Sugammadex: A New Wheel Has Been Invented · prevent cholinergic crisis that can ... due to respiratory failure or myasthenic crisis. ... A systematic review of sugammadex vs neostigmine

Sugammadex:

A New Wheel Has Been Invented

Ashlee A. Wheeler, BSN, RN, SRNA

Disclaimer Statement

Conflict of Interest: None

I have not received any compensation for this

presentation.

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.

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

15th, 2015.

Is indicated for the reversal of neuromuscular blockade caused

by the aminosteroid non-depolarizing muscle relaxants

rocuronium bromide or vecuronium bromide

What's in a name…

• Su-in Sugammadex stands for sugar

• -gammadex stands for the structural molecule gamma-

cyclodextrin

• There are 3 naturally occurring cyclodextrins

• Alpha

• Beta

• Gamma

• Sugammadex is a modified γ-cyclodextrin

Encapsulating

• Intermolecular (van der Waals’)

forces

• Thermodynamic (hydrogen)

bonds

• Hydrophobic interactions

• 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

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

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

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

Contraindications

Absolute contraindication is:

known hypersensitivity to

sugammadex or any of its

components.

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 rocuronium-

sugammadex complex can be filtered by high-flux dialysis filters

but not low-flux

High-flux filters allow molecules that are 500-40,000 Da to pass

Sugammadex exceeds 2,000 Da

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.

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

Considerations: Pharmacology

Compatible delivery fluids:

Normal Saline

5% Dextrose

Ringer’s Lactate

Physically incompatible:

Verapamil

Ondansetron (Zofran)

Ranitidine (Zantac)

5% Dextrose in Normal Saline

2.5% Dextrose in 0.45% Normal

Saline

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

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-0.001609442%

“Sugammadex appears to be a safe and well-tolerated

agent”

No deaths have been related to the administration of

sugammadex

Side Effects

Hypotension

Coughing

Nausea

Vomiting

Dry Mouth

Sensation of a change in

temperature

Abnormal level of N-

Acetylglucosaminidase in the

urine

Most Frequent Adverse Effects:

Appear to be more frequent at higher clinical doses

Reactions are typically seen within 5 minutes of administration

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

Dosing: Re-administration

Options for neuromuscular block after sugammadex 2-4 mg/kg

administration:

Succinylcholine

Benzylisoquinolinium agents

Cisatracurium or Atracurium

Rocuronium* or Vecuronium*

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

Dose

Train of Four

Reversal of 1.2 mg/kg Rocuronium

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

Figure1:Time(Minutes)fromAdministrationofBRIDIONorNeostigmineattheReappearanceofT2afterRocuroniumtotheT4/T1Rationto0.9

Figure2:Time(Minutes)fromAdministrationofBRIDIONorNeostigmineattheReappearanceofT2afterVecuroniumtoRecoveryoftheT4/T1Ratioto0.9

Cost

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 $88.28

4 mg/kg $161.69/5 mL vial $161.69

16 mg/kg 3 x 5 mL vial =

$485.07

1 x 2 mL vial =

$88.28

$573.35

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)

$58.51/10 mL vial $89.65

Glycopyrrolate 200 mcg per 1 mg

of neostigmine

$31.14/5 mL vial

(1mg)

Sugammadex 2 mg/kg $88.59/2 mL vial $88.59

Cost

Prices from New Hanover Medical Group-Wilmington NC

J. Wheeler, personal communication, September 1,

2016

Can Sugammadex be cost-

effective?

• 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

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

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 ED95 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

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

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

SpO2 decreased to 80%

No carotid pulse detected CPR started

IV fluids administered

Increasing doses of epinephrine, initial 200 mcg, 800 mcg, 1 mg

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

SpO2 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

Questions??

References

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References

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