Bridion 100 mg/mL Injection

BRIDION is indicated for the routine reversal of neuromuscular blockade induced by rocuronium or vecuronium. BRIDION is also indicated for the immediate reversal of neuromuscular blockade at 3 minutes after administration of rocuronium. For the paediatric population, BRIDION is only recommended for routine reversal of rocuronium induced blockade in children above 7 years of age.

Posology
BRIDION Injection should be administered under the supervision of an anaesthetist. BRIDION Injection should be administered intravenously as a single bolus injection. The bolus injection may be given rapidly, within 10 seconds, into an existing IV line.

Special populations
Renal Impairment
For mild and moderate renal impairment (creatinine clearance u2265 30 and < 80 mL/min): The dose recommendations are the same as for adults without renal impairment. The use of BRIDION in patients with severe renal impairment including patients requiring dialysis (CrCl < 30 mL/min) is not recommended (see section 4.4). Studies in patients with severe renal impairment do not provide sufficient safety information to support the use of BRIDION in these patients.

Hepatic impairment
For mild to moderate hepatic impairment: As BRIDION is mainly excreted renally no dose adjustments are required. Studies in patients with hepatic impairment have not been conducted. Caution should be exercised when considering the use of BRIDION in patients with severe hepatic impairment or when hepatic impairment is accompanied by coagulopathy (see section 4.4).

Elderly (u2265 65 years of age)
After administration of BRIDION at reappearance of T2 following a rocuronium induced blockade, the median time to recovery of the T4/T1 ratio to 0,9 in adults (18 to 64 years) was 2,2 minutes, in elderly adults (65 to 74 years) it was 2,6 minutes and in very elderly adults (75 years or more) it was 3,6 minutes. Even though the recovery times in elderly tend to be slower, the same dose recommendation as for adults should be followed (see section 4.4).

Obese Patients
In obese patients, the dose of BRIDION should be based on actual body weight. The same dose recommendations as for adults should be followed.

Paediatric population
The data for the paediatric population are limited (one study only for reversal of rocuronium induced blockade at reappearance of T2). There is insufficient information on the use of BRIDION for children < 7 years of age. There is no information on BRIDION use for neonates. Therefore BRIDION is not recommended for use in these populations.

Children and Adolescents
For reversal of rocuronium induced blockade at reappearance of T2 in children and adolescents (7 to 17 years) 2 mg/kg BRIDION is recommended. Immediate reversal in children and adolescents has not been investigated and is therefore not recommended.

BRIDION 100 mg/mL may be diluted to 10 mg/mL to increase the accuracy of dosing in the paediatric population, 7 years and older.

Method of administration
BRIDION can be injected into the intravenous line of a running infusion with the following intravenous solutions: Sodium chloride 9 mg/mL (0,9 %), glucose 50 mg/mL (5 %), sodium chloride 4,5 mg/mL (0,45 %) and glucose 25 mg/mL (2,5 %), Ringeru2019s lactate solution, Ringeru2019s solution, glucose 50 mg/mL (5 %) in sodium chloride 9 mg/mL (0,9 %). For paediatric patients BRIDION can be diluted using sodium chloride 9 mg/mL (0,9 %) to a concentration of 10 mg/mL. BRIDION has only been administered as a single bolus injection in clinical trials. The use of an appropriate neuromuscular monitoring technique is recommended to monitor the recovery of the neuromuscular blockade. When certain medicines that may cause displacement interactions are administered parenterally within 7,5 hours of BRIDION, patients should be monitored for signs of recurrence of neuromuscular blockade. The recommended dose of BRIDION depends on the level of neuromuscular blockade to be reversed. The recommended dose does not depend on the anaesthetic regimen. BRIDION can be used to reverse different levels of rocuronium or vecuronium induced neuromuscular blockade.

Routine Reversal of Neuromuscular Blockade
A dose of 4 mg/kg BRIDION is recommended if recovery has reached 1 to 2 post-tetanic counts (PTC) (profound blockade) following administration of rocuronium or vecuronium induced blockade (see section 4.4). A dose of 2 mg/kg BRIDION is only recommended if spontaneous recovery has reached the reappearance of T2 (shallow blockade) following rocuronium or vecuronium induced blockade (see section 4.4).

Immediate Reversal
If there is a clinical need for immediate reversal at 3 minutes following administration of rocuronium, a dose of 16 mg/kg BRIDION is recommended. There is no data to recommend the use of BRIDION for immediate reversal following vecuronium induced blockade.

BRIDION is contraindicated in patients with known hypersensitivity to sugammadex sodium or to any of the inactive ingredients of BRIDION.

BRIDION is not to be used to reverse depolarising neuromuscular blocking agents. Waiting times for re-administration with non-depolarising neuromuscular blocking agents (NMBA) after reversal with BRIDION. Re-administration of rocuronium or vecuronium after a recommended dose reversal (up to 4 mg/kg sugammadex):

• Minimum waiting time
• NMBA (e.g. rocuronium and vecuronium) and dose to be administered

5 minutes 1,2 mg/kg rocuronium
4 hours 0,6 mg/kg rocuronium or 0,1 mg/kg vecuronium

When rocuronium 1,2 mg/kg is administered within 30 minutes after reversal with BRIDION, the onset of neuromuscular blockade may be delayed up to approximately 4 minutes and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes. Based on PK modelling the recommended waiting time in patients with mild or moderate renal impairment for re-use of 0,6 mg/kg rocuronium or 0,1 mg/kg vecuronium after routine reversal with sugammadex should be 24 hours. If a shorter waiting time is required, the rocuronium dose for a new neuromuscular blockade should be 1,2 mg/kg.

