Sugammadex sandoz

Package leaflet: Information for the user

Sugammadex Sandoz, 100 mg/ml, solution for injection
Sugammadexum
Please read all of this leaflet carefully before this medicine is given to you because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your anaesthetist or another 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 Sandoz is and what it is used for
2. What you need to know before Sugammadex Sandoz is given
3. How Sugammadex Sandoz is given
4. Possible side effects
5. How to store Sugammadex Sandoz
6. Contents of the pack and other information

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

What Sugammadex Sandoz is
Sugammadex Sandoz contains the active substance sugammadex. Sugammadex Sandoz is considered a selective relaxant binding agent because it acts only on specific muscle relaxants – rocuronium bromide or vecuronium bromide.

What Sugammadex Sandoz is used for
For certain types of surgery, the patient's muscles must be completely relaxed. This allows the surgeon to perform the procedure more easily. During general anaesthesia, muscle-relaxing medicines are therefore given. These are known as neuromuscular blocking agents and include rocuronium bromide and vecuronium bromide. Since these medicines also relax the muscles used for breathing, assisted ventilation (artificial ventilation) is required during and after surgery until the patient's own breathing returns.

Sugammadex Sandoz is used to speed up the recovery of muscle function after surgery, enabling the patient to breathe independently again sooner. It works by binding to rocuronium bromide or vecuronium bromide in the body. The medicine can be used in adults when rocuronium bromide or vecuronium bromide has been administered. It can also be used in newborns, infants, young children, children and adolescents (from birth up to 17 years of age) when rocuronium bromide has been given.

2. What you need to know before Sugammadex Sandoz is given

When not to use Sugammadex Sandoz

• if the patient is allergic to sugammadex or to any of the other ingredients of this medicine (listed in section 6). → If this applies to the patient, inform the anaesthetist.

Warnings and precautions
Talk to the anaesthetist before Sugammadex Sandoz is given if:

• the patient currently has or has previously had kidney problems. This is important because Sugammadex Sandoz is eliminated from the body via the kidneys.
• the patient currently has or has previously had liver problems.
• the patient has fluid retention (oedema).
• the patient has diseases known to increase the risk of bleeding (coagulation disorders) or is taking anticoagulant medicines.

Sugammadex Sandoz and other medicines
Tell the anaesthetist about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take. Sugammadex Sandoz may affect the action of other medicines or other medicines may affect the action of Sugammadex Sandoz.

Some medicines reduce the effectiveness of Sugammadex Sandoz. It is especially important to inform the anaesthetist if the patient has recently taken:

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

Sugammadex Sandoz may affect the effectiveness of hormonal
contraceptives
Sugammadex Sandoz may reduce the effectiveness of hormonal contraceptives, including oral contraceptives ("the pill"), vaginal ring, implant, or transdermal therapeutic system releasing progestagen (hormonal intrauterine device), because it reduces the amount of hormone delivered. The amount of progestagen lost due to the use of Sugammadex Sandoz is approximately equivalent to missing one oral contraceptive tablet.

→ If taking an oral contraceptive ("the pill") on the same day that Sugammadex Sandoz is administered, follow the instructions provided in the hormonal contraceptive leaflet regarding missed tablets.

→ If using other hormonal contraceptives (such as a vaginal ring, implant, or hormonal intrauterine device), use an additional non-hormonal contraceptive method (e.g. condoms) for the next 7 days and follow the recommendations in the leaflet for that product.

Effect on blood test results
Sugammadex Sandoz usually does not affect laboratory test results. However, it may affect blood tests measuring levels of a hormone called progesterone. Please consult your doctor if progesterone blood levels need to be measured on the same day that Sugammadex Sandoz is administered.

Pregnancy and breastfeeding
If the patient is pregnant, suspects she may be pregnant, or is breastfeeding, she should consult her anaesthetist.

Sugammadex Sandoz may still be used in pregnant patients, but this should be discussed with the doctor beforehand.

