Sugammadex Piramal

Package leaflet: Information for the user

Sugammadex Piramal 100 mg/mL solution for injection

sugammadex
Please read this leaflet carefully before you are given this medicine because it
contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your anaesthetist or doctor.
• If you get any side effects, talk to your anaesthetist or another doctor. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet

1. What Sugammadex Piramal is and what it is used for
2. What you need to know before Sugammadex Piramal is administered
3. How Sugammadex Piramal is administered
4. Possible side effects
5. How to store Sugammadex Piramal
6. Contents of the pack and other information

1. What Sugammadex Piramal is and what it is used for

What Sugammadex Piramal is
Sugammadex Piramal contains the active substance sugammadex. Sugammadex Piramal is considered
to be a selective relaxant binding agent because it specifically binds to certain muscle relaxants,
namely rocuronium bromide or vecuronium bromide.
What Sugammadex Piramal is used for
During certain types of surgery, muscles need to be completely relaxed. This makes the surgeon’s task easier. For this purpose, muscle relaxant medicines are added to the general anaesthesia being administered. These medicines are called neuromuscular blocking agents, and include rocuronium bromide and vecuronium bromide. Since these medicines also relax the muscles that control breathing, assistance with breathing (known as artificial ventilation) is required during and after surgery, until you are able to breathe on your own again.
Sugammadex Piramal is used to speed up muscle recovery after surgery so that you can breathe independently again as soon as possible. It works by binding to rocuronium bromide or vecuronium bromide present in the body. It can be used in adults whenever rocuronium bromide or vecuronium bromide is used.
It can also be used in neonates, infants, toddlers, children, and adolescents (from birth up to 17 years of age) when rocuronium bromide is used.

2. What you need to know before Sugammadex Piramal is administered

Do not receive Sugammadex Piramal

• if you are allergic to sugammadex or to any of the excipients of this medicine (listed in section 6). Inform your anaesthetist if this applies to you.

Warnings and precautions
Inform your anaesthetist before Sugammadex Piramal is administered

• if you have or have previously had kidney disease. This is important because Sugammadex Piramal is eliminated from the body through the kidneys.
• if you have or have previously had liver disease.
• if you have fluid retention (oedema).
• if you have conditions known to increase the risk of bleeding (blood coagulation disorders) or if you are taking anticoagulant therapy.

Other medicines and Sugammadex Piramal
Inform your anaesthetist if you are taking, have recently taken, or might take any other
medicines. Sugammadex Piramal may affect or be affected by other medicines.
Some medicines reduce the effect of Sugammadex Piramal
It is particularly important that you inform your anaesthetist if you have recently taken:

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

Sugammadex Piramal may affect hormonal contraceptives
Sugammadex Piramal may reduce the effectiveness of hormonal contraceptives – including oral contraceptive pills, vaginal ring, implant, or intrauterine hormonal system (IUS) – because it reduces the amount of absorbed progestogenic hormone. The amount of progestogen lost when receiving Sugammadex Piramal is approximately equivalent to missing one dose of the oral contraceptive pill.
→ If you need to take your oral contraceptive pill on the same day that Sugammadex Piramal is administered, follow the instructions in the contraceptive pill’s package leaflet regarding a missed dose.
→ If you are using other hormonal contraceptives (e.g. a vaginal ring, implant, or IUS), you must use an additional non-hormonal contraceptive method (such as a condom) for the next 7 days and follow the instructions in the product leaflet.
Effects on blood test results
In general, Sugammadex Piramal has no effect on blood test results. However, it may interfere with the results of a test measuring blood levels of a hormone called progesterone.
Please consult your doctor if testing for progesterone levels is required on the same day you receive Sugammadex Piramal.
Pregnancy and breastfeeding
Inform your anaesthetist if you are pregnant or may be pregnant, or if you are breastfeeding.
You may still receive Sugammadex Piramal, but you should discuss this with your doctor first.
It is not known whether sugammadex passes into breast milk. Your anaesthetist will help you decide whether to discontinue breastfeeding or to avoid treatment with sugammadex, taking into account the benefits of breastfeeding for the child and the benefits of Sugammadex Piramal for the mother.
Driving and using machines
Sugammadex Piramal has no known influence on the ability to drive vehicles or operate machinery.
Sugammadex Piramal contains sodium
This medicine contains up to 9.7 mg of sodium (a key component of table salt) per mL. This corresponds to 0.5% of the maximum daily recommended dietary intake of sodium for an adult.

