BYFAVO 50mg concentrate powder for injection / infusion solution medication leaflet

Byfavo 50 mg powder for concentrate for solution for injection/infusion

Each vial contains remimazolam besylate equivalent to 50 mg remimazolam.

After reconstitution each mL of concentrate contains 5 mg remimazolam.

Dilution is required to reach final concentration of 1-2 mg/mL.

Each vial contains 198 mg of dextran 40 for injection

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for injection/infusion (powder for concentrate).

White to off-white powder.

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

Remimazolam must only be given in hospitals or adequately equipped day therapy units by physicianstrained 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 otherresuscitation facilities should be immediately available at all times (see section 4.4).

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

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 ofthe 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 of0.1-2.5 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 oneminute can be given according to clinical requirements. A maximum of three (3) boluses not less than5 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 titrateddown to facilitate more rapid recovery from the anaesthetic effects.

Elderly, American Society of Anesthesiologists Physical Status (ASA-PS) III-IV patients and patientswith 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 thereforeof particular relevance when deciding upon individualised dose adjustments for these patients (seesection 4.4). The starting dose should be considered at the lower range.

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

The metabolising enzyme (carboxylesterase-1 [CES-1]) for remimazolam is predominantly located inthe liver and the clearance of remimazolam is affected by increasing stages of hepatic impairment (seesection 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 bemore pronounced and last longer than in healthy subjects. No dose adjustments are required butcareful attention should be paid to the timing of titration doses and remimazolam should be carefullytitrated to effect in these patients (see section 4.4).

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

Other populations

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

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

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

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

Unstable myasthenia gravis.

Cardiorespiratory adverse reactions

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

Special attention is required for elderly patients (≥65 years of age), for patients with impairedrespiratory 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. Inpatients with longer-term opioid use, caution is advised; it should not be presumed that these effectswill 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 concomitantuse has the potential to increase the clinical effects of remimazolam, possibly including respiratorydepression (see section 4.5).

Chronic CNS depressant use

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

Remimazolam should be administered only by health care professionals trained in anaesthesia in asetting fully equipped for the monitoring and support of respiratory and cardiovascular function.

Administering personnel must be adequately trained in the recognition and management of expectedadverse reactions including respiratory and cardiac resuscitation (see section 4.2). The physicianshould also be aware of the typical time taken for patients to recover from the effects of remimazolamand concomitant opioid used in the clinical trials (see section 5.1), but that this may vary in individualpatients. Patients should be closely monitored until they are judged by the healthcare professional tobe sufficiently recovered.

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

The clinical effects may be more pronounced and last longer in patients with severe hepaticimpairment due to reduced clearance (see section 5.2). These patients may be more susceptible torespiratory 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 whenprescribing or administering remimazolam where there is concern about an increased risk of misuse orabuse.

Delirium

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

Paradoxical reactions

Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsionsand muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement andassault, have been reported to occur with benzodiazepines. These reactions are more likely to occur inelderly 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 somepatients 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 remimazolamduring the last hour of anaesthesia (see section 4.8.).

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.

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 likelyto 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, sedativeantidepressants, non-recent H1-antihistamines and centrally acting antihypertensive medicinalproducts.

Concomitant use of remimazolam and opioids may result in profound sedation and respiratorydepression. 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 maymarkedly enhance the sedative effect of remimazolam (see section 4.4).

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use ofremimazolam 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 duringpregnancy.

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

There are no human data on the effects of remimazolam on fertility. In animal studies there was noeffect 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 receivingremimazolam, the patient should be warned not to drive a vehicle or operate a machine untilcompletely recovered. A physician should decide when the patient can be allowed to go home orresume normal activities. It is recommended that the patient is given appropriate advice and supportwhen returning home after discharge (see section 4.4).

