BYFAVO 20mg powder for injection medication leaflet

Byfavo 20 mg powder for solution for injection

Each vial contains remimazolam besylate equivalent to 20 mg remimazolam.

After reconstitution each mL contains 2.5 mg remimazolam.

Each vial contains 79.13 mg of dextran 40 for injection.

For the full list of excipients, see section 6.1.

Powder for solution for injection.

White to off-white powder.

Remimazolam is indicated in adults for procedural sedation.

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

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

Opioid co-administered medicinal products are known to increase the sedative effect of remimazolamand 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 ageand/or with ASA-PS# III-IV and/orbody weight < 50 kg

Procedural Induction Inductionsedation Administer opioid* Administer opioid*with Wait 1-2 min Wait 1-2 minopioid** Initial dose: Initial dose:

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

Wait 2 min Wait 2 min

Maintenance/titration Maintenance/titration

Injection: 2.5 mg (1 mL) over 15 sec Injection: 1.25-2.5 mg (0.5-1 mL) over15 sec

Maximal total dose administrated in the Maximal total dose administrated in theclinical trials was 33 mg. clinical trials was 17.5 mg.

Procedural Induction Inductionsedation Injection: 7 mg (2.8 mL) over 1 min Injection: 2.5-5 mg (1-2 mL) over 1 minwithout Wait 2 min Wait 2 minopioid

Maintenance/titration Maintenance/titration

Injection: 2.5 mg (1 mL) over 15 sec Injection: 1.25-2.5 mg (0.5-1 mL) over15 sec

Maximal total dose administrated in the Maximal total dose administrated in theclinical trials was 33 mg. 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 administeredin clinical trials see section 5.1.

# American Society of Anesthesiologists Physical Status

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 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 thereforeof particular relevance when deciding upon individualised dosage adjustments for these patients (seesections 4.4).

No dosage 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.

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

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

Hypersensitivity to the active substance, other benzodiazepines or 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 (corresponding to the time of maximum concentration of remimazolam) beforeresolving within about 30 minutes after the end of administration. This increase in heart rate coincideswith a decrease in blood pressure and it may confound QT correction for heart rate translating into asmall prolongation in QTcF in the first few minutes 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 profound sedation, respiratory depression,coma and death. In patients with longer-term opioid use, caution is advised; it should not be presumedthat 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 concomitantuse has the potential to increase the clinical effects of remimazolam, possibly including severesedation 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) maydevelop tolerance to the sedative effects of remimazolam. Hence, a larger cumulative dose ofremimazolam may be required to achieve the desired level of sedation. It is recommended to followthe titration regimen in section 4.2 and titrate up based on the patient’s sedation-response, until thedesired depth of sedation is achieved. (see section 4.5)

Remimazolam should be administered only by health care professionals experienced in sedation whoare not involved in conducting the procedure, in a setting fully equipped for the monitoring andsupport of respiratory and cardiovascular function. Administering personnel must be adequatelytrained in the recognition and management of expected adverse reactions including respiratory andcardiac resuscitation (see section 4.2). Patients should be monitored closely during and after theprocedure for signs and symptoms of respiratory depression and sedation. The physician should alsobe aware of the typical time taken for patients to recover from the effects of remimazolam andconcomitant 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). Special attention is required for the timing oftitration doses (see section 4.2). These patients may be more susceptible to respiratory depression (seesection 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.

Dextran

This medicinal product contains 79.13 mg of dextran 40 for injection in each vial. Dextrans can causeanaphylactic/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 (seesections 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 (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 toadminister remimazolam, then discontinuation of breastfeeding for 24 hours after 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, using the recovery data from the pivotal clinical trials as a basis for theirdecision (see section 5.1). 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 are hypotension(37.2%), respiratory depression (13.1%), and bradycardia (6.8%). Safety precautions must be taken tomanage the occurrence of these adverse reactions in clinical practice (see section 4.4).

Adverse reactions associated with intravenous remimazolam observed in controlled clinical trials inprocedural sedation and the postmarketing setting are tabulated below in Table 2 according to the

MedDRA system organ classification and frequency. Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.. Frequency groupings are as follows: verycommon (≥ 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

Not known Anaphylactic reaction

Common Headache

Common Dizziness

Uncommon Somnolence

Common Bradycardia1*

Very common Hypotension2*

Very common Respiratory depression3*

Uncommon Hiccups

Common Nausea

Common Vomiting

Uncommon Chills

Uncommon Feeling cold1 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, bloodpressure 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, andrespiratory distress.

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

Table 3: Selected adverse reactions

Adverse reaction Mild Moderate Severe

Reported event term

Bradycardia

Bradycardia 6.0% 0.1% 0.4%

Hypotension 30.1% 1.1% 0.1%

Diastolic hypotension 8.7% 0 0

Hypoxia 8.0% 0.9% 0.3%

Respiratory rate decreased 1.5% 0.4% 0

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

In controlled trials in procedural sedation, patients ≥65 years old had a higher frequency of eventsgrouped 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 forhypotension (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. Seealso sections 4.2 and 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 dedicated trialassessing remimazolam in hepatic impairment. See also 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 and symptoms: dizziness, confusion,drowsiness, blurred vision or nystagmus, agitation, weakness, hypotension, bradycardia, respiratorydepression and coma.

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. The effects of remimazolam on the

CNS are dependent on the dose administered intravenously and presence or absence of other medicinalproducts. Remimazolam binds to benzodiazepine sites of gamma amino butyric acid type A [GABAA]receptors with high affinity, while its carboxylic acid metabolite (CNS7054) has approximately300 times lower affinity for these receptors. Remimazolam does not show clear selectivity betweensubtypes of the GABAA receptor.

The primary pharmacodynamic effect of remimazolam is sedation.

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.

Depth, duration and recovery from sedation is dose-dependent. Time to fully alert was 10 min for0.075 mg/kg of remimazolam.

Remimazolam can cause anterograde amnesia after administration, which prevents patients fromremembering events occurring during the procedure. Brice questionnaire data from 743 remimazolam-treated patients, assessed 10 minutes after the patient became fully alert and one day after theprocedure, show that 76% of patients had no recollection of the procedure.

The efficacy of remimazolam was based on two pivotal studies CNS7056-006 and CNS7056-008 inadult patients (aged 18 to 95 years) with ASA-PS I-III who were scheduled for colonoscopy orbronchoscopy, respectively. The safety database for remimazolam additionally comprised a dedicatedsafety and efficacy trial in ASA-PS III/IV patients, CNS7056-015.

CNS7056-006 and CNS7056-008 are two Phase 3 double-blind, randomised, active- and placebo-controlled clinical trials in adult patients undergoing colonoscopy and bronchoscopy, respectively. Allpatients received fentanyl for analgesia before and during the procedure (50 or 75 µg or a reduceddose for elderly/debilitated patients and supplemental doses of 25 µg at least 5 min apart, as needed,but not to exceed 200 µg). Patients were randomised to remimazolam, midazolam dosed according tothe U.S. local approved posology, or placebo with rescue midazolam dosed at the investigator’sdiscretion.

The remimazolam and placebo groups were double-blinded, while the midazolam arm was open-labeldue to the different dosing regimen for midazolam. After pre-treatment with fentanyl to ensureanalgesia, patients received an initial dose of 5.0 mg (2 mL) remimazolam or matching placebo over1 minute or 1.75 mg midazolam over 2 minutes (or 1.0 mg midazolam for patients ≥ 60 years of age ordebilitated or chronically ill). For the remimazolam and placebo arms, supplemental doses of 2.5 mg(1 mL) at least 2 min apart were allowed until adequate sedation was achieved, and as necessary tomaintain sedation. For midazolam, supplemental doses of 1.0 mg over 2 minutes with 2 minutesbetween doses (or 0.5 mg for patients aged ≥ 60 years or debilitated or chronically ill) were allowed toachieve and maintain adequate sedation.

The number of top-up doses and total doses of remimazolam, rescue midazolam and fentanyladministered are presented in Table 4.

Table 4: Number of top-up doses and total doses of remimazolam, rescue midazolam andfentanyl in Phase 3 clinical trials with intravenous remimazolam (Safety set)

CNS7056-006 CNS7056-008

Parameter Remimazolam Midazolam Placebo Remimazolam Midazolam Placebo(mean ± standard (N=296) (N=102) (rescue (N=303) (N=69) (rescuedeviation) midazolam) midazolam)(N=60) (N=59)

Number of top-up 2.2 ± 1.6 3.0 ± 1.1 5.1 ± 0.5 2.6 ± 2.0 2.8 ± 1.6 4.1 ± 0.8doses of study drug

Total doses of study 10.5 ± 4.0 3.9 ± 1.4 0 11.5 ± 5.1 3.2 ± 1.5 0drug [mg]

Total doses of 0.3 ± 2.1 3.2 ± 4.0 6.8 ± 4.2 1.3 ± 3.5 2.6 ± 3.0 5.9 ± 3.7rescue midazolam[mg]

Total doses of 88.9 106.9 121.3 81.9 107.0 119.9fentanyl [µg] ± 21.7 ± 32.7 ± 34.4 ± 54.3 ± 60.6 ± 80

The safety set consists of all randomised patients who receive any amount of study drug.

The primary endpoint, success of procedure was defined as meeting all of the following:

* Completion of the colonoscopy/bronchoscopy procedure, AND

* No requirement for a rescue sedative medication, AND

* No requirement of more than 5 doses of study medication within any 15 min window (formidazolam: no requirement of more than 3 doses within any 12 min window).

Statistically significant higher success rates were observed for the difference between remimazolamand placebo (p< 0.0001; Table 5 and Table 6). Comparisons between remimazolam and midazolamare descriptive and significance testing was not performed. In the dedicated safety and efficacy trial in

ASA-PS III/IV patients, CNS7056-015, similar results were observed, the procedure success rate was27/32 (84.4%) for remimazolam, and 0% for placebo.

Table 5: Procedure success rates in Phase 3 clinical trials with intravenous remimazolam forprocedure duration < 30 minutes (intent-to-treat set)

Trial CNS7056-006 CNS7056-008

Placebo Placebo(rescue (rescue

Treatment arm

Remimazolam Midazolam midazolam) Remimazolam Midazolam midazolam)(N=297) (N=100) (N=58) (N=280) (N=69) (N=58)

Procedure success [N (%)] 272 (91.6%) 26 (26.0%) 1 (1.7%) 232 (82.9%) 22 (31.9%) 2 (3.5%)

Procedure failure [N (%)] 25 (8.4%) 74 (74.0%) 57 (98.3%) 48 (17.1%) 47 (68.1%) 56 (96.6%)

Rescue sedative 9 63 55 38 37 53medication taken [N]

Too many doses within 17 55 42 10 10 10time [N]7 2 1 9 5 3

Procedure not completed[N]

The intent-to-treat analysis set includes all patients who were randomised.

Table 6: Procedure success rates in Phase 3 clinical trials with intravenous remimazolam forprocedure duration ≥ 30 minutes (intent-to-treat set)

Trial CNS7056-006 CNS7056-008

Placebo Placebo(rescue (rescue

Treatment arm

Remimazolam Midazolam midazolam) Remimazolam Midazolam midazolam)(N=1) (N=3) (N=2) (N=30) (N=4) (N=5)

Procedure success [N (%)] 0 0 0 18 (60.0%) 2 (50.0%) 1 (20.0%)

Procedure failure [N (%)] 1 (100%) 3 (100.0%) 2 (100%) 12 (40.0%) 2 (50.0%) 4 (80.0%)

Rescue sedative medication 1 3 2 11 2 4taken [N]

Too many doses within 1 1 2 4 0 0time [N]

Procedure not completed 0 0 0 0 0 0[N]

The intent-to-treat analysis set includes all patients who were randomised.

The onset and recovery profile of remimazolam was characterised by time-to-event secondaryendpoints assessed in the two Phase 3 trials, CNS7056-006 and CNS7056-008. Time to start ofprocedure was shorter (p < 0.01) in remimazolam group compared to placebo (rescue midazolam)group (Table 7). Time to recovery is presented according to procedure duration (Tables 8 and 9).

Table 7: Time to start of procedure in Phase 3 clinical trials with intravenous remimazolam(intent-to-treat set)

Trial CNS7056-006 CNS7056-008

Placebo Placebo

Treatment arm Remimazolam Midazolam (rescue Remimazolam Midazolam (rescuemidazolam) midazolam)

Number of 296 102 60 300 68 60patients in analysis

Median (95% CI) 4.0 19.0 19.5 4.1 15.5 17.0(-, -) (17.0, 20.0) (18.0, 21.0) (4.0, pct. 4.8) (13.8, 16.7) (16.0, 17.5)

Min, max 0, 26 3, 32 11, 36 1, 41 3, 53 4, 29

The Intent-to-treat analysis set includes all patients who were randomised.

Table 8: Time to recovery in Phase 3 clinical trials with intravenous remimazolam for procedureduration < 30 minutes (Intent-to-treat set)

Trial CNS7056-006 CNS7056-008

Placebo

Placebo

Remimazola Remimazola (rescue

Treatment arm Midazolam (rescue Midazolamm m midazolammidazolam))

Time to Fully Alert1 from Last Dose (minutes)

Number of 284 97 57 268 63 54patients inanalysis

Median (95% CI) 13.0 23.0 29.0 10.3 18.0 17.5(13.0, 14.0) (21.0, 26.0) (24.0, 33.0) (9.8, 12.0) (11.0, 20.0) (13.0, 23.0)

Min, max 3, 51 5, 68 9, 81 1, 92 2, 78 5, 119

Time to Ready for Discharge2 from Last Dose (minutes)

Number of 294 98 58 260 62 53patients inanalysis

Median (95% CI) 51.0 56.5 60.5 62.5 70.0 85.0(49.0, 54.0) (52.0, 61.0) (56.0, 67.0) (60.0, 65.0) (68.0, 87.0) (71.0,107.0)

Min, max 19, 92 17, 98 33, 122 15, 285 27, 761 40, 178

Time to Back to Normal3 from Last Dose (hours)

Number of 292 95 54 230 56 46patients inanalysis

Median (95% CI) 3.2 5.7 5.3 5.4 7.3 8.8(3.0, 3.5) (4.5, 6.9) (3.3, 7.2) (4.6, 6.2) (5.2, 16.4) (6.7, 17.0)

Min, max 0, 77 1, 34 1, 23 0, 46 1, 35 2, 30

Note1: Fully alert is defined as the first of three consecutive MOAA/S measurements of 5 after start time of the last dose ofstudy or rescue drug.

Note2: Ready for discharge time was determined by a walking test.

Note3: Date and time of ´back to normal´ in the patient´s subjective view were recorded via telephone contact by the studynurse on Day 4 (+3/-1 days) after the procedure.

The Intent-to-treat analysis set includes all patients who were randomised.