3. How Sugammadex Piramal is administered

Sugammadex Piramal will be administered to you by the anaesthetist, or under the anaesthetist's supervision.
The dose
The anaesthetist will determine the appropriate dose of Sugammadex Piramal for you, taking into consideration:

• your body weight
• the extent to which the muscle relaxant is still affecting you.

The usual dose is 2–4 mg per kg of body weight in patients of any age. A dose of 16 mg/kg may be used in adults if rapid reversal of muscle relaxation is required.

How Sugammadex Piramal is administered
Sugammadex Piramal will be administered by the anaesthetist as a single intravenous injection.
If you are given more Sugammadex Piramal than recommended
Since your condition will be closely monitored by the anaesthetist, it is unlikely that you will receive an excessive amount of Sugammadex Piramal. However, if this were to happen, it is unlikely to cause you any problems.
If you have any doubts about the use of this medicine, consult the anaesthetist or another doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
If such side effects occur during anaesthesia, they will be detected and treated by the anaesthetist.

Common side effects (may affect up to 1 in 10 people)

• Cough
• Breathing difficulties which may include coughing or movements as if waking up or gasping for breath
• Light anaesthesia – you may begin to come out of deep sleep, and therefore may require additional anaesthetic. This could cause the patient to move or cough at the end of surgery
• Complications during the procedure such as changes in heart rate, coughing or movements
• Decrease in blood pressure due to the surgical procedure

Uncommon side effects (may affect up to 1 in 100 people)

• In patients with a history of lung problems, shortness of breath due to muscle contractions of the airways (bronchospasm) has been observed
• Allergic reactions (hypersensitivity to the medicine) – such as skin rash, redness of the skin, swelling of the tongue and/or throat, shortness of breath, changes in blood pressure or heart rate, which sometimes may lead to severe drops in blood pressure. Severe allergic or allergic-like reactions can be life-threatening. Allergic reactions have been reported more commonly in healthy, awake volunteers
• Return of muscle relaxation after surgery.

Frequency not known (frequency cannot be estimated from the available data)

• When Sugammadex Piramal is administered, severe slowing of the heart and slowing of the heart to cardiac arrest may occur.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your anaesthetist or doctor. You can also report side effects directly via the national reporting system referred to in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Sugammadex Piramal

Storage will be handled by healthcare professionals.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and label after "Exp.". The expiry date refers to the last day of that month.
Keep the vial in the carton to protect the medicine from light.
After first opening and dilution, store at 2-8°C and use within 48 hours.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Sugammadex Piramal contains

• The active substance is sugammadex. 1 mL of injectable solution contains sodium sugammadex equivalent to 100 mg of sugammadex. Each 2 mL vial contains sodium sugammadex equivalent to 200 mg of sugammadex. Each 5 mL vial contains sodium sugammadex equivalent to 500 mg of sugammadex.
• The excipients are water for injections, hydrochloric acid and/or sodium hydroxide (for pH adjustment). (see section 2 "Sugammadex Piramal contains sodium").

