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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 [see Adverse Reactions]. 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. (See Table 1.)
Click on icon to see table/diagram/imageWhen 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 readministration of the other drug, the administration of a therapeutically equivalent drug (preferably from a different chemical class), and/or non-pharmacological interventions as appropriate [see Interactions].
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 [see Interactions]. 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 [see Pharmacology under Actions].
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 [see Dosage & Administration, Adverse Reactions).
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.
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 SUGAMMADEX 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.
Cardiac Patients: One trial of 76 patients who were diagnosed with or have a history of cardiac disease (e.g., patients with 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 T2. The trial showed that the median time to recovery of the 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 [see Dosage & Administration].
Pulmonary Patients: One trial of 77 patients who were diagnosed with or have 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 T2). The trial showed that for these patients the median time to recovery of the 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. [See Dosage & Administration, Adverse Reactions].
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.
Renal Impairment: SUGAMMADEX is not recommended for use in patients with severe renal impairment, including those requiring dialysis [see as follows]. With regard to the recommended waiting time for re-administration in patients with mild or moderate renal impairment, see Waiting Times for Readministration of Neuromuscular Blocking Agents for Intubation Following Reversal with SUGAMMADEX [see Waiting Times for Re-Administration of Neuromuscular Blocking Agents for Intubation Following Reversal with SUGAMMADEX].
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 [see Use in the Elderly as follows]. 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 [see Precautions, Pharmacology under Actions].
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 [see Precautions].
Use in Pregnancy & Lactation: See Use in Pregnancy & Lactation section for further information.
Use in Children: The safety and efficacy of SUGAMMADEX in pediatric patients have not been established.
Use in the Elderly: 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 [see Dosage & Administration].
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 [see Renal Impairment as previously mentioned, Pharmacology under Actions].
