Sugammadex Teva 100 mg/mL

/ Teva Israel LTD, Israel

Sugammadex should only be administered by, or under the supervision of an anaesthetist.
The recommended dose of sugammadex depends on the level of neuromuscular blockade to be reversed. The recommended dose does not depend on the anaesthetic regimen. Sugammadex can be used to reverse different levels of rocuronium or vecuronium induced neuromuscular blockade.
See prescribing information for full details.

Reversal of neuromuscular blockade induced by rocuronium or vecuronium.

* Hypersensitivity to the active substance or to any of the excipients.
* Severe renal impairment (including patients requiring dialysis (CrCl < 30 ml/min).
* Severe hepatic impairment.

As is normal post-anaesthetic practice following neuromuscular blockade, it is recommended to monitor the patient in the immediate post-operative period for untoward events including recurrence of neuromuscular blockade.
Monitoring respiratory function during recovery
Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored following reversal of neuromuscular blockade. Even if recovery from neuromuscular blockade is complete, other medicinal products used in the peri- and post-operative 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.
Effect on haemostasis:
In a study in volunteers doses of 4 mg/kg and 16 mg/kg of sugammadex resulted in maximum mean prolongations of the activated partial thromboplastin time (aPTT) by 17 and 22% respectively and prothrombin time international normalised ratio [PT(INR)] by 11 and 22% respectively. These limited mean aPTT and PT(INR) prolongations were of short duration (≤ 30 minutes).Based on the clinical data-base (N=3,519) and on a specific study in 1184 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 sugammadex 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 sugammadex to these patients it’s needs to decide if the benefits outweigh the possible risk of bleeding complications taking in to consideration the patients history of bleeding episodes and type of surgery scheduled. If sugammadex is administered to these patients monitoring of haemostasis and coagulation parameters is recommended.
Waiting times for re-administration with neuromuscular blocking agents after reversal with sugammadex: After routine reversal with sugammadex (up to 4 mg/kg), rocuronium can be re-administered at 1.2 mg/kg after just 5 minutes, while a 4-hour waiting period is needed for lower doses of rocuronium (0.6 mg/kg) or vecuronium (0.1 mg/kg). When rocuronium is re-administered within 30 minutes of sugammadex, the onset may be delayed by up to 4 minutes and the duration shortened by up to 15 minutes. For patients with mild or moderate renal impairment, the recommended waiting time extends to 24 hours for lower doses of rocuronium or vecuronium, unless using the higher 1.2 mg/kg rocuronium dose. After immediate reversal with high-dose sugammadex (16 mg/kg), a 24-hour waiting period is suggested before re-administering any steroidal neuromuscular blocking agent. If neuromuscular blockade is needed before the recommended waiting time has elapsed, a non-steroidal neuromuscular blocking agent should be used instead. The onset of a depolarizing neuromuscular blocking agent might be slower than expected due to receptor occupation by the previous blocking agent.
Renal impairment: The use of sugammadex in patients with severe renal impairment is contraindicated and is not reccomended in patients requiring dialysis
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: In rare instances, marked bradycardia has been observed within minutes after the administration of sugammadex for reversal of neuromuscular blockade.Bradycardia may occasionally lead to cardiac arrest. Patients should be closely monitored for haemodynamic changes during and after reversal of neuromuscular blockade.Treatment with anti-cholinergic agents such as atropine should be administered if clinically significant bradycardia is observed.

Hepatic impairment: Sugammadex is not metabolised nor excreted by the liver; therefore, dedicated studies in patients with hepatic impairment have not been conducted. Patients with severe hepatic impairment should not be treated with Sugammadex.In case hepatic impairment is accompanied by coagulopathy see the information on the effect on haemostasis.

Use in Intensive Care Unit (ICU): Sugammadex has not been investigated in patients receiving rocuronium or vecuronium in the ICU setting.

