BRIDION ® is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. BRIDION is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. ( 1 )
Contraindications
BRIDION 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 [see Warnings and Precautions (5.1) , Adverse Reactions (6) ] . Known hypersensitivity to sugammadex or any of its components.
( 4 )
Warnings and precautions
Anaphylaxis : Anaphylaxis has occurred in 0.3% of healthy volunteers. Observe patients for an appropriate period of time after administration. ( 5.1 ) Marked Bradycardia : Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after administration. Monitor for hemodynamic changes and administer anticholinergic agents such as atropine if clinically significant bradycardia is observed.
( 5.2 ) Respiratory Function Monitoring : Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Should neuromuscular blockade persist after BRIDION or recur following extubation, take appropriate steps to provide adequate ventilation. ( 5.3 , 5.4 ) Waiting Times for Re-Administration of Neuromuscular Blocking Agent : If re-administration of a neuromuscular blocking agent is required after reversal with BRIDION, waiting times should be based on the dose of BRIDION, and the renal function of the patient.
Consider use of a nonsteroidal neuromuscular blocking agent. ( 5.5 )
5.1
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Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions [see Contraindications (4) , Adverse Reactions (6.1) ] . 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, parallel-group, 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.
5.2Marked Bradycardia 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 (6.2) ] . 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.
5.3Respiratory 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 adequate ventilation.
5.4Risk 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 (14.1) ] . Thus, it is important to monitor ventilation until recovery occurs.
5.5Waiting 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 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 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 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.
5.6 Interactions Potentially Affecting the Efficacy of Other Drugs 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 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 [see Drug Interactions (7.3) ] .
5.7Risk of Recurrence of Neuromuscular Blockade Due to Displacement Interactions Recurrence
of neuromuscular blockade may occur due to displacement of rocuronium or vecuronium from BRIDION by other drugs [see Drug Interactions (7.2) ] . 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 Clinical Pharmacology (12.3) ] .
5.8Risk 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 (2.1) , Adverse Reactions (6.1) ] .
5.9 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.
5.10Risk of Coagulopathy and Bleeding
BRIDION doses up to 16 mg/kg were associated with increases in the coagulation parameters activated partial thromboplastin time (
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Interactions
Toremifene : Recovery could be delayed in patients using toremifene. ( 7.2 ) Hormonal contraceptives : Patients using hormonal contraceptives must use an additional, non-hormonal method of contraception for the next 7 days following BRIDION administration. ( 5.6 , 7.3 )
7.1Summary
The information reported in sections 7.2 – 7.4 is based on binding affinity between BRIDION 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.
7.2Interactions Potentially Affecting the Efficacy of
BRIDION 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 BRIDION 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.
7.3Interaction Potentially Affecting the Efficacy of Hormonal Contraceptives
In vitro binding studies indicate that BRIDION may bind to progestogen, thereby decreasing progestogen exposure. Therefore, the administration of a bolus dose of BRIDION 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 BRIDION 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.
7.4Interference with Laboratory Tests
BRIDION 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.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
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.
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 [see Nonclinical Toxicology (13.2) ] , 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.
Adverse reactions
The following serious adverse reactions are described elsewhere in the labeling: Anaphylaxis and Hypersensitivity [see Contraindications (4) , Warnings and Precautions (5.1) ] Marked Bradycardia [see Warnings and Precautions (5.2) ] Most common adverse reactions (reported in ≥10% of patients at a 2, 4, or 16 mg/kg BRIDION dose and higher than the placebo rate): vomiting, pain, nausea, hypotension, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
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 BRIDION 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 BRIDION 2 mg/kg or 4 mg/kg. Adverse reactions reported in ≥10% of patients at a 2, 4, or 16 mg/kg BRIDION 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 BRIDION 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% Sugammadex Placebo Body System Preferred Term 2 mg/kg (N=895) n (%) 4 mg/kg (N=1921) n (%) 16 mg/kg (N=98) n (%) (N=544) n (%) Injury, poisoning and procedural complications Incision site pain 58 (6) 106 (6) 4 (4) 6 (1) Procedural complication 13 (1) 27 (1) 8 (8) 3 (1) Airway complication of anesthesia 11 (1) 13 (1) 9 (9) 0 Anesthetic complication 8 (1) 14 (1) 9 (9) 1 (<1) Wound hemorrhage 5 (1) 38 (2) 0 8 (1) Recurrence of neuromuscular blockade 0 1 (<1) 2 (2) 0 Gastrointestinal disorders Nausea Combinations of preferred terms are as follows: Nausea includes preferred terms nausea and procedural nausea Vomiting includes preferred terms vomiting and procedural vomiting Abdominal pain includes preferred terms abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, and epigastric discomfort Pain includes preferred terms pain and procedural pain Red blood cell count decreased includes preferred terms red blood cell count decreased, hemoglobin decreased, and hematocrit decreased Electrocardiogram QT interval abnormal includes preferred terms electrocardiogram QT interval abnormal and electrocardiogram QT interval prolonged Hypertension includes preferred terms hypertension, procedural hypertension, and blood pressure increased Hypotension includes preferred terms hypotension, procedural hypotension, and blood pressure decreased Tachycardia includes preferred terms tachycardia and heart rate increased Bradycardia includes preferred terms bradycardia and heart rate decreased 208 (23) 503 (26) 23 (23) 127 (23) Vomiting 98 (11) 236 (12) 15 (15) 57 (10) Abdominal pain 48 (5) 68 (4) 6 (6) 17 (3) Flatulence 17 (2) 51 (3) 1 (1) 10 (2) Dry mouth 9 (1) 5 (<1) 2 (2) 0 General disorders and administration site conditions Pain 434 (48) 993 (52) 35 (36) 207 (38) Pyrexia 77 (9) 109 (6) 5 (5) 17 (3) Chills 30 (3) 61 (3) 7 (7) 27 (5) Nervous system disorders Headache 61 (7) 99 (5) 10 (10) 42 (8) Dizziness 44 (5) 67 (3) 6 (6) 13 (2) Hypoesthesia 12 (1) 24 (1) 3 (3) 9 (2) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 42 (5) 66 (3) 5 (5) 27 (5) Cough 13 (1) 49 (3) 8 (8) 11 (2) Musculoskeletal and connective tissue disorders Pain in extremity 13 (1) 35 (2) 6 (6) 15 (3) Musculoskeletal pain 16 (2) 33 (2) 1 (1) 6 (1) Myalgia 5 (1) 17 (1) 2 (2) 3 (1) Psychiatric disorders Insomnia 20 (2) 103 (5) 5 (5) 22 (4) Anxiety 14 (2) 19 (1) 3 (3) 1 (<1) Restlessness 3 (<1) 17 (1) 2 (2) 2 (<1) Depression 2 (<1) 5 (<1) 2 (2) 0 Investigations Red blood cell count decreased 13 (1) 34 (2) 1 (1) 2 (<1) Electrocardiogram QT interval abnormal 13 (1) 7 (<1) 6 (6) 4 (1) Blood creatine phosphokinase increased 9 (1) 14 (1) 2 (2) 1 (<1) Vascular disorders Hypertension 48 (5) 96 (5) 9 (9) 38 (7) Hypotension 33 (4) 102 (5) 13 (13) 20 (4) Skin and subcutaneous tissue disorders Pruritus 17 (2) 50 (3) 2 (2) 9 (2) Erythema 5 (1) 31 (2) 0 6 (1) Metabolism and nutrition disorders Hypocalcemia 15 (2) 12 (1) 0 4 (1) Cardiac disorders Tachycardia 17 (2) 29 (2) 5 (5) 4 (1) Bradycardia 9 (1) 21 (1) 5 (5) 6 (1) Surgical and medical procedures Hysterectomy 0 0 2 (2) 0 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% [see Warnings and Precautions (5.1) ] . 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 BRIDION 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 [see Warnings and Precautions (5.8) ] . Bronchospasm In one dedicated clinical trial and in post-marketing data, in patients with a history of pulmonary complications [see Use in Specific Populations (8.9) ] , bronchospasm was reported as a possibly related adverse event.
6.2Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of BRIDION. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Cases of marked bradycardia and bradycardia with cardiac arrest have been observed within minutes after administration of sugammadex [see Warnings and Precautions (5.2) ] .
Other cardiac rhythm abnormalities have included atrial fibrillation, atrioventricular block, cardiac/cardiorespiratory arrest, ST segment changes, supraventricular tachycardia/e
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