4 February 2011 SUGAMMADEX. S Maharaj. Department of Anaesthetics

Transcription

1 4 February 2011 SUGAMMADEX S Maharaj Commentator: S Belhaj Moderator: A Hunter Department of Anaesthetics

2 CONTENTS INTRODUCTION... 3 NEOSTIGMINE AND ATTEMPTS TO REPLACE IT... 4 SUCCINYLCHOLINE AND ATTEMPTS TO REPLACE IT... 5 Why replace Succinylcholine?... 5 Novel compounds independent of Plasma Cholinesterase for breakdown... 6 CYCLODEXTRIN CHARACTERISTICS... 7 DISCOVERY OF THE MODIFIED CYCLODEXTRIN SUGAMMADEX... 9 PHARMACOLOGY Mechanism of Action Pharmacokinetics and Metabolism CLINICAL EVALUATION Reversal of Moderate Block Reversal of Profound Block Rapid Reversal SPECIAL POPULATIONS SAFETY SPECIAL WARNINGS AND PRECAUTIONS FOR USE UNCERTAINTIES Costing CONCLUSION REFERENCES Page 2 of 31

3 INTRODUCTION Since the introduction of curare, neuromuscular blocking agents (NMBAs) have allowed us to immobilize patients and improve medical and surgical interventions. The synthesis and development of new NMBAs have produced agents that are close to ideal 1. Unfortunately, NMBA reversal agents have not been improved upon. The cholinesterase inhibitor drugs first used to reverse curare currently remain the standard for reversing all NMBAs. The indirect action of cholinesterase inhibitors is limited in its ability to reverse neuromuscular blockade, and is associated with numerous side effects. Neostigmine was the first of the synthetic anticholinesterases to be used and it is still widely employed although it was introduced as long ago as The neuromuscular effects of succinylcholine were discovered in These 2 compounds have long been targeted for obsolescence, not because of their antiquity alone but also because of their inferior pharmacology. However, they remain in use today, neostigmine widely and succinylcholine more often than desired. Neostigmine remains the standard drug at the end of surgery for reversal of nondepolarizing neuromuscular block. Succinylcholine remains the standard for rapid sequence intubation and when rapid recovery of neuromuscular transmission is important. Over the decades, efforts to improve the safety and efficacy of reversal have resulted in the introduction of pyridostigmine and edrophonium; and efforts to replace succinylcholine have resulted in numerous new neuromuscular blocking drugs of value. A new class of drugs, selective relaxant binding agents (SRBAs), has the potential to overcome the limitations of cholinesterase inhibitors. The first SRBA to be introduced is sugammadex, a modified gamma cyclodextrin (CD) with the chemical formula C 72 H 104 Na 8 O 48 S 8. Unlike the cholinesterase inhibitors, which indirectly and competitively antagonize NMBA s by increasing acetylcholine (ACh), sugammadex acts by directly encapsulating, binding, and inactivating NMBAs. Page 3 of 31

4 NEOSTIGMINE AND ATTEMPTS TO REPLACE IT Neostigmine has narrow margin of safety, with small therapeutic index 2. Its utilization in large doses by intravenous injection to reverse neuromuscular block would be unthinkable had it not been possible to prevent or reduce its adverse effects with atropine. Even then, the results remain unsatisfactory. It is ineffective against profound block. Respiratory and airway problems due to muscle weakness still occur in the recovery room. Furthermore, once patients receive neostigmine, it becomes difficult to relax them again if, for example, they need to return to surgery soon to check postoperative bleeding. As long as cholinergic excess exists at the neuromuscular junction, neither depolarizing nor non depolarizing relaxants will work normally. Cardiovascular, airway, respiratory, and gastrointestinal disturbances are potential adverse effects of the cholinesterase inhibitors, even if co-administered with an anticholinergic. Patients with sick sinus and autonomic neuropathy might experience cholinergic adverse effects without effective protection from the atropine. In anaesthesia, a large dose of edrophonium, such as 1 mg/kg administered intravenously with an appropriate dose of atropine, was subsequently found to be as effective as neostigmine in the reversal of neuromuscular block at the end of surgery. However, clinicians often perceive edrophonium as shorter acting and less efficacious in the reversal of profound block, especially profound block from longacting relaxants. Page 4 of 31

