Bridion Drug Information

® is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adult and pediatric patients undergoing surgery. BRIDION is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adult and pediatric patients undergoing surgery.

Important Dosing and

Administration Information BRIDION dosing is based on actual body weight. BRIDION (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 BRIDION administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred.

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

From the time of BRIDION 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 BRIDION does not depend on the anesthetic regimen.

Preparation of dilution for pediatric use: BRIDION 100 mg/mL may be diluted to a concentration of 10 mg/mL, using 0.9% sodium chloride injection, USP, to increase the accuracy of dosing in the pediatric population. To prepare the required dose, aseptically transfer all the contents of the 2 mL vial of BRIDION 2-mL single-dose vials containing 200 mg sugammadex (100 mg/mL) to a bottle (or intravenous bag) containing 18 mL of 0.9% sodium chloride injection, to achieve a final concentration of 10 mg/mL sugammadex. The diluted solution should be used immediately.

BRIDION injection is a single-dose sterile solution without preservatives. Discard any unused portion from the vial.

Recommended Dosing

BRIDION can be used to reverse different levels of rocuronium- or vecuronium-induced neuromuscular blockade. For rocuronium and vecuronium: A dose of 4 mg/kg BRIDION 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 BRIDION is recommended if spontaneous recovery has reached the reappearance of the second twitch (T 2 ) in response to TOF stimulation following rocuronium- or vecuronium-induced neuromuscular blockade.

For rocuronium only: A dose of 16 mg/kg BRIDION 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 BRIDION following administration of vecuronium has not been studied. Immediate reversal in pediatric patients has not been studied.

Drug Compatibility May inject

BRIDION 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 BRIDION and other drugs. Do not mix BRIDION with other products except those listed above. BRIDION 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.

Clinical 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. Adult Patients 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 58 106 4 6 Procedural complication 13 27 8 3 Airway complication of anesthesia 11 13 9 0 Anesthetic complication 8 14 9 1 (<1) Wound hemorrhage 5 38 0 8 Recurrence of neuromuscular blockade 0 1 (<1) 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 208 503 23 127 Vomiting 98 236 15 57 Abdominal pain 48 68 6 17 Flatulence 17 51 1 10 Dry mouth 9 5 (<1) 2 0 General disorders and administration site conditions Pain 434 993 35 207 Pyrexia 77 109 5 17 Chills 30 61 7 27 Nervous system disorders Headache 61 99 10 42 Dizziness 44 67 6 13 Hypoesthesia 12 24 3 9 Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 42 66 5 27 Cough 13 49 8 11 Musculoskeletal and connective tissue disorders Pain in extremity 13 35 6 15 Musculoskeletal pain 16 33 1 6 Myalgia 5 17 2 3 Psychiatric disorders Insomnia 20 103 5 22 Anxiety 14 19 3 1 (<1) Restlessness 3 (<1) 17 2 2 (<1) Depression 2 (<1) 5 (<1) 2 0 Investigations Red blood cell count decreased 13 34 1 2 (<1) Electrocardiogram QT interval abnormal 13 7 (<1) 6 4 Blood creatine phosphokinase increased 9 14 2 1 (<1) Vascular disorders Hypertension 48 96 9 38 Hypotension 33 102 13 20 Skin and subcutaneous tissue disorders Pruritus 17 50 2 9 Erythema 5 31 0 6 Metabolism and nutrition disorders Hypocalcemia 15 12 0 4 Cardiac disorders Tachycardia 17 29 5 4 Bradycardia 9 21 5 6 Surgical and medical procedures Hysterectomy 0 0 2 0 Pediatric Patients 2 to <17 years of age The safety of BRIDION has been assessed in a randomized, active-controlled study of pediatric patients 2 to <17 years of age, with 242 receiving treatment with BRIDION. Adverse events occurring in ≥5% of pediatric patients are presented in Table 3. The safety profile was generally consistent with that observed in adults.

Table 3: Pediatric Patients (2 to <17 years of age) with Adverse Events Incidence ≥5% in One or More Treatment Groups Up to 7 Days Post-Treatment Sugammadex 2 mg/kg Sugammadex 4 mg/kg n (%) n (%) Subjects in population 51 191 with one or more specific adverse events 40 143 with no specific adverse events 11 48 Cardiac disorders 5 16 Bradycardia Combines preferred terms of bradycardia and sinus bradycardia Every subject is counted a single time for each applicable row and column. A system organ class or specific adverse event appears in this table only if its incidence in one or more of the columns meets the incidence criterion in the table title, after rounding. 5 13 Eye disorders 3 1 Gastrointestinal disorders 8 35 Nausea 1 12 Vomiting 4 20 Injury, poisoning and procedural complications 34 121 Incision site pain 3 6 Procedural nausea 4 9 Procedural pain 30 111 Procedural vomiting 3 5 Birth to <2 years of age The safety of BRIDION has been assessed in a randomized, double-blinded, active comparator-controlled study of pediatric patients from birth to <2 years of age, with 107 receiving treatment with BRIDION. Adverse events occurring in ≥5% of pediatric patients are presented in Table 4. The safety profile was generally consistent with that observed in pediatric patients from 2 to <17 years of age and adults. Table 4: Pediatric Participants (Birth to <2 Years) with Specific Adverse Events Incidence ≥ 5% in One or More Treatment Groups Up to 7 Days Post-Treatment Sugammadex 2 mg/kg Sugammadex 4 mg/kg n (%) n (%) Every participant is counted a single time for each applicable row and column.

A system organ class or specific adverse event appears in this table only if its incidence in one or more of the columns meets the incidence criterion in the table title, after rounding. Participants in population 44 63 with one or more specific adverse events 30 43 with no specific adverse events 14 20 Cardiac disorders 3 0 Gastrointestinal disorders 6 4 Vomiting 4 1 General disorders and administration site conditions 5 6 Pyrexia 3 3 Infections and infestations 3 0 Injury, poisoning and procedural complications 19 35 Procedural pain 18 34 Procedural vomiting 3 1 Metabolism and nutrition disorders 3 2 Respiratory, thoracic and mediastinal disorders 5 3 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 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 . 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.

Post-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 . Other cardiac rhythm abnormalities have included atrial fibrillation, atrioventricular block, cardiac/cardiorespiratory arrest, electrocardiographic (ECG) ST segment changes, supraventricular tachycardia/extrasystoles, tachycardia, ventricular fibrillation, and ventricular tachycardia. Anaphylaxis associated with ECG ST segment changes (elevation or depression) consistent with myocardial ischemia or coronary spasm has also been reported.

General Disorders and Administration Site Conditions: Cases of BRIDION not having the intended effect. Immune System Disorders: Hypersensitivity events including anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, and Type 1 hypersensitivity have been reported . Respiratory, Thoracic, and Mediastinal Disorders: Events of laryngospasm, dyspnea, wheezing, pulmonary edema, and respiratory arrest have been reported.

Summary

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.

Interactions 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.

Interaction 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.

Interference 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 Risk Summary There are no clinical trial data on BRIDION use in pregnant women to inform any drug-associated risks. The available data from the pharmacovigilance safety database and published literature on BRIDION use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of malformations 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 , it is possible that these findings may be attributable to drug. There was no evidence of malformations 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.

Pediatric Use The safety and effectiveness of BRIDION for reversal of neuromuscular blockade induced by rocuronium bromide or vecuronium bromide have been established in pediatric patients from birth and older. Use of BRIDION in these age groups is supported by evidence from adequate and well-controlled studies of BRIDION. In pediatric patients, the safety profile is generally consistent with that observed in adults . 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.

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 . Known hypersensitivity to sugammadex or any of its components.

In premarketing clinical trials, one case of accidental overdose with 40 mg/kg BRIDION was reported without significant effects. BRIDION can be removed using hemodialysis with a high-flux filter, but not with a low-flux filter. Based upon clinical studies, BRIDION concentrations in plasma are reduced with a high-flux filter by about 70% after a 3- to 6-hour dialysis session.