BYFAVO Powder for solution for injection Ref.[10184] Active ingredients: Remimazolam

Dose finding studies determined the IV dosing recommendation of the initial 5 mg bolus, followed by 2.5 mg top-up doses. Median time to peak sedation, defined as the lowest Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score after the initial dose, in the Phase 3 trials was 3 to 3.5 minutes and median time to fully alert, defined as time to the first of three consecutive MOAA/S scores of five, following the last dose of BYFAVO was 11 to 14 minutes.

Cardiac Electrophysiology

In a thorough QT study, 57 healthy volunteers were given an IV push of 10 mg or 20 mg BYFAVO, intravenous midazolam (2.5 mg or 7.5 mg) or placebo, or a single tablet of moxifloxacin 400 mg given orally. The largest mean placebo-adjusted change-from-baseline QTc (upper bound of 2-sided 90% confidence interval) was 6.7 (9.5) ms, 10.7 (13.4) ms, 4.5 (7.3) ms, and 8.1 (10.8) ms, respectively, after treatment with 10 mg or 20 mg BYFAVO, or 2.5 mg or 7.5 mg midazolam.

BYFAVO treatment is associated with increases in heart rate. The largest mean placebo-adjusted change-from-baseline HR (upper bound of 2-sided 90% confidence interval) was 12.3 (14.2) bpm and 15.2 (17.1) bpm, respectively, after treatment with 10 mg and 20 mg BYFAVO.

• BYFAVO has a terminal elimination half-life from plasma of 37 to 53 minutes.
• Mean distribution half-life (t_1/2α) is between 0.5 and 2 minutes.
• Half-life (t_1/2) is prolonged with increasing severity of hepatic impairment leading to a need for careful dose titration in patients with severe hepatic impairment.
• Clearance (54 to 75 L/h) is not related to body weight.
• In healthy subjects at least 80% and in colonoscopy patients 50% to 60% of dose is excreted in urine as inactive metabolite.

Absorption

BYFAVO is administered intravenously. BYFAVO overall maximum plasma concentration (C_max) after IV administration of 0.01 to 0.5 mg/kg was 189 to 6,960 ng/mL, and overall area under the concentration versus time curve from time 0 to infinity (AUC_0-∞) was 12.1 to 452 ng∙h/mL; BYFAVO cumulative dose versus BYFAVO total exposure (AUC_0-∞) suggested a close to dose-proportional relationship. Metabolite C_max was achieved approximately 20-30 minutes post dose. Metabolite AUC_0-∞ was 231 to 7,090 ng∙h/mL.

Distribution

BYFAVO volume of distribution (V_z) was 0.76 to 0.98 L/kg. Plasma protein binding of BYFAVO was >91%, primarily to human serum albumin.

Elimination

BYFAVO has a terminal elimination half-life from plasma of 37 to 53 minutes and mean distribution half-life (t_1/2α) is between 0.5 and 2 minutes.

Metabolism

The main route of metabolism of BYFAVO is via conversion to primary inactive metabolite CNS7054, which is then subject to hydroxylation and glucuronidation. Conversion to CNS7054 is mediated by tissue carboxylesterases (primarily type 1A), with no meaningful contribution by cytochrome P450 enzymes. The t_1/2 of the metabolite was 2.4 to 3.8 hours.

Excretion

In colonoscopy patients, approximately 0.003% BYFAVO is excreted unchanged in urine, and 50% to 60% is excreted in urine as the metabolite CNS7054.

Specific Populations

Pediatric Patients

There were no pediatric patients who received BYFAVO.

Patients with Renal Impairment

The pharmacokinetics of BYFAVO were not altered in patients with mild to end stage renal disease not requiring dialysis. In a renal impairment study, BYFAVO PK parameters (e.g., AUC and C_max) were not statistically different in subjects with varying degrees of renal function (from normal to severely impaired). Increased exposure to inactive metabolite CNS7054 was observed with increasing degree of renal impairment.

Patients with Hepatic Impairment

A Phase 1 open-label, single-dose trial evaluated the PK and safety of BYFAVO given as an IV bolus of 0.1 mg/kg over 1 minute in subjects with hepatic impairment (8 moderately hepatically impaired subjects and 3 severely hepatically impaired subjects) and 9 matched healthy subjects.

The C_max values of total BYFAVO were 10% to 20% lower in subjects with hepatic impairment than in healthy subjects. Larger V_z (33% increase in moderately impaired and 41% increase in severely impaired) and V_ss (50% increase in moderately impaired and 115% increase in severely impaired), and prolonged t_1/2 (60 minutes in moderately impaired and 105 minutes in severely impaired as compared to 42 minutes in healthy subjects), of BYFAVO were observed with increasing severity of hepatic impairment. Sedation lasted longer and recovery took longer for subjects with hepatic impairment compared to healthy subjects. The average duration of loss of consciousness and recovery time was 3.2 minutes and 12.1 minutes, respectively for subjects in the moderately hepatically impaired group. These times were 2.0 minutes and 16.7 minutes, respectively, for the subjects in the severely hepatically impaired group. Healthy control subjects had a loss of consciousness of 1.6 minutes and a recovery time of 8.0 minutes.

In patients with severe hepatic impairment, the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, less frequency of supplemental doses may be needed to achieve the level of sedation required for the procedure. All patients should be monitored for sedation-related cardiorespiratory complications.

Other Specific Populations

Age, sex, race, and weight had no clinically relevant effect on BYFAVO pharmacokinetics.

Drug Interactions

BYFAVO and the metabolite CNS7054 caused no relevant inhibition of cytochrome P450 isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. There were no inducing effects on CYP1A2, 2B6, and 3A4. BYFAVO was not a relevant substrate of a panel of human drug transporters (OATP1B1, OATP1B3, BCRP).

No relevant inhibition of human drug transporters (OAT3, OCT2, OATP1B1, OATP1B3, OAT1, BCRP) was seen with BYFAVO or CNS7054. Remifentanil did not influence the hydrolysis of BYFAVO by human liver S9 fractions, reducing the possibility of an interaction by competition for liver carboxylesterases.

These results together show a very low potential of BYFAVO for pharmacokinetic drug interactions.

Carcinogenesis

Long-term animal studies have not been performed to evaluate the carcinogenic potential of remimazolam.

Mutagenesis

Remimazolam was not mutagenic or clastogenic when evaluated in an in vitro bacterial reverse mutation assay (Ames test), an in vivo rat micronucleus assay, mouse lymphoma cells, in vivo rat bone marrow micronucleus assay, or comet assay.

Impairment of Fertility

In a study that did not test exposures comparable to the MRHD of 30 mg/day, there were no adverse effects on male or female fertility when male rats were treated for 28 days prior to mating and female rats were treated for 14 days prior to mating with up to 30 mg/kg remimazolam via intravenous bolus (approximately 0.03 times the MRHD based on AUC).

There was no impact on female fertility when female rabbits were administered remimazolam by intravenous infusion (up to 4 hours/day) up to 20 mg/kg/day (approximately 17 times the MRHD of 30 mg/day based on AUC) from 14 days prior to mating.

No adverse effects on histology of the testes and epididymides or evaluation of spermatid count, sperm motility, and sperm morphology were reported in a repeat-dose toxicity study in which male minipigs were administered remimazolam by intravenous infusion (6 hours) up to 120 mg/kg/day (approximately 400 times the MRHD based on AUC) for 28 days followed by a 14-day recovery period.

Published studies in animals demonstrate that the use of anesthetic agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures against the potential risks suggested by the nonclinical data [See Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.4)].

The safety and efficacy of BYFAVO compared to a saline placebo with midazolam rescue treatment group and an open-label midazolam treatment group was evaluated in three randomized, double-blind, multicenter Phase 3 studies conducted in 969 adult patients receiving procedural sedation.

14.1 Colonoscopy Study 1 (NCT 02290873)

This Phase 3 study was conducted in 461 ASA-PS class I to III patients undergoing colonoscopy. BYFAVO 5 mg (2 mL) IV was administered as an initial bolus, followed by 2.5 mg (1 mL) top-up doses versus placebo 2 mL administered as an initial bolus, followed by 1 mL top-up doses. Midazolam rescue was dosed per investigator discretion in both treatment groups. Fentanyl was administered as an analgesic pre-treatment at an initial dose of 50 to 75 mcg IV (or a reduced dose for ASA-PS Class III patients) immediately prior to administration of the initial dose of study medication. Top-up doses of fentanyl 25 mcg every 5 to 10 minutes were allowed until analgesia was adequate or a maximum dose of 200 mcg had been administered. Supplemental oxygen was administered prior to the start of the procedure and continued at a rate of 1 to 5 L/minute until the patient was fully alert after procedure completion. Colonoscopy started when adequate sedation was achieved, defined as an MOAA/S score ≤3. The primary efficacy endpoint for BYFAVO versus placebo was success of the colonoscopy procedure, defined as a composite of the following:

• Completion of the colonoscopy procedure, AND
• No requirement for a rescue sedative medication, AND
• No requirement for more than 5 doses of study medication within any 15-minute window.

There were 63 patients (13.8%) who were aged 65 years or older, 218 patients (47.6%) who were male, 339 (74.0%) who were white, 80 (17.5%) who were Black or African American, 31 (6.8%) who were Asian, and 73 (15.9%) who were Hispanic or Latino. There were 143 patients in ASA-PS class I, 285 in ASA-PS class II, and 30 in ASA-PS class III. As shown in Table 6, the colonoscopy sedation success rate was statistically significantly higher in the BYFAVO group than in the placebo group.

Table 6. Colonoscopy Sedation Success Rate – Colonoscopy Study 1:

n/N = number of successes/number of subjects in group.

The reasons for procedural sedation failure are shown in Table 7.

Table 7. Reasons for Procedural Sedation Failure – Colonoscopy Study 1:

Table 8 shows the number of top-up doses required, and the total doses of study medication, fentanyl, and rescue medication administered.

Table 8. Number of Top-up Doses and Total Doses of Study Medication, Fentanyl, and Rescue Medication – Colonoscopy Study 1:

Summaries of the time to start procedure, duration of procedure, time to fully alert, and time to ready for discharge are shown in Table 9.

Table 9. Time to Start Procedure, Duration of Procedure, Time to Fully Alert, and Time to Ready for Discharge for the Remimazolam Cohort – Colonoscopy Study 1:

* Patients who were unable to start the procedure were excluded.
^† Patients who did not successfully complete the procedure were excluded.

14.2 Bronchoscopy Study (NCT 02296892)

This Phase 3 study was conducted in 431 ASA-PS class I to III patients undergoing bronchoscopy. BYFAVO 5 mg (2 mL) IV was administered as an initial bolus, followed by 2.5 mg (1 mL) top-up doses versus placebo 2 mL administered as an initial bolus, followed by 1 mL top-up doses. Midazolam rescue was dosed per investigator discretion in both treatment groups. Fentanyl was administered as an analgesic pre-treatment at an initial dose of 25 to 50 mcg IV immediately prior to administration of the initial dose of study medication. Top-up doses of fentanyl 25 mcg every 5 to 10 minutes were allowed until analgesia was adequate. A maximum dose of fentanyl 200 mcg was recommended. Supplemental oxygen was administered prior to the start of the procedure and continued at a rate of 1 to 15 L/minute until the patient was fully alert after procedure completion. Bronchoscopy started when adequate sedation was achieved, defined as an MOAA/S score ≤3. The primary efficacy endpoint for BYFAVO versus placebo was successful sedation for the bronchoscopy procedure, defined as a composite of the following:

• Completion of the bronchoscopy procedure, AND
• No requirement for a rescue sedative medication, AND
• No requirement for more than 5 doses of study medication within any 15-minute window.

There were 209 patients (48.5%) who were 65 years or older, 198 patients (45.9%) who were male, 358 (83.1%) who were white, 62 (14.4%) who were Black or African American, 5 (1.2%) who were Asian, and 8 (1.9%) who were Hispanic or Latino. There were 15 patients in ASA-PS class I, 254 in ASA-PS class II, and 162 in ASA-PS class III. As shown in Table 10, the bronchoscopy sedation success rate was statistically significantly higher for the BYFAVO group than for the placebo group.

Table 10. Bronchoscopy Success Rates:

n/N = number of successes/number of subjects in group.

The reasons for procedural sedation failure are shown in Table 11.

Table 11. Reasons for Procedural Sedation Failure – Bronchoscopy Study:

Table 12 shows the number of top-up doses required, and the total doses of study medication, fentanyl, and rescue medication administered.

Table 12. Number of Top-up Doses and Total Doses of Study Medication, Fentanyl, and Rescue Medication – Bronchoscopy Study:

Summaries of the time to start procedure, duration of procedure, time to fully alert, and time to ready for discharge are shown in Table 13.

Table 13. Time to Start Procedure, Duration of Procedure, Time to Fully Alert and Time to Ready for Discharge for the Remimazolam Cohort – Bronchoscopy Study:

* Patients who were unable to start the procedure were excluded.
^† Patients who did not successfully complete the procedure were excluded.

14.3 Colonoscopy Study 2 (NCT 02532647)

This Phase 3 study was conducted in 77 ASA-PS class III and IV patients undergoing colonoscopy. BYFAVO 2.5 mg (1 mL) to 5 mg (2 mL) IV was administered as an initial bolus, followed by 1.25 mg (0.5 mL) to 2.5 mg (1 mL) top-up doses versus placebo 1 to 2 mL administered with midazolam rescue, dosed per investigator discretion. Fentanyl was administered as an analgesic pre-treatment at an initial maximum dose of 50 mcg (with dose reduction for debilitated patients), immediately prior to administration of the initial dose of study medication. Top-up doses of fentanyl 25 mcg every 5 to 10 minutes were allowed until analgesia was adequate or a maximum dose of 200 mcg had been administered. Supplemental oxygen was administered prior to the start of the procedure and continued at a rate of up to 4 L/minute until the patient was fully alert after procedure completion. Colonoscopy started when adequate sedation was achieved, defined as an MOAA/S score ≤3.

The primary objective of the study was to assess the safety of multiple doses of BYFAVO compared to placebo and midazolam. Procedure success was a secondary objective and was defined as follows:

• Completion of the colonoscopy procedure, AND
• No requirement for a rescue sedative medication, AND
• No requirement for more than 5 doses of study medication within any 15-minute window.

The total patient population, including all randomized patients who received any amount of study medication, comprised 31 patients in the remimazolam group, 16 patients in the placebo group, and 30 patients in the midazolam group. There were two patients, one each in the remimazolam and midazolam treatment groups, who were randomized, but did not receive a dose of study medication.

There were 31 patients (40.2%) who were aged 65 years or older, 43 patients (55.8%) who were male, 57 (74.0%) who were white, 19 (24.7%) who were Black or African American, 1 (1.30%) who was Asian, and none who were Hispanic or Latino. There were 40 patients in ASA-PS class III and 37 patients in ASA-PS class IV.

Patients in the remimazolam group received a mean (± SD) of 9.0 (± 3.7) mg of remimazolam and a mean (± SD) of 2.5 (± 10.2) mg of midazolam compared to 7.2 (± 2.5) mg in the placebo group. The mean total dose of fentanyl was lower in the remimazolam group (mean ± SD: 59.7 ± 15.4 mcg) than in the placebo group (mean ± SD: 67.2 ± 21.8 mcg).

In the remimazolam group, 90.3% of patients did not receive any rescue sedative medication, compared to 0.0% in the placebo group.

There were no serious adverse reactions and no discontinuations due to adverse reactions observed in the remimazolam group. The incidence of hypotension (SMQ) was 61.3% in the remimazolam group and 75% in the placebo group.

No inferential statistical tests were performed in this trial. Patients who received BYFAVO for sedation during scheduled colonoscopy responded at a numerically greater rate than patients who received placebo (randomized analysis population – remimazolam: 27/32 [84.4%]; placebo: 0/16 [0%]).