Remimazolam (Byfavo®): A Comprehensive Pharmacological and Clinical Monograph

Section I: Drug Identity and Physicochemical Characteristics

1.1. Overview and Classification

Remimazolam is an ultra-short-acting intravenous (IV) benzodiazepine (BDZ) sedative and anesthetic agent.[1] It is classified as an imidazobenzodiazepine and was developed as a modern alternative to the widely used short-acting benzodiazepine, midazolam.[3] The defining characteristic of remimazolam is its classification as a "soft drug".[1] This pharmacological design concept involves creating a therapeutically active molecule that is intentionally engineered to be metabolically fragile. This fragility ensures rapid and predictable biotransformation into inactive metabolites within the body, leading to a swift termination of its pharmacological effects upon cessation of administration.[2]

This "soft drug" principle is the cornerstone of remimazolam's clinical value. The drug's name itself, "Remi-mazolam," was deliberately conceived by its developers to signal its therapeutic identity: it combines the well-understood sedative and amnestic properties of a benzodiazepine like midazolam with the ultra-short-acting pharmacokinetic profile of the opioid remifentanil, which is also metabolized by non-specific esterases.[6] This conceptual linkage underscores a sophisticated development strategy—applying a proven pharmacological design principle from one therapeutic class (opioids) to another (benzodiazepines) to address the well-documented clinical limitations of older agents, namely prolonged and unpredictable sedation.

1.2. Nomenclature and Identifiers

For clarity in research, clinical practice, and regulatory contexts, remimazolam is identified by a variety of names and codes.

• Generic Name: Remimazolam.[3]
• Brand Names: The drug is marketed globally under several brand names, reflecting its regional licensing partnerships. These include Byfavo® in the United States, the European Union, and South Korea; Anerem® in Japan; Aptimyda™ in the European Union; and Ruima® in China.[2]
• Development Codes and Synonyms: During its development, it was referred to as CNS-7056 (or CNS 7056), ONO-2745, and WHO 9232.[3]
• Salt Forms: Remimazolam is formulated as a salt to improve its stability and solubility. The form approved in the US and Europe is remimazolam besylate (benzenesulfonate).[1] A different salt form, remimazolam tosylate, has also been developed and approved in China.[11]
• Database Identifiers: Key identifiers used in major scientific and regulatory databases include:
• DrugBank ID: DB12404.[3]
• CAS Number: 308242-62-8.[3]
• PubChem CID: 9867812.[1]
• FDA UNII: 7V4A8U16MB.[3]

1.3. Chemical Structure and Properties

The pharmacological behavior of remimazolam is a direct consequence of its specific molecular architecture. Its structure contains the core imidazobenzodiazepine ring system responsible for its sedative effects, but with a critical modification that dictates its unique metabolism.

The key structural feature is a methyl-propionate ester side chain attached to the diazepine ring.[4] This ester linkage is the metabolic "Achilles' heel" that makes remimazolam a soft drug, as it serves as the target for rapid hydrolysis by tissue esterases.[4] This intentional structural design element is what differentiates it from other benzodiazepines and is responsible for its ultra-short duration of action.

Its physicochemical properties are summarized in Table 1. Notably, its formulation as a water-soluble, lyophilized powder provides a significant clinical advantage. When reconstituted, it forms a painless injectate, contrasting sharply with lipid emulsion-based anesthetics like propofol, which are frequently associated with injection site pain.[2]

Table 1: Drug Identification and Chemical Properties

Attribute	Value	Source(s)
IUPAC Name	methyl 3-benzodiazepin-4-yl]propanoate	1
Molecular Formula	C21​H19​BrN4​O2​	1
Molecular Weight	439.31 g/mol	10
Physical Appearance	Off-White to Pale Yellow solid powder	11
Solubility	Water-soluble upon reconstitution; Soluble in DMSO; Slightly soluble in Chloroform, Methanol	6
Predicted Boiling Point	583.5±60.0 °C	11
Predicted Density	1.48±0.1 g/cm3	11
InChIKey	CYHWMBVXXDIZNZ-KRWDZBQOSA-N	1

Section II: Core Pharmacology

The clinical profile of remimazolam is defined by a familiar pharmacodynamic mechanism combined with a novel and highly advantageous pharmacokinetic profile. This section deconstructs how the drug acts on the body and how the body acts on the drug.

2.1. Pharmacodynamics (Mechanism of Action)

Remimazolam exerts its sedative, anxiolytic, and amnestic effects through the classical benzodiazepine pathway, acting as a potent positive allosteric modulator (PAM) of the gamma-aminobutyric acid type A (GABAA​) receptor.[10]

• Receptor Binding and Modulation: The GABAA​ receptor is the primary inhibitory neurotransmitter receptor in the mammalian central nervous system (CNS). It is a ligand-gated ion channel that, when activated by its endogenous ligand GABA, allows chloride ions (Cl−) to flow into the neuron.[15] Remimazolam binds with high affinity to the specific benzodiazepine (BDZ) recognition site on the GABAA​ receptor complex. This site is located at the extracellular interface between the alpha (α) and gamma (γ) subunits, a location distinct from the GABA binding site itself.[5]
• Conformational Change and Effect: The binding of remimazolam to the BDZ site induces a conformational change in the receptor that increases the affinity of GABA for its own binding sites.[19] This allosteric modulation potentiates the effect of GABA, leading to an increased frequency of the chloride channel opening.[6] The resulting influx of negatively charged chloride ions causes hyperpolarization of the postsynaptic neuronal membrane, making it more difficult for the neuron to fire an action potential. This widespread enhancement of inhibitory neurotransmission produces the characteristic CNS depressant effects of benzodiazepines, including sedation, anxiolysis, muscle relaxation, and amnesia.[2]
• Subtype Selectivity and Potency: Remimazolam does not exhibit significant selectivity among the various GABAA​ receptor subtypes.[4] However, some evidence suggests it is slightly more potent at receptors containing the α1​ subunit, a subtype widely believed to mediate the sedative effects of benzodiazepines.[15] In terms of potency, it is considered to be approximately half as potent as midazolam for achieving procedural sedation.[6] Its high binding affinity is quantified by its pKi values (a logarithmic measure of binding affinity) of 7.53, 7.50, and 7.56 against flunitrazepam binding in human, rat, and micropig brain homogenates, respectively.[11]

The mechanism of remimazolam is therefore not novel; it leverages a well-understood pathway. Its clinical distinction arises not from how it works, but from how long it works, a property dictated entirely by its pharmacokinetics.

2.2. Pharmacokinetics (ADME)

The pharmacokinetic profile of remimazolam is its defining feature and the primary source of its clinical advantages over older benzodiazepines. Its ADME (Absorption, Distribution, Metabolism, and Excretion) properties are characterized by rapid onset, minimal accumulation, and predictable, swift elimination.