Description of the appearance of Sugammadex Piramal and package contents
Sugammadex Piramal is a clear, colourless to slightly yellow-brown injectable solution.
It is available in two different pack sizes, containing either 10 vials with 2 mL of injectable solution or
10 vials with 5 mL of injectable solution.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Piramal Critical Care B.V
Rouboslaan 32 ,
2252 TR Voorschoten
The Netherlands
More detailed information on this medicinal product is available on the website of the European Medicines Agency, https://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals:

For detailed information, refer to the Summary of Product Characteristics (SmPC) of
Sugammadex Piramal.
Therapeutic indications and dosage
Reversal of neuromuscular blockade induced by rocuronium or vecuronium in adults.
For the paediatric population: sugammadex is recommended only for routine reversal of rocuronium-induced
neuromuscular blockade in paediatric patients from birth to 17 years of age.
Sugammadex must be administered only by an anaesthetist or under their supervision. Adequate
neuromuscular monitoring techniques are recommended to monitor recovery from neuromuscular blockade
(see SmPC, section 4.4).
Adults
Routine reversal:
If recovery from rocuronium- or vecuronium-induced blockade has reached a post-tetanic count (PTC) of at
least 1–2, the recommended dose of sugammadex is 4 mg/kg body weight. The median time to recovery of a
0.9 T/T ratio is approximately 3 minutes (see SmPC, section 5.1).
A dose of 2 mg/kg body weight of sugammadex is recommended when spontaneous recovery has reached the
reappearance of T after rocuronium- or vecuronium-induced blockade. The median time to recovery of a 0.9
T/T ratio is approximately 2 minutes (see SmPC, section 5.1).
Use of the recommended doses for routine reversal results in a slightly faster median recovery time to a T/T
ratio of 0.9 for rocuronium compared to vecuronium-induced neuromuscular blockade (see SmPC, section
5.1).
Immediate reversal of rocuronium-induced blockade:
When immediate reversal after administration of rocuronium is clinically required, a dose of 16 mg/kg body
weight of sugammadex is recommended. When 16 mg/kg body weight of sugammadex is administered 3
minutes after a 1.2 mg/kg bolus dose of rocuronium bromide, a median time to recovery of a 0.9 T/T ratio of
approximately 1.5 minutes can be expected (see SmPC, section 5.1).
There are no data to recommend the use of sugammadex for immediate reversal after vecuronium-induced
blockade.
Re-administration of sugammadex:
In the rare event of recurrent neuromuscular blockade in the postoperative setting (see SmPC, section 4.4),
following an initial dose of 2 mg/kg or 4 mg/kg of sugammadex, administration of a further dose of
sugammadex 4 mg/kg is recommended.
After a second dose of sugammadex, the patient must be closely monitored to ensure recovery of
neuromuscular function.
Renal impairment:
The use of sugammadex in patients with severe renal impairment (including patients requiring dialysis (CrCl
< 30 mL/min)) is not recommended (see SmPC, section 4.4).
Obese patients:
In obese patients, including those with pathological obesity (body mass index ≥ 40 kg/m²), the dose of
sugammadex should be based on actual body weight. The same dosing recommendations as for adults
should be followed.
Paediatric population (from birth to 17 years of age)
Sugammadex Piramal 100 mg/mL may be diluted to 10 mg/mL to improve dosing accuracy in the paediatric
population (see SmPC, section 6.6).
Routine reversal:
A dose of 4 mg/kg of sugammadex is recommended for reversal of rocuronium-induced blockade when
recovery has reached a PTC of at least 1–2.
A dose of 2 mg/kg of sugammadex is recommended for reversal of rocuronium-induced blockade upon
reappearance of T (see SmPC, section 5.1).
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the SmPC.
Special warnings and precautions for use
As in standard post-anaesthetic practice, after neuromuscular blockade, patients should be monitored in the
immediate postoperative period for adverse events, including recurrence of neuromuscular blockade.
Respiratory function monitoring during recovery:
After reversal of neuromuscular blockade, patients should receive respiratory support until adequate
spontaneous ventilation is restored. Even when neuromuscular blockade has been fully reversed, other
medicinal products used in the peri- and post-operative period may impair respiratory function, and therefore
respiratory support may still be required.
If neuromuscular blockade recurs after extubation, adequate ventilation must be provided.
Recurrence of neuromuscular blockade:
In clinical studies involving subjects treated with rocuronium or vecuronium, where sugammadex was
administered at doses indicated for deep neuromuscular blockade, a recurrence rate of 0.20% of
neuromuscular blockade was observed based on neuromuscular monitoring or clinical evidence. Use of lower
doses than those recommended may increase the risk of recurrence of neuromuscular blockade after initial
reversal and is not recommended (see SmPC, section 4.2 and section 4.8).
Effect on haemostasis:
In a study in volunteers, doses of 4 mg/kg and 16 mg/kg of sugammadex resulted in a maximum mean
prolongation of the activated partial thromboplastin time (aPTT) of 17% and 22%, and of the international
normalised ratio of prothrombin time [PT(INR)] of 11% and 22%, respectively. These minor mean
prolongations of aPTT and PT(INR) were of short duration (≤ 30 minutes). Based on clinical databases (N=3,519) and a specific study in 1,184 patients undergoing hip fracture surgery/major joint replacement surgery, there was no clinically relevant effect of sugammadex administered at 4 mg/kg alone or in combination with anticoagulants on the incidence of peri- or post-operative bleeding complications.
In vitro studies have shown a pharmacodynamic interaction (prolongation of aPTT and PT) with vitamin K
antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban, and dabigatran. In
patients receiving routine post-operative anticoagulant prophylaxis, this pharmacodynamic interaction is not
clinically relevant. Caution should be exercised when considering the use of sugammadex in patients
receiving anticoagulant therapy for a pre-existing or co-morbid condition.
An increased risk of bleeding cannot be excluded in patients:

