Included as part of the PRECAUTIONS section.
Anaphylaxis And Hypersensitivity
Clinicians should be prepared for the possibility of drug
hypersensitivity reactions (including anaphylactic reactions) and take the
necessary precautions [see CONTRAINDICATIONS, ADVERSE REACTIONS].
Potentially serious hypersensitivity reactions, including
anaphylaxis, have occurred in patients treated with BRIDION. The nature and
frequency of anaphylaxis and hypersensitivity associated with BRIDION
administration were evaluated in a randomized, double-blind,
placebo-controlled, parallelgroup, repeat-dose study in which 375 subjects were
randomized to receive 3 doses of BRIDION 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 BRIDION was 0.3% (n=1 in the BRIDION 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.
Cases of marked bradycardia, some of which have resulted
in cardiac arrest, have been observed within minutes after the administration
of BRIDION [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 BRIDION
administration or recur following extubation, take appropriate steps to provide
Risk Of Prolonged Neuromuscular Blockade
In clinical trials, a small number of patients
experienced a delayed or minimal response to the administration of BRIDION [see
Clinical Studies]. Thus, it is important to monitor ventilation until
Waiting Times For Re-Administration Of Neuromuscular
Blocking Agents For Intubation Following Reversal With BRIDION
A minimum waiting time is necessary before administration
of a steroidal neuromuscular blocking agent after administration of BRIDION.
Table 1: Re-administration of Rocuronium or Vecuronium
after Reversal (up to 4 mg/kg BRIDION)
|Minimum Waiting Time
||NMBA and Dose to be Administered
||1.2 mg/kg rocuronium
||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 BRIDION, 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 BRIDION 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 BRIDION, a waiting time of 24 hours
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
Due to the administration of BRIDION, 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 DRUG INTERACTIONS].
Risk Of Recurrence Of Neuromuscular Blockade Due To Displacement
Recurrence of neuromuscular blockade may occur due to
displacement of rocuronium or vecuronium from BRIDION by other drugs [see
DRUG 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 BRIDION [see
Risk Of Recurrence Of Neuromuscular Blockade With Lower
Than Recommended Dosing
The use of lower than recommended doses of BRIDION may
lead to an increased risk of recurrence of neuromuscular blockade after initial
reversal and is not recommended [see DOSAGE AND ADMINISTRATION, ADVERSE
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
BRIDION 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 BRIDION 4 mg/kg administration.
This clinical trial did not demonstrate an increased blood loss or anemia
incidence with BRIDION 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.
BRIDION is not recommended for use in patients with
severe renal impairment, including those requiring dialysis [see Use in
Specific Populations]. 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 BRIDION [see Waiting Times for Re-Administration of Neuromuscular Blocking Agents for Intubation
Following Reversal with BRIDION].
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
BRIDION 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
Do not use BRIDION to reverse neuromuscular blockade
induced by steroidal neuromuscular blocking agents other than rocuronium or
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies to evaluate the carcinogenic
potential of sugammadex have not been conducted.
Sugammadex and its mono OH-derivative tested negatively
in in vitro bacterial reverse mutation assays (Ames test), in vitro chromosomal
aberration assays in human peripheral blood lymphocytes, and in vivo micronucleus
assays in mice and rats.
Impairment Of Fertility
A fertility and early embryonic development study in
Sprague-Dawley rats in which male rats were treated daily for 29 days prior to
mating and through the mating period and female rats were treated daily for 14
days prior to mating to Day 5 post-coitum via intravenous administration of
sugammadex at 20, 100, and 500 mg/kg (0.2, 1, and 6 times the MRHD of 16 mg/kg,
respectively, based on AUC comparison) did not show adverse effects on
Use In Specific Populations
There are no data on BRIDION 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 [see Data]. 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.
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
treatmentrelated 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 [see Nonclinical Toxicology], 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.
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 [see Data]. The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need for
BRIDION and any potential adverse effects on the breastfed infant from BRIDION
or from the underlying maternal condition.
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
[see Use in Specific Populations].
Females And Males Of Reproductive Potential
Upon administration of BRIDION, 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 BRIDION administration
[see DRUG INTERACTIONS].
The safety and efficacy of BRIDION 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-observedeffect- 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.
BRIDION 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 BRIDION 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 BRIDION 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 AND 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 Use in Specific Populations,
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 Specific Populations]. 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. BRIDION 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 WARNINGS AND PRECAUTIONS, CLINICAL
BRIDION is not metabolized nor excreted by the liver;
therefore, dedicated trials in patients with hepatic impairment have not been
conducted. Exercise caution when administering BRIDION to patients with hepatic
impairment accompanied by coagulopathy or severe edema [see WARNINGS AND
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 BRIDION 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
BRIDION dose groups. This is similar to the median values observed in the other
trials; therefore, no dosage adjustment is necessary [see DOSAGE AND
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 BRIDION 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 BRIDION and 1.9 minutes after a dose of 4 mg/kg BRIDION. This is
similar to the median values observed in the other trials; therefore, no dosage
adjustment is necessary. [See DOSAGE AND ADMINISTRATION, ADVERSE