• Absorption and Onset of Action: Following intravenous administration, remimazolam achieves peak sedation rapidly, with an onset of action ranging from 1.5 to 3.5 minutes.[19] This is demonstrably faster than midazolam, allowing for a quicker start to medical procedures.[3]
• Distribution: Remimazolam has a relatively small steady-state volume of distribution (Vss​) of approximately 35 L (or 0.76-0.98 L/kg), which is significantly smaller than that of midazolam (approx. 82 L).[4] This small Vss​ indicates that the drug has limited distribution into peripheral tissues, which contributes to its minimal accumulation and rapid offset of effect. It is highly bound to plasma proteins (approx. 91-92%), primarily to serum albumin.[4]
• Metabolism: The "Soft Drug" Advantage: The metabolism of remimazolam is the key to its unique profile.

1. Esterase Hydrolysis: As a "soft drug," remimazolam is engineered with a metabolically labile ester linkage in its structure.[4] It is rapidly and extensively hydrolyzed by non-specific tissue esterases, with liver carboxylesterase-1 (CES1) being the primary enzyme, into its main metabolite, CNS-7054.[2]
2. Inactive Metabolite: This carboxy acid metabolite, CNS-7054, is pharmacologically inactive, possessing a 300- to 400-fold lower affinity for the GABAA​ receptor than the parent remimazolam molecule.[2] This ensures that once metabolized, the drug's effect is terminated.
3. Independence from Cytochrome P450: Critically, the metabolism of remimazolam is not dependent on the cytochrome P450 (CYP450) enzyme system in the liver. Furthermore, it does not induce or inhibit these enzymes.[5] This is a fundamental departure from midazolam, which is metabolized by CYP3A4. The CYP450 system is notorious for high inter-patient genetic variability and susceptibility to drug-drug interactions. By bypassing this pathway, remimazolam achieves a more consistent and predictable metabolic profile across different patients and reduces the risk of pharmacokinetic drug interactions.

• Excretion: The inactive CNS-7054 metabolite is primarily eliminated from the body via the kidneys. Over 80% of an administered dose is excreted in the urine as this metabolite, with a negligible amount (<0.003%) of the parent drug being excreted unchanged.[4]
• Clearance and Half-Life: The unique metabolism of remimazolam results in exceptionally favorable clearance characteristics.
• Elimination Half-Life (t1/2​): The terminal elimination half-life is very short, ranging from 37 to 70 minutes.[3]
• Clearance (CL): Remimazolam exhibits high systemic clearance, approximately 70 L/h, which is roughly three times that of midazolam and is notably independent of body weight.[4]
• Context-Sensitive Half-Time (CSHT): The CSHT is the time required for the plasma drug concentration to decrease by 50% after stopping a continuous infusion. For remimazolam, the CSHT is short (approximately 7.5 minutes) and, crucially, remains stable and does not significantly increase with the duration of the infusion.[4] This contrasts sharply with midazolam, whose CSHT increases substantially with longer infusions, leading to unpredictable and prolonged recovery. Remimazolam's CSHT profile is more comparable to that of propofol.

This combination of rapid, organ-independent metabolism, high clearance, and a short, stable CSHT directly translates into the primary clinical benefits of remimazolam: a highly controllable and titratable sedative effect, minimal drug accumulation, and a rapid, predictable recovery profile. These pharmacokinetic advantages have significant downstream implications for clinical workflow and patient management. The predictability of recovery can reduce time spent in post-anesthesia care units (PACU), potentially increasing procedural throughput in high-volume environments like endoscopy suites. While the drug itself may have a higher acquisition cost than older generics, the potential for enhanced operational efficiency and reduced downstream costs associated with prolonged monitoring and recovery could render it pharmacoeconomically favorable in certain settings. The drug's value, therefore, extends beyond its immediate clinical effect to its potential to optimize the entire peri-procedural pathway.

Table 2: Summary of Key Pharmacokinetic Parameters (Remimazolam vs. Midazolam)

Pharmacokinetic Parameter	Remimazolam	Midazolam	Clinical Implication	Source(s)
Metabolism Pathway	Tissue Esterases (non-CYP450)	Cytochrome P450 (CYP3A4)	Lower potential for drug-drug interactions and genetic variability; more predictable metabolism.	15
Active Metabolites	No	Yes	Recovery from remimazolam is not prolonged by active metabolites.	4
Systemic Clearance (CL)	High (~70 L/h)	Moderate (~23 L/h)	Faster drug elimination from the body.	4
Volume of Distribution (Vss​)	Small (~35 L)	Large (~82 L)	Less tissue accumulation, contributing to a faster offset of effects.	4
Elimination Half-Life (t1/2​)	Short (37-70 min)	Longer (1.8-6.4 hours)	Rapid termination of drug effect after administration ceases.	3
Context-Sensitive Half-Time (CSHT)	Short (~7.5 min), stable with infusion duration	Longer (~40 min after 3h), increases with infusion duration	Predictable and rapid recovery even after prolonged infusions. Highly titratable.	4

Section III: Clinical Application and Administration

The unique pharmacological profile of remimazolam has positioned it as a valuable tool in various clinical settings, translating its rapid and predictable action into tangible benefits for both patients and healthcare providers. Its application ranges from approved indications for short procedures to broader off-label use in more complex anesthetic scenarios.

3.1. Approved and Investigational Indications

Remimazolam's regulatory approvals have been granted progressively across the globe, often for different initial indications, reflecting diverse clinical development strategies.

• Procedural Sedation: This is the most widely approved indication.
• In the United States, the FDA approved remimazolam in July 2020 for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.[3]
• In the European Union, it was approved for the same indication in March 2021.[3]
• China also approved it for procedural sedation in July 2020.[14]
• These approvals were largely based on robust data from trials in patients undergoing colonoscopy and bronchoscopy.[3]
• General Anesthesia:
• Remimazolam received its first-ever global approval in Japan in January 2020 for the induction and maintenance of general anesthesia.[8]
• South Korea and the European Union have also approved it for general anesthesia in adults, with the EU approval granted in April 2023.[1]
• In the US, while not formally FDA-approved for this indication, its use for general anesthesia is reported extensively in the literature, highlighting a perceived clinical need and confidence among practitioners that extends beyond its narrow initial approval.[6] This discrepancy between the conservative US label and broader international approvals suggests its full clinical role is still being defined post-market by real-world evidence and practice.
• Investigational and Compassionate Use:
• Intensive Care Unit (ICU) Sedation: Remimazolam's favorable pharmacokinetics, particularly its stable CSHT, make it an attractive candidate for sedation in the ICU. It has been used for this purpose on a compassionate basis in Belgium and is considered a promising future indication based on positive Phase II study results.[6] A pilot study has directly compared its use against propofol for long-term sedation in mechanically ventilated ICU patients.[35]

3.2. Dosage, Reconstitution, and Administration

Safe and effective use of remimazolam requires adherence to precise guidelines for preparation and administration, with dosing tailored to the patient, procedure, and regional regulatory recommendations.

