A Broad Range of Patients. A Broad Range of Procedures ≤30 Minutes in Duration.

Clinical Trial Design

The safety and efficacy of BYFAVO was compared to a saline placebo with midazolam rescue treatment arm and an open-label midazolam treatment arm. 986 adult patients (ITT population) received procedural sedation in three randomized, double-blind, multicenter Phase 3 trials. The pivotal studies consisted of a Bronchoscopy Study in ASA I-III patients (N=446), a Colonoscopy Study in ASA I-III patients (N=461), and a Colonoscopy Study in ASA III-IV patients (N=79).1-5

Clinical_Design

BYFAVO Was Studied in a Broad and Complex Range of Low- and High-Risk Adult Patients

Patient Demographics

BYFAVO was studied in a broad and complex range of low- and high-risk adult patients. Patient demographics, as shown for the safety population, were similar between the BYFAVO and placebo with midazolam rescue arms in each study.1-5,*

Characteristics
Bronchoscopy
ASA I-III
(N=431)
Colonoscopy
ASA I-III
(N=458)
Colonoscopy
ASA III-IV
(N=77)
Mean age years (range)
62.3 (22-95)
54.9 (19-92)
62.5 (42-84)
Age <65, %
51.5
86.2
59.7
Age >65, %
48.5
13.8
40.3
Sex, male %
45.9
47.6
55.8
Mean weight, lb (range)
177.7 (70.4-402.6)
182.8 (88.0-316.8)
198.9 (125.4-374.0)
Mean BMI kg/m2 (range)
28.3 (14-45)
29.0 (17-40)
30.8 (22-55)
ASA, % (n)
I
3.5 (15)
31.2 (143)
0
II
58.9 (254)
62.2 (285)
0
III
37.6 (162)
6.6 (30)
51.9 (40)
IV
0
0
48.1 (37)

Patient demographics are shown for the mITT population (safety population).

Procedural Sedation Success Achieved Across Procedures of Various Stimulation, Invasiveness, and Duration (≤30 Minutes)

The primary endpoint was defined as a composite of the following components1,3,4:

  • Completion of procedure, AND
  • No need for rescue medication (midazolam only in these trials), AND
  • No requirement for the following top-up doses:
    • >5 total doses of BYFAVO in any 15-minute interval
    • >3 total doses of midazolam in any 12-minute interval in the open-label midazolam arm, according to the midazolam prescribing information

Procedural Sedation Success Rate by Treatment—Primary Endpoint1-5

Procedural_Success_Rate_By_Treatment

Per FDA study requirement, midazolam was dosed per its US prescribing information and may not be reflective of clinical practice. Additionally, no direct or statistical comparisons between BYFAVO and open-label midazolam can be provided. Analysis was performed with the ITT population (all randomized patients).

Procedure Completion Rates1-5

% (n/N)
BYFAVO
Placebo With
Midazolam Rescue
Open-Label
Midazolam
Pooled
97.3% (623/640)
97.1% (135/139)
96.1% (199/207)

Procedural completion was a component of the composite for procedural success (primary endpoint for the Bronchoscopy and Colonoscopy, ASA I-III, studies, and a secondary endpoint for the Colonoscopy, ASA III-IV, study). Similar rates of procedural completion were observed across all treatment arms (ITT population).

BYFAVO Offers a Predictable Level of Sedation

In the BYFAVO arms, analysis of MOAA/S by time point assessments demonstrated a steep response curve immediately after administration to an adequate level of sedation to begin the procedure with a quick recovery.2,4 Median time to peak sedation was 3.0-3.5 minutes; median time to fully alert following last dose was 11.0-14.0 minutes.1

Bronchoscopy, ASA I-III

BronchoscopyGraph3

The target level of sedation (MOAA/S = 2-4) was maintained for a median 96.7% of the total procedure time in the BYFAVO arm of the Bronchoscopy, ASA I-III, study.2

Colonoscopy, ASA I-III

ColonoscopyGraph

The target level of sedation (MOAA/S = 2-4) was maintained for a median 92.9% of the total procedure time in the BYFAVO arm of the Colonoscopy, ASA I-III, study.2

Due to study protocol design and how open-label midazolam was dosed per its US prescribing information, time to onset in placebo and open-label midazolam arms is likely prolonged. Analyses were performed with the safety population.

Incidence of Lowest MOAA/S Score2

The data below reflect the percentages of adult patients by lowest MOAA/S score reached at any time throughout the procedure from the three placebo-controlled Phase 3 studies.

BYFAVO
(N=630)
Placebo With
Midazolam Rescue
(N=135)
Open-Label
Midazolam
(N=201)
MOAA/S = 2-4 target sedation level, % (n)
81.5% (514)
88.1% (119)
91.0% (183)
MOAA/S = 0-1, % (n)
18.3% (115)
11.9% (16)
8.5% (17)
Median total time with MOAA/S at 0-1 (range), minutes
4.0 (0.5-45.9)
6.0 (1.0-32.4)
3.0 (1.0-51.0)

Data shown are from the safety population.

Concomitant use of benzodiazepines, including BYFAVO, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. See Boxed Warning.

Quick Postprocedure Recovery Time

Time to Fully Alert After End of Procedure—Secondary Endpoint1-5

Time_to_Fully_Alert_After_End_of_Procedure

Rapid offset: median time to fully alert after end of procedure for the BYFAVO arms was ≤6 minutes.

Time to fully alert was defined as the first of three consecutive MOAA/S scores of 5 (alert) after the end of the procedure. Due to study protocol, the advantages of BYFAVO for recovery time may be understated, as midazolam is generally administered more rapidly and in higher doses in clinical practices, resulting in a more prolonged recovery in the open-label midazolam arms. The secondary endpoints were prespecified. These endpoints were not adequately powered nor error controlled, and observed treatment differences cannot be regarded as statistically significant. Analysis was performed with the ITT population (all randomized patients).

Indication and Important Safety Information

WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS

Indication

BYFAVO is a benzodiazepine indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.

Important Safety Information

WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS

Personnel and Equipment for Monitoring and Resuscitation

  • Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO.
  • Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation.
  • BYFAVO has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and during the recovery period.
  • Resuscitative drugs, and age- and size-appropriate equipment for bag-valve-mask–assisted ventilation must be immediately available during administration of BYFAVO.

Risks From Concomitant Use With Opioid Analgesics and Other Sedative-Hypnotics

Concomitant use of benzodiazepines, including BYFAVO, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. Continuously monitor patients for respiratory depression and depth of sedation.

Contraindication

BYFAVO is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40.

Personnel and Equipment for Monitoring and Resuscitation

Clinically notable hypoxia, bradycardia, and hypotension were observed in Phase 3 studies of BYFAVO. Continuously monitor vital signs during sedation and through the recovery period. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Resuscitative drugs, and age- and size-appropriate equipment for bag-valve-mask–assisted ventilation must be immediately available during administration of BYFAVO. Consider the potential for worsened cardiorespiratory depression prior to using BYFAVO concomitantly with other drugs that have the same potential (eg, opioid analgesics or other sedative-hypnotics). Administer supplemental oxygen to sedated patients through the recovery period. A benzodiazepine reversal agent (flumazenil) should be immediately available during administration of BYFAVO.

Risks From Concomitant Use With Opioid Analgesics and Other Sedative-Hypnotics

Concomitant use of BYFAVO and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of IV BYFAVO can be accentuated when administered with other CNS depressant medications (eg, other benzodiazepines and propofol). Titrate the dose of BYFAVO when administered with opioid analgesics and sedative-hypnotics to the desired clinical response. Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA III or IV patients.

Hypersensitivity Reactions

BYFAVO contains dextran 40, which can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis. BYFAVO is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40.

Neonatal Sedation

Use of benzodiazepines during the later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) in the neonate. Observe newborns for signs of sedation and manage accordingly.

Pediatric Neurotoxicity

Published animal studies demonstrate that anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of this is not clear. However, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life but may extend out to approximately 3 years of age in humans.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Adverse Reactions

The most common adverse reactions reported in >10% of patients (N=630) receiving BYFAVO 5-30 mg (total dose) and undergoing colonoscopy (two studies) or bronchoscopy (one study) were: hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension.

Use in Specific Populations

Pregnancy
There are no data on the specific effects of BYFAVO on pregnancy. Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation and respiratory depression.

Lactation
Monitor infants exposed to BYFAVO through breast milk for sedation, respiratory depression, and feeding problems. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 5 hours after BYFAVO administration.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established. BYFAVO should not be used in patients less than 18 years of age.

Geriatric Use
No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, there is a potential for greater sensitivity (eg, faster onset, oversedation, confusion) in some older individuals. Administer supplemental doses of BYFAVO slowly to achieve the level of sedation required and monitor all patients closely for cardiorespiratory complications.

Hepatic Impairment

In patients with severe hepatic impairment, the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, lower 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.

