4.1. Therapeutic indications

Remimazolam 50 mg is indicated in adults for intravenous induction and maintenance of general anaesthesia.

4.2. Posology and method of administration

Remimazolam must only be given in hospitals or adequately equipped day therapy units by physicians trained in anaesthesia.

Circulatory and respiratory functions should be constantly monitored (e.g. electrocardiogram (ECG), pulse oximetry) and facilities for maintenance of patent airways, artificial ventilation, and other resuscitation facilities should be immediately available at all times (see section 4.4).

Posology

The dose of Byfavo should be individualised based on the response of the patient and premedications used.

Supplementary opioid analgesic agents are usually given in combination with Byfavo.

Induction of anaesthesia

The rate of infusion of remimazolam should be set to 6 mg/min and measured against the response of the patient until clinical signs show the onset of anaesthesia and, in cases where needed, could be up-titrated to a maximum of 12 mg/min.

Most adult patients are likely to require 10-40 mg Byfavo.

Maintenance of anaesthesia

Anaesthesia is maintained by administering remimazolam by continuous infusion.

Recommended starting dose for maintenance of anaesthesia is 1 mg/min remimazolam with a range of 0.1-2.5 mg/min based on clinical judgement in order to maintain satisfactory anaesthesia.

For maintenance of anaesthesia, during the ongoing infusion, additional boluses of 6 mg over one minute can be given according to clinical requirements. A maximum of three (3) boluses not less than 5 min apart can be administered within 60 min.

Towards the end of surgery (e.g. 15 min before the end) the dose of remimazolam may be titrated down to facilitate more rapid recovery from the anaesthetic effects.

Special populations

Elderly, American Society of Anesthesiologists Physical Status (ASA-PS) III-IV patients and patients with body weight < 50 kg

Elderly patients and patients with ASA-PS III-IV may be more sensitive to the effects of anaesthetics. Before administration of remimazolam a careful assessment of the overall condition of patients ≥ 65 years of age and/or with ASA-PS III-IV, especially with low body weight (< 50 kg), is therefore of particular relevance when deciding upon individualised dose adjustments for these patients (see section 4.4). The starting dose should be considered at the lower range.

Renal impairment

No dose adjustment is required in any grade of renal impairment (including patients with glomerular filtration rate [GFR] < 15 mL/min).

Hepatic impairment

The metabolising enzyme (carboxylesterase-1 [CES-1]) for remimazolam is predominantly located in the liver and the clearance of remimazolam is affected by increasing stages of hepatic impairment (see section 5.2). No dose adjustment is recommended for patients with mild (Child-Pugh scores 5 and 6) or moderate (Child-Pugh scores 7 to 9) hepatic impairment. In patients with severe hepatic impairment (Child-Pugh scores 10 to 15; data from only 3 subjects in clinical trials), the clinical effects may be more pronounced and last longer than in healthy subjects. No dose adjustments are required but careful attention should be paid to the timing of titration doses and remimazolam should be carefully titrated to effect in these patients (see section 4.4).

Paediatric population

The safety and efficacy of remimazolam in children and adolescents aged 0 to <18 years have not yet been established. No data are available.

Other populations

The safety and efficacy of remimazolam in patients undergoing intracranial surgery and patients with pre-existing cognitive disorders have not yet been established. No data are available.

Method of administration

Remimazolam is for intravenous use. Remimazolam must be reconstituted and diluted before use with sodium chloride 9 mg/mL (0.9%) solution for injection.

For instructions on reconstitution and dilution of the medicinal product before administration, and on administration with other fluids see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance, other benzodiazpines or to any of the excipients listed in section 6.1.

Unstable myasthenia gravis.

4.4. Special warnings and precautions for use

Cardiorespiratory adverse reactions

Cardiorespiratory adverse reactions have been reported with the use of remimazolam, including respiratory depression, bradycardia and hypotension. Remimazolam administration can be associated with a transient increase in heart rate (10-20 beats per minute) starting as early as 30 seconds after the start of dosing. This increase in heart rate coincides with a decrease in blood pressure and it may confound QT correction for heart rate translating into a small prolongation in QTcF in the first few minutes following dosing.

Special attention is required for elderly patients (≥65 years of age), for patients with impaired respiratory and/or cardiac function or for patients with poorer general health status (see section 4.2).

Concomitant use of opioids

Concomitant use of remimazolam and opioids may result in respiratory depression, coma and death. In patients with longer-term opioid use, caution is advised; it should not be presumed that these effects will be attenuated (see section 4.5).

Concomitant use of alcohol / Central Nervous System (CNS) depressants

The concomitant use of remimazolam with alcohol or/and CNS depressants should be avoided. Alcohol intake should be avoided for 24 hours before remimazolam administration. Such concomitant use has the potential to increase the clinical effects of remimazolam, possibly including respiratory depression (see section 4.5).

Chronic CNS depressant use

Patients who receive chronic benzodiazepine therapy (e.g., for insomnia or anxiety disorders) may develop tolerance to the sedative/hypnotic effects of remimazolam. Hence, a larger cumulative dose of remimazolam may be required to achieve the desired level of anaesthesia. A similar effect may also be observed with other CNS depressants. It is recommended to follow the titration regimen in section 4.2 and titrate up based on the patient's response, until the desired depth of anaesthesia is achieved (see section 4.5).

Monitoring

Remimazolam should be administered only by health care professionals trained in anaesthesia in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function. Administering personnel must be adequately trained in the recognition and management of expected adverse reactions including respiratory and cardiac resuscitation (see section 4.2). The physician should also be aware of the typical time taken for patients to recover from the effects of remimazolam and concomitant opioid used in the clinical trials (see section 5.1), but that this may vary in individual patients. Patients should be closely monitored until they are judged by the healthcare professional to be sufficiently recovered.

Amnesia

Remimazolam can cause anterograde amnesia. Amnesia, if prolonged, can present problems in outpatients, who are scheduled for discharge following intervention. After receiving remimazolam, patients should be assessed and discharged from hospital or consulting room by their physician, only with appropriate advice and support.

Hepatic impairment

The clinical effects may be more pronounced and last longer in patients with severe hepatic impairment due to reduced clearance (see section 5.2). These patients may be more susceptible to respiratory depression (see section 4.8).

Myasthenia gravis

Particular care should be taken when administering remimazolam to a patient with myasthenia gravis (see section 4.3).

Drug abuse and physical dependence

Remimazolam has an abuse and dependence-inducing potential. This should be considered when prescribing or administering remimazolam where there is concern about an increased risk of misuse or abuse.

Delirium

Post-operative delirium and related neuropsychiatric events occur with reported incidence rate ranging from 4 to 53.3% in various published studies with sedatives or anaesthetic agents used for surgery or deep sedation in the intensive care. Risk factors include, but are not limited to, old age, pre-existent cognitive disorders, length and depth of anaesthesia or sedation, higher doses of longer acting benzodiazepines, metabolic disorders such as diabetes, electrolyte disorders, hypoxia, hypercapnia, hypotension, and infections. Although it is unclear whether remimazolam can itself cause or contribute to the risk of post-operative delirium, the lowest effective dose should be used. If post-operative delirium occurs, besides appropriate treatment of the delirium itself, any addressable risk factors should be appropriately treated. Patients should not be discharged prior to full recovery of cognition due to the potential risk of e.g. accidents.

Paradoxical reactions

Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported to occur with benzodiazepines. These reactions are more likely to occur in elderly patients, with high doses and/or when the injection is given rapidly.

Prolonged effect of medicinal product

Prolonged effect of remimazolam (sedation, time to orientation) was observed postoperatively in some patients after the end of remimazolam administration. This occurred more frequently in elderly (≥ 65 years old) patients, those with ASA III-IV and those receiving higher dose rates of remimazolam during the last hour of anaesthesia (see section 4.8.).

Excipients

This medicinal product contains 198 mg of dextran 40 for injection in each 50 mg vial.

Dextrans can cause anaphylactic/anaphylactoid reactions in some patients.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic drug interactions

Remimazolam is metabolised by CES, type 1A. No in vivo drug interaction study was conducted. In vitro data is summarised in section 5.2.

Pharmacodynamic drug interactions

Increased sedation with CNS depressants and opioids

The co-administration of remimazolam with opioids and CNS depressants, including alcohol, is likely to result in enhanced sedation and cardiorespiratory depression. Examples include opiate derivatives (used as analgesics, antitussives or substitutive treatments), antipsychotics, other benzodiazepines (used as anxiolytics or hypnotics), barbiturates, propofol, ketamine, etomidate, sedative antidepressants, non-recent H1-antihistamines and centrally acting antihypertensive medicinal products.

Concomitant use of remimazolam and opioids may result in profound sedation and respiratory depression. Patients should be monitored for respiratory depression and depth of sedation/anaesthesia (see sections 4.2 and 4.4).

Alcohol intake should be avoided for 24 hours before remimazolam administration since it may markedly enhance the sedative effect of remimazolam (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of remimazolam in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Byfavo during pregnancy.

Breastfeeding

It is unknown whether remimazolam and its main metabolite (CNS7054) are excreted in human breast milk. Available toxicological data in animals have shown excretion of remimazolam and CNS7054 in milk (see section 5.3). A risk to newborns/infants cannot be excluded; therefore, administration of remimazolam to breastfeeding mothers should be avoided. If there is a need to administer remimazolam, then discontinuation of breastfeeding for 24 hours after stop of administration is advised.

Fertility

There are no human data on the effects of remimazolam on fertility. In animal studies there was no effect on mating or fertility with remimazolam treatment (see section 5.3).

