Брайдан

Reversal of neuromuscular blockade induced by rocuronium or vecuronium in adults.

For the paediatric population: sugammadex is only recommended for routine reversal of rocuronium induced blockade in children and adolescents aged 2 to 17 years.

Posology

Sugammadex should only be administered by, or under the supervision of an anaesthetist.

The use of an appropriate neuromuscular monitoring technique is recommended to monitor the recovery of neuromuscular blockade.

The recommended dose of sugammadex depends on the level of neuromuscular blockade to be reversed.

The recommended dose does not depend on the anaesthetic regimen.

Sugammadex can be used to reverse different levels of rocuronium or vecuronium induced neuromuscular blockade:

Adults

Routine reversal:

A dose of 4 mg/kg sugammadex is recommended if recovery has reached at least 1-2 post-tetanic counts (PTC) following rocuronium or vecuronium induced blockade. Median time to recovery of the T₄/T₁ ratio to 0.9 is around 3 minutes.

A dose of 2 mg/kg sugammadex is recommended, if spontaneous recovery has occurred up to at least the reappearance of T₂ following rocuronium or vecuronium induced blockade. Median time to recovery of the T₄/T₁ ratio to 0.9 is around 2 minutes.

Using the recommended doses for routine reversal will result in a slightly faster median time to recovery of the T₄/T₁ ratio to 0.9 of rocuronium when compared to vecuronium induced neuromuscular blockade.

Immediate reversal of rocuronium-induced blockade:

If there is a clinical need for immediate reversal following administration of rocuronium a dose of 16 mg/kg sugammadex is recommended. When 16 mg/kg sugammadex is administered 3 minutes after a bolus dose of 1.2 mg/kg rocuronium bromide, a median time to recovery of the T₄/T₁ ratio to 0.9 of approximately 1.5 minutes can be expected.

There is no data to recommend the use of sugammadex for immediate reversal following vecuronium induced blockade.

Re-administration of sugammadex:

In the exceptional situation of recurrence of neuromuscular blockade post-operatively after an initial dose of 2 mg/kg or 4 mg/kg sugammadex, a repeat dose of 4 mg/kg sugammadex is recommended. Following a second dose of sugammadex, the patient should be closely monitored to ascertain sustained return of neuromuscular function.

Re-administration of rocuronium or vecuronium after sugammadex:

For waiting times for re-administration of rocuronium or vecuronium after reversal with sugammadex, see section 4.4.

Additional information on special population

Renal impairment:

The use of sugammadex in patients with severe renal impairment (including patients requiring dialysis (CrCl < 30 mL/min)) is not recommended.

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For mild and moderate renal impairment (creatinine clearance > 30 and < 80 mL/min): the dose recommendations are the same as for adults without renal impairment.

Elderly patients:

After administration of sugammadex at reappearance of T₂ following a rocuronium induced blockade, the median time to recovery of the T₄/T₁ ratio to 0.9 in adults (18-64 years) was 2.2 minutes, in elderly adults (65-74 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.

Obese patients:

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

Hepatic impairment:

Studies in patients with hepatic impairment have not been conducted. Caution should be exercised when considering the use of sugammadex in patients with severe hepatic impairment or when hepatic impairment is accompanied by coagulopathy.

For mild to moderate hepatic impairment: as sugammadex is mainly excreted renally no dose adjustments are required.

Paediatric population

The data for the paediatric population are limited (one study only for reversal of rocuronium induced blockade at reappearance of T₂).

Children and adolescents:

For routine reversal of rocuronium induced blockade at reappearance of T₂ in children and adolescents (2-17 years) 2 mg/kg sugammadex is recommended.

Брайдан 100 mg/mL may be diluted to 10 mg/mL to increase the accuracy of dosing in the paediatric population.

Other routine reversal situations have not been investigated and are therefore not recommended until further data become available.

Immediate reversal in children and adolescents has not been investigated and is therefore not recommended until further data become available.

Term newborn infants and infants:

There is only limited experience with the use of sugammadex in infants (30 days to 2 years), and term newborn infants (less than 30 days) have not been studied. The use of sugammadex in term newborn infants and infants is therefore not recommended until further data become available.

Method of administration

Sugammadex should be administered intravenously as a single bolus injection. The bolus injection should be given rapidly, within 10 seconds, into an existing intravenous line. Sugammadex has only been administered as a single bolus injection in clinical trials.

As is normal post-anaesthetic practice following neuromuscular blockade, it is recommended to monitor the patient in the immediate post-operative period for untoward events including recurrence of neuromuscular blockade.