Table 9: Time to recovery in Phase 3 clinical trials with intravenous remimazolam for procedureduration ≥30 minutes (Intent-to-treat set)

Trial CNS7056-006 CNS7056-008

Placebo

Placebo

Remimazola Remimazola (rescue

Treatment arm Midazolam (rescue Midazolamm m midazolammidazolam))

Time to Fully Alert1 from Last Dose (minutes)

Number of 1 3 2 30 4 5patients inanalysis

Median (95% CI) 6.0 (N/A) 27.0 22.5 34.8 26.1 48.0(25.0, (21.0, 24.0) (16.2, 47.4) (16.0, 42.0) (22.0,28.0) 123.0)

Min, max 6, 6 25, 28 21, 24 4, 114 16, 42 22, 123

Time to Ready for Discharge2 from Last Dose (minutes)

Number of 1 3 2 29 4 5patients inanalysis

Median (95% CI) 58.0 66.0 60.0 83.0 63.5 95.0(N/A) (58.0, (52.0, 68.0) (72.0, 103.0) (38.0, 98.0) (73.0,74.0) 157.0)

Min, max 58, 58 58, 74 52, 68 26, 165 38, 98 73, 157

Time to Back to Normal3 from Last Dose (hours)

Number of 1 3 2 19 4 3patients inanalysis

Median (95% CI) 3.3 8.1 5.2 16.7 2.7 9.1(N/A) (7.0, 14.4) (4.6, 5.8) (4.7, 21.0) (0.9, 5.1) (3.6, 37.0)

Min, max 3, 3 7, 14 5, 6 3, 38 1, 5 4, 37

Note1: Fully alert is defined as the first of three consecutive MOAA/S measurements of 5 after start time of the last dose ofstudy or rescue drug.

Note2: Ready for discharge time was determined by a walking test.

Note3: Date and time of ´back to normal´ in the patient´s subjective view were recorded via telephone contact by the studynurse on Day 4 (+3/-1 days) after the procedure.

The Intent-to-treat analysis set includes all patients who were randomised.

N/A: not applicable

Clinical Safety

In procedures less than 30 minutes, the incidence of treatment-emergent adverse events was 80.9%,90.8%, and 82.3% in the remimazolam, midazolam, and placebo group, respectively. In procedures30 minutes or longer, the incidence of treatment-emergent adverse events was 87.1% in theremimazolam group, and 100% in both the midazolam and the placebo groups.

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 sedation (see section 4.2for 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 (Vz) 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 the 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. Clearance is high (68±12 L/h)and not related to body weight. In healthy subjects at least 80% of the remimazolam dose is excretedin urine as CNS7054 within 24 hours. Only traces (< 0.1%) of unchanged remimazolam are detectedin urine.

Remimazolam dose versus remimazolam maximal plasma concentration (Cmax) and total exposure(AUC0-∞) suggested a dose-proportional relationship in human volunteers in the dose range 0.01-0.5 mg/kg.

Special population

There is no significant effect of age on the pharmacokinetics of remimazolam given for proceduralsedation (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 the one used in clinical practice:

Primary lesions due to a mechanical irritation of the vessel wall during the puncture procedure can beaggravated by concentrations of remimazolam above 1 to 2 mg/mL (infusion) or above 5 mg/mLduring bolus administration.

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 and rabbits. Theinactive main metabolite CNS7054 was detected in the plasma of suckling rabbit kits, however it isnot known if remimazolam is transferred via milk to suckling offspring.

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 blue polypropyleneflip-off cap.

Pack size: 10 vial pack

Byfavo must be reconstituted under aseptic conditions before administration.

Byfavo should be reconstituted by adding 8.2 mL of sodium chloride 9 mg/mL (0.9%) solution forinjection. The reconstituted solution is clear, colourless to pale yellow and practically free from visibleparticulate matter and contains 2.5 mg/mL of remimazolam. The solution is to be discarded if visibleparticulate matter or discolouration is observed. Byfavo is for single use only. Once opened thecontent of the vial should normally be used immediately (section 6.3). For instructions onadministration see section 4.2.

Administration with other fluids

When Byfavo is reconstituted in sodium chloride (0.9%), 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)

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/1/20/1505/001

Date of first authorisation: March 26, 2021

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

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