• Preparation and Reconstitution: Remimazolam is supplied as a sterile, preservative-free, lyophilized powder in a 20 mg single-patient-use vial. It must be reconstituted immediately before use by adding 8.2 mL of sterile 0.9% Sodium Chloride Injection, USP. The vial should be gently swirled until the contents are fully dissolved, yielding a clear, colorless to pale yellow solution with a final concentration of 2.5 mg/mL.[16]
• Procedural Sedation Dosing: Dosing recommendations vary slightly between major regulatory bodies.
• US FDA Guidelines: For most adult patients, induction is achieved with a 5 mg IV push over 1 minute. For patients with higher anesthetic risk (ASA Physical Status III or IV), a reduced dose of 2.5-5 mg over 1 minute is recommended. Maintenance of sedation is achieved with supplemental doses of 2.5 mg IV over 15 seconds as needed (1.25-2.5 mg for ASA III/IV patients). A critical safety measure is that at least 2 minutes must elapse between any supplemental doses to allow for the peak effect to be observed.[22]
• EU EMA Guidelines: The European guidelines are more stratified, explicitly accounting for concomitant opioid use, age, and patient condition. For adults under 65 receiving opioids, the initial dose is 5 mg over 1 minute. Without opioids, a higher initial dose of 7 mg is used. For elderly patients (≥ 65 years) or those with an ASA-PS of III-IV, a lower initial dose of 2.5-5 mg is recommended, with maintenance doses of 1.25-2.5 mg.[41] This granular approach reflects a detailed consideration of factors known to influence sedative requirements.
• General Anesthesia Dosing (International/Off-Label): While an optimal dosing strategy is still being established, approved labeling in Japan and South Korea recommends an induction infusion of 6-12 mg/kg/h until loss of consciousness, followed by a maintenance infusion of 1 mg/kg/h (maximum 2 mg/kg/h).[33] Clinical experience reported in the literature often involves an induction bolus of 0.2-0.4 mg/kg followed by a maintenance infusion of 1-2 mg/kg/hr.[6]
• Fluid Compatibility: Remimazolam is compatible with common IV fluids such as 0.9% Sodium Chloride, 5% Dextrose, and Ringer's Solution. However, it is incompatible with Lactated Ringer's and Acetated Ringer's solutions, as precipitation can occur. This is a critical practical consideration to prevent infusion line occlusion and administration errors.[6]

Table 3: Recommended Dosing for Procedural Sedation (FDA vs. EMA)

Patient Scenario	US FDA Recommended Dose (Induction / Maintenance)	EU EMA Recommended Dose (Induction / Maintenance)	Key Considerations	Source(s)
Standard Adult (<65 years, ASA I-II)	5 mg IV over 1 min / 2.5 mg IV over 15 sec	With Opioid: 5 mg IV over 1 min / 2.5 mg IV over 15 sec Without Opioid: 7 mg IV over 1 min / 2.5 mg IV over 15 sec	EMA guidelines explicitly adjust induction dose based on opioid use. Wait at least 2 minutes between doses.	22
Elderly (≥65 years) or ASA III-IV	2.5 - 5 mg IV over 1 min / 1.25 - 2.5 mg IV over 15 sec	2.5 - 5 mg IV over 1 min / 1.25 - 2.5 mg IV over 15 sec	Dose reduction and careful titration are universally recommended for vulnerable populations due to potential for increased sensitivity.	6

3.3. Clinical Value and Strategic Positioning

Remimazolam is not merely a replacement for older drugs but is strategically positioned to address specific clinical challenges where the profiles of midazolam or propofol are suboptimal.

• Fast-Track Surgery and Outpatient Settings: The rapid and highly predictable recovery from remimazolam makes it an ideal agent for ambulatory surgery and outpatient procedures. Patients regain alertness and cognitive function quickly, facilitating earlier discharge and improving procedural throughput.[10]
• Vulnerable and High-Risk Populations: Its organ-independent metabolism and favorable hemodynamic profile make it a preferred choice for patients in whom other agents pose a greater risk. This includes:
• Elderly Patients: Who are more susceptible to the prolonged effects of midazolam and the hypotensive effects of propofol.[42]
• Patients with Hepatic or Renal Impairment: Remimazolam's esterase metabolism bypasses compromised organ function, offering a more predictable and safer profile.[6]
• Hemodynamically Unstable Patients: Its minimal impact on blood pressure and heart rate makes it valuable in cardiac catheterization labs, trauma surgery, and for patients with limited cardiopulmonary reserve.[6]
• Non-Operating Room Anesthesia (NORA): Remimazolam is increasingly used in NORA settings where patient access and monitoring can be challenging. Its safety profile is advantageous for GI and pulmonary endoscopy, interventional radiology procedures, and MRI sedation, where it can provide adequate sedation and amnesia with less cardiorespiratory compromise.[6]
• Neurosurgery: In procedures like awake craniotomies, remimazolam's rapid on/off characteristics allow for sedation during painful parts of the procedure (e.g., surgical incision) while permitting rapid awakening for intraoperative neurological testing.[6]

Section IV: Safety, Tolerability, and Risk Management

While remimazolam offers a favorable safety profile compared to its predecessors, it is a potent CNS depressant that requires rigorous monitoring and risk management. Its safety profile is characterized by a predictable set of adverse effects, specific contraindications, and a crucial interaction with opioids.

4.1. Adverse Event Profile

Clinical trials have established a consistent profile of adverse reactions associated with remimazolam administration.

• Common Adverse Reactions: The most frequently observed adverse events are extensions of the drug's primary pharmacological effects on the cardiovascular and respiratory systems.
• Hemodynamic Effects: Changes in blood pressure are very common. Hypotension is the most cited adverse event, reported in over 10% of patients in procedural sedation studies and up to 51% in general anesthesia trials. Paradoxically, hypertension (both systolic and diastolic) has also been commonly reported.[3] Bradycardia (slow heart rate) is also a common finding.[30]
• Respiratory Effects: Respiratory depression, including hypoxia (low blood oxygen), is a very common adverse event, occurring in over 10% of patients receiving the drug for procedural sedation.[3]
• Other Common Effects: Other frequently reported side effects include headache, dizziness, nausea, and vomiting.[45] Involuntary patient movement during infusion has also been noted as a potential issue.[15]
• Hepatotoxicity: A significant safety advantage of remimazolam is its lack of liver toxicity. Its non-hepatic, esterase-mediated metabolism means it has not been associated with elevations in serum aminotransferases or cases of clinically apparent drug-induced liver injury. The National Institute of Diabetes and Digestive and Kidney Diseases' LiverTox database assigns it a Likelihood Score of "E," indicating it is an unlikely cause of liver injury.[1]

4.2. Contraindications, Warnings, and Precautions

The use of remimazolam is governed by specific contraindications and a prominent boxed warning that emphasizes the need for a controlled and monitored environment.