4.7. Effects on ability to drive and use machines

Remimazolam has a major influence on the ability to drive and use machines. Prior to receiving remimazolam, the patient should be warned not to drive a vehicle or operate a machine until completely recovered. A physician should decide when the patient can be allowed to go home or resume normal activities. It is recommended that the patient is given appropriate advice and support when returning home after discharge (see section 4.4).

4.8. Undesirable effects

Summary of the safety profile

The most frequent adverse reactions in patients with intravenous remimazolam for general anaesthesia are hypotension (51%), nausea (22.1%), vomiting (15.2%), and bradycardia (12.8%). Safety precautions must be taken to manage the occurrence of hypotension and bradycardia in clinical practice (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions associated with intravenous remimazolam observed in controlled clinical trials in general anaesthesia are tabulated below in Table 1 according to the MedDRA system organ classification and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequency groupings are as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (cannot be estimated from available data).

Table 1: Tabulated list of adverse reactions

Immune system disorders

Not known

Anaphylactic reaction

Psychiatric disorders

Common

Agitation

Nervous system disorders

Common

Headache

Dizziness

Cardiac disorders

Very common

Bradycardia1*

Vascular disorders

Very common

Hypotension2*

Respiratory, thoracic and mediastinal disorders

Common

Uncommon

Respiratory depression3*

Hiccups

Gastrointestinal disorders

Very common

Very common

Uncommon

Nausea

Vomiting

Glossoptosis

General disorders and administration site conditions

Common

Common

Uncommon

Chills

Drug effect prolonged4*

Hypothermia

1 Bradycardia covers the following identified events: bradycardia, sinus bradycardia, and heart rate decreased.

2 Hypotension covers the following identified events: hypotension, procedural hypotension, post procedural hypotension, blood pressure decreased, mean arterial pressure decreased, orthostatic hypotension and orthostatic intolerance.

3 Respiratory depression covers the following identified events: hypoxia, respiratory rate decreased, dyspnoea, oxygen saturation decreased, hypopnoea, respiratory depression, and respiratory disorder.

4 Drug effect prolonged covers the following identified events: delayed recovery from anaesthesia, somnolence, and therapeutic product effect prolonged.

* See description of selected adverse reactions

Description of selected adverse reactions

The reported adverse reactions hypotension, respiratory depression and bradycardia represent medical concepts which encompass a group of events (refer to footnotes 1 - 3 under table 1); the incidence of those reported in at least 1% of patients who received remimazolam are presented in table 2 below by severity level:

Table 2: Selected adverse reactions

Adverse reaction

Reported event term

Mild

Moderate

Severe

Bradycardia

Bradycardia

6.1%

3.7%

0.3%

Heart rate decreased

1.2%

0.6%

0%

Hypotension

Blood pressure decreased

18%

2.1%

0%

Hypotension

14.8%

9.7%

0.6%

Mean arterial pressure decreased

3%

0.1%

0%

Procedural hypotension

2.5%

0.6%

0%

Respiratory depression

Oxygen saturation decreased

3.7%

0.7%

0.3%

Hypoxia

3%

0.3%

0%

Other special populations

Elderly and/or patients with ASA-PS III-IV

Cardio-respiratory events

In controlled trials in general anaesthesia, patients ≥65 years old had a higher frequency of events grouped under the terms hypotension (64.2% vs 35.4%), respiratory depression (11.6% vs 5.8%) and bradycardia (19% vs 4.5%) than patients below 65 years old. Patients with ASA-PS III-IV also showed higher frequencies for hypotension (70.2% vs 32.6%), respiratory depression (15.7% vs 2.4%) and bradycardia (18.1% vs. 6.9%) than patients with ASA-PS I-II (see sections 4.2 and 4.4).

Prolonged sedation

In controlled trials in general anaesthesia, patients ≥65 years old had a higher frequency of events grouped under the term drug effect prolonged (11% vs 2.3%) than patients below 65 years old. Patients with ASA-PS III-IV also showed higher frequencies for drug effect prolonged (12.7% vs 1.2%) than patients with ASA-PS I-II (see section 4.4).

Patients with hepatic impairment

Respiratory depression (hypoxia/oxygen saturation decreased) was reported in 2 of 8 subjects with moderate hepatic impairment, and 1 of 3 with severe hepatic impairment enrolled in a dedicated clinical trial assessing remimazolam in hepatic impairment (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Symptoms

The symptoms of remimazolam overdose are expected to be an extension of its pharmacological actions and may present with one or more of the following signs: hypotension, bradycardia, and respiratory depression.

Management of overdose

The patient's vital signs should be monitored and supportive measures should be started as indicated by the patient's clinical state including securing airway passages, assuring adequate ventilation and establishing adequate intravenous access. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with remimazolam is known or suspected.

Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Flumazenil will only reverse benzodiazepine-induced effects but will not reverse the effects of other concomitant medicinal products, e.g. that of opioids.

Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. However, since the elimination half-life of flumazenil is approximately the same as remimazolam the risk of re-sedation after flumazenil administration is low.