The US Food and Drug Administration’s (FDA’s) Anesthetic and Analgesic Drug Products Advisory Committee voted 6 to 4 against recommending bupivacaine liposomal injectable suspension (Exparel, Pacira Pharmaceuticals Inc) as a nerve block to treat regional postsurgical pain.
Although the vote was close, the committee believed the drug company did not adequately demonstrate the drug’s safety and efficacy.
“I wasn’t convinced of the data that was presented here at the FDA of both efficacy and safety. I think Exparel is going to be an excellent local anesthetic…. It’s just a shame that we didn’t see the data here today. I think that there will continue to be either pre- or postlabel clinical studies that will be convincing, and probably as long as the safety data pans out, it will be a very widely used local anesthetic someday,” said voting committee member Ronald S. Litman, DO, professor of anesthesiology and pediatrics, Perelman School of Medicine, University of Pennsylvania; attending anesthesiologist, The Children’s Hospital of Philadelphia; and medical director, Institute for Safe Medication Practices, all in Philadelphia, Pennsylvania.
As reported by Medscape Medical News, the FDA approved bupivacaine liposomal injectable suspension in 2011 for “administration into the surgical site to produce postsurgical analgesia.”
Initial sNDA Rejected by FDA
According to the company, when the drug is used for regional analgesia as part of a multimodal approach, it may offer steady pain control during the acute postoperative period for a longer time compared with local analgesia. It may also reduce the need for opioids and result in faster patient mobilization, shorter hospital stays, and lower healthcare costs.
The company submitted a supplemental new drug application (sNDA) for the proposed indication — “single-dose infiltration to produce local analgesia and as a nerve block to produce regional analgesia” — on May 5, 2014. However, the FDA did not approve the sNDA at that time.
For the initial sNDA, the company submitted results from two multicenter, randomized, placebo-controlled clinical trials: 402-C-322 (study 322) and 302-C-323 (study 323). Both studies used 266 mg of the study drug for the nerve block and allowed the use of rescue opioids.
The primary endpoint for both studies was an area under the curve (AUC) analysis of a numeric rating scale for pain intensity while at rest during the first 72 hours. Secondary endpoints for both studies were total opioid use, percentage of patients who were opioid-free, and time to first opioid.
In study 322, researchers randomly assigned 185 patients in the United States and Eastern Europe undergoing posterolateral thoracotomy in a 1:1 ratio to receive an intercostal nerve block or placebo. This study did not find efficacy of the study drug against placebo.
In study 323, researchers randomly assigned 183 patients in the United States undergoing total knee arthroplasty in a 1:1 ratio to receive a femoral nerve block or placebo via an epidural catheter using ultrasound guidance.
This study demonstrated the drug’s efficacy compared with placebo but did not demonstrate the duration of the nerve block (only the first 72 hours) or adequately report cardiac safety data. Thus, it did not adequately characterize the safety profile of the study drug when used for femoral nerve block. The study met the secondary endpoint of total postsurgical opioid consumption during the first 72 hours, but not time to first opioid rescue. In addition, it did not have an active control arm with immediate-release bupivacaine.
The FDA requested that the applicant demonstrate efficacy from an adequate and well-controlled trial in one or more additional clinical settings and to adequately characterize safety for femoral block with the study drug. The FDA also asked the company to assess toxicity through the median time of maximum concentration.
Current sNDA Application
For the current application, the company submitted data from two additional clinical trials, study 402-C-326 (study 326) and study 402-C-327 (study 327). Both were phase 3 multicenter, randomized, double-blind, placebo-controlled studies conducted in the United States and Western Europe.
For both studies, different patients underwent both partial and full pharmacokinetics (PK) sampling through 120 hours. The researchers calculated PK parameters from patients who had full PK sampling. Secondary endpoints were total opioid use, percentage of patients who were opioid-free, and time to first opioid.
Study 326 evaluated the efficacy, safety, and PK of femoral nerve block with bupivacaine liposomal injectable suspension for postsurgical analgesia in 230 patients undergoing total knee arthroplasty. The researchers randomly assigned patients in a 1:1:1 ratio to receive a single 20-mL dose of 133 mg of the study drug (10 mL study drug + 10 mL normal saline), 266 mg of the study drug (20 mL study drug), or placebo (20 mL normal saline) via needle, at least 1 hour before surgery under ultrasound guidance. All patients also received 8 mL of bupivacaine HCl (0.5%) diluted with normal saline as a periarticular infiltration before placement of the prosthesis, for a total bupivacaine dose of 173 mg, 306 mg, and 40 mg, respectively.
The study did not meet its primary endpoint, AUC of a visual analog scale (VAS) at 72 hours.
Study 327 evaluated the efficacy, safety, and PK of brachial plexus nerve block (interscalene or supraclavicular) with bupivacaine liposomal injectable suspension for postsurgical analgesia in 140 patients undergoing total shoulder arthroplasty or rotator cuff repair.
The researchers randomly assigned patients in a 1:1 ratio to receive a single 20-mL dose of 133 mg (10 mL study drug + 10 mL normal saline) or 266 mg (20 mL study drug) of the study drug or placebo (20 mL normal saline) via syringe at least 1 hour before surgery using ultrasound guidance.
The study did not meet its primary endpoint, AUC of VAS at 48 hours.
“The proposed dose of up to 266 mg may be effective for interscalene block and possibly for femoral block, but it does not appear to be effective in any other blocks that have been evaluated by the Sponsor. In addition, contradictory study findings in the two femoral nerve studies make it difficult to determine the efficacy of Exparel when administered as a femoral nerve block,” the FDA notes in a briefing document.
Fall Risk, Nerve Injury?
The company failed to characterize the onset and duration of sensory and motor block following femoral nerve block and nerve blocks in general, which places patients at risk for falls and unrecognized nerve injury, the FDA explains in the briefing document.
The incidence of falls in study 323 was 2.6% in patients who received the study drug, compared with none among patients in the placebo group.
Study 326 did not include an immediate-release bupivacaine femoral nerve block as a comparator group; therefore, it is unclear whether any quadriceps weakness would have resulted from prolonged femoral nerve block with any local anesthetic or whether the study drug increases the risk.
The applicant submitted a reanalysis of Holter monitor and electrocardiogram (ECG) date from studies 322 and 323. They also included new ECG data from studies 326 and 327; they found no evidence of cardiac toxicity associated with the study drug.
“At the end of the day, I think being that this was a medication that had already been approved, I think there was enough information for me from a safety and efficacy perspective to vote ‘yes.’ With respect to the falls, I think a lot of it has to do with what’s done on an institutional basis with respect to people who are fall risks and not the medication itself,” said voting committee member Kevin L. Zacharoff, MD, faculty and clinical instructor, pain and medical ethics, State University of New York Stony Brook School of Medicine, and ethics committee chair, St. Catherine of Siena Medical Center, Smithtown, New York.
“I voted ‘yes,’ with the proviso that the current restriction on bupivacaine within 96 hours was generalized to all local anesthetics, that some preclinical lipid emulsion therapy studies were done [to] make sure there isn’t an interaction between liposomes and lipid emulsion, and finally, an active comparison in the brachial plexus study to show more prolonged use or benefit,” said temporary voting committee member Gregory Terman, MD, PhD, professor, Department of Anesthesiology and Pain Medicine and the Graduate Program in Neuroscience; and director, University of Washington Medical Center Acute Pain Service, University of Washington, Seattle.
“I voted ‘no’; I also had concerns about the efