Myladion 100 Mg Solution

MYLADION 100 mg/mL is indicated for the routine reversal of neuromuscular blockade induced by rocuronium or vecuronium. MYLADION 100 mg/mL is also indicated for the immediate reversal of neuromuscular blockade at 3 minutes after rocuronium administration. For the paediatric population: MYLADION 100 mg/mL is only recommended for routine reversal of rocuronium induced blockade in children above 7 years of age.

Posology MYLADION 100 mg/mL should be administered under the supervision of an anaesthetist. MYLADION 100 mg/mL can be injected into the intravenous line of a running infusion with the following intravenous solutions: Sodium chloride 9 mg/mL (0,9 %), glucose 50 mg/mL (5 %), sodium chloride 4,5 mg/mL (0,45 %) and glucose 25 mg/mL (2,5 %), Ringeru2019s lactate solution, Ringeru2019s solution, glucose 50 mg/mL (5 %) in sodium chloride 9 mg/mL (0,9 %).

For paediatric patients MYLADION 100 mg/mL can be diluted using sodium chloride 9 mg/mL (0,9 %) to a concentration of 10 mg/mL. The use of an appropriate neuromuscular monitoring technique is recommended to monitor the recovery of the neuromuscular blockade. When certain medicines that may cause displacement interactions are administered parenterally within 7,5 hours of MYLADION 100 mg/mL, patients should be monitored for signs of recurrence of neuromuscular blockade.

The recommended dose of MYLADION 100 mg/mL depends on the level of neuromuscular blockade to be reversed. The recommended dose does not depend on the anaesthetic regimen. MYLADION 100 mg/mL can be used to reverse different levels of rocuronium or vecuronium induced neuromuscular blockade.

Routine Reversal of Neuromuscular Blockade A dose of 4 mg/kg MYLADION 100 mg/mL is recommended if recovery has reached 1 to 2 post-tetanic counts (PTC) (profound blockade) following administration of rocuronium or vecuronium induced blockade (see section 4.4).

A dose of 2 mg/kg MYLADION 100 mg/mL is only recommended if spontaneous recovery has reached the reappearance of T2 (shallow blockade) following rocuronium or vecuronium induced blockade (see section 4.4).

Immediate Reversal If there is a clinical need for immediate reversal at 3 minutes following administration of rocuronium, a dose of 16 mg/kg MYLADION 100 mg/mL is recommended. There is no data to recommend the use of MYLADION 100 mg/mL for immediate reversal following vecuronium induced blockade.

Special populations Renal Impairment For mild and moderate renal impairment (creatinine clearance u2265 30 and < 80 mL/min): The dose recommendations are the same as for adults without renal impairment. The use of MYLADION 100 mg/mL in patients with severe renal impairment including patients requiring dialysis (CrCl < 30 mL/min) is not recommended (see section 4.4). Studies done in patients with severe renal impairment do not provide sufficient safety information to support the use of MYLADION 100 mg/mL in these patients.

Elderly Patients After administration of MYLADION 100 mg/mL 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 to 64 years) was 2,2 minutes, in elderly adults (65 to 74 years) it was 2,6 minutes and in very elderly adults (75 years or more) it was 3,6 minutes. Even though the recovery times in elderly tend to be slower, the same dose recommendation as for adults should be followed (see section 4.4).

Obese Patients In obese patients, the dose of MYLADION 100 mg/mL should be based on actual body weight. The same dose recommendations as for adults should be followed.

Hepatic Impairment For mild to moderate hepatic impairment: As MYLADION 100 mg/mL is mainly excreted renally no dose adjustments are required. Studies in patients with hepatic impairment have not been conducted. Caution should be exercised when considering the use of MYLADION 100 mg/mL in patients with severe hepatic impairment or when hepatic impairment is accompanied by coagulopathy (see section 4.4).

Paediatric Population The data for the paediatric population are limited (one study only for reversal of rocuronium induced blockade at reappearance of T2). There is insufficient information on the use of MYLADION 100 mg/mL for children < 7 years of age. There is no information on MYLADION 100 mg/mL use for neonates. Therefore MYLADION 100 mg/mL is not recommended for use in these populations. Children and Adolescents For reversal of rocuronium induced blockade at reappearance of T2 in children and adolescents (7 to 17 years) 2 mg/kg MYLADION 100 mg/mL is recommended. Immediate reversal in children and adolescents has not been investigated and is therefore not recommended. MYLADION 100 mg/mL may be diluted to 10 mg/mL to increase the accuracy of dosing in the paediatric population, 7 years and older.

