1. A Comprehensive Approach for Optimizing the Surgical & Clinical Outcomes
Ahmed Gomaa
Medical Advisor, Gulf-MSD

2. Neuromuscular Blockade Management2

3. The 3 Pillars of General Anesthesia
Analgesia
Facilitate intubation of the trachea
Provide a relaxed, immobile surgical field
Now before we continue, it is important to realize that we are talking about General Anesthesia today, the kind of anesthesia where you will be asleep during surgery. And generally, when we are talking about General Anesthesia, we talk about the three pillars of anesthesia. Hypnosis to make sure you are asleep, analgesia to make sure you do not have pain and finally muscle relaxation. There actually are two reasons for having muscle relaxation: The first reason is to relax the vocal cords and enable intubation to take place in order to protect the airway as soon as possible. The second reason is to completely paralyze the patient, in order for the surgeon to have optimal surgical conditions.
Hypnosis
Muscle Relaxation

4. Characteristics of Available of NMBAs
Neuromuscular Block Management
Characteristics of Available of NMBAs
DEPOLARISZING
DEPOLARISZING
Mimics acetylcholine causing prolonged depolarization of the post-junctional membrane
Rapid onset [ 30 – 60 secs] and Short duration [5 – 10 mins]
Broken down by plasma cholinesterase
Intubation, very short procedures
No known reversal agent
SUCCINYLCHOLINE [SUXAMETHONIUM)
NON-DEPOLARISZING
NON-DEPOLARISZING
Competitive antagonist at the post-junctional nicotinic receptor
Relatively quick onset [60 – 180 secs] and Medium – long duration [30 – 120 mins]
Intubation, procedures of all durations
All may be reversed at moderate levels of block using neostigmine
AMINOSTEROIDS
Undergo hepatic metabolism
ROCURONIUM, VECURONIUM, PANCURONIUM
BENZOISOQUINOLINES
Organ-independent elimination [Hoffman degradation]
ATRACURIUM, CIS-ATRACURIUM 4

5. NMB Monitoring

6. Clinical Tests Are Not a Substitute for Objective Monitoring
Neuromuscular Block Management
Clinical Tests Are Not a Substitute for Objective Monitoring
Key point:
Clinical tests are not a substitute for objective monitoring
Recent studies have investigated whether clinical tests are predictive of residual neuromuscular blockade (NMB), defined as a train-of-four (TOF) ratio of <0.9.1,2 In a study of 640 surgical patients, Cammu et al found that the residual NMB incidence was 38% in outpatients and 47% in inpatients.1 As shown in this bar graph, the clinical tests had little ability to predict residual paralysis.
In a study of 526 surgical patients conducted by Debaene et al, 45% had a TOF ratio <0.9 upon arrival at the postanesthesia care unit.2 The 5-second head lift test had a sensitivity of 11%, and the tongue depressor test had a sensitivity of 13%. The investigators concluded that the sensitivity of these clinical tests was too low in their ability to detect TOF <0.9 to recommend their use in the clinical setting.
References
1. Cammu G, De Witte J, De Veylder J et al. Postoperative residual paralysis in outpatients versus inpatients. Anesth Analg. 2006;102:
2. Debaene B, Plaud B, Dilly M-P et al. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology. 2003;98:
Cammu G, et al. Anesth Analg. 2006;102: 7 7

7. PNS

8. Neuromuscular Block Management
Objective Monitoring of Neuromuscular Blockade: Qualitative and Quantitative Techniques
Technique
Description
Comments
Visual assessment (qualitative)
Based on direct visual observation
Minor changes are difficult to determine
Tactile assessment (qualitative)
Anesthetist’s finger serves as force transducer
More accurate than visual assessment, less accurate than quantitative techniques
Mechanomyography (quantitative)
Measures mechanical force of muscle contraction
Most accurate, but equipment is bulky and difficult to set up and use
Electromyography (EMG) (quantitative)
Measures electrical activity of stimulated muscle
EMG signal can be compromised by external factors
Accelerometry (quantitative)
Measures acceleration of movement of stimulated muscle
Developed for routine clinical use in the operating room
Techniques used in the objective monitoring of neuromuscular blockade (NMB) are the qualitative assessment of visual and tactile responses by the anesthetist and three quantitative techniques: mechanomyography, electromyography, and acceleromyography.1,2 Visual and tactile assessments are the least accurate and reliable methods.2 Of the three quantitative techniques, mechanomyography is considered the gold standard method for assessing evoked responses.1 However, both mechanomyography and electromyography have practical limitations and are usually employed in research environments, whereas acceleromyography is generally used in clinical practice.1,2
Commercially produced acceleromyography devices are small, portable, and relatively easy to set up and use.1 Acceleration of the stimulated muscle is quantified using a small piezoelectric crystal embedded in a transducer. Some investigations have shown a good correlation between train-of-four (TOF) values obtained with acceleromyography and mechanomyography, although other studies suggest that acceleromyography may underestimate TOF ratios during recovery from NMB.
References
1. Murphy GS. Residual neuromuscular blockade: incidence, assessment, and relevance in the postoperative period. Minerva Anestesiol. 2006;72:
2. Pollard BJ. Neuromuscular monitoring. Current Anaesth Crit Care. 2004;15:
Murphy GS, et al. Minerva Anestesiol. 2006;72:
Pollard BJ. Curr Anaesth Crit Care. 2004;15: 9 9

9. TOF Watch Explain 0.9 is full recovery according current definitions.
Good set up, no bumping, no transferring to rooms
CIAC - EvdH