• with hereditary deficiencies of vitamin K-dependent coagulation factors;
• with pre-existing coagulopathies;
• treated with coumarin derivatives and with an INR greater than 3.5;
• using anticoagulants and receiving a dose of 16 mg/kg of sugammadex. If there is a medical need to administer sugammadex to these patients, the anaesthetist must decide whether the benefits outweigh the potential risks of bleeding complications, taking into account the patient's history of bleeding episodes and the type of planned surgical procedure. If sugammadex is administered to these patients, monitoring of haemostasis and coagulation parameters is recommended.

Time intervals for re-administration of neuromuscular blocking agents after reversal with
sugammadex:
Table 1: Re-administration of rocuronium or vecuronium after routine reversal (up to 4 mg/kg
of sugammadex):

The onset of neuromuscular block may be prolonged by up to approximately 4 minutes, and the duration of neuromuscular block may be reduced by up to approximately 15 minutes following re-administration of 1.2 mg/kg of rocuronium within 30 minutes after administration of sugammadex.
Based on pharmacokinetic models in patients with mild or moderate renal impairment, the recommended waiting time for re-use of 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium after routine reversal with sugammadex is 24 hours. If a shorter waiting time is required, the dose of rocuronium for a new neuromuscular block should be 1.2 mg/kg.
Re-administration of rocuronium or vecuronio after immediate reversal (16 mg/kg sugammadex):
For the very rare cases where this may be necessary, a waiting time of 24 hours is recommended.
If a neuromuscular block must be re-established before the recommended waiting time has elapsed, a non-steroidal neuromuscular blocking agent should be used. The onset of effect of a depolarizing neuromuscular blocking agent may be slower than expected, as a substantial fraction of postjunctional nicotinic receptors may still be occupied by the neuromuscular blocking agent.

Renal impairment:
The use of sugammadex is not recommended in patients with severe renal impairment, including those requiring dialysis (see SmPC, section 5.1).

Light anaesthesia:
In clinical studies, signs of light anaesthesia (movements, coughing, grimacing, and endotracheal tube sucking) have occasionally been observed following intentional reversal of neuromuscular block during anaesthesia.
If neuromuscular block is reversed while anaesthesia is still maintained, additional doses of anaesthetic and/or opioid should be administered as clinically indicated.

Marked bradycardia:
In rare cases, marked bradycardia has been observed a few minutes after administration of sugammadex for reversal of neuromuscular block. Bradycardia may occasionally lead to cardiac arrest (see SmPC, section 4.8). Patients must be closely monitored for haemodynamic changes during and after reversal of neuromuscular block. If clinically significant bradycardia occurs, treatment with anticholinergic agents such as atropine should be administered.