It is not known whether sugammadex passes into breast milk. The anaesthetist will help the patient decide whether to stop breastfeeding or to refrain from treatment with sugammadex, taking into account the benefits of breastfeeding for the child and the benefits of treatment with Sugammadex Sandoz for the mother.

Driving and using machines
The effect of Sugammadex Sandoz on the ability to drive and use machines is unknown.

Sugammadex Sandoz contains sodium
This medicine contains 9.7 mg of sodium (the main component of table salt) in each millilitre.

A 2 ml vial contains less than 23 mg of sodium, meaning it is essentially "sodium-free".

A 5 ml vial contains 48.5 mg of sodium (the main component of table salt), equivalent to 2.5% of the maximum daily intake of 2 g sodium recommended by the World Health Organization for adults.

3. How the medicine Sugammadex Sandoz is administered

Sugammadex Sandoz is administered by an anaesthesiologist or under the supervision of an anaesthesiologist.
Dosage
The anaesthesiologist will adjust the dose of Sugammadex Sandoz based on:

• the patient's body weight
• the degree of muscle relaxant effect in the patient. The usual dose ranges from 2 mg/kg body weight (b.w.) to 4 mg/kg b.w. in patients of all ages. If rapid reversal of muscle relaxation is required, a dose of 16 mg/kg b.w. may be used in adults.

How Sugammadex Sandoz is administered
Sugammadex Sandoz is administered by an anaesthesiologist as a single intravenous injection through an intravenous line.
Administration of a higher than recommended dose of Sugammadex Sandoz
Since the anaesthesiologist closely monitors the patient's condition, overdose of Sugammadex Sandoz is unlikely. Nevertheless, if such an event occurs, no problems are expected to arise.
If you have any further doubts regarding the use of this medicine, please consult your anaesthesiologist or another physician.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
If any of the following adverse reactions occur during anaesthesia, they will be noticed and treated by the anaesthetist.

Common adverse reactions (may affect fewer than 1 in 10 people)

• Coughing
• Breathing difficulties, including coughing or movement, such as during waking up or taking a breath
• Light anaesthesia – the patient may start to wake up from deep sleep and may require additional anaesthetic. This may cause movement or coughing towards the end of surgery
• Complications during the procedure, such as changes in heart rate, coughing or movement
• Decreased arterial blood pressure related to the surgical procedure

Uncommon adverse reactions (may affect fewer than 1 in 100 people)

• Shortness of breath due to bronchial muscle spasm (bronchospasm) occurring in patients with a history of lung disease
• Allergic reactions (hypersensitivity to the medicine) – such as rash, redness of the skin, swelling of the tongue and/or throat, shortness of breath, changes in blood pressure or heart rhythm, sometimes leading to severe drop in blood pressure. Severe allergic reactions or allergic-like reactions may be life-threatening.

Allergic reactions have been reported more frequently in healthy, awake volunteers.

• Return of muscle tone to normal after surgery.

Frequency not known

• After administration of Sugammadex Sandoz, severe cases of bradycardia, including slowing of the heart rate up to cardiac arrest, are possible.

Reporting of adverse reactions
If any adverse symptoms occur, including any adverse symptoms not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw,
tel.: + 48 22 49 21 301, fax: + 48 22 49 21 309, website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Sugammadex Sandoz

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton after EXP. The expiry date refers to the last day of the stated month.
Do not freeze. Store the vial in the original packaging to protect it from light.

After first opening
After first opening of the vial, chemical and physical stability of the ready-to-use solution has been demonstrated for 96 hours at a temperature of 2 °C to 8 °C in the absence of light, and at a temperature of 20 °C to 25 °C in the presence of light (solution withdrawn using a needle or spike).
Additionally, the injection solution withdrawn as described above has demonstrated chemical and physical stability in polypropylene syringes for 96 hours at 2 °C to 8 °C in the absence of light, and at 20 °C to 25 °C in the presence of light.
From a microbiological standpoint, the medicinal product should be used immediately. If the solution is not used immediately, the user is responsible for the storage duration and conditions thereafter, which should under no circumstances exceed 24 hours at 2 °C to 8 °C, unless the opening and withdrawal were performed under controlled and validated aseptic conditions.

