SUGAMMADEX FRESENIUS KABI 100mg / ml injectible solution medication leaflet

Sugammadex Fresenius Kabi 100 mg/mL solution for injection

1 mL contains sugammadex sodium equivalent to 100 mg sugammadex.

Each vial of 1 mL contains sugammadex sodium equivalent to 100 mg sugammadex.

Each vial of 2 mL contains sugammadex sodium equivalent to 200 mg sugammadex.

Each vial of 5 mL contains sugammadex sodium equivalent to 500 mg sugammadex.

Contains up to 9.7 mg/mL sodium (see section 4.4).

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear and colourless to slightly yellow solution, free from visible particles.

The pH is between 7 and 8 and osmolality is between 300 and 500 mOsm/kg.

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

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

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 recoveryof neuromuscular blockade (see section 4.4).

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 inducedneuromuscular blockade:

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/T1ratio to 0.9 is around 3 minutes (see section 5.1).

A dose of 2 mg/kg sugammadex is recommended, if spontaneous recovery has occurred up to at leastthe reappearance of T2 following rocuronium or vecuronium induced blockade. Median time to recoveryof the T4/T1 ratio to 0.9 is around 2 minutes (see section 5.1).

Using the recommended doses for routine reversal will result in a slightly faster median time to recoveryof the T4/T1 ratio to 0.9 of rocuronium when compared to vecuronium induced neuromuscular blockade(see section 5.1).

Immediate reversal of rocuronium-induced blockade:

If there is a clinical need for immediate reversal following administration of rocuronium a dose of16 mg/kg sugammadex is recommended. When 16 mg/kg sugammadex is administered 3 minutes aftera bolus dose of 1.2 mg/kg rocuronium bromide, a median time to recovery of the T4/T1 ratio to 0.9 ofapproximately 1.5 minutes can be expected (see section 5.1).

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

Re-administration of sugammadex:

In the exceptional situation of recurrence of neuromuscular blockade post-operatively (see section 4.4)after an initial dose of 2 mg/kg or 4 mg/kg sugammadex, a repeat dose of 4 mg/kg sugammadex isrecommended. Following a second dose of sugammadex, the patient should be closely monitored toascertain 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 populations

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 elderlyadults (65-74 years) it was 2.6 minutes and in very elderly adults (75 years or more) it was3.6 minutes. Even though the recovery times in elderly tend to be slower, the same doserecommendation as for adults should be followed (see section 4.4).

The use of sugammadex 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 supportthe use of sugammadex in these patients (see also section 5.1).

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

Studies in patients with hepatic impairment have not been conducted. Caution should be exercisedwhen considering the use of sugammadex in patients with severe hepatic impairment or when hepaticimpairment is accompanied by coagulopathy (see section 4.4).

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

Obese patients:

In obese patients, including morbidly obese patients (body mass index ≥ 40 kg/m2), the dose ofsugammadex should be based on actual body weight. The same dose recommendations as for adultsshould be followed.

Children and adolescents (2-17 years):

Sugammadex Fresenius Kabi100 mg/mL may be diluted to 10 mg/mL to increase the accuracy ofdosing in the paediatric population (see section 6.6).

Routine reversal:

A dose of 4 mg/kg sugammadex is recommended for reversal of rocuronium induced blockade ifrecovery has reached at least 1-2 PTC.

A dose of 2 mg/kg is recommended for reversal of rocuronium induced blockade at reappearance of T2(see section 5.1).

Immediate reversal:

Immediate reversal in children and adolescents has not been investigated.

Term newborn infants and infants (30 days to 2 years):

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

Sugammadex should be administered intravenously as a single bolus injection. The bolus injectionshould be given rapidly, within 10 seconds, into an existing intravenous line (see section 6.6).