• Contraindications: Remimazolam is strictly contraindicated in patients with:

1. A history of severe hypersensitivity reaction to dextran 40 or products containing it. The Byfavo® formulation contains dextran 40 as an excipient, which can cause severe anaphylactic reactions.[6]
2. Unstable myasthenia gravis, a neuromuscular disease where benzodiazepines can exacerbate muscle weakness, particularly of the respiratory muscles.[30]

• US FDA Boxed Warning: The prescribing information includes a boxed warning with two main components:

1. Personnel and Equipment for Monitoring and Resuscitation: Remimazolam must only be administered by personnel specifically trained in the administration of procedural sedation and advanced airway management, and who are not simultaneously involved in conducting the diagnostic or therapeutic procedure. The setting must be fully equipped for monitoring and supporting respiratory and cardiovascular function, and resuscitative drugs, age-appropriate airway equipment, and a specific benzodiazepine reversal agent (flumazenil) must be immediately available.[22]
2. Risks from Concomitant Use with Opioid Analgesics: The co-administration of benzodiazepines, including remimazolam, with opioid analgesics can result in profound sedation, severe respiratory depression, coma, and death. Patients receiving this combination must be continuously monitored for depth of sedation and respiratory status.[13]

• Precautions in Specific Populations:
• Pregnancy: Remimazolam crosses the placenta. Use during late pregnancy can result in neonatal sedation (respiratory depression, lethargy, hypotonia) and/or neonatal withdrawal syndrome. Newborns exposed in utero should be monitored accordingly.[7]
• Lactation: While human data are limited, remimazolam is present in animal milk and is likely to be present in human milk. To minimize infant exposure, it is recommended that breastfeeding be withheld for a period of 5 to 24 hours after administration.[7]
• Pediatric Use: The safety and effectiveness of remimazolam have not been established in pediatric patients. Like other anesthetic agents that modulate GABA receptors, there is a theoretical concern for potential adverse effects on brain development in children under 3 years of age with prolonged or repeated exposure.[7]
• Elderly Patients: Older adults may exhibit increased sensitivity to the effects of remimazolam, including longer-lasting drowsiness and a higher risk of cardiorespiratory complications. Dose reduction and slower titration are recommended.[6]
• Hepatic Impairment: In patients with severe hepatic impairment (Child-Pugh class C), drug clearance is reduced, leading to increased exposure and prolonged elimination. Careful dose titration and potentially a lower frequency of supplemental doses are necessary.[4]
• Renal Impairment: No dose adjustments are required for patients with renal disease, including end-stage renal disease not requiring dialysis.[6]

4.3. Drug Interaction Profile

The drug interaction profile of remimazolam is dominated by predictable pharmacodynamic synergism, with a notable lack of pharmacokinetic interactions.

• Pharmacodynamic Interactions: The primary concern is the additive or synergistic CNS depression when remimazolam is co-administered with other depressant medications. This includes opioid analgesics, other benzodiazepines, propofol, alcohol, sedative antihistamines, and antipsychotics. Such combinations significantly increase the risk of over-sedation, hypotension, and life-threatening respiratory depression, necessitating careful dose titration and vigilant patient monitoring.[5]
• Pharmacokinetic Interactions: Because remimazolam is metabolized by tissue esterases and not by the cytochrome P450 system, the potential for pharmacokinetic drug-drug interactions is minimal. This is a significant advantage over midazolam and simplifies its use in patients on multiple medications that are substrates, inhibitors, or inducers of CYP enzymes.[15]
• Decreased Efficacy: The therapeutic effect of remimazolam can be diminished by xanthines such as aminophylline, which are adenosine receptor antagonists and have a CNS-stimulating effect.[5]

4.4. Overdose and Reversal

Overdose with remimazolam manifests as an exaggeration of its known pharmacological effects. Management is supportive, with the critical advantage of a specific reversal agent.

• Symptoms of Overdose: Manifestations include profound drowsiness progressing to coma, confusion, ataxia, severe respiratory depression, and hypotension.[5]
• Management: Treatment is primarily supportive. This involves maintaining a patent airway, providing assisted ventilation as needed, and managing hypotension with intravenous fluids, repositioning, and vasopressor agents if necessary.[46]
• Specific Antagonist (Reversal Agent): The sedative and respiratory depressant effects of remimazolam can be specifically and rapidly reversed by the competitive benzodiazepine antagonist flumazenil. The immediate availability of flumazenil is a required safety standard for remimazolam administration.[2] This provides a crucial safety net that is absent for other common sedatives like propofol. While resedation after reversal is considered unlikely due to remimazolam's short half-life, it has been reported and care must be taken, especially after long infusions or in patients with severe liver disease.[6]

The safety profile of remimazolam thus represents a distinct clinical trade-off. It effectively mitigates the primary risk associated with propofol—hemodynamic instability—while retaining the primary risk inherent to all benzodiazepines: respiratory depression, especially when combined with opioids. However, it fundamentally alters this risk calculation by providing a specific and effective reversal agent, flumazenil, a safety feature that propofol lacks. This positions remimazolam not as an absolutely "safer" drug, but as an agent with a different and, in many scenarios, more manageable risk profile, allowing for a more strategic, risk-stratified approach to anesthesia.

4.5. Abuse and Dependence Potential

As a member of the benzodiazepine class, remimazolam is subject to control and has an inherent potential for abuse and dependence.

• Legal Status: In the United States and Canada, remimazolam is classified as a DEA Schedule IV controlled substance. This scheduling indicates a low potential for abuse and low risk of dependence relative to substances in Schedule III.[1]
• Addiction and Dependence Potential: Studies suggest that remimazolam has an addictive potential that is comparable to its parent compound, midazolam.[15] However, the risk of abuse and dependence in its intended clinical context is considered low. This is because it is administered exclusively intravenously by trained professionals in a controlled medical setting and has poor oral bioavailability, limiting its potential for diversion and misuse.[15] Patients with a history of substance abuse should still be treated with caution.

Section V: Comparative Clinical Evidence: A Synthesis of Head-to-Head Trials

The clinical value of a new anesthetic agent is ultimately determined by its performance relative to established standards of care. An extensive body of clinical trial evidence and subsequent meta-analyses has compared remimazolam directly against midazolam and propofol, providing a clear picture of its relative strengths and weaknesses.