After dilution
After dilution, physico-chemical stability of the ready-to-use solution has been demonstrated for 48 hours at a temperature of 2 °C to 25 °C. From a microbiological standpoint, the medicine should be used immediately after dilution. If the medicine is not used immediately, the user is responsible for the storage period and conditions prior to use. The solution should not be stored for longer than 24 hours at 2 °C to 8 °C, unless it was diluted under controlled and validated aseptic conditions.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. Such measures will help protect the environment.

6. Contents of the pack and other information

What the medicine contains

• The active substance is sugammadex. Each ml of injection 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 other ingredients are: water for injections, hydrochloric acid, concentrated (for pH adjustment) and (or) sodium hydroxide (for pH adjustment).

What Sugammadex Sandoz looks like and contents of the pack
Sugammadex Sandoz is a solution for injection. It is a clear, colourless to slightly yellowish-brown solution, practically free from particulate matter, contained in colourless type I glass vials with grey rubber stoppers.
Two pack sizes are available, containing either 10 vials of 2 ml or 10 vials of 5 ml of solution for injection.

Marketing Authorisation Holder
Sandoz GmbH
Biochemiestrasse 10
6250 Kundl
Austria

Manufacturer
Lek Pharmaceuticals d.d.
Verovškova 57
1526 Ljubljana
Slovenia

This medicine is authorised for supply in the European Economic Area and the United Kingdom (Northern Ireland) under the following names:
Netherlands Sugammadex Sandoz 100 mg/ml, solution for injection
Austria Sugammadex Sandoz 100 mg/ml - Injektionslösung
Belgium Sugammadex Sandoz 100 mg/ml solution for injection
Czech Republic Sugammadex Sandoz
Germany Sugammadex HEXAL 100 mg/ml Injektionslösung
Greece Sugammadex/Sandoz 100 mg/mL ενέσιμο διάλυμα
Spain Sugammadex Sandoz 100 mg/ml solución inyectable EFG
Finland Sugammadex Sandoz 100 mg/ml injektioneste, liuos
Croatia Sugamadeks Sandoz 100 mg/ml otopina za injekciju
Ireland Sugammadex Rowex 100 mg/ml solution for injection
France Sugammadex GNR 25 mg/ml, solution à diluer pour perfusion
Ireland Sugammadex Rowex 25 mg/ml concentrate for solution for infusion
Italy Sugammadex Sandoz
Poland Sugammadex Sandoz
Portugal Sugamadex Sandoz
Romania Sugammadex Sandoz 100 mg/ml soluție injectabilă
Slovenia Sugamadeks Sandoz 100 mg/ml raztopina za injiciranje
Northern Ireland Sugammadex Sandoz 100 mg/ml solution for injection
Denmark Sugammadex Sandoz
Norway Sugammadex Sandoz

For further information about this medicine, please contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warsaw
tel. 22 209 70 00
(logo of the marketing authorisation holder)

The following information is intended for healthcare professionals only:

Detailed information is available in the Summary of Product Characteristics (SmPC) for Sugammadex Sandoz.

Indications and dosage

Reversal of neuromuscular blockade induced by rocuronium or
vecuronium in adults.
Children and adolescents: sugammadex is recommended only for routine reversal of rocuronium-induced
neuromuscular blockade in children and adolescents from birth to 17 years of age.
Sugammadex should be administered only by an anaesthesiologist or under the supervision of an anaesthesiologist.
Appropriate neuromuscular monitoring techniques are recommended to monitor the course of reversal of neuromuscular blockade (see SmPC, section 4.4).

Adults

Routine reversal of blockade
After blockade induced by rocuronium or vecuronium, when recovery has reached at least 1–2 post-tetanic counts (PTC), sugammadex is recommended at a dose of 4 mg/kg body weight (bw). The median time to return of the T4/T1 ratio to 0.9 is approximately 3 minutes (see SmPC, section 5.1).
After blockade induced by rocuronium or vecuronium, when spontaneous recovery has occurred up to the reappearance of T2, sugammadex is recommended at a dose of 2 mg/kg bw. The median time to return of the T4/T1 ratio to 0.9 is approximately 2 minutes (see SmPC, section 5.1).
Use of the recommended doses for routine reversal will result in slightly shorter median times to return of the T4/T1 ratio to 0.9 for rocuronium-induced neuromuscular blockade compared to vecuronium (see SmPC, section 5.1).

