV patients, CNS7056-015.
CNS7056-006 and CNS7056-008 are two Phase 3 double-blind, randomised, active- and placebocontrolled clinical trials in adult patients undergoing colonoscopy and bronchoscopy, respectively. All patients received fentanyl for analgesia before and during the procedure (50 or 75 µg or a reduced dose for elderly/debilitated patients and supplemental doses of 25 µg at least 5 min apart, as needed, but not to exceed 200 µg). Patients were randomised to remimazolam, midazolam dosed according to the U.S. local approved posology, or placebo with rescue midazolam dosed at the investigator’s discretion.
The remimazolam and placebo groups were double-blinded, while the midazolam arm was open-label due to the different dosing regimen for midazolam. After pre-treatment with fentanyl to ensure analgesia, patients received an initial dose of 5.0 mg (2 mL) remimazolam or matching placebo over 1 minute or 1.75 mg midazolam over 2 minutes (or 1.0 mg midazolam for patients ≥ 60 years of age or debilitated or chronically ill). For the remimazolam and placebo arms, supplemental doses of 2.5 mg (1 mL) at least 2 min apart were allowed until adequate sedation was achieved, and as necessary to maintain sedation. For midazolam, supplemental doses of 1.0 mg over 2 minutes with 2 minutes between doses (or 0.5 mg for patients aged ≥ 60 years or debilitated or chronically ill) were allowed to achieve and maintain adequate sedation.
The number of top-up doses and total doses of remimazolam, rescue midazolam and fentanyl administered are presented in Table 4.
Table 4. Number of top-up doses and total doses of remimazolam, rescue midazolam and fentanyl in Phase 3 clinical trials with intravenous remimazolam (Safety set):
| CNS7056-006 | CNS7056-008 | |||||
|---|---|---|---|---|---|---|
| Parameter (mean ± standard deviation) | Remimazolam (N=296) | Midazolam (N=102) | Placebo (rescue midazolam) (N=60) | Remimazolam (N=303) | Midazolam (N=69) | Placebo (rescue midazolam) (N=59) |
| Number of top-up doses of study drug | 2.2 ± 1.6 | 3.0 ± 1.1 | 5.1 ± 0.5 | 2.6 ± 2.0 | 2.8 ± 1.6 | 4.1 ± 0.8 |
| Total doses of study drug [mg] | 10.5 ± 4.0 | 3.9 ± 1.4 | 0 | 11.5 ± 5.1 | 3.2 ± 1.5 | 0 |
| Total doses of rescue midazolam [mg] | 0.3 ± 2.1 | 3.2 ± 4.0 | 6.8 ± 4.2 | 1.3 ± 3.5 | 2.6 ± 3.0 | 5.9 ± 3.7 |
| Total doses of fentanyl [µg] | 88.9 ± 21.7 | 106.9 ± 32.7 | 121.3 ± 34.4 | 81.9 ± 54.3 | 107.0 ± 60.6 | 119.9 ± 80 |
The safety set consists of all randomised patients who receive any amount of study drug.
The primary endpoint, success of procedure was defined as meeting all of the following:
Statistically significant higher success rates were observed for the difference between remimazolam and placebo (p< 0.0001; Table 5 and Table 6). Comparisons between remimazolam and midazolam are descriptive and significance testing was not performed. In the dedicated safety and efficacy trial in ASA-PS III/IV patients, CNS7056-015, similar results were observed, the procedure success rate was 27/32 (84.4%) for remimazolam, and 0% for placebo.
Table 5. Procedure success rates in Phase 3 clinical trials with intravenous remimazolam for procedure duration <30 minutes (intent-to-treat set):
| Trial | CNS7056-006 | CNS7056-008 | ||||
|---|---|---|---|---|---|---|
| Treatment arm | Remimazolam (N=297) | Midazolam (N=100) | Placebo (rescue midazolam) (N=58) | Remimazolam (N=280) | Midazolam (N=69) | Placebo (rescue midazolam) (N=58) |
| Procedure success [N (%)] | 272 (91.6%) | 26 (26.0%) | 1 (1.7%) | 232 (82.9%) | 22 (31.9%) | 2 (3.5%) |
| Procedure failure [N (%)] Rescue sedative medication taken [N] Too many doses within time [N] Procedure not completed [N] | 25 (8.4%) 9 17 7 | 74 (74.0%) 63 55 2 | 57 (98.3%) 55 42 1 | 48 (17.1%) 38 10 9 | 47 (68.1%) 37 10 5 | 56 (96.6%) 53 10 3 |
The intent-to-treat analysis set includes all patients who were randomised.
Table 6. Procedure success rates in Phase 3 clinical trials with intravenous remimazolam for procedure duration ≥30 minutes (intent-to-treat set):
| Trial | CNS7056-006 | CNS7056-008 | ||||
|---|---|---|---|---|---|---|
| Treatment arm | Remimazolam (N=1) | Midazolam (N=3) | Placebo (rescue midazolam) (N=2) | Remimazolam (N=30) | Midazolam (N=4) | Placebo (rescue midazolam) (N=5) |
| Procedure success [N (%)] | 0 | 0 | 0 | 18 (60.0%) | 2 (50.0%) | 1 (20.0%) |
| Procedure failure [N (%)] Rescue sedative medication taken [N] Too many doses within time [N] Procedure not completed [N] | 1 (100%) 1 1 0 | 3 (100.0%) 3 1 0 | 2 (100%) 2 2 0 | 12 (40.0%) 11 4 0 | 2 (50.0%) 2 0 0 | 4 (80.0%) 4 0 0 |
The intent-to-treat analysis set includes all patients who were randomised.
The onset and recovery profile of remimazolam was characterised by time-to-event secondary endpoints assessed in the two Phase 3 trials, CNS7056-006 and CNS7056-008. Time to start of procedure was shorter (p<0.01) in remimazolam group compared to placebo (rescue midazolam) group (Table 7). Time to recovery is presented according to procedure duration (Tables 8 and 9).
Table 7. Time to start of procedure in Phase 3 clinical trials with intravenous remimazolam (intent-to-treat set):
| Trial | CNS7056-006 | CNS7056-008 | ||||
|---|---|---|---|---|---|---|
| Treatment arm | Remimazolam | Midazolam | Placebo (rescue midazolam) | Remimazolam | Midazolam | Placebo (rescue midazolam) |
| Number of patients in analysis | 296 | 102 | 60 | 300 | 68 | 60 |
| Median (95% CI) | 4.0 (-, -) | 19.0 (17.0, 20.0) | 19.5 (18.0, 21.0) | 4.1 (4.0, 4.8) | 15.5 (13.8, 16.7) | 17.0 (16.0, 17.5) |
| Min, max | 0, 26 | 3, 32 | 11, 36 | 1, 41 | 3, 53 | 4, 29 |
The Intent-to-treat analysis set includes all patients who were randomised.