5 Germine 3-acetate, 4-aminopyridine and 3,4-diaminopyridine once held great promise as novel reversal agents 3. Germine causes repetitive firing at the motor nerve terminal, it increases acetylcholine output. At the muscle, it causes a sustained contraction, as if a miniature tetanus. The aminopyridines prolong the potassium current of the cell membrane, thereby prolonging the contractile process. Because of adverse effects, neither the germine nor the aminopyridine compounds succeeded as clinical reversal agents 3. SUCCINYLCHOLINE AND ATTEMPTS TO REPLACE IT In their first article on succinylcholine, Foldes et al 4 described fast onset and fast offset of the neuromuscular effect of succinylcholine and stated that the relaxing effect occurred within 1 minute, making it easy to control the muscle tone at will. At the time, succinylcholine appeared to be close to ideal. Unfortunately, before the article was printed, an addendum to the article already stated that since the submission of the article for publication, several cases of prolonged paralysis had been reported. Nevertheless, succinylcholine went on to become very popular all over the world, peaking at annual sales of 2,233 kg in 1980 to 1981 in the United States alone 5. With experience, more and more adverse effects of succinylcholine appeared. As better relaxants became available, succinylcholine became gradually restricted to fewer and fewer indications and for shorter durations 5. At present, most anesthesiologists limit their use of succinylcholine for rapid sequence intubation; for airway management where fast neuromuscular recovery is desired; and for short procedures such as cardioversion, electric shock therapy, and laryngoscopy. Why replace Succinylcholine? On hindsight, succinylcholine is far from ideal, not only because of its inferior safety profiles, but also because it loses the desirable fast recovery upon continuous use. Even in phase I type block, with 1-mg/kg dose, oxygen saturation studies have shown that succinylcholine is not short acting enough in the cannot-intubate-cannotventilate scenario 6. Lee 5 classified the adverse effects of succinylcholine. The main categories are as follows: depolarization (myalgia, fasciculation, and masseter and extraocular muscle spasm), changing characteristics of block, and idiosyncratic responses such as malignant hyperthermia. Several of these, such as malignant hyperthermia, were novel to medicine and highly fatal until dantrolene was introduced to control the hypermetabolic process. Defective, diminished, atypical, or silent plasma Page 5 of 31

6 cholinesterases; hyperkalaemia associated with burn and nerve injury; reflex bradycardia; ganglionic excitation; and cardiac dysrhythmia in burn and in certain myopathies are some other causes of concern with succinylcholine. Inferior as it is, succinylcholine survives into its sixth decade (1952 to the present) by just a few distinctive advantages; namely, low cost, fast onset, fast recovery, and non-toxicity of metabolites. As soon as these advantages are met by another relaxant, one would expect that succinylcholine will readily retire. Many cost-effective nondepolarizing relaxants already beat succinylcholine in safety and efficacy profiles. Novel compounds independent of Plasma Cholinesterase for breakdown TAAC3 is an ultrashort nondepolarizing tropinyl diester neuromuscular blocking agent 7. It is faster in onset and shorter in duration of action than succinylcholine, and it is noncumulative. Its pharmacologic profile is benign. Among all neuromuscular blocking compounds acting alone, it came closest to beating succinylcholine. However, it failed the toxicity test. The culprit appears to be a very transient nephrotoxic metabolite, produced by a Hofmann-like elimination process. Page 6 of 31

7 CYCLODEXTRIN CHARACTERISTICS Natural CDs are found in nature wherever starch sources, bacteria, and appropriate environmental conditions exist. The glucopyranose units of amylose starch are enzymatically restructured by bacteria such as Bacillus macerans, creating the natural CDs 8. The natural CDs consist of rings of six, seven, or eight glucopyranose units named alpha, beta, and gamma, respectively (figure 2). The glucopyranose units are attached by alpha 1 4 linkages in a circular arrangement. This arrangement creates a truncated cone that points the hydroxyl groups outward along the rims while directing the alpha 1 4 linkages inward (above). Page 7 of 31

8 The narrow opening is called the primary face, and the larger opening is called the secondary face. The negatively charged hydroxyl groups lining the primary and secondary faces are responsible for the water solubility of these molecules. The interior of the CD is lined by the carbon atoms and alpha1 4 linkages creating a lipophilic cavity. The steric nature of CDs creates a water soluble molecule that possesses a cavity capable of surrounding and binding a lipophilic molecule. The main pharmacologic benefit extracted from this structural arrangement is encapsulation of appropriately sized lipophilic molecules or drugs and the promotion of aqueous solubility 9. Historically, CDs have been considered excipients (inert adjuncts) lacking pharmacologic activity but useful for improving the formulation of other active compounds. CD encapsulation of lipophilic drugs, which are difficult to solubilise, allows their dissolution in water, which is biologically better tolerated than the organic solvents currently used. Although CDs possess aqueous solubility and an affinity for lipophilic molecules, the relative potency of these characteristics varies between different CDs. Close size approximation of lipophilic molecules to their corresponding CD is necessary to allow non-covalent thermodynamic interactions to occur promoting the formation of an inclusion complex. The approximate cavity sizes of the natural CDs are: gamma (0.8 nm), beta (0.6 nm), alpha (0.5 nm) 9. Once inside a CD cavity, thermodynamic attractions including electrostatic interaction, van der Waals interaction, hydrophobic interaction, hydrogen bonding, release of conformational strain, exclusion of cavity bound high-energy water, and charge-transfer interaction may contribute to the formation of the inclusion complex 10. An inclusion complex, also known as a host-guest assembly, is the newly formed molecular entity of a CD and its encapsulated lipophilic molecule. Modification of the natural CDs allows improvement of their aqueous solubility and thermodynamic attractions for a particular guest molecule. The ability to improve upon the base characteristics of natural CDs has led to the discovery of a CD that promises the unique drug effect of NMBA encapsulation with resultant termination of the paralytic effect. Page 8 of 31

9 DISCOVERY OF THE MODIFIED CYCLODEXTRIN SUGAMMADEX The impetus for discovery of the modified gamma CD sugammadex was the desire to improve the solubility of the NMBA rocuronium 11. Rocuronium is a nondepolarizing NMBA with a steroidal backbone that is commercially prepared in an aqueous solution adjusted to a ph of 4.0. Researchers at Organon Laboratories wanted to solubilize rocuronium without the acidic mannitol phosphate buffer solvent used in the current formulation. The exploration of suitable solvents led to CDs, which have been known and used to solubilize lipophilic molecules for over 100 years 8. Understanding the potential to achieve CD encapsulation specific for rocuronium, researchers explored many modifications of the alpha, beta, and gamma CDs. The candidate CD chosen to solubilize rocuronium was the modified gamma CD Org (sugammadex). Sugammadex is a modified gamma CD with every 6th carbon hydroxyl group substituted with a thioether linked to a carboxyl group. The thioether linkages extend the cavity length allowing complete encapsulation of the rocuronium molecule while increasing the area over which thermodynamic attractions can occur 12. A secondary benefit provided by the negatively charged carboxyl groups is an increased aqueous solubility of the sugammadex molecule. X-ray crystallography has shown very close size compatibility between sugammadex and the rocuronium molecule 12. Furthermore, it was found to be one of the most stable complexes of a CD and its guest molecule, with an association constant (Ka) of M The discovery of sugammadex s extremely high binding affinity for rocuronium changed the research focus from in vitro drug solubilization to the Page 9 of 31

10 novel concept of in vivo drug extraction 12. The new concept of encapsulation termination of the effects of NMBAs was born. The high lipophilic binding affinity of sugammadex raised concerns about potential undesirable binding to endogenous and exogenous steroidal compounds. These concerns were addressed during early studies. Zhang found over 40 lipophilic, steroidal, and non steroidal drugs typically given during an anesthetic case had affinities with sugammadex that ranged from times less than that of rocuronium 8. These drugs include induction agents (propofol, thiopenthone), narcotics (fentanyl, remifentanyl), antibiotics (vancomycin, gentamycin), bronchodilators (salbutamol, aminophyline), cardiovascular drugs (atropine, digoxin, ephedrine, phentolamine, verapamil), and steroids (cortisone, hydrocortisone). Clinical studies also showed no evidence of interaction with or alteration of the volatile inhalation anesthetic sevoflurane or the intravenous anesthetic propofol 13. Thus, sugammadex has high selectivity for the aminosteroidal NMBAs. Page 10 of 31

11 PHARMACOLOGY Mechanism of Action Sugammadex is the first CD created to perform its own drug effect. The process of sugammadex reversal of NMBA effects can be broken down into two component parts, direct molecular encapsulation and mass extraction of NMBAs from the nicotinic junction into the plasma. Sugammadex is administered intravenously and remains in the plasma without diffusing or being transported to other compartments. In the plasma, sugammadex encapsulates and non-covalently binds aminosteroidal NMBAs with a one-to-one ratio. The plasma encapsulation of NMBA molecules prevents their diffusion into the peripheral compartment for attachment to nicotinic ACh receptors. In addition, NMBA molecules already attached to extracellular nicotinic receptors, causing neuromuscular blockade are rapidly drawn into the plasma and encapsulated. This removal of NMBA molecules from nicotinic ACh receptors occurs because of the concentration gradient created by sugammadex binding of the NMBAs in the plasma 14. Page 11 of 31