Method of administration MYLADION 100 mg/mL should be administered intravenously as a single bolus injection. The bolus injection may be given rapidly, within 10 seconds, directly into a vein or into an existing IV line (see section 6.6).

Hypersensitivity to sugammadex sodium or to any of the excipients of MYLADION 100 mg/mL (see section 6.1).

MYLADION 100 mg/mL is not to be used to reverse depolarising neuromuscular blocking medicines. With post-anaesthetic practice following neuromuscular blockade, it is recommended to monitor the patient in the immediate post-operative period for untoward events including recurrence of neuromuscular blockade.

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 medicines used in the peri- and postoperative period could depress respiratory function and therefore ventilatory support might still be required. Should neuromuscular blockade reoccur following extubation, adequate ventilation should be provided.

Recurrence of neuromuscular blockade: In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex was administered using a dose labelled for the depth of neuromuscular blockade, an incidence of 0,20 % was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring 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 and section 4.8).

Effect on haemostasis: In a study done in volunteers, doses of 4 mg/kg and 16 mg/kg of sugammadex resulted in maximum mean prolongations of the activated partial thromboplastin time (aPTT) and prothrombin time international normalized ratio [PT(INR)]. These limited mean aPTT and PT(INR) prolongations were of short duration (u2264 30 minutes). Based on the clinical findings and on a specific study done in patients undergoing hip fracture/major joint replacement surgery there was no clinically relevant effect of sugammadex 4 mg/kg alone or in combination with anticoagulants on the incidence of peri- or post-operative bleeding complications.

In in vitro experiments a pharmacodynamic interaction (aPTT and PT prolongation) was noted with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. In patients receiving routine post-operative prophylactic anticoagulation this pharmacodynamic interaction is not clinically relevant. Caution should be exercised when considering the use of MYLADION 100 mg/mL in patients receiving therapeutic anticoagulation for a pre-existing or co-morbid condition. An increased risk of bleeding cannot be excluded in patients:

• with hereditary vitamin K dependent clotting factor deficiencies;
• with pre-existing coagulopathies;
• on coumarin derivates and at an INR above 3,5;
• using anticoagulants who receive a dose of 16 mg/kg sugammadex.

If there is a medical need to give MYLADION 100 mg/mL to these patients the anaesthesiologist needs to decide if the benefits outweigh the possible risk of bleeding complications taking into consideration the patients history of bleeding episodes and type of surgery scheduled. If MYLADION 100 mg/mL is administered to these patients monitoring of haemostasis and coagulation parameters is recommended.

Waiting times for re-administration with neuromuscular blocking medicines (NMBA) after reversal with MYLADION 100 mg/mL: Re-administration of rocuronium or vecuronium after routine reversal (up to 4 mg/kg sugammadex): Minimum waiting time NMBA and dose to be administered 5 minutes 1,2 mg/kg rocuronium 4 hours 0,6 mg/kg rocuronium or 0,1 mg/kg vecuronium. The onset of neuromuscular blockade may be prolonged up to approximately 4 minutes, and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes after re-administration of rocuronium 1,2 mg/kg within 30 minutes after MYLADION 100 mg/mL administration. 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 MYLADION 100 mg/mL 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): A waiting time of 24 hours is recommended. If neuromuscular blockade is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking medicine should be used. The onset of a depolarizing neuromuscular blocking medicine might be slower than expected, because a substantial fraction of postjunctional nicotinic receptors can still be occupied by the neuromuscular blocking medicine.

Renal impairment: MYLADION 100 mg/mL is not recommended for use in patients with severe renal impairment, creatinine clearance < 30 mL/min, including those requiring dialysis (see section 5.1). Because of the estimated prolonged half-life of sugammadex in severe renally impaired patients, a full neuromuscular blockade may not be achieved after re-use of 0,6 mg/kg rocuronium or 0,1 mg/kg vecuronium within 24 hours after sugammadex reversal.

