Sugammadex Injection

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

Mechanism Of Action

BRIDION is a modified gamma cyclodextrin. It forms a complex with the neuromuscular blocking agents rocuronium and vecuronium, and it reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction. This results in the reversal of neuromuscular blockade induced by rocuronium and vecuronium.

Pharmacodynamics

BRIDION has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose response trials of rocuronium-induced blockade (0.6, 0.9, 1 and 1.2 mg/kg with and without maintenance doses) and vecuronium-induced blockade (0.1 mg/kg with or without maintenance doses) at different time points/depths of block. In these trials a clear dose-response relationship was observed.

BRIDION may contain up to 7% of the mono OH-derivative of sugammadex. In preclinical pharmacology studies, the mono OH-derivative was demonstrated to have ~50% of the affinity as sugammadex for rocuronium and vecuronium and that product with up to 7% of the mono OH-derivative has nearly similar efficacy in reversing rocuronium- or vecuronium-induced blockade.

Although sugammadex has greatest affinity for aminosteroid neuromuscular blocking agents such as rocuronium and vecuronium, plasma levels of endogenous or exogenous compounds with a similar steroidal structure, such as some hormones, hormonal contraceptives, and pheromones may also be reduced following administration of sugammadex [see DRUG INTERACTIONS].

Cardiac Electrophysiology

At a dose 2 times the maximum recommended dose, sugammadex does not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics

The sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for non-complex-bound and complex-bound sugammadex in anesthetized patients.

Distribution

The observed steady-state volume of distribution of sugammadex is approximately 11 to 14 liters in adult patients with normal renal function (based on conventional, non-compartmental pharmacokinetic analysis). Neither sugammadex nor the complex of sugammadex and rocuronium binds to plasma proteins or erythrocytes, as was shown in vitro using male human plasma and whole blood. Sugammadex exhibits linear kinetics in the dosage range of 1 to 16 mg/kg when administered as an IV bolus dose.

In nonclinical drug distribution studies, sugammadex is retained in sites of active mineralization, such as bone and teeth, with a mean half-life of 172 and 8 days, respectively [see Use in Specific Populations, Nonclinical Toxicology].

Metabolism

In clinical studies, no metabolites of sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination.

Elimination

In adult anesthetized patients with normal renal function, the elimination half-life (t½) of sugammadex is about 2 hours and the estimated plasma clearance is about 88 mL/min (based on compartmental pharmacokinetic analysis). A mass balance study demonstrated that > 90% of the dose was excreted within 24 hours. Ninety-six percent (96%) of the dose was excreted in urine, of which at least 95% could be attributed to unchanged sugammadex. Excretion via feces or expired air was less than 0.02% of the dose. Administration of BRIDION to healthy volunteers resulted in increased renal elimination of rocuronium in complex.

Patients With Renal Impairment

Sugammadex is known to be substantially excreted by the kidney. The half-life of sugammadex in patients with mild, moderate and severe renal impairment is 4, 6, and 19 hours, respectively.

In one study, exposure to sugammadex was prolonged, leading to 17-fold higher overall exposure in patients with severe renal impairment. Low concentrations of sugammadex are detectable for at least 48 hours post-dose in patients with severe renal impairment.

In a second study comparing subjects with moderate or severe renal impairment to subjects with normal renal function, sugammadex clearance progressively decreased and t½ was progressively prolonged with declining renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively. Sugammadex concentrations were no longer detectable beyond 7 days post-dose in subjects with severe renal impairment.

Age: Geriatric Population

Geriatric patients may have mild or moderate renal impairment. Population pharmacokinetic analysis indicated that, beyond the effects of a decreased creatinine clearance, increased age has limited impact on sugammadex PK parameters [see Use in Specific Populations].

Sex

No pharmacokinetic differences between male and female subjects were observed.

Race

In a study in healthy Japanese and Caucasian subjects no clinically relevant differences in pharmacokinetic parameters were observed. Limited data do not indicate differences in pharmacokinetic parameters in Black or African Americans.

Animal Toxicology And/Or Pharmacology

Bone and teeth retention of sugammadex occurred in rats after intravenous injection, with mean halflives of 172 and 8 days, respectively. Sugammadex bound to hydroxyapatite in an in vitro study and distributed in the bone formation area where hydroxyapatite is present for mineralization in vivo.

In adult rat bone toxicity studies, a single dose of sugammadex at 2000 mg/kg (approximately 24 times the maximum recommended human dose (MRHD) of 16 mg/kg by AUC comparison) administered to adult rats caused a slight increase in bone resorption, but had no effect on teeth color. No adverse bone effects were seen following a single dose of sugammadex at 500 mg/kg (4 times the MRHD dose of 16 mg/kg based on plasma AUC comparison).

In a bone repair study, adult rats were treated with intravenous sugammadex weekly for 6 weeks at 0, 30, 120, and 500 mg/kg (approximately 0.4, 1, and 6 times the MRHD, respectively, by AUC comparison). Based on histological data, high dose animals with post-fracture treatment, showed a statistically significant increase in callus formation and decrease in bone formation, suggesting a potential for a slight delay in the bone healing process. However there were no statistically significant effects on bone volume or bone mineral density.

In juvenile animal studies, bone and teeth deposition was significantly higher in juvenile rats compared to adults. In addition, sugammadex administered to juvenile rats daily for 4 weeks caused slight bone length decrease (approximately 3%), which did not recover after an 8-week treatment-free period, and reversible whitish discoloration of the teeth at a dose approximately 0.6 times the MRHD, while weekly administration for 8 weeks did not produce similar changes in bone and teeth at doses up to 1.2 times the MRHD [see Use in Specific Populations].

Clinical Studies

Controlled Clinical Studies

Comparative Study Of BRIDION Versus Neostigmine As A Reversal Agent For Neuromuscular Blockade Induced By Rocuronium Or Vecuronium At Reappearance Of T2 (Moderate Blockade)

A multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study comparing BRIDION and neostigmine enrolled 189 patients (87 women and 102 men, 95% were ASA class 1 and 2 and 99% were Caucasian, median weights were 72 kg and 76 kg and median ages were 50 years and 51 years in the rocuronium and vecuronium groups, respectively). Patients were randomly assigned to the rocuronium or vecuronium group and underwent elective surgical procedures under general anesthesia that required endotracheal intubation and maintenance of neuromuscular blockade. The surgical procedures were mainly endocrine, ocular, ENT, abdominal (gynecological, colorectal, urological), orthopedic, vascular, or dermatological. At the reappearance of T2, after the last dose of rocuronium or vecuronium, 2 mg/kg BRIDION or 50 mcg/kg neostigmine was administered in a randomized order as a

single bolus injection. The time from start of administration of BRIDION or neostigmine to recovery of the TOF (T4/T1) ratio to 0.9 was assessed. Generally, a T4/T1 ratio ≥ 0.9 correlates with recovery from neuromuscular blockade.

Return of the T4/T1 ratio to 0.9 after the reappearance of T2 was overall faster with BRIDION 2 mg/kg as compared to neostigmine 50 mcg/kg in the setting of rocuronium or vecuronium-induced neuromuscular blockade (Figures 1 and 2).

Figure 1: Time (Minutes ) from Administration of BRIDION or Neostigmine at the Reappearance of T2 after Rocuronium to Recovery of the T4/T1 Ratio to 0.9

Figure 2: Time (Minutes ) from Administration of BRIDION or Neostigmine at the Reappearance of T2 after Vecuronium to Recovery of the T4/T1 Ratio to 0.9

Comparative Study Of BRIDION Versus Neostigmine As A Reversal Agent For Neuromuscular Blockade Induced By Rocuronium Or Vecuronium At 1 To 2 PTCs (Deep Blockade)

A multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study comparing BRIDION and neostigmine enrolled 157 patients (86 women and 71 men; 8% ASA class 1, 71% class 2, and 21% class 3; 79% Caucasian; median weights of 81 kg and 84 kg, and median ages of 54 years and 56 years in the rocuronium and vecuronium groups, respectively). Patients were randomly assigned to the rocuronium or vecuronium group and underwent elective surgical procedures under general anesthesia that required endotracheal intubation and maintenance of neuromuscular blockade. The surgical procedures were mainly abdominal (gynecological, colorectal, urological), orthopedic, reconstructive, or neurological. At 1 to 2 PTCs, after the last dose of rocuronium or vecuronium, 4 mg/kg BRIDION or 70 mcg/kg neostigmine was administered in a randomized order as a single bolus injection. The time from start of administration of BRIDION or neostigmine to recovery of the TOF (T4/T1) ratio to 0.9 was assessed, although neostigmine was not expected to reverse neuromuscular blockade at a depth of 1 to 2 PTCs. Generally, a T4/T1 ratio ≥ 0.9 correlates with recovery from neuromuscular blockade.

Return of the T4/T1 ratio to 0.9 in patients with 1 to 2 PTCs with BRIDION 4 mg/kg had a wider range of recovery times but the median time to recovery was comparable to the study of reversal at T2 (2.7 minutes with 25th and 75th  percentiles of 2.1 and 4.3 minutes for rocuronium [N=37], and 3.3 minutes with 25th  and 75th  percentiles of 2.3 and 6.6 minutes for vecuronium [N=47]). There were 7 and 6 censored observations in the rocuronium and vecuronium groups, respectively.

Reversal Of Neuromuscular Blockade 3 Minutes After Rocuronium 1.2 mg/kg

Time to recovery from neuromuscular blockade induced by succinylcholine compared with recovery from neuromuscular blockade induced by rocuronium followed 3 minutes later with BRIDION was assessed in a multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study. The study was conducted in 110 patients (64 women and 46 men, ASA class 1 and 2, 78% were Caucasian, median weight was 70 kg, median age was 43 years). Patients underwent elective surgical procedures under general anesthesia that required endotracheal intubation and a short duration of neuromuscular relaxation. The laparoscopic or open surgical procedures were mainly gynecological, orthopedic, or reconstructive. Return of the first twitch in a TOF (T1) to 10% of baseline was compared between BRIDION 16 mg/kg for reversal of rocuronium 1.2 mg/kg versus spontaneous recovery from succinylcholine 1 mg/kg.

Recovery to T1 of 10% of baseline (relative to the time of administration of rocuronium or succinylcholine) was overall faster in the rocuronium/BRIDION group compared with succinylcholine alone (Table 3).

Table 3: Time (minutes ) from Start of Administration of Rocuronium or Succinylcholine to Recovery of T1 to 10% of Baseline

	Treatment Regimen
	Rocuronium (1.2 mg/kg) and BRIDION (16 mg/kg)	Succinylcholine (1 mg/kg)
N	55	55
Mean (SD)	4.4 (0.7)	7.1 (1.6)
Median (Range)	4.2 (3.5 - 7.7)	7.1 (3.8 - 10.5)

The following serious adverse reactions are described elsewhere in the labeling:

• Anaphylaxis and Hypersensitivity [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]
• Marked Bradycardia [see WARNINGS AND PRECAUTIONS]

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.

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%

Body System Preferred Term	Sugammadex			Placebo (N=544) n (%)
	2 mg/kg (N=895) n (%)	4 mg/kg (N=1921) n (%)	16 mg/kg (N=98) 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*	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
* 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

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]. 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].

Bronchospasm

In one dedicated clinical trial and in post-marketing data, in patients with a history of pulmonary complications [see Use in Specific Populations], 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 [see WARNINGS AND PRECAUTIONS]. Other cardiac rhythm abnormalities have included atrial fibrillation, atrioventricular block, cardiac/cardiorespiratory arrest, ST segment changes, supraventricular tachycardia/extrasystoles, tachycardia, ventricular fibrillation, and ventricular tachycardia.

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 [see WARNINGS AND PRECAUTIONS].

Respiratory, Thoracic, and Mediastinal Disorders: Events of laryngospasm, dyspnea, wheezing, pulmonary edema, and respiratory arrest have been reported.

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