Remimazolam

1 INDICATIONS 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 )

12.1 Mechanism of Action BYFAVO is a benzodiazepine. BYFAVO binds to brain benzodiazepine sites (gamma amino butyric acid type A [GABA A ] receptors), while its carboxylic acid metabolite (CNS7054) has a 300 times lower affinity for the receptor. BYFAVO, like other benzodiazepines, did not show clear selectivity between subtypes of the GABA A receptor.

2 DOSAGE 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 [see Warnings and Precautions (5.1) ] . Peak sedation occurs approximately 3 to 3.5 minutes after an initial 5 mg intravenous injection of BYFAVO given over a 1-minute period [see Clinical Pharmacology (12.2) ]. 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 [see Clinical Studies (14) ] . 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 [see Clinical Studies (14) ] . 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 ma

6 ADVERSE 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

5 WARNINGS 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 [see Dosage and Administration (2.1) ] . 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) [see Drug Interactions (7.1) ]. Administer supplemental oxygen to sedated patients through the recovery period. A benzodiazepine reversal agent (flumazenil) should be immediately available during administration of BYFAVO [see Overdosage (10) ]. 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 [see Drug Interactions (7.1) ]. 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 [see Contraindications (4) , Adverse Reactions (6) ]. 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 [see Use in Specific Populations (8.1) ]. 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 be

4 CONTRAINDICATIONS 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 )

10 OVERDOSAGE Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2) ] . Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. Management of Overdosage In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help Line (1-800-222-1222), or medical toxicologist for additional overdosage management recommendations.