Light anaesthesia: When neuromuscular blockade was reversed intentionally in the middle of anaesthesia in clinical trials, signs of light anaesthesia were noted occasionally (movement, coughing, grimacing and suckling of the tracheal tube). If neuromuscular blockade is reversed, while anaesthesia is continued, additional doses of anaesthetic and/or opioid should be given as clinically indicated.

Marked bradycardia: Marked bradycardia has been observed within minutes after the administration of MYLADION 100 mg/mL for reversal of neuromuscular blockade. Cases of bradycardia with cardiac arrest have been reported. (See section 4.8.) Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anti-cholinergic medicines such as atropine should be administered if clinically significant bradycardia is observed.

Hepatic impairment: MYLADION 100 mg/mL is not metabolised nor excreted by the liver; therefore dedicated studies in patients with hepatic impairment have not been conducted. Patients with severe hepatic impairment should be treated with great caution. In case hepatic impairment is accompanied by coagulopathy, see the information on the Effect on haemostasis above.

Use in Intensive Care Unit (ICU): MYLADION 100 mg/mL has not been investigated in patients receiving rocuronium or vecuronium in the ICU setting.

Use for reversal of neuromuscular blocking medicines other than rocuronium or vecuronium: MYLADION 100 mg/mL should not be used to reverse block induced by nonsteroidal neuromuscular blocking medicines such as succinylcholine or benzylisoquinolinium compounds. MYLADION 100 mg/mL should not be used for reversal of neuromuscular blockade induced by steroidal neuromuscular blocking medicines other than rocuronium or vecuronium, since there are no efficacy and safety data for these situations. Limited data are available for reversal of pancuronium induced blockade, but it is advised not to use MYLADION 100 mg/mL in this situation.

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

Hypersensitivity reactions: Medical practitioners attending the patient should be prepared for the possibility of medicine hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions (see section 4.8).

Patients on a controlled sodium diet: Each mL solution contains up to 9,7 mg sodium. A dose of 23 mg sodium is considered essentially 'sodium-free'. If more than 2,4 mL solution needs to be administered, this should be taken into consideration by patients on a controlled sodium diet.

The information in this section is based on binding affinity between MYLADION 100 mg/mL and other medicines, non-clinical experiments, clinical studies and simulations using a model taking into account the pharmacodynamic effect of neuromuscular blocking medicines and the pharmacokinetic interaction between neuromuscular blocking medicines and sugammadex. Based on these data, no clinically significant pharmacodynamic interaction with other medicines is expected, with exception of the following:

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

Interactions potentially affecting the efficacy of MYLADION 100 mg/mL (displacement interactions): Due to the administration of certain medicines after sugammadex, like rocuronium or vecuronium, these could be displaced from MYLADION 100 mg/mL. As a result recurrence of neuromuscular blockade might be observed. In this situation the patient must be ventilated. Administration of the medicine 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 medicine occurring within a period of 7,5 hours after MYLADION 100 mg/mL 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 MYLADION 100 mg/mL could occur. Medical practitioners attending the patient should be aware that 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 cause some delay in the recovery of the T4/T1 ratio to 0,9. No recurrence of neuromuscular blockade is expected in the post-operative phase, since the infusion rate of fusidic acid is over a period of several hours and the blood levels are cumulative over 2-3 days. For re-administration of MYLADION 100 mg/mL see section 4.2.

Interactions potentially affecting the efficacy of other medicine (capturing interactions): Administration of MYLADION 100 mg/mL, could render certain medicines to become less effective due to a lowering of the (free) plasma concentrations. If such a situation is observed, the medical practitioner is advised to consider the re-administration of the medicine, the administration of a therapeutically equivalent medicine (preferably from a different chemical class) and/or non-pharmacological interventions as appropriate.

Hormonal contraceptives: The interaction between 4 mg/kg sugammadex and a progestogen was predicted to lead to a decrease in progestogen exposure (34 % of AUC) similar to the decrease seen when a daily dose of an oral contraceptive is taken 12 hours too late, which might lead to a reduction in effectiveness. For oestrogens, the effect is expected to be lower. Therefore the administration of a bolus dose of MYLADION 100 mg/mL is considered to be equivalent to one missed daily dose of oral contraceptive steroids (either combined or progestogen only). If MYLADION 100 mg/mL is administered at the same day as an oral contraceptive is taken reference is made to missed dose advice in the package leaflet of the oral contraceptive. In the case of non-oral hormonal contraceptives, the patient must use an additional non hormonal contraceptive method for the next 7 days and refer to the advice in the package leaflet of the product.

Interactions due to the lasting effect of rocuronium or vecuronium: Special attention should be paid to the possibility of recurrence of neuromuscular blockade when medicines which potentiate neuromuscular blockade are used in the post-operative period [the package leaflet of rocuronium or vecuronium will have a list of the specific medicines which potentiate neuromuscular blockade]. In the case of recurrence of neuromuscular blockade, the patient may require mechanical ventilation and re-administration of MYLADION 100 mg/mL (see section 4.2).

Interference with laboratory tests: In general MYLADION 100 mg/mL does not interfere with laboratory tests, with the possible exception of the serum progesterone assay. Interference with this test is observed at sugammadex plasma concentrations of 100 microgram/mL (peak plasma level following 8 mg/kg bolus injection). In a study in volunteers doses of 4 mg/kg and 16 mg/kg of sugammadex resulted in maximum mean prolongations of aPTT by 17 and 22 % respectively and of PT(INR) by 11 and 22 % respectively. These limited mean aPTT and PT(INR) prolongations were of short duration (u2264 30 minutes). In in vitro experiments a pharmacodynamic interaction (aPTT and PT prolongation) was noted with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran (see section 4.4). Paediatric population No formal interaction studies have been performed. The above-mentioned interactions for adults and the warnings in section 4.4 should also be taken into account for the paediatric population.

Pregnancy The safety in pregnant women has not been established. Caution should be exercised when administering MYLADION 100 mg/mL to pregnant women.

Lactation It is unknown whether MYLADION 100 mg/mL is excreted in human breast milk. Animal studies have shown excretion of sugammadex in breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from MYLADION 100 mg/mL therapy.

Fertility The effects with MYLADION 100 mg/mL on human fertility have not been investigated. Animal studies to evaluate fertility do not reveal harmful effects.

MYLADION 100 mg/mL has no known influence on the ability to drive and use machines.

a. Summary of the safety profile MYLADION 100 mg/mL is administered concomitantly with neuromuscular blocking medicines and anaesthetics in surgical patients. The causality of adverse events is therefore difficult to assess. The most frequently reported adverse reactions in surgical patients were cough, airway complication of anaesthesia, anaesthetic complications, procedural hypotension and procedural complication.

b. Tabulated summary of adverse reactions MedDRA system organ class Frequency Adverse reactions Immune system disorders Less frequent Hypersensitivity reactions (see section 4.4) Nervous system disorders Frequent Dysgeusia Respiratory, thoracic and mediastinal disorders Frequent Cough Injury, poisoning and procedural complications Frequent Airway complication of anaesthesia Anaesthetic complication (see section 4.4) Procedural hypotension Procedural complication

c. Description of selected adverse reactions Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers. In clinical trials of surgical patients these reactions were reported uncommonly and for post-marketing reports the frequency is unknown. These reactions varied from isolated skin reactions to serious systemic reactions (i.e. anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to sugammadex. Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, swelling of tongue, swelling of pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal.

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 anaesthetic procedure-related spontaneous breath of patient.

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

Procedural Complication: Procedural complications included coughing, tachycardia, bradycardia, movement, and increase in heart rate.

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).

Recurrence of neuromuscular blockade: In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex was administered using a dose labelled for the depth of neuromuscular blockade (N=2,022), an incidence of 0,20 % was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence (see section 4.4).

Additional information on special populations Pulmonary patients: In post-marketing data and in one dedicated clinical trial in patients with a history of pulmonary complications, bronchospasm was reported as a possibly related adverse event. The medical practitioner should be aware of the possible occurrence of bronchospasm in patients with a history of pulmonary complications.

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 of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Based on clinical studies conducted, 1 case of an accidental overdose with 40 mg/kg was reported without any significant adverse reactions. In a human tolerance study conducted, sugammadex was administered in doses up to 96 mg/kg. No dose related adverse events nor serious adverse events were reported. MYLADION 100 mg/mL can be removed using haemodialysis with a high flux filter, but not with a low flux filter. Based upon clinical studies, sugammadex concentrations in plasma are reduced by up to 70 % after a 3 to 6-hour dialysis session.