5.1. Comparison with Midazolam

When compared to its predecessor, midazolam, remimazolam consistently demonstrates superior efficacy, speed, and predictability in the setting of procedural sedation.

• Efficacy and Onset: Remimazolam achieves a significantly higher rate of procedural success than midazolam. Pooled analyses and individual trials show success rates for remimazolam often exceeding 80%, compared to rates of around 30% for midazolam when used as a sole sedative.[24] This superior efficacy is coupled with a much faster and more predictable onset of action. The time from the first dose to the start of the procedure is significantly shorter with remimazolam (e.g., median of 3-6 minutes) compared to midazolam (median of 8-16 minutes).[24]
• Recovery Profile: The most striking advantage of remimazolam over midazolam is its recovery profile. Recovery to full alertness is significantly faster and, critically, more predictable. Median recovery times for remimazolam are typically around 6 minutes, whereas they can be 12-14 minutes or longer for midazolam.[24] This is a direct consequence of remimazolam's rapid esterase metabolism, which results in less inter-patient variability compared to the CYP450-dependent metabolism of midazolam.[51]
• Adjunctive Analgesia and Safety: An interesting finding from integrated analyses is that patients sedated with remimazolam required significantly less concomitant fentanyl for analgesia than those sedated with midazolam.[51] While the overall incidence of adverse events is often comparable between the two drugs, some studies have noted a lower incidence of hypotension with remimazolam and a lower requirement for the reversal agent flumazenil.[52]

The evidence strongly suggests that for procedural sedation, remimazolam is not just an alternative to midazolam, but a significant improvement, offering more reliable sedation, faster onset, and a much quicker, more predictable return to baseline function.

Table 5: Head-to-Head Comparison: Remimazolam vs. Midazolam for Procedural Sedation

Clinical Endpoint	Remimazolam Finding	Midazolam Finding	Comparative Result	Clinical Significance	Source(s)
Procedural Success Rate	High (>80%)	Low (~30%)	Remimazolam significantly superior (OR ~9.0)	More reliable sedation, fewer rescue medications needed.	24
Time to Onset of Sedation	Fast (Median 3-6 min)	Slow (Median 8-16 min)	Remimazolam significantly faster	Reduces procedure wait times and improves workflow efficiency.	24
Time to Full Recovery	Fast (Median ~6 min)	Slower (Median ~12-14 min)	Remimazolam significantly faster	Allows for quicker patient turnover and discharge.	24
Predictability (Variability)	Low inter-patient variability	High inter-patient variability	Remimazolam significantly more predictable	More consistent patient response, simplifying management.	51
Fentanyl Requirement	Lower	Higher	Remimazolam required significantly less fentanyl	May indicate better intrinsic sedative properties or less discomfort.	51
Overall Safety	Generally comparable	Generally comparable	No major differences in overall AE incidence in most trials.	Both are considered safe when used appropriately.	24

5.2. Comparison with Propofol

The comparison between remimazolam and propofol is more nuanced and represents the most critical decision point for clinicians choosing a primary agent for sedation or general anesthesia. The choice involves a trade-off between speed of onset and hemodynamic safety.

• Efficacy and Onset: In terms of achieving successful sedation or anesthesia, the two drugs are generally considered equivalent, with similar procedural success rates reported in meta-analyses.[53] However, propofol has a consistently faster onset of action. The time to loss of consciousness is significantly shorter with propofol than with remimazolam.[33]
• Recovery Profile: The recovery data present a complex picture.
• Objective Recovery Time: Several meta-analyses show that remimazolam is associated with faster emergence from sedation and shorter stays in the recovery room compared to propofol.[54] One study in elderly patients undergoing endoscopy found that recovery time with remimazolam was dramatically shorter (2.6 min vs. 10.8 min) but this was in the context of routine flumazenil administration for reversal.[57]
• Subjective Quality of Recovery (QoR): When recovery is measured using patient-reported outcome tools like the QoR-15 score, meta-analyses have found no significant difference between remimazolam and propofol on postoperative days 1, 2, or 3.[58] This suggests that while objective recovery metrics may favor remimazolam, the overall subjective patient experience of recovery is similar for both drugs.
• Safety Profile: This is the area where remimazolam demonstrates its most significant advantages.
• Hemodynamic Stability: Remimazolam is consistently and significantly associated with a lower incidence of hypotension and bradycardia compared to propofol across numerous studies and meta-analyses.[33] This superior cardiovascular stability is its primary safety advantage.
• Respiratory Safety: Remimazolam is also associated with a lower risk of respiratory depression and hypoxemia than propofol.[53]
• Injection Site Pain: Remimazolam is a water-soluble formulation and causes virtually no injection site pain, a common and bothersome side effect of the lipid-based propofol emulsion.[54]

In synthesis, remimazolam is not a universal replacement for propofol but rather a vital complementary agent. The choice between them becomes a strategic clinical decision. For procedures where maximum speed of onset is critical in a hemodynamically stable patient, propofol may remain the agent of choice. However, for patients where hemodynamic stability is paramount—such as the elderly, the critically ill, or those with cardiovascular comorbidities—remimazolam offers a demonstrably safer alternative. The availability of flumazenil as a specific reversal agent further solidifies its position as a go-to drug for high-risk scenarios. This paradigm expands the anesthesiologist's toolkit, enabling a more personalized and risk-stratified approach to patient care, moving practice away from a "one-size-fits-all" model.

Table 6: Head-to-Head Comparison: Remimazolam vs. Propofol

Clinical Endpoint	Remimazolam Finding	Propofol Finding	Comparative Result	Clinical Significance	Source(s)
Procedural Success Rate	High, similar to propofol	High, similar to remimazolam	No significant difference	Both are highly effective agents for sedation/anesthesia.	54
Time to Onset of Sedation	Slower	Faster	Propofol significantly faster	Propofol is preferred for rapid sequence induction or when speed is critical.	54
Time to Recovery	Faster emergence / shorter PACU stay (objective)	Slower emergence / longer PACU stay (objective)	Remimazolam faster in objective time-to-event measures.	May improve procedural throughput.	54
Quality of Recovery (QoR)	Similar subjective QoR-15 scores	Similar subjective QoR-15 scores	No significant difference on POD 1-3	Patient's overall feeling of recovery is comparable for both drugs.	58
Hypotension	Significantly lower incidence	Significantly higher incidence	Remimazolam superior (RR ~0.3-0.4)	Major safety advantage for remimazolam, especially in vulnerable patients.	54
Respiratory Depression	Significantly lower incidence	Significantly higher incidence	Remimazolam superior (RR ~0.3-0.5)	Enhanced respiratory safety profile for remimazolam.	54
Injection Site Pain	Virtually none	Common	Remimazolam significantly superior	Improves patient comfort during induction.	54
Reversal Agent	Specific antagonist (Flumazenil) available	No specific antagonist available	Major safety advantage for remimazolam	Allows for rapid termination of effect in an emergency.	6

Section VI: Development and Regulatory History

The journey of remimazolam from a laboratory concept to a globally approved medication is a modern case study in pharmaceutical development, illustrating the complex interplay between large pharmaceutical companies, smaller specialty firms, and global regulatory bodies.

6.1. Discovery and Development Pathway

Remimazolam was originally synthesized in the late 1990s at the Research Triangle Park laboratories of Glaxo Wellcome (now GlaxoSmithKline).[3] The discovery program was a direct outgrowth of the team's success with remifentanil and was specifically aimed at applying the same "soft drug," esterase-mediated metabolism principle to the benzodiazepine class to create a novel sedative with a short and predictable duration of action.[14]

Despite identifying remimazolam as a promising lead compound, Glaxo Wellcome shelved the project for strategic reasons, a common occurrence in large pharmaceutical companies managing vast research portfolios.[14] The compound's development was subsequently revived when the program was acquired by the small biotechnology company TheraSci. Through a series of further acquisitions, the asset eventually landed with CeNeS and then PAION AG, a German specialty pharmaceutical company that became the primary driver of its clinical development.[14] PAION, in turn, established a network of regional partnerships to navigate the complex landscape of global commercialization, licensing the drug to companies such as Cosmo Pharmaceuticals and its sub-licensee Acacia Pharma for the US market, Hana Pharm in South Korea, and Yichang Humanwell in China.[3] This development path highlights a common model in the modern pharmaceutical ecosystem, where innovation originating in large pharma is often nurtured and brought to market through the focused efforts of smaller, specialized companies and their international partners.

6.2. Global Regulatory Milestones

Following its extensive clinical development program, remimazolam achieved a rapid succession of marketing authorizations from major health authorities around the world, albeit with different initial indications reflecting regional development and regulatory strategies.

• Japan (PMDA): Japan was the first country to approve remimazolam (Anerem®) on January 23, 2020, for the indication of general anesthesia.[8]
• United States (FDA): Cosmo Pharmaceuticals submitted the New Drug Application (NDA) to the FDA on April 9, 2019.[62] On July 2, 2020, the FDA approved remimazolam (Byfavo®) for the induction and maintenance of procedural sedation in adults for procedures lasting 30 minutes or less. The approval was based on evidence from three pivotal Phase 3 clinical trials in patients undergoing colonoscopy and bronchoscopy (NCT02290873, NCT02296892, and NCT02532647).[3]
• China (NMPA): Remimazolam was approved for procedural sedation in July 2020.[14]
• South Korea (MFDS): Remimazolam was approved for general anesthesia, following the precedent set in Japan.[27]
• European Union (EMA): PAION submitted the Marketing Authorisation Application (MAA) in November 2019. The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion in January 2021.[3] The European Commission granted marketing authorization for Byfavo® for procedural sedation in March 2021.[3] Subsequently, following a separate submission, the EC approved remimazolam for the induction and maintenance of general anesthesia in April 2023, bringing its European indication in line with its use in Japan and South Korea.[32]

Table 4: Summary of Global Regulatory Approvals and Indications

Regulatory Body	Region/Country	Brand Name	Date of Approval	Approved Indication(s)	Source(s)
PMDA	Japan	Anerem®	January 2020	General Anesthesia	8
FDA	United States	Byfavo®	July 2020	Procedural Sedation (≤30 min)	3
NMPA	China	Ruima®	July 2020	Procedural Sedation	14
MFDS	South Korea	Byfavo®	(by 2021)	General Anesthesia	27
EMA	European Union	Byfavo® / Aptimyda™	March 2021	Procedural Sedation	3
EMA	European Union	Byfavo® / Aptimyda™	April 2023	General Anesthesia	32

Section VII: Concluding Analysis and Future Perspectives

Remimazolam represents a significant and intelligent incremental innovation in the field of anesthesiology. By applying the proven "soft drug" design principle to the benzodiazepine class, it successfully addresses the primary pharmacokinetic limitations of its predecessors. It is not a complete paradigm shift, as its mechanism of action is well-established, but it perfects the benzodiazepine profile for procedural and anesthetic use. Its ultimate impact on clinical practice will be determined by the ability of healthcare systems to leverage its safety and efficiency benefits to justify its higher cost.

7.1. Synthesis of Clinical Advantages and Limitations

A comprehensive review of the evidence reveals a clear and consistent profile of remimazolam's strengths and weaknesses.

• Key Advantages:
• Predictable Pharmacokinetics: Its rapid, organ-independent metabolism by tissue esterases results in a short, stable context-sensitive half-time, leading to a predictable recovery profile with low inter-patient variability.[3]
• Superior Safety Profile vs. Propofol: It demonstrates a significantly lower incidence of hypotension, bradycardia, and respiratory depression compared to propofol, making it a safer choice for hemodynamically unstable or vulnerable patients.[53]
• Availability of a Reversal Agent: The existence of flumazenil as a specific, effective antagonist provides a critical safety net that is unavailable for propofol, allowing for the rapid termination of sedation in an emergency.[6]
• Favorable Tolerability: The water-soluble formulation is not associated with injection site pain, a common issue with propofol.[6]
• Utility in Vulnerable Populations: Its metabolism is not dependent on liver or kidney function, making it a valuable agent for patients with organ compromise.[15]
• Key Limitations:
• Acquisition Cost: As a branded drug, its cost is significantly higher than that of generic mainstays like midazolam and propofol, which can be a barrier to widespread adoption.[6]
• Slower Onset vs. Propofol: Propofol provides a faster onset of unconsciousness, which may be preferable in situations requiring very rapid induction.[54]
• Risk of Respiratory Depression: As a benzodiazepine, it carries a risk of respiratory depression, which is significantly potentiated by concomitant opioid use, as highlighted in its FDA boxed warning.[48]
• Limited Long-Term and Special Population Data: There is a lack of extensive data on long-term neurocognitive outcomes (e.g., postoperative delirium) and on its use in pediatric and pregnant populations.[6]
• Reconstitution Requirement: Unlike ready-to-use formulations, remimazolam requires reconstitution prior to administration, adding a step to the clinical workflow.[37]

7.2. Future Research Directions

While the core profile of remimazolam is well-established, several key areas warrant further investigation to fully define its role in clinical practice.

• Long-Term ICU Sedation: While pilot studies are promising, large-scale, randomized controlled trials are needed to confirm its efficacy and safety for continuous sedation in critically ill patients for periods longer than 24-48 hours.[34]
• Postoperative Neurocognitive Outcomes: Rigorous studies are required to determine the relationship between remimazolam administration and the incidence of postoperative delirium (POD) and long-term postoperative cognitive dysfunction (POCD), especially in elderly and other at-risk populations.[6]
• Pediatric Applications: The development of a pediatric indication is a logical next step. This will require dedicated pharmacokinetic, efficacy, and safety trials to establish appropriate dosing and confirm its safety profile in children of various age groups.[44]
• Pharmacoeconomic Analyses: To justify its higher cost, robust health economic studies are needed to quantify the downstream cost savings that may result from its use, such as reduced PACU time, lower rates of complication-related interventions, and increased procedural throughput.[6]
• Quality of Recovery: Further research into its effects on subjective patient-reported outcomes, such as postoperative fatigue and sleep quality, will help to provide a more holistic understanding of its recovery profile compared to other agents.[58]

In conclusion, remimazolam stands as a testament to rational drug design. It offers a compelling combination of efficacy, safety, and predictability that positions it as a first-line agent for many procedural sedation scenarios and a vital alternative to propofol for general anesthesia in high-risk patients. Its future as a standard of care will depend on continued research to fill the remaining knowledge gaps and on the generation of strong pharmacoeconomic evidence to support its value proposition within resource-conscious healthcare systems.

Works cited

1. Remimazolam | C21H19BrN4O2 | CID 9867812 - PubChem, accessed July 28, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/9867812
2. Remimazolam: pharmacological characteristics and clinical applications in anesthesiology - Anesthesia and Pain Medicine, accessed July 28, 2025, https://www.anesth-pain-med.org/upload/pdf/apm-21115.pdf
3. Remimazolam - Wikipedia, accessed July 28, 2025, https://en.wikipedia.org/wiki/Remimazolam
4. Remimazolam: pharmacological characteristics and clinical ..., accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8841266/
5. Remimazolam: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 28, 2025, https://go.drugbank.com/drugs/DB12404
6. Remimazolam: Patient Safety Considerations of a Novel, Practice ..., accessed July 28, 2025, https://www.apsf.org/article/remimazolam-patient-safety-considerations-of-a-novel-practice-changing-drug-in-perioperative-medicine/
7. Remimazolam Uses, Side Effects & Warnings - Drugs.com, accessed July 28, 2025, https://www.drugs.com/mtm/remimazolam.html
8. Remimazolam: First Approval - PubMed, accessed July 28, 2025, https://pubmed.ncbi.nlm.nih.gov/32274703/
9. Decision Explained Medicine: remimazolam (brand name: Byfavo®), accessed July 28, 2025, https://scottishmedicines.org.uk/media/7035/de-remimazolam-byfavo-smc2454.pdf
10. CAS 308242-62-8: Remimazolam - CymitQuimica, accessed July 28, 2025, https://cymitquimica.com/cas/308242-62-8/
11. CNS 7056 | 308242-62-8 - ChemicalBook, accessed July 28, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32627691.htm
12. Remimazolam | 308242-62-8 - SynZeal, accessed July 28, 2025, https://www.synzeal.com/en/remimazolam-besylate
13. Byfavo (Remimazolam for Injection): Side Effects, Uses, Dosage, Interactions, Warnings, accessed July 28, 2025, https://www.rxlist.com/byfavo-drug.htm
14. Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent, accessed July 28, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.690875/full
15. A comprehensive review of remimazolam for sedation - PMC, accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8567764/
16. Remimazolam as a Primary Agent for Brief Invasive and Noninvasive Procedures: A Case Series - PMC, accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10079368/
17. Remimazolam, 308242-62-8, 98 (HPLC) Sigma-Aldrich, accessed July 28, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/sml3467
18. CAS 308242-62-8 - Sigma-Aldrich, accessed July 28, 2025, https://www.sigmaaldrich.com/US/en/search/308242-62-8?focus=products&page=1&perpage=30&sort=relevance&term=308242-62-8&type=cas_number
19. Remimazolam in General Anesthesia: A Comprehensive Review of Its Applications and Clinical Efficacy - Dove Medical Press, accessed July 28, 2025, https://www.dovepress.com/remimazolam-in-general-anesthesia-a-comprehensive-review-of-its-applic-peer-reviewed-fulltext-article-DDDT
20. pmc.ncbi.nlm.nih.gov, accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8567764/#:~:text=Mechanism%20of%20Action,in%20the%20central%20nervous%20system.
21. What is the mechanism of Remimazolam Besylate? - Patsnap Synapse, accessed July 28, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-remimazolam-besylate
22. Remimazolam Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed July 28, 2025, https://www.drugs.com/dosage/remimazolam.html
23. Remimazolam (Professional Patient Advice) - Drugs.com, accessed July 28, 2025, https://www.drugs.com/ppa/remimazolam.html
24. (PDF) Safety and Efficacy of Remimazolam Compared With Placebo ..., accessed July 28, 2025, https://www.researchgate.net/publication/328086091_Safety_and_Efficacy_of_Remimazolam_Compared_With_Placebo_and_Midazolam_for_Moderate_Sedation_During_Bronchoscopy
25. BYFAVO for Sedation in Adults Undergoing Procedures Lasting Less than 30 Mins | ACCP, accessed July 28, 2025, https://accp1.org/Members/ACCP1/5Publications_and_News/BYFAVO-Sedation-Adults-Procedures-Lasting-30-Mins.aspx
26. Remimazolam - LiverTox - NCBI Bookshelf, accessed July 28, 2025, https://www.ncbi.nlm.nih.gov/books/NBK593300/
27. paion announces us fda approval of remimazolam (byfavotm) for the induction and maintenance of procedural sedation, accessed July 28, 2025, https://www.paion.com/newsdetails/paion-announces-us-fda-approval-of-remimazolam-byfavotm-for-the-induction-and-maintenance-of-procedural-sedation
28. Efficacy and Safety of Remimazolam for Procedural Sedation: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis - Frontiers, accessed July 28, 2025, https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.641866/full
29. Byfavo, accessed July 28, 2025, https://byfavo.com/
30. Byfavo | European Medicines Agency (EMA), accessed July 28, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/byfavo
31. paion receives positive chmp opinion recommending approval of byfavo(r) (remimazolam) in procedural sedation, accessed July 28, 2025, https://www.paion.com/newsdetails/paion-receives-positive-chmp-opinion-recommending-approval-of-byfavor-remimazolam-in-procedural-sedation
32. PAION receives European Commission approval of remimazolam for the Induction and maintenance of general anesthesia in adults, accessed July 28, 2025, https://www.paion.com/newsdetails/paion-receives-european-commission-approval-of-remimazolam-for-the-induction-and-maintenance-of-general-anesthesia-in-adults
33. Remimazolam (BYFAVO) National Drug Monograph Addendum August 2024 | VA.gov, accessed July 28, 2025, https://www.va.gov/formularyadvisor/DOC_PDF/MON_Remimazolam_BYFAVO_Addendum_Aug_2024.pdf
34. Remimazolam: An Updated Review of a New Sedative and Anaesthetic - PMC, accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9675580/
35. Efficacy and Safety of Remimazolam Besylate Versus Propofol for Sedation in Mechanically Ventilated ICU Patients | ClinicalTrials.gov, accessed July 28, 2025, https://www.clinicaltrials.gov/study/NCT04790734
36. Remimazolam besylate versus propofol for long-term sedation during invasive mechanical ventilation: a pilot study | springermedizin.de, accessed July 28, 2025, https://www.springermedizin.de/remimazolam-besylate-versus-propofol-for-long-term-sedation-duri/23504706
37. Byfavo Dosage Guide - Drugs.com, accessed July 28, 2025, https://www.drugs.com/dosage/byfavo.html
38. Dosing & Administration - Byfavo, accessed July 28, 2025, https://byfavo.com/dosing-and-administration
39. Byfavo (remimazolam), frequency-based adverse effects, comprehensive interactions, contraindications, pregnancy & lactation schedules, and cost information. - Medscape Reference, accessed July 28, 2025, https://reference.medscape.com/drug/byfavo-remimazolam-4000019
40. APPLICATION NUMBER: - 212295Orig1s000 CLINICAL REVIEW(S) - accessdata.fda.gov, accessed July 28, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212295Orig1s000MedR.pdf
41. Byfavo, remimazolam - EMA, accessed July 28, 2025, https://www.ema.europa.eu/en/documents/product-information/byfavo-epar-product-information_en.pdf
42. Full article: Profile of Remimazolam in Anesthesiology: A Narrative Review of Clinical Research Progress, accessed July 28, 2025, https://www.tandfonline.com/doi/full/10.2147/DDDT.S375957
43. FDA Approves Byfavo (remimazolam injection) for the Induction and Maintenance of Procedural Sedation-CliniExpert, accessed July 28, 2025, https://www.cliniexpert.com/article/230.html
44. Remimazolam: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed July 28, 2025, https://www.rxlist.com/remimazolam/generic-drug.htm
45. Package leaflet: Information for the patient Byfavo 20 mg powder for solution for injection remimazolam This medicine is subject, accessed July 28, 2025, https://www.medicines.org.uk/emc/files/pil.12746.pdf
46. Remimazolam (Byfavo) | Davis's Drug Guide - Nursing Central, accessed July 28, 2025, https://nursing.unboundmedicine.com/nursingcentral/view/Davis-Drug-Guide/110837/all/remimazolam
47. Remimazolam (intravenous route) - Side effects & uses - Mayo Clinic, accessed July 28, 2025, https://www.mayoclinic.org/drugs-supplements/remimazolam-intravenous-route/description/drg-20490791
48. This label may not be the latest approved by FDA. For current ..., accessed July 28, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212295s000lbl.pdf
49. Remimazolam Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 28, 2025, https://www.drugs.com/sfx/remimazolam-side-effects.html
50. go.drugbank.com, accessed July 28, 2025, https://go.drugbank.com/drugs/DB12404#:~:text=As%20benzodiazepines%20as%20a%20class,of%20drug%20dependence%20or%20abuse.
51. Efficacy of remimazolam versus midazolam for procedural sedation ..., accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9010109/
52. (PDF) Safety and efficacy of remimazolam compared with midazolam during bronchoscopy: a single-center, randomized controlled study - ResearchGate, accessed July 28, 2025, https://www.researchgate.net/publication/375832917_Safety_and_efficacy_of_remimazolam_compared_with_midazolam_during_bronchoscopy_a_single-center_randomized_controlled_study
53. Efficacy and Safety of Remimazolam in Endoscopic ... - Frontiers, accessed July 28, 2025, https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.655042/full
54. Comparison of the Safety and Efficacy of Remimazolam and ... - MDPI, accessed July 28, 2025, https://www.mdpi.com/1648-9144/61/4/646
55. (PDF) Safety and efficacy comparison of remimazolam and propofol for intravenous anesthesia during gastroenteroscopic surgery of older patients: A meta-analysis - ResearchGate, accessed July 28, 2025, https://www.researchgate.net/publication/378768143_Safety_and_efficacy_comparison_of_remimazolam_and_propofol_for_intravenous_anesthesia_during_gastroenteroscopic_surgery_of_older_patients_A_meta-analysis
56. Efficacy and safety of remimazolam vs. propofol for general ..., accessed July 28, 2025, https://www.spandidos-publications.com/10.3892/br.2024.1891
57. (PDF) Comparison of the recovery time of remimazolam besylate and propofol for gastrointestinal endoscopy sedation in elderly patients - ResearchGate, accessed July 28, 2025, https://www.researchgate.net/publication/381027565_Comparison_of_the_recovery_time_of_remimazolam_besylate_and_propofol_for_gastrointestinal_endoscopy_sedation_in_elderly_patients?_share=1
58. Comparing subjective quality of recovery between remimazolam- and propofol-based total intravenous anesthesia for surgical procedures: a meta-analysis - PubMed Central, accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11409698/
59. Comparison of remimazolam-based and propofol-based total intravenous anesthesia on postoperative quality of recovery - BINASSS, accessed July 28, 2025, https://www.binasss.sa.cr/nov22/45.pdf
60. Safety and efficacy of remimazolam versus propofol during EUS: a multicenter randomized controlled study - PubMed, accessed July 28, 2025, https://pubmed.ncbi.nlm.nih.gov/38580132/
61. Efficacy and safety of remimazolam in bronchoscopic sedation: A ..., accessed July 28, 2025, https://www.wjgnet.com/2307-8960/full/v12/i6/1120.htm
62. Byfavo (remimazolam) FDA Approval History - Drugs.com, accessed July 28, 2025, https://www.drugs.com/history/byfavo.html
63. EMA committee recommends 13 medicines for approval in January meeting, accessed July 28, 2025, https://www.europeanpharmaceuticalreview.com/news/141449/ema-committee-recommends-13-medicines-for-approval-in-january-meeting/
64. Remimazolam in General Anesthesia: A Comprehensive Review of Its Applications and Clinical Efficacy - PubMed Central, accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11314436/
65. The effect of remimazolam and propofol on post-hysteroscopy sleep quality under general anesthesia: a post hoc analysis - Frontiers, accessed July 28, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1618190/full