Byfavo

Pharmacotherapeutic group: Psycholeptics, hypnotics and sedatives, ATC code: N05CD14. Mechanism of action 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 [GABA A ] 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 GABA A receptor. Pharmacodynamic effects 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 remimazolam-treated 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. Clinical efficacy and safety 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 placebo-controlled 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: • Completion of the colonoscopy/bronchoscopy procedure, AND • No requirement for a rescue sedative medication, AND • No requirement of more than 5 doses of study medication within any 15 min window (for midazolam: no requirement of more than 3 doses within any 12 min window). 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 Alert 1 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 Discharge 2 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 Normal 3 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 Note 1 : 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. Note 2 : Ready for discharge time was determined by a walking test. Note 3 : 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 Alert 1 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 Discharge 2 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 Normal 3 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 Note 1 : 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. Note 2 : Ready for discharge time was determined by a walking test. Note 3 : 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 Clinical Safety 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. Paediatric population 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).