October 28, 2008
Sugammadex Study First to Show Rapid Reversal of Profound Rocuronium-Induced Muscle Relaxation is Possible
KENILWORTH, N.J., Oct. 28 /PRNewswire-FirstCall/ -- Schering-Plough Corp., today announced that a study published in the November 2008 issue of the medical journal, Anesthesiology (Vol. 109, No. 5)(1) demonstrated that sugammadex produced a significantly more rapid recovery from profound rocuronium-induced muscle relaxation than the conventional reversal agent neostigmine. Importantly, this is the first comparative study to demonstrate that rapid reversal of profound rocuronium-induced muscle relaxation is possible. In the study, the median time to recovery was 2.7 minutes in the sugammadex group versus 49.0 minutes in the neostigmine group.
Sugammadex is a novel selective relaxant binding agent that works in an entirely new and unique way to encapsulate the muscle relaxant molecule and render it inactive. Sugammadex is approved and marketed in the European Union as BRIDION(R)."This study demonstrates that sugammadex is the first agent to permit rapid reversal of a profound level of rocuronium-induced neuromuscular blockade," said lead author R. Kevin Jones, M.D., attending anesthesiologist, Saddleback Memorial Medical Center, Laguna Hills, Calif. "This finding with sugammadex will likely have important clinical implications for how muscle relaxation is managed, providing anesthesiologists with greater control in maintaining the level of blockade necessary during surgery, while allowing for rapid recovery once surgery is completed."
The study, known as the Signal trial, was a Phase III, multicenter, randomized, parallel-group, safety-assessor blinded study that compared the efficacy and safety of sugammadex versus neostigmine/glycopyrrolate in the reversal of profound rocuronium-induced neuromuscular blockade. Traditionally, reversal of nondepolarizing neuromuscular blocking agents (NMBAs) such as rocuronium or vecuronium has been achieved by using acetylcholinesterase inhibitors, such as neostigmine. However, these older agents cannot rapidly reverse profound neuromuscular blockade.
Neuromuscular blockade plays several critical roles in general anesthesia. Anesthesiologists use muscle relaxation to improve surgical conditions and to facilitate intubation and mechanical ventilation. Reversal agents reverse the effects of muscle relaxants, enabling patients to regain normal muscle function sooner and breathe on their own again.
Studies have shown that in clinical practice, patients are often extubated before complete recovery has occurred, leaving the patients at risk of associated postoperative complications such as airway obstruction or pulmonary complications. Residual neuromuscular blockade, which is an important cause of NMBA-associated morbidity in surgical patients, was not reported in any patient in this study.
"These results demonstrate the efficacy of sugammadex in rapidly reversing profound rocuronium-induced neuromuscular blockade, an option that is not possible with conventional reversal agents," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "This study shows that sugammadex offers advantages over neostigmine and may help improve anesthesia management in the millions of surgeries where muscle relaxation agents are used."
In the Signal study, sugammadex or neostigmine was administered at reappearance of 1-2 post-tetanic counts (profound neuromuscular blockade). The primary efficacy endpoint of the study was time from sugammadex or neostigmine/glycopyrrolate administration to return of the train-of-four (TOF) ratio to 0.9. Profound neuromuscular blockade reversal with sugammadex 4 mg/kg was about 17 times faster than with neostigmine 70 mcg/kg (geometric mean times were 2.9 minutes versus 50.4 minutes, respectively [P
The study enrolled surgical patients, aged 18 years or older with American Society of Anesthesiology physical status I-IV. Seventy-four patients were randomized to receive sugammadex (4.0 mg/kg) or neostigmine (70 mcg/kg) plus glycopyrrolate (14 mcg/kg) and completed the study. Anesthetized patients received an intubating dose of rocuronium (0.6 mg/kg), with maintenance doses (0.15 mg/kg) as required. Neuromuscular monitoring was performed by acceleromyography.
In the study, sugammadex was well tolerated in the 37 patients who received the treatment, and its safety profile overall was comparable with that of neostigmine. Safety data from the study showed that the most frequently reported adverse events (AEs) for patients in both groups included procedural pain, nausea and incision-site complications. Serious adverse events (SAEs) were reported for two patients in the sugammadex group (postoperative infection and postoperative ileus) and three patients in the neostigmine group (nausea/pain/dyspnea, gastric perforation/procedural complication and postoperative ileus). No SAE was considered study drug-related. Only one patient (neostigmine group) discontinued from the study because of two SAEs (gastric perforation/procedural complication) and subsequently recovered. No cases of hypersensitivity were reported in the study.
Text of the full study titled, "Reversal of Profound Rocuronium-induced Blockade with Sugammadex: A Randomized Comparison with Neostigmine," can be found on the Anesthesiology website at http://www.anesthesiology.org/.
Important Safety Information about BRIDION
BRIDION (sugammadex) was approved for marketing by the European Commission in July 2008. BRIDION should only be administered by or under the supervision of an anesthesiologist. The use of an appropriate neuromuscular monitoring technique is recommended to monitor the recovery of neuromuscular blockade. The use of BRIDION in patients with severe renal impairment is not recommended.
In clinical trials, the most commonly reported adverse reaction was metal or bitter taste. Also commonly reported were anesthetic complications, indicative of the restoration of neuromuscular function, including movement of a limb or the body or coughing during the anesthetic procedure or during surgery, grimacing, or suckling on the endotracheal tube. In a few individuals, allergic-like reactions (i.e. flushing, erythematous rash) following sugammadex were reported.
Status of Sugammadex New Drug Applications
In the United States, the U.S. Food and Drug Administration (FDA) in July 2008 issued a "not-approvable" letter for sugammadex for the reversal of muscle relaxation during general anesthesia. This action was taken by FDA despite a unanimous recommendation for approval by the FDA Advisory Committee on Anesthetics and Life Support in March 2008. Schering-Plough plans to work with the agency to address the issues, which are primarily related to hypersensitivity/allergic reactions, and remains committed to bringing this important medical advance to those who are waiting for it in the United States.
In Japan, a New Drug Application seeking marketing approval of sugammadex has been filed with the Japanese Ministry of Health, Labour and Welfare (MHLW) and is currently under review. New Drug Applications for sugammadex also have been filed with health authorities in a number of other countries and are currently under review.
Schering-Plough acquired sugammadex through its combination with Organon BioSciences in November 2007.
Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription and consumer products as well as to animal health products. Schering-Plough's vision is to "Earn Trust, Every Day" with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., USA, and its Web site is http://www.schering-plough.com/.
SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the plans for, the potential of and the potential market for BRIDION. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details of these and other risks and uncertainties that may impact forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Item 8.01 of the company's 8-K filed Oct. 21, 2008.
(1) Jones RK, Caldwell JE, Brull SJ, Soto RG Reversal of Profound Rocuronium-induced Blockade with Sugammadex: A Randomized Comparison with Neostigmine. Anesthesiology. 2008;109(5):816-824.
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