Use for reversal of neuromuscular blocking agents other than rocuronium or vecuronium: Sugammadex should not be used to reverse block induced by nonsteroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds. Sugammadex should not be used for reversal of neuromuscular blockade induced by steroidal neuromuscular blocking agents other than rocuronium or vecuronium, since there are no efficacy and safety data for these situations. Limited data are available for reversal of pancuronium induced blockade, but it is advised not to use sugammadex in this situation.
Delayed recovery: Conditions associated with prolonged circulation time such as cardiovascular disease, old age, or oedematous state (e.g., severe hepatic impairment) may be associated with longer recovery times.
See prescribing information for full details.

Common: Cough, airway complication of anaesthesia, anaesthetic complication, procedural hypotension, procedural complication.

The information in this section is based on binding affinity between sugammadex and other medicinal products, non-clinical experiments, clinical studies and simulations using a model taking in to account the pharmacodynamic effect of neuromuscular blocking agents and the pharmacokinetic interaction between neuromuscular blocking agents and sugammadex. Based on these data, no clinically significant pharmacodynamic interaction with other medicinal products is expected, with exception of the following:
* For toremifene and fusidic acid displacement interactions could not be excluded (no clinically relevant capturing interactions are expected).
* For hormonal contraceptives a clinically relevant capturing interaction could not be excluded (no displacement interactions are expected).
Interactions potentially affecting the efficacy of sugammadex (displacement interactions): Due to the administration of certain medicinal products after sugammadex, theoretically rocuronium or vecuronium could be displaced from sugammadex. As a result recurrence of neuromuscular blockade might be observed. In this situation the patient must be ventilated. Administration of the medicinal product which caused displacement should be stopped in case of an infusion.
In situations when potential displacement interactions can be anticipated, patients should be carefully monitored for signs of recurrence of neuromuscular blockade (approximately upto 15 minutes) after parenteral administration of another medicinal product occurring within a period of 7.5 hours after sugammadex administration. Toremifene: For toremifene, which has a relatively high binding affinity for sugammadex and for which relatively high plasma concentrations might be present, some displacement of vecuronium or rocuronium from the complex with sugammadex could occur. Clinicians 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 give some delay in the recovery of the T4/T1 ratio to 0.9. No recurrence of neuromuscular blockade is expected in the post-operative phase, since the infusion rate of fusidic acid is over a period of several hours and the blood levels are cumulative over 2-3 days.
Interactions potentially affecting the efficacy of other medicinal products (capturing interactions): Due to the administration of sugammadex, certain medicinal products could become less effective due to a lowering of the (free) plasma concentrations. If such a situation is observed, the clinician is advised to consider the re-administration of the medicinal product, the administration of a therapeutically equivalent medicinal product (preferably from a different chemical class) and/or non-pharmacological interventions as appropriate.
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 sugammadex is considered to be equivalent to one missed daily dose of oral contraceptive steroids (either combined or progestogen only). If sugammadex is administered at the same day as an oral contraceptive is taken reference is made to missed dose advice in the package leaflet of the oral contraceptive. In the case of non-oral hormonal contraceptives, the patient must use an additional non hormonal contraceptive method for the next 7 days and refer to the advice in the package leaflet of the product.
Interactions due to the lasting effect of rocuronium or vecuronium: When medicinal products which potentiate neuromuscular blockade are used in the post- operative period special attention should be paid to the possibility of recurrence of neuromuscular blockade. Please referto the package leaflet of rocuronium or vecuronium for a list of the specific medicinal products which potentiate neuromuscular blockade. In case recurrence of neuromuscular blockade is observed, the patient may require mechanical ventilation and re-administration of sugammadex.
Interference with laboratory tests: In general, sugammadex does not interfere with laboratory tests, with the possible exception of the serum progesterone assay. Interference with this test is observed at sugammadex plasma concentrations of 100 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 (≤ 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.

Pregnancy: For sugammadex no clinical data on exposed pregnancies are available. Caution should be exercised when administering sugammadex to pregnant women.
Lactation: It is unknown whether sugammadex is excreted in human breast milk. Oral absorption of cyclodextrins in general is low and no effect on the suckling child is anticipated following a single dose to the breast- feeding woman.A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from sugammadex therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

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