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

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

Posology

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

Opioid co-administered medicinal products are known to increase the sedative effect of remimazolam and to depress the ventilatory response to carbon dioxide stimulation (see sections 4.4 and 4.5).

Table 1. Dosing guidelines for adults*:

^* 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 administered in clinical trials see section 5.1.
^# American Society of Anesthesiologists Physical Status

Special populations

Elderly, American Society of Anesthesiologists Physical Status (ASA-PS) III-IV patients and patients with 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 therefore of particular relevance when deciding upon individualised dosage adjustments for these patients (see sections 4.4).

Renal impairment

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

Hepatic impairment

The metabolising enzyme (carboxylesterase-1 [CES-1]) for remimazolam is predominantly located in the liver and the clearance of remimazolam is affected by increasing stages of hepatic impairment (see section 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 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 (see section 4.4).

Paediatric population

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

Method of administration

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

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

Symptoms

The symptoms of remimazolam overdose are expected to be an extension of its pharmacological actions and may present with one or more of the following signs and symptoms: dizziness, confusion, drowsiness, blurred vision or nystagmus, agitation, weakness, hypotension, bradycardia, respiratory depression and coma.

Management of overdose

The patient’s vital signs should be monitored and supportive measures should be started as indicated by the patient’s clinical state including securing airway passages, assuring adequate ventilation and establishing adequate intravenous access. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with remimazolam is known or suspected.

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

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

Unopened vials:

4 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 precludes the 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 polypropylene flip-off cap.

Pack size: 10 vial pack.

Instructions for use

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 for injection. The reconstituted solution is clear, colourless to pale yellow and practically free from visible particulate matter and contains 2.5 mg/mL of remimazolam. The solution is to be discarded if visible particulate matter or discolouration is observed. Byfavo is for single use only. Once opened the content of the vial should normally be used immediately (section 6.3). For instructions on administration 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 dihydrate 0.33 g/L)

Disposal

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