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Bridion

Generic Name: Sugammadex
Class: Antidotes
Molecular Formula: C72H112O48S8
CAS Number: 343306-71-8

Introduction

Sugammadex, a modified gamma cyclodextrin, is a reversal agent for rocuronium- or vecuronium-induced neuromuscular blockade.1

Uses for Bridion

Sugammadex has the following uses:

Sugammadex is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery.1

Bridion Dosage and Administration

General

Sugammadex is available in the following dosage form(s) and strength(s):

  • 200 mg/2 mL (100 mg/mL) in a single-dose vial for bolus injection.1

  • 500 mg/5 mL (100 mg/mL) in a single-dose vial for bolus injection.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Monitor for twitch responses to determine the timing and dose for sugammadex administration.1

  • Administer as a single bolus injection.

  • For rocuronium and vecuronium: 4 mg/kg is recommended if spontaneous recovery of the twitch response has reached 1 to 2 post-tetanic counts (PTC) and there are no twitch responses to train-of-four (TOF) stimulation.1

  • For rocuronium and vecuronium: 2 mg/kg is recommended if spontaneous recovery has reached the reappearance of the second twitch in response to TOF stimulation.1

  • For rocuronium only: 16 mg/kg is recommended if there is a clinical need to reverse neuromuscular blockade soon (approximately 3 minutes) after administration of a single dose of 1.2 mg/kg of rocuronium.1

For information regarding readministration of rocuronium or vecuronium after reversal of neuromuscular blockade with sugammadex, see Waiting Times for Re-administration of Neuromuscular Blocking Agents for Intubation Following Reversal with Sugammadex, under Warnings/Precautions in Cautions.

Cautions for Bridion

Contraindications

Known hypersensitivity to sugammadex or any of its components.1

Warnings/Precautions

Anaphylaxis and Hypersensitivity

Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions.1

Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with sugammadex. The nature and frequency of anaphylaxis and hypersensitivity associated with sugammadex administration were evaluated in a randomized, double-blind, placebo-controlled, parallel-group, repeat-dose study in which 375 subjects were randomized to receive 3 doses of sugammadex IV with a 5 week washout period: 151 subjects received 4 mg/kg, 148 received 16 mg/kg and 76 received placebo. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous sugammadex was 0.3% (n=1 in the sugammadex 16 mg/kg group on the first dose). Signs and symptoms included conjunctival edema, urticaria, erythema, swelling of the uvula and reduction in peak expiratory flow within 5 minutes of dose administration. The most common hypersensitivity adverse reactions reported were nausea, pruritus and urticaria and showed a dose response relationship, occurring more frequently in the 16 mg/kg group compared to the 4 mg/kg and placebo groups.1

Anaphylaxis has also been reported in the post-marketing setting, including at doses less than 16 mg/kg. The most commonly described clinical features in reports of anaphylaxis were dermatologic symptoms (including urticaria, rash, erythema, flushing and skin eruption) and clinically important hypotension often requiring the use of vasopressors for circulatory support. In addition, prolonged hospitalization and/or the use of additional respiratory support until full recovery (re-intubation, prolonged intubation, manual or mechanical ventilation) have been noted in a number of the anaphylaxis reports.1

Marked Bradycardia

Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of sugammadex. Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents, such as atropine, should be administered if clinically significant bradycardia is observed.1

Respiratory Function Monitoring During Recovery

Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Even if recovery from neuromuscular blockade is complete, other drugs used in the peri- and post-operative period could depress respiratory function and therefore ventilatory support might still be required.1

Should neuromuscular blockade persist after sugammadex administration or recur following extubation, take appropriate steps to provide adequate ventilation.1

Risk of Prolonged Neuromuscular Blockade

In clinical trials, a small number of patients experienced a delayed or minimal response to the administration of sugammadex. Thus, it is important to monitor ventilation until recovery occurs.1

Waiting Times for Re-administration of Neuromuscular Blocking Agents for Intubation Following Reversal with Sugammadex

A minimum waiting time is necessary before administration of a steroidal neuromuscular blocking agent after administration of sugammadex.1

Table 1: Re-administration of Rocuronium or Vecuronium after Reversal (up to 4 mg/kg Sugammadex)

Minimum Waiting Time

Neuromuscular Blocking Agent 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

When rocuronium 1.2 mg/kg is administered within 30 minutes after reversal with sugammadex, the onset of neuromuscular blockade may be delayed up to approximately 4 minutes and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes.1