Immediate reversal of rocuronium-induced blockade
If immediate reversal of blockade after administration of rocuronium is clinically required, sugammadex is recommended at a dose of 16 mg/kg bw. If sugammadex 16 mg/kg bw is administered 3 minutes after a bolus dose of rocuronium bromide 1.2 mg/kg bw, the median time to return of the T4/T1 ratio to 0.9 is expected to be approximately 1.5 minutes (see SmPC, section 5.1).
There are no data supporting the use of sugammadex for immediate reversal of vecuronium-induced blockade.

Repeat administration of sugammadex
In exceptional cases of recurrence of neuromuscular blockade after surgery (see SmPC, section 4.4), after an initial dose of 2 mg/kg bw or 4 mg/kg bw, a repeat dose of sugammadex 4 mg/kg bw is recommended. After administration of a second dose of sugammadex, patients should be carefully monitored to ensure full recovery of neuromuscular transmission.

Renal impairment
Sugammadex is not recommended in patients with severe renal impairment [including patients requiring dialysis (CrCl < 30 ml/min)] (see SmPC, section 4.4).

Obese patients
In obese patients, including morbidly obese patients (body mass index [BMI] ≥ 40 kg/m²), the dose of sugammadex should be based on actual body weight. Dosing recommendations for adults should be followed.

Children and adolescents (from birth to 17 years of age)
Sugammadex Sandoz 100 mg/ml may be diluted to a concentration of 10 mg/ml to improve dosing accuracy in children and adolescents (see SmPC, section 6.6).

Routine reversal of blockade
To reverse rocuronium-induced blockade when recovery has reached at least 1–2 PTC, sugammadex is recommended at a dose of 4 mg/kg bw. To reverse rocuronium-induced blockade at reappearance of T2, a dose of 2 mg/kg bw is recommended (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 is standard anaesthetic practice following neuromuscular blockade, patients should be closely monitored postoperatively for unexpected events, including recurrence of neuromuscular blockade.

Monitoring of respiratory function during reversal
Mechanical ventilation should be maintained in patients until spontaneous respiratory function returns after reversal of neuromuscular blockade. Even if reversal of neuromuscular blockade is complete, other drugs used in the pre- and postoperative period may impair respiratory function, and mechanical ventilation may still be required. If recurrence of neuromuscular blockade occurs after extubation, appropriate ventilation should be provided.

Recurrence of neuromuscular blockade
In clinical trials involving patients who received rocuronium or vecuronium, with sugammadex administered at doses dependent on the degree of neuromuscular blockade, recurrence of neuromuscular blockade was observed in 0.20% of patients based on neuromuscular monitoring or clinical evidence. Use of lower than recommended doses may increase the risk of recurrence of neuromuscular blockade after initial reversal. Such use is not recommended (see SmPC, sections 4.2 and 4.8).

Effect on haemostasis
In a study in volunteers, sugammadex at doses of 4 mg/kg bw and 16 mg/kg bw caused a maximum mean prolongation 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. This limited mean prolongation of aPTT and PT (INR) was short-lived (≤ 30 minutes). Based on the clinical database (n = 3,519) and results from a study in 1,184 patients undergoing hip fracture surgery/total hip arthroplasty, no clinically relevant effect of sugammadex 4 mg/kg bw, used as monotherapy or in combination with anticoagulants, on the incidence of peri- and postoperative bleeding complications was observed.
In vitro studies have shown pharmacodynamic interactions (prolongation of aPTT and PT) with vitamin K antagonists, unfractionated heparin, low molecular weight heparins, rivaroxaban, and dabigatran. In patients receiving routine postoperative anticoagulant prophylaxis, such pharmacodynamic interactions are not clinically relevant. Caution should be exercised when considering the use of sugammadex in patients receiving anticoagulant therapy due to pre-existing or concomitant disorders.
An increased risk of bleeding cannot be excluded in the following patients:

