AHFS Class:

• Benzodiazepines 28:24.08

Generic Name(s):

• Remimazolam

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

Remimazolam besylate is a benzodiazepine.1

Procedural Sedation

Remimazolam is used for induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.1

Clinical Experience

Safety and efficacy of remimazolam for procedural sedation are supported principally by results of 3 randomized, double-blind, multicenter phase 3 trials; 2 studies were conducted in patients undergoing colonoscopy, and 1 study was conducted in patients undergoing bronchoscopy.1,2,3,4

Colonoscopy

One study enrolled 461 adults with American Society of Anesthesiologists (ASA) risk status I-III undergoing colonoscopy.1,2 Patients were randomized in a 30:6:10 ratio to receive remimazolam, placebo, or open-label midazolam.2 All patients received an initial dose of fentanyl immediately prior to administration of the study medication; additional fentanyl doses were permitted every 5-10 minutes until analgesia was adequate or a maximum dose of 200 mcg had been administered.1,2 Remimazolam 5 mg was administered as an initial IV bolus, followed by additional doses of 2.5 mg.1,2 Open-label midazolam was administered as an initial IV bolus of 1.75 mg followed by additional 1 mg doses (or an initial IV bolus of 1 mg followed by additional 0.5 mg doses for patients who were ≥60 years of age, debilitated, or chronically ill).2 Colonoscopy was initiated when adequate sedation was achieved, defined as a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score ≤3.1,2 The primary endpoint was procedure success rates between the remimazolam and placebo groups; success was defined as completion of the colonoscopy procedure with no requirement for a rescue sedative medication and no requirement for >5 doses of study medication in any 15-minute window.1,2 For patients assigned to receive open-label midazolam, success was defined as completion of the colonoscopy procedure with no requirement for a rescue sedative medication and no requirement for >3 doses of study medication in any 12-minute window.2 The mean age of patients enrolled in the trial was 54.4 years, with 13.8% of patients being ≥65 years of age.1,2 Most patients (74%) were white, and 47.6% were male; 143, 285, and 30 patients were ASA risk status I, II, and III, respectively.1,2 The colonoscopy success rate was 91.3% in the remimazolam group, 25.2% in the open-label midazolam group, and 1.7% in the placebo group.1,2 The percentage of patients not requiring rescue medication was 96.6% in the remimazolam group compared with 5% in the placebo group and 35.9% in the midazolam group; the percentage of patients not exceeding the prespecified number of study medication doses within the predefined time interval was 94% in the remimazolam group compared with 26.7% in the placebo group and 45.6% in the midazolam group.2

An additional randomized controlled trial enrolled 77 patients with ASA risk status III-IV undergoing colonoscopy.1,3 Patients were randomized in a 2:1:2 ratio to receive remimazolam, placebo, or open-label midazolam.3 All patients received an initial dose of fentanyl immediately prior to administration of the study medication; additional fentanyl doses were permitted every 5-10 minutes until analgesia was adequate or a maximum dose of 200 mcg had been administered.1,3 Remimazolam 2.5-5 mg was administered as an initial IV bolus, followed by additional doses of 1.25-2.5 mg.1,3 Open-label midazolam was administered as a 1 mg initial IV bolus followed by additional 0.5 mg doses.3 Colonoscopy was initiated when adequate sedation was achieved, defined as MOAA/S score ≤3.1,3 The trial was primarily designed to assess safety, but a secondary endpoint was success of the colonoscopy procedure; for patients assigned to receive remimazolam or placebo, success was defined as completion of the colonoscopy procedure with no requirement for a rescue sedative medication and no requirement for >5 doses of study medication in any 15-minute window.1,3 For patients assigned to receive open-label midazolam, success was defined as completion of the colonoscopy procedure with no requirement for a rescue sedative medication and no requirement for >3 doses of study medication in any 12-minute window.3 The mean age of patients enrolled in the trial was 62.5 years, with 40.2% of patients being ≥65 years of age.1,3 Most patients (74%) were white, and 55.8% were male; 40 and 37 patients were ASA risk status III and IV, respectively.1,3 The colonoscopy success rate was 87.1% in the remimazolam group, 13.3% in the open-label midazolam group, and 0% in the placebo group.3 The percentage of patients not requiring rescue medication was 90.3% in the remimazolam group compared with 0% in the placebo group and 20% in the midazolam group; the percentage of patients not exceeding the prespecified number of study medication doses within the predefined time interval was 90.3% in the remimazolam group compared with 12.5% in the placebo group and 13.3% in the midazolam group.1,3

Bronchoscopy

A randomized controlled trial enrolled 431 adults with ASA risk status I-III undergoing bronchoscopy.1,4 Patients were randomized in a 30:6:6 ratio to receive remimazolam, placebo, or open-label midazolam.4 All patients received an initial dose of fentanyl immediately prior to administration of the study medication; top-up fentanyl doses were permitted every 5-10 minutes until analgesia was adequate or a maximum dose of 200 mcg had been administered.1,4 Remimazolam 5 mg was administered as an initial IV bolus, followed by 2.5 mg top-up doses.1,4 Open-label midazolam was administered as an initial IV bolus of 1.75 mg followed by 1 mg top-up doses (or an initial IV bolus of 1 mg followed by 0.5 mg top-up doses for patients who were ≥60 years of age, debilitated, or chronically ill).4 Bronchoscopy was initiated when adequate sedation was achieved, defined as MOAA/S score ≤3.1,4 The primary endpoint for remimazolam versus placebo was success of the bronchoscopy procedure; success was defined as completion of the bronchoscopy procedure with no requirement for a rescue sedative medication and no requirement for >5 doses of study medication in any 15-minute window.1,4 For patients assigned to receive open-label midazolam, success was defined as completion of the colonoscopy procedure with no requirement for a rescue sedative medication and no requirement for >3 doses of study medication in any 12-minute window.4 The mean age of patients enrolled in the trial was 62.3 years, with 48.5% of patients being ≥65 years of age.1,4 Most patients (83.1%) were white, and 45.9% were male; 15, 254, and 162 patients were ASA risk status I, II, and III, respectively.1,4 The bronchoscopy success rate was 80.6% in the remimazolam group, 32.9% in the open-label midazolam group, and 4.8% in the placebo group.1,4 The percentage of patients not requiring rescue medication was 84.2% in the remimazolam group compared with 9.5% in the placebo group and 46.6% in the midazolam group; the percentage of patients not exceeding the prespecified number of study medication doses within the predefined time interval was 95.5% in the remimazolam group compared with 84.1% in the placebo group and 86.3% in the midazolam group.4

Clinical Perspective

Procedural sedation is a technique in which sedatives or dissociative agents are administered with or without analgesics to allow patients to tolerate painful or unpleasant medical procedures; a depressed state of consciousness is intentionally induced while cardiorespiratory function is maintained.821,822,823,824,825 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.821,824 Sedation is a continuum ranging from minimal sedation to general anesthesia; airway reflexes and cardiorespiratory function may be impaired if a deeper than intended level of sedation is produced.821,822,823 Because all sedatives and opioids, excluding ketamine, are capable of producing any sedation depth (depending on dose and patient response), it is more meaningful to focus clinical decisions and management on sedation depth and adequate ventilation rather than the specific drug itself, recognizing that different drugs have different pharmacological properties, windows of effect, and side effects.824 The appropriate level of sedation and choice of sedative/analgesic agents should be individualized according to the specific procedure and needs of the patient.822,823,825

Remimazolam has a short onset of action and distribution half-life; sedative effects of the drug can be reversed by flumazenil.5 Such characteristics may provide a benefit over other non-benzodiazepine medications used for procedural sedation.5 In clinical studies, procedure success rates appeared to decrease with increasing duration of the procedure, suggesting that remimazolam may be best suited for procedures of relatively short duration (i.e., lasting no longer than 30 minutes).5

General

Pretreatment Screening

• Prior to use of remimazolam, consider the potential for worsened cardiorespiratory depression when other drugs with potential for cardiorespiratory depression (e.g., opioid analgesics or other sedative-hypnotics) are used concomitantly.1

Patient Monitoring

• Continuously monitor patients for signs of hypoventilation, airway obstruction, and apnea, using capnography, pulse oximetry, and clinical assessment.1 The risk of profound sedation, respiratory depression, coma, and death is increased in those receiving concomitant opioid analgesics and other sedative hypnotics with remimazolam.1
• Continuously monitor vital signs during sedation and during procedural recovery.1

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.1
• Prior to administration of remimazolam, confirm that flumazenil (a benzodiazepine reversal agent) is immediately available.1
• Individualize dosing and titrate to desired effect; titrate subsequent doses based on clinical judgment and assessment of the depth of sedation.1 If maintenance of procedural sedation is inadequate, consider alternative medications.1
• Only allow personnel trained in administering procedural sedation to administer remimazolam.1 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.1
• Administer supplemental oxygen to patients under sedation through the recovery period.1

Administration

IV Administration

Administer remimazolam by IV injection.1

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.1 Vials of remimazolam do not contain preservative; prepare product immediately before use.1 Protect vials from light once removed from packaging.1

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.1 Remimazolam also has been shown to be compatible with Ringer's solution, a solution containing sodium chloride, potassium chloride, and calcium chloride dihydrate.1 Compatibility with other agents has not been adequately evaluated.1 Do not mix remimazolam with other drugs or fluids prior to administration.1

Reconstitution

Reconstitute the lyophilized powder vial by adding 8.2 mL of 0.9% sodium chloride injection using aseptic technique for a final concentration of 2.5 mg/mL.1 When injecting the 0.9% sodium chloride injection into the vial, direct the stream of solution to the wall of the vial.1 Gently swirl, and do not shake until the contents of the vial are fully dissolved.1

Store unopened vials of remimazolam at 20-25°C (excursions permitted between 15-30°C).1 Reconstituted vials may be stored for up to 8 hours at 20-25°C, protected from light.1 After 8 hours, discard any unused portion of the vial.1

Rate of Administration

For induction of procedural sedation, the remimazolam dose should be administered over a 1-minute time period.1

For maintenance of procedural sedation, remimazolam doses should be administered over 15 seconds.1 Allow at least 2 minutes to elapse prior to administration of any supplemental dose.1

Dosage

Dosage of remimazolam besylate is expressed in terms of remimazolam.1 Individualize and titrate remimazolam dosage to desired clinical effect.1

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 fentanyl dose of 200 mcg.1 Concomitant administration of fentanyl up to a total dose of 200 mcg appears safe in patients receiving remimazolam; however, careful titration and continuous monitoring of sedation depth is recommended.5

Procedural Sedation

Induction

For induction of procedural sedation, administer an initial IV remimazolam dose of 5 mg over a 1-minute time period.1

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

Maintenance

If necessary, supplemental doses of 2.5 mg remimazolam IV over 15 seconds may be administered for maintenance sedation.1 Allow at least 2 minutes to elapse prior to administration of any supplemental doses.1

Lower doses may be needed for maintenance of procedural sedation in patients with ASA physical status III-IV (at the discretion of the physician).1 If necessary, supplemental remimazolam doses of 1.25-2.5 mg IV over 15 seconds may be given in such patients.1 Allow at least 2 minutes to elapse prior to the administration of any supplemental doses.1

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations in mild to severe hepatic impairment.1 However, in severe hepatic impairment, the manufacturer states that the dose of remimazolam should be carefully titrated to effect; supplemental doses of remimazolam may be needed less frequently to achieve the desired level of sedation in severe hepatic impairment due to a prolonged elimination half-life.1

Monitor all patients, regardless of the level of hepatic function, for cardiorespiratory complications with remimazolam.1

Renal Impairment

The manufacturer makes no specific dosage recommendations in renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations in geriatric patients.1

Contraindications

• Hypersensitivity to dextran 40 or products containing dextran 40.1

Warnings/Precautions

Personnel and Equipment for Monitoring and Resuscitation

A boxed warning regarding the appropriate personnel and equipment needed for monitoring and resuscitation with the use of remimazolam is included in the product labeling.1 In phase 3 studies, clinically significant hypoxia, bradycardia, and hypotension were observed in patients administered remimazolam.1 Continuously monitor vital signs during sedation with remimazolam and throughout the recovery period.1 Prior to use, consider concomitant medications (e.g., opioid analgesics or other sedative-hypnotics) that may increase the risk of cardiorespiratory depression.1 Confirm that a benzodiazepine reversal agent (flumazenil) is immediately available during administration of remimazolam for treatment of overdosage.1

Only personnel trained in administering procedural sedation should administer remimazolam.1 Personnel administering remimazolam must be trained in the monitoring and management of airway obstruction, hypoventilation, and apnea, and must have the ability to maintain a patent airway, provide supportive ventilation, and administer cardiovascular resuscitation.1

Prior to administration of remimazolam, confirm that resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation are immediately available.1

Supplemental oxygen should be administered to patients under sedation through the recovery period.1

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

A boxed warning regarding the concomitant use of opioid analgesics and other sedative hypnotics is included in the product labeling for remimazolam.1 Use of benzodiazepines such as remimazolam concomitantly with opioid analgesics may result in profound sedation, respiratory depression, coma, and death; use with other benzodiazepines or propofol may accentuate the sedative effects of remimazolam due to CNS depression.1 When remimazolam is used concomitantly with opioid analgesics or sedative hypnotics, the dose of remimazolam should be carefully titrated to the desired clinical response.1 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 physical status III or IV patients, where the likelihood of occurrence is greater.1

Hypersensitivity Reactions

Dextran 40 is a component of remimazolam that can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis.1 The use of remimazolam is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40.1

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).1 Monitor neonates exposed to benzodiazepines during pregnancy or labor for signs of sedation or withdrawal, and provide appropriate management.1

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 lead to long-term cognitive deficiencies.1 Based on animal data across different species, the window of time when effects from anesthetic and sedative agents is most pronounced is during the third trimester of pregnancy through the first few months of life, but may extend to approximately 3 years of age in humans.1

The clinical significance of this finding is not known; the benefits of appropriate anesthesia in pregnant women and pediatric individuals should be balanced with the potential risks suggested by nonclinical animal data.1

Other data in children suggest that similar cognitive deficits can be caused by repeated or prolonged exposures to anesthetic agents at an early a however, it is unclear whether the cognitive defects may be due to anesthetic or sedative drug administration or other factors such as the surgery or the patient's underlying medical condition.1 Because no specific anesthetic or sedative agents are reported safer than any other, decisions regarding elective procedures must take into consideration the benefits and risks.1

Drug Abuse and Dependence

Remimazolam, a benzodiazepine, has potential for abuse.1 In a human abuse potential study conducted in recreational sedative abusers, remimazolam (5 and 10 mg IV) produced responses on positive subjective measures such as “Drug Liking,” “Overall Drug Liking,” “Take Drug Again,” and “Good Drug Effects” that were similar to those produced by the sedative midazolam (2.5 and 5 mg) and greater than the responses on these measures that were produced by placebo.1

In a physical dependence study in monkeys, chronic administration of remimazolam produced withdrawal signs (tremors, muscle rigidity, restlessness, impaired motor activity, and a reduction in food consumption upon drug discontinuation).1 One monkey exhibited systemic convulsions and dissociation from the environment.1 These behaviors are consistent with benzodiazepine withdrawal, suggesting that remimazolam produces physical dependence.1

Specific Populations

Pregnancy

Data are insufficient to inform the drug-associated risk of remimazolam use in pregnancy.1 Available data on the use of benzodiazepines in pregnancy have not established an associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.1 Since benzodiazepines such as remimazolam have been reported to cross the placenta, respiratory depression and sedation in neonates may occur.1 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).1 Monitor infants exposed to benzodiazepines in utero during pregnancy or labor for signs of sedation and respiratory compromise, and provide appropriate management.1

Lactation

It is not known whether remimazolam or its metabolites are distributed into human milk.1 The effects on breast-fed infants or on the production of milk are not known.1 Because remimazolam is present in animal milk, it is likely that it will be present in human milk.1 Infants exposed to benzodiazepines through breast milk have been reported to show symptoms of sedation.1 Monitor remimazolam-exposed infants for signs of sedation, feeding problems, and poor weight gain.1 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.1

Pediatric Use

Safety and efficacy in pediatric patients have not been established.1 Available efficacy data in the adult population cannot be extrapolated to the pediatric patient population.1 Published juvenile animal studies demonstrate that administration of anesthetic and sedative agents, such as remimazolam during rapid brain growth or synaptogenesis, may result in widespread loss of neuronal and oligodendrocyte cells, causing changes in neurogenesis and the morphology of synapse.1 Based on animal data across different species, the window of time when effects from anesthetic and sedative agents is most pronounced is during the third trimester of pregnancy through the first few months of life, but may extend to approximately 3 years of age in children.1 Use of ketamine for 3 hours in primates undergoing light anesthesia has not been shown to increase neuronal cell loss; however, regimens utilizing isoflurane for 5 hours or greater has shown increased neuronal cell loss, and has been associated with prolonged cognitive deficits in memory and learning.1 The clinical significance of this finding is not known; the benefits of appropriate anesthesia in pregnant women and pediatric individuals should be balanced with the potential risks suggested by nonclinical animal data.1

Geriatric Use

In studies of remimazolam for procedural sedation, no overall differences in safety or efficacy were observed between geriatric patients 65 years of age and older and younger patients; other clinical experience has not identified differences in response to remimazolam between elderly and younger adults.1 Due to the potential for greater sensitivity to remimazolam resulting in a faster onset of loss of consciousness and a longer duration of sedation in some older adults, supplemental doses of remimazolam should be administered slowly to achieve the level of sedation required for the procedure.1 If administering remimazolam, monitor all patients for cardiorespiratory complications.1

Hepatic Impairment

Carefully titrate the dose of remimazolam to effect in patients with severe hepatic impairment.1 Based on the clinical status of the patient, a lower frequency of supplemental doses may be needed to achieve the necessary level of procedural sedation.1 Monitor all patients receiving remimazolam for cardiorespiratory complications due to sedation.1

Renal Impairment

Pharmacokinetic studies of patients with mild to end-stage renal disease not requiring dialysis indicate that remimazolam pharmacokinetics are not altered.1 In a study involving patients with varying degrees of renal impairment (normal to severely impaired), AUC and peak plasma concentrations were not significantly different among subjects; however, increased exposure to the inactive metabolite CNS7054 was observed with increasing renal impairment.1

Obese Patients

Body mass index (BMI) does not appear to impact the efficacy or safety profile of remimazolam.5

Common Adverse Effects

Adverse reactions reported in more than 10% of patients receiving remimazolam for procedural sedation in clinical studies include hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension.1

Conversion of remimazolam to its primary inactive metabolite, CNS7054, is primarily mediated by tissue carboxylesterases (primarily type 1A), with no meaningful contribution from cytochrome P-450 (CYP) isoenzymes.1 Remimazolam and its metabolite CNS7054 cause no relevant inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, or induction of CYP1A2, 2B6, and 3A4.1

Remimazolam is not a substrate of the transporters organic anion transporter polypeptide (OATP) 1B1, OATP1B3, or breast cancer resistance protein (BCRP).1 Remimazolam and its metabolite CNS7054 do not inhibit organic anion transporter (OAT) 3, organic cation transporter (OCT) 2, OATP1B1, OATP1B3, OAT1, or BCRP.1 These properties indicate a very low potential for pharmacokinetic drug interactions with remimazolam.1

Fentanyl

In clinical studies of remimazolam, patients received fentanyl 25-75 mcg for analgesia prior to the first dose of remimazolam with additional doses up to a total of 200 mcg fentanyl.1 Concomitant use of fentanyl appeared to increase the duration of the procedure and adverse events, and decrease the procedure success rate.5 Concomitant administration of fentanyl up to total doses of 200 mcg appears safe; however, careful titration and continuous assessment of depth of sedation is recommended.5

Remifentanil

Since remifentanil does not influence the hydrolysis of liver S9 fractions, there is low potential for a pharmacokinetic drug interaction with remimazolam.1

Description

Remimazolam is a benzodiazepine that is structurally similar to midazolam.5 Remimazolam binds to benzodiazepine receptor sites (gamma amino butyric acid type A [GABA-A] receptors) in the brain.1 The inactive metabolite of remimazolam (CNS7054) has a 300 times lower affinity for the receptor.1 Similar to other benzodiazepines, remimazolam is non-selective between subtypes of the GABA-A receptor.1 The sedative effects of remimazolam can be reversed with flumazenil.1

Following IV administration, the mean distribution half-life of remimazolam is 0.5-2 minutes.1 In clinical studies, median time to peak sedation based on the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) occurred approximately 3-3.5 minutes after an initial 5-mg IV injection given over a 1-minute time period.1 The 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.1 Maximum plasma concentrations of the primary inactive remimazolam metabolite (CNS7054) are achieved within 20-30 minutes post-dose.1 Remimazolam is greater than 91% protein-bound in human serum albumin.1 The elimination half-life of remimazolam is 37-53 minutes.1 In patients with hepatic impairment, the elimination half-life of remimazolam is prolonged.1 Conversion of remimazolam besylate to its primary inactive metabolite is mediated by tissue carboxylesterases; the elimination half-life of the inactive metabolite is 2.4-3.8 hours.1 In healthy subjects, 80% or more of the remimazolam dose is excreted in urine as inactive metabolite CNS7054.1 In colonoscopy patients, 50-60% of the dose is excreted in urine as inactive metabolite CNS7054, and 0.003% of the dose is excreted unchanged in urine.1 There are no clinically relevant effects on the pharmacokinetics of remimazolam based on age, sex, race, and weight.1

Advice to Patients

• Advise patients to notify their healthcare provider about the use of alcohol or medications.1 Alcohol and other CNS depressants, such as opioid analgesics and benzodiazepines, can have an additive effect when administered with remimazolam.1
• 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.1
• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Benzodiazepines cross the placenta and may produce respiratory depression, sedation, and/or neonatal withdrawal syndrome in neonates.1 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).1
• 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.1 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.1
• Inform patients of other important precautionary information.1 (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.

1. Acacia Pharma, Ltd. BYFAVO® (remimazolam besylate) INTRAVENOUS prescribing information. 2023 Jan.

2. Rex DK, Bhandari R, Desta T, et al. A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2018;88(3):427-437.e6.

3. Rex DK, Bhandari R, Lorch DG, Meyers M, Schippers F, Bernstein D. Safety and efficacy of remimazolam in high risk colonoscopy: A randomized trial. Dig Liver Dis. 2021;53(1):94-101.

4. Pastis NJ, Yarmus LB, Schippers F, et al. Safety and Efficacy of Remimazolam Compared With Placebo and Midazolam for Moderate Sedation During Bronchoscopy. Chest. 2019;155(1):137-146.

5. Food and Drug Administration. FDA summary review: application number 212295Orig1s000FDA. From the FDA website. Accessed 2023 Mar 6. [Web]

821. Policy statement: procedural sedation in the emergency department. American College of Emergency Physicians. Updated June 2017. Accessed February 17, 2023. from website. [Web]

822. Godwin SA, Burton JH, Gerardo CJ et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2014; 63:247-58.e18.

823. Practice Guidelines for Moderate Procedural Sedation and Analgesia 2018: A Report by the American Society of Anesthesiologists Task Force on Moderate Procedural Sedation and Analgesia, the American Association of Oral and Maxillofacial Surgeons, American College of Radiology, American Dental Association, American Society of Dentist Anesthesiologists, and Society of Interventional Radiology. Anesthesiology. 2018; 128:437-479.

824. Green SM, Roback MG, Krauss BS, et al. Unscheduled Procedural Sedation: A Multidisciplinary Consensus Practice Guideline. Ann Emerg Med. 2019;73(5):e51-e65.

825. ACR-SIR practice parameter for minimal and/or moderate sedation/analgesia. American College of Radiology. Updated 2020. Accessed February 17, 2023. from website. [Web]