Consumer medicine information

Bridion

Sugammadex

BRAND INFORMATION

Brand name

Bridion

Active ingredient

Sugammadex

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bridion.

What is in this leaflet

This leaflet answers some common questions about BRIDION.

It does not contain all the available information. It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given BRIDION against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, tell your doctor.

Keep this leaflet. You may need to read it again.

What BRIDION is used for

BRIDION belongs to a group of medicines called Selective Relaxant Binding Agents. It is used to speed up recovery of your muscles after an operation.

During some operations, your muscles must be completely relaxed. This makes it easier for the surgeon to perform the operation. To make your muscles relax, the general anaesthetic includes muscle relaxants such as Esmeron and Norcuron. Because the muscles needed for breathing also become relaxed, you will need help with your breathing (artificial ventilation) during and after your operation until you can breathe on your own again.

BRIDION is used to stop the muscle relaxants working. It does this by combining with Esmeron or Norcuron in your body.

BRIDION is given to speed up your recovery from the muscle relaxant - for example, at the end of an operation to allow you to breathe normally earlier.

Your doctor will have explained why you are being treated with BRIDION.

Ask your doctor if you want any more information about this medicine.

BRIDION is not addictive.

Before you are given BRIDION

You may already have been given BRIDION Injection. Your doctor will have considered the situation carefully and decided to use it.

When you must not be given it

You must not be given BRIDION if:

  • you are allergic to sugammadex or have an allergy to any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the tongue and/or throat
  • rash or red skin

Before you are given it

Tell your doctor if you have kidney disease or have had it in the past. This is important because BRIDION is removed from your body by the kidneys.

Tell your doctor if you have any diseases known to give an increased risk of bleeding (disturbance of blood clotting).

Tell your doctor if you have liver disease or have had it in the past.

Tell your doctor if you have fluid retention (oedema).

Tell your doctor if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor if you are pregnant or might be pregnant or are breast-feeding. Your doctor will discuss the risks and benefits of using BRIDION if you are pregnant or breast-feeding.

BRIDION is not recommended for infants less than 2 years of age.

If you have not told your doctor about any of the above, tell them before you are given BRIDION.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop. BRIDION may affect other medicines or be affected by them.

Tell your doctor if you are taking or have recently taken:

  • toremifene (used to treat breast cancer)
  • fusidic acid (an antibiotic)
  • flucloxacillin (an antibiotic)

These medicines can reduce the effect of BRIDION.

Tell your doctor if you are using a hormonal contraceptive such as the "PILL", vaginal ring, implants or hormonal Intrauterine System (IUS). BRIDION can make hormonal contraceptives less effective because it reduces how much you get of the hormone progestogen. The amount of progestogen lost by using BRIDION is about the same as missing one oral contraceptive Pill.

If you are taking the PILL the same day as BRIDION is given to you, follow the instructions for a missed dose in the Pill's package insert.

If you are using OTHER hormonal contraceptives (such as a vaginal ring, implant or IUS), you should use an additional non-hormonal contraceptive method (such as a condom) for the next 7 days.

Laboratory tests: In general, BRIDION does not have an effect on laboratory tests. However it may affect the results of a blood test for a hormone called progesterone.

How BRIDION is given

BRIDION is given as a single injection through an intravenous line.

The doctor will work out the dose of BRIDION you need based on:

  • your weight
  • how much muscle relaxant is still affecting you

The usual dose is 2 - 4 mg per kg body weight. A dose of 16 mg per kg can be used only in adults if urgent recovery from muscle relaxation is needed.

The dose of BRIDION for children and adolescents between 2-17 years old is 2 mg per kg.

Overdose

As your doctor will be monitoring your condition carefully, it is unlikely that you will be given too much BRIDION. Even if this happens, it is unlikely to cause any problems.

After having BRIDION

Things to be careful of

Your doctor will tell you when it is safe to drive and operate potentially dangerous machinery. As far as it is known, BRIDION has no effect on alertness or concentration.

Side effects

Like all medicines, BRIDION can cause side effects, but not everyone gets them.