Hepatic impairment:
Since sugammadex is neither metabolized nor excreted hepatically, no studies have been conducted in patients with hepatic impairment. Patients with severe hepatic impairment should be treated with great caution. If hepatic impairment is accompanied by coagulopathy, refer to information regarding effects on haemostasis.

Use in intensive care units:
Sugammadex has not been studied in patients who have received rocuronium or vecuronium in an intensive care unit.

Use for reversal of blockade induced by neuromuscular blockers other than rocuronium and vecuronium:
Sugammadex must not be used to reverse blockade induced by non-steroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinoline compounds.
Sugammadex must not be used to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents other than rocuronium and vecuronium, as efficacy and safety data are not available under these circumstances. Limited data are available on reversal of pancuronium-induced blockade, but use of sugammadex in this context is not recommended.

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

Hypersensitivity reactions to the drug:
Physicians must be prepared for the possibility of hypersensitivity reactions to the drug (including anaphylactic reactions) and take appropriate precautions (see SmPC, section 4.8).

Sodium:
This medicinal product contains up to 9.7 mg of sodium per mL, equivalent to 0.5% of the maximum daily intake recommended by the WHO, which corresponds to 2 g of sodium for an adult.

Interaction with other medicinal products and other forms of interaction
The information reported in this section is based on the binding affinity between sugammadex and other medicinal products, non-clinical studies, clinical studies, and simulations using a model that considered the pharmacodynamic effect of neuromuscular blocking agents and the pharmacokinetic interaction between neuromuscular blocking agents and sugammadex. Based on these data, clinically significant pharmacodynamic interactions with other medicinal products are not expected, except for the following:
For toremifene and fusidic acid, displacement interactions could not be excluded (no clinically relevant sequestration interactions are expected).
For oral hormonal contraceptives, a clinically relevant sequestration interaction could not be excluded (no displacement interactions are expected).

Interactions that may compromise the efficacy of sugammadex (displacement interactions):
Administration of certain medicinal products after sugammadex may theoretically displace rocuronium or vecuronium from sugammadex. This may result in recurrence of neuromuscular block. In such an event, the patient must be ventilated. If an infusion is ongoing, administration of the medicinal product causing displacement must be stopped. In situations where potential displacement interactions may be anticipated, if another medicinal product is administered parenterally within 7.5 hours after sugammadex administration, patients must be closely monitored for signs of recurrence of neuromuscular block (for a maximum period of approximately 15 minutes).

Toremifene:
With regard to toremifene, which has a relatively high binding affinity for sugammadex and for which relatively high plasma concentrations may be present, some displacement of vecuronium or rocuronium from sugammadex may occur. Physicians should be aware that restoration of a T /T ratio of 0.9 may therefore be delayed in patients who have received toremifene on the same day as surgery.

Intravenous administration of fusidic acid:
The use of fusidic acid in the preoperative phase may result in some delay in restoring a T /T ratio of 0.9. Recurrence of neuromuscular block is not expected in the postoperative phase, as the infusion rate of fusidic acid has a duration of several hours and blood levels are cumulative over 2–3 days. For re-administration of sugammadex, see SmPC, section 4.2.

Interactions that may compromise the efficacy of other medicinal products (sequestration interactions):
Administration of sugammadex may cause reduced efficacy of certain medicinal products due to decreased plasma (free) concentrations. If such a situation occurs, the physician should consider re-administering the medicinal product, administering a therapeutically equivalent medicinal product (preferably from a different chemical class), and/or implementing non-pharmacological interventions, as appropriate.

Hormonal contraceptives:
It has been estimated that the interaction between 4 mg/kg sugammadex and a progestogen results in a reduction in progestogen exposure (34% of AUC) similar to that observed when a daily oral contraceptive dose is delayed by 12 hours, an event that may reduce contraceptive efficacy. For estrogens, the effect is presumed to be less pronounced.
Therefore, administration of a bolus dose of sugammadex is considered equivalent to missing one daily dose of oral steroidal contraceptives (combined or progestogen-only). If sugammadex is administered on the same day as an oral contraceptive is taken, reference should be made to the instructions in the contraceptive’s package leaflet regarding missed doses. For non-oral hormonal contraceptives, the patient should use an additional non-hormonal contraceptive method for the following 7 days and refer to the instructions in the product leaflet.

Interactions due to prolonged effect of rocuronium or vecuronium:
Particular caution should be exercised when using medicinal products in the postoperative period that may potentiate neuromuscular block, due to the potential recurrence of neuromuscular block. Refer to the product leaflet of rocuronium or vecuronium for a list of specific medicinal products that potentiate neuromuscular block. If recurrence of neuromuscular block occurs, the patient may require mechanical ventilation and re-administration of sugammadex (see SmPC, section 4.2).

Fertility, pregnancy and lactation

Pregnancy
Clinical data on pregnancies exposed to sugammadex are not available.
Animal studies do not indicate direct or indirect harmful effects with regard to pregnancy, embryonic/fetal development, parturition or postnatal development.
Caution should be exercised when administering this medicinal product to pregnant women.

Lactation
It is not known whether sugammadex is excreted in human milk. Animal studies have shown excretion of sugammadex in milk. Oral absorption of cyclodextrins in general is low, and effects on the breastfed infant after a single dose administered to a breastfeeding woman are not expected.
A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from treatment with sugammadex, taking into account the benefit of breastfeeding for the child and the benefit of treatment for the woman.

Fertility
The effects of sugammadex on fertility in humans have not been studied. Animal studies assessing fertility did not reveal harmful effects.

Undesirable effects

Summary of safety profile
Sugammadex Piramal is administered concomitantly with neuromuscular blocking agents and anaesthetics in surgical patients. Therefore, causality of adverse events is difficult to assess. The most commonly reported adverse reactions in surgical patients were cough, anaesthesia-related respiratory complication, anaesthesia-related complication, procedural hypotension, and procedure-related complication (Common (≥ 1/100, < 1/10)).

Table 2: Table of adverse reactions
The safety of sugammadex has been evaluated in 3,519 unique subjects through a safety database from combined phase I–III studies. In placebo-controlled studies where subjects received anaesthesia and/or neuromuscular blocking agents (1,078 subjects exposed to sugammadex versus 544 exposed to placebo), the following adverse reactions were reported:
[Very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000)]

