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Bridion®: The First Selective Relaxant Binding Agent for Reversal of Neuromuscular Blockade

Thursday, April 27, 2017  
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Student Submission: Bridion®: The First Selective Relaxant Binding Agent for Reversal of Neuromuscular Blockade
Author: Dorela Priftanji, PharmD Candidate 2017
Faculty Advisor: Nicole Schroeder, PharmD, BCPS, BCCCP Assistant Prof. Clinical Pharmacy

Bridion® (sugammadex)‎ is the first selective relaxant binding agent approved by the U.S. Food and Drug Administration (FDA) in December 2015 for reversal of neuromuscular blockade produced by rocuronium bromide and vecuronium bromide.1-2 The agent is marketed by Merck and Company Inc. based in New Jersey. Neuromuscular blocking agents induce temporary paralysis in patients undergoing surgery who require tracheal intubation or general anesthesia to minimize involuntary movements.3 Sugammadex offers an antidote for faster recovery and restoration of spontaneous breathing in patients requiring neuromuscular blockade in order to avoid residual paralysis. Advantages over the current standard of care (i.e. acetylcholinesterase inhibitor neostigmine) include rapid reversal at any depth of blockade and avoidance of cholinergic adverse effects. 1-2

Sugammadex is a modified gamma cyclodextrin supplied as an injection solution for intravenous use. The drug encapsulates rocuronium or vecuronium in plasma, limiting the amount of free neuromuscular-blocking agent in the neuromuscular junction and preventing its binding on nicotinic receptors to restore muscle function. Pharmacokinetic and pharmacodynamic properties of sugammadex are reported in table 1. 2

The timing and dosing of sugammadex administration rely on twitch responses and monitoring of spontaneous recovery. Recommended sugammadex dosing is dependent on the depth of blockade and can range from 2-4 mg/kg as a single bolus dose via IV push over 10 seconds (table 2). Specifically for immediate reversal of rocuronium-induced blockage, a single 16 mg/kg dose can be administered three minutes after 1.2 mg/kg rocuronium has been delivered. Variable waiting times (5 minutes - 24 hours) must be considered for readministration of rocuronium or vecuronium following sugammadex administration (table 3). A nonsteroidal neuromuscular-blocking agent may be used if instant neuromuscular blockade is required. Clinically significant drug interactions due to binding alterations are expected when sugammadex is used in conjunction with toremifene or hormonal contraceptives.2

The most common adverse reactions reported with sugammadex are hypotension, headache, nausea, vomiting, and pain at injection site. Serious adverse effects include QT interval prolongation, anaphylaxis, and marked bradycardia, some of which have resulted in cardiac arrest, thereby requiring hemodynamic monitoring for patients receiving sugammadex. 1-2 Ventilatory support is obligatory for patients receiving sugammadex until sufficient spontaneous respiration is reestablished. The agent is also associated with a rise in coagulation parameters, including aPTT, PT, and INR, which should be monitored in patients receiving therapeutic anticoagulation or thromboprophylaxis. Sugammadex is contraindicated in patients with known hypersensitivity to the medication or any of its components. Safety and efficacy of sugammadex have not been established in pediatric patients or pregnancy and use is not recommended in the setting of severe renal impairment (CrCl <30 mL/min). 2

The safety and efficacy of sugammadex were evaluated in three Phase 3 clinical trials, which reported a faster return to recovery for patients in the sugammadex treatment groups (table 4). 2,4-6

Table 1: Pharmacokinetic and pharmacodynamic properties 

 Onset of action  < 3 minutes 
 t½ elimination Normal: 2 hours 
Retained in sites of mineralization: Bone: 172 days; Teeth: 8 days 
 Volume of distribution  11-14 L
 Metabolism  No hepatic metabolism
 Plasma clearance  88 mL/min 
 Excretion

 Renal elimination (96%)

 

Table 2: Dosing recommendations  

 Sugammadex dose (IV)* Clinical condition: twitch response/ spontaneous recovery following rocuronium or vecuronium induced neuromuscular blockade
 4 mg/kg  Spontaneous recovery of twitch response reached 1-2 PTC
No twitch responses to TOF stimulation 
 2 mg/kg Spontaneous recovery reached reappearance of the T2 
In response to TOF stimulation
 16 mg/kg   Clinical need to reverse neuromuscular blockade 3 minutes after administration of a single dose of 1.2 mg/kg of rocuronium^

 

PTC: post-tetanic counts; TOF: train-of-four; T2: second twitch
*Sugammadex dosing is based on actual body weight  
^For rocuronium only; Efficacy of 16 mg/kg sugammadex following vecuronium has not been studied

Table 3: Waiting times for readministration of neuromuscular blockade after sugammadex delivery 

Minimum Waiting Time Neuromuscular blocking agent and dose to be administered
 5 minutes 1.2 mg/kg rocuronium
 4 hours Normal renal: 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium
 24 hours Mild or moderate renal impairment: 
0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium
 Rocuronium or vecuronium after reversal of rocuronium with 16 mg/kg sugammadex
 

Table 4: Controlled trials summary 

   Comparative Study of Bridion vs. Neostigmine at Reappearance of T2 (Moderate Blockade) 4 Comparative Study of Bridion vs. Neostigmine at 1 to 2 PTCs 
(Deep Blockade) 5
Reversal of Neuromuscular Blockade 3 Minutes after Rocuronium 1.2 mg/kg 6 
Design   Randomized, parallel, active-controlled, safety-assessor blinded study; 198 patients  Randomized, parallel, active-controlled, safety-assessor blinded study; 157 patients Randomized, parallel-group, active-controlled, safety-assessor blinded study; 110 patients 
 Arms  2 mg/kg Bridion 
vs.
50 mcg/kg neostigmine
 4 mg/kg Bridion

vs.

70 mcg/kg neostigmine
Bridion 16 mg/kg for reversal of rocuronium 1.2 mg/kg vs. 
spontaneous recovery from succinylcholine 1 mg/kg
 Results Return of the T4/T1 ratio to 0.9 after reappearance of T2 was faster with Bridion compared to neostigmine Return of T4/T1 ratio to 0.9 with Bridion had wider range of recovery, but faster compared to neostigmine Recovery to T1 of 10% of baseline faster in rocuronium/Bridion group compared with succinylcholine alone

 

References
1. U.S. Food and Drug Administration. FDA approves Bridion to reverse effects of neuromuscular blocking drugs used during surgery. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477512.htm Accessed August 28, 2016. 
2. Bridion (sugammadex) [prescribing information]. Whitehouse Station, NJ; Merck & Co, Inc: December 2015.
3. Donati F. Sugammadex: a cyclodextrin to reverse neuromuscular blockade in anesthesia. Expert Opin Pharmacother. 2008;9(8):1375-1386. 
4. Blobner M, et al. Bridion vs. neostigmine reversal agent for NMB induced by rocuronium or vecuronium at reappearance of T2 (Moderate Blockade). Eur J Anaesthesiol. 2010;27:874-881. 
5. Jones, et al. Comparative Study of BRIDION versus Neostigmine as a Reversal Agent for Neuromuscular Blockade Induced by Rocuronium or Vecuronium at 1 to 2 PTCs (Deep Blockade). Anesthesiology. 2008;109:816-824. 
6. Lee, et al. Reversal of Neuromuscular Blockade 3 Minutes after Rocuronium 1.2 mg/kg. Anesthesiology. 2009;110:1020-1025.

 

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