If these side effects occur while you are under anaesthetic, they will be seen and treated by your anaesthetist.

  • Cough.
  • Airway difficulties that may include coughing or moving as if you are waking or taking a breath.
  • Light anaesthesia - you may start to come out of deep sleep and need more anaesthetic. This might cause you to move or cough at the end of the operation.
  • Complications during your procedure such as changes in heart rate, coughing or moving.
  • Decreased blood pressure due to the procedure.
  • Allergic reactions such as a rash or red skin, swelling of the tongue and/or throat, shortness of breath, changes in blood pressure or heart rate, sometimes resulting in a serious decrease in blood pressure. Severe allergic or allergic-like reactions can be life threatening. Allergic reactions were reported more commonly in healthy, conscious volunteers.
  • Shortness of breath due to muscle cramps of the airways (bronchospasm) occurred in patients with a history of lung problems.
  • Return of muscle relaxation after the operation.
  • Severe slowing of the heart and slowing of the heart up to cardiac arrest may occur when Bridion is administered.

If after your operation, you notice any side effects tell your doctor.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some patients.

Ask your doctor to answer any questions you may have.

Storage

BRIDION is stored in the hospital according to the storage conditions on the pack.

Product description

What it looks like

BRIDION is a colourless to slightly yellow solution for injection.

BRIDION is available as

  • 200 mg/2 mL pack of 10 vials
  • 500 mg/5 mL pack of 10 vials

Ingredients

It contains 200mg or 500mg sugammadex (as sodium salt) as the active ingredient.

It also contains hydrochloric acid and/or sodium hydroxide for pH adjustment and Water for Injections.

Distributor

In Australia :

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road,
Macquarie Park, NSW 2113

Australian Registration Numbers:
AUST R 147716 (200 mg)
AUST R 148263 (500mg)

In New Zealand :

Merck Sharp & Dohme (New Zealand) Limited
PO Box 99-851
Newmarket
Auckland 1149

® = Registered Trademark

This leaflet was updated February 2020

Ref: S-CCPPI-MK8616-SOi-062015

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Bridion

Active ingredient

Sugammadex

Schedule

S4

 

1 Name of Medicine

Sugammadex (as sodium salt).

6.7 Physicochemical Properties

Molecular Formula: C72H104O48S8Na8.
Molecular mass: 2178.01.
Chemical Name: octakis (6-S-(2-carboxyethyl)-6- thio) cyclomaltooctaose octasodium salt.

Chemical structure.


CAS number.

343306-79-6.

2 Qualitative and Quantitative Composition

Sugammadex is a white to off-white powder. It is soluble at room temperature in water, normal saline and 5% mannitol in water.
Bridion solution for injection contains sugammadex 100 mg/mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Bridion solution for injection is a clear and colourless to slightly yellow solution. The pH is between 7 and 8 and osmolality is between 300 and 500 mOsm/kg.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 (SRBA). It forms a complex with the neuromuscular blocking agents rocuronium or vecuronium and it 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 trials.

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

Routine reversal.

The ability of sugammadex to routinely reverse shallow or profound neuromuscular blockade induced by rocuronium or vecuronium was studied in three multicentre trials in adults.

1. Comparative study of sugammadex versus neostigmine as a reversal agent of neuromuscular blockade induced and maintained by rocuronium or vecuronium, at 1-2 PTCs.

In a multicentre, randomised, parallel group, comparative, active controlled, safety assessor blinded study comparing sugammadex and neostigmine, 157 patients (86 females and 71 males, the majority were Caucasian and ASA class 2 and 3, the median age in the rocuronium and vecuronium groups were 54 and 56 years, respectively) who were scheduled for a surgical procedure under general anaesthesia (induction with propofol, maintenance with sevoflurane) with the use of a neuromuscular blocker for endotracheal intubation and maintenance of neuromuscular blockade, 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 microgram/kg neostigmine was administered in a randomised order as single bolus injections. The time from start of administration of sugammadex or neostigmine to recovery of the T4/T1 ratio to 0.9 was assessed. See Table 3.
The geometric mean times to recovery of the T4/T1 ratio to 0.9 after rocuronium or vecuronium induced neuromuscular blockade were 17.3 times and 14.9 times faster, respectively, following the administration of sugammadex, compared with neostigmine.