12 That is, the shift to a low concentration of unbound NMBA molecules in the plasma causes the higher concentration of extracellular NMBA molecules to detach from the ACh receptors and diffuse into the plasma. Once back in the plasma, these NMBA molecules are quickly encapsulated and bound by sugammadex. This process occurs rapidly, restoring motor function. The two-fold process of one-to-one encapsulation/binding in the plasma and the concentration gradient mediated extraction of NMBAs from the nicotinic Ach receptors results in fast and effective termination of neuromuscular blockade by sugammadex. The ability of sugammadex to encapsulate and reverse the effects of aminosteroidal NMBAs varies between agents. Sugammadex reverses rocuronium greater than vecuronium and much greater than pancuronium 15,16. Pharmacokinetics and Metabolism Sugammadex has no affinity for binding to plasma proteins 17. When administered to volunteers who had not received a neuromuscular blocking agent, doses of mg/kg of sugammadex had a clearance rate of 88 ml/minute, an elimination half-life of 1.8 hours, and a volume of distribution of L. 18 Approximately 75%of the dose was eliminated renally. Between 59% and 80% of the sugammadex dose is excreted renally in the first 24 hours after administration. 18 The kinetics of sugammadex appeared to be linear when the sugammadex dose was increased from 0.1 to 8.0 mg/kg. 18 In the absence of sugammadex, rocuronium is eliminated mainly by biliary excretion (75%) and to a lesser degree by renal and faecal routes. 19 In contrast, the plasma clearance of sugammadex alone is approximately one third that of rocuronium alone. Because of the soluble nature of the sugammadex rocuronium complex, urinary excretion of the complex is the major route for the elimination of the complexed rocuronium (65% 97% of the administered dose is recovered in urine). 17 Metabolism of sugammadex is at most very limited, and the drug is thus eliminated in the urine mostly unchanged. Page 12 of 31

13 CLINICAL EVALUATION The efficacy of reversal with sugammadex has been studied in three clinical conditions that mirror the recommended dose ranges: 1) if reversal of shallow block (defined as spontaneous recovery to reappearance of the second twitch, T2, of the TOF) is desired, a dose of 2 mg/kg is recommended; 2) for reversal of deep block (defined as spontaneous recovery to at least 1 2 post-tetanic counts, PTC1 2), a dose of 4 mg/kg is recommended; 3) for rescue in the scenario of a large dose administration when there is no evidence of any spontaneous recovery in the cannot intubate-cannot ventilate setting, a dose of 16 mg/kg is recommended. These doses of sugammadex were used for subsequent clinical trials that formed the basis for approval by the European Medicines Agency (EMEA). Based on the published tolerance intervals (97.5% confidence level), a dose of 2 mg/kg of sugammadex for reversal of shallow block (return of T2) will result in complete reversal (TOF 0.9) in 90% of patients within three minutes after rocuronium administration, and within 5.9 min after vecuronium administration. Based on the same tolerance intervals (97.5% confidence level), a dose of 4 mg/kg of sugammadex for reversal of deep block (administered at PTC1 2) will result in complete reversal (TOF 0.9) in 90% of patients within 3.9 min after rocuronium administration (no confidence intervals were calculated for vecuronium at this deep level of block). 24 Finally, for immediate reversal of block (within 3 5 minutes of administration of 1.2 mg/kg of rocuronium), the mean time for complete spontaneous recovery was minutes (range, minutes), while a dose of sugammadex of 16 mg/kg resulted in complete recovery within a mean of 1.6 min (range min). 24 The evidence base for efficacy of sugammadex includes randomised trials comparing rocuronium or vecuronium + sugammadex with one another, or placebo, or with appropriate active comparators for reversal of moderate or profound block or for immediate reversal. There are a limited number of trials, many of which were dose-finding studies with very few patients exposed to the relevant doses of sugammadex. Total numbers of patients receiving 2 mg, 4 mg and 16 mg of sugammadex in the pooled phase I III trials were 606, 582 and 99, respectively. Page 13 of 31