Table 8. Time to recovery in Phase 3 clinical trials with intravenous remimazolam for procedure duration <30 minutes (Intent-to-treat set):
| Trial | CNS7056-006 | CNS7056-008 | ||||
|---|---|---|---|---|---|---|
| Treatment arm | Remimazolam | Midazolam | Placebo (rescue midazolam) | Remimazolam | Midazolam | Placebo (rescue midazolam) |
| Time to Fully Alert1 from Last Dose (minutes) | ||||||
| Number of patients in analysis | 284 | 97 | 57 | 268 | 63 | 54 |
| Median (95% CI) | 13.0 (13.0, 14.0) | 23.0 (21.0, 26.0) | 29.0 (24.0, 33.0) | 10.3 (9.8, 12.0) | 18.0 (11.0, 20.0) | 17.5 (13.0, 23.0) |
| Min, max | 3, 51 | 5, 68 | 9, 81 | 1, 92 | 2, 78 | 5, 119 |
| Time to Ready for Discharge2 from Last Dose (minutes) | ||||||
| Number of patients in analysis | 294 | 98 | 58 | 260 | 62 | 53 |
| Median (95% CI) | 51.0 (49.0, 54.0) | 56.5 (52.0, 61.0) | 60.5 (56.0, 67.0) | 62.5 (60.0, 65.0) | 70.0 (68.0, 87.0) | 85.0 (71.0, 107.0) |
| Min, max | 19, 92 | 17, 98 | 33, 122 | 15, 285 | 27, 761 | 40, 178 |
| Time to Back to Normal3 from Last Dose (hours) | ||||||
| Number of patients in analysis | 292 | 95 | 54 | 230 | 56 | 46 |
| Median (95% CI) | 3.2 (3.0, 3.5) | 5.7 (4.5, 6.9) | 5.3 (3.3, 7.2) | 5.4 (4.6, 6.2) | 7.3 (5.2, 16.4) | 8.8 (6.7, 17.0) |
| Min, max | 0, 77 | 1, 34 | 1, 23 | 0, 46 | 1, 35 | 2, 30 |
Note1: Fully alert is defined as the first of three consecutive MOAA/S measurements of 5 after start time of the last dose of study or rescue drug.
Note2: Ready for discharge time was determined by a walking test.
Note3: Date and time of ´back to normal´ in the patient´s subjective view were recorded via telephone contact by the study nurse on Day 4 (+3/-1 days) after the procedure.
The Intent-to-treat analysis set includes all patients who were randomised.
Table 9. Time to recovery in Phase 3 clinical trials with intravenous remimazolam for procedure duration ≥30 minutes (Intent-to-treat set):
| Trial | CNS7056-006 | CNS7056-008 | ||||
|---|---|---|---|---|---|---|
| Treatment arm | Remimazolam | Midazolam | Placebo (rescue midazolam) | Remimazolam | Midazolam | Placebo (rescue midazolam) |
| Time to Fully Alert1 from Last Dose (minutes) | ||||||
| Number of patients in analysis | 1 | 3 | 2 | 30 | 4 | 5 |
| Median (95% CI) | 6.0 (N/A) | 27.0 (25.0, 28.0) | 22.5 (21.0, 24.0) | 34.8 (16.2, 47.4) | 26.1 (16.0, 42.0) | 48.0 (22.0, 123.0) |
| Min, max | 6, 6 | 25, 28 | 21, 24 | 4, 114 | 16, 42 | 22, 123 |
| Time to Ready for Discharge2 from Last Dose (minutes) | ||||||
| Number of patients in analysis | 1 | 3 | 2 | 29 | 4 | 5 |
| Median (95% CI) | 58.0 (N/A) | 66.0 (58.0, 74.0) | 60.0 (52.0, 68.0) | 83.0 (72.0, 103.0) | 63.5 (38.0, 98.0) | 95.0 (73.0, 157.0) |
| Min, max | 58, 58 | 58, 74 | 52, 68 | 26, 165 | 38, 98 | 73, 157 |
| Time to Back to Normal3 from Last Dose (hours) | ||||||
| Number of patients in analysis | 1 | 3 | 2 | 19 | 4 | 3 |
| Median (95% CI) | 3.3 (N/A) | 8.1 (7.0, 14.4) | 5.2 (4.6, 5.8) | 16.7 (4.7, 21.0) | 2.7 (0.9, 5.1) | 9.1 (3.6, 37.0) |
| Min, max | 3, 3 | 7, 14 | 5, 6 | 3, 38 | 1, 5 | 4, 37 |
Note1: Fully alert is defined as the first of three consecutive MOAA/S measurements of 5 after start time of the last dose of study or rescue drug.
Note2: Ready for discharge time was determined by a walking test.
Note3: Date and time of ´back to normal´ in the patient´s subjective view were recorded via telephone contact by the study nurse on Day 4 (+3/-1 days) after the procedure.
The Intent-to-treat analysis set includes all patients who were randomised.