Re-administration of rocuronium or vecuronium after immediate reversal (16 mg/kg sugammadex): A waiting time of 24 hours is recommended. If neuromuscular blockade is required before the recommended waiting time has passed, a non-steroidal neuromuscular blocking agent should be used. The onset of a depolarising neuromuscular blocking agent might be slower than expected, because a substantial fraction of post-junctional nicotinic receptors may still be occupied by the neuromuscular blocking agent.

Medicine Hypersensitivity
Doctors should be prepared for the possibility of medicine hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions.

Renal Impairment
BRIDION is not recommended for use in patients with severe renal impairment, creatinine clearance < 30 mL/min, including requiring dialysis (see section 5.2). Because of the estimated prolonged half-life of sugammadex in severe renally impaired patients, a full neuromuscular blockade may not be achieved after re-use of 0,6 mg/kg rocuronium or 0,1 mg/kg vecuronium within 24 hours after sugammadex reversal.

Marked Bradycardia
Marked bradycardia has been observed within minutes after the administration of BRIDION for reversal of neuromuscular blockade. Cases of bradycardia with cardiac arrest have been reported (see section 4.8). Patients should be closely monitored for haemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents such as atropine should be administered if clinically significant bradycardia is observed.

Monitoring Respiratory Function during Recovery
Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored following reversal of neuromuscular block. Even if recovery from neuromuscular blockade is complete, other medicines used in the peri- and post-operative period could depress respiratory function and therefore ventilatory support might still be required. Should neuromuscular blockade re-occur following extubation, adequate ventilation should be provided.

Effect on Haemostasis
In a study in volunteers, doses of 4 mg/kg and 16 mg/kg of BRIDION resulted in maximum mean prolongations of aPTT by 17 and 22 % respectively and of PT (INR) by 11 and 22 % respectively. These limited mean aPTT and PT (INR) prolongations were of short duration (u2264 30 minutes). Based on the clinical database (n=3 519) there was no clinically relevant effect of BRIDION alone or in combination with anticoagulants on the incidence of peri- or post-operative bleeding complications. In a specific study in 1 184 surgical patients who were concomitantly treated with an anticoagulant, small and transient increases were observed in aPTT and PT(INR) associated with sugammadex 4 mg/kg, which did not translate into an increased bleeding risk with sugammadex compared with usual treatment. In vitro experiments additional aPTT and PT prolongation was noted for sugammadex in combination with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. Since bleeding risk has not been studied systematically at higher doses than sugammadex 4 mg/kg, coagulation parameters should be carefully monitored according to routine clinical practice in patients with known coagulopathies and in patients using anticoagulants who receive a dose of 16 mg/kg sugammadex.

Delayed Recovery
Conditions associated with prolonged circulation time such as cardiovascular disease, old age (see section 4.2 for the time to recovery in elderly) or oedematous state (e.g. severe hepatic impairment) may be associated with longer recovery times.

Hepatic Impairment
BRIDION is not metabolised nor excreted by the liver; therefore dedicated studies in patients with hepatic impairment have not been conducted. Hepatic impairment may be accompanied by coagulopathy (see the information on the Effect on Haemostasis above).

Light Anaesthesia
When neuromuscular blockade was reversed intentionally in the middle of anaesthesia in clinical trials, signs of light anaesthesia were noted occasionally (movement, coughing, grimacing and sucking of the tracheal tube). If neuromuscular blockade is reversed, while anaesthesia is continued, additional doses of anaesthetic and/or opioid should be given as clinically indicated.

Use in Intensive Care Unit (ICU)
BRIDION has not been investigated in patients receiving rocuronium or vecuronium in the ICU setting.

Use for Reversal of Neuromuscular Blocking Agents other than Rocuronium or Vecuronium
BRIDION should not be used to reverse block induced by non-steroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds. BRIDION should not be used for reversal of neuromuscular blockage induced by steroidal neuromuscular blocking agents other than rocuronium or vecuronium, since there are no efficacy and safety data for these situations. Limited data are available for reversal of pancuronium induced blockage, but it is advised not to use BRIDION in this situation.

The information reported in this section is based on binding affinity between BRIDION and other medicines, non-clinical experiments, clinical studies and simulations using a model taking into account the pharmacodynamic effect of neuromuscular blocking agents and sugammadex. Based on these data, no clinically significant pharmacodynamic interaction with other medicines are expected, with the exception of toremifene, fusidic acid and hormonal contraceptives. For these medicines, a clinically relevant interaction could not be excluded. No clinically relevant interactions were reported during the clinical development. Due to the administration of certain medicines after sugammadex, theoretically rocuronium or vecuronium could be displaced from BRIDION. As a result, recurrence of neuromuscular blockade might be observed. In this situation the patient must be ventilated. Administration of medicines which caused displacement should be stopped in case of an infusion. In situations when potential displacement interactions can be anticipated, patients should be carefully monitored for signs of re-occurrence of blockade (approximately up to 15 minutes), after parenteral administration of another medicine occurring within a period of 7,5 hours after BRIDION administration.

BRIDION should be used cautiously when co-administered with:

Toremifene
For toremifene, which has a relatively high binding affinity for sugammadex and for which relatively high plasma concentrations might be present, some displacement of vecuronium or rocuronium from the complex with BRIDION could occur. The recovery of the train of four ratio, T4/T1 to 0,9 could therefore be delayed in patients who have received toremifene on the same day of surgery (see section 4.4).

Intravenous Administration of Fusidic Acid
The use of fusidic acid in the pre-operative phase may cause some delay in the recovery of the T4/T1 ratio to 0,9. No recurrence of neuromuscular blockade is expected in the post-operative phase, since the infusion rate of fusidic acid is over a period of several hours and the blood levels are cumulative over 2 to 3 days.

Hormonal Contraceptives
In a simulation performed with a PK-PD model, it was found that the interaction between 4 mg/kg BRIDION and a progestogen could lead to a decrease in progestogen exposure (34 % of AUC) similar to the decrease seen when a daily dose of an oral contraceptive is taken 12 hours too late, which might lead to a reduction in effectiveness. Therefore, the administration of a bolus dose of BRIDION is considered to be equivalent to one missed daily dose of oral contraceptive steroids.

Please refer to the missed dose advice in the package insert of the oral contraceptive, for any action required if an oral contraceptive is taken on the same day that BRIDION is administered. In the case of non-oral hormonal contraceptives, the patient must use an additional non-hormonal contraceptive method for the next 7 days.

Interference with Laboratory Tests
BRIDION has been shown to interfere with the serum progesterone assay. This interference was observed in plasma samples spiked with a concentration of BRIDION in the same range as obtained for Cmax after a dose of 16 mg/kg. Additional information on special populations
Paediatric Population
No formal interaction studies have been performed. The above-mentioned interactions for adults and the warnings should also be taken into account for the paediatric population.

Pregnancy
The safety in pregnant women has not been established.

Breastfeeding
Excretion of sugammadex in human milk has not been studied but can be expected based on the pre-clinical data. Animal studies have shown excretion of sugammadex in breast milk. Caution should be exercised when administering BRIDION to breastfeeding women.

BRIDION has no known influence on the ability to drive and use machines.

Summary of the safety profile
The most commonly reported adverse reactions in surgical patients were cough, airway complication, anaesthesia complications, procedural hypotension and procedural complications (Common (u2265 1/100 to < 1/10)). The safety of sugammadex has been evaluated in 3 519 unique subjects across a pooled phase I-III safety database. The following adverse reactions were reported in placebo-controlled trials where subjects received anaesthesia and/or neuromuscular blocking agents (1078 subject exposures to sugammadex versus 544 to placebo): [Very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 1/10 000 to < 1/1 000), very rare (< 1/10 000)]

System organ class Frequencies Adverse reactions (Preferred terms) Immune system disorders Uncommon Drug hypersensitivity reactions (see section 4.4) Respiratory, thoracic and mediastinal disorders Common Cough Injury, poisoning and procedural complications Common Airway complication of Anaesthesia Anaesthetic complication (see section 4.4) Procedural hypotension Procedural complication

Description of selected adverse reactions
In clinical studies, the investigator reported terms for complications resulting from anaesthesia or surgery were grouped in the adverse event categories below, and included the following: Airway Complication of Anaesthesia Airway complications of anaesthesia included bucking against the endotracheal tube, coughing, mild bucking, arousal reaction during surgery, coughing during the anaesthetic procedure or during surgery or contra breath (spontaneous breath of patient, anaesthetic procedure related). Anaesthetic Complications Anaesthetic complications, indicative of the restoration of neuromuscular function, include movement of a limb or the body or coughing during the anaesthetic procedure or during surgery, grimacing or sucking on the endotracheal tube.

Procedural Complication
Procedural complications included coughing, tachycardia, bradycardia, movement and increase in heart rate.

Recurrence of Neuromuscular Blockade
In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex was administered using a dose labelled for the depth of neuromuscular blockade (N=2 022), an incidence of 0,20 % was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence. The use of lower than recommended doses may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended. In cases where recurrence of neuromuscular blockade is observed, the patient must be ventilated.

Medicine Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers (for information on volunteers, see Information on healthy volunteers below). In clinical trials of surgical patients these reactions were reported uncommonly and for post-marketing reports the frequency is unknown. These reactions varied from isolated skin reactions to serious systemic reactions (i.e. anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to BRIDION. Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, swelling of tongue, swelling of the pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal.

BRIDION can be removed using haemodialysis with a high-flux filter, but not with a low-flux filter. Based upon clinical studies, BRIDION concentrations in plasma are reduced with a high-flux filter by about 70 % after a 3- to 6-hour dialysis session.