2. Comparative study of sugammadex versus neostigmine as a reversal agent of neuromuscular blockade induced by rocuronium or vecuronium, at reappearance of T2.

In a multicentre, randomised, parallel group, comparative, active controlled, safety assessor blinded study comparing sugammadex and neostigmine, 189 patients (87 females and 102 males, the majority were Caucasian and ASA class 1 and 2, the median age in the rocuronium and vecuronium groups were 50 and 51 years, respectively) who were scheduled for a surgical procedure with general anaesthesia (with sevoflurane) with the use of a neuromuscular blocker for endotracheal intubation and maintenance of neuromuscular blockade, 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 microgram/kg neostigmine was administered in a randomised order as single bolus injections. The time from start of administration of sugammadex or neostigmine to recovery of the T4/T1 ratio to 0.9 was assessed. See Table 4.
The geometric mean times to recovery of the T4/T1 ratio to 0.9 after rocuronium or vecuronium induced neuromuscular blockade were 12.7 times and 6.7 times faster, respectively, following the administration of sugammadex, compared with neostigmine.

3. Comparative study of rocuronium and sugammadex versus cisatracurium and neostigmine when neuromuscular blockade is reversed at reappearance of T2.

In a multicentre, randomised, parallel group, comparative, active controlled, safety assessor blinded study comparing rocuronium and sugammadex versus cisatracurium and neostigmine, 73 patients (36 females and 37 males, the majority were Caucasian and ASA class 1 and 2, the median age was 43 years) who were scheduled for a surgical procedure under general anaesthesia (with propofol) with the use of a neuromuscular blocker for endotracheal intubation and maintenance of neuromuscular blockade, were randomised to rocuronium followed by 2 mg/kg sugammadex or cisatracurium followed by 50 microgram/kg neostigmine. The reversal agents were administered as single bolus injections at the reappearance of T2. The time from start of administration of sugammadex or neostigmine to recovery of the T4/T1 ratio to 0.9 was assessed. See Table 5.
The geometric mean time to recovery of the T4/T1 ratio to 0.9 following reversal of rocuronium-induced neuromuscular blockade by sugammadex was 4.3 times faster than the geometric mean time to recovery of the T4/T1 ratio to 0.9 following reversal of cisatracurium induced neuromuscular blockade by neostigmine.

Immediate reversal.

A multicentre, randomised, parallel group, comparative, active controlled, safety assessor blinded study in 110 adult patients (64 females and 46 males, the majority were Caucasian and ASA class 1 and 2, the median age was 43 years scheduled for a surgical procedure with general anaesthesia with propofol) was conducted to assess the time to recovery from neuromuscular blockade induced by suxamethonium compared with recovery from neuromuscular blockade induced by rocuronium followed 3 minutes later with sugammadex. Recovery to T1 of 10% after neuromuscular blockade induced by 1.2 mg/kg rocuronium reversed at 3 minutes by 16 mg/kg sugammadex was compared to spontaneous recovery after a neuromuscular blockade induced by 1 mg/kg suxamethonium. See Table 6.
The mean time to a T1 of 10% (relative to the time of administration of rocuronium or suxamethonium) was approximately 2.7 minutes faster in the rocuronium + sugammadex group compared with suxamethonium alone.
In a pooled analysis, the following recovery times for 16 mg/kg sugammadex after 1.2 mg/kg rocuronium bromide were reported. See Table 7.

Renal impairment.

Two open labelled 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 post-tetanic counts (PTC) (4 mg/kg, N = 68). In the other study, sugammadex was administered at the reappearance of T2 (2 mg/kg, N = 30). Recovery from neuromuscular blockade was modestly longer for patients with severe renal impairment relative to patients without renal impairment. No residual or recurrence of neuromuscular blockade was reported for patients with severe renal impairment in these studies.

