Remimazolam

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.

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 and titrate up based on the patient’s sedation-response, until the desired depth of sedation is achieved.

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.

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.

Special attention is required for patients with impaired respiratory and/or cardiac function or for patients with poorer general health status.

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. As a precautionary measure, it is preferable to avoid the use of remimazolam during pregnancy.

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. 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.

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. It is recommended that the patient is given appropriate advice and support when returning home after discharge.

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.

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 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:

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 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:

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.

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.