The recommended waiting time in patients with mild or moderate renal impairment for re-use of 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium after reversal with up to 4 mg/kg sugammadex should be 24 hours. If a shorter waiting time is required, the rocuronium dose for a new neuromuscular blockade should be 1.2 mg/kg.1

For re-administration of rocuronium or administration of vecuronium after reversal of rocuronium with 16 mg/kg sugammadex, a waiting time of 24 hours is suggested.1

If neuromuscular blockade is required before the recommended waiting time has elapsed, use a nonsteroidal neuromuscular blocking agent. 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.1

Interactions Potentially Affecting the Efficacy of Other Drugs

Due to the administration of sugammadex, certain drugs, including hormonal contraceptives, could become less effective due to a lowering of the (free) plasma concentrations. In this situation, consider the re-administration of the other drug, the administration of a therapeutically equivalent drug (preferably from a different chemical class), and/or non-pharmacological interventions as appropriate.1

Risk of Recurrence of Neuromuscular Blockade Due to Displacement Interactions

Recurrence of neuromuscular blockade may occur due to displacement of rocuronium or vecuronium from sugammadex by other drugs. In this situation the patient may require mechanical ventilation. Administration of the drug which caused displacement should be stopped in case of an infusion. The risk of displacement reactions will be the highest in the time period equivalent to 3 times the half-life of sugammadex.1

Risk of Recurrence of Neuromuscular Blockade with Lower Than Recommended Dosing

The use of lower than recommended doses of sugammadex may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended.1

Risk of Recurrence of Neuromuscular Blockade Due to the Administration of Drugs That Potentiate Neuromuscular Blockade

When drugs which potentiate neuromuscular blockade are used in the post-operative phase, special attention should be paid to the possibility of recurrence of neuromuscular blockade. Refer to the package insert for rocuronium or vecuronium for a list of the specific drugs which potentiate neuromuscular blockade. In case recurrence of neuromuscular blockade is observed, the patient may require mechanical ventilation.1

Risk of Coagulopathy and Bleeding

Sugammadex doses up to 16 mg/kg were associated with increases in the coagulation parameters activated partial thromboplastin time (aPTT) and prothrombin time/international normalized ratio [PT(INR)] of up to 25% for up to 1 hour in healthy volunteers.1

In patients undergoing major orthopedic surgery of the lower extremity who were concomitantly treated with heparin or low molecular weight heparin for thromboprophylaxis, increases in aPTT and PT(INR) of 5.5% and 3.0%, respectively, were observed in the hour following sugammadex 4 mg/kg administration. This clinical trial did not demonstrate an increased incidence of blood loss or anemia with sugammadex compared with usual treatment. The rate of adjudicated bleeding events within 24 hours was 2.9% for sugammadex and 4.1% for usual care. The rate of post-operative anemia was 21% for sugammadex and 22% for usual care. The mean 24-hour drainage volume was 0.46 L for sugammadex and 0.48 L for usual care. The need for any post-operative transfusion was 37% for sugammadex and 39% for usual care.1

In vitro experiments demonstrated additional aPTT and PT(INR) prolongations for sugammadex in combination with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban, and dabigatran up to ~25% and ~50% at Cmax levels of sugammadex corresponding to 4 mg/kg and 16 mg/kg doses, respectively.1

Since bleeding risk has been studied systematically with only heparin and low molecular weight heparin thromboprophylaxis and 4 mg/kg doses of sugammadex, coagulation parameters should be carefully monitored in patients with known coagulopathies and in those being treated with therapeutic anticoagulation, receiving thromboprophylaxis drugs other than heparin and low molecular weight heparin, or receiving thromboprophylaxis drugs and who then receive a dose of 16 mg/kg sugammadex.1

Renal Impairment

Sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis.1

Light Anesthesia

When neuromuscular blockade was reversed intentionally in the middle of anesthesia in clinical trials (e.g., when investigating urgent reversal), signs of light anesthesia were noted occasionally (movement, coughing, grimacing and suckling of the tracheal tube).1

Reversal After Rocuronium or Vecuronium Administration in the ICU

Sugammadex has not been studied for reversal following rocuronium or vecuronium administration in the ICU.1

Reversal of Neuromuscular Blocking Agents Other Than Rocuronium or Vecuronium

Do not use sugammadex to reverse blockade induced by nonsteroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds.1

Do not use sugammadex to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents other than rocuronium or vecuronium.1

Specific Populations

Pregnancy

Risk Summary: There are no data on sugammadex use in pregnant women to inform any drug-associated risks. In animal reproduction studies, there was no evidence of teratogenicity following daily intravenous administration of sugammadex to rats and rabbits during organogenesis at exposures of up to 6 and 8 times, respectively, the maximum recommended human dose (MRHD) of 16 mg/kg. However, there was an increase in the incidence of incomplete ossification of the sternebra and reduced fetal body weights in the rabbit study at 8 times the MRHD, which is a dose level in which maternal toxicity was also observed. In a pre- and postnatal development study, sugammadex treatment resulted in an increase in early postnatal loss, which correlated with maternal behavior (increased incidence of pup cannibalism), at exposures equivalent to the MRHD and higher. The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.1

Animal Data: In an embryofetal development study in rats, pregnant animals received daily intravenous administration of sugammadex at 0, 20, 100, and 500 mg/kg (0.2, 1, and 6-times the MRHD of 16 mg/kg/day, respectively, based on AUC comparison) during organogenesis (Gestational Days 6 - 17). No treatment-related maternal and embryofetal changes were observed.1

In another embryofetal development study, pregnant New Zealand white rabbits received daily intravenous administration of sugammadex at 0, 20, 65, 200 mg/kg (0.6, 2, and 8 times the MRHD, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-18). Fetal body weight decreases (10 and 14%, respectively) were observed in the offspring at maternal doses of 65 mg/kg and 200 mg/kg. In addition, incomplete ossification of sternebra, and unossified 1st metacarpal were noted at a maternal dose of 200 mg/kg/day. Maternal toxicity was also observed at 200 mg/kg. Considering the observed effects of sugammadex on bone, it is possible that these findings may be attributable to drug. There was no evidence of teratogenicity at any dose.1

In a prenatal and postnatal development study, pregnant rats were administered sugammadex intravenously at 0, 30, 120, and 500 mg/kg (0.3, 1, and 6 times the MRHD, respectively, based on AUC comparison) from Gestational Day 6 to Postnatal Day 21 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning). Postnatal loss during Postnatal Day 1-4 was noted across control litters and treated litters from dams receiving sugammadex as a result of pup cannibalization by dams. Overall incidence of affected litters was 2, 1, 4, and 3 litters, respectively, at 0, 30, 120, or 500 mg/kg/day. The reason for the increased cannibalization is not known. An effect of sugammadex on steroidal hormones and/or pheromones cannot be ruled out. In addition, there were no drug-related effects on parturition in rats during evaluations for prenatal or postnatal development.1

Lactation

No data are available regarding the presence of sugammadex in human milk, the effects of sugammadex on the breast fed infant, or the effects of sugammadex on milk production. However, sugammadex is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sugammadex and any potential adverse effects on the breastfed infant from sugammadex or from the underlying maternal condition.1

In a milk excretion study in rat dams following a single intravenous dose of 20 mg/kg sugammadex on Postnatal Day 9, the maximum drug level was achieved at about 30 minutes after dosing with a ratio of milk to plasma level approximately 1:1. The oral exposure via milk did not induce effects on survival, body weight, and physical or behavioral developmental parameters monitored in rats in the prenatal and postnatal development studies.1

Females and Males of Reproductive Potential

Upon administration of sugammadex, the efficacy of hormonal contraceptives may be reduced for up to 7 days. Advise female patients of reproductive potential using hormonal contraceptives to use an additional, non-hormonal contraceptive for the next 7 days following sugammadex administration.1

Pediatric Use

The safety and efficacy of sugammadex in pediatric patients have not been established.1

Juvenile Animal Studies: In a bone deposition study, sugammadex concentrations were significantly higher in juvenile rats compared to adult rats (13% versus 3% of the administered dose, respectively) following a single intravenous (IV) dose at 30 mg/kg (0.3 times the MRHD based on adult AUC comparison).1

In a juvenile animal bone toxicity study, 7-day old rats were dosed intravenously once daily for 28 days with 0, 30, 120, and 500 mg/kg sugammadex (approximately 0.1, 0.6, and 3 times the MRHD, respectively, by adult AUC comparison). Sugammadex at 120 and 500 mg/kg decreased ulna and femur bone lengths by approximately 3%, which did not recover after an 8-week treatment-free period. Reversible whitish discoloration and disturbance of enamel formation were also observed in the incisors at these dose levels. In molars, this effect was only observed at 500 mg/kg. The no-observed-effect-level (NOEL) was 30 mg/kg.1

In a second juvenile animal bone toxicity study, 7-day old rats were dosed once weekly for 8 weeks with 0, 7.5, 30, and 120 mg/kg (up to 1.2 times the MRHD of 16 mg/kg based on adult AUC comparison). No adverse effects on bone or teeth were noted.1

Geriatric Use

Sugammadex has been administered in a dedicated clinical study to a total of 102 geriatric patients that compared the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg sugammadex given at the reappearance of the second twitch (T2) in 65-74 year-olds (N=62) and >75 year-olds (N=40) compared with 18-64 year-olds (N=48). The median time to recovery of the TOF (T4/T1) ratio to 0.9 in 18-64 year-olds was 2.2 minutes; in 65-74 year-olds it was 2.5 minutes, and in >75 year-olds it was 3.6 minutes. For time to recovery from neuromuscular blockade induced by rocuronium following administration of 4 mg/kg sugammadex given at 1-2 post-tetanic counts (PTCs), results across clinical trials revealed a median recovery of 2.5 minutes for geriatric patients (≥65 years, N=63) versus 2.0 minutes, for adults aged 18-64 years (N=359). Hence no dose adjustment is necessary in geriatric patients with normal organ function.1

This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.1

Renal Impairment

This drug is known to be substantially excreted by the kidney. Effect of mild or moderate renal impairment on sugammadex pharmacokinetics (PK) and pharmacodynamics (PD) was obtained from a study in elderly patients. Although clearance of the drug decreased in elderly subjects with mild and moderate renal impairment, there was no significant difference in the ability of sugammadex to reverse the pharmacodynamic effect of rocuronium. Hence, no dosage adjustment is necessary for mild and moderate renal impairment. Sugammadex is not recommended for use in patients with severe renal impairment due to insufficient safety information combined with the prolonged and increased overall exposure in these patients.1

Hepatic Impairment

Sugammadex is not metabolized nor excreted by the liver; therefore, dedicated trials in patients with hepatic impairment have not been conducted. Exercise caution when administering sugammadex to patients with hepatic impairment accompanied by coagulopathy or severe edema.1

Cardiac Patients

One trial of 76 patients who were diagnosed with or had a history of cardiac disease (e.g., ischemic heart disease, chronic heart failure, or arrhythmia) of primarily NYHA (New York Heart Association) Class II investigated time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg or 4 mg/kg sugammadex given at the reappearance of the second twitch (T2). The trial showed that the median time to recovery of the TOF (T4/T1) ratio to 0.9 was 1.7 minutes and 1.3 minutes, respectively, in the 2 mg/kg and 4 mg/kg sugammadex dose groups. This is similar to the median values observed in the other trials; therefore, no dosage adjustment is necessary.1

Pulmonary Patients

One trial of 77 patients who were diagnosed with or had a history of pulmonary complications investigated the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg or 4 mg/kg sugammadex given at the first signs of recovery (reappearance of the second twitch [T2]). The trial showed that for these patients the median time to recovery of the TOF (T4/T1) ratio to 0.9 was 2.1 minutes after a dose of 2 mg/kg sugammadex and 1.9 minutes after a dose of 4 mg/kg sugammadex. This is similar to the median values observed in the other trials; therefore, no dosage adjustment is necessary.1

Common Adverse Effects

Most common adverse reactions (reported in ≥10% of patients at a 2, 4, or 16 mg/kg sugammadex dose and higher than the placebo rate): vomiting, pain, nausea, hypotension, and headache.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Toremifene: Recovery could be delayed in patients using toremifene.1

  • Hormonal contraceptives: Patients using hormonal contraceptives must use an additional, non-hormonal method of contraception for the next 7 days following sugammadex administration.1

Actions

Mechanism of Action

Sugammadex is a modified gamma cyclodextrin. It forms a complex with the neuromuscular blocking agents rocuronium and vecuronium, and it reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction. This results in the reversal of neuromuscular blockade induced by rocuronium and vecuronium.1

Advice to Patients

Patient Counseling Information

Advise females of reproductive potential using hormonal contraceptives that sugammadex may reduce the contraceptive effect. Instruct females to use an additional, non-hormonal method of contraception for the next 7 days following sugammadex administration.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Solution

100 mg /1 mL

Bridion

Merck Sharp & Dohme Corp.

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: September 15, 2016
Last reviewed: September 15, 2016
Date modified: October 12, 2016

References

1. Merck Sharp & Dohme Corp.. BRIDION (sugammadex) INTRAVENOUS prescribing information. 2015 Dec.

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