Effects on QTc-interval.

In three dedicated clinical studies (N = 287) sugammadex alone, sugammadex in combination with rocuronium or vecuronium and sugammadex in combination with propofol or sevoflurane was not associated with clinically relevant QT/QTc prolongation. The integrated ECG and adverse event results of phase 2/3 studies support this conclusion.

Cardiac patients.

One trial of 76 patients who were diagnosed with or have a history of cardiac disease (e.g. patients with ischemic heart disease, chronic heart failure, or arrhythmia) of primarily NYHA (New York Heart Association) Class II investigated time to recovery from neuromuscular blockade induced by rocuronium 0.6 mg/kg following administration of 2 mg/kg or 4 mg/kg Bridion given at the reappearance of T2. The trial showed that the median time to recovery of the T4/T1 ratio to 0.9 was 1.7 minutes and 1.3 minutes, respectively, in the 2 mg/kg and 4 mg/kg Bridion dose groups. This is similar to the median values observed in other trials; therefore, no dosage adjustment is necessary (see Section 4.2 Dose and Method of Administration).

Pulmonary patients.

One trial of 77 patients who were diagnosed with or have a history of pulmonary complications investigated the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of the 2 mg/kg or 4 mg/kg Bridion given at the first signs of recovery (reappearance of T2). The trial showed that for these patients the median time to recovery of the T4/T1 ratio to 0.9 was 2.1 minutes after a dose of 2 mg/kg Bridion and 1.9 minutes after a dose of 4 mg/kg Bridion. This is similar to the median values observed in the other trials; therefore, no dosage adjustment is necessary (see Section 4.2 Dose and Method of Administration).

5.2 Pharmacokinetic Properties

The sugammadex pharmacokinetic parameters were calculated from the total sum of noncomplex and complex-bound concentrations of sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for noncomplex-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, noncompartmental pharmacokinetic analysis). Neither sugammadex nor the complex of sugammadex and rocuronium bind 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.

Excretion.

The elimination half-life (t1/2) of sugammadex in adult anaesthetised patients with normal renal function is about 2.0 hours and plasma clearance is estimated to be 88 mL/min. A mass balance study demonstrated that > 90% of the dose was excreted within 24 hours. Overall 96% of the dose was excreted in the 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 with sugammadex.

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. 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 postdose 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 t1/2 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 postdose in subjects with severe renal insufficiency.
A summary of sugammadex pharmacokinetic parameters stratified by age and renal function is presented in Table 8.

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: Clearance (CL) was 9% lower and volume of distribution (Vss) was 12% lower in the Japanese compared to the Caucasian subjects, but after body weight normalisation these parameters were similar in both ethnic groups. Limited data does not indicate differences in pharmacokinetic parameters in Black or African Americans.

Body weight.

Although no clinical trials have examined the pharmacokinetics of sugammadex in obese and normal individuals population pharmacokinetic analysis of adult and elderly patients showed no clinically relevant relationship of clearance and volume of distribution with body weight.

5.3 Preclinical Safety Data

Genotoxicity.

Sugammadex was not genotoxic in in vitro tests for bacterial reverse mutation and chromosomal aberrations in human lymphocytes, and in in vivo micronucleus tests for clastogenicity.

Carcinogenicity.

Carcinogenicity studies were not done given the intended single dose use of sugammadex and given the absence of genotoxic potential.

4 Clinical Particulars

4.1 Therapeutic Indications

Reversal of neuromuscular blockade induced by rocuronium or vecuronium.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

In volunteers, sugammadex has been administered repeatedly in 2 to up to 3 dosing periods. However, there is no experience with sugammadex on repeated exposure in patients.

Immediate reversal.

There are no data for immediate reversal following vecuronium blockade (see Section 4.2 Dose and Method of Administration).

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 drugs used in the peri- and postoperative period could depress respiratory function and, therefore, ventilatory support might still be required. Should neuromuscular blockade recur 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 labeled for the depth of neuromuscular blockade (N = 2022), an incidence of 0.2% 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 (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Effect on haemostasis.