Monitoring respiratory function during recovery:

Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored following reversal of neuromuscular blockade. Even if recovery from neuromuscular blockade is complete, other medicinal products used in the peri- and postoperative period could depress respiratory function and therefore ventilatory support might still be required.

Should neuromuscular blockade reoccur following extubation, adequate ventilation should be provided.

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, 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.

Effect on haemostasis:

In a study in volunteers doses of 4 mg/kg and 16 mg/kg of sugammadex resulted in maximum mean prolongations of the activated partial thromboplastin time (aPTT) by 17 and 22% respectively and prothrombin time international normalized ratio [PT(INR)] by 11 and 22% respectively. These limited mean aPTT and PT(INR) prolongations were of short duration (≤ 30 minutes). Based on the clinical data-base (N=3,519) and on a specific study in 1184 patients undergoing hip fracture/major joint replacement surgery there was no clinically relevant effect of sugammadex 4 mg/kg alone or in combination with anticoagulants on the incidence of peri- or post-operative bleeding complications.

In in vitro experiments a pharmacodynamic interaction (aPTT and PT prolongation) was noted with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. In patients receiving routine post-operative prophylactic anticoagulation this pharmacodynamic interaction is not clinically relevant. Caution should be exercised when considering the use of sugammadex in patients receiving therapeutic anticoagulation for a pre-existing or co-morbid condition.

An increased risk of bleeding cannot be excluded in patients:

- with hereditary vitamin K dependent clotting factor deficiencies;

- with pre-existing coagulopathies;

- on coumarin derivates and at an INR above 3.5;

- using anticoagulants who receive a dose of 16 mg/kg sugammadex.

If there is a medical need to give sugammadex to these patients the anaesthesiologist needs to decide if the benefits outweigh the possible risk of bleeding complications taking into consideration the patients history of bleeding episodes and type of surgery scheduled. If sugammadex is administered to these patients monitoring of haemostasis and coagulation parameters is recommended.

Waiting times for re-administration with neuromuscular blocking agents after reversal with sugammadex:

Re-administration of rocuronium or vecuronium after routine reversal (up to 4 mg/kg sugammadex):

The onset of neuromuscular blockade may be prolonged up to approximately 4 minutes, and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes after re-administration of rocuronium 1.2 mg/kg within 30 minutes after sugammadex administration.

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):

For the very rare cases where this might be required, a waiting time of 24 hours is suggested.

If neuromuscular blockade is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking agent should be used. The onset of a depolarizing neuromuscular blocking agent might be slower than expected, because a substantial fraction of postjunctional nicotinic receptors can still be occupied by the neuromuscular blocking agent.

Renal impairment:

Sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis.

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 suckling 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.

Marked bradycardia:

In rare instances, marked bradycardia has been observed within minutes after the administration of sugammadex for reversal of neuromuscular blockade. Bradycardia may occasionally lead to cardiac arrest. Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anti-cholinergic agents such as atropine should be administered if clinically significant bradycardia is observed.

Hepatic impairment:

Sugammadex is not metabolised nor excreted by the liver; therefore dedicated studies in patients with hepatic impairment have not been conducted. Patients with severe hepatic impairment should be treated with great caution. In case hepatic impairment is accompanied by coagulopathy see the information on the effect on haemostasis.

Use in Intensive Care Unit (ICU):

Sugammadex 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:

Sugammadex should not be used to reverse block induced by nonsteroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds.

Sugammadex should not be used for reversal of neuromuscular blockade 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 blockade, but it is advised not to use sugammadex in this situation.

Delayed recovery:

), or oedematous state (e.g., severe hepatic impairment) may be associated with longer recovery times.

Drug hypersensitivity reactions:

Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions.

Patients on a controlled sodium diet:

Each mL solution contains up to 9.7 mg sodium. A dose of 23 mg sodium is considered essentially 'sodium-free'. If more than 2.4 mL solution needs to be administered, this should be taken into consideration by patients on a controlled sodium diet.

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

Summary of the safety profile

Брайдан is administered concomitantly with neuromuscular blocking agents and anaesthetics in surgical patients. The causality of adverse events is therefore difficult to assess.

The most commonly reported adverse reactions in surgical patients were cough, airway complication of anaesthesia, anaesthetic complications, procedural hypotension and procedural complication (Common (> 1/100 to < 1/10)).

Tabulated list of adverse reactions

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 (1,078 subject exposures to sugammadex versus 544 to placebo):

[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)]

Description of selected adverse reactions

Drug hypersensitivity reactions:

Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers (for information on volunteers, see Information on healthy volunteers below).