• with congenital deficiency of vitamin K-dependent clotting factors;
• with pre-existing coagulopathies;
• receiving coumarin derivatives with INR (international normalised ratio) above 3.5;
• receiving anticoagulant therapy who are to receive sugammadex at a dose of 16 mg/kg bw.
  If there is a medical need to administer sugammadex to these patients, the anaesthesiologist must decide, taking into account the patient's history of bleeding episodes and the type of planned procedure, whether the benefits outweigh the potential risk of haemorrhagic complications. In such patients, monitoring of haemostasis and coagulation parameters is recommended when sugammadex is administered.

Re-intubation intervals for neuromuscular blocking agents (NMBA) after reversal by sugammadex
Table 1: Re-administration of rocuronium or vecuronium after routine reversal (sugammadex dose up to 4 mg/kg bw)

After re-administration of rocuronium at a dose of 1.2 mg/kg body weight within 30 minutes following sugammadex administration, the onset of neuromuscular blockade may be prolonged to approximately 4 minutes, and the duration of this blockade may be shortened to approximately 15 minutes.
Based on the PK model, in patients with mild or moderate renal impairment, after routine reversal of blockade by sugammadex, it is recommended to wait 24 hours before re-administering rocuronium at a dose of 0.6 mg/kg body weight or vecuronium at a dose of 0.1 mg/kg body weight. If a shorter waiting time is required, rocuronium at a dose of 1.2 mg/kg body weight should be administered to induce a new neuromuscular blockade.
Re-administration of rocuronium or vecuronium after immediate reversal (sugammadex at a dose of 16 mg/kg body weight): in very rare cases where such management may be necessary, a waiting period of 24 hours is recommended.
If neuromuscular blockade is required before the recommended waiting time has elapsed, a non-depolarizing neuromuscular blocking agent should be used. A depolarizing neuromuscular blocking agent may have a slower onset than expected, as a significant proportion of postsynaptic nicotinic receptors may still be occupied by the neuromuscular blocking agent.

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

Light anaesthesia
In clinical trials, when reversal of neuromuscular blockade was performed during anaesthesia (i.e., when the purpose was to study reversal), signs of light anaesthesia (movement, coughing, facial grimacing, and sucking on the endotracheal tube) were sometimes observed.
When reversing neuromuscular blockade during ongoing anaesthesia, additional doses of anaesthetic and/or opioid should be administered according to clinical indications.

Significant bradycardia
In rare cases, significant bradycardia has been observed within minutes after administration of sugammadex for reversal of neuromuscular blockade. Occasionally, bradycardia may lead to cardiac arrest (see SmPC, section 4.8). Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. In the event of clinically significant bradycardia, anticholinergic drugs such as atropine should be administered.

Hepatic impairment
Sugammadex is not metabolized or excreted by the liver; therefore, studies in patients with hepatic impairment have not been conducted. Extreme caution should be exercised when administering sugammadex to patients with severe hepatic impairment (see SmPC, section 4.2). If hepatic impairment is associated with coagulopathy, information regarding the product’s effect on hemostasis should be reviewed.

Intensive care units
The use of sugammadex has not been studied in intensive care units for patients receiving rocuronium or vecuronium.

Use for reversal of blockade induced by neuromuscular blocking agents other than rocuronium or vecuronium:
Sugammadex should not be used to reverse blockade induced by non-depolarizing neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds.
Sugammadex should not be used to reverse blockade induced by steroidal neuromuscular blocking agents other than rocuronium or vecuronium, as there are no data on efficacy and safety for such compounds. Limited data are available on reversal of pancuronium-induced blockade, but sugammadex is not recommended for use in such situations.

Delayed reversal of blockade
Conditions associated with reduced blood flow, such as cardiovascular disease, advanced age (see SmPC, section 4.2, time to recovery in elderly patients), or edematous states (e.g., severe hepatic impairment), may be associated with a prolonged time to recovery of neuromuscular transmission.