10. Assessing the Depth of Blockade
Neuromuscular Block Management
Assessing the Depth of Blockade
TOF Ratio Measurement
Four twitches delivered at 2 Hz
Post-tetanic Count [PTC] Measurement
50 Hz pulse for one second followed by 2 Hz stimulation
TOF Ratio
1.0 or 100%
TOF Ratio
0.25 or 25%
Tetanic Burst
2 PTC’s
Post-tetanic response
TOF response
This slide provides an explanation of the various depths of neuromuscular blockade.
Reference
1. Fuchs-Buder T, Claudius C, Skovgaard LT et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents. II: the Stockholm revision. Acta Anaesthesiol Scand. 2007;51:
Level of block
Intense block
Deep block
Moderate block
Response to TOF Stimulation
Twitch Count 0
Twitch Count 0
Twitch Count 1-3
Response to Tetanic Burst
PTC 0
PTC ≥1
Deeper Blockade 11 11 11 11

11. Spontaneous Recovery/Reversal
Requires passive redistribution and subsequent metabolism/excretion of NMBA
Clinician would have to minimize re-dosing of NMBA towards the end of the procedure
Allow blockade to wear off in time for extubation as soon as procedure is completed
Shallow or no blockade at the end of the procedure can result in:
Inadvertent reflexive patient movement (if not supplemented with increased hypnotic agent)
Suboptimal surgical and closure conditions
Extrusion of abdominal contents during closure
Inability to approximate wound for closure

12. Neuromuscular Block Management
Great Variability in Reversal After a Single Intubating Dose of Neuromuscular Blocking Agent
All patients (n = 526)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0 50
100
150
200
250
300
350
400
TOF Ratio
Time (min) 70
TOF <0.7 60
TOF <0.9 50 40
Patients (%) * * 30 20 * * 10
Key point:
Incidents of residual paralysis were seen as long as 2 hours after administration
Debaene et al studied the incidence of residual blockade after a single intubating dose of intermediate-duration nondepolarizing neuromuscular blocking agents. In this trial, train-of-four (TOF) ratios were measured at different time points. On the left, the results were plotted on a graph of TOF ratio versus time showing that among the 526 patients, 85 (16%) had a TOF ratio <0.7 and 237 (45%) had a TOF ratio <0.9 on arrival in the PACU. This trial found that the incidence of residual paralysis defined as TOF <0.9 was 45.0%, 41.6%, and 46.8% for rocuronium, atracurium, and vecuronium, respectively. Incidents of residual paralysis were seen as long as 2 hours after administration of the neuromuscular blocking agent.1 The graph to the right displays the percent of patients achieving either a TOF ratio of 0.7 or 0.9 in relationship to time. Collectively, these graphs clearly demonstrate the great inter-patient variability with regard to spontaneous reversal.
Reference
1. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology. 2003;98:
<60 n=23
[60-90] n=101
[90-120] n=164
>120 n=238
min
*Significantly different from TOF <0.9 (P<0.01).
Debaene B ,et al. Anesthesiology. 2003;98: 13 13 13

13. Pharmacological Reversal of NMB: MOA of Available Reversal Agents
Indirect mechanism
Acetylcholinesterase (AChE) inhibitors
Neostigmine
Edrophonium
Pyridostigmine
All 3 agents inhibit the breakdown of ACh, indirectly raising levels of ACh at both nicotinic and muscarinic receptors
Direct encapsulation of NMBA
Selective Relaxant Binding Agent (SRBA)
Sugammadex
Directly encapsulates rocuronium and vecuronium and renders them inactive at receptor site 14

14. Limitations of Current Reversal agents (Cholinesterase Inhibitors)
Neuromuscular Block Management
Limitations of Current Reversal agents (Cholinesterase Inhibitors)
Relatively slow in reversing neuromuscular blockade Limited ability to reverse deep blockade Efficacy influenced by maintenance anesthetics Well-known side effect profile Require concomitant administration of anticholinergics
Key point:
Cholinesterase inhibitors have limitations
There are many drawbacks to the use of cholinesterase inhibitors in the reversal of neuromuscular blockade. When compared with Sugammadex, the most prominent characteristic of cholinesterase inhibitors is that they are relatively slow at reversing neuromuscular blockade. Another important limitation of cholinesterase inhibitors is the fact that these drugs are incapable of reversing deep blockade, as documented by Kopman et al and Bartkowski.1,2 Their efficacy is also influenced by the maintenance anesthetic used during the procedure, making their effects even more variable.3
Aside from efficacy, cholinesterase inhibitors are renowned for their side effects if they are not properly managed. These effects are mostly cardiovascular (ie, heart rate, blood pressure) but also include smooth muscle contractions and postoperative nausea and vomiting at higher doses.4,5
These side effects are due to an abundance of acetylcholine. To mitigate these effects, the use of cholinesterase inhibitors should be accompanied by the administration of anticholinergics.
References
1. Kopman AF, Kopman DJ, Ng J, Zank LM. Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function. J Clin Anesth. 2005;17:30-35.
2. Bartkowski RR. Incomplete reversal of pancuronium neuromuscular blockade by neostigmine, pyridostigmine, and edrophonium. Anesth Analg. 1987;66:
3. Kim KS, Cheong MA, Lee HJ, Lee JM. Tactile assessment for the reversibility of rocuronium-induced neuromuscular blockade during propofol or sevoflurane anesthesia. Anesth Analg. 2004;99:
4. Tramer MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on postoperative nausea and vomiting and risk of residual paralysis. A systematic review. Br J Anaesth. 1999;82:
5. Caldwell JE. Reversal of residual neuromuscular block with neostigmine at one to four hours after a single intubating dose of vecuronium. Anesth Analg. 1995;80:
Bartkowski RR. Anesth Analg. 1987;66:
Kim KS, et al. Anesth Analg. 2004;99:
Kopman AF, et al. J Clin Anesth. 2005;17:30-35. 15 15 15

