Bridion 100 mg/ml solution for injection

1 ml contains sugammadex sodium equivalent to 100 mg sugammadex.

2 ml contains sugammadex sodium equivalent to 200 mg sugammadex.

5 ml contains sugammadex sodium equivalent to 500 mg sugammadex.

For a full list of excipients, see section 6.1.

Excipient(s):

Each ml contains 9.7 mg sodium (see section 4.4).

Solution for injection (injection).

Clear and colourless to slightly yellow solution.

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.

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

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. 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 (see section 4.4). When certain medicinal products that may cause displacement interactions are administered parenterally within a period of 6 hours of sugammadex, the patient should be monitored for signs of recurrence of neuromuscular blockade (see section 4.4 and 4.5).

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 (see section 5.1).

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 (see section 5.1).

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 (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 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 (see section 5.1).

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 (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 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:

A waiting time of 24 hours should be taken into account (see section 4.4).

Additional information on special population

Renal impairment:

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.

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 support the use of sugammadex in these patients (see also section 5.1).

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 (see section 4.4).

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:

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

Studies in patients with hepatic impairment have not been conducted and therefore patients with severe hepatic impairment should be treated with great caution (see section 4.4).

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. 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.

Bridion 100 mg/ml may be diluted to 10 mg/ml to increase the accuracy of dosing in the paediatric population (see section 6.6).

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 directly into a vein or 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.

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 trials recurrence of neuromuscular blockade was reported mainly when sub-optimal doses (in dose finding studies) were administered. In order to prevent recurrence of neuromuscular blockade, the recommended doses for routine or immediate reversal (see section 4.2) should be used.

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 (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=1738) there was no clinically relevant effect of sugammadex 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 can not 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:

If re-administration of rocuronium or vecuronium is required a waiting time of 24 hours is recommended.

If neuromuscular blockade is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking agent should be used.

Renal impairment:

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

Interactions due to the lasting effect of rocuronium or vecuronium:

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

Potential interactions:

• Capturing interactions:

Due to the administration of sugammadex, certain medicinal products could become less effective due to a lowering of the (free) plasma concentrations (see section 4.5, hormonal contraceptives).

If such a situation is observed, the clinician is advised to consider the re-administration of the medicinal product, the administration of a therapeutically equivalent medicinal product (preferably from a different chemical class) and/or non-pharmacological interventions as appropriate.

• Displacement interactions:

Due to the administration of certain medicinal products after sugammadex, theoretically rocuronium or vecuronium could be displaced from sugammadex. As a result recurrence of neuromuscular blockade might be observed. In this situation the patient must be ventilated. Administration of the medicinal product 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 recurrence of neuromuscular blockade (approximately up to 15 minutes) after parenteral administration of another medicinal product occurring within a period of 6 hours after sugammadex administration. Displacement interactions are at present only expected for a few drugs substances (toremifene and fusidic acid, see section 4.5).

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.

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.

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:

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 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 (see section 4.8).

Patients on a controlled sodium diet:

Each ml solution contains 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.

QTc-interval prolongation:

Two thorough QTc trials (N=146), both in conscious volunteers, demonstrated that sugammadex alone or in combination with rocuronium or vecuronium is not associated with QTc interval prolongation. The one-sided 95% upper confidence limits for the QTc difference to placebo were well below the 10 ms margin for each of the 12-13 evaluated timepoints in both studies.

In the clinical program, a few cases of QTc prolongation were reported (QTc> 500 msec or QTc increases> 60 msec) in clinical trials in which patients received sugammadex in combination with sevoflurane or propofol. During anaesthesia several medicinal products with the potential to prolong QTc (e.g. sevoflurane) are administered. The routine precautions for treating arrhythmia should be taken into consideration.

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

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

For hormonal contraceptives a clinically relevant capturing interaction could not be excluded (no displacement interactions are expected).

Interactions potentially affecting the efficacy of sugammadex (see also section 4.4):

Toremifene:

For toremifene, which has a relatively high affinity constant and relatively high plasma concentrations, some displacement of vecuronium or rocuronium from the complex with sugammadex could occur. The recovery of the T₄/T₁ ratio to 0.9 could therefore be delayed in patients who have received toremifene on the same day of the operation.

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 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 2-3 days. For re-administration of sugammadex see section 4.2.

Interactions potentially affecting the efficacy of other medicinal products (see also section 4.4):

Hormonal contraceptives:

The interaction between 4 mg/kg sugammadex and a progestogen was predicted to 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. For estrogens, the effect is expected to be lower. Therefore the administration of a bolus dose of sugammadex is considered to be equivalent to one missed daily dose of oral contraceptive steroids (either combined or progestogen only). If sugammadex is administered at the same day as an oral contraceptive is taken reference is made to missed dose advice in the package leaflet of the oral contraceptive. In the case of non-oral hormonal contraceptives, the patient must use an additional non hormonal contraceptive method for the next 7 days and refer to the advice in the package leaflet of the product.