Procedural Complication:

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

Marked bradycardia:

In post-marketing, isolated cases of marked bradycardia and bradycardia with cardiac arrest have been observed within minutes after administration of sugammadex.

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.

Information on healthy volunteers:

A randomised, double-blind study examined the incidence of drug hypersensitivity reactions in healthy volunteers given up to 3 doses of placebo (N=76), sugammadex 4 mg/kg (N=151) or sugammadex 16 mg/kg (N=148). Reports of suspected hypersensitivity were adjudicated by a blinded committee. The incidence of adjudicated hypersensitivity was 1.3%, 6.6% and 9.5% in the placebo, sugammadex 4 mg/kg and sugammadex 16 mg/kg groups, respectively. There were no reports of anaphylaxis after placebo or sugammadex 4 mg/kg. There was a single case of adjudicated anaphylaxis after the first dose of sugammadex 16 mg/kg (incidence 0.7%). There was no evidence of increased frequency or severity of hypersensitivity with repeat dosing of sugammadex.

In a previous study of similar design, there were three adjudicated cases of anaphylaxis, all after sugammadex 16 mg/kg (incidence 2.0%).

In the Pooled Phase 1 database, AEs considered common (> 1/100 to < 1/10) or very common (> 1/10) and more frequent among subjects treated with sugammadex than in the placebo group, include dysgeusia (10.1%), headache (6.7%), nausea (5.6%), urticaria (1.7%), pruritus (1.7%), dizziness (1.6%), vomiting (1.2%) and abdominal pain (1.0%).

Additional information on special populations

Pulmonary patients:

In post-marketing data and in one dedicated clinical trial in patients with a history of pulmonary complications, bronchospasm was reported as a possibly related adverse event. As with all patients with a history of pulmonary complications the physician should be aware of the possible occurrence of bronchospasm.

Paediatric population

A limited database suggests that the safety profile of sugammadex (up to 4 mg/kg) in paediatric patients was similar to that in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

In clinical studies, 1 case of an accidental overdose with 40 mg/kg was reported without any significant adverse reactions. In a human tolerance study sugammadex was administered in doses up to 96 mg/kg. No dose related adverse events nor serious adverse events were reported.

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

Pharmacotherapeutic group: all other therapeutic products, antidotes, ATC code: V03AB35

Mechanism of action:

Sugammadex is a modified gamma cyclodextrin which is a Selective Relaxant Binding Agent. It forms a complex with the neuromuscular blocking agents rocuronium or vecuronium in plasma and thereby reduces the amount of neuromuscular blocking agent available to bind to nicotinic receptors in the neuromuscular junction. This results in the reversal of neuromuscular blockade induced by rocuronium or vecuronium.

Pharmacodynamic effects:

Sugammadex has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose response studies of rocuronium induced blockade (0.6, 0.9, 1.0 and 1.2 mg/kg rocuronium bromide with and without maintenance doses) and vecuronium induced blockade (0.1 mg/kg vecuronium bromide with or without maintenance doses) at different time points/depths of blockade. In these studies a clear dose-response relationship was observed.

Clinical efficacy and safety:

Sugammadex can be administered at several time points after administration of rocuronium or vecuronium bromide:

Routine reversal - deep neuromuscular blockade:

In a pivotal study patients were randomly assigned to the rocuronium or vecuronium group. After the last dose of rocuronium or vecuronium, at 1-2 PTCs, 4 mg/kg sugammadex or 70 mcg/kg neostigmine was administered in a randomised order. The time from start of administration of sugammadex or neostigmine to recovery of the T₄/T₁ ratio to 0.9 was:

Time (minutes) from administration of sugammadex or neostigmine at deep neuromuscular blockade (1-2 PTCs) after rocuronium or vecuronium to recovery of the T₄/T₁ ratio to 0.9

Routine reversal - moderate neuromuscular blockade:

In another pivotal study patients were randomly assigned to the rocuronium or vecuronium group. After the last dose of rocuronium or vecuronium, at the reappearance of T₂, 2 mg/kg sugammadex or 50 mcg/kg neostigmine was administered in a randomised order. The time from start of administration of sugammadex or neostigmine to recovery of the T₄/T₁ ratio to 0.9 was:

Time (minutes) from administration of sugammadex or neostigmine at reappearance of T₂ after rocuronium or vecuronium to recovery of the T₄/T₁ ratio to 0.9