15. Side Effects Associated With Current Reversal Agents
Neuromuscular Block Management
Side Effects Associated With Current Reversal Agents
AChE inhibitors in the reversal of neuromuscular block can cause
Bradycardia
Hypersalivation
Bronchospasm
Increased bronchial secretions
Urinary frequency
Nausea and vomiting
Coadministration of antimuscarinic agents aids in preventing cholinergic effects but may result in*
Tachycardia
Dryness of mouth and nose
Mydriasis
Urinary retention
Key point:
Current reversal agents are associated with several side effects
Recovery from neuromuscular blockade is often hastened by the administration of cholinesterase inhibitors such as neostigmine, pyridostigmine, or edrophonium. While effective, cholinesterase inhibitors have limitations. Not only do they increase the amount of acetylcholine at the neuromuscular junction, cholinesterase inhibition increases the availability of acetylcholine at the muscarinic receptors, which may result in bradycardia, hypersalivation, bronchospasm, increased bronchial secretions, urinary frequency, and nausea and vomiting.1 Furthermore, the use of these agents may not completely avoid the occurrence of residual neuromuscular blockade even after large doses. This was found even after use of intermediate-acting neuromuscular blockers, which are sometimes not monitored because of their decreased incidence of residual neuromuscular blockade.2 Spontaneous recovery will depend on the inherent pharmacokinetics of the neuromuscular blocking agent administered for the surgical procedure.
References
1. Neostigmine Methylsulfate [package insert]. Shirley, NY: American Regent Laboratories, Inc; 2002.
2. Kim KS, Lew SH, Cho HY, Cheong MA. Residual paralysis induced by either vecuronium or rocuronium after reversal with pyridostigmine. Anesth Analg. 2002;95:
Neostigmine Methylsulfate Injection [package insert]; 2002.
Atropine Sulfate Injection, USP [package insert]; 2003.
Glycopyrrolate Injection, USP [package insert]; 2006.
*Atropine use causes dose-dependent adverse effects. 16 16 16

16. Administration at 95% Twitch Depression
Neuromuscular Block Management
Ceiling Effect of Cholinesterase Inhibitors Demonstrated in the Rat Diaphragm
Administration at 95% Twitch Depression
The ability of ChE inhibitors to reverse to adequate TOF ratios is inherently limited due to a ceiling effect that exists at deeper levels of neuromuscular blockade
1.0
Concentration (µm)
0.8
0.6
0.4
0.2
0.0
.001
0.01
0.1 1 10
100
Neostigmine
Pyridostigmine
Edrophonium
TOF Ratio
In this study a rat diaphragm was used as the in vitro environment to test the ability of neostigmine, pyridostigmine, and edrophonium to reverse pancuronium at 2 different levels of block (60% and 95%).1 The two levels of block were achieved via a pancuronium dose response curve that was studied in the rat diaphragm model prior to administration of the cholinesterase inhibitors. The concentrations of the cholinesterase inhibitors spanned beyond the clinical range to establish a dose-response curve. The drugs showed a ceiling effect for reversal of tension and fade. This can be seen by observing the supra-clinical doses that did not result in an increase in TOF ratio. This is due to the nature of the reversal because true antagonism, which would have an almost infinite ability to reverse is not what occurs when these agents are used. Instead, there is a pharmacologic competition between the pancuronium and acetylcholine at the neuromuscular junction. This is exceeded by the inhibition of acetylcholinesterase, causing an increased concentration of acetylcholine that overcomes the pancuronium at the junction. In this regard, cholinesterase inhibitors indirectly inhibit the neuromuscular blockade explaining the ceiling effect that they display.
Reference
1. Bartkowski RR. Incomplete reversal of pancuronium neuromuscular blockade by neostigmine, pyridostigmine, and edrophonium. Anesth Analg. 1987;66:
ChE, cholinesterase.
Bartkowski RR. Anesth Analg. 1987;66: 17 17 17

17. Neuromuscular Block Management
Great Variability in Reversal Is Seen Depending on the Administered Anesthetic* † †
Key point:
There is great variability in the level of reversal; depending on the administered anesthetic
Neostigmine 70 μg/kg and glycopyrrolate 14 μg/kg were administered after neuromuscular blockade was induced with a bolus injection of rocuronium 0.6 mg/kg and maintained with rocuronium 0.1 mg/kg. Patients were randomly selected to receive either propofol or sevoflurane as a maintenance anesthetic. Objective monitoring was performed using train-of-four stimulation and mechanomyography. Neostigmine was administered at the reappearance of the first, second, third, or fourth twitch.1 The results showed great variability among the groups with regard to the level of reversal achieved based on the administered anesthetic.
Reference
1. Kim KS, Cheong MA, Lee HJ, Lee JM. Tactile assessment for the reversibility of rocuronium-induced neuromuscular blockade during propofol or sevoflurane anesthesia. Anesth Analg. 2004;99: T1 T2
*Rocuronium 0.1 mg/kg followed by neostigmine 70 μg/kg.
†P < PROP, propofol; SEVO, sevoflurane.
Kim KS, et al. Anesth Analg. 2004;99: 18 18 18

18. Neuromuscular Block Management
High Incidence of Residual Neuromuscular Blockade at the Time of Tracheal Extubation
<0.9
Murphy et al conducted a study to assess train-of-four (TOF) ratios immediately before tracheal extubation, when clinicians had determined that full recovery of neuromuscular function had occurred using standard clinical criteria. All of the 120 patients, who underwent elective gynecologic or general surgical procedures, received rocuronium for neuromuscular blockade (NMB), and all were reversed with neostigmine.
Immediately before tracheal extubation, the mean TOF ratio was 0.67 ± 0.2. As shown in the bar graph, acceptable neuromuscular recovery, defined as a TOF ratio ≥0.9, was present in only 12% of patients immediately before removal of the endotracheal tube. Based on these findings, the investigators speculated that complete recovery from NMB is rarely present at the time of tracheal extubation.
Reference
1. Murphy GS, Szokol JW, Marymont JH, Franklin M, Avram MJ, Vender JS. Residual paralysis at the time of tracheal extubation. Anesth Analg. 2005; 100:
<0.7
TOF Ratio
≥0.9
Murphy GS, et al. Anesth Analg. 2005;100: 19 19 19

19. Neuromuscular Block Management
Independent of the Definition of Residual Neuromuscular Blockade, Postoperative Incidence Can Still Be High
Study
NMBA Administered
Reversal
Definition of Residual Block, (TOF ratio)
Incidence of Residual Block, n (%)
Bevan et al
Pancuronium
Atracurium
Vecuronium
+/-
<0.7
17/47 (36)
2/46 (4)
5/57 (9)
Hayes et al
Rocuronium
<0.8
32/50 (64)
26/50 (52)
19/48 (39)
Baillard et al
239/568 (42)
Debaene et al
Intermediate-acting agents
<0.9
85/526 (16)
237/526 (45)
Kim et al -
70/274 (25)
35/203 (15)
Murphy et al +
14/35 (40)
2/34 (5.9)
Key point:
Regardless of the definition used for residual neuromuscular blockade (NMB) — train-of-four (TOF) <0.7 or <0.9 — the incidence is still high
The studies described in this slide show that regardless of the definition used to define residual NMB (ie, TOF <0.7 or <0.9), the incidence is still high. The long-acting agent pancuronium displays rates as high as 40% when using a TOF ratio of <0.7. Intermediate-acting agents, which are less likely to cause residual NMB, still show rates as high as 42% even when the definition used is TOF ratio of <0.7. These rates can rise even higher (>60%) when using the definition of a TOF ratio of <0.9.1
These data indicate the widespread nature of this issue and how more than half of patients receiving these agents can experience residual NMB.
Reference
1. Murphy GS. Residual neuromuscular blockade: incidence, assessment, and relevance in the postoperative period. Minerva Anestesiol. 2006;72:
+, used in patients; +/- used in some patients; -, not used in patients.
Murphy GS. Minerva Anestesiol. 2006;72: 20 20 20

20. Potential Sequelae of Inadequate Reversal/Residual Blockade
Immediate [PACU/Recovery Room]
Late
Immediate [PACU/Recovery Room]
Late
Neuromuscular Block Management
Potential Sequelae of Inadequate Reversal/Residual Blockade
Hypoxemia (SaO2 ≤ 93% on 3L min O2 via nasal canula) Hypercapnia (pCO2 ≥ 46 mm Hg) Upper airway problems Difficulty swallowing Diaphragmatic breathing Poor head lift Poor grip strength Diplopia or blurred vision Dysarthria General discomfort Rarely, re-intubation
Pulmonary complications
Coughing
Expectoration
Pain on breathing
Atelectasis
Pneumonia, including aspiration pneumonia
Late complications are separated in time and location from residual blockade and cause and effect are difficult to establish 21

21. Neuromuscular Block Management
Limited Recognition of TOF Ratio ≥0.9 as the Standard for Acceptable Recovery
On the basis of extensive evidence from many clinical studies, a train-of-four (TOF) ratio ≥0.9 is now considered the gold standard for acceptable recovery from neuromuscular blockade.1
However, the results of a survey recently conducted at 12 anesthesia departments throughout the United Kingdom suggest that there may be limited awareness of this new definition.2 Of the 534 consultants, trainees, and nonconsultant career-grade staff members who answered the survey, nearly 70% replied that a TOF ratio ≤85% was the threshold for safe extubation, and nearly one quarter of respondents identified the threshold ratio as being ≤69%.
References
1. Murphy GS. Residual neuromuscular blockade: incidence, assessment, and relevance in the postoperative period. Minerva Anestesiol. 2006;72:
2. Grayling M, Sweeney BP. Recovery from neuromuscular blockade: a survey of practice. Anaesthesia. 2007;62:
Grayling M, Sweeney BP. Anaesthesia. 2007;62: 22 22 22

22. Neuromuscular Block Management
Conclusions
Quantitative monitoring is essential for the accurate detection of residual NMB, but it is used infrequently by a substantial proportion of clinicians Even when residual NMB is defined as a TOF ratio of <0.7, it is frequently observed in the PACU The consequences of residual NMB can be serious, including a range of critical respiratory events and an increased use of health care resources A TOF ratio ≥0.9 is the current standard for acceptable recovery from NMB, although it is not consistently recognized or used Many practices, especially quantitative monitoring, have the potential to reduce the incidence of residual NMB, but this problem is likely to persist Routine reversal of neuromuscular blocking drugs with an agent recognized as having a favorable risk:benefit ratio might reduce the incidence of residual NMB
Quantitative monitoring is essential for the accurate detection of residual neuromuscular blockade (NMB), but it is used infrequently by a substantial proportion of clinicians.
Even when residual NMB is defined as a train-of-four (TOF) ratio of <0.7, it is frequently observed in the postanesthesia care unit (PACU). When the current value (TOF ratio ≥0.9) is used, incidence rates often approach or exceed 50%.
The consequences of residual NMB can be serious, including a range of critical respiratory events and an increased use of health care resources. 23 23

23. What can not be measured, can not be managed
Peter Drucker

24. Breakthrough in reversal

25. Reversal of muscle block – an unmet need
Anesthesiologists have learned to work round limitations in NMB and its reversal:
with current reversal agents
providing rapid emergency block (RSI)
The market into which Sugammadex is being launched has not changed for many years, in terms of products used for both inducing and reversing neuromuscular blockade (NMB)
This is not because the current management of NMB is ideal. Far from it.
Problems exist around which anesthesiologists have learned to work – part of the ‘art and craft’ of anesthesiology of which practitioners are rightly proud
The limitations lie in two main areas:
Limitations with reversal agents BEFORE Sugammadex
Limitations with options for providing rapid block in emergency situations – i.e. rapid sequence induction or intubation
Let’s look at these in a bit more detail next 26

26. Scene 1 Acetylcholine Cholinesterase
In the following 4 scenes the mechanisms by which neuromuscular function, blockade, and reversal take place will be depicted. The main purpose of these animations is to demonstrate the novelty and superiority of encapsulation using Sugammadex versus traditional reversal with cholinesterase inhibitors.
This first scene shows the manner in which normal neuromuscular function takes place. As you can see, the acetylcholine (shown in blue) is released from the nerve axon into the synaptic cleft. From there, the acetylcholine binds to the nicotinic acetylcholine receptor on the muscle endplate. Once there is a sufficient number acetylcholine receptors are filled, a electrical depolarization of the postjunctional membrane takes place. This process allows for the conduction of the muscle action potential and, subsequently, the contraction of skeletal muscles (shown as a flash).
Cholinesterase (depicted as rotating arrows), degrades the acetylcholine into acetate and choline, thus allowing the body to recycle the neurotransmitter for future release. This enzyme is important since it is exploited in traditional reversal as illustrated later in scene 3.
Reference
1. Booij LHDJ. Neuromuscular transmission and its pharmacological blockade. Part 1: Neuromuscular transmission and general aspects of its blockade. Pharm World Sci. 1997;19:1-12.