Sugammadex has only been administered as a single bolus injection in clinical trials.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Monitoring respiratory function during recovery:

Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored followingreversal of neuromuscular blockade. Even if recovery from neuromuscular blockade is complete, othermedicinal products used in the peri- and post-operative period could depress respiratory function andtherefore 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 wasadministered 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 orclinical evidence. The use of lower than recommended doses may lead to an increased risk ofrecurrence of neuromuscular blockade after initial reversal and is not recommended (see section 4.2and section 4.8).

Effect on haemostasis:

In a study in volunteers doses of 4 mg/kg and 16 mg/kg of sugammadex resulted in maximum meanprolongations of the activated partial thromboplastin time (aPTT) by 17 and 22% respectively andprothrombin time international normalised ratio [PT(INR)] by 11 and 22% respectively. These limitedmean aPTT and PT(INR) prolongations were of short duration (≤ 30 minutes). Based on the clinicaldata-base (N=3,519) and on a specific study in 1184 patients undergoing hip fracture/major jointreplacement surgery there was no clinically relevant effect of sugammadex 4 mg/kg alone or incombination 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 withvitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban anddabigatran. In patients receiving routine post-operative prophylactic anticoagulation thispharmacodynamic interaction is not clinically relevant. Caution should be exercised when consideringthe use of sugammadex in patients receiving therapeutic anticoagulation for a pre-existing orco-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 ifthe benefits outweigh the possible risk of bleeding complications taking into consideration the patientshistory of bleeding episodes and type of surgery scheduled. If sugammadex is administered to thesepatients monitoring of haemostasis and coagulation parameters is recommended.

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

Table 1: Re-administration of rocuronium or vecuronium after routine reversal (up to 4 mg/kgsugammadex):

Minimum waiting time NMBA and dose to be administered5 minutes 1.2 mg/kg rocuronium4 hours 0.6 mg/kg rocuronium or0.1 mg/kg vecuronium

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

Based on PK modelling the recommended waiting time in patients with mild or moderate renalimpairment for re-use of 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium after routine reversal withsugammadex should be 24 hours. If a shorter waiting time is required, the rocuronium dose for a newneuromuscular blockade should be 1.2 mg/kg.

Re-administration of rocuronium or vecuronium after immediate reversal (16 mg/kg sugammadex): Forthe 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 nonsteroidalneuromuscular blocking agent should be used. The onset of a depolarizing neuromuscular blockingagent might be slower than expected, because a substantial fraction of postjunctional nicotinic receptorscan still be occupied by the neuromuscular blocking agent.

Sugammadex is not recommended for use in patients with severe renal impairment, including thoserequiring dialysis (see section 5.1).

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 thetracheal tube).

If neuromuscular blockade is reversed, while anaesthesia is continued, additional doses of anaestheticand/or opioid should be given as clinically indicated.

Marked bradycardia:

In rare instances, marked bradycardia has been observed within minutes after the administration ofsugammadex for reversal of neuromuscular blockade. Bradycardia may occasionally lead to cardiacarrest. (See section 4.8.) Patients should be closely monitored for haemodynamic changes during andafter reversal of neuromuscular blockade. Treatment with anti-cholinergic agents such as atropine shouldbe administered if clinically significant bradycardia is observed.

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

Use in Intensive Care Unit (ICU):

Sugammadex has not been investigated in patients receiving rocuronium or vecuronium in the ICUsetting.

Use for reversal of neuromuscular blocking agents other than rocuronium or vecuronium:

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

Sugammadex should not be used for reversal of neuromuscular blockade induced by steroidalneuromuscular blocking agents other than rocuronium or vecuronium, since there are no efficacy andsafety 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:

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

Active substance hypersensitivity reactions:

Clinicians should be prepared for the possibility of active substance hypersensitivity reactions (includinganaphylactic reactions) and take the necessary precautions (see section 4.8).

This medicinal product contains up to 9.7 mg sodium per mL, equivalent to 0.5% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

The information in this section is based on binding affinity between sugammadex and other medicinalproducts, non-clinical experiments, clinical studies and simulations using a model taking into account thepharmacodynamic effect of neuromuscular blocking agents and the pharmacokinetic interaction betweenneuromuscular blocking agents and sugammadex. Based on these data, no clinically significantpharmacodynamic interaction with other medicinal products is expected, with exception of thefollowing:

For toremifene and fusidic acid displacement interactions could not be excluded (no clinically relevantcapturing interactions are expected).

For hormonal contraceptives a clinically relevant capturing interaction could not be excluded (nodisplacement interactions are expected).

Interactions potentially affecting the efficacy of sugammadex (displacement interactions):

Due to the administration of certain medicinal products after sugammadex, theoretically rocuronium orvecuronium could be displaced from sugammadex. As a result recurrence of neuromuscular blockademight be observed. In this situation the patient must be ventilated. Administration of the medicinalproduct which caused displacement should be stopped in case of an infusion. In situations when potentialdisplacement interactions can be anticipated, patients should be carefully monitored for signs ofrecurrence of neuromuscular blockade (approximately up to 15 minutes) after parenteral administrationof another medicinal product occurring within a period of 7.5 hours after sugammadex administration.

Toremifene:

For toremifene, which has a relatively high binding affinity for sugammadex and for which relativelyhigh plasma concentrations might be present, some displacement of vecuronium or rocuronium from thecomplex with sugammadex could occur. Clinicians should be aware that the recovery of the T4/T1 ratioto 0.9 could therefore be delayed in patients who have received toremifene on the same day of theoperation.

Intravenous administration of fusidic acid:

The use of fusidic acid in the pre-operative phase may give some delay in the recovery of the T4/T1 ratioto 0.9. No recurrence of neuromuscular blockade is expected in the post-operative phase, since theinfusion rate of fusidic acid is over a period of several hours and the blood levels are cumulative over2-3 days. For re-administration of sugammadex see section 4.2.

Interactions potentially affecting the efficacy of other medicinal products (capturing interactions):

Due to the administration of sugammadex, certain medicinal products could become less effective due toa lowering of the (free) plasma concentrations. If such a situation is observed, the clinician is advised toconsider the re-administration of the medicinal product, the administration of a therapeutically equivalentmedicinal product (preferably from a different chemical class) and/or non- pharmacological interventionsas appropriate.

The interaction between 4 mg/kg sugammadex and a progestogen was predicted to lead to a decrease inprogestogen exposure (34% of AUC) similar to the decrease seen when a daily dose of an oralcontraceptive is taken 12 hours too late, which might lead to a reduction in effectiveness. For oestrogens,the effect is expected to be lower. Therefore, the administration of a bolus dose of sugammadex isconsidered to be equivalent to one missed daily dose of oral contraceptive steroids (either combined orprogestogen only). If sugammadex is administered at the same day as an oral contraceptive is takenreference is made to missed dose advice in the package leaflet of the oral contraceptive. In the case ofnon-oral hormonal contraceptives, the patient must use an additional non hormonal contraceptivemethod for the next 7 days and refer to the advice in the package leaflet of the medicinal product.

Interactions due to the lasting effect of rocuronium or vecuronium:

When medicinal products which potentiate neuromuscular blockade are used in the post-operative periodspecial attention should be paid to the possibility of recurrence of neuromuscular blockade. Please referto the package leaflet of rocuronium or vecuronium for a list of the specific medicinal products whichpotentiate neuromuscular blockade. In case recurrence of neuromuscular blockade is observed, thepatient may require mechanical ventilation and re-administration of sugammadex (see section 4.2).

In general sugammadex does not interfere with laboratory tests, with the possible exception of theserum progesterone assay. Interference with this test is observed at sugammadex plasma concentrationsof 100 microgram/mL (peak plasma level following 8 mg/kg bolus injection).

In a study in volunteers doses of 4 mg/kg and 16 mg/kg of sugammadex resulted in maximum meanprolongations 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 (≤ 30 minutes).

In in vitro experiments a pharmacodynamic interaction (aPTT and PT prolongation) was noted withvitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban anddabigatran (see section 4.4).

No formal interaction studies have been performed. The above mentioned interactions for adults and thewarnings in section 4.4 should also be taken into account for the paediatric population.

For sugammadex no clinical data on exposed pregnancies are available.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,embryonic/foetal development, parturition or postnatal development.

Caution should be exercised when administering sugammadex to pregnant women.

It is unknown whether sugammadex is excreted in human breast milk. Animal studies have shownexcretion of sugammadex in breast milk. Oral absorption of cyclodextrins in general is low and noeffect on the suckling child is anticipated following a single dose to the breast-feeding woman.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain fromsugammadex therapy, taking into account the benefit of breast feeding for the child and the benefit oftherapy for the woman.

The effects with sugammadex on human fertility have not been investigated. Animal studies toevaluate fertility do not reveal harmful effects.

Sugammadex Fresenius Kabi has no known influence on the ability to drive and use machines.

Sugammadex Fresenius Kabi is administered concomitantly with neuromuscular blocking agents andanaesthetics 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 complicationof anaesthesia, anaesthetic complications, procedural hypotension and procedural complication(Common (≥ 1/100 to < 1/10)).

Table 2: Tabulated list of adverse reactions

The safety of sugammadex has been evaluated in 3,519 unique subjects across a pooled phase I-IIIsafety database. The following adverse reactions were reported in placebo controlled trials wheresubjects received anaesthesia and/or neuromuscular blocking agents (1,078 subject exposures tosugammadex 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)]

System organ class Frequencies Adverse reactions(Preferred terms)

Immune system disorders Uncommon Active substancehypersensitivityreactions (see section 4.4)

Respiratory, thoracic and Common Coughmediastinal disorders

Injury, poisoning Common Airway complication ofandprocedural complications anaesthesia

Anaesthetic complication(see section 4.4)

Procedural hypotension

Procedural complication

Active substance hypersensitivity reactions:

Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers (forinformation on volunteers, see Information on healthy volunteers below). In clinical trials of surgicalpatients these reactions were reported uncommonly and for post-marketing reports the frequency isunknown.

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 sugammadex.

Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe)hypotension, tachycardia, swelling of tongue, swelling of pharynx, bronchospasm and pulmonaryobstructive events. Severe hypersensitivity reactions can be fatal.

In post-marketing reports, hypersensitivity has been observed for sugammadex as well as forsugammadex-rocuronium complex.

Airway complication of anaesthesia:

Airway complications of anaesthesia included bucking against the endotracheal tube, coughing, mildbucking, arousal reaction during surgery, coughing during the anaesthetic procedure or during surgery,or anaesthetic procedure-related spontaneous breath of patient.

Anaesthetic complication:

Anaesthetic complications, indicative of the restoration of neuromuscular function, include movement ofa limb or the body or coughing during the anaesthetic procedure or during surgery, grimacing, orsuckling on the endotracheal tube. See section 4.4 light anaesthesia.

Procedural complication:

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

Marked bradycardia:

In post-marketing, isolated cases of marked bradycardia and bradycardia with cardiac arrest have beenobserved within minutes after administration of sugammadex (see section 4.4).

Recurrence of neuromuscular blockade:

In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex wasadministered using a dose labelled for the depth of neuromuscular blockade (N=2,022), an incidence of0.20% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring orclinical evidence (see section 4.4).

Information on healthy volunteers:

A randomised, double-blind study examined the incidence of active substance hypersensitivity reactionsin healthy volunteers given up to 3 doses of placebo (N=76), sugammadex 4 mg/kg (N=151) orsugammadex 16 mg/kg (N=148). Reports of suspected hypersensitivity were adjudicated by a blindedcommittee. 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 ofanaphylaxis after placebo or sugammadex 4 mg/kg. There was a single case of adjudicated anaphylaxisafter the first dose of sugammadex 16 mg/kg (incidence 0.7%). There was no evidence of increasedfrequency or severity of hypersensitivity with repeat dosing of sugammadex.

