Sugammadex: A New Wheel Has Been Invented. Ashlee A. Wheeler, BSN, RN, SRNA

Transcription

1 Sugammadex: A New Wheel Has Been Invented Ashlee A. Wheeler, BSN, RN, SRNA

2 Disclaimer Statement Conflict of Interest: None I have not received any compensation for this presentation.

3 Objectives The participant will be able to Describe the mechanism of action for sugammadex. List the indications and contraindications for the use of sugammadex. Explain when to utilize doses of 2 mg/kg, 4 mg/kg, and 16 mg/kg of sugammadex.

4 What is Sugammadex? It is the first drug in a new class of medications called selective relaxant binding agents Brand name is Bridion Received U.S. Food and Drug (FDA) approval on December 15 th, Is indicated for the reversal of neuromuscular blockade caused by the aminosteroid non-depolarizing muscle relaxants rocuronium bromide or vecuronium bromide

5 What's in a name Su-in Sugammadex stands for sugar -gammadex stands for the structural molecule gammacyclodextrin There are 3 naturally occurring cyclodextrins Alpha Beta Gamma Sugammadex is a modified γ-cyclodextrin

6 Encapsulating The exterior of the structure is hydrophilic and the interior is lipophilic It is able to bind with rocuronium or vecuronium in a tight 1:1 ratio Sugammadex has a high association rate and very low dissociation rate Estimated that for every 25 million rocuronium-sugammadex complexes that form, only one dissociates Intermolecular (van der Waals ) forces Thermodynamic (hydrogen) bonds Hydrophobic interactions

7 Sugammadex-How does it work? When administered it binds with the free floating drug in the blood plasma This causes a concentration gradient to form, moving rocuronium from the neuromuscular junction back into the blood plasma where it can continue to be encapsulated by sugammadex

8 Metabolism and Elimination Neither sugammadex or the sugammadex-rocuronium complex undergoes any metabolism and does not form any metabolites within the body Both sugammadex and the sugammadex-rocuronium complex are cleared by the kidneys nearly 100% Normal glomerular filtration rate: 70% excreted in 6 hours over 90% within 24 hours

9 Indications Intravenous administration Reversal of neuromuscular blockade induced by: Rocuronium bromide Vecuronium bromide Currently only approved for use in adults In Europe it is also been approved for the reversal of rocuronium in children and adolescents

10 Contraindications Absolute contraindication is: known hypersensitivity to sugammadex or any of its components.

11 Considerations: Renal Impairment Patients with renal impairment: currently only recommended in patients who have a creatinine clearance greater than 30 ml/min In patients with a creatinine clearance less than 30 ml/min it can take 48 hours or more for the rocuronium-sugammadex molecule to be eliminated It is not known how long the complex will stay bound within the body In a study by Cammu et al. (2012) it was found that the rocuroniumsugammadex complex can be filtered by high-flux dialysis filters but not low-flux High-flux filters allow molecules that are ,000 Da to pass Sugammadex exceeds 2,000 Da

12 Considerations: Chemotherapy Patients who are currently on prescribed chemotherapy drug Toremifene There could be a delay in reversal if Toremifene has been given the same day as the surgery.

13 Considerations: Oral Contraceptives Women taking oral birth control with estrogen or progestogen complexes: Sugammadex will bind to the progestogen and block it, therefore it is the equivalent of missing a dose If given sugammadex, an alternative means of birth control should be used for seven days post administration

14 Considerations: Pharmacology Compatible delivery fluids: Normal Saline 5% Dextrose Ringer s Lactate 5% Dextrose in Normal Saline 2.5% Dextrose in 0.45% Normal Saline Physically incompatible: Verapamil Ondansetron (Zofran) Ranitidine (Zantac)

15 Safety Concerns Application submitted to the FDA and the European Union authorities in 2008 European Union authorities-approved FDA-denied due to concerns about hypersensitivity reactions in healthy volunteers who received high does The incidence of hypersensitivity in all studies was less than 1% Since its European approval in 2008 there have been over 9 million patient exposures-15 probable cases of sugammadex anaphylaxis worldwide

16 Study by Godai et al, (2012) show 3 suspected cases of sugammadex-induced hypersensitivity reactions over a 1 year period out of 1864 patient exposures % Sugammadex appears to be a safe and well-tolerated agent No deaths have been related to the administration of sugammadex

17 Side Effects Most Frequent Adverse Effects: Hypotension Coughing Nausea Vomiting Sensation of a change in temperature Abnormal level of N- Acetylglucosaminidase in the urine Reactions are typically seen within 5 minutes of administration Appear to be more frequent at higher clinical doses Dry Mouth