In a study of volunteers, doses of 4 mg/kg and 16 mg/kg of sugammadex resulted in maximum mean prolongations of activated partial thromboplastin time (aPTT) by 17 and 22%, respectively and of prothrombin time international normalised ratio (PT (INR)) by 11 and 22%, respectively. These limited mean aPPT and PT (INR) prolongations were of short duration (≤ than 30 minutes). Although there is limited data on peri- or postoperative bleeding events in the clinical trial database (N = 3519), there is no indication of a clinically relevant increased incidence of bleeding events after sugammadex alone, or after sugammadex in combination with anticoagulants.
In a specific study in 1184 surgical patients who were concomitantly treated with an anticoagulant, small and transient increases were observed in aPTT and PT(INR) associated with sugammadex 4 mg/kg, which did not translate into an increased bleeding risk with sugammadex compared with usual treatment.
In in vitro experiments additional aPPT and PT prolongation was noted for sugammadex in combination with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. Considering the transient nature of the limited prolongation of aPTT and PT caused by sugammadex alone or on top of these anticoagulants, it is unlikely that sugammadex had an increased risk of bleeding. Since bleeding risk has not been studied systematically at higher doses than sugammadex 4 mg/kg, coagulation parameters should be carefully monitored in patients using anticoagulants who receive a dose of 16 mg/kg sugammadex. Since there is no information on the use of sugammadex in patients with known coagulopathies, it is recommended that these patients have their aPTT, PT and PT (INR) monitored after administration of sugammadex.

Interactions due to the lasting effect of rocuronium or vecuronium.

When drugs which potentiate neuromuscular blockade are used in the post-operative period, special attention should be paid to the possibility of recurrence of blockade. Please refer to the product information for rocuronium or vecuronium for a list of the specific drugs which potentiate neuromuscular blockade. In case recurrence of blockade is observed, it is advised to ventilate the patient.

Anaesthetic complication.

When neuromuscular blockade was reversed in the middle of anaesthesia in clinical trials, i.e. when investigating immediate reversal, 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 (see Section 4.8 Adverse Effects (Undesirable Effects)).

Marked bradycardia.

In rare instances, marked bradycardia has been observed within minutes after administration of sugammadex for reversal of neuromuscular blockade. Isolated cases of bradycardia with cardiac arrest have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be closely monitored for haemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents such as atropine should be administered if clinically significant bradycardia is observed.

Use in ICU.

Sugammadex has not been investigated in the ICU setting.

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

Sugammadex should not be used to reverse blockade induced by nonsteroidal neuromuscular blocking agents such as suxamethonium 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 sugammadex is not recommended to reverse blockade induced with pancuronium.

Delayed recovery.

Conditions associated with prolonged circulation time such as cardiovascular disease, old age (see Section 4.2 Dose and Method of Administration), or oedematous state (e.g. severe hepatic impairment) may be associated with longer recovery times.

Drug hypersensitivity.

Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions. The risk of drug hypersensitivity reactions appears to be dose dependent (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects)).

Nonclinical toxicity.

In rat studies sugammadex showed an affinity for and persistence in bones and to a lesser extent teeth, which may reflect binding to hydroxyapatite. Bone changes suggestive of slight resorption were seen after single administration of a high dose (2000 mg/kg) in adult rats, which resulted in a drug exposure (AUC) that was 90-fold that in humans with the 4 mg/kg dose. Disruption of the enamel epithelium and abnormal white incisor discolouration were observed after daily dosing of juvenile rats for 4 weeks, but there was a high safety margin based on estimates of incisor concentrations. The clinical significance of these findings is unknown.

Use in hepatic impairment.

Sugammadex is not metabolised or excreted by the liver; therefore, dedicated 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 (see Effect on haemostasis).

Use in renal impairment.

Sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Special populations, Elderly patients; Section 5.2 Pharmacokinetic Properties, Special populations.

Paediatric use.

Bridion should not be given to children aged less than 2 years.
Limited safety and efficacy data support use of Bridion in children aged from 2 years for routine reversal at doses to 4 mg/kg.
Efficacy and safety of Bridion for immediate reversal in children have not been assessed.

Effects on laboratory tests.

In general sugammadex does not interfere with laboratory tests, with the possible exception of the serum progesterone assay. Interference with this test was observed at sugammadex plasma concentrations of 100 microgram/mL, which is in the same range as Cmax values observed after a dose of 16 mg/kg.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Sugammadex has no potential to cause drug-drug interaction due to inhibition or induction of drug metabolising enzymes. The mechanism of potential drug-drug interaction is through binding of sugammadex to other compounds, which cannot be assessed via traditional drug-drug interaction studies. Therefore, a combined strategy (based on binding affinity between sugammadex and other drugs, preclinical experiments simulations of a Pharmacokinetic-Pharmacodynamic (PK-PD) model and clinical studies) was applied to assess both the capturing and displacement interactions. Based on these data no clinically significant pharmacodynamic interactions with other drugs are expected, with the exception of toremifene, fusidic acid, and hormonal contraceptives (see below). For these drugs a clinically relevant interaction could not be excluded.
No clinically relevant interactions were reported during clinical development in approximately 1700 patients.

Paediatric population.

No formal interaction studies have been performed. The interactions for adults and the warnings should also be taken into account for the paediatric population (see Section 4.4 Special Warnings and Precautions for Use).

Interactions potentially affecting the efficacy of sugammadex.

Displacement interactions.

Due to the administration of certain drugs 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 7.5 hours after sugammadex administration.

Toremifene.

For toremifene, which has a relatively high binding affinity for sugammadex and for which relatively high plasma concentrations might be present, some displacement of vecuronium or rocuronium from the complex with 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 T4/T1 ratio to 0.9. However, 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.

Flucloxacillin.

Based on the binding affinity of sugammadex for flucloxacillin and PK modelling, it could not be excluded that high doses of flucloxacillin might cause some displacement of rocuronium or vecuronium from sugammadex causing some delay in the recovery for the T4/T1 ratio to 0.9. However, in 6 healthy male and female volunteers (age < 45 y - mean 33 y; mean weight 75 kg) no evidence of reoccurrence of neuromuscular blocking was seen using adductor pollicis acceleromyography (TOF SX). Based on these results, it may be concluded that the displacement potential by flucloxacillin is not clinically relevant.

Interactions potentially affecting the efficacy of other drugs.

Capturing interactions.

Due to the administration of sugammadex, certain drugs could become less effective due to a lowering of the (free) plasma concentrations. Theoretically, for certain drugs (acute) withdrawal effects could also be expected after administration of sugammadex.
When such a situation (reduced effect and/or withdrawal effect) is observed, the clinician is advised to consider the readministration of the drug, the administration of a therapeutically equivalent drug (preferably from a different chemical class) and/or nonpharmacological interventions as appropriate.

Hormonal contraceptives.

In a simulation performed with a PK/PD model, it was found that the interaction between 4 mg/kg sugammadex and a progestogen could lead to a decrease in progestogen exposure (34% of AUC) similar to the decrease seen when a daily dose of an oral contraceptive is taken 12 hours too late, which might lead to a reduction in effectiveness. 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). Refer to the missed dose advice in the package insert of the oral contraceptive for any actions required if an oral contraceptive is taken on the same day that sugammadex is administered.
In the case of non-oral hormonal contraceptives, the patient must use an additional non-hormonal contraceptive method for the next 7 days.

Re-administration with neuromuscular blocking agents after reversal with sugammadex.

