REMIMAZOLAM: 137 Adverse Event Reports & Safety Profile

Each glass, single-patient-use, sterile vial of BYFAVO (remimazolam) for injection contains 20 mg remimazolam, equivalent to 27.2 mg remimazolam besylate. Remimazolam is a benzodiazepine. Its chemical description is 4H-imidazol[1,2-a][1,4]benzodiazepine-4-propionic acid, 8-bromo-1-methyl-6-(2-pyridinyl)-(4S)-, methyl ester, benzenesulfonate (1:1). The structural formulas are shown below. Molecular weight of BYFAVO (free base): 439.3 g/mol. Molecular weight of BYFAVO besylate: 597.5 g/mol. BYFAVO besylate powder is sparingly soluble in water. BYFAVO 20 mg contains: 82 mg dextran 40 and 55 mg lactose monohydrate as bulking agents/stabilizers. The pH is adjusted with hydrochloride/sodium hydroxide. Upon reconstitution with saline, BYFAVO has a pH of 2.9 to 3.9.

Chemical

Structure

AND USAGE BYFAVO ® is indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less. BYFAVO (remimazolam) for injection is a benzodiazepine indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less. ( 1 )

AND ADMINISTRATION Individualize and titrate BYFAVO dosing to desired clinical effect. ( 2.2 )

Adult

Patients : Administer an initial dose intravenously as a 5 mg push injection over a 1-minute time period. ( 2.2 ) If necessary, administer supplemental doses of 2.5 mg intravenously over a 15-second time period. At least 2 minutes must elapse prior to the administration of any supplemental dose. ( 2.2 ) ASA III-IV Patients (at the discretion of the physician) : Based on the general condition of the patient, administer 2.5 mg to 5 mg over 1-minute time period. ( 2.2 ) If necessary, administer supplemental doses of 1.25 mg to 2.5 mg intravenously over a 15-second time period. At least 2 minutes must elapse prior to the administration of any supplemental dose. ( 2.2 )

2.1 Important Dosage and Administration Instructions BYFAVO can depress respiration. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment. 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. Supplemental oxygen, resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO. A benzodiazepine reversal agent should be immediately available. Continuously monitor vital signs during sedation and through the recovery period <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Peak sedation occurs approximately 3 to 3.5 minutes after an initial 5 mg intravenous injection of BYFAVO given over a 1-minute period <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span>. Titrate subsequent doses of BYFAVO on the basis of clinical judgment and assessment of the depth of sedation. If maintenance of procedural sedation is inadequate, consider alternative medications <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> .

2.2 Basic Dosing Information Individualize BYFAVO dosing and titrate to desired clinical response. In clinical studies, fentanyl 25 to 75 mcg was administered for analgesia prior to the first dose of BYFAVO. Supplemental doses of fentanyl were administered as needed for analgesia <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . Recommended dosing guidelines: Induction of Procedural Sedation For adult patients: Administer 5 mg intravenously over a 1-minute time period. For ASA ASA = American Society of Anesthesiologists Physical Status Classification System III and IV patients: Administer 2.5 mg to 5 mg intravenously over 1 minute based on the general condition of the patient. Maintenance of Procedural Sedation (as needed) For adult patients: Administer 2.5 mg intravenously over 15 seconds. At least 2 minutes must elapse prior to administration of any supplemental dose. For ASA III and IV patients: Administer 1.25 mg to 2.5 mg intravenously over 15 seconds. At least 2 minutes must elapse prior to administration of any supplemental dose.

2.3 Preparation Reconstitution of BYFAVO (remimazolam) for injection Strict aseptic technique must be maintained during handling of BYFAVO. This product does not contain preservative. Once removed from packaging, protect vials from light. Each single-patient-use vial contains 20 mg BYFAVO lyophilized powder for reconstitution. The product must be prepared immediately before use. To reconstitute, add 8.2 mL sterile 0.9% Sodium Chloride Injection, USP, to the vial, directing the stream of solution toward the wall of the vial. Gently swirl the vial (do not shake) until the contents are fully dissolved. The reconstituted product will deliver a final concentration of 2.5 mg/mL solution of BYFAVO. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Upon reconstitution, the solution should be a clear, colorless to pale yellow solution. Discard if particulate matter or discoloration is observed. If not used immediately, reconstituted BYFAVO may be stored in the vial for up to 8 hours under controlled room temperature at 20°C to 25°C (68°F to 77°F).

After

8 hours, any unused portion must be discarded.

2.4 Administration with Other Fluids BYFAVO has been shown to be compatible with the following intravenous fluids: 0.9% Sodium Chloride Injection, USP 5% Dextrose Injection, USP 20% Dextrose Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP. BYFAVO has also been shown to be compatible with Ringer&apos;s Solution, a solution containing Sodium Chloride, Potassium Chloride and Calcium Chloride Dihydrate. BYFAVO has been shown to be incompatible with the following intravenous fluids: Lactated Ringer&apos;s Solution, a solution containing Sodium Chloride, Sodium Lactate, Potassium Chloride, and Calcium Chloride Dihydrate.

Lactated

Ringer's Solution is also known as Ringer's Lactate Solution, Compound Sodium Lactate Solution, and Hartmann's Solution.

Acetated

Ringer's Solution, a solution containing Sodium Chloride, Sodium Acetate, Potassium Chloride, and Calcium Chloride Dihydrate. BYFAVO compatibility with other agents has not been adequately evaluated. Do not mix BYFAVO with other drugs or fluids prior to administration.

BYFAVO is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40 [see Warnings and Precautions (5.3) ]. Hypersensitivity to dextran 40. ( 4 )

REACTIONS The following serious adverse reactions are discussed in greater detail in other sections: Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ] The most common adverse reactions (>10%) in patients receiving BYFAVO for procedural sedation are hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Acacia Pharma at 1-877-357-9237 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of BYFAVO was evaluated in three prospective, randomized, double-blind, multicenter, parallel group clinical studies in 630 patients undergoing colonoscopy (two studies) or bronchoscopy (one study).

Colonoscopy Study

1 and the bronchoscopy study evaluated American Society of Anesthesiologists (ASA) physical status I to III patients, and Colonoscopy Study 2 evaluated ASA III and IV patients. All three studies evaluated the safety of BYFAVO compared to placebo with midazolam rescue and an open-label midazolam treatment arm. Patients were administered a total dose ranging from 5 to 30 mg of BYFAVO. In these studies, the most common adverse reactions (incidence greater than 10%) following BYFAVO administration were hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension. There were two patients who experienced an adverse reaction that led to discontinuation of study drug. One patient in the BYFAVO arm in the bronchoscopy study discontinued treatment due to bradycardia, hypertension, hypotension, hypoxia, and respiratory rate increase. One patient in the open-label midazolam arm in Colonoscopy Study 2 discontinued due to respiratory acidosis. No deaths were reported during the studies.

Tables

1-3 provide a summary of the common adverse reactions observed in each of the three Phase 3 studies with BYFAVO.

Table

1: Common Adverse Reactions in Colonoscopy Study 1 (Incidence >2%), ASA I to III Adverse Reaction BYFAVO N = 296 Placebo (with Midazolam Rescue 57/60 (95%) patients received midazolam rescue. ) N = 60 Midazolam N = 102 n (%) n (%) n (%)

Hypotension

Hypotension defined as a fall in systolic BP to ≤80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 115 (39%) 25 (42%) 63 (62%)

Hypertension

Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 59 (20%) 17 (28%) 18 (18%)

Bradycardia

33 (11%) 7 (12%) 16 (16%) Diastolic hypertension 29 (10%) 6 (10%) 9 (9%)

Tachycardia

23 (8%) 7 (12%) 13 (13%) Diastolic hypotension 23 (8%) 4 (7%) 9 (9%) Systolic hypertension 16 (5%) 5 (8%) 6 (6%)

Table

2: Common Adverse Reactions in Bronchoscopy Study (Incidence >2%)

Adverse

Reaction BYFAVO N = 303 Placebo (with Midazolam Rescue 57/59 (97%) patients received midazolam rescue. ) N = 59 Midazolam N = 69 n (%) n (%) n (%)

Hypotension

Hypotension defined as a fall in systolic BP to ≤80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 99 (33%) 28 (47%) 23 (33%)