Abuse and Dependence

BYFAVO is a federally controlled substance (CIV) because it contains remimazolam which has the potential for abuse and physical dependence.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088

Please click to access full Prescribing Information.

BYF HCP ISI 10/2020

Indication and Important Safety Information

WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS

Indication

BYFAVO is a benzodiazepine indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.

Important Safety Information

WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS

Personnel and Equipment for Monitoring and Resuscitation

  • Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO.
  • Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation.
  • BYFAVO has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and during the recovery period.
  • Resuscitative drugs, and age- and size-appropriate equipment for bag-valve-mask–assisted ventilation must be immediately available during administration of BYFAVO.

Risks From Concomitant Use With Opioid Analgesics and Other Sedative-Hypnotics

Concomitant use of benzodiazepines, including BYFAVO, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. Continuously monitor patients for respiratory depression and depth of sedation.

Contraindication

BYFAVO is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40.

Personnel and Equipment for Monitoring and Resuscitation

Clinically notable hypoxia, bradycardia, and hypotension were observed in Phase 3 studies of BYFAVO. Continuously monitor vital signs during sedation and through the recovery period. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Resuscitative drugs, and age- and size-appropriate equipment for bag-valve-mask–assisted ventilation must be immediately available during administration of BYFAVO. Consider the potential for worsened cardiorespiratory depression prior to using BYFAVO concomitantly with other drugs that have the same potential (eg, opioid analgesics or other sedative-hypnotics). Administer supplemental oxygen to sedated patients through the recovery period. A benzodiazepine reversal agent (flumazenil) should be immediately available during administration of BYFAVO.

Risks From Concomitant Use With Opioid Analgesics and Other Sedative-Hypnotics

Concomitant use of BYFAVO and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of IV BYFAVO can be accentuated when administered with other CNS depressant medications (eg, other benzodiazepines and propofol). Titrate the dose of BYFAVO when administered with opioid analgesics and sedative-hypnotics to the desired clinical response. Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA III or IV patients.

Hypersensitivity Reactions

BYFAVO contains dextran 40, which can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis. BYFAVO is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40.

Neonatal Sedation

Use of benzodiazepines during the later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) in the neonate. Observe newborns for signs of sedation and manage accordingly.

Pediatric Neurotoxicity

Published animal studies demonstrate that anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of this is not clear. However, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life but may extend out to approximately 3 years of age in humans.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Adverse Reactions

The most common adverse reactions reported in >10% of patients (N=630) receiving BYFAVO 5-30 mg (total dose) and undergoing colonoscopy (two studies) or bronchoscopy (one study) were: hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension.

Use in Specific Populations

Pregnancy
There are no data on the specific effects of BYFAVO on pregnancy. Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation and respiratory depression.

Lactation
Monitor infants exposed to BYFAVO through breast milk for sedation, respiratory depression, and feeding problems. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 5 hours after BYFAVO administration.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established. BYFAVO should not be used in patients less than 18 years of age.

Geriatric Use
No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, there is a potential for greater sensitivity (eg, faster onset, oversedation, confusion) in some older individuals. Administer supplemental doses of BYFAVO slowly to achieve the level of sedation required and monitor all patients closely for cardiorespiratory complications.

Hepatic Impairment

In patients with severe hepatic impairment, the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, lower 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.

Abuse and Dependence

BYFAVO is a federally controlled substance (CIV) because it contains remimazolam which has the potential for abuse and physical dependence.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088

Please click to access full Prescribing Information.

BYF HCP ISI 10/2020

ASA=American Society of Anesthesiologists Physical Status. BMI=body mass index. CI=confidence interval. CYP450=cytochrome P450. ITT=intent-to-treat. IV=intravenous. mITT=modified intent-to-treat. MOAA/S=Modified Observer’s Assessment of Alertness and Sedation.
References: 1. Byfavo [package insert]. Indianapolis, IN: Acacia Pharma Inc; 2020. 2. Acacia Pharma. Data on File. 3. Rex DK, Bhandari R, Desta T, et al. A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2018;88(3):427-437. 4. Pastis NJ, Yarmus LB, Schippers F. Safety and efficacy of remimazolam compared with placebo and midazolam for moderate sedation during bronchoscopy. Chest. 2019;155(1);137-147. 5. Rex DK, Bhandari R, Lorch DG, et al. Safety and efficacy of remimazolam in high risk colonoscopy: a randomized trial. Dig Liver Dis. 2021;53(1):94-101.