Clinical Pharmacology Corner: FDA Approves BYFAVO (Remimazolam)

FDA Approves BYFAVO (Remimazolam) for Induction and Maintenance of Procedural Sedation in Adults Undergoing Procedures Lasting 30 Minutes or Less

On July 2, 2020, the U.S. Food and Drug Administration (FDA) approved BYFAVO (remimazolam) for inducing and maintaining procedural sedation in adults undergoing procedures lasting 30 minutes or less. The approved recommended initial and supplemental dosage of BYFAVO for adult or debilitated patients (ASA III-IV) is listed below. Individualize BYFAVO dosing and titrate to desired clinical response. At least 2 minutes must elapse prior to the administration of any supplemental doses.

• For adult patients:
• Initial: 5 mg intravenous (IV) push over 1 minute.
• Maintenance of Procedural Sedation: 2.5 mg IV over 15 seconds, if necessary.
• For debilitated patients (ASA III-IV), based on physician’s discretion:
• Initial: 2.5 to 5 mg over 1 minute based on patient’s condition.
• Maintenance of Procedural Sedation: 1.25 to 2.5 mg over 15 seconds.

BYFAVO has been associated with hypoxia, bradycardia, and hypotension. 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, age- and size-appropriate equipment for bag/valve/mask assisted ventilation, and a benzodiazepine reversal agent must be immediately available during administration of BYFAVO.

Concomitant use of benzodiazepines with 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.

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

Additional information regarding dosage and administration, as well as important warnings and precautions about personnel and equipment for monitoring and resuscitation, risks from concomitant use with opioid analgesics and other sedative-hypnotics, hypersensitivity reactions, neonatal sedation, and pediatric neurotoxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Remimazolam was a benzodiazepine.

General PK: Remimazolam C_max was 189 to 6,960 ng/ml and AUC_0-inf was 12.1 to 452 ng∙h/ml following IV administration of 0.01 to 0.5 mg/kg (0.14 to 7 times the maximum approved recommended dosage based on 70 kg). Remimazolam AUC_0-inf increased in a close to dose-proportional manner.

Distribution: Remimazolam V_z was 0.76 to 0.98 L/kg and protein binding was > 91%, primarily to human serum albumin. 

Elimination: Remimazolam terminal elimination half-life (t_1/2) was 37 to 53 minutes and a mean distribution half-life (t_1/2α) between 0.5 and 2 minutes.

Metabolism: Remimazolam was primarily metabolized by tissue carboxylesterases (primarily type 1A) to an inactive metabolite, which was then subjected to futher hydroxylation and glucuronidation.

Excretion: Approximately 0.003% of remimazolam was excreted unchanged in urine and 50% to 60% is excreted in urine as inactive metabolite in colonoscopy patients.

Drug Interactions

Opioid Analgesics and Sedative Hypnotics: Titrate BYFAVO to desired clinical response when use concomitantly with opioid analgesics and sedative-hypnotics. Continuously monitor vital signs during sedation and through the recovery period. The sedative effect of BYFAVO can be accentuated by concomitant use of CNS depressant medications, including opioid analgesics, other benzodiazepines, and propofol.

Use in Specific Populations

No clinically significant effects in BYFAVO pharmacokinetics were identified based on age, sex, race, body weight, or in patients with mild renal impairment to end stage renal disease not requiring dialysis. BYFAVO was not studied in pediatric patients.

Hepatic Impairment: Sedation lasted longer, and recovery took longer for subjects with hepatic impairment compared to healthy subjects. In patients with severe hepatic impairment, the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, fewer 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.

Efficacy and Safety

Efficacy of BYFAVO was demonstrated in three randomized, double-blind, multi-center Phase 3 studies conducted in adult patients who receiving procedural sedation. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (> 10%) in patients receiving BYFAVO for procedural sedation are hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension.

Full prescribing information is available at https://go.usa.gov/xwSfJ.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.