Remimazolam

Medically reviewed by Drugs.com. Last updated on Mar 18, 2024.

Index Terms

• Byfavo
• Remimazolam besylate

Pharmacologic Category

• Benzodiazepine

Pharmacology

Binds to brain benzodiazepine sites (GABA-A receptors) while its carboxylic acid metabolite (CNS7054) has a 300 times lower affinity for the receptor. Remimazolam does not show a clear selectivity between subtypes of the GABA-A receptor

Distribution

V_d: 0.76 to 0.98 L/kg.

Metabolism

Via conversion to primary inactive metabolite CNS7054 by tissue carboxylesterases (primarily type 1A), which is then subject to hydroxylation and glucuronidation.

Excretion

Urine (0.003% [unchanged]; 50 to 60% [inactive metabolite]).

Time to Peak

Sedation: 3 to 3.5 minutes (single dose); 11 to 14 minutes (multiple dose).

Duration of Action

11 to 14 minutes after last dose.

Half-Life Elimination

37 to 53 minutes.

Protein Binding

>91%; primarily to albumin.

Special Populations: Renal Function Impairment

In patients with renal impairment, AUC and C_max was not significantly different from normal to severe renal impairment.

Special Populations: Hepatic Function Impairment

In patients with moderate to severe impairment, C_max was reduced by 10% and 20%, half-life is prolonged by 60 and 105 minutes, and volume of distribution increased by 33% and 41%, respectively, compared to healthy patients.

Use: Labeled Indications

Sedation: Induction and maintenance of procedural sedation in adults undergoing procedures lasting ≤30 minutes.

Contraindications

Severe hypersensitivity to dextran 40 or products containing dextran 40.

Dosing: Adult

Sedation:

Note: Individualize dosing and titrate to desired clinical effect; subsequent doses should be titrated on the basis of clinical judgement and assessment of the depth of sedation; if maintenance of procedural sedation is inadequate, consider alternative medications.

Induction of procedural sedation:

Healthy adults: IV: 5 mg over 1 minute.

American Society of Anesthesiologists physical status III or IV patients: IV: 2.5 to 5 mg over 1 minute based on general condition of patient.

Maintenance of procedural sedation:

Healthy adults: IV: 2.5 mg over 15 seconds as needed; at least 2 minutes must elapse prior to administration of any supplemental dose.

American Society of Anesthesiologists physical status III or IV patients: IV: 1.25 to 2.5 mg over 15 seconds as needed; at least 2 minutes must elapse prior to administration of any supplemental dose.

Dosing: Geriatric

Refer to adult dosing; use caution and administer supplemental doses slowly.

Reconstitution

Reconstitute with 8.2 mL NS to a final concentration of 2.5 mg/mL; direct stream of solution toward the wall of the vial and gently swirl (do not shake) until the contents are fully dissolved. After reconstitution, solution should be a clear, colorless to a pale yellow solution.

Administration

IV: Administer IV induction dose over 1 minute and maintenance dose over 15 seconds. Only persons trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer remimazolam.

Storage

Prior to reconstitution, store vial at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Prepare immediately before use; if not used immediately, reconstituted solution may be stored in the vial for up to 8 hours at 20°C to 25°C (68°F to 77°F). Protect vials from light once removed from packaging.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Consider therapy modification

Fosphenytoin: Benzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Melatonin: May enhance the sedative effect of Benzodiazepines. Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Bradycardia (4% to 11%), decreased diastolic blood pressure (8% to 14%), hypertension (20% to 28%), hypotension (33% to 39%; increased diastolic blood pressure 10% to 25%), systolic hypertension (5% to 22%)

Respiratory: Hypoxia (22%), tachypnea (14%)

1% to 10%:

Cardiovascular: Tachycardia (8%)

Gastrointestinal: Nausea (4%)

Nervous system: Headache (3%)

Miscellaneous: Fever (4%)

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis, may occur due to the presence of dextran.

Disease-related concerns:

• Hepatic impairment: Use caution in patients with severe hepatic impairment; carefully titrate to effect; lower frequency of supplemental doses may be needed.

Concurrent drug therapy issues:

• Concomitant use with opioids: [US Boxed Warning]: Concomitant use of benzodiazepines, including remimazolam, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death; sedative effect may be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. These respiratory effects are more likely to occur in patients with obstructive sleep apnea, the elderly, and the American Society of Anesthesiologists physical status III or IV patients. Continuously monitor patients for respiratory depression and depth of sedation.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly patients: Potential for faster onset of loss of consciousness and longer duration of action. Sedating drugs may cause confusion and over sedation in the elderly; use with caution.

• Pediatric: Neurotoxicity may occur in pediatric patients (unapproved use), particularly after repeated or prolonged exposures to anesthetic agents early in life, which may result in adverse cognitive or behavioral effects; weigh benefits against risks of anesthesia prior to elective procedures.

Other warnings/precautions:

• Personnel and equipment for monitoring and resuscitation: [US Boxed Warning]: Only personnel trained in the administration of procedural sedation should administer remimazolam and 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. Remimazolam has been associated with hypoxia, bradycardia, and hypotension; continuously monitor vital signs during sedation and during the recovery period. Resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration.

Monitoring Parameters

Monitor vital signs continuously (during sedation and through the recovery period), especially for signs of respiratory depression, hypotension, hypoventilation, airway obstruction, apnea, and oxygen desaturation; cardiorespiratory complications (especially in elderly and hepatic impairment patients).

Pregnancy Considerations

Benzodiazepines cross the placenta.

Teratogenic effects have been observed with some benzodiazepines; however, data are inconsistent and additional studies are needed. Based on data from other benzodiazepines, neonatal hypotonia, lethargy, respiratory depression, sedation, and withdrawal symptoms may occur following in utero exposure to remimazolam.

Based on animal data, repeated or prolonged use of general anesthetic and sedation medications that block N-methyl-D-aspartate receptors and/or potentiate GABA activity may affect brain development.

The American College of Obstetricians and Gynecologists recommends that pregnant women should not be denied medically necessary surgery regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 775 2019).

Patient Education

What is this drug used for?

• It is used to calm you before a procedure.

• It is used to cause sleep during a procedure.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• High or low blood pressure like very bad headache or dizziness, passing out, or change in eyesight

• Fast heartbeat

• Slow heartbeat

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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