Remimazolam (Monograph)

Brand name: Byfavo
Drug class: Benzodiazepines
Chemical name: methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
Molecular formula: C₂₁H₁₉BrN₄O₂
CAS number: 308242-62-8

Medically reviewed by Drugs.com on Apr 24, 2023. Written by ASHP.

Introduction

Benzodiazepine.

Uses for Remimazolam

Procedural Sedation

Used for induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.

Agents used for procedural sedation include opioids, benzodiazepines, barbiturates, ketamine, propofol, dexmedetomidine, etomidate, and nitrous oxide; there is no single agent or combination of agents that can be recommended for every patient or sedation procedure. Appropriate level of sedation and choice of sedative/analgesic agents should be individualized according to the specific procedure and needs of the patient.

Remimazolam Dosage and Administration

General

Pretreatment Screening

• Prior to use of remimazolam, consider concomitant drugs that can increase the potential for cardiorespiratory depression (e.g., opioid analgesics or other sedative-hypnotics).

Patient Monitoring

• Continuously monitor patients for signs of hypoventilation, airway obstruction, and apnea, using capnography, pulse oximetry, and clinical assessment. The risk of profound sedation, respiratory depression, coma, and death is increased in those receiving concomitant opioid analgesics and other sedative hypnotics with remimazolam.

• Continuously monitor vital signs during sedation and during procedural recovery.

Other General Considerations

• Prior to administration of remimazolam, confirm that resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation are immediately available.

• Prior to administration of remimazolam, confirm that flumazenil (a benzodiazepine reversal agent) is immediately available.

• Individualize dosing and titrate to desired effect; titrate subsequent doses based on clinical judgment and assessment of the depth of sedation. If maintenance of procedural sedation is inadequate, consider alternative medications.

• Only allow personnel trained in administering procedural sedation to administer remimazolam. Personnel administering remimazolam must be trained in the monitoring and management of airway obstruction, hypoventilation, and apnea, and be able to maintain a patent airway, administer supportive ventilation, and administer cardiovascular resuscitation.

• Administer supplemental oxygen to patients under sedation through the recovery period.

Administration

IV Administration

Administer by IV injection.

Each single-use vial contains 20 mg of remimazolam as a lyophilized powder, equivalent to 27.2 mg of remimazolam besylate, and must be reconstituted prior to use. Vials of remimazolam do not contain preservative; prepare product immediately before use. Protect vials from light once removed from packaging.

Remimazolam is compatible with the following fluids: 0.9% sodium chloride injection, 5% dextrose injection, 20% dextrose injection, 5% dextrose and 0.45% sodium chloride injection. Remimazolam also has been shown to be compatible with Ringer's solution, a solution containing sodium chloride, potassium chloride, and calcium chloride dihydrate. Compatibility with other agents has not been adequately evaluated.

Do not mix remimazolam with other drugs or fluids prior to administration.

Reconstitution

Reconstitute lyophilized powder by adding 8.2 mL of 0.9% sodium chloride injection using aseptic technique for a final concentration of 2.5 mg/mL. When injecting the 0.9% sodium chloride injection into vial, direct stream of solution to vial wall. Gently swirl (do not shake) until contents are fully dissolved.

Rate of Administration

For induction of procedural sedation, administer dose IV over a 1-minute time period.

For maintenance of procedural sedation, administer doses IV over 15 seconds. Allow at least 2 minutes to elapse prior to administration of any supplemental dose.

Dosage

Dosage of remimazolam besylate is expressed in terms of remimazolam. Individualize and titrate remimazolam dosing to desired clinical effect; titrate subsequent doses based on clinical judgment and assessment of the depth of sedation.

In clinical studies, fentanyl 25–75 mcg (with reduced doses for debilitated patients) was administered for analgesia immediately prior to the first dose of remimazolam with additional supplemental doses permitted up to a maximum total dose of 200 mcg. Concomitant fentanyl administration up to total dose of 200 mcg appears safe; however, careful titration and continuous monitoring of sedation depth is recommended.

Adults

Procedural Sedation

Induction

IV

5 mg IV over a 1-minute time period.

Lower doses may be needed for induction in American Society of Anesthesiologists (ASA) physical status III–IV patients (at the discretion of the physician). Based on general condition of patient, may administer 2.5–5 mg IV over a 1-minute time period.

Maintenance

IV

If necessary, administer supplemental doses of 2.5 mg IV over 15 seconds for maintenance sedation. At least 2 minutes must elapse prior to administration of any supplemental dose.