Hypertension

Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 85 (28%) 9 (15%) 19 (28%) Diastolic hypertension 77 (25%) 15 (25%) 16 (23%) Systolic hypertension 67 (22%) 13 (22%) 17 (25%)

Hypoxia

66 (22%) 12 (20%) 13 (19%) Respiratory rate increased 43 (14%) 6 (10%) 10 (14%) Diastolic hypotension 41 (14%) 17 (29%) 16 (23%)

Nausea

12 (4%) 2 (3%) 2 (3%)

Bradycardia

11 (4%) 4 (7%) 4 (6%)

Pyrexia

11 (4%) 1 (2%) 1 (1%)

Headache

8 (3%) 0 (0%) 3 (4%)

Table

3: Common Adverse Reactions in Colonoscopy Study 2 (Incidence >2%), ASA III and IV Adverse Reaction BYFAVO N = 31 Placebo (with Midazolam Rescue 16/16 (100%) patients received midazolam rescue. ) N = 16 Midazolam N = 30 n (%) n (%) n (%)

Hypotension

Hypotension defined as a fall in systolic BP to ≤80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 18 (58%) 11 (69%) 17 (57%)

Hypertension

Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 13 (42%) 6 (38%) 13 (43%) Respiratory acidosis 6 (19%) 2 (13%) 8 (27%) Diastolic hypertension 3 (10%) 0 (0%) 0 (0%) Systolic hypertension 2 (6%) 0 (0%) 0 (0%)

Bradycardia

1 (3%) 1 (6%) 4 (13%) Respiratory rate decreased 1 (3%) 1 (6%) 2 (7%) Diastolic hypotension 1 (3%) 1 (6%) 0 (0%) Blood pressure diastolic increased 1 (3%) 0 (0%) 0 (0%) Blood pressure increased 1 (3%) 0 (0%) 0 (0%) Blood pressure systolic increased 1 (3%) 0 (0%) 0 (0%) Upper respiratory tract infection 1 (3%) 0 (0%) 0 (0%) Adverse reaction data from Colonoscopy Study 1 and the bronchoscopy study analyzed according to the cumulative dose of concomitant fentanyl (<100 mcg, 100-150 mcg and >150 mcg) suggest an increase in some adverse reactions with increasing fentanyl dose, such as hypotension, hypertension, bradycardia, hypoxia, and increased respiratory rate (see Table 4 and Table 5 ). There were too few patients in each fentanyl stratum in Colonoscopy Study 2 to perform this analysis.

Table

4: Common Adverse Reactions Incidence >2% of patients. in Colonoscopy Study 1 by Cumulative Fentanyl Dose BYFAVO Placebo (with Midazolam Rescue 57/60 (95%) patients received midazolam rescue. )

Midazolam

Fentanyl dose (mcg) <100 100-150 >150 <100 100-150 >150 <100 100-150 >150 N = 148 N = 146 N = 2 N = 9 N = 43 N = 8 N = 31 N = 62 N = 9 Adverse Reaction n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

Hypotension

Hypotension defined as a fall in systolic BP to ≤80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 49 (33%) 64 (44%) 2 (100%) 5 (56%) 17 (40%) 3 (38%) 18 (58%) 36 (58%) 9 (100%)

Hypertension

Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 24 (16%) 35 (24%) 0 (0%) 1 (11%) 14 (33%) 2 (25%) 3 (10%) 12 (19%) 3 (33%)

Bradycardia

12 (8%) 20 (14%) 1 (50%) 0 (0%) 5 (12%) 2 (25%) 1 (3%) 13 (21%) 2 (22%) Diastolic hypertension 9 (6%) 20 (14%) 0 (0%) 0 (0%) 3 (7%) 3 (38%) 2 (6%) 7 (11%) 0 (0%)

Tachycardia

10 (7%) 12 (8%) 1 (50%) 0 (0%) 6 (14%) 1 (13%) 2 (6%) 8 (13%) 3 (33%) Diastolic hypotension 10 (7%) 13 (9%) 0 (0%) 0 (0%) 3 (7%) 1 (13%) 3 (10%) 4 (6%) 2 (22%) Systolic hypertension 5 (3%) 11 (8%) 0 (0%) 0 (0%) 3 (7%) 2 (25%) 4 (13%) 2 (3%) 0 (0%)

Table

5: Common Adverse Reactions Incidence >2% of patients. in Bronchoscopy Study by Cumulative Fentanyl Dose BYFAVO Placebo (with Midazolam Rescue 57/59 (97%) patients received midazolam rescue. )

Midazolam

Fentanyl dose (mcg) <100 100-150 >150 <100 100-150 >150 <100 100-150 >150 N = 215 N = 63 N = 25 N = 26 N = 18 N = 15 N = 29 N = 27 N = 13 Adverse Reaction n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

Hypotension

Hypotension defined as a fall in systolic BP to ≤ 80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 52 (24%) 32 (51%) 16 (64%) 7 (27%) 9 (50%) 12 (80%) 7 (24%) 7 (26%) 9 (69%)

Hypertension

Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 43 (20%) 25 (40%) 18 (72%) 2 (8%) 2 (11%) 5 (33%) 3 (10%) 8 (30%) 8 (62%) Diastolic hypertension 65 (30%) 12 (19%) 0 (0%) 11 (42%) 3 (17%) 1 (7%) 10 (34%) 6 (22%) 0 (0%) Systolic hypertension 55 (26%) 11 (17%) 1 (4%) 10 (38%) 3 (17%) 0 (0%) 9 (31%) 6 (22%) 2 (15%)

Hypoxia

35 (16%) 22 (35%) 9 (36%) 6 (23%) 2 (11%) 4 (27%) 2 (7%) 5 (19%) 6 (46%) Respiratory rate increased 22 (10%) 12 (19%) 9 (36%) 1 (4%) 2 (11%) 3 (20%) 2 (7%) 5 (19%) 3 (23%) Diastolic hypotension 28 (13%) 13 (21%) 0 (0%) 8 (31%) 7 (39%) 2 (13%) 7 (24%) 6 (22%) 3 (23%)

Nausea

9 (4%) 1 (2%) 2 (8%) 0 (0%) 0 (0%) 2 (13%) 1 (3%) 1 (4%) 0 (0%)

Bradycardia

3 (1%) 4 (6%) 4 (16%) 2 (8%) 1 (6%) 1 (7%) 0 (0%) 2 (7%) 2 (15%)

Pyrexia

7 (3%) 2 (3%) 2 (8%) 0 (0%) 0 (0%) 1 (7%) 1 (3%) 0 (0%) 0 (0%)

Headache

5 (2%) 2 (3%) 1 (4%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 3 (11%) 0 (0)%

AND PRECAUTIONS Hypersensitivity Reactions : Hypersensitivity reactions including anaphylaxis may occur. ( 5.3 )

Neonatal

Sedation and Withdrawal Syndrome : Receiving benzodiazepines during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.4 , 8.1 )

Pediatric

Neurotoxicity : In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. ( 5.5 )

5.1 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . Consider the potential for worsened cardiorespiratory depression prior to using BYFAVO concomitantly with other drugs that have the same potential (e.g., opioid analgesics or other sedative-hypnotics) <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>. Administer supplemental oxygen to sedated patients through the recovery period. A benzodiazepine reversal agent (flumazenil) should be immediately available during administration of BYFAVO <span class="opacity-50 text-xs">[see Overdosage (10) ]</span>.

5.2 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>. The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including 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.

5.3 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 <span class="opacity-50 text-xs">[see Contraindications (4) , Adverse Reactions (6) ]</span>.

5.4 Neonatal Sedation and Withdrawal Syndrome Receiving benzodiazepines late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to benzodiazepines, including BYFAVO, during pregnancy or labor for signs of sedation and monitor neonates exposed to benzodiazepines during pregnancy for signs of withdrawal and manage these neonates accordingly <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span>.

5.5 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of 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 these findings is not clear. However, based on the available data, 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 three years of age in humans <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.4) , Nonclinical Pharmacology (13.2) ]</span> . Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. 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.

INTERACTIONS

7.1 Opioid Analgesics and Other Sedative-Hypnotics The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including opioid analgesics, other benzodiazepines, and propofol. Continuously monitor vital signs during sedation and through the recovery period. Titrate the dose of BYFAVO when administered with opioid analgesics and sedative-hypnotics to the desired clinical response <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.