Revergam 200 Mg/2 Ml/500 Mg Solution

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

Posology: REVERGAM should be administered under the supervision of an anaesthetist. 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 REVERGAM, patients should be monitored for signs of recurrence of neuromuscular blockade. The recommended dose of REVERGAM depends on the level of neuromuscular blockade to be reversed. The recommended dose does not depend on the anaesthetic regimen. REVERGAM 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 REVERGAM is recommended if recovery has reached at least 1 u2013 2 post- tetanic counts (PTC) following rocuronium or vecuronium induced blockade (see section 4.4). A dose of 2 mg/kg REVERGAM 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 REVERGAM is recommended. There is no data to recommend the use of REVERGAM for immediate reversal following vecuronium induced blockade.

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

Elderly patients After administration of REVERGAM 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 patients 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 REVERGAM 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 REVERGAM 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 REVERGAM 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. There is insufficient information on the use of REVERGAM for children < 7 years of age. There is no information on REVERGAM use for neonates. Therefore REVERGAM is not recommended for use in these populations. Children and adolescents For routine reversal of rocuronium induced blockade at reappearance of T2 in children and adolescents (7 to 17 years) 2 mg/kg REVERGAM is recommended. Immediate reversal in children and adolescents has not been investigated and is therefore not recommended. REVERGAM 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: REVERGAM 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. For information on compatibility of REVERGAM with infusion solutions, see section 6.6.

Hypersensitivity to sugammadex sodium or to any of the components of REVERGAM (see section 6.1).

REVERGAM is not to be used to reverse depolarising neuromuscular blocking medicines. Wating times for re-administration with neuromuscular blocking medicines (NMBM) after reversal with REVERGAM Re-administration of rocuronium or vecuronium after a recommended dose reversal (up to 4 mg/kg of REVERGAM): Minimum waiting time NMBM 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 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 REVERGAM 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 REVERGAM): A waiting time of 24 hours is recommended. If neuromuscular blockade is required before the recommended waiting time has passed, a non-steroidal neuromuscular blocking medicine should be used. The onset of a depolarising neuromuscular blocking medicine might be slower than expected, because a substantial fraction of post-junctional nicotinic receptors may still be occupied by the neuromuscular blocking medicine.

Medicine hypersensitivity Medical practitioners should be prepared for the possibility of medicine hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions.

Renal impairment REVERGAM is not recommended for use in patients with severe renal impairment, creatinine clearance < 30 mL/min, including patients requiring dialysis (see section 5.2). 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 REVERGAM reversal.

Marked bradycardia Marked bradycardia has been observed within minutes after the administration of REVERGAM for reversal of neuromuscular blockade. Cases of bradycardia with cardiac arrest have been reported (see section 4.8). Patients should be closely monitored for haemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic medicines such as atropine should be administered if clinically significant bradycardia is observed.

Monitoring respiratory function during recovery Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored following reversal of neuromuscular block. Even if recovery from neuromuscular blockade is complete, other medicines used in the peri- and post-operative period could depress respiratory function and therefore ventilatory support might still be required. Should neuromuscular blockade re-occur following extubation, adequate ventilation should be provided.

Effect on haemostasis In in-vitro experiments additional aPTT and PT prolongation was noted for REVERGAM in combination with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. In a study in volunteers, doses of 4 mg/kg and 16 mg/kg of REVERGAM 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). There was no clinically relevant effect of REVERGAM alone or in combination with anticoagulants on the incidence of peri- or post-operative bleeding complications. Since there is no information on the use of REVERGAM in patients with known coagulopathies, coagulation parameters should be carefully monitored according to routine clinical practice.

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 patients), or oedematous state (e.g. severe hepatic impairment) may be associated with longer recovery times.

Hepatic impairment REVERGAM is not metabolised nor excreted by the liver; therefore dedicated studies in patients with hepatic impairment have not been conducted. Hepatic impairment may be accompanied by coagulopathy (see the information on the Effect on haemostasis above).

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 sucking 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.

Use in intensive care unit REVERGAM 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 REVERGAM should not be used to reverse block induced by non-steroidal neuromuscular blocking medicines such as succinylcholine or benzylisoquinolinium compounds. REVERGAM should not be used for reversal of neuromuscular blockage 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 blockage, but it is advised not to use REVERGAM in this situation.

The information reported in this section is based on binding affinity between REVERGAM and other medicines, non-clinical experiments, clinical studies and simulations using a model taking into account the pharmacodynamic effect of neuromuscular blocking medicines and REVERGAM. Based on these data, no clinically significant pharmacodynamic interaction with other medicines are expected, with the exception of toremifene, fusidic acid and hormonal contraceptives. For these medicines, a clinically relevant interaction could not be excluded. No clinically relevant interactions were reported during the clinical development. Due to the administration of certain medicines after sugammadex, theoretically rocuronium or vecuronium could be displaced from REVERGAM. As a result, recurrence of neuromuscular blockade might be observed. In this situation the patient must be ventilated. Administration of medicines 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 re-occurrence of blockade (approximately up to 15 minutes), after parenteral administration of another medicine occurring within a period of 7,5 hours after REVERGAM administration.

REVERGAM should be used cautiously when co-administered with: Toremifene For toremifene, which has a relatively high affinity constant and relatively high plasma concentrations, some displacement of vecuronium or rocuronium from the complex with REVERGAM could occur. The recovery of the train of four ratio, T4/T1, to 0,9 could therefore be delayed in patients who have received toremifene on the same day of surgery (see section 4.4). 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 to 3 days. Hormonal contraceptives In a simulation performed with a PK-PD model, it was found that the interaction between 4 mg/kg REVERGAM and a progestogen could lead to a decrease in progestogen exposure (34 % of AUC) similar to the decrease seen when a daily dose of an oral contraceptive is taken 12 hours too late, which might lead to a reduction in effectiveness. Therefore, the administration of a bolus dose of REVERGAM is considered to be equivalent to one missed daily dose of oral contraceptive steroids. Please refer to the missed dose advice in the package insert of the oral contraceptive, for any action required if an oral contraceptive is taken on the same day that REVERGAM is administered. In the case of non-oral hormonal contraceptives, the patient must use an additional non-hormonal contraceptive method for the next 7 days. Interactions due to the lasting effect of rocuronium or vecuronium When medicines 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 refer to the professional information of rocuronium or vecuronium for a list of the specific medicines which potentiate neuromuscular blockade. In case recurrence of neuromuscular blockade is observed, the patient may require mechanical ventilation and re-administration of REVERGAM. Interference with laboratory tests REVERGAM has been shown to interfere with the serum progesterone assay. This interference was observed in plasma samples spiked with a concentration of REVERGAM in the same range as obtained for Cmax after a dose of 16 mg/kg. Paediatric population No formal interaction studies have been performed. The above-mentioned interactions for adults and the warnings should also be taken into account for the paediatric population.

Pregnancy: The safety of REVERGAM in pregnant women has not been established. Breastfeeding: Excretion of REVERGAM in human milk has not been studied, but can be expected based on pre-clinical data. Fertility: The effects of REVERGAM on human fertility has not been investigated. Animal studies to evaluate fertility do not reveal harmful effects.

REVERGAM has no influence on the ability to drive and use machines.

Tabulated list of adverse reactions: Immune system disorders Less frequent: Medicine hypersensitivity reactions Nervous system disorders Frequent: Dysgeusia Respiratory, thoracic and mediastinal disorders Frequent Cough Injury, poisoning and procedural complications: Frequent (with sub-optimal doses): Prolonged neuromuscular blockade, procedural hypotension, procedural complication Less frequent: Anaesthetic complication

Description of selected adverse reactions: Anaesthetic complications Anaesthetic complications, indicative of the restoration of neuromuscular function, including movement of a limb or the body or coughing during the anaesthetic procedure or during surgery, grimacing, or sucking on the endotracheal tube, were judged to be related to treatment in about 1 % of the patients and in none of the placebo group. Most occurrences of anaesthetic complications were mild to moderate. Recurrence of neuromuscular blockade In the database of pooled phase I to III studies with a placebo group, the incidence of recurrence of neuromuscular blockade as measured with neuromuscular monitoring was 2 % after REVERGAM and 0 % in the placebo group. Virtually all of these cases were from dose-finding studies in which a sub-optimal dose (< 2 mg/kg) was administered. In cases where recurrence of neuromuscular blockade is observed, the patient must be ventilated. Medicine hypersensitivity reactions Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers (for information on volunteers, see Information on healthy volunteers below). 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 REVERGAM. Symptoms associated with these reactions can include: Flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, swelling of the tongue, swelling of the pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal.

Information on healthy volunteers Hypersensitivity reactions, including anaphylaxis, have been observed with REVERGAM. In a study in healthy volunteers, hypersensitivity reactions were reported frequently with sugammadex 16 mg/kg and less frequently with sugammadex 4 mg/kg or placebo. In this study, dose dependent trends were also observed for dysgeusia, nausea and flushing. Marked bradycardia In post-marketing, cases of marked bradycardia and bradycardia with cardiac arrest have been observed within minutes after administration of sugammadex (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. Paediatric patients A limited database suggests that the safety profile of REVERGAM (up to 4 mg/kg) in paediatric patients above 7 years old, was similar to that in adults. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of REVERGAM is important. It allows continued monitoring of the benefit/risk balance of REVERGAM. Health care providers are asked to report any suspected adverse reactions via the u201cAdverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

REVERGAM can be removed using haemodialysis with a high-flux filter, but not with a low-flux filter. Based upon clinical studies, REVERGAM concentrations in plasma are reduced with a high-flux filter by about 70 % after a 3 to 6 hour dialysis session.