27. Scene 2 Acetylcholine Cholinesterase Rocuronium
Because the contraction of skeletal muscles is ultimately dependent on the ability of acetylcholine to attach to its receptor, the blockade of such receptors would inhibit skeletal muscle contraction. This process of neuromuscular blockade is depicted here in scene 2.
Rocuronium (shown in green), a neuromuscular blocking agent, readily fills the nicotinic acetylcholine receptor. In doing so the acetylcholine is unable to attach to its receptor resulting in neuromuscular blockade and paralysis (note that no flash takes place).
Reference
1. Booij LHDJ. Neuromuscular transmission and its pharmacological blockade. Part 1: Neuromuscular transmission and general aspects of its blockade. Pharm World Sci. 1997;19:1-12.

28. Cholinesterase Inhibitor
Scene 3
Acetylcholine
Cholinesterase
Rocuronium
Cholinesterase Inhibitor
Traditional reversal, as shown here in scene 3, exploits cholinesterase (depicted as rotating arrows). This works based on the simple fact that rocuronium, as well as other neuromuscular blocking agents, are competitive antagonists of the nicotinic acetylcholine (ACh) receptor. For this reason, all one has to do is provide enough competition for the same receptor, namely with ACh, to cause the displacement of rocuronium from the nicotinic ACh receptor.
To provide for the necessary amount of ACh to cause this displacement, cholinesterase is blocked using cholinesterase inhibitors (e.g. neostigmine, edrophonium, pyridostigmine). The blockade of this enzyme causes a flood of acetylcholine into the synaptic cleft, displacing the rocuronium, and allowing for acetylcholine to reattach and neuromuscular function to return (shown as a flash).
The problem with this method is that too much acetylcholine is often released, resulting in cholinergic adverse events such as bradycardia, bronchospasm, increased bronchial secretions etc. To combat these adverse events, the appropriate amount of antimuscarinics (e.g. glycopyrrolate, atropine) are administered, but they too can cause anticholinergic adverse events such as tachycardia, bronchodilation, dry mouth etc.
Reference
1. Fisher DM. Clinical pharmacology of neuromuscular blocking agents. American Journal of Health System Pharmacy 1999;56:S4-S9.

29. Scene 4 Acetylcholine Cholinesterase Rocuronium Sugammadex
This final scene shows reversal via encapsulation with sugammadex (shown in orange). In contrast to traditional reversal which affects the cholinergic system, resulting in related adverse events, Sugammadex works by directly encapsulating rocuronium or vecuronium (not shown here). This method has no influence on the cholinergic system, giving Sugammadex a superior adverse events profile that is similar to placebo.1,2
As sugammadex is administered, free rocuronium is rapidly encapsulated due to sugammadex’s high affinity for the neuromuscular blocking agents rocuronium and vecuronium. This rapid encapsulation creates a concentration gradient, which draws rocuronium away from the nicotinic acetylcholine receptor, allowing for the return of acetylcholine to its receptor and the restoration of neuromuscular function (shown as a flash).1
References
1. Adam JM, Bennett DJ, Bom A et al. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships. J Med Chem. 2002;45:
2. Berner C. Integrated Summary of Safety. September 2007.

30. Scientific Platform (Clinical Overview)31

31. Sailing in the Sugammadex Sea of Studies

32. Types of Phase 3 Trials Special Populations Comparative Shallow Block
Renal
Pediatric
Elderly
Pulmonary
Cardiac
Bridging Trials (Japan/EU)
After Rocuronium Infusion
PNS vs TOF Watch SX
Incidence of residual NMB at extubation
Comparative
vs. Neostigmine
Shallow Block
Profound Block
vs. succinylcholine
vs. cis-atracurium
Routine Use
15 min after last dose of rocuronium

33. The Pivotal Trials Signal – Trial 302 Spectrum – Trial 303
Highlights of Phase 3 Results
The Pivotal Trials
Aurora – Trial 301
Signal – Trial 302
Spectrum – Trial 303

34. A Breakthrough in Reversal – Moderate Block35
A Breakthrough in Reversal – Moderate Block 35

35. Study 19.4.301 – AURORA Study Design and Conduct
CSR , p 16 A
Multicenter, randomized, parallel-group, comparative, active-controlled, safety assessor–blinded Carried out from November 2005 through March 2006 Conducted at 13 sites in seven European countries (Austria, Belgium, Germany, Italy, Spain, Sweden, United Kingdom)
CSR , p 15 A
CSR , p 60 A
Study was a multicenter, randomized, parallel-group, comparative, active-controlled, safety assessor–blinded study.1
It was carried out from November 2005 through March 2006.
The study was conducted at 13 sites in seven European countries (Austria, Belgium, Germany, Italy, Spain, Sweden, and the United Kingdom).
Reference
1. CSR
CSR , p 16 A
CSR , p 15 A
CSR , p 60 A
Data from AURORA trial.