Reversal by sugammadex of the neuromuscular blockade induced by rocuronium was compared to the reversal by neostigmine of the neuromuscular blockade induced by cis-atracurium. At the reappearance of T₂ a dose of 2 mg/kg sugammadex or 50 mcg/kg neostigmine was administered. Sugammadex provided faster reversal of neuromuscular blockade induced by rocuronium compared to neostigmine reversal of neuromuscular blockade induced by cis-atracurium:

Time (minutes) from administration of sugammadex or neostigmine at reappearance of T₂ after rocuronium or cis-atracurium to recovery of the T₄/T₁ ratio to 0.9

For immediate reversal:

The time to recovery from succinylcholine-induced neuromuscular blockade (1 mg/kg) was compared with sugammadex (16 mg/kg, 3 minutes later) - induced recovery from rocuronium-induced neuromuscular blockade (1.2 mg/kg).

Time (minutes) from administration of rocuronium and sugammadex or succinylcholine to recovery of the T₁ 10%

In a pooled analysis the following recovery times for 16 mg/kg sugammadex after 1.2 mg/kg rocuronium bromide were reported:

Time (minutes) from administration of sugammadex at 3 minutes after rocuronium to recovery of the T₄/T₁ ratio to 0.9, 0.8 or 0.7

Renal impairment:

Two open label studies compared the efficacy and safety of sugammadex in surgical patients with and without severe renal impairment. In one study, sugammadex was administered following rocuronium induced blockade at 1-2 PTCs (4 mg/kg; N=68); in the other study, sugammadex was administered at reappearance of T₂ (2 mg/kg; N=30). Recovery from blockade was modestly longer for patients with severe renal impairment relative to patients without renal impairment. No residual neuromuscular blockade or recurrence of neuromuscular blockade was reported for patients with severe renal impairment in these studies.

The sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for non-complex-bound and complex-bound sugammadex in anaesthetised subjects.

Distribution:

The observed steady-state volume of distribution of sugammadex is approximately 11 to 14 litres in adult patients with normal renal function (based on conventional, non-compartmental pharmacokinetic analysis). Neither sugammadex nor the complex of sugammadex and rocuronium binds to plasma proteins or erythrocytes, as was shown in vitro using male human plasma and whole blood. Sugammadex exhibits linear kinetics in the dosage range of 1 to 16 mg/kg when administered as an IV bolus dose.

Metabolism:

In preclinical and clinical studies no metabolites of sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination.

Elimination:

In adult anaesthetized patients with normal renal function the elimination half-life (t_1/2) of sugammadex is about 2 hours and the estimated plasma clearance is about 88 mL/min. A mass balance study demonstrated that > 90% of the dose was excreted within 24 hours. 96% of the dose was excreted in urine, of which at least 95% could be attributed to unchanged sugammadex. Excretion via faeces or expired air was less than 0.02% of the dose. Administration of sugammadex to healthy volunteers resulted in increased renal elimination of rocuronium in complex.

Special populations:

Renal impairment and age:

In a pharmacokinetic study comparing patients with severe renal impairment to patients with normal renal function, sugammadex levels in plasma were similar during the first hour after dosing, and thereafter the levels decreased faster in the control group. Total exposure to sugammadex was prolonged, leading to 17-fold higher exposure in patients with severe renal impairment. Low concentrations of sugammadex are detectable for at least 48 hours post-dose in patients with severe renal insufficiency.

In a second study comparing subjects with moderate or severe renal impairment to subjects with normal renal function, sugammadex clearance progressively decreased and t_1/2 was progressively prolonged with declining renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively. Sugammadex concentrations were no longer detectable beyond 7 days post-dose in subjects with severe renal insufficiency.

A summary of sugammadex pharmacokinetic parameters stratified by age and renal function is presented below:

CV=coefficient of variation

Gender:

No gender differences were observed.

Race:

In a study in healthy Japanese and Caucasian subjects no clinically relevant differences in pharmacokinetic parameters were observed. Limited data does not indicate differences in pharmacokinetic parameters in Black or African Americans.

Body weight:

Population pharmacokinetic analysis of adult and elderly patients showed no clinically relevant relationship of clearance and volume of distribution with body weight.

Physical incompatibility has been reported with verapamil, ondansetron and ranitidine.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

Брайдан 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%), Ringers lactate solution, Ringers solution, glucose 50 mg/mL (5%) in sodium chloride 9 mg/mL (0.9%).

The infusion line should be adequately flushed (e.g., with 0.9% sodium chloride) between administration of Брайдан and other drugs.

Use in the paediatric population

For paediatric patients Брайдан can be diluted using sodium chloride 9 mg/mL (0.9%) to a concentration of 10 mg/mL.

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

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain