Sugammadex

Sugammadex (Bridion®), a modified γ-cyclodextrin, is the first selective relaxant binding agent indicated to reverse the neuromuscular blockade induced during general anaesthesia to facilitate surgical procedures. The mechanism of action of sugammadex differs from that of other commonly used reversal agents, such as neostigmine and edrophonium. In the EU, sugammadex is recommended for use in the reversal of rocuronium- or vecuronium-induced moderate or deep muscle relaxation in adult (including elderly) patients and reversal of rocuronium-induced moderate muscle relaxation in paediatric patients (aged 2–17 years). Sugammadex is also approved in Australia, Iceland, New Zealand and Norway.

In clinical trials in adult surgical patients with relatively good health, sugammadex at recommended doses provided rapid reversal of rocuronium- or vecuronium-induced neuromuscular blockade with a low incidence of residual or recurrent neuromuscular blockade and was generally well tolerated. In paediatric patients, sugammadex effectively reversed rocuronium-induced neuromuscular blockade and was generally well tolerated. Several factors associated with the use of sugammadex have yet to be determined, such as the efficacy and safety in patients with poorer health or in those with neuromuscular disorders, the incidence of infrequent adverse events in larger patient populations and the cost effectiveness of the drug relative to existing reversal agents. Nevertheless, sugammadex is a useful addition to the reversal agents commonly employed in anaesthetic practice.

Sugammadex encapsulates and inactivates rocuronium; it selectively binds to free rocuronium molecules with high affinity at a molar ratio of 1:1. The resulting inactive complex is eliminated from the body according to the pharmacokinetic properties of sugammadex. Sugammadex also has high affinity for vecuronium. In several phase I and II trials, sugammadex demonstrated dose-dependent reversal of rocuronium- or vecuronium-induced blockade when administered at the reappearance of the second twitch of the train-of-four stimulation (T₂) or at a post-tetanic count of 1–2 (1–2 PTC), or 3–15 minutes after the administration of the neuromuscular blocking agent. Sugammadex has no clinically relevant effects on the cardiovascular and haemodynamic systems (including corrected QT interval prolongation).

Intravenous sugammadex demonstrates linear pharmacokinetic properties over the dose range of 1–16 mg/kg. The steady-state volume of distribution after a single dose is ≈1-14 L. Sugammadex and the sugammadex-rocuronium complex do not bind to plasma proteins or erythrocytes. Sugammadex does not appear to undergo metabolism and is primarily excreted in the urine as unchanged drug; the elimination half-life is 1.8 hours. Administration of sugammadex following that of rocuronium increases the plasma concentration of rocuronium (in a manner dependent on the dose of sugammadex), shortens its elimination half-life (by ≈30%) and increases the urinary excretion (by 2- to 3-fold) of rocuronium; however, these changes are not associated with an increase in the level of neuro-muscular blockade. Unlike rocuronium, the sugammadex-rocuronium complex is not eliminated via the biliary route. Renal impairment (but not hepatic impairment or patient age) delays the elimination of sugammadex and the sugammadex-rocuronium complex, and the use of sugammadex in patients with severe renal impairment is not recommended.

The efficacy of sugammadex has been evaluated in several well designed phase III trials in adult (including elderly) or paediatric surgical patients. In adult patients, sugammadex 2 mg/kg reversed rocuronium 0.6 mg/kg or vecuronium O.l mg/kg significantly faster than neostigmine 50 μg/kg plus glycopyrrolate 10 μg/kg, when administered at the reappearance of T₂. In addition, the reversal of rocuronium 0.6 mg/kg by sugammadex 2 mg/kg was significantly faster than the reversal of cisatracurium 0.15 mg/kg by neostigmine 50μg/kg plus glycopyrrolate 10μg/kg. Sugammadex 4 mg/kg reversed rocuronium 0.6 mg/kg or vecuronium 0.1 mg/kg significantly faster than neostigmine 70 μg/kg plus glycopyrrolate 14 μg/kg, when administered at 1–2 PTC. When administered 3 minutes after rocuronium, sugammadex 16 mg/kg reversed rocuronium 1.2 mg/kg significantly faster than the spontaneous recovery after suxamethonium chloride (succinylcholine).

The time to reverse neuromuscular blockade with sugammadex 2 mg/kg administered at the reappearance of T₂ following rocuronium 0.6 mg/kg was slower in elderly than in younger adult patients; however, reversal was reached in <4 minutes in the majority (75.5%) of elderly patients. In infants, children, adolescents and adults receiving sugammadex 2 mg/kg following rocuronium 0.6 mg/kg, the mean time to neuromuscular blockade reversal was <1.9 minutes. The efficacy of sugammadex 2 mg/kg did not differ between patients with normal renal function and those with severe renal impairment. Underlying cardiac or pulmonary disease had no effect on the efficacy of sugammadex.

Sugammadex was generally well tolerated in clinical trials in surgical patients (including elderly or paediatric patients, or patients with renal impairment or cardiac or pulmonary disease) or healthy volunteers. The majority of adverse events considered to be related to sugammadex were mild to moderate in severity. The most commonly reported adverse events in any study group were procedural pain, nausea and vomiting. In pooled analyses, the tolerability profile of sugammadex was generally similar to that of placebo or neostigmine plus glycopyrrolate; serious adverse events were infrequent. Uncommon adverse events include anaesthetic complications and dysgeusia in awake healthy volunteers, which were more frequent with higher than recommended doses of sugammadex (≥16 mg/kg), and residual or recurrent neuromuscular blockade which was more frequent with lower than recommended doses of sugammadex (<2mg/kg).