5.1 Anaphylaxis and Hypersensitivity
Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions [see Contraindications (4), Adverse Reactions (6.1)].
Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with BRIDION. The nature and frequency of anaphylaxis and hypersensitivity associated with BRIDION administration were eva luated in a randomized, double-blind, placebo-controlled, parallel-group, repeat-dose study in which 375 subjects were randomized to receive 3 doses of BRIDION IV with a 5 week washout period: 151 subjects received 4 mg/kg, 148 received 16 mg/kg and 76 received placebo. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous BRIDION was 0.3% (n=1 in the BRIDION 16 mg/kg group on the first dose). Signs and symptoms included conjunctival edema, urticaria, erythema, swelling of the uvula and reduction in peak expiratory flow within 5 minutes of dose administration. The most common hypersensitivity adverse reactions reported were nausea, pruritus and urticaria and showed a dose response relationship, occurring more frequently in the 16 mg/kg group compared to the 4 mg/kg and placebo groups.
Anaphylaxis has also been reported in the post-marketing setting, including at doses less than 16 mg/kg. The most commonly described clinical features in reports of anaphylaxis were dermatologic symptoms (including urticaria, rash, erythema, flushing and skin eruption); and clinically important hypotension often requiring the use of vasopressors for circulatory support. In addition prolonged hospitalization and/or the use of additional respiratory support until full recovery (re-intubation, prolonged intubation, manual or mechanical ventilation) have been noted in a number of the anaphylaxis reports.
5.2 Marked Bradycardia
Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of BRIDION [see Adverse Reactions (6.2)]. Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents, such as atropine, should be administered if clinically significant bradycardia is observed.
5.3 Respiratory Function Monitoring During Recovery
Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Even if recovery from neuromuscular blockade is complete, other drugs used in the peri- and post-operative period could depress respiratory function and therefore ventilatory support might still be required.
Should neuromuscular blockade persist after BRIDION administration or recur following extubation, take appropriate steps to provide adequate ventilation.
5.4 Risk of Prolonged Neuromuscular Blockade
In clinical trials, a small number of patients experienced a delayed or minimal response to the administration of BRIDION [see Clinical Studies (14.1)]. Thus, it is important to monitor ventilation until recovery occurs.
5.5 Waiting Times for Re-Administration of Neuromuscular Blocking Agents for Intubation Following Reversal with BRIDION
A minimum waiting time is necessary before administration of a steroidal neuromuscular blocking agent after administration of BRIDION.
When rocuronium 1.2 mg/kg is administered within 30 minutes after reversal with BRIDION, the onset of neuromuscular blockade may be delayed up to approximately 4 minutes and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes.
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 reversal with up to 4 mg/kg BRIDION 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.
For re-administration of rocuronium or administration of vecuronium after reversal of rocuronium with 16 mg/kg BRIDION, a waiting time of 24 hours is suggested.
If neuromuscular blockade is required before the recommended waiting time has elapsed, use a nonsteroidal neuromuscular blocking agent. The onset of a depolarizing neuromuscular blocking agent might be slower than expected, because a substantial fraction of postjunctional nicotinic receptors can still be occupied by the neuromuscular blocking agent.
5.6 Interactions Potentially Affecting the Efficacy of Other Drugs
Due to the administration of BRIDION, certain drugs, including hormonal contraceptives, could become less effective due to a lowering of the (free) plasma concentrations. In this situation, consider the re-administration of the other drug, the administration of a therapeutically equivalent drug (preferably from a different chemical class), and/or non-pharmacological interventions as appropriate [see Drug Interactions (7.3)].
5.7 Risk of Recurrence of Neuromuscular Blockade Due to Displacement Interactions
Recurrence of neuromuscular blockade may occur due to displacement of rocuronium or vecuronium from BRIDION by other drugs [see Drug Interactions (7.2)]. In this situation the patient may require mechanical ventilation. Administration of the drug which caused displacement should be stopped in case of an infusion. The risk of displacement reactions will be the highest in the time period equivalent to 3 times the half-life of BRIDION [see Clinical Pharmacology (12.3)].
5.8 Risk of Recurrence of Neuromuscular Blockade with Lower Than Recommended Dosing
The use of lower than recommended doses of BRIDION may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended [see Dosage and Administration (2.1), Adverse Reactions (6.1)].
5.9 Risk of Recurrence of Neuromuscular Blockade Due to the Administration of Drugs that Potentiate Neuromuscular Blockade
When drugs which potentiate neuromuscular blockade are used in the post-operative phase, special attention should be paid to the possibility of recurrence of neuromuscular blockade. Refer to the package insert for rocuronium or vecuronium for a list of the specific drugs which potentiate neuromuscular blockade. In case recurrence of neuromuscular blockade is observed, the patient may require mechanical ventilation.
5.10 Risk of Coagulopathy and Bleeding
BRIDION doses up to 16 mg/kg were associated with increases in the coagulation parameters activated partial thromboplastin time (aPTT) and prothrombin time/international normalized ratio [PT(INR)] of up to 25% for up to 1 hour in healthy volunteers.
In patients undergoing major orthopedic surgery of the lower extremity who were concomitantly treated with heparin or low molecular weight heparin for thromboprophylaxis, increases in aPTT and PT(INR) of 5.5% and 3.0%, respectively, were observed in the hour following BRIDION 4 mg/kg administration. This clinical trial did not demonstrate an increased blood loss or anemia incidence with BRIDION compared with usual treatment. The rate of adjudicated bleeding events within 24 hours was 2.9% for sugammadex and 4.1% for usual care. The rate of post-operative anemia was 21% for sugammadex and 22% for usual care. The mean 24-hour drainage volume was 0.46 L for sugammadex and 0.48 L for usual care. The need for any post-operative transfusion was 37% for sugammadex and 39% for usual care.
In vitro experiments demonstrated additional aPTT and PT(INR) prolongations for sugammadex in combination with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban, and dabigatran up to ~25% and ~50% at Cmax levels of sugammadex corresponding to 4 mg/kg and 16 mg/kg doses, respectively.
Since bleeding risk has been studied systematically with only heparin and low molecular weight heparin thromboprophylaxis and 4 mg/kg doses of sugammadex coagulation parameters should be carefully monitored in patients with known coagulopathies, being treated with therapeutic anticoagulation, receiving thromboprophylaxis drugs other than heparin and low molecular weight heparin, or receiving thromboprophylaxis drugs and who then receive a dose of 16 mg/kg sugammadex.
5.11 Renal Impairment
BRIDION is not recommended for use in patients with severe renal impairment, including those requiring dialysis [see Use in Specific Populations (8.6)]. With regard to the recommended waiting time for re-administration in patients with mild or moderate renal impairment, see Waiting Times for Re-administration of Neuromuscular Blocking Agents for Intubation Following Reversal with BRIDION [see Warnings and Precautions (5.5)].
5.12 Light Anesthesia
When neuromuscular blockade was reversed intentionally in the middle of anesthesia in clinical trials, e.g., when investigating urgent reversal, signs of light anesthesia were noted occasionally (movement, coughing, grimacing and suckling of the tracheal tube).
5.13 Reversal after Rocuronium or Vecuronium Administration in the ICU
BRIDION has not been studied for reversal following rocuronium or vecuronium administration in the ICU.
5.14 Reversal of Neuromuscular Blocking Agents Other Than Rocuronium or Vecuronium
Do not use BRIDION to reverse blockade induced by nonsteroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds.
Do not use BRIDION to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents other than rocuronium or vecuronium.