36. Study 19.4.301 – AURORA Study Objectives
CSR ,
p 13 A
Primary: To demonstrate faster recovery from rocuronium- or vecuronium-induced NMB after reversal at reappearance of T2 by Sugammadex 2 mg/kg versus neostigmine 50 µg/kg Secondary: To evaluate the safety of a single dose of Sugammadex 2 mg/kg and neostigmine 50 µg/kg administered to adult subjects
CSR
p 13 A
Study , also called the AURORA trial, investigated the use of Sugammadex® (sugammadex) for the reversal of moderate neuromuscular blockade (NMB).
The primary objective of Study was to demonstrate faster recovery from rocuronium- or vecuronium-induced NMB after reversal at reappearance of T2 by Sugammadex 2 mg/kg versus neostigmine 50 µg/kg.1
The secondary study objective was to evaluate the safety of a single dose of Sugammadex 2 mg/kg and neostigmine 50 µg/kg administered to adult subjects.
Reference
1. CSR
NMB, neuromuscular blockade.
Data from AURORA trial.

37. Study 19.4.301 – AURORA Inclusion Criteria
CSR , p 17 A
ASA class 1 to 4 Aged ≥18 years Scheduled for surgical procedure with general anesthesia with the use of rocuronium or vecuronium for endotracheal intubation and maintenance of NMB Scheduled for surgical procedure in supine position Provided written informed consent
CSR , p 17 A
Patients in American Society of Anesthesiologists class 1 through 4 who were at least 18 years of age were eligible for inclusion in study
Eligible subjects were scheduled for a surgical procedure with general anesthesia with the use of rocuronium or vecuronium for endotracheal intubation and maintenance of neuromuscular blockade.
They were scheduled for surgical procedures in the supine position and had given written informed consent.
Reference
1. CSR
ASA, American Society of Anesthesiologists;
NMB, neuromuscular blockade.
Data from AURORA trial.

38. Study 19.4.301 – AURORA Baseline Characteristics: Rocuronium Group
CSR , p 67 A
Characteristic
Sugammadex (n=48)
Neostigmine (n=48)
Total (n=96)
Age (years), mean (SD)
51 (16)
48 (14)
50 (15)
Sex (male), n (%)
31 (65)
24 (50)
55 (57)
Weight (kg), mean (SD)
73 (14)
76 (15)
74 (14)
Height (cm), mean (SD)
170 (9)
170 (10)
Race, n (%)
White
46 (96)
48 (100)
94 (98)
Not Hispanic or Latino
43 (90)
39 (81)
82 (85)
ASA class (1 or 2), n (%)
92 (96)
CSR , p 67 A
This table summarizes demographic and other baseline characteristics for patients in Study who were randomized to receive rocuronium. Among rocuronium recipients, analysis revealed no relevant differences between the two treatment groups with respect to age, body weight, height, race, or American Society of Anesthesiologists class.1
More males were enrolled in the Sugammadex® (sugammadex) group (65%) compared to the neostigmine group (50%).
Fewer subjects of Hispanic or Latino ethnicity were treated in the Sugammadex group (10%) than in the neostigmine group (19%).
Reference
1. CSR
ASA, American Society of Anesthesiologists.
Data from AURORA trial.

39. Study 19.4.301 – AURORA Primary Efficacy Variable: Rocuronium
17.6
In study , the primary efficacy variable was the time from start of administration of study medication to recovery of the T4/T1 ratio to 0.9.
As shown in this bar graph, in the intent-to-treat population of rocuronium recipients, the median time from administration of study medication to recovery of the T4/T1 ratio to 0.9 was 1.4 minutes (1 minute 24 seconds) in the Sugammadex® (sugammadex) group compared with 17.6 minutes (17 minutes 36 seconds) in the neostigmine group.
Times from the start of administration of Sugammadex to recovery of the T4/T1 ratio to 0.9 ranged from 55 seconds to 5 minutes 25 seconds in the Sugammadex group, and from 3 minutes 40 seconds to 106 minutes 53 seconds in the neostigmine group.
Reference
1. CSR
1.4
Sugammadex (n=48)
NEO, neostigmine; TOF, train-of-four.
Data from AURORA trial. 42

40. Study 19.4.301 – AURORA Faster TOF Recovery With Sugammadex43
Study – AURORA Faster TOF Recovery With Sugammadex
Rocuronium 0.6 mg/kg
Sugammadex 2 mg/kg
(%)
100 50
10:21:06
10:32:38
10:44:08
10:55:38
11:07:08
11:18:53
11:30:38
11:42:08
11:53:53
12:04:39
12:13:56
Rocuronium 0.6 mg/kg
Neostigmine 50 µg/kg
(%)
100 50
7:49:34
7:59:34
8:09:34
8:19:34
8:29:49
8:39:49
8:50:03
9:00:19
9:10:19
9:20:34
9:30:49
9:41:04
This slide shows train-of-four (TOF) tracings from two patients enrolled in Study The patient at the top was treated with rocuronium 0.6 mg/kg followed by Sugammadex® (sugammadex) 2 mg/kg. The other patient was treated with rocuronium followed by neostigmine 50 μg/kg. The solid blue lines represent the height of the muscle twitches and the dashed orange line is the value of the TOF ratio.
Comparison of the tracings shows that TOF recovery is substantially more rapid with Sugammadex than with neostigmine.
Reference
1. CSR
Data from AURORA trial. 43

41. A Breakthrough in Reversal – Deep Block47
A Breakthrough in Reversal – Deep Block 47

42. Study 19.4.302 – SIGNAL Study Design and Conduct
CSR , p 19 A
Multicenter, randomized, parallel-group, comparative, active-controlled, safety assessor–blinded Carried out from November 2005 through November 2006 Conducted at eight sites in the United States
CSR , p 18 A
CSR , p 17 A
CSR , p 19 A
Study was a multicenter, randomized, parallel-group, comparative, active-controlled, safety assessor–blinded study.1
It was carried out from November 2005 through November 2006.
A total of 10 centers in the United States were initiated to conduct the trial, but two of these centers did not enroll any subjects.
Reference
1. CSR
CSR , p 18 A
CSR , p 17 A
Data from SIGNAL trial.

