Byfavo · 4.6 Fertility, pregnancy and lactation · 2

HOS-287925 · has-adverse-reaction-information · PDF-Seite 6

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 6 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 Headache Common Dizziness Uncommon Somnolence Cardiac disorders Common Bradycardia1* Vascular disorders Very common Hypotension2* Respiratory, thoracic and mediastinal disorders Very common Respiratory depression3* Uncommon Hiccups Gastrointestinal disorders Common Nausea Common Vomiting General disorders and administration site conditions Uncommon Chills Uncommon 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 hyp

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HOS-287931 · has-adverse-reaction-information · PDF-Seite 23

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 Respiratory depression3* Uncommon Hiccups Gastrointestinal disorders Very common Nausea Very common Vomiting Uncommon Glossoptosis General disorders and administration site conditions Common Chills Common Drug effect prolonged4* Uncommon 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,

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HOS-287927 · has-contraindication-information · PDF-Seite 20

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

HOS-287921 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance, other benzodiazepines or any of the excipients listed in section 6.1. Unstable myasthenia gravis.

HOS-287920 · has-indication-information · PDF-Seite 2

Remimazolam is indicated in adults for procedural sedation.

HOS-287926 · has-indication-information · PDF-Seite 18

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

HOS-287923 · has-interaction-information · PDF-Seite 5

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 5 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).

HOS-287929 · has-interaction-information · PDF-Seite 22

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).

HOS-287924 · has-pregnancy-information · PDF-Seite 6

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).

HOS-287930 · has-pregnancy-information · PDF-Seite 22

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).

HOS-287928 · has-warning-information · PDF-Seite 20

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 concomitan

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HOS-287922 · has-warning-information · PDF-Seite 4

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 4 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 adver

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