Sugammadex

{{DrugProjectFormSinglePage |authorTag=Martin Nino [1] |genericName=Sugammadex |aOrAn=a |drugClass=modified gamma cyclodextrin |indicationType= |indication=reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery |adverseReactions=vomiting, pain, nausea, hypotension, and headache (≥10%) |fdaLIADAdult=======Indications====== Sugammadex is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery.

Dosage

Sugammadex injection, for intravenous use, should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents.

Doses and timing of Sugammadex administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred.

Administer Sugammadex intravenously as a single bolus injection. The bolus injection may be given over 10 seconds, into an existing intravenous line. Sugammadex has only been administered as a single bolus injection in clinical trials.

From the time of Sugammadex administration until complete recovery of neuromuscular function, monitor the patient to assure adequate ventilation and maintenance of a patent airway. Satisfactory recovery should be determined through assessment of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation.

The recommended dose of Sugammadex does not depend on the anesthetic regimen.

• Recommended Dosing

Sugammadex can be used to reverse different levels of rocuronium- or vecuronium-induced neuromuscular blockade.

• For rocuronium and vecuronium:

• A dose of 4 mg/kg Sugammadex 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 following rocuronium- or vecuronium-induced neuromuscular blockade.
• A dose of 2 mg/kg Sugammadex is recommended if spontaneous recovery has reached the reappearance of the second twitch (T2) in response to TOF stimulation following rocuronium- or vecuronium-induced neuromuscular blockade.

• For rocuronium only:

• A dose of 16 mg/kg Sugammadex 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. The efficacy of the 16 mg/kg dose of Sugammadex following administration of vecuronium has not been studied.

Sugammadex dosing is based on actual body weight.

• Drug Compatibility

May inject Sugammadex into the intravenous line of a running infusion with the following intravenous solutions:

• 0.9% sodium chloride
• 5% dextrose
• 0.45% sodium chloride and 2.5% dextrose
• 5% dextrose in 0.9% sodium chloride
• isolyte P with 5% dextrose
• Ringer's lactate solution
• Ringer's solution

Ensure the infusion line is adequately flushed (e.g., with 0.9% sodium chloride) between administration of Sugammadex and other drugs.

Do not mix Sugammadex with other products except those listed above.

Sugammadex is physically incompatible with verapamil, ondansetron, and ranitidine.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit. |fdaLIADPed=The safety and efficacy of Sugammadex in pediatric patients have not been established. |contraindications=Sugammadex is contraindicated in patients with known hypersensitivity to Sugammadex or any of its components. Hypersensitivity reactions that occurred varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to Sugammadex. |warnings=

Anaphylaxis and Hypersensitivity

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

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.

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.

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.

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.

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

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.

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.

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

This image is provided by the National Library of Medicine.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 blood loss or anemia incidence 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.

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.

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, 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.

Renal Impairment

Sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis. With regard to the recommended waiting time for re-administration in patients with mild or moderate renal impairment, see Waiting Times for Re-administration of Neuromuscular Blocking Agents for Intubation Following Reversal with Sugammadex.

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).

Reversal after Rocuronium or Vecuronium Administration in the ICU

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

Reversal of Neuromuscular Blocking Agents Other Than Rocuronium or Vecuronium

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

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

|clinicalTrials= Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect 2914 subjects exposed to 2, 4, or 16 mg/kg Sugammadex and 544 to placebo in pooled Phase 1-3 studies. The population was 18 to 92 years old, 47% male and 53% female, 34% ASA (American Society of Anesthesiologists) Class 1, 51% ASA Class 2, and 14% ASA Class 3, and 82% Caucasian. Most subjects received a single dose of Sugammadex 2 mg/kg or 4 mg/kg.

Adverse reactions reported in ≥10% of patients at a 2, 4, or 16 mg/kg Sugammadex dose with a rate higher than the placebo rate are: vomiting, pain, nausea, hypotension, and headache.

All adverse reactions occurring in ≥2% of subjects treated with Sugammadex and more often than placebo for adult subjects who received anesthesia and/or neuromuscular blocking agent in pooled Phase 1 to 3 studies are presented in Table 2.

• Table 2: Percent of Subject Exposures in Pooled Phase 1 to 3 Studies with Adverse Reactions Incidence ≥ 2%

This image is provided by the National Library of Medicine.

• Anaphylaxis and Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, have occurred in both premarketing clinical trials and in post-marketing spontaneous reports. In a dedicated hypersensitivity study in healthy volunteers, the frequency of anaphylaxis was 0.3%. These reactions varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to Sugammadex.

Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, swelling of tongue, swelling of pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal.

A randomized, double-blind study examined the incidence of drug hypersensitivity reactions in healthy volunteers given up to 3 doses of placebo (N=76), Sugammadex 4 mg/kg (N=151) or Sugammadex 16 mg/kg (N=148). Reports of suspected hypersensitivity were adjudicated by a blinded committee. The incidence of adjudicated hypersensitivity was 1%, 7% and 9% in the placebo, Sugammadex 4 mg/kg and Sugammadex 16 mg/kg groups, respectively. There were no reports of anaphylaxis after placebo or Sugammadex 4 mg/kg. There was a single case of adjudicated anaphylaxis after the first dose of Sugammadex 16 mg/kg. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous Sugammadex was 0.3%. There was no evidence of increased frequency or severity of hypersensitivity with repeat dosing.

In a previous study of similar design, there were three adjudicated cases of anaphylaxis, all after Sugammadex 16 mg/kg (incidence 1% in the 298 healthy volunteers treated with Sugammadex).

• Recurrence of Neuromuscular Blockade

In clinical studies with subjects treated with rocuronium or vecuronium, where Sugammadex was administered using a dose labeled for the depth of neuromuscular blockade (N=2022), an incidence of <1% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence.

• Bronchospasm

In one dedicated clinical trial and in post-marketing data, in patients with a history of pulmonary complications, bronchospasm was reported as a possibly related adverse event.

|drugInteractions=

• Summary

The information reported in the next sections is based on binding affinity between Sugammadex and other drugs, preclinical experiments, clinical studies and simulations of a pharmacokinetic-pharmacodynamic (PK-PD) model. Based on these considerations, no clinically significant pharmacodynamic interactions with other drugs are expected, with the exception of toremifene and hormonal contraceptives.

• Interactions Potentially Affecting the Efficacy of Sugammadex

• Toremifene

For toremifene, which has a relatively high binding affinity for Sugammadex and for which relatively high plasma concentrations might be present, some displacement of vecuronium or rocuronium from the complex with Sugammadex could occur. The recovery to TOF ratio to 0.9 could therefore be delayed in patients who have received toremifene on the same day of surgery.

• Interaction Potentially Affecting the Efficacy of Hormonal Contraceptives

In vitro binding studies indicate that Sugammadex may bind to progestogen, thereby decreasing progestogen exposure. Therefore, the administration of a bolus dose of Sugammadex is considered to be equivalent to missing dose(s) of oral contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day that Sugammadex is administered, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days.

In the case of non-oral hormonal contraceptives, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days.

• Interference with Laboratory Tests

Sugammadex may interfere with the serum progesterone assay. Interference with this test was observed at Sugammadex plasma concentrations of 100 mcg/mL, which may be observed for up to 30 minutes after a 16 mg/kg dose. |useInPregnancyFDA=

• 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.

• Data

• 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.

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.

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 (GD) 6 to Postnatal Day (PND) 21 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning). Postnatal loss during PND 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.

|useInNursing=

• Risk Summary

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.

• Data

In a milk excretion study in rat dams following 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 the behavioral developmental parameters monitored in rats in the prenatal and postnatal development studies.

|useInPed= The safety and efficacy of Sugammadex in pediatric patients have not been established.

• Juvenile Animal Studies

In a bone deposition study, Sugammadex concentrations were significantly higher in juvenile rats compared to adult rats (13% vs. 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).

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.

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.

|useInGeri= Sugammadex has been administered in a dedicated clinical study to a total 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 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 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.

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. |useInRenalImpair= This drug is known to be substantially excreted by the kidney. Effect of mild or moderate renal impairment (creatine clearance ≥30 and ≤80 mL/min) on Sugammadex PK and PD was obtained from a study in elderly patients. Although clearance of 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 (creatine clearance <30 mL/min) due to insufficient safety information combined with the prolonged and increased overall exposure in these patients. |useInHepaticImpair= 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. |administration= |overdose= |drugBox=

Sugammadex
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