When rocuronium 1.2 mg/kg is administered within 30 minutes after reversal with Bridion, the onset of neuromuscular blockade may be delayed up to approximately 4 minutes and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Sugammadex at doses of up to 500 mg/kg/day did not affect fertility in rats. This dose resulted in a drug exposure (AUC) that was 28-fold that in humans with the single 4 mg/kg dose.
(Category B2)
There are no clinical data for exposed pregnancies. In animal studies with administration over the whole period of organogenesis, sugammadex did not affect foetal development at doses resulting in drug exposures (AUC) that were 28-fold (rats) and 31-fold (rabbits) that in humans with the single 4 mg/kg dose. A maternotoxic dose in rabbits (drug exposure 32-fold that in humans with the single 4 mg/kg dose) resulted in reduced foetal weight and impaired skeletal ossification. Because animal studies are not always predictive of human responses, sugammadex should be used in pregnant women only when the benefits outweigh potential effects on the foetus.
It is not known if sugammadex is excreted in human milk, but excretion in rat milk has been demonstrated. Rat offspring development was unaffected by oral exposure via the milk in a pre- and post-natal development study.
Caution should be exercised when administering sugammadex to a breast-feeding woman.

4.8 Adverse Effects (Undesirable Effects)

The safety of sugammadex has been evaluated in 3519 subjects across the Pooled Phase I-III safety database.
In the subset of Pooled Placebo controlled trials where subjects received anaesthesia and/or neuromuscular blocking agents (1078 subject exposures to sugammadex versus 544 to placebo), the following adverse events occurred in ≥ 2% of subjects treated with sugammadex. See Table 2.
For the adverse events listed in Table 2, only cough, airway complication of anaesthesia, anaesthetic complication, procedural hypotension and procedural complication occurred at least twice as often in subjects treated with sugammadex compared to placebo.
In clinical studies, the investigator reported terms for complications resulting from anaesthesia or surgery were grouped in the adverse event categories below, and included the following.

Airway complication of anaesthesia.

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

Anaesthetic complication.

This complication, indicative of the restoration of neuromuscular function (movement of a limb or the body or coughing during anaesthetic procedure or during surgery, grimacing or suckling on the endotracheal tube), was judged to be related to treatment with sugammadex in about 3% of the patients and < 1% of the placebo group. Most occurrences of anaesthetic complications were mild to moderate.

Procedural complication.

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

Description of selected adverse reactions.

The following adverse reactions were biologically plausible irrespective of incidence, or for which a causal relationship could not be excluded and which could be clinically relevant in the anticipated setting.

Recurrence of neuromuscular blockade.

In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex was administered using a dose labeled for the depth of neuromuscular blockade (N = 2022), an incidence of 0.20% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence (see Section 4.4 Special Warnings and Precautions for Use).

Drug hypersensitivity reactions.

Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and healthy volunteers. In clinical trials of surgical patients, these reactions were reported uncommonly (≥ 1/1000 to < 1/100) 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, swelling of tongue, swelling of pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal.
Information on healthy volunteers: A randomised, double blind study examined the incidence of drug hypersensitivity reactions in healthy volunteers given up to 3 repeat 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%).
The most common adverse reaction in pooled healthy volunteers was dysgeusia (10%).

Marked bradycardia.

In post-marketing, isolated cases of marked bradycardia and bradycardia with cardiac arrest have been observed within minutes after administration of sugammadex (see Section 4.4 Special Warnings and Precautions for Use).

Pulmonary patients.

In post-marketing data and in one dedicated clinical trial in patients with a history of pulmonary complications (see Section 5.1 Pharmacodynamic Properties, Clinical trials), 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 suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

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.

Adults.

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

Routine reversal.

A dose of 4.0 mg/kg sugammadex is recommended if recovery has reached 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 Pharmacodynamic Properties, Clinical trials).
A dose of 2.0 mg/kg sugammadex is recommended, if spontaneous recovery has occurred up to 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 Pharmacodynamic Properties, Clinical trials).
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 induced blockade, when compared to vecuronium induced neuromuscular blockade (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Immediate reversal.

If there is a clinical need for immediate reversal following administration of rocuronium, a dose of 16.0 mg/kg sugammadex is recommended. Administration of 16.0 mg/kg sugammadex 3 minutes following a bolus dose of 1.2 mg/kg rocuronium bromide provides a median time to recovery of the T4/T1 ratio to 0.9 of approximately 1.5 minutes (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
There are no data to recommend the use of sugammadex for immediate reversal following vecuronium-induced blockade.

Paediatric population.