43. Study 19.4.302 – SIGNAL Study Objectives
CSR , p 16 A.
Primary: To demonstrate faster recovery from rocuronium- or vecuronium-induced NMB after reversal at a block of 1 to 2 PTCs by Sugammadex 4 mg/kg versus neostigmine 70 µg/kg Secondary: To evaluate the safety of a single dose of Sugammadex 4 mg/kg and neostigmine 70 µg/kg administered to adult subjects
CSR p 16 A.
Study , which is also called the SIGNAL trial, investigated the use of Sugammadex® (sugammadex) for the reversal of deep neuromuscular blockade.
The primary objective of Study was to demonstrate faster recovery from rocuronium- or vecuronium-induced neuromuscular blockade after reversal at a block of 1 to 2 posttetanic counts by Sugammadex 4 mg/kg versus neostigmine 70 µg/kg.1
The secondary study objective was to evaluate the safety of a single dose of Sugammadex 4 mg/kg and neostigmine 70 µg/kg administered to adult subjects.
Reference
1. CSR
NMB, neuromuscular blockade; PTC, posttetanic count.
Data from SIGNAL trial.

44. Study 19.4.302 – SIGNAL Inclusion Criteria
CSR , p 20 A
ASA class 1 to 4 Aged ≥18 years Scheduled for surgical procedure with general anesthesia with the use of rocuronium or vecuronium for endotracheal intubation and maintenance of NMB Scheduled for surgical procedure in supine position Provided written informed consent
CSR , p 20 A
The inclusion criteria for Study were the same as those in Study
Patients in American Society of Anesthesiologists class 1 through 4 who were at least 18 years of age were eligible for inclusion.1
Eligible subjects were scheduled for a surgical procedure with general anesthesia with the use of rocuronium or vecuronium for endotracheal intubation and maintenance of neuromuscular block.
They were scheduled for surgical procedures in the supine position and had given written informed consent.
Reference
1. CSR
ASA, American Society of Anesthesiologists;
NMB, neuromuscular blockade.
Data from SIGNAL trial.

45. Study 19.4.302 – SIGNAL Baseline Characteristics: Rocuronium Group
CSR , p 86 A
Characteristic
Sugammadex (n=37)
Neostigmine (n=38)
Total (n=75)
Age (years), mean (SD)
52 (14)
54 (11)
53 (13)
Sex (male), n (%)
16 (43)
17 (45)
33 (44)
Weight (kg), mean (SD)
90 (32)
85 (23)
88 (27)
Height (cm), mean (SD)
170 (10)
169 (10)
Race, n (%)
White
32 (86)
34 (89)
66 (88)
Not Hispanic or Latino
34 (92)
35 (92)
69 (92)
ASA class (1 or 2), n (%)
28 (76)
33 (87)
61 (81)
CSR , p 85 A, 86 A
This table summarizes demographic and other baseline characteristics for patients in Study who were randomized to receive rocuronium. Among rocuronium recipients, the Sugammadex® (sugammadex) and neostigmine treatment groups were generally similar with respect to demographic and other baseline characteristics.1
The proportion of American Society of Anesthesiologists class 1 or 2 patients was somewhat higher in the neostigmine group (87%) than in the Sugammadex group (76%). There were no ASA class 4 patients in either group.
Reference
1. CSR
ASA, American Society of Anesthesiologists.
Data from SIGNAL trial.

46. Study 19.4.302 – SIGNAL Primary Efficacy Variable: Rocuronium49
The primary efficacy variable in Study was the time from the start of study medication administration to recovery of the T4/T1 ratio to 0.9.1
As shown in this bar graph, in the intent-to-treat population of rocuronium recipients, the median time from administration of study medication to recovery of the T4/T1 ratio to 0.9 was 2.7 minutes in the Sugammadex® (sugammadex) group compared with 49 minutes in the neostigmine group.
Times from the start of study medication administration to recovery of the T4/T1 ratio to 0.9 ranged from 1 minute 13 seconds to 16 minutes 5 seconds in the Sugammadex group, and from 13 minutes 16 seconds to 145 minutes 40 seconds in the neostigmine group.
Reference
1. CSR
2.7
Sugammadex (n=37)
NEO, neostigmine.
Data from SIGNAL trial. 54

47. Study 19.4.302 – SIGNAL Faster TOF Recovery With Sugammadex55
Study – SIGNAL Faster TOF Recovery With Sugammadex
100 80 60 40 20
Patients Achieving a T4 /T1 Ratio of 0.9 (%)
120
140
160
Time (min)
ROC followed by Sugammadex
ROC followed by NEO
This graph shows the time to full recovery from deep rocuronium-induced neuromuscular blockade after administration of Sugammadex® (sugammadex) or neostigmine and the percentage of patients who achieved a T4/T1 ratio of 0.9 at various time points.1
An exploratory analysis showed that the total rocuronium dose (intubating dose alone vs intubating dose plus maintenance doses) had no effect on the recovery time with Sugammadex.2
References
1. CSR
2. Jones RK, Caldwell JE, Brull SJ, Soto R. Faster reversal of profound rocuronium-induced neuromuscular blockade with sugammadex vs neostigmine. Anesthesiology. 2007;107:A1577.
Jones (2007), A1577, A
Data from SIGNAL trial.
Jones RK et al. Anesthesiology. 2007;107:A1577.
NEO, neostigmine; ROC, rocuronium; TOF, train-of-four. 55 55

48. Neuromuscular Blockade After Reversal With Sugammadex58
Neuromuscular Blockade After Reversal With Sugammadex 58

49. Recurrence of Blockade: Incidence and Prevention
SMPC, p 8 A
In pooled phase 1 to 3 studies with a placebo group, the incidence of recurrence of NMB was 2% after Sugammadex and 0% after placebo Nearly all cases were observed in dose-finding studies in which a suboptimal dose (<2 mg/kg) was administered To prevent recurrence of NMB, recommended doses for routine or immediate reversal should be used
SMPC, p 4 D
In the database of pooled phase 1 to 3 studies with a placebo group, the incidence of recurrence of blockade as measured with neuromuscular monitoring was 2% after Sugammadex® (sugammadex) and 0% after placebo administration.1
Virtually all of these cases were observed in dose-finding studies in which a suboptimal dose (<2 mg/kg) was administered.
To prevent the recurrence of neuromuscular blockade, the recommended doses for routine or immediate reversal should be used.
Reference
1. Sugammadex® (sugammadex) [Summary of Product Characteristics]. N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands; August 2008.
NMB, neuromuscular blockade.
Sugammadex® [summary of product characteristics]. Organon, Europe; 2008.

50. Recurrence of Blockade: Administration of Repeat Dose
SMPC, p 3 I
Postoperative recurrence of blockade after initial dose of 2 mg/kg or 4 mg/kg Sugammadex is unusual Repeat dose of 4 mg/kg Sugammadex is recommended Patients should be closely monitored to ascertain sustained return of neuromuscular function
In the unusual situation of postoperative recurrence of blockade after an initial dose of 2 mg/kg or 4 mg/kg Sugammadex® (sugammadex), a repeat dose of 4 mg/kg Sugammadex is recommended.1
Following the second dose of Sugammadex, the patient should be closely monitored to ascertain the sustained return of neuromuscular function.
Reference
1. Sugammadex® (sugammadex) [Summary of Product Characteristics]. N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands; August 2008.
SMPC, p 3 I
Sugammadex® [summary of product characteristics]. Organon, Europe; 2008.

51. Efficacy Highlights Clear dose response
Consistent efficacy results over all trials
Much faster recovery with sugammadex as compared to neostigmine
No dose adjustments necessary in special patient populations

52. Selected Safety Information

53. Selected Safety Information
Therapeutic indications
Reversal of neuromuscular blockade induced by rocuronium or vecuronium in adults.
For the paediatric population: sugammadex is only recommended for routine reversal of rocuronium induced blockade in children and adolescents aged 2 to 17 years.
Posology and method of administration
Posology:
Sugammadex should only be administered by, or under the supervision of an anaesthetist. The use of an appropriate neuromuscular monitoring technique is recommended to monitor the recovery of neuromuscular blockade. 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
Adults
Routine reversal:
A dose of 4 mg/kg sugammadex is recommended if recovery has reached at least 1-2 post-tetanic counts (PTC) following rocuronium or vecuronium induced blockade. Median time to recovery of the T4/T1 ratio to 0.9 is around 3 minutes. A dose of 2 mg/kg sugammadex is recommended, if spontaneous recovery has occurred up to at least the reappearance of T2 following rocuronium or vecuronium induced blockade. Median time to recovery of the T4/T1 ratio to 0.9 is around 2 minutes.

54. Selected Safety Information
Immediate reversal of rocuronium-induced blockade: If there is a clinical need for immediate reversal following administration of rocuronium a dose of 16 mg/kg sugammadex is recommended. When 16 mg/kg sugammadex is administered 3 minutes after a bolus dose of 1.2 mg/kg rocuronium bromide, a median time to recovery of the T4/T1 ratio to 0.9 of approximately 1.5 minutes can be expected. There is no data to recommend the use of sugammadex for immediate reversal following vecuronium induced blockade. Re-administration of sugammadex: In the exceptional situation of recurrence of neuromuscular blockade post-operatively after an initial dose of 2 mg/kg or 4 mg/kg sugammadex, a repeat dose of 4 mg/kg sugammadex is recommended. Following a second dose of sugammadex, the patient should be closely monitored to ascertain sustained return of neuromuscular function. Additional information on special population Elderly patients: Even though the recovery times in elderly tend to be slower, the same dose recommendation as for adults should be followed. Obese patients: In obese patients, the dose of sugammadex should be based on actual body weight. The same dose recommendations as for adults should be followed. Method of administration Sugammadex should be administered intravenously as a single bolus injection. The bolus injection should be given rapidly, within 10 seconds, into an existing intravenous line. Sugammadex has only been administered as a single bolus injection in clinical trials.

55. Selected Safety Information
Contraindications
Sugammadex is contraindicated in patients with known Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 in the prescribing information. Hypersensitivity reactions that occurred 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.
Special warnings and precautions for use
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 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:
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.

56. Selected Safety Information
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 and prothrombin time international normalized ratio. These limited mean 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. If sugammadex is administered to these patients monitoring of haemostasis and coagulation parameters is recommended. 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

57. Selected Safety Information
Re-administration of rocuronium or vecuronium after immediate reversal (16 mg/kg sugammadex): For the very rare cases where this might be required, a waiting time of 24 hours is suggested. If neuromuscular blockade is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking agent should be used. 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. Renal impairment: Sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis 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 hemodynamic 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. Use in Intensive Care Unit (ICU): Sugammadex has not been investigated in patients receiving rocuronium or vecuronium in the ICU setting.

58. Selected Safety Information
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. Interaction with other medicinal products and other forms of interaction 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 up to 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.

59. Selected Safety Information
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. For re-administration of sugammadex see section 4.2 in the prescribing information. 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: 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.

60. Selected Safety Information
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 refer to 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. Paediatric population No formal interaction studies have been performed. The above mentioned interactions for adults and the warnings section should also be taken into account for the paediatric population. Pregnancy and lactation: Pregnancy: For sugammadex no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development. Caution should be exercised when administering sugammadex to pregnant women. Undesirable effects Bridion is administered concomitantly with neuromuscular blocking agents and anaesthetics in surgical patients. The causality of adverse events is therefore difficult to assess. The most commonly reported adverse reactions in surgical patients were cough, airway complication of anaesthesia, anaesthetic complications, procedural hypotension and procedural complication (Common (≥ 1/100 to < 1/10)).

61. Q&A
Any Questions?