Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer remimazolam. 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. 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 of remimazolam.
Concomitant use of benzodiazepines, including remimazolam, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of intravenous remimazolam can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. Continuously monitor patients for respiratory depression and depth of sedation.
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetics were not altered in patients with mild to severe renal impairment.
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.
Severe impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling; use caution and carefully titrate to effect; lower frequency of supplemental doses may be needed.
Refer to adult dosing; use caution and administer supplemental doses slowly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Byfavo: 20 mg (1 ea) [contains dextran 40, lactose monohydrate]
No
C-IV
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.
Sedation: Induction and maintenance of procedural sedation in adults undergoing procedures lasting ≤30 minutes.
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%)
Severe hypersensitivity to dextran 40 or products containing dextran 40.
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.
• Respiratory disease: Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.
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.
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.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: 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. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: 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. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk C: 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. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
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. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
OLANZapine: Benzodiazepines may enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: 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. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: 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. Risk D: Consider therapy modification
Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: 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. Risk D: Consider therapy modification
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).
It is not known if remimazolam is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Lactating women may express and discard milk for 5 hours after administration to decrease potential exposure to an infant via breast milk. Monitor breastfed infants for sedation, respiratory depression, and feeding problems.
The Academy of Breast Feeding Medicine recommends postponing elective surgery until milk supply and breastfeeding are established. Milk should be expressed ahead of surgery when possible. In general, when the child is healthy and full term, breastfeeding may resume, or milk may be expressed once the mother is awake and in recovery. For children who are at risk for apnea, hypotension, or hypotonia, milk may be saved for later use when the child is at lower risk (ABM [Reece-Stremtan 2017]).
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).
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
Duration: 11 to 14 minutes after last dose.
Distribution: Vd: 0.76 to 0.98 L/kg.
Protein binding: >91%; primarily to albumin.
Metabolism: Via conversion to primary inactive metabolite CNS7054 by tissue carboxylesterases (primarily type 1A), which is then subject to hydroxylation and glucuronidation.
Half-life elimination: 37 to 53 minutes.
Time to peak: Sedation: 3 to 3.5 minutes (single dose); 11 to 14 minutes (multiple dose).
Excretion: Urine (0.003% [unchanged]; 50% to 60% [inactive metabolite]).
Renal impairment: In patients with renal impairment, AUC and Cmax was not significantly different from normal to severe renal impairment.
Hepatic impairment: In patients with moderate to severe impairment, Cmax 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.
Solution (reconstituted) (Byfavo Intravenous)
20 mg (per each): $46.80
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