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.
The use of higher doses (as for immediate reversal) in children and adolescents has not been investigated and is, therefore, not recommended until further data become available.
Bridion may be diluted to increase the accuracy of dosing in the paediatric population (see Method of administration).

Neonates and infants.

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

Special populations.

Renal impairment.

The dose recommendations for mild and moderate renal impairment (creatinine clearance between 30 and 80 mL/min) are the same as for adults without renal impairment. For re-administration with rocuronium or vecuronium (see Section 4.4 Special Warnings and Precautions for Use) for waiting times.
Sugammadex is not recommended for use in patients with severe renal impairment (including patients requiring dialyses) (see Section 4.4 Special Warnings and Precautions for Use). Studies in patients with severe renal impairment do not provide sufficient safety information to support the use of sugammadex in these patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Hepatic impairment.

The dose recommendations are the same as for adults without hepatic impairment, as sugammadex is mainly excreted renally. For use of sugammadex when hepatic impairment is accompanied by coagulopathy (see Section 4.4 Special Warnings and Precautions for Use).

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) it was 3.6 minutes. Even though the recovery time in elderly tends to be slower, the same dose recommendation as for adults should be followed (see Section 4.4 Special Warnings and Precautions for Use).

Obese patients.

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

Method of administration.

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

Compatibility.

Bridion can be injected into the intravenous line of a running infusion with the following intravenous solutions: 0.9% sodium chloride; 5% dextrose, Gelofusine; 0.45% sodium chloride and 2.5% dextrose; Ringers lactate solution; Ringers solution; Lactec; Lactec D and G; Hespander; Veen-F; Physio 140; 5% dextrose in 0.9% sodium chloride; and isolyte P with 5% dextrose.
For paediatric patients, Bridion can be diluted using 0.9% sodium chloride to a concentration of 25 mg/mL (see Section 6.3 Shelf Life; Section 6.4 Special Precautions for Storage).

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

If re-administration of rocuronium or vecuronium is required after reversal with sugammadex (up to 4 mg/kg), the following waiting times are recommended (see Table 1).
When rocuronium is re-administered after sugammadex onset and duration times may be affected (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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.

4.7 Effects on Ability to Drive and Use Machines

The usual precautionary measures after a general anaesthetic should be taken for ambulatory patients.

4.9 Overdose

In clinical studies, 1 case of an accidental overdose with 40 mg/kg was reported without any significant side effects. In a human tolerance study sugammadex was well tolerated in doses up to 96 mg/kg. Sugammadex can be removed using haemodialysis with a high flux filter. Based upon clinical studies, sugammadex concentrations in plasma are reduced with a high flux filter by about 70% after a 3-6 hour dialysis session.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Bridion solution for injection contains hydrochloric acid and sodium hydroxide for pH adjustment and water for injections.

6.2 Incompatibilities

Bridion must not be mixed with other medical products except those mentioned (see Section 4.2 Dose and Method of Administration, Compatibility). The infusion line should be adequately flushed (e.g. with 0.9% sodium chloride) between administration of Bridion and other drugs.
Physical incompatibility was observed with verapamil, ondansetron and ranitidine.

6.3 Shelf Life

Bridion has a 3-year shelf-life when stored under the recommended storage conditions (see Section 6.4 Special Precautions for Storage). When not protected from light, the vial should be used within 5 days.
Contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.
After dilution with infusion fluids (see Section 4.2 Dose and Method of Administration), chemical and physical in-use stability has been demonstrated for 48 hours at 2 - 25°C. From a microbiological view point, the diluted product should be used immediately.

6.4 Special Precautions for Storage

Store below 30°C. Do not freeze. Protect from light.
For storage conditions of the diluted medicinal product see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Bridion 100 mg/1 mL: Single-use injection vial of hydrolytic resistant glass closed with a grey chlorobutyl rubber closure. The rubber closure is held in position on the glass vial by a roll-on aluminium crimp-cap with a “flip-off” seal. The rubber stopper in the vial does not contain latex.
Pack size: 2 mL (10 vials) or 5 mL (10 vials).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes