BYFAVO Powder for solution for injection Ref.[51524] Active ingredients: Remimazolam

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.

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).

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).

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).

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:

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:

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 ASAPS 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 the national reporting system listed in Appendix V.

Incompatibilities between Byfavo and co-administered solutions may result in precipitation/turbidity which may cause occlusion of vascular access site. Byfavo is incompatible with lactated Ringer’s solution (also known as compound sodium lactate solution or Hartmann’s solution), acetated Ringer’s solution, and bicarbonated Ringer’s solution for infusion and other alkaline solutions since the solubility of the product is low at pH of 4 or higher.

This medicinal product must not be mixed or co-administered through the same infusion line with other medicinal products except those mentioned in section 6.6.