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Bridion

Generic Name: Sugammadex Sodium
Class: Antidotes
Chemical Name: C72H104Na8O48S8
Molecular Formula: 6A,6B,6C,6D,6E,7F,6G,6H-Octakis-S-(2-carboxyethyl)-6A,6B,6C,6D,6E,6F,6G,6H-octathio-γ-cyclodextrin
CAS Number: 343306-79-6

Introduction

Selective relaxant binding agent; modified γ-cyclodextrin.1 3 4 7 15 17 18

Uses for Bridion

Reversal of Neuromuscular Blockade

Used to reverse neuromuscular blockade induced by rocuronium or vecuronium in patients undergoing surgery.1 2 3 4 5 6

Reduces time to recovery of neuromuscular function when administered at moderate (reappearance of the second twitch [T2] in a train-of-four [TOF] stimulation) or deep (1–2 posttetanic counts [PTC] and no twitch responses to TOF stimulation) neuromuscular blockade compared with neostigmine.1 2 3 4 5 6

Highest recommended dose of 16 mg/kg may be used for immediate reversal of profound neuromuscular blockade induced by high-dose (1.2 mg/kg) rocuronium bromide if clinically indicated; when given shortly (approximately 3 minutes) after the onset of blockade, reduces time to recovery of neuromuscular function compared with spontaneous recovery from succinylcholine.1 6 15 20

Effective reversal agent for steroidal neuromuscular blocking agents rocuronium and vecuronium only; do not use for reversal of nonsteroidal neuromuscular blocking agents (e.g., succinylcholine, benzylisoquinolinium compounds [atracurium, mivacurium]).1 121

Not studied in the intensive care unit (ICU) setting.1

Bridion Dosage and Administration

General

Reversal of Neuromuscular Blockade

  • Administer only by trained clinicians experienced in the use of neuromuscular blocking agents and reversal agents. 1

  • Monitor patient for adequate ventilation and maintenance of patent airway until complete recovery of neuromuscular function (based on assessment of skeletal muscle tone, respiratory measurements, and response to peripheral nerve stimulation).1 120 121 122 123 Adequate recovery of neuromuscular function generally defined as a TOF ratio ≥0.9 in addition to the patient's ability to maintain satisfactory ventilation and a patent airway.1 120 121 123

  • Ventilatory support required until recovery of adequate spontaneous respiration and ability to maintain a patent airway is assured.1 (See Respiratory Function Monitoring under Cautions.)

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by direct IV (“bolus”) injection over 10 seconds into an existing IV line.1 The drug has only been administered as a single direct IV injection in clinical studies.1

Dosage

Available as sugammadex sodium; dosage expressed in terms of sugammadex.1

Determine appropriate dose and timing based on twitch response monitoring and the extent of spontaneous recovery that has occurred.1 Dose does not depend on the anesthetic regimen used.1

Calculate dose based on actual body weight.1

Adults

Routine Reversal of Rocuronium- or Vecuronium-induced Neuromuscular Blockade
IV

For reversal of moderate blockade (i.e., spontaneous recovery has reached the reappearance of T2 in a TOF stimulation) following rocuronium or vecuronium: 2 mg/kg.1

For reversal of deep blockade (i.e., spontaneous recovery of the twitch response has reached 1–2 PTC and no twitch responses to TOF stimulation) following rocuronium or vecuronium: 4 mg/kg.1

Immediate Reversal of Rocuronium-induced Neuromuscular Blockade
IV

For reversal immediately (approximately 3 minutes) after a single 1.2-mg/kg dose of rocuronium bromide if clinically indicated: 16 mg/kg.1

Efficacy of the 16-mg/kg dose for rapid reversal of vecuronium not established.1

Special Populations

Hepatic Impairment

No specific dosage recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment: No dosage adjustment required.1

Severe renal impairment, including dialysis: Use not recommended.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustment required.1 However, careful dosage selection advised because of age-related decreases in renal function.1

Cautions for Bridion

Contraindications

  • Known hypersensitivity to sugammadex or any ingredient in the formulation.1

Warnings/Precautions

Anaphylaxis and Hypersensitivity

Serious, potentially fatal, hypersensitivity reactions reported.1 12 13 20 Manifestations have ranged from isolated skin reactions (e.g., flushing, urticaria, erythematous rash) to more severe systemic reactions (e.g., anaphylaxis) requiring use of vasopressors, prolonged hospitalization, and/or additional respiratory support.1 12

Monitor for hypersensitivity reactions and ensure ability to manage such reactions.1

Bradycardia

Marked bradycardia may occur minutes after sugammadex administration; cardiac arrest precipitated by bradycardia also reported.1 Closely monitor for hemodynamic changes and administer anticholinergic agents (e.g., atropine) if clinically important bradycardia occurs.1

Respiratory Function Monitoring

Delayed or minimal reversal of neuromuscular blockade following sugammadex administration has occurred in some patients.1 Neuromuscular blockade also may recur following extubation.1 Respiratory depression may persist after complete recovery of neuromuscular function.1

Monitor respiratory function and provide ventilatory support until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured.1 If neuromuscular blockade persists or recurs, take appropriate steps to provide adequate ventilation.1

Readministration of Neuromuscular Blocking Agents

If readministration of a steroidal neuromuscular blocking agent is necessary (e.g., for intubation) after reversal with sugammadex, observe a minimum wait time based on dose of sugammadex and renal function.1

Following administration of sugammadex (2 or 4 mg/kg), a minimum wait time of 5 minutes is recommended before readministration of rocuronium bromide 1.2 mg/kg, and a minimum wait time of 4 hours is recommended before readministration of rocuronium bromide 0.6 mg/kg or vecuronium bromide 0.1 mg/kg.1 If rocuronium bromide 1.2 mg/kg is administered ≤30 minutes after sugammadex, the onset of neuromuscular blockade may be delayed up to approximately 4 minutes and the duration of blockade shortened by approximately 15 minutes.1

Following administration of sugammadex 16 mg/kg, a minimum wait time of 24 hours is recommended before rocuronium or vecuronium is readministered.1

In patients with mild or moderate renal impairment, a minimum wait time of 24 hours is recommended after administration of sugammadex (2 or 4 mg/kg) before rocuronium bromide 0.6 mg/kg or vecuronium bromide 0.1 mg/kg is readministered.1 If a shorter wait time is necessary, the rocuronium bromide dose for a new blockade should be 1.2 mg/kg.1

If neuromuscular blockade is required before the recommended wait times have elapsed, consider use of a nonsteroidal neuromuscular blocking agent (e.g., succinylcholine).1 However, onset of neuromuscular blockade with depolarizing neuromuscular blocking agents may be delayed in this setting.1

Recurrence of Neuromuscular Blockade

Risk of recurrence of neuromuscular blockade may be increased with concurrent use of certain drugs (i.e., drugs that displace rocuronium or vecuronium from sugammadex binding sites) or use of lower than recommended doses of sugammadex.1 Mechanical ventilation may be required.1

Risk also may be increased with use of drugs that potentiate neuromuscular blockade during postoperative period; consult prescribing information for rocuronium or vecuronium for specific drugs that may potentiate neuromuscular blockade.1 (See Interactions.)

Coagulopathy and Bleeding

Increased coagulation parameters (e.g., aPTT, PT, INR) observed.1 However, does not appear to correlate with an increased risk of bleeding.1

Risk of bleeding not evaluated with sugammadex 16 mg/kg in patients receiving thromboprophylaxis drugs.1 Risk of bleeding also not evaluated in patients with known coagulopathies or receiving therapeutic anticoagulation or thromboprophylaxis with drugs other than heparin and low molecular weight heparin.1 Carefully monitor coagulation parameters in such patients.1

Light Anesthesia

Signs of light anesthesia (e.g., movement, coughing, grimacing, suckling of the tracheal tube) may be noted if neuromuscular blockade is reversed during anesthesia.1

Specific Populations

Pregnancy

No data regarding use of sugammadex in pregnant women.1 Teratogenicity not observed in animal studies; however, incomplete ossification and reduced fetal body weight observed at dose exposures greater than the maximum recommended human dose.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Consider benefits of breast-feeding and importance of the drug to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Has been used in some pediatric patients for reversal of moderate rocuronium-induced neuromuscular blockade.7 Some evidence suggests similar efficacy and safety in pediatric patients 2–17 years of age and adults.9

Animal toxicity studies indicate possible adverse effects on developing bone; increased bone deposition, decreased bone length, and tooth enamel abnormalities observed in juvenile animals receiving daily IV doses of sugammadex.1

Geriatric Use

Median time to recovery following administration of sugammadex 2 mg/kg at reappearance of T2 after rocuronium-induced blockade was 2.5 and 3.6 minutes in geriatric patients 65–74 and ≥75 years of age, respectively, compared with 2.2 minutes in patients 18–64 years of age.1 Median time to recovery following sugammadex 4 mg/kg at 1–2 PTC was 2.5 minutes in geriatric patients ≥65 years of age compared with 2 minutes in younger adults.1

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment; not metabolized or excreted by the liver.1 Use with caution in patients with hepatic impairment accompanied by coagulopathy or severe edema.1

Renal Impairment

Not recommended in patients with severe renal impairment, including those requiring dialysis, because of prolonged and increased overall drug exposure and insufficient experience in such patients.1 8 (See Renal Impairment under Dosage and Administration.)

If patients with mild or moderate renal impairment require readministration of a neuromuscular blocking agent, a minimum wait time may be required.1 (See Readministration of Neuromuscular Blocking Agents under Cautions.)

Common Adverse Effects

Vomiting,1 pain,1 nausea,1 hypotension,1 headache.1

Interactions for Bridion

Not likely to be metabolized by CYP isoenzymes; therefore, CYP-mediated drug interactions not expected.1 22

Specific Drugs

Drug

Interaction

Comments

Hormonal contraceptives

Potential decreased exposure and reduced efficacy of hormonal contraceptive1

Advise women to use an additional, non-hormonal method of contraception for 7 days following sugammadex administration1

Toremifene

Displacement of rocuronium or vecuronium by toremifene can result in recurrence of neuromuscular blockade1

Recovery of neuromuscular function may be delayed1

Bridion Pharmacokinetics

Pharmacokinetics of sugammadex are based on the total concentration of free plus complex-bound sugammadex; the pharmacokinetics of complex-bound sugammadex are assumed to be the same as those of free sugammadex.1

Absorption

Bioavailability

Exhibits linear pharmacokinetics over dose range of 1–16 mg/kg.1

Onset

Recovery of neuromuscular function occurred at approximately 1.4–2.1 minutes when administered at reappearance of T2 for rocuronium- or vecuronium-induced neuromuscular blockade.1

Recovery of neuromuscular function occurred at approximately 2.7–3.3 minutes when administered at 1–2 PTC for rocuronium- or vecuronium-induced neuromuscular blockade.1

Distribution

Extent

Distributes into and is retained in sites of active mineralization (e.g., bone, teeth).1

Not known if distributed into milk.1

Plasma Protein Binding

None.1

Elimination

Metabolism

Not metabolized.1

Elimination Route

Excreted principally in urine as unchanged drug; <0.02% excreted in the feces or expired.1 >90% of a dose excreted within 24 hours.1

Hemodialysis using a high-flux filter removes about 70% of the drug over 3–6 hours.1

Half-life

Plasma: About 2 hours.1

Bone and teeth: 172 and 8 days, respectively.1

Special Populations

Plasma elimination half-life is 4, 6, or 19 hours in patients with mild, moderate, or severe renal impairment, respectively.1

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).1 Protect from light; use within 5 days if not protected from light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Dextrose 2.5% in sodium chloride 0.45%

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water

Isolyte P in dextrose 5%

Ringer's injection

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Y-Site Compatibility1

Incompatible

Ondansetron

Ranitidine

Verapamil

Actions

  • A modified γ-cyclodextrin that binds selectively to and forms a complex with (i.e., encapsulates) steroidal nondepolarizing neuromuscular blocking agents (e.g., rocuronium, vecuronium); reduces amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction and thus reverses neuromuscular blockade. 1 3 4 7 15 17 18 121

  • Forms a complex with free rocuronium or vecuronium molecules in plasma in a 1:1 ratio.1 Because of cyclodextrin structure (hydrophilic molecule with a lipophilic core), specifically encapsulates lipophilic (e.g., steroidal) molecules.1 15 18

  • Exhibits higher binding affinity for rocuronium than vecuronium and a much lower affinity for pancuronium.15 121

  • No affinity for succinylcholine, mivacurium, atracurium, or cisatracurium.15 18 121

Advice to Patients

  • Importance of informing women that sugammadex can substantially decrease the effectiveness of hormonal contraceptives, including oral and non-oral forms; advise women to use additional nonhormonal forms of contraception for 7 days after sugammadex administration.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Sugammadex Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

100 mg (of sugammadex) per mL

Bridion

Merck

AHFS DI Essentials. © Copyright 2017, Selected Revisions December 8, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Merck & Co., Inc. Bridion (sugammadex) injection prescribing information. Whitehouse Station, NJ; 2016 Sep.

2. Blobner M, Eriksson LI, Scholz J et al. Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomised, controlled trial. Eur J Anaesthesiol. 2010; 27:874-81. [PubMed 20683334]

3. Khuenl-Brady KS, Wattwil M, Vanacker BF et al. Sugammadex provides faster reversal of vecuronium-induced neuromuscular blockade compared with neostigmine: a multicenter, randomized, controlled trial. Anesth Analg. 2010; 110:64-73. [PubMed 19713265]

4. Jones RK, Caldwell JE, Brull SJ et al. Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine. Anesthesiology. 2008; 109:816-24. [PubMed 18946293]

5. Lemmens HJ, El-Orbany MI, Berry J et al. Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine. BMC Anesthesiol. 2010; 10:15. [PubMed 20809967]

6. Lee C, Jahr JS, Candiotti KA et al. Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine. Anesthesiology. 2009; 110:1020-5. [PubMed 19387176]

7. Merck Sharp & Dohme Ltd. Bridion (sugammadex) solution for injection. Annex I: Summary of product characteristics. Hertfordshire, United Kingdom; 2013 Jun.

8. Panhuizen IF, Gold SJ, Buerkle C et al. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment. Br J Anaesth. 2015; 114:777-84. [PubMed 25829395]

9. Plaud B, Meretoja O, Hofmockel R et al. Reversal of rocuronium-induced neuromuscular blockade with sugammadex in pediatric and adult surgical patients. Anesthesiology. 2009; 110:284-94. [PubMed 19194156]

12. Takazawa T, Tomita Y, Yoshida N et al. Three suspected cases of sugammadex-induced anaphylactic shock. BMC Anesthesiol. 2014; 14:92. [PubMed 25349529]

13. Tsur A, Kalansky A. Hypersensitivity associated with sugammadex administration: a systematic review. Anaesthesia. 2014; 69:1251-7. [PubMed 24848211]

14. Rahe-Meyer N, Fennema H, Schulman S et al. Effect of reversal of neuromuscular blockade with sugammadex versus usual care on bleeding risk in a randomized study of surgical patients. Anesthesiology. 2014; 121:969-77. [PubMed 25208233]

15. Schaller SJ, Fink H. Sugammadex as a reversal agent for neuromuscular block: an evidence-based review. Core Evid. 2013; 8:57-67. [PubMed 24098155]

16. Zwiers A, van den Heuvel M, Smeets J et al. Assessment of the potential for displacement interactions with sugammadex: a pharmacokinetic-pharmacodynamic modelling approach. Clin Drug Investig. 2011; 31:101-11. [PubMed 21067251]

17. Keating GM. Sugammadex: A Review of Neuromuscular Blockade Reversal. Drugs. 2016; 76:1041-52. [PubMed 27324403]

18. Schaller SJ, Lewald H. Clinical pharmacology and efficacy of sugammadex in the reversal of neuromuscular blockade. Expert Opin Drug Metab Toxicol. 2016; 12:1097-108. [PubMed 27463265]

19. Fujita A, Ishibe N, Yoshihara T et al. Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Acta Anaesthesiol Taiwan. 2014; 52:54-8. [PubMed 25016508]

20. Food and Drug Administration. Summary Review: NDA#022225. From FDA website.

22. Food and Drug Administration. Clinical pharmacology and biopharmaceutics review: NDA#022225. From FDA website.

120. Bevan DR, Donati F, Kopman AF. Reversal of neuromuscular blockade. Anesthesiology. 1992; 77:785-805. [PubMed 1416176]

121. Srivastava A, Hunter JM. Reversal of neuromuscular block. Br J Anaesth. 2009; 103:115-29. [PubMed 19468024]

122. Brull SJ, Murphy GS. Residual neuromuscular block: lessons unlearned. Part II: methods to reduce the risk of residual weakness. Anesth Analg. 2010; 111:129-40. [PubMed 20442261]

123. Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010; 111:120-8. [PubMed 20442260]

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