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

In the Pooled Phase 1 database, adverse events (AEs) considered common (≥ 1/100 to < 1/10) or verycommon (≥ 1/10) and more frequent among subjects treated with sugammadex than in the placebogroup, 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 pulmonarycomplications, bronchospasm was reported as a possibly related adverse event. As with all patients witha history of pulmonary complications the physician should be aware of the possible occurrence ofbronchospasm.

In studies of paediatric patients 2 to 17 years of age, the safety profile of sugammadex (up to 4 mg/kg)was generally similar to the profile observed in adults.

Morbidly obese patients

In one dedicated clinical trial in morbidly obese patients, the safety profile was generally similar to theprofile in adult patients in pooled Phase 1 to 3 studies (see Table 2).

Patients with severe systemic disease

In a trial in patients who were assessed as American Society of Anesthesiologists (ASA) Class 3 or 4(patients with severe systemic disease or patients with severe systemic disease that is a constant threatto life), the adverse reaction profile in these ASA Class 3 and 4 patients was generally similar to thatof adult patients in pooled Phase 1 to 3 studies (see Table 2). See section 5.1.

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.

In clinical studies, 1 case of an accidental overdose with 40 mg/kg was reported without any significantadverse 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 to6-hour dialysis session.

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

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

Sugammadex has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose responsestudies of rocuronium induced blockade (0.6, 0.9, 1.0 and 1.2 mg/kg rocuronium bromide with andwithout maintenance doses) and vecuronium induced blockade (0.1 mg/kg vecuronium bromide with orwithout maintenance doses) at different time points/depths of blockade. In these studies a clear dose-response relationship was observed.

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

Routine reversal-deep neuromuscular blockade:

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

Table 3: Time (minutes) from administration of sugammadex or neostigmine at deepneuromuscular blockade (1-2 PTCs) after rocuronium or vecuronium to recovery of the T4/T1ratio to 0.9

Neuromuscular blocking agent Treatment regimen

Sugammadex (4 mg/kg) Neostigmine (70 mcg/kg)

Rocuronium

N 37 37

Median (minutes) 2.7 49.0

Range 1.2-16.1 13.3-145.7

Vecuronium

N 47 36

Median (minutes) 3.3 49.9

Range 1.4-68.4 46.0-312.7

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 or50 mcg/kg neostigmine was administered in a randomised order. The time from start of administrationof sugammadex or neostigmine to recovery of the T4/T1 ratio to 0.9 was:

Table 4: 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

Neuromuscular blocking agent Treatment regimen

Sugammadex (2 mg/kg) Neostigmine (50 mcg/kg)

Rocuronium

N 48 48

Median (minutes) 1.4 17.6

Range 0.9-5.4 3.7-106.9

Vecuronium

N 48 45

Median (minutes) 2.1 18.9

Range 1.2-64.2 2.9-76.2

Reversal by sugammadex of the neuromuscular blockade induced by rocuronium was compared to thereversal by neostigmine of the neuromuscular blockade induced by cis-atracurium. At thereappearance 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 toneostigmine reversal of neuromuscular blockade induced by cis-atracurium:

Table 5: 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

Neuromuscular blocking agent Treatment regimen

Rocuronium and sugammadex Cis-atracurium and neostigmine(2 mg/kg) (50 mcg/kg)

N 34 39

Median (minutes) 1.9 7.2

Range 0.7-6.4 4.2-28.2

For immediate reversal:

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

Table 6: Time (minutes) from administration of rocuronium and sugammadex or succinylcholineto recovery of the T1 10%

Neuromuscular blocking agent Treatment regimen

Rocuronium and sugammadex Succinylcholine(16 mg/kg) (1 mg/kg)

N 55 55

Median (minutes) 4.2 7.1

Range 3.5-7.7 3.7-10.5

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

Table 7: Time (minutes) from administration of sugammadex at 3 minutes after rocuronium torecovery of the T4/T1 ratio to 0.9, 0.8 or 0.7

T4/T1 to 0.9 T4/T1 to 0.8 T4/T1 to 0.7

N 65 65 65

Median 1.5 1.3 1.1(minutes)

Range 0.5-14.3 0.5-6.2 0.5-3.3

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

Morbidly obese patients:

A trial of 188 patients who were diagnosed as morbidly obese investigated the time to recovery frommoderate or deep neuromuscular blockade induced by rocuronium or vecuronium. Patients received2 mg/kg or 4 mg/kg sugammadex, as appropriate for level of block, dosed according to either actualbody weight or ideal body weight in random, double-blinded fashion. Pooled across depth of block andneuromuscular blocking agent, the median time to recover to a train-of-four (TOF) ratio ≥ 0.9 inpatients dosed by actual body weight (1.8 minutes) was statistically significantly faster (p < 0.0001)compared to patients dosed by ideal body weight (3.3 minutes).

A trial of 288 patients aged 2 to < 17 years investigated the safety and efficacy of sugammadex versusneostigmine as a reversal agent for neuromuscular blockade induced by rocuronium or vecuronium.

Recovery from moderate block to a TOF ratio of ≥ 0.9 was significantly faster in the sugammadex2 mg/kg group compared with the neostigmine group (geometric mean of 1.6 minutes for sugammadex2 mg/kg and 7.5 minutes for neostigmine, ratio of geometric means 0.22, 95% CI (0.16, 0.32),(p<0.0001)). Sugammadex 4 mg/kg achieved reversal from deep block with a geometric mean of2.0 minutes, similar to results observed in adults. These effects were consistent for all age cohortsstudied (2 to < 6; 6 to < 12; 12 to < 17 years of age) and for both rocuronium and vecuronium. Seesection 4.2.

Patients with severe systemic disease:

A trial of 331 patients who were assessed as ASA Class 3 or 4 investigated the incidence oftreatment-emergent arrhythmias (sinus bradycardia, sinus tachycardia, or other cardiac arrhythmias) afteradministration of sugammadex.

In patients receiving sugammadex (2 mg/kg, 4 mg/kg, or 16 mg/kg), the incidence of treatment-emergentarrhythmias was generally similar to neostigmine (50 μg/kg up to 5 mg maximum dose) + glycopyrrolate(10 μg/kg up to 1 mg maximum dose). The adverse reaction profile in ASA Class 3 and 4 patients wasgenerally similar to that of adult patients in pooled Phase 1 to 3 studies; therefore, no dosage adjustmentis necessary. See section 4.8.

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

The observed steady-state volume of distribution of sugammadex is approximately 11 to 14 litres inadult patients with normal renal function (based on conventional, non-compartmental pharmacokineticanalysis). Neither sugammadex nor the complex of sugammadex and rocuronium binds to plasmaproteins 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 IVbolus dose.

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

In adult anaesthetised patients with normal renal function the elimination half-life (t1/2) ofsugammadex is about 2 hours and the estimated plasma clearance is about 88 mL/min. A mass balancestudy demonstrated that > 90% of the dose was excreted within 24 hours. 96% of the dose wasexcreted in urine, of which at least 95% could be attributed to unchanged sugammadex. Excretion viafaeces or expired air was less than 0.02% of the dose. Administration of sugammadex to healthyvolunteers resulted in increased renal elimination of rocuronium in complex.

Renal impairment and age:

In a pharmacokinetic study comparing patients with severe renal impairment to patients with normalrenal function, sugammadex levels in plasma were similar during the first hour after dosing, andthereafter 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 ofsugammadex 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 normalrenal function, sugammadex clearance progressively decreased and t1/2 was progressively prolonged withdeclining renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severerenal impairment, respectively. Sugammadex concentrations were no longer detectable beyond 7 dayspost-dose in subjects with severe renal insufficiency.

Table 8: A summary of sugammadex pharmacokinetic parameters stratified by age and renalfunction is presented below:

Selected Patient Characteristics Mean Predicted PK Parameters (CV*%)

Demographics Renal function Clearance Volume of Elimination

Age Creatinine clearance (mL/min) distribution at half-life (hr)

Body weight (mL/min) steady state (L)

Adult Normal 100 84 (24) 13 2 (22)40 years Impaired Mild 50 47 (25) 14 4 (22)75 kg Moderate 30 28 (24) 14 7 (23)

Severe 10 8 (25) 15 24 (25)

Elderly Normal 80 70 (24) 13 3 (21)75 years Impaired Mild 50 46 (25) 14 4 (23)75 kg Moderate 30 28 (25) 14 7 (23)

Severe 10 8 (25) 15 24 (24)

Adolescent Normal 95 72 (25) 10 2 (21)15 years Impaired Mild 48 40 (24) 11 4 (23)56 kg Moderate 29 24 (24) 11 6 (24)

Severe 10 7 (25) 11 22 (25)

Middle childhood Normal 60 40 (24) 5 2 (22)9 years Impaired Mild 30 21 (24) 6 4 (22)29 kg Moderate 18 12 (25) 6 7 (24)

Severe 6 3 (26) 6 25 (25)

Early childhood Normal 39 24 (25) 3 2 (22)4 years Impaired Mild 19 11 (25) 3 4 (23)16 kg Moderate 12 6 (25) 3 7 (24)

Severe 4 2 (25) 3 28 (26)

*CV=coefficient ofvariation

No gender differences were observed.

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

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

Obesity:

In one clinical study in morbidly obese patients, sugammadex 2 mg/kg and 4 mg/kg was dosed accordingto actual body weight (n=76) or ideal body weight (n=74). Sugammadex exposure increased in a dose-dependent, linear manner following administration according to actual body weight or ideal body weight.

No clinically relevant differences in pharmacokinetic parameters were observed between morbidly obesepatients and the general population.

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity potential, and toxicity to reproduction, localtolerance or compatibility with blood.

Sugammadex is rapidly cleared in preclinical species, although residual sugammadex was observed inbone and teeth of juvenile rats. Preclinical studies in young adult and mature rats demonstrate thatsugammadex does not adversely affect tooth colour or bone quality, bone structure, or bone metabolism.

Sugammadex has no effects on fracture repair and remodelling of bone.

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

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

3 years

After first opening and dilution chemical and physical in-use stability has been demonstrated for48 hours at 2°C to 25°C. From a microbiological point of view, the diluted product should be usedimmediately. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilutionhas taken place in controlled and validated aseptic conditions.

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

Do not freeze.

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

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

1 mL, 2 mL and 5 mL of solution in type-I glass vial closed with chlorobutyl grey rubber stoppers withaluminium flip-off over seal.

Pack sizes: 10 vials of 1 mL, 2 mL and 5 mL.

Not all pack-sizes may be marketed.

Sugammadex Fresenius Kabi can be injected into the intravenous line of a running infusion with thefollowing intravenous solutions: sodium chloride 9 mg/mL (0.9%), glucose 50 mg/mL (5%), sodiumchloride 4.5 mg/mL (0.45%) and glucose 25 mg/mL (2.5%), Ringers lactate solution, Ringerssolution, glucose 50 mg/mL (5%) in sodium chloride 9 mg/mL (0.9%).

The infusion line should be adequately flushed (e.g., with sodium chloride 9 mg/mL (0.9%)) betweenadministration of Sugammadex Fresenius Kabi and other medicinal products.

Use in the paediatric population

For paediatric patients Sugammadex Fresenius Kabi can be diluted using sodium chloride 9 mg/mL(0.9%) to a concentration of 10 mg/mL (see section 6.3).

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

Fresenius Kabi Deutschland GmbH

Else-Kröner-Straße 1,61352 Bad Homburg v.d.Höhe

Germany

EU/1/22/1663/001

EU/1/22/1663/002

EU/1/22/1663/003

Date of first authorisation: 15 July 2022

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

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