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

Adverse reactions associated with intravenous remimazolam observed in controlled clinical trials ingeneral anaesthesia are tabulated below in Table 1 according to the MedDRA system organclassification and frequency. Within each frequency grouping, adverse reactions are presented in orderof 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

Not known Anaphylactic reaction

Common Agitation

Common Headache

Dizziness

Very common Bradycardia1*

Very common Hypotension2*

Common Respiratory depression3*

Uncommon Hiccups

Very common Nausea

Very common Vomiting

Uncommon Glossoptosis

Common Chills

Common Drug effect prolonged4*

Uncommon Hypothermia1 Bradycardia covers the following identified events: bradycardia, sinus bradycardia, and heart rate decreased.2 Hypotension covers the following identified events: hypotension, procedural hypotension, post proceduralhypotension, blood pressure decreased, mean arterial pressure decreased, orthostatic hypotension andorthostatic 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

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

Table 2: Selected adverse reactions

Adverse reaction Mild Moderate Severe

Reported event term

Bradycardia

Bradycardia 6.1% 3.7% 0.3%

Heart rate decreased 1.2% 0.6% 0%

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%

Oxygen saturation decreased 3.7% 0.7% 0.3%

Hypoxia 3% 0.3% 0%

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 eventsgrouped under the terms hypotension (64.2% vs 35.4%), respiratory depression (11.6% vs 5.8%) andbradycardia (19% vs 4.5%) than patients below 65 years old. Patients with ASA-PS III-IV alsoshowed 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 eventsgrouped 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% vs1.2%) than patients with ASA-PS I-II (see section 4.4).

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V

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

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

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

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

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

Pharmacotherapeutic group: Psycholeptics, hypnotics and sedatives, ATC code: N05CD14.

Remimazolam is an ultra-short acting benzodiazepine sedative/hypnotic. The effects of remimazolamon the CNS are dependent on the dose administered intravenously and presence or absence of othermedicinal products. Remimazolam binds to benzodiazepine sites of gamma amino butyric acid type A[GABAA] receptors with high affinity, while its carboxylic acid metabolite (CNS7054) hasapproximately 300 times lower affinity for these receptors. Remimazolam does not show clearselectivity between subtypes of the GABAA receptor.

The primary pharmacodynamic effect of remimazolam is sedation and hypnosis.

Sedation is observed starting at single bolus doses of 0.05 to 0.075 mg/kg in healthy young adults,with an onset of 1 to 2 min following dosing. Induction of mild to moderate sedation is associated withplasma levels of around 0.2 μg/mL. Loss of consciousness is seen at doses of 0.1 mg/kg (elderly) or0.2 mg/kg (healthy young adults) and associated with plasma concentrations of around 0.65 μg/mL.

During maintenance of anaesthesia plasma concentrations of remimazolam are normally in the rangeof 1 µg/mL when remifentanil was co-administered. Time to fully alert was 10 min for 0.075 mg/kg ofremimazolam.

Remimazolam can cause anterograde amnesia after administration, which prevents patients fromremembering events occurring during the procedure.

The efficacy of remimazolam was based on two pivotal studies CNS7056-022 and ONO-2745-05 inadult patients (aged 20 to 91 years) with ASA-PS I-IV who were undergoing mixed elective surgeries.

The database for remimazolam additionally comprised additional propofol-controlled clinical trials incardiac surgeries (CNS7056-010 and CNS7056-011).

ONO-2745-05: This was a phase IIb/III multicenter, randomized, parallel-group trial of remimazolamcompared with propofol in surgical patients rated as ASA class I or II undergoing general anaesthesiaconducted in Japan. Remimazolam was administered at a dose of 6 (n=158) or 12 mg/kg/h (n=156) bycontinuous intravenous infusion until loss of consciousness. After loss of consciousness, continuousintravenous infusion at a dose of 1 mg/kg/h was started, after which the infusion rate was adjusted asappropriate (maximum allowed dose, 2 mg/kg/h) based on monitoring of the general condition ofindividual subjects until the end of the surgery.

CNS7056-022: This was a European, confirmatory trial to establish non-inferior efficacy and superiorhaemodynamic stability of remimazolam compared with propofol for induction and maintenance ofgeneral anaesthesia during elective surgery in patients rated as ASA class III or IV. Patients wererandomly assigned to the remimazolam (n=270) or the propofol arm (n=95). Remimazolam wasadministered at a dose of 6 mg/min for 3 min, followed by 2.5 mg/min for 7 min and 1.5 mg/min foran additional 10 min. Thereafter general anaesthesia was maintained with an infusion rate of 1 mg/minwith adjustments between 0.7-2.5 mg/min based on monitoring of the general condition of individualsubjects until the end of surgery.

The primary endpoints in the pivotal clinical trials, were defined as :

* Percentage of general anaesthesia maintenance time with Narcotrend index (NCI) ≤60(CNS7056-022)

* Functional capability as a general anaesthetic as assessed by a composite of 3 variables:

“intraoperative awakening or recall”, “requirement of rescue sedation with other sedatives”and “body movement.” (ONO-2745-05).

The primary endpoint was reached in both clinical trials (see table 3). All doses of remimazolam werenon-inferior to propofol.

Table 3: Primary endpoints from pivotal clinical trials

CNS7056-022 ONO-2745-05

RMZ61 PROP RMZ62 RMZ123 PROP

Capability as a general - - 100% 100% 100%anaesthetic

Mean time Narcotrend 95% 99% - - -index ≤ 60

Induction dose 6 mg/min (1), 6 mg/kg/h (2) or 12 mg/kg/h (3); RMZ; remimazolam, PROP: propofol

In CNS7056-022, haemodynamic stability, assessed as absolute or relative hypotension andvasopressor use, was a key secondary endpoint. This was assessed during the period before start ofsurgery and is summarised in table 4. Remimazolam treated patients had fewer events of mean arterialpressure (MAP) of 1 min below 65 mmHg and fewer vasopressor dosing events.

Table 4: Secondary endpoints in phase 3 clinical trial CNS7056-022

Remimazolam Propofol

Endpoint

N = 270 N = 95

MAP < 65 mmHg

MAP <65 mmHg within start of IMP to 15 minutesafter first skin incision over 1 minute, number ofevents

Mean ± Standard deviation 6.62 ± 6.604 8.55 ± 8.944

CI 95% (5.83 to 7.41) (6.75 to 10.4)

Median (minimum, maximum) 5 (2, 10) 6 (3, 11)

Difference of least square means between treatments1.9292 (0.2209 - 3.6375)(95% CI)

Norepinephrine Use

Norepinephrine boluses or infusion or continuousinfusion over 2 minutes, number of events

Mean ± Standard deviation 14.06 ± 13.540 19.86 ± 14.560

CI 95% (12.4 to 15.7) (16.9 to 22.8)

Median (minimum, maximum) 12 (0, 63) 21 (0, 66)

Difference of least square means between5.8009 (2.5610 - 9.0409)treatments (95% CI)

MAP < 65 mmHg AND/OR Norepinephrine use

Number of events

Mean ± Standard deviation 20.68 ± 16.444 28.41 ± 17.468

CI 95% (18.7 to 22.6) (24.9 to 31.9)

Median (minimum, maximum) 21 (0, 68) 30 (0, 75)

Difference of least square means between treatments7.7301 (3.8090 - 11.651)(95% CI)

IMP = investigational medicinal product; MAP = mean arterial pressure

The onset and recovery profile of remimazolam was characterised by time-to-event secondaryendpoints assessed in the pivotal clinical trials. In each trial, time to recovery endpoints were slightlylonger in the remimazolam groups than in the propofol group (table 5).

