Reverse Mechanism of Action

Pharmacology: Pharmacodynamics: SUGAMMADEX 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.
SUGAMMADEX 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 Interactions].
Mechanism Of Action: SUGAMMADEX 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.
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 Precautions and Nonclinical Toxicology under Actions].
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 (t_1/2) 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 SUGAMMADEX 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.
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 the Elderly under Precautions].
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.
Toxicology: Animal Toxicology And/Or Pharmacology: Bone and teeth retention of Sugammadex occurred in rats after intravenous injection, with mean half-lives 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 Juvenile Animal Studies under Precautions].
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment Of Fertility: Carcinogenesis: Long-term animal studies to evaluate the carcinogenic potential of Sugammadex have not been conducted.
Mutagenesis: 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: See Use in Pregnancy & Lactation.