N/A: not applicable
In procedures less than 30 minutes, the incidence of treatment-emergent adverse events was 80.9%, 90.8%, and 82.3% in the remimazolam, midazolam, and placebo group, respectively. In procedures 30 minutes or longer, the incidence of treatment-emergent adverse events was 87.1% in the remimazolam group, and 100% in both the midazolam and the placebo groups.
The European Medicines Agency has deferred the obligation to submit the results of studies with Byfavo in one or more subsets of the paediatric population in the condition of sedation (see section 4.2 for information on paediatric use).
Remimazolam is administered intravenously.
Remimazolam has a mean distribution half-life (t1/2α) of 0.5 to 2 min. Its volume of distribution (Vz) is 0.9 L/kg. Remimazolam and its main metabolite (CNS7054) show moderate (~90%) binding to plasma proteins, predominantly albumin.
Remimazolam is an ester drug that is rapidly converted into the pharmacologically inactive carboxylic acid metabolite (CNS7054) by CES-1, mainly located in the liver.
The main route of metabolism of remimazolam is via conversion to CNS7054, which is then to a small extent further metabolized by hydroxylation and glucuronidation. Conversion to CNS7054 is mediated by liver carboxylesterases (primarily type 1A), with no meaningful contribution by cytochrome P450 enzymes.
In vitro studies have shown no evidence that remimazolam or CNS7054 inhibit cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2B6 and CYP2C8. There is no induction of the main inducible P450 isoenzymes 1A2, 2B6, and 3A4 in man. In vitro studies showed no clinically relevant influence of CES inhibitors and substrates on the metabolism of remimazolam. Remimazolam was not a relevant substrate of a panel of human drug transporters (OATP1B1, OATP1B3, BCRP, and MDR1 (=P-glycoprotein)). The same is true of CNS7054, tested for MRP2-4. By contrast, CNS7054 was found to be a substrate of MDR1 and BCRP. No or no relevant inhibition of the human drug transporters, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, MATE2-K, BCRP, BSEP, or MDR1, was seen with remimazolam or CNS7054.
Remimazolam has a mean elimination half-life (t1/2β) of 7 to 11 minutes. Clearance is high (68±12 L/h) and not related to body weight. In healthy subjects at least 80% of the remimazolam dose is excreted in urine as CNS7054 within 24 hours. Only traces (<0.1%) of unchanged remimazolam are detected in urine.
Remimazolam dose versus remimazolam maximal plasma concentration (Cmax) and total exposure (AUC0-∞) suggested a dose-proportional relationship in human volunteers in the dose range 0.01-0.5 mg/kg.
There is no significant effect of age on the pharmacokinetics of remimazolam given for procedural sedation (see section 4.2).
The pharmacokinetics of remimazolam were not altered in patients with mild to end stage renal disease not requiring dialysis (including patients with a GFR <15 mL/min) (see section 4.2).
Severe impairment of hepatic function resulted in a reduced clearance and, as a consequence, a prolonged recovery from sedation (see sections 4.2 and 4.8).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxicity.
The following adverse reaction was not observed in clinical studies, but was seen in animals infused with the dosing solution of concentrations similar to the one used in clinical practice:
Primary lesions due to a mechanical irritation of the vessel wall during the puncture procedure can be aggravated by concentrations of remimazolam above 1 to 2 mg/mL (infusion) or above 5 mg/mL during bolus administration.
Reproductive toxicity studies performed at the maximum tolerated dose level revealed no influence on male or female fertility and on reproductive function parameters. In embryotoxicity studies in rats and rabbits, even at the highest dose levels, which displayed maternal toxicity, only marginal embryotoxic effects were observed (reduced foetal weight and slightly increased incidences of early and total resorptions). Remimazolam and its main metabolite are excreted in breast milk of rats and rabbits. The inactive main metabolite CNS7054 was detected in the plasma of suckling rabbit kits, however it is not known if remimazolam is transferred via milk to suckling offspring.
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