18 Dosing Regimen Dose range: 2 mg/kg if 2/4 twitches are present in response to train-of-four; 4 mg/kg if no TOF twitches are present but 1-2 post-tetanic counts are seen 16 mg/kg within 3 minutes of 1.2 mg/kg rocuronium, in a cannot intubate cannot ventilate situation Delivered as a bolus within 10 seconds. Onset: Less than 3 minutes

19 Dosing: Re-administration Options for neuromuscular block after sugammadex 2-4 mg/kg administration: Succinylcholine Benzylisoquinolinium agents Cisatracurium or Atracurium Rocuronium* or Vecuronium*

20 Dosing: Re-administration Rocuronium* or Vecuronium* Up to 4mg/kg of sugammadex 5 minutes 1.2 mg/kg rocuronium ** 4 hours 0.6 mg/kg rocuronium 0.1 mg/kg vecuronium 16 mg/kg of sugammadex 24 hours Rocuronium or Vecuronium ** Onset may be delayed up to 4 minutes ** Duration shortened up to 15 minutes

21 Dose

22 Train of Four

23 Reversal of 1.2 mg/kg Rocuronium

24 Compared to Neostigmine This mechanism of action, as you can see, is completely different from neostigmine No parasympathetic effects. No anticholinergic drugs required. Speed of reversal has been found to be 3-8 times faster than neostigmine

25 Figure 1: 2: Time (Minutes) from Administration of BRIDION of BRIDION or Neostigmine or Neostigmine at the at Reappearance the Reappearance of T 2 after of T2 Vecuronium after Rocuronium to Recovery to of the the T4/T1 T 4 /T 1 Ration to to

26 Cost Prices from York Hospital Reversal for 100kg patient Drug Dose Price per vial $ to reverse a 100kg patient Neostigmine 0.05 mg/kg (max 5mg) $13.21/10 ml vial $39.39 Glycopyrrolate 200 mcg per 1 mg of neostigmine $13.09/2 ml vial (2 vials, 800mcg) $26.18 Sugammadex 2 mg/kg $88.28/2 ml vial $ mg/kg $161.69/5 ml vial $ mg/kg 3 x 5 ml vial = $ x 2 ml vial = $88.28 $573.35

27 Cost Prices from New Hanover Medical Group-Wilmington NC Drug Dose Price per vial $ to reverse a 100kg patient Neostigmine Glycopyrrolate 0.05 mg/kg (max 5mg) 200 mcg per 1 mg of neostigmine $58.51/10 ml vial $89.65 $31.14/5 ml vial (1mg) Sugammadex 2 mg/kg $88.59/2 ml vial $88.59 J. Wheeler, personal communication, September 1, 2016

28 Can Sugammadex be costeffective? In a study by Carron et al. (2016) they looked at the clinical outcomes and the cost-effectiveness of sugammadex Cost savings were shown by decreasing the recovery time from neuromuscular blockage in the OR Additional savings: Reducing rate of postoperative residual curarization Time spent in the recovery room Decreased the rate of unexpected ICU admissions

29 Patient Populations Children: Not currently FDA approved for the use in patients 17 years of age Elderly: >65 years old. No difference in dose recommendations as long as kidney function is normal, recovery time may be prolonged from < 2 minutes to < 4 minutes Obesity: Dose based on actual body weight Pregnancy and breast feeding: Animal studies showed no signs of direct or indirect negative side effects Unknown if it is excreted in breast milk; animal studies do show a degree of excretion Oral absorption of sugammadex is low and no effects on infants are expected

30 Myasthenia Gravis Autoimmune disease resulting in a decrease in the number of postsynaptic acetylcholine receptors Patients are treated with anticholinesterase medications such as pyridostigmine Typically neuromuscular blocking agents are avoided in these patients These patients are resistant to succinylcholine requiring higher doses to achieve paralysis They can show sensitivity to nondepolarizing neuromuscular blockers requiring ½ of the ED 95 dose to achieve paralysis Reversing nondepolarizing neuromuscular blockers is avoided to prevent cholinergic crisis that can occur since patients are currently on these medications for their illness

31 Myasthenia Gravis-Continued Sugammadex may change the anesthetic treatment for these patients. Study by Ulke et al. (2013) enrolled 10 patients with myasthenia gravis who were scheduled for a video-assisted thoracoscopic extended thymectomy (VATET) All patients received 0.3 mg/kg of rocuronium for intubation and supplemental doses if required; total dose of rocuronium was 48 mg (±16 mg) At the end of the case all patients received 2 mg/kg of sugammadex All patient s achieved a train of four ratio of >0.9. All were extubated in the operating room and none required mechanical ventilation due to respiratory failure or myasthenic crisis

32 Case Study- Rocuronium Anaphylaxis 33-year-old, 77 kg, female laparoscopic procedure for the investigation of infertility 30 seconds after receiving 30 mg of rocuronium Tachycardia 122 beats per minute Cough Difficult mask ventilation After intubation-visual confirmation of tube placement No carbon dioxide detected on capnography Airway pressures were elevated Sp O2 decreased to 80% No carotid pulse detected CPR started IV fluids administered Increasing doses of epinephrine, initial 200 mcg, 800 mcg, 1 mg

33 Case Study-Continued 19 minutes into resuscitation 4 mg of epinephrine 2000 ml of Lactated Ringer s 1500 ml of colloid 500 mg of sugammadex (6.5 mg/kg) administered during chest compressions 45 seconds after administration during chest compressions, patient opened her eyes and reached for the endotracheal tube Blood pressure 111/56 Heart rate 126 beats minute Sp O2 97% Patient was transferred to an off site intensive care unit Within 30 minutes of arrival to the ICU patient was extubated and no vasopressor support was required Patient was discharged 48 hours after the event with no additional complications and no recollection of the event

34 Questions??

35 References Abad Gurumeta, A., Ripollés Melchor, J., Casans Francés, R., Espinosa, A., Martínez Hurtado, E., Fernández Pérez, C.,... & Calvo Vecino, J. M. (2015). A systematic review of sugammadex vs neostigmine for reversal of neuromuscular blockade. Anaesthesia, 70(12), Barash, P. G., Cullen, B. F., Stoelting, R. K., Cahalan, M. K., Stock, M. C., & Ortega, R. (2013). Clinical anesthesia (7 th ed.). Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins. Cammu, G., Van Vlem, B., van den Heuvel, M., Stet, L., el Galta, R., Eloot, S., & Demeyer, I. (2012). Dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment. British journal of anaesthesia, 109(3), Carron, M., Baratto, F., Zarantonello, F., & Ori, C. (2016). Sugammadex for reversal of neuromuscular blockade: a retrospective analysis of clinical outcomes and cost-effectiveness in a single center. ClinicoEconomics and outcomes research: CEOR, 8, 43. Chambers, L. (2016). Pharmacy and therapeutics committee formulary review sugammadex (Bridion). [Handout]. Wellspan. Godai, K., Hasegawa-Moriyama, M., Kuniyoshi, T., Kakoi, T., Ikoma, K., Isowaki, S.,... & Kanmura, Y. (2012). Three cases of suspected sugammadex-induced hypersensitivity reactions. British journal of anaesthesia, 109(2), Ledowski, T. (2015). Sugammadex: What do we know and what do we still need to know? A review of the recent (2013 to 2014) literature. Anaesthesia & Intensive Care, 43(1). McDonnell, N. J., Pavy, T. J. G., Green, L. K., & Platt, P. R. (2011). Sugammadex in the management of rocuronium- induced anaphylaxis. British journal of anaesthesia, 106(2), Merck Sharp & Dohme Corp. (2015). Sugammadex [package insert]. Retrieved April 14, 2016 from Nag, K., Singh, D. R., Shetti, A. N., Kumar, H., Sivashanmugam, T., & Parthasarathy, S. (2013). Sugammadex: A revolutionary drug in neuromuscular pharmacology. Anesthesia, Essays and Researches, 7(3), 302.

36 References Naguib, M. (2007). Sugammadex: Another milestone in clinical neuromuscular pharmacology. Anesthesia & Analgesia, 104(3), Peeters, P. A., van den Heuvel, M. W., van Heumen, E., Passier, P. C., Smeets, J. M., van Iersel, T., & Zwiers, A. (2010). Safety, tolerability and pharmacokinetics of sugammadex using single high doses (up to 96 mg/kg) in healthy adult subjects. Clinical drug investigation, 30(12), Schaller, S. J., & Fink, H. (2013). Sugammadex as a reversal agent for neuromuscular block: an evidence-based review. Core Evid, 8(8), Sungur Ulke, Z., Yavru, A., Camci, E., Ozkan, B., Toker, A., & Senturk, M. (2013). Rocuronium and sugammadex in patients with myasthenia gravis undergoing thymectomy. Acta Anaesthesiologica Scandinavica, 57(6), UpToDate. (2016). Sugammadex: Drug Information. In: UpToDate online. Retrieved from: source=search_result&search=sugammadex&selectedtitle=1%7e25 Welliver, M. (2006). New drug sugammadex: A selective relaxant binding agent. AANA journal, 74(5). Welliver, M., & Cheek, D. (2009). An update on sugammadex sodium. AANA journal, 77(3). Welliver, M., Cheek, D., Osterbrink, J., & McDonough, J. (2015). Worldwide experience with sugammadex sodium: Implications for the United States. AANA journal, 83(2), 107. Williamson, R. M., Mallaiah, S., & Barclay, P. (2011). Rocuronium and sugammadex for rapid sequence induction of obstetric general anaesthesia. Acta Anaesthesiologica Scandinavica, 55(6),

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