14 Evidence concerning the safety of sugammadex comes from trials involving 1926 patients treated with sugammadex at doses ranging from < 2 to 32 mg/kg; most patients received one of the standard doses of 2, 4 or 16 mg/kg. Overall rates of adverse events were similar between sugammadex administered after rocuronium or vecuronium and comparators (neostigmine or placebo). The most significant adverse events following treatment with sugammadex appear to be anaesthetic complications (up to 3%) and possibly allergic reactions. Recurrence of blockade and residual blockade were reported in clinical trials but most cases were in patients receiving sub therapeutic doses and hence not of clinical significance. Reversal of Moderate Block In the four relevant randomised dose-finding trials, reversal of moderate block was faster and more predictable with sugammadex 2 mg/kg than placebo; median times to recovery of the TOF ratio to 0.9 ranged from 1.3 to 1.7 minutes with rocuronium + sugammadex 2 mg/kg, and 2.3 to 2.9 minutes with vecuronium + sugammadex 2 mg/kg, compared with minutes with placebo. The recovery times found for sugammadex are comparable with those reported in published pooled analyses (presumably of many of the same trials): the weighted average of 1.7 minutes reported by Abrishami et al. 26 for reversal of rocuroniuminduced moderate block, and the medians of 1.9 minutes for rocuronium + sugammadex and 2.3 minutes for vecuronium + sugammadex in the pooled analyses of Blobner et al. 27 In the more clinically relevant comparison with neostigmine, sugammadex again produced quicker and more reliable recovery of the TOF ratio to 0.9, with median (range) times of 1.4 ( ) versus 17.6 ( ) minutes when rocuronium was used in each group and 2.1 ( ) versus 18.9 ( ) minutes with vecuronium. The figures for vecuronium + sugammadex suggest a greater inter individual variability in response to sugammadex following vecuronium compared with rocuronium. In addition, the comparison of rocuronium + sugammadex with cisatracurium + neostigmine reported respective medians (ranges) of 1.9 ( ) versus 7.3 ( ). Again, these findings were similar to the medians reported by Blobner et al. 27 and Khuenl-Brady et al. 28 (1.9 minutes for rocuronium + sugammadex, 2.3 minutes for Page 14 of 31

15 vecuronium + sugammadex, 17.6 minutes for rocuronium + neostigmine, and 18.9 minutes for vecuronium + neostigmine). These results suggest a clear pharmacological benefit of sugammadex over the current standard treatment for reversal of moderate NMB, i.e. N&G. However, whilst the faster and more predictable reversal obtained with sugammadex could save time and allow more efficient scheduling of procedures, no data were available on resource use or patient-reported outcomes to demonstrate these efficiency gains in practice. The time savings achieved with sugammadex compared with neostigmine, might also be reduced by careful monitoring and early administration of neostigmine but it is uncertain how far current clinical practice reflects this ideal. The ability of the anaesthetist to predict the end of the procedure and reduce the level of blockade accordingly may vary depending on such factors as the experience of the anaesthetist and his/ her experience of working with a particular surgeon. Page 15 of 31

16 Reversal of Profound Block Reversal of profound blockade is a very important indication because there is unmet clinical need. Within current anaesthetic practice there are no reversal agents capable of rapid recovery times from profound NMB. The most commonly used reversal agent, neostigmine, is only effective when the patient has recovered to at least a T2 level, i.e. moderate block, such that when reversal of a deeper level of block is required, the anaesthetist must wait for partial spontaneous recovery to occur before administering neostigmine. A single RCT demonstrated that not only is N&G relatively ineffective for the reversal of profound block, but that sugammadex (4 mg/kg) is capable of reversing both rocuronium- and vecuronium-induced block at PTC 1 2 (profound level). Median (range) times to recovery of the TOF ratio to 0.9 were 2.7 ( ) minutes for rocuronium + sugammadex, 49.0 ( ) minutes for rocuronium + neostigmine, 3.3 ( ) for vecuronium + sugammadex and 49.9 ( ) for vecuronium + neostigmine. As in reversal of moderate block, the range of recovery times with sugammadex was wider following vecuronium than rocuronium. Additional dose-finding studies demonstrated a more rapid and predictable reversal of profound blockade with sugammadex compared with placebo. This potentially has implications for both the management of patients and duration of the NMB in terms of safety, and time spent waiting for recovery after the end of surgery. This could facilitate better management of the NMB and reduce time to recovery at the end of the operation. Page 16 of 31