Description of selected adverse reactions
Drug hypersensitivity reactions:
Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers (for information on volunteers, see below, Healthy volunteers information). In clinical studies of surgical patients, these reactions were reported as uncommon, and in post-marketing reports, the frequency is unknown.
These reactions ranged from isolated skin reactions to severe systemic reactions (such as anaphylaxis, anaphylactic shock) and occurred in patients who had no prior exposure to sugammadex.
Symptoms associated with these reactions may include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, tongue swelling, pharyngeal swelling, bronchospasm, and obstructive pulmonary events. Severe hypersensitivity reactions may be fatal.
In post-marketing reports, hypersensitivity to sugammadex and to the sugammadex-rocuronium complex has been observed.
Anaesthesia-related respiratory complications:
Anaesthesia-related respiratory complications included resistance against the endotracheal tube, coughing, mild resistance to intubated breathing, emergence reaction during surgery, coughing during anaesthetic or surgical procedure, or patient's spontaneous breathing related to the anaesthetic procedure.
Anaesthesia complications:
Anaesthesia complications indicating recovery of neuromuscular function include limb or body movement, coughing during anaesthetic or surgical procedure, grimacing, or endotracheal tube sucking. See SmPC, section 4.4 "light anaesthesia".
Procedure-related complications:
Procedure-related complications included cough, tachycardia, bradycardia, movement, and increased heart rate.
Marked bradycardia:
In post-marketing experience, isolated cases of marked bradycardia and bradycardia with cardiac arrest have been observed a few minutes after administration of sugammadex (see SmPC, section 4.4).
Return of neuromuscular block:
In clinical studies in subjects treated with rocuronium or vecuronium, where sugammadex was administered at a dose indicated for deep neuromuscular block (N=2,022), an incidence of 0.20% of return of neuromuscular block was observed based on neuromuscular monitoring or clinical evidence (see SmPC, section 4.4).
Information on healthy volunteers:
A randomised, double-blind study evaluated the incidence of drug hypersensitivity reactions in healthy volunteers who received up to 3 doses of placebo (N=76), sugammadex 4 mg/kg (N=151), or sugammadex 16 mg/kg (N=148). Suspected hypersensitivity reactions were adjudicated by a blinded committee. The adjudicated incidence of 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 repeated doses of sugammadex.
In a previous study with a similar design, there were three adjudicated cases of anaphylaxis, all after sugammadex 16 mg/kg (incidence 2.0%).
In the pooled Phase 1 clinical trial database, adverse events considered common (≥ 1/100, < 1/10) or very common (≥ 1/10) and more frequent in subjects treated with sugammadex than in the placebo group include dysgeusia (10.1%), headache (6.7%), nausea (5.6%), urticaria (1.7%), pruritus (1.7%), dizziness (1.6%), vomiting (1.2%), and abdominal pain (1.0%).
Additional information on special populations
Patients with history of pulmonary complications:
In post-marketing data and in a dedicated clinical study conducted in patients with a history of pulmonary complications, bronchospasm was reported as an adverse event possibly related to the medicinal product. As with all patients with a history of pulmonary complications, physicians should be aware of the possible occurrence of bronchospasm.
Paediatric population
In studies in paediatric patients from birth to 17 years of age, the safety profile of sugammadex (up to 4 mg/kg) was generally similar to that observed in adults.
Patients with pathological obesity
In a dedicated clinical study in patients with pathological obesity, the safety profile was generally similar to that observed in adult patients in pooled Phase 1 to 3 studies (see Table 2).
Patients with severe systemic disease
In a study in patients classified as American Society of Anesthesiologists (ASA) Class 3 or 4 (patients with severe systemic disease or patients with severe systemic disease representing a constant life threat), the adverse reaction profile in ASA Class 3 and 4 patients was generally similar to that observed in adult patients in pooled Phase 1 to 3 studies (see Table 2); see SmPC, section 5.1.
Overdose
One case of accidental overdose with a dose of 40 mg/kg body weight has been reported in clinical trials, with no significant adverse reactions. In a human tolerability study, sugammadex was administered at doses up to 96 mg/kg body weight. No dose-related adverse events or serious adverse events were reported.
Sugammadex can be removed by haemodialysis using a high-flux filter, but not with a low-flux filter. Based on clinical studies, plasma concentrations of sugammadex are reduced by up to 70% after a dialysis session lasting 3 to 6 hours.
List of excipients
Hydrochloric acid 3.7% (to adjust pH) and/or sodium hydroxide (to correct pH)
Water for injections
Shelf life
3 years
After first opening and dilution, chemical and physical in-use stability have been demonstrated for 48 hours at a temperature between 2 °C and 25 °C. From a microbiological point of view, the diluted medicinal product should be used immediately. If not used immediately, storage times and conditions prior to use are the responsibility of the user; normally not exceeding 24 hours at a temperature between 2 °C and 8 °C, unless dilution has been carried out under validated aseptic and controlled conditions.
Special precautions for storage
Store below 30 °C.
Do not freeze.
Keep the vial in the outer packaging to protect from light.
For storage conditions of the diluted medicinal product, see SmPC, section 6.3.
Special precautions for disposal and handling
Sugammadex Piramal may be injected into an intravenous infusion line containing 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%), Ringer's lactate solution, Ringer's solution, glucose 50 mg/mL (5%) in sodium chloride 9 mg/mL (0.9%).
The infusion line should be adequately flushed (e.g., with 0.9% sodium chloride) between administration of Sugammadex Piramal and other medicinal products.
Use in the paediatric population
For paediatric patients, Sugammadex Piramal may be diluted with sodium chloride 9 mg/mL (0.9%) to a concentration of 10 mg/mL (see SmPC, section 6.3).