4.1. Therapeutic indications

Remimazolam is indicated in adults for procedural sedation.

4.2. Posology and method of administration

Remimazolam must only be administered by healthcare professionals experienced in sedation. The patient should be monitored throughout by a separate healthcare professional, who is not involved in the conduct of the procedure, and whose sole task is to monitor the patient. This personnel must be trained in the detection and management of airway obstruction, hypoventilation and apnoea, including the maintenance of a patent airway, supportive ventilation and cardiovascular resuscitation. The patient´s respiratory and cardiac function must be continuously monitored. Resuscitative medicinal products and age- and size-appropriate equipment for restoring airway patency and bag/valve/mask ventilation must be immediately available. A benzodiazepine reversal medicinal product (flumazenil) must be immediately available for use.

Posology

Remimazolam dosing should be individually titrated to an effective dose which provides the desired level of sedation and minimises adverse reactions (see Table 1). Additional doses can be administered as needed to induce or maintain the desired level of sedation. At least 2 minutes should elapse prior to administration of any supplemental dose in order to fully assess the sedative effect. If 5 doses of remimazolam within 15 minutes do not result in the desired level of sedation then an additional or another sedative should be considered. Remimazolam is associated with fast onset and offset of sedation. In clinical trials, peak sedation occurred 3-3.5 minutes after the initial bolus and patients became fully alert 12-14 minutes from last dose of remimazolam.

Opioid co-administered medicinal products are known to increase the sedative effect of remimazolam and to depress the ventilatory response to carbon dioxide stimulation (see sections 4.4 and 4.5).

Table 1: Dosing guidelines for adults*

Adults < 65 years of age

Elderly ≥ 65 years of age and/or with ASA-PS# III-IV and/or body weight < 50 kg

Procedural sedation with opioid**

Induction

Administer opioid*

Wait 1-2 min

Initial dose: Injection: 5 mg (2 mL) over 1 min

Wait 2 min

Maintenance / titration Injection: 2.5 mg (1 mL) over 15 sec

Maximal total dose administrated in the clinical trials was 33 mg.

Induction

Administer opioid*

Wait 1-2 min

Initial dose: Injection: 2.5-5 mg (1-2 mL) over 1 min

Wait 2 min

Maintenance / titration Injection: 1.25-2.5 mg (0.5-1 mL) over 15 sec

Maximal total dose administrated in the clinical trials was 17.5 mg.

Procedural sedation without opioid

Induction Injection: 7 mg (2.8 mL) over 1 min

Wait 2 min

Maintenance / titration Injection: 2.5 mg (1 mL) over 15 sec

Maximal total dose administrated in the clinical trials was 33 mg.

Induction Injection: 2.5-5 mg (1-2 mL) over 1 min

Wait 2 min

Maintenance / titration Injection: 1.25-2.5 mg (0.5-1 mL) over 15 sec

Maximal total dose administrated in the clinical trials was 17.5 mg.

* For administration to patients concomitantly taking opioids, CNS depressants, alcohol or benzodiazepines see section 4.4.

** e.g. 50 micrograms fentanyl or a suitably reduced dose for elderly or debilitated patients. For fentanyl doses administered in clinical trials see section 5.1.

# American Society of Anesthesiologists Physical Status

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 sedatives. 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 dosage adjustments for these patients (see sections 4.4).

Renal impairment

No dosage 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.

Method of administration

Remimazolam is for intravenous use. Remimazolam must be reconstituted before use with sodium chloride (0.9%) solution for injection.

For instructions on reconstitution 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 benzodiazepines or 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 (corresponding to the time of maximum concentration of remimazolam) before resolving within about 30 minutes after the end of administration. 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 profound sedation, 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 / 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 severe sedation or clinically relevant 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 effects of remimazolam. Hence, a larger cumulative dose of remimazolam may be required to achieve the desired level of sedation. It is recommended to follow the titration regimen in section 4.2 and titrate up based on the patient's sedation-response, until the desired depth of sedation is achieved. (see section 4.5)

Monitoring

Remimazolam should be administered only by health care professionals experienced in sedation who are not involved in conducting the procedure, 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). Patients should be monitored closely during and after the procedure for signs and symptoms of respiratory depression and sedation. 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). Special attention is required for the timing of titration doses (see section 4.2). 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.

Excipients

Dextran

This medicinal product contains 79.13 mg of dextran 40 for injection in each 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 (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 (for details 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 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, using the recovery data from the pivotal clinical trials as a basis for their decision (see section 5.1). 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 are hypotension (37.2%), respiratory depression (13.1%), and bradycardia (6.8%). Safety precautions must be taken to manage the occurrence of these adverse reactions in clinical practice (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions associated with intravenous remimazolam observed in controlled clinical trials in procedural sedation and the postmarketing setting are tabulated below in Table 2 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 2: Tabulated list of adverse reactions

Immune system disorders

Not known

Anaphylactic reaction

Nervous system disorders

Common

Common

Uncommon

Headache

Dizziness

Somnolence

Cardiac disorders

Common

Bradycardia1*

Vascular disorders

Very common

Hypotension2*

Respiratory, thoracic and mediastinal disorders

Very common

Uncommon

Respiratory depression3*

Hiccups

Gastrointestinal disorders

Common

Common

Nausea

Vomiting

General disorders and administration site conditions

Uncommon

Uncommon

Chills

Feeling cold

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

2 Hypotension covers the following identified events: hypotension, diastolic hypotension, blood pressure decreased, blood pressure decreased systolic, and blood pressure decreased diastolic.

3 Respiratory depression covers the following identified events: hypoxia, respiratory rate decreased, respiratory acidosis, bradypnoea, dyspnoea, oxygen saturation decreased, breath sounds abnormal, hypopnoea, respiratory depression, and respiratory distress.

* 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 2); the incidence of those reported in at least 1% of patients who received remimazolam are presented in Table 3 below by severity level:

Table 3: Selected adverse reactions

Adverse reaction

Reported event term

Mild

Moderate

Severe

Bradycardia

Bradycardia

6.0%

0.1%

0.4%

Hypotension

Hypotension

30.1%

1.1%

0.1%

Diastolic hypotension

8.7%

0

0

Respiratory depression

Hypoxia

8.0%

0.9%

0.3%

Respiratory rate decreased

1.5%

0.4%

0

Other special populations

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

In controlled trials in procedural sedation, patients ≥65 years old had a higher frequency of events grouped under the terms hypotension (47.0% vs 33.3%) and respiratory depression (22.8% vs 9.0%) than patients below 65 years old. Patients with ASA-PS III-IV also showed higher frequencies for hypotension (43.6% vs 35.6%) and respiratory depression (17.6% vs 11.8%) than patients with ASA-PS I-II. Older age and higher ASA-PS were not associated with a higher frequency of bradycardia. See also sections 4.2 and 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 trial assessing remimazolam in hepatic impairment. See also 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 and symptoms: dizziness, confusion, drowsiness, blurred vision or nystagmus, agitation, weakness, hypotension, bradycardia, respiratory depression and coma.

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.