Table 5: Induction and recovery endpoints in phase 3 clinical trials

Median time CNS 7056-022 ONO-2745-05

RMZ1 PROP4 RMZ62 RMZ123 PROP

Induction endpoints

- Time to loss of 2.5 min 3 min 100.5 s 87.5 s 80 sconsciousness

Patients (n) 268 95 150 150 7595% CI 2.5 - 2.8 min 3.0 - 3.2 min NA NA NA

Q1; Q3 2.0; 3.3 min 2.5; 3.7 min NA NA NA

Min; Max NA NA 24; 165 s 30; 170 s 17; 280 s

Median time CNS 7056-022 ONO-2745-05

RMZ1 PROP4 RMZ62 RMZ123 PROP

Recovery endpoints

Time from stop of

IMP§ administrationto

- Extubation 12 min 11 min 15.5 min 18 min 12 min

Patients (n) 263 95 150 150 7595% CI 11 - 13 min 10 - 12 min NA NA NA

Q1; Q3 8; 18 min 8; 15 min NA NA NA

Min; Max NA NA 3; 104 min 2; 58 min 3; 42 min

- Awakening# 15 min 12 min 12 min 12 min 10 min

Patients (n) 257 95 150 150 7595% CI 13 - 17 min 10 - 13 min NA NA NA

Q1; Q3 9; 26 min 8; 16 min NA NA NA

Min; Max NA NA 1; 87 min 0; 50 min 0; 24 min

- Orientation## 54 min 30 min 21 min 21 min 14 min

Patients (n) 262 95 149 149 7595% CI 47 - 61 min 27 - 33 min NA NA NA

Q1; Q3 31; 88 min 22; 48 min NA NA NA

Min; Max NA NA 3; 106 min 2; 125 min 4; 86 min

- Modified Aldrete 53 min 37 minscore ≥9

Patients (n) 260 9495% CI 44 - 58 min 28 - 45 min NA NA NA

Q1; Q3 30; 98 min 21; 88 min…Min; Max NA NA

- Discharge from 25 min 25 min 16 minoperation room

Patients (n) 150 150 7595% CI NA NA NA NA NA

Q1; Q3 NA NA NA

Min; Max 4; 144 min 5; 125 min 5; 87 min

Induction doses remimazolam (1) 6 mg/min, (2) 6 mg/kg/h or (3) 12 mg/kg/h, (4) propofol dose equipotentto remimazolam# ONO-2745-05: eye opening; CNS7056-022: response to verbal command ((MOAA/S≥4)## ONO-2745-05: stating date of birth; CNS7056-022: orientation to place, time, situation and person§ Investigational medicinal product

Clinical Safety

The incidence of treatment-emergent adverse events in the propofol-controlled trials was 90.7% in thelow induction dose remimazolam groups, 83.7% in the high induction dose remimazolam groups and92.5% in the propofol groups. Particularly the incidence of haemodynamic adverse events was lowerfor the remimazolam dose groups as compared to the propofol groups (table 6).

Table 6: Number of patients with haemodynamic instability adverse events in propofol-controlled clinical trials

Total number of patients remimazolam propofol

N=671 N=226

Number of patients with events

Hypotension n (n/N%) [95%CI] 344 (51.3%) [47.5-55.0] 150 (66.4%) [59.0-72.2]

Bradycardia n (n/N%) [95%CI] 96 (14.3%) [11.9-17.2] 50 (22.1%) [17.2-28.0]

The European Medicines Agency has deferred the obligation to submit the results of studies with

Byfavo in one or more subsets of the paediatric population in the condition of general anaesthesia (seesection 4.2 for information on paediatric use).

Remimazolam is administered intravenously.

Remimazolam has a mean distribution half-life (t1/2α) of 0.5 to 2 min. Its volume of distribution (Vd) is0.9 L/kg. Remimazolam and its main metabolite (CNS7054) show moderate (~90%) binding to plasmaproteins, predominantly albumin.

Remimazolam is an ester drug that is rapidly converted into a pharmacologically inactive carboxylicacid metabolite (CNS7054) by CES-1, mainly located in the liver.

The main route of metabolism of remimazolam is via conversion to CNS7054, which is then to a smallextent further metabolized by hydroxylation and glucuronidation. Conversion to CNS7054 is mediatedby liver carboxylesterases (primarily type 1A), with no meaningful contribution by cytochrome P450enzymes.

In vitro studies have shown no evidence that remimazolam or CNS7054 inhibit cytochrome P450isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2B6 and CYP2C8. There is noinduction of the main inducible P450 isoenzymes 1A2, 2B6, and 3A4 in man. In vitro studies showedno clinically relevant influence of CES inhibitors and substrates on the metabolism of remimazolam.

Remimazolam was not a relevant substrate of a panel of human drug transporters (OATP1B1,

OATP1B3, BCRP, and MDR1 (=P-glycoprotein)). The same is true of CNS7054, tested for MRP2-4.

By contrast, CNS7054 was found to be a substrate of MDR1 and BCRP. No or no relevant inhibitionof the human drug transporters, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, MATE2-K,

BCRP, BSEP, or MDR1, was seen with remimazolam or CNS7054.

Remimazolam has a mean elimination half-life (t1/2ß) of 7 to 11 minutes. The simulated contextsensitive half-time after an infusion of 4 h is 6.6 ± 2.4 minutes. Clearance is high (68 ± 12 L/h) and notrelated to body weight. In healthy subjects at least 80% of the remimazolam dose is excreted in urineas CNS7054 within 24 hours. Only traces (<0.1%) of unchanged remimazolam are detected in urine.

Remimazolam dose versus remimazolam maximal plasma concentration (Cmax) and total exposure(AUC0-∞) suggested a dose-proportional relationship in human volunteers in the dose range0.01-0.5 mg/kg.

Special population

There is no significant effect of age on the pharmacokinetics of remimazolam (see section 4.2).

The pharmacokinetics of remimazolam were not altered in patients with mild to end stage renaldisease not requiring dialysis (including patients with a GFR < 15 mL/min) (see section 4.2).

Severe impairment of hepatic function resulted in a reduced clearance and, as a consequence, aprolonged recovery from sedation (see sections 4.2 and 4.8).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single and repeated dose toxicity and genotoxicity.

The following adverse reaction was not observed in clinical studies, but was seen in animals infusedwith the dosing solution of concentrations similar to those used in clinical practice: primary lesionsdue to a mechanical irritation of the vessel wall during the puncture procedure can be aggravated byconcentrations of remimazolam above 1 to 2 mg/mL (infusion) or above 5 mg/mL during bolusadministration.

Reproduction and development

Reproductive toxicity studies performed at the maximum tolerated dose level revealed no influence onmale or female fertility and on reproductive function parameters. In embryotoxicity studies in rats andrabbits, even at the highest dose levels, which displayed maternal toxicity, only marginal embryotoxiceffects were observed (reduced foetal weight and slightly increased incidences of early and totalresorptions). Remimazolam and its main metabolite are excreted in breast milk of rats,rabbits andsheeps. The inactive main metabolite CNS7054 was detected in the plasma of suckling rabbit kits. Insuckling lambs, oral administration of remimazolam spiked milk resulted in negligable bioavalibility.

Dextran 40 for injection

Lactose monohydrate

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Incompatibilities between Byfavo and co-administered solutions may result in precipitation/turbiditywhich may cause occlusion of vascular access site. Byfavo is incompatible with lactated Ringer’ssolution (also known as compound sodium lactate solution or Hartmann’s solution), acetated Ringer’ssolution, and bicarbonated Ringer’s solution for infusion and other alkaline solutions since thesolubility 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 withother medicinal products except those mentioned in section 6.6.

Unopened vials4 years

In-use stability after reconstitution

Chemical and physical in use stability has been demonstrated for 24 hours at 20°C to 25°C.

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludesthe risk of microbial contamination, the product should be used immediately. If not used immediately,in-use storage times and conditions are the responsibility of the user.

This medicinal product does not require any special temperature storage conditions.

Keep the vials in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Type 1 glass vial with a stopper (bromobutyl rubber) and seal (aluminium) with green polypropyleneflip-off cap.

Pack size: 10 vial pack

Each vial is for single use only.

Reconstitution and dilution of the product should be conducted using aseptic techniques. Once openedthe contents of the vial should be used immediately (section 6.3).

Byfavo should be reconstituted by adding 10 mL of sodium chloride 9 mg/mL (0.9%) solution forinjection and swirled gently until the powder has entirely dissolved. Reconstituted Byfavo will beclear and colourless to light yellow. The solution is to be discarded if visible particulate matter ordiscolouration is observed.

For administration, the reconstituted solution must be further diluted. The appropriate volume ofreconstituted remimazolam solution must be withdrawn from the vial(s) and added to a syringe orinfusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection in order to achieve afinal concentration of 1-2 mg/ml remimazolam (table 7).

Table 7 Dilution instructions

Reconstituted solution Final concentration 2 mg/mL Final concentration 1 mg/mL5 mg/mL Dilute 10 mL of reconstituted Dilute 10 mL of reconstitutedsolution with 15 mL of sodium solution with 40 mL of sodium(50 mg reconstituted with 10 mL) chloride (0.9%) solution for chloride (0.9%) solution forinjection injection

For instructions on administration see section 4.2.

Administration with other fluids

When Byfavo is reconstituted and diluted for use in sodium chloride (0.9%) as described above,compatibility has been shown with:

Glucose 5% w/v intravenous infusion,

Glucose 20% w/v solution for infusion,

Sodium chloride 0.45% w/v and glucose 5% w/v solution for infusion,

Sodium chloride 0.9% w/v intravenous infusion,

Ringers solution (sodium chloride 8.6 g/L, potassium chloride 0.3 g/L, calcium chloride dihydrate0.33 g/L)

This medicinal product must not be mixed or co-administered through the same infusion line withmedicinal products other than those fluids described in this section.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

PAION Pharma GmbH

Heussstraße 2552078 Aachen

Germany

Tel: +800 4453 4453e-mail: info@paion.com

EU/1/20/1505/002

Date of first authorisation: 26 March 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.