17 Rapid Reversal The ability to rapidly reverse high-dose rocuronium-induced NMB using a high dose (16 mg/kg) of sugammadex is potentially another important benefit of sugammadex. When rapid induction of NMB is required, the main current option is to use succinylcholine, which is effective with the added benefit of rapid recovery, should that be necessary, but has a wide range of potentially dangerous adverse effects. High-dose rocuronium could be used for rapid induction of blockade, but carries the danger that the patient could not be recovered rapidly if the need arose; sugammadex enables this danger to be overcome. Thus, high-dose rocuronium with 16-mg/kg sugammadex could potentially replace succinylcholine, providing at least as rapid induction and reversal of blockade when necessary, with fewer adverse effects. In the event of a cannot intubate cannot ventilate emergency, in either the rapid induction or routine intubation setting, there is currently no reversal agent available and invasive treatment is required to prevent the risk of hypoxia leading to permanent brain damage or death. The main evidence for sugammadex for rapid reversal of NMB comes from a single RCT 29 that demonstrated that recovery of T1 to 10% of control values is significantly faster (p < by analysis of variance) following blockade induced by rocuronium and reversal by sugammadex 16 mg/kg than blockade induced by succinylcholine followed by spontaneous recovery. The primary end point used in this study was recovery of T1 to 10% of control value, a relevant end point for comparison with succinylcholine but one that was not used in any of the other studies. The clinical relevance of this end point is uncertain because, although some signs of breathing Page 17 of 31

18 may be present, T1 of 10% does not represent a sufficient degree of recovery to allow safe extubation. However, the more clinically relevant end point of recovery of the TOF ratio to 0.9 was also measured in this study in the sugammadex group, giving a median of 1.7 minutes (range ). The wide range of times required to reach this end point in the active-control study may be of concern if there is a significant group of patients for whom sugammadex, even at 16 mg/kg, is not fully effective. Similar median times of less than 2 minutes from administration of 16-mg/kg sugammadex to recovery of the TOF ratio to 0.9 were obtained in the placebo-controlled dose finding studies. A potential issue with the use of 16-mg/kg sugammadex in an emergency is that the relevant clinical trials were only simulations of this situation, and the appropriate dose of sugammadex was drawn up and ready for immediate administration. In routine practice, drawing up this dose in advance in anticipation of a very rare event would be highly wasteful and expensive. On the other hand, the time required to prepare the dose, including opening three ampoules and drawing the contents into a syringe, would increase the time the patient was exposed to hypoxia. The exact time this might take under the stress of an emergency situation is difficult to estimate. The benefit of sugammadex in terms of facilitating the handling of cannot intubate cannot ventilate emergencies and avoiding catastrophic events, such as hypoxic brain damage and death, is difficult to assess fully until the drug has been widely used in clinical practice. Page 18 of 31

19 SPECIAL POPULATIONS Phase III clinical trials have also explored the effects of sugammadex in pediatric and elderly patients, and in patients with renal, pulmonary, and cardiac disease. Paediatrics A study by Plaud 31 investigated rocuronium-induced (0.6 mg/kg) neuromuscular blockade in 8 infants (age 28 days to 23 months), 24 children (age 2 11 years), 31 adolescents (age years), and 28 adults (age years) anesthetized with propofol and opioids or caudal anesthesia. When shallow neuromuscular block was confirmed by TOF 2/4, sugammadex doses of mg/kg were administered. A dose-dependent time to TOF ratio 0.9 was demonstrated in all groups except the infant group due to the low number of subjects. The median time to recovery was less than 3 minutes with sugammadex doses of 1.0, 2.0, and 4.0 mg/kg in all groups. Elderly The efficacy of sugammadex for the reversal of shallow rocuronium-induced neuromuscular blockade (TOF 2/4) was studied in 48 adult patients (age years), 62 elderly (age years), and 40 old elderly patients (age <75 years) 31. All patients received rocuronium 0.6 mg/kg followed by sugammadex 2 mg/kg at a Page 19 of 31

20 TOF 2/4. The mean time to recovery of the TOF ratio to 0.9 was 2.3 minutes in the adult group, 2.6 minutes in the elderly group, and 3.6 minutes in the old elderly group. The estimated time to TOF 0.9 in all patients over 65 years of age was 2.9 minutes versus 2.3 minutes in the adult group. Renal Impairment The effectiveness of sugammadex for the reversal of rocuronium-induced neuromuscular blockade was assessed in 15 patients with impaired renal function (creatinine clearance < 30 ml/min) and 15 patients with normal renal function (creatinine clearance >80 ml/min) 32. All patients were anesthetized with propofol and opioids, and had neuromuscular blockade induced with rocuronium 0.6 mg/kg. At the reappearance of TOF 2/4, sugammadex 2.0 mg/kg was administered. The mean time to recovery of TOF ratio to 0.9 was 2.0 minutes in the renal impaired group and 1.7 minutes in group with normal renal function. The authors reported no signs of recurarization or adverse effects, and concluded that sugammadex rapidly and completely reverses rocuronium-induced neuromuscular blockade in patients with normal or impaired renal function. Cardio-pulmonary Disease Patients with pulmonary disease were studied to examine the possible respiratory effects of sugammadex. Seventy seven patients 18 years or older, ASA class II-III, with a known history or diagnosis of pulmonary disease were anaesthetised and administered rocuronium (0.6 mg/kg) 33. At the end of surgery and reappearance of TOF 2/4, sugammadex 2.0 or 4.0 mg/kg was administered. The mean time to Page 20 of 31

21 recovery of the TOF ratio to 0.9 was 1.8 minutes in the sugammadex 4.0 mg/kg group, and 2.1 minutes for the 2.0 mg/kg group. Two serious episodes of bronchospasm occurred that were considered possibly related to sugammadex, both of which were in the 4.0 mg/kg dose group. Both patients had a history of asthma. No alterations in respiratory rate or recurarization were observed in any patients. The authors concluded sugammadex was well tolerated and effective for the reversal of rocuronium-induced neuromuscular blockade in patients with pulmonary disease. One hundred twenty-one patients with cardiac disease (NYHA class II-III, ASA class II-IV, age years) undergoing elective non-cardiac surgery, were anesthetized and received rocuronium 34. At the reappearance of TOF 2/4, sugammadex 2.0 or 4.0 mg/kg was administered. The mean time to a TOF ratio of 0.9 was found to be 1.7 minutes with sugammadex 2.0 mg/kg and 1.4 minutes with the 4.0 mg/kg dose. The authors disclosed two serious adverse events (SAEs) relating to prolongation of the QTc interval in the placebo and sugammadex groups. Of these, one case of QTc interval prolongation in each treatment group (placebo and sugammadex group) was considered by the investigator to be possibly related to study treatment. Analysis of the mean QTc interval using the Fridericia correction was performed. Safe and effective use of sugammadex in cardiac patients was concluded. However, the general anesthetics used in this study, which may cause QTc prolongation, were not disclosed in this preliminary report. Page 21 of 31

22 SAFETY The safety of sugammadex has been evaluated based on an integrated safety database of approximately 1,700 patients and 120 volunteers. The most commonly reported adverse reaction, dysgeusia (metal or bitter taste), was generally reported after doses of 32 mg/kg of sugammadex or higher. In a few individuals, allergic-like reactions (ie, flushing, erythematous rash) following sugammadex were reported. In one of these individuals, a mild allergic reaction was confirmed. 21 Several studies have investigated the effects of sugammadex on the QTc interval. All of the published data to this point suggest that sugammadex does not significantly prolong the QTc interval. Prolongation was defined as an absolute QTc value > 500 msec, or an increase in baseline QTc of at least 60 msec. 21 There also was no evidence that sugammadex may predispose patients to QTc prolongation when sugammadex was administered in conjunction with drugs known for their propensity to prolong the QTc (such as propofol and sevoflurane). 21 Even in a subgroup of patients with severe heart disease, sugammadex did not induce QTc prolongation. 23 There have been no reports of clinically significant effects of sugammadex on hemodynamic variables (blood pressure, heart rate), respiration, or thermoregulation. 21 Common (incidence 1% 10%) adverse effects are similar for sugammadex and placebo. They include anesthetic complications (movement, coughing, grimacing, or suckling on the tracheal tube). While sugammadex has been approved by EMEA for clinical use in several European countries, the US Food and Drug Administration issued a not approvable letter (August 2008), citing concerns about hypersensitivity and allergic reactions. This was despite its advisory committee tabling a report that advocated the drugs approval. It is hoped that additional clinical and safety data will soon become available from the European experience, and may influence the US Food and Drug Administration decisions on the approval of sugammadex. Page 22 of 31

23 SPECIAL WARNINGS AND PRECAUTIONS FOR USE 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 medicinal products used in the peri- and postoperative 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. Waiting times for re-administration of NMBA s: If re-administration of rocuronium or vecuronium is required a waiting time of 24 hours is recommended. If neuromuscular blockade is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking agent should be used. Renal impairment: In patients with severe renal failure (creatinine clearance < 30 ml/min) the excretion of sugammadex or the sugammadex-rocuronium complex was delayed, however in these patients there were no signs of re-occurrence of neuromuscular blockade. Data from a limited number of renally impaired patients requiring dialysis indicate an inconsistent decrease of plasma levels of sugammadex by haemodialysis. The use of sugammadex in patients with severe renal impairment is not recommended. Potential interactions: 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 readministration 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. Displacement interactions: Due to the administration of certain medicinal products after sugammadex, theoretically rocuronium or vecuronium could be displaced from sugammadex. As Page 23 of 31

24 a result re-occurrence of 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 re-occurrence of blockade (approximately up to 15 minutes) after parenteral administration of another medicinal product occurring within a period of 6 hours after sugammadex administration. Displacement interactions are at present only expected for a few drugs substances (toremifene, flucloxacillin and fusidic acid). For toremifene, which has a relatively high affinity constant and relatively high plasma concentrations, some displacement of vecuronium or rocuronium from the complex with sugammadex could occur. The recovery of the T 4 /T 1 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 and high dose flucloxacillin (infusion of 500 mg or more), may cause some displacement of rocuronium or vecuronium from sugammadex. Use for reversal of neuromuscular blocking agents other than rocuronium or vecuronium: Limited data are available for reversal of pancuronium induced blockade, but it is advised not to use sugammadex in this situation. Allergic reactions: Clinicians should be prepared for the possibility of allergic reactions and take the necessary precautions. Pregnancy and lactation: 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. It is unknown whether sugammadex is excreted in human breast milk. Animal studies have shown excretion of sugammadex in breast milk. Oral absorption of cyclodextrins in general is low and no effects on the suckling child are anticipated following a single dose to the breast-feeding woman. Sugammadex can be used during breast-feeding. Page 24 of 31

25 Overdose: In clinical studies, 1 case of an accidental overdose with 40 mg/kg was reported without any significant undesirable effects. 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. Hormonal contraceptives: The interaction between 4 mg/kg sugammadex and a progesterone was predicted to lead to a decrease in progesterone exposure (34 % of AUC) similar to the decrease seen when a missed daily dose of an oral contraceptive is taken 12 hours too late, which might lead to a reduction in effectiveness. For estrogens, 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 progesterone 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. Page 25 of 31

26 UNCERTAINTIES Several uncertainties remain: Sugammadex combinations should be formally compared with all commonly used NMBA reversal agent combinations. This could be done through a MTC, subject to access to all data, and data being available from older trials that are comparable with those from the newer sugammadex trials. The benefits of sugammadex 16 mg/kg are difficult to assess fully until this dose has been used more widely in clinical practice an analysis of the proportion of patients who do not recover within 5 minutes would be informative. The incidence and significance of rare but serious adverse effects, such as anaphylactic/ allergic reactions, will become clearer when larger numbers of patients have been exposed to sugammadex. The patients in the sugammadex trials were mainly relatively young, and in ASA classes I II, and may not be fully representative of those who would receive sugammadex in routine clinical practice. The reductions in recovery time with sugammadex seen in the clinical trials may represent the maximum that can be achieved and the benefits in normal clinical practice will remain uncertain pending wider adoption and evaluation of sugammadex. In the routine setting, the key economic uncertainties surround the productivity benefits of reduced time in recovery, in particular the value of operating room staff time and the proportion of any reduction in recovery time that can be put to productive use. In the rapid induction and/or reversal setting, the key uncertainties surround the baseline rate of mortality due to succinylcholine, the relative risk of mortality due to sugammadex and the probability of a cannot intubate, cannot ventilate event occurring. It is possible that sugammadex results in further resource savings than those considered by allowing additional operations to be fitted into the working day and/or by reducing the costs associated with serious adverse events; however, there are no suitable data to provide a basis for such modeling. Page 26 of 31

27 Costing A comparison between sugammadex and neostigmine + glycopyrollate reveals just how far away we are from the use of the former in routine clinical practice in this country. The possible drivers for differences between the costs and health outcomes of each strategy were identified as the cost of acquiring each drug; the time spent in recovery; and rates of recurrence of block or residual block associated with the anesthetic strategies. Page 27 of 31

28 CONCLUSION Despite the significant advances in the chemistry of neuromuscular blocking agents, the promise of the perfect or ideal drug remains illusory. However, the significant improvements made in the last few decades in the pharmacology of relaxants and reversal agents have improved clinical care and patient safety. Even if we do not yet have a fast-onset, highly reliable, short duration, rapidly reversible, noncumulative nondepolarising drug, the characteristics of the perfect drug are within reach. By combining the rapid onset of a drug like rocuronium with the fast reversal and stable hemodynamic profile of the selective reversal agent sugammadex, the promise of rapid onset of block with rapid and reliable offset has become reality. And because reversal by sugammadex is independent of the depth of neuromuscular block, the morbidity associated with the cannot-ventilate/ cannot-intubate clinical scenario may be avoided; moreover, the lack of disassociation of the rocuronium/ sugammadex complex, will ensure that the recurrence or persistence of residual weakness will become an oddity of the past. Page 28 of 31

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