Remimazolam Besylate

FDA Drug Information • Also known as: Byfavo

Brand Names: Byfavo
Dosage Form: INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type: DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION, AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS AND OTHER SEDATIVE-HYPNOTICS See full prescribing information for complete boxed warning Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO. ( 2.1 , 5.1 ) 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. ( 2.1 , 5.1 ) BYFAVO has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and through the recovery period. ( 2.1 , 5.1 ) Resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO. ( 2.1 , 5.1 ) 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. ( 5.2 , 7.1 ) 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 [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] . 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 [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] . BYFAVO has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and during the recovery period [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] . 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) , Warnings and Precautions (5.1) ]. 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 [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ] .

Description

11 DESCRIPTION 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

What Is Remimazolam Besylate Used For?

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 )

Dosage and Administration

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...

Side Effects (Adverse Reactions)

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%)...

Drug Interactions

7 DRUG 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 [see Warnings and Precautions (5.2) ].

Contraindications

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 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.4) , Clinical Considerations ]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ). In animal studies, reduced fetal weights but no evidence of malformations or embryofetal lethality were noted in a study in which pregnant rabbits were treated intravenously with 4 times the maximum recommended human dose (MRHD) of 30 mg during organogenesis. Adequate rodent reproductive and developmental toxicology studies have not been completed to fully evaluate the effects of BYFAVO. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to BYFAVO during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to BYFAVO during pregnancy for...

Overdosage

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....

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING BYFAVO (remimazolam) for injection, for intravenous use is supplied as follows: NDC 71390-011-11: Carton of 10 × 12 mL vials. Each 12 mL glass vial of BYFAVO (NDC 71390-011-00) provides a sterile lyophilized white to off-white powder intended for single-patient use only and contains 20 mg remimazolam (equivalent to 27.2 mg remimazolam besylate) ready for reconstitution. Store at controlled room temperature 20°C to 25°C (68°F to 77°F) excursions between 15° and 30°C (59° and 86°F) are allowed. Reconstituted BYFAVO can 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). Protect vials from light once they are removed from packaging. Discard unused portion.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.