Lower doses may be needed for maintenance in ASA III–IV patients (at the discretion of the physician). If necessary, may administer supplemental doses of 1.25–2.5 mg IV over 15 seconds. At least 2 minutes must elapse prior to administration of any supplemental dose.

Special Populations

Hepatic Impairment

No specific dosage recommendations, but manufacturer states to carefully titrate dose to effect.

Half-life is prolonged with increasing severity of hepatic impairment. In patients with severe hepatic impairment, less frequency of supplemental doses may be needed to achieve desired level of sedation.

Monitor all patients for cardiorespiratory complications.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Remimazolam

Contraindications

• Hypersensitivity to dextran 40.

Warnings/Precautions

Personnel and Equipment for Monitoring and Resuscitation

Clinically significant hypoxia, bradycardia, and hypotension observed. (See Boxed Warning.)

Continuously monitor vital signs during sedation and through recovery period. Prior to use, consider concomitant medications (e.g., opioid analgesics or other sedative-hypnotics) that may increase the risk of cardiorespiratory depression. Confirm that a benzodiazepine reversal agent (flumazenil) is immediately available during administration of remimazolam for treatment of overdosage.

Only allow personnel trained in the administration of procedural sedation to administer the drug. Personnel administering remimazolam must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, and have the ability to maintain a patent airway, provide supportive ventilation, and administer cardiovascular resuscitation.

Prior to administration, confirm that resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation are immediately available.

Administer supplemental oxygen to sedated patients through recovery period.

Risks from Concomitant Use with Opioid Analgesics and Other Sedative-hypnotics

Concomitant use of benzodiazepines such as remimazolam with opioid analgesics may result in profound sedation, respiratory depression, coma, and death; concomitant use with other CNS depressants such as propofol may accentuate sedative effects of remimazolam. (See Boxed Warning.) When administering remimazolam with opioid analgesics and sedative-hypnotics, carefully titrate dose of remimazolam to the desired clinical response.

Provide continuous monitoring for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation in sedated patients, particularly in those with obstructive sleep apnea, the elderly, and ASA III or IV patients, where the likelihood of occurrence is greater.

Hypersensitivity Reactions

Remimazolam contains dextran 40, which can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis. Contraindicated for use in patients with history of severe hypersensitivity reaction to dextran 40.

Neonatal Sedation and Withdrawal Syndrome

Receiving benzodiazepines late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or neonatal withdrawal syndrome (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties). Monitor neonates exposed to benzodiazepines during pregnancy or labor for signs of sedation or withdrawal, and provide appropriate management.

Pediatric Neurotoxicity

Available animal data indicate that anesthetic and sedative use for longer than 3 hours that blocks NMDA receptors and/or potentiates GABA activity may increase neuronal apoptosis in the developing brain and result in long-term cognitive deficiencies. Clinical significance not known; benefits of appropriate anesthesia in pregnant women and pediatric individuals should be balanced with potential risks suggested by nonclinical animal data. No specific anesthetic or sedative agents are reported safer than any other; decisions regarding elective procedures must take into consideration the benefits and risks.

Drug Abuse and Dependence

Remimazolam, a benzodiazepine, has potential for abuse. Remimazolam produced responses on positive subjective measures such as “Drug Liking,” “Overall Drug Liking,” “Take Drug Again,” and “Good Drug Effects” that were similar to midazolam and greater than placebo.

Specific Populations

Pregnancy

Data insufficient to inform drug-associated risk. Benzodiazepines reported to cross the placenta; respiratory depression and sedation in neonates may occur.

Neonates exposed late in pregnancy or during labor have been reported to show symptoms of sedation (respiratory depression, lethargy, hypotonia) and neonatal withdrawal syndrome (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties). Monitor infants exposed to benzodiazepines in utero during pregnancy or labor for signs of sedation and respiratory compromise, and provide appropriate management.

Lactation

Unknown if excreted into breastmilk. Remimazolam present in animal milk.

Consider pumping and discarding breast milk during treatment and for 5 hours (approximately 5 elimination half-lives) after administration of remimazolam in order to minimize potential infant drug exposure.

Monitor exposed infants for sedation, feeding problems, and poor weight gain.

Pediatric Use

Safety and efficacy in pediatric patients not established. Available efficacy data in adults cannot be extrapolated to pediatric population.

Based on animal data across different species, window of time when effects from anesthetic and sedative agents is most pronounced is during third trimester of pregnancy through first few months of life, but may extend to approximately 3 years of age in children.

Balance benefits of appropriate anesthesia in pregnant women and pediatric individuals with potential risks suggested by nonclinical animal data.

Geriatric Use

No overall differences in safety or efficacy reported in patients 65 years of age and older. Because of potential for greater sensitivity (a faster onset of loss of consciousness and a longer duration of sedation), administer supplemental doses slowly to achieve the required level of sedation.

Monitor all patients for cardiorespiratory complications.

Hepatic Impairment

Severe hepatic impairment: half-life of remimazolam prolonged; carefully titrate dose of remimazolam to effect.

Monitor all patients, regardless of level of hepatic impairment, for sedation-related cardiorespiratory complications.

Renal Impairment

Pharmacokinetics not altered in mild to end-stage renal disease not requiring dialysis.

Obese Patients

BMI does not appear to impact efficacy or safety profile of remimazolam.

Common Adverse Effects

Adverse reactions (>10%): hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, diastolic hypotension.

Drug Interactions

Conversion of remimazolam to its primary inactive metabolite, CNS7054, primarily mediated by tissue carboxylesterases (primarily type 1A), with no meaningful contribution from CYP isoenzymes. Remimazolam and its metabolite CNS7054 cause no relevant inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, or induction of CYP1A2, 2B6, and 3A4.

Remimazolam is not a substrate of the transporters organic anion transporter polypeptide (OATP) 1B1, OATP1B3, or breast cancer resistance protein (BCRP). Remimazolam and its metabolite CNS7054 do not inhibit organic anion transporter (OAT) 3, organic cation transporter (OCT) 2, OATP1B1, OATP1B3, OAT1, or BCRP.

Very low potential for pharmacokinetic drug interactions.

Fentanyl

Concomitant use of fentanyl increased duration of procedure and adverse events, and decreased the procedure success rate. Concomitant administration of fentanyl up to total doses of 200 mcg appears safe; however, careful titration and continuous assessment of depth of sedation recommended.

Remifentanil

No influence on the hydrolysis of liver S9 fractions; low potential for interaction with remimazolam.

Remimazolam Pharmacokinetics

Absorption

Bioavailability

Total exposure based on AUC has close dose-proportional relationship to cumulative doses of remimazolam.

Onset

Median time to peak sedation based on the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) occurred approximately 3–3.5 minutes after initial 5-mg IV injection given over a 1-minute time period.

Duration

Median time to full alertness, based on the time to the first of 3 consecutive MOAA/S scores of 5 following the last dose was 11–14 minutes.

Distribution

Extent

Distributed into animal milk; likely present in human milk.

Following IV administration, mean distribution half-life is between 0.5–2 minutes.

Plasma Protein Binding

>91% protein-bound in human serum albumin.

Elimination

Metabolism

Conversion to the primary metabolite CNS7054 mediated by tissue carboxylesterases.

Elimination Route

In healthy subjects, 80% or more of the remimazolam dose excreted in urine as inactive metabolite.

In colonoscopy patients, 50–60% of the dose excreted in urine as inactive metabolite; 0.003% of the dose excreted unchanged in urine.

Half-life

Elimination half-life 37–53 minutes.

Special Populations

No clinically relevant effects on the pharmacokinetics of remimazolam based on age, sex, race, and weight.

Stability

Storage

Parenteral

Injection

Store lyophilized powder at 20–25°C (excursions permitted between 15–30°C).

Reconstituted vials may be stored for up to 8 hours from 20–25°C; protect from light. After 8 hours, discard any unused portion.

Actions

• Benzodiazepine that binds to brain benzodiazepine sites (gamma amino butyric acid type A [GABA-A] receptors).

• The inactive metabolite of remimazolam (CNS7054) has a 300 times lower affinity for the receptor.

• Similar to other benzodiazepines, remimazolam is non-selective between subtypes of the GABA-A receptor.

Advice to Patients

• Advise patients to notify their healthcare provider about the use of alcohol or medications. Alcohol and other CNS depressants, such as opioid analgesics and benzodiazepines, can have an additive effect when administered with remimazolam.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.

• Benzodiazepines cross the placenta and may produce respiratory depression, sedation, and/or neonatal withdrawal syndrome in neonates. Advise mothers exposed to remimazolam during pregnancy or labor to monitor neonates for signs of sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, feeding difficulties).

• Advise women who are breastfeeding to consider reducing infant exposure by pumping and discarding breast milk for 5 hours after receiving remimazolam for procedural sedation. Instruct women who are breastfeeding to monitor exposed infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if observed.

• Inform patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Remimazolam besylate preparations are subject to control under the Federal Controlled Substances Act of 1970 as a scheduled (C-IV) drug.

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