Interference with laboratory tests:

In general sugammadex does not interfere with laboratory tests, with the possible exception of the serum progesterone assay. Interference with this test is observed at sugammadex plasma concentrations of 100 μg/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 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 ( 30 minutes).

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 (see section 4.4).

Paediatric population

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

Pregnancy

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.

Breast-feeding

It is unknown whether sugammadex is excreted in human breast milk. Animal studies have shown excretion of sugammadex in breast milk. Oral absorption of cyclodextrins in general is low and no effect on the suckling child is anticipated following a single dose to the breast-feeding woman.

Sugammadex can be used during breast-feeding.

Fertility

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

No studies on the effects on the ability to drive and use machines have been performed.

The safety of sugammadex has been evaluated based on an integrated safety database of approximately 1,700 patients and 120 volunteers. The most commonly reported adverse reactions in surgical patients were anaesthetic complications (Common [ 1/100 to < 1/10]).

The following undesirable effects associated with sugammadex use have been reported for surgical patients in clinical trials:

Drug 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 sugammadex.

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

Anaesthetic complication:

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 suckling on the endotracheal tube. See section 4.4 light anaesthesia.

Awareness:

In sugammadex treated subjects a few cases of awareness were reported. The relation to sugammadex is uncertain.

Recurrence of neuromuscular blockade:

In the data-base of pooled phase I-III studies with a placebo group, the incidence of recurrence of neuromuscular blockade as measured with neuromuscular monitoring was 2% after sugammadex and 0% in the placebo group. Virtually all of these cases were from dose-finding studies in which a sub-optimal dose (less than 2 mg/kg) was administered (see section 4.4).

Information on healthy volunteers:

Hypersensitivity reactions, including anaphylaxis, have been observed with sugammadex. In a study in healthy conscious volunteers (placebo, N=150; 4 mg/kg, N=148; and 16 mg/kg, N=150), hypersensitivity reactions were reported commonly with sugammadex 16 mg/kg (n=7, 4.7%), uncommonly with sugammadex 4 mg/kg (n=1, 0.7%), and none with placebo (n=0, 0%).

In this study, dose dependent trends were also observed for dysgeusia, nausea and flushing.

Additional information on special populations

Pulmonary patients:

In one clinical trial in patients with a history of pulmonary complications bronchospasm was reported as a possibly related adverse event in two patients and a causal relationship could not be fully excluded. 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.

In clinical studies, 1 case of an accidental overdose with 40 mg/kg was reported without any significant undesirable effects. 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, 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 effective half-life of sugammadex is about 2.5 hours and the estimated plasma clearance is about 75 ml/min (based on compartmental pharmacokinetic analysis, using three compartments). 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 two pharmacokinetic studies comparing patients with severe renal impairment to patients with normal renal function, sugammadex levels in plasma were similar during at least the first 20 minutes after dosing, and thereafter the levels decreased faster in the control group. Total exposure to sugammadex was prolonged, leading to approximately 15-fold higher exposure in patients with severe renal impairment. In some of the patients with severe renal insufficiency, sugammadex levels were minimally detectable in plasma one month after dosing.

Predicted pharmacokinetic parameters of sugammadex by age group and renal function based on compartmental modelling (using three compartments) are presented below:

Mean and coefficient of variation (CV in %) are presented.

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.

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

Sugammadex is rapidly cleared from most organs; however some retention of compound occurs in bone and teeth in the rat. The most likely component involved in the reversible binding is hydroxy apatite, the inorganic matrix in these tissues. Preclinical studies in young adult and mature rats have shown that this retention does not adversely affect tooth colour or bone quality, structure, turnover and development. In juvenile rats whitish discoloration was observed in the incisors and disturbance of enamel formation was observed upon repeated dosing, however at exposure levels of 48-480 times the clinical exposure at 4 mg/kg.

Hydrochloric acid 3.7% and or sodium hydroxide (to adjust pH)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 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 for 48 hours at 2°C to 25°C. From a microbiological point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store below 30°C. 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.

Single use type I glass vial closed with grey chlorobutyl rubber stoppers with aluminium crimp-cap and flip-off seal.

The rubber stopper of the vial does not contain latex.

Pack sizes: 10 vials of 2 ml or 10 vials of 5 ml.

Not all pack-sizes may be marketed.

If Bridion is administered via the same infusion line that is also used for other medicinal products, it is important that the infusion line is adequately flushed (e.g. with sodium chloride 9 mg/ml (0.9% solution)) between administration of Bridion and medicinal products for which incompatibility with Bridion has been demonstrated or for which compatibility with Bridion has not been established.

Sugammadex 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%).

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

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

N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands

EU/1/08/466/001

EU/1/08/466/002

25 July 2008

27 February 2012

Prescription Only Medicine

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu