BRIDION (Page 5 of 7)

11 DESCRIPTION

BRIDION (sugammadex) injection, for intravenous use, contains sugammadex sodium, a modified gamma cyclodextrin chemically designated as 6A ,6B ,6C ,6D ,6E ,6F ,6G ,6H -Octakis-S-(2-carboxyethyl)-6A ,6B ,6C ,6D ,6E ,6F ,6G ,6H -octathio-γ -cyclodextrin sodium salt (1:8) with a molecular weight of 2178.01. The structural formula is:

Chemical Structure
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BRIDION is supplied as a sterile, non-pyrogenic aqueous solution that is clear, colorless to slightly yellow-brown for intravenous injection only. Each mL contains 100 mg sugammadex, which is equivalent to 108.8 mg sugammadex sodium. The aqueous solution is adjusted to a pH of between 7 and 8 with hydrochloric acid and/or sodium hydroxide. The osmolality of the product is between 300 and 500 mOsmol/kg.

BRIDION may contain up to 7 mg/mL of the mono OH-derivative of sugammadex [see Clinical Pharmacology (12.2)]. This derivative is chemically designated as 6A ,6B ,6C ,6D ,6E ,6F ,6G -Heptakis-S-(2-carboxyethyl)-6A ,6B ,6C ,6D ,6E ,6F ,6G -heptathio-γ -cyclodextrin sodium salt (1:7) with a molecular weight of 2067.90. The structural formula is:

Chemical Structure
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12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 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 (7.3)].

Cardiac Electrophysiology

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

12.3 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 (8.4), Nonclinical Toxicology (13.2)].

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 (t1/2 ) 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 t1/2 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.

Geriatric Patients

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 (8.5, 8.6)].

Pediatric Patients

Sugammadex pharmacokinetic parameters were estimated in pediatric patients 2 to <17 years of age with patients enrolled into 3 age groups (2 to <6, 6 to <12 and 12 to <17 years of age) and intravenous doses of 2 or 4 mg/kg sugammadex administered for reversal of moderate or deep neuromuscular blockade, respectively. Both clearance and volume of distribution increase with increasing age in pediatric patients.

Sugammadex exposure (AUC0-inf and Cmax ) increased in a dose-dependent, linear manner following administration of 2 and 4 mg/kg across patients 2 to <17 years of age. Sugammadex exposure was approximately 40% lower in patients 2 to <6 years of age following administration of 2 or 4 mg/kg sugammadex compared to older pediatric patients (6 to <17 years) and adults; however, this difference was not clinically relevant [see Clinical Studies (14.1)].

The observed steady-state volume of distribution of sugammadex is approximately 3 to 10 liters and clearance is approximately 38 to 95 mL/min resulting in a half-life of approximately 1-2 hours in pediatric patients 2 to <17 years of age.

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.

Obesity

In one clinical study of obese patients with a body mass index ≥40 kg/m2 , sugammadex 2 mg/kg and 4 mg/kg was dosed according to ABW (n=76) or IBW (n=74). Sugammadex exposure increased in a dose-dependent, linear manner following administration according to ABW or IBW. No clinically relevant differences in pharmacokinetic parameters were observed between obese patients and the general population, when dosed according to ABW. [See Use in Specific Populations (8.10).] Systemic exposure of sugammadex is approximately 50% lower with IBW dosing compared to ABW.

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