Hypersensitivity reactions to the medicinal product
Clinicians should be prepared for the possibility of hypersensitivity reactions to the medicinal product (including anaphylactic reactions) and should take appropriate precautionary measures (see SmPC, section 4.8).

Sodium
The medicinal product contains up to 9.7 mg of sodium per 1 ml.
2 ml vial
The medicinal product contains less than 1 mmol of sodium (23 mg) per vial, meaning it is essentially “sodium-free.”
5 ml vial
The medicinal product contains 48.5 mg of sodium per vial, equivalent to 2.5% of the maximum daily sodium intake recommended by WHO for adults (2 g).

Interactions with other medicinal products and other forms of interaction
The information in this section is based on binding affinity between sugammadex and other drugs, non-clinical experience, clinical studies, and model simulations incorporating the pharmacodynamic effects of neuromuscular blocking agents and pharmacokinetic interactions between neuromuscular blocking agents and sugammadex. Based on these data, clinically significant pharmacodynamic interactions with other drugs are not expected, except as described below:

For toremifene and fusidic acid, displacement interactions cannot be excluded (clinically significant sequestration-related interactions are not expected).
For hormonal contraceptives, clinically significant sequestration-related interactions cannot be excluded (displacement interactions are not expected).

Interactions potentially affecting the efficacy of sugammadex (displacement interactions)
Theoretically, administration of certain medicinal products after sugammadex may result in displacement of rocuronium or vecuronium from the sugammadex complex. This may lead to recurrence of neuromuscular blockade. In such cases, the patient must be ventilated. If an infusion is ongoing, administration of the medicinal product causing the displacement reaction should be discontinued. When a displacement interaction is anticipated, patients should be carefully monitored for recurrence of neuromuscular blockade (approximately for 15 minutes) after intravenous administration of another medicinal product within 7.5 hours following sugammadex administration.

Toremifene:
Toremifene has relatively high affinity for sugammadex and may reach relatively high plasma concentrations, potentially displacing vecuronium or rocuronium from the sugammadex complex. Therefore, physicians should be aware that the time to recovery of the T4/T1 ratio to 0.9 may be prolonged in patients who received toremifene on the day of surgery.

Intravenous administration of fusidic acid:
Preoperative use of fusidic acid may slightly prolong the time to recovery of the T4/T1 ratio to 0.9. Recurrence of neuromuscular blockade in the postoperative period is not expected, as fusidic acid infusion lasts several hours and blood test results are visible after 2–3 days. See re-administration of sugammadex (see SmPC, section 4.2).

Interactions potentially affecting the efficacy of other medicinal products (sequestration interactions)
Following administration of sugammadex, some medicinal products may be less effective due to reduced free plasma concentrations. If such a situation occurs, consideration should be given to re-administering the medicinal product, administering a therapeutically equivalent medicinal product (preferably from a different chemical class), and/or applying a non-pharmacological intervention.

Hormonal contraceptives:
An interaction between sugammadex at a dose of 4 mg/kg body weight and progestogens has been shown to reduce progestogen exposure (34% AUC), similar to the reduction seen when the daily dose of a hormonal contraceptive is taken 12 hours late, potentially leading to reduced efficacy. The effect appears to be less pronounced for estrogens. Therefore, administration of sugammadex as a bolus is considered equivalent to missing the daily dose of orally administered hormonal contraceptives (both combined hormonal contraceptives and progestogen-only contraceptives). The recommendations in the package leaflet regarding missed contraceptive doses should be followed if an oral contraceptive was taken on the same day as sugammadex administration.
For non-oral hormonal contraceptives, an additional non-hormonal contraceptive method should be used for the next 7 days, and the recommendations in the contraceptive’s package leaflet should be consulted.

Interactions resulting from prolonged action of rocuronium or vecuronium
If medicinal products that may enhance neuromuscular blockade are used in the postoperative period, particular attention should be paid to the possibility of recurrence of neuromuscular blockade (see SmPC, section 4.4). Refer to the list of specific medicinal products that potentiate neuromuscular blockade provided in the package insert for rocuronium or vecuronium. In case of recurrence of neuromuscular blockade, mechanical ventilation and re-administration of sugammadex may be necessary (see SmPC, section 4.2).

Effects on fertility, pregnancy, and lactation
Pregnancy
There are no clinical data on the use of sugammadex in pregnant women.
Animal studies have not shown direct or indirect harmful effects on pregnancy, embryo/fetal development, parturition, or postnatal development.
Sugammadex should be used with caution in pregnant women.

Breastfeeding
It is unknown whether sugammadex passes into human milk. Animal studies confirm that sugammadex is excreted in milk. Oral absorption of cyclodextrins is generally low, and no effect on the breastfed infant is expected after a single dose of sugammadex in a breastfeeding woman.
A decision must be made whether to discontinue breastfeeding or to discontinue sugammadex, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility
The effect of sugammadex on fertility has not been studied in humans. Animal studies have not shown any harmful effects on fertility.

Adverse reactions
Summary of the safety profile
Sugammadex Sandoz is administered to patients undergoing surgical procedures in conjunction with neuromuscular blocking agents and anaesthetics. Therefore, it is difficult to establish a causal relationship for adverse reactions.

The most frequently reported adverse reactions in patients undergoing surgical procedures are cough, respiratory complications related to anaesthesia, complications related to anaesthesia, procedure-related hypotension, and procedure-related complications (Common (≥ 1/100 to < 1/10)).

Table 2: Tabulated list of adverse reactions
The safety of sugammadex was evaluated based on a pooled safety database from Phase I–III studies involving 3,519 individual patients. The following adverse reactions were reported in placebo-controlled trials in which patients received anaesthesia and/or neuromuscular blocking agents (1,078 patients received sugammadex, 544 patients received placebo).
Adverse reactions are categorized by system organ class and frequency of occurrence: [Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000)]

Description of selected adverse reactions
Hypersensitivity reactions to the medicinal product
Hypersensitivity reactions, including anaphylaxis, have been observed in some patients and volunteers (information regarding volunteers is provided below under "Information on healthy volunteers"). In clinical trials involving surgical patients, these reactions were reported uncommonly, while the frequency of hypersensitivity reactions in post-marketing surveillance is unknown.
Hypersensitivity reactions varied from local skin reactions to severe systemic reactions (i.e., anaphylaxis, anaphylactic shock) and occurred in patients who had not previously received sugammadex.
Symptoms associated with these reactions included: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, tongue swelling, throat swelling, bronchospasm, and episodes of pulmonary obstruction. Severe hypersensitivity reactions may result in death.
Post-marketing reports have documented hypersensitivity to both sugammadex and the sugammadex-rocuronium complex.

Respiratory complications related to anesthesia:
Respiratory complications related to anesthesia included coughing on the endotracheal tube, coughing, mild coughing, emergence during surgery, coughing during anesthesia or during surgery, or spontaneous patient breathing associated with the anesthetic procedure.

Complications related to anesthesia:
Complications related to anesthesia indicating return of neuromuscular function included limb or body movements or coughing during the anesthetic procedure or during surgery, facial grimacing, or biting the endotracheal tube (see SmPC, section 4.4).

Procedure-related complications:
Procedure-related complications included coughing, tachycardia, bradycardia, movement, and rapid heartbeat.

Marked bradycardia:
In the post-marketing period, rare cases of marked bradycardia and bradycardia with cardiac arrest within minutes after administration of sugammadex have been observed (see SmPC, section 4.4).

Recurrence of neuromuscular blockade:
In clinical trials involving patients who received rocuronium or vecuronium, and in whom sugammadex was administered at a dose dependent on the degree of neuromuscular blockade (n = 2,022), recurrence of neuromuscular blockade was observed at a frequency of 0.20%, based on neuromuscular transmission monitoring or clinical evidence (see SmPC, section 4.4).

Information on healthy volunteers:
In a randomized, double-blind, placebo-controlled trial, the frequency of hypersensitivity reactions to the medicinal product was evaluated in healthy volunteers who received up to 3 doses of placebo (n = 76), sugammadex 4 mg/kg body weight (n = 151), or sugammadex 16 mg/kg body weight (n = 148). Suspected hypersensitivity cases were adjudicated by a committee in a blinded manner. The frequency of confirmed hypersensitivity cases in the placebo, sugammadex 4 mg/kg, and sugammadex 16 mg/kg groups was 1.3%, 6.6%, and 9.5%, respectively. No cases of anaphylaxis were reported following placebo or sugammadex 4 mg/kg administration. Following the first dose of sugammadex 16 mg/kg, a single case of confirmed anaphylaxis occurred (incidence 0.7%). No increased frequency or severity of hypersensitivity reactions was observed with repeated administration of sugammadex.
In an earlier study with a similar design, three confirmed cases of anaphylaxis occurred, all after administration of sugammadex 16 mg/kg (incidence 2%).

In the pooled Phase I clinical trial database, adverse reactions occurring commonly (≥ 1/100 to < 1/10) or very commonly (≥ 1/10) and more frequently in patients receiving sugammadex than in the placebo group included: taste disturbance (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 specific patient groups

Patients with lung diseases:
In post-marketing data and in one clinical trial specifically conducted in patients with a history of pulmonary complications, bronchospasm was reported as an adverse event possibly related to treatment. The possibility of bronchospasm should be considered in all patients with a history of pulmonary complications.

Children and adolescents
In studies involving children and adolescents aged from birth to 17 years, the safety profile of sugammadex (up to 4 mg/kg body weight) was generally similar to that observed in adults.

Morbidly obese patients
In one clinical trial specifically conducted in morbidly obese patients, the safety profile was generally similar to that observed in adult patients in combined Phase I–III trials (see Table 2).

Patients with severe systemic disease
In a study conducted in patients classified according to the American Society of Anesthesiologists (ASA) classification as ASA Class 3 or 4 (patients with severe systemic disease or patients with severe systemic disease constituting a constant threat to life), the adverse reaction profile in these ASA Class 3 or 4 patients was generally similar to that observed in adult patients in combined Phase I–III trials (see Table 2 and section 5.1).

Overdose
In clinical trials, one case of accidental overdose was reported following administration of 40 mg/kg without significant adverse reactions. In a human tolerance study, sugammadex was well tolerated at doses up to 96 mg/kg. No dose-dependent adverse events or serious adverse events were reported.
Sugammadex can be removed from the body by high-flux hemodialysis, but not by low-flux hemodialysis. Based on clinical studies, plasma concentrations of sugammadex were reduced by up to 70% after a dialysis session lasting 3 to 6 hours.

List of excipients
Hydrochloric acid, concentrated (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections

Shelf life
3 years

After first opening
Chemical and physical stability has been demonstrated for 96 hours during use at 2°C–8°C protected from light and at 20°C–25°C without protection from light (withdrawal of solution using a needle or injection puncture).
Furthermore, the solution for injection withdrawn as described above is chemically and physically stable in polypropylene syringes for 96 hours at 2°C–8°C protected from light and at 20°C–25°C without protection from light.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C–8°C, unless opening and withdrawal occurred under controlled and validated aseptic conditions.

After dilution
Chemical and physical stability has been demonstrated for 48 hours during use at 2°C–25°C. From a microbiological standpoint, the diluted product should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user and normally should not exceed 24 hours at 2°C–8°C, unless dilution was performed under controlled and validated aseptic conditions.

Special precautions for storage
Do not freeze.
Store vials in the outer packaging to protect from light.
Storage conditions for the diluted medicinal product, see SmPC, section 6.3.

Special precautions for disposal and preparation of the medicinal product for use
Sugammadex Sandoz may be administered intravenously as part of a continuous 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%), lactated Ringer's 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 solution) between administration of Sugammadex Sandoz and other medications.

Use in pediatric patients
In pediatric patients, Sugammadex Sandoz may be diluted with sodium chloride 9 mg/ml (0.9%) to a concentration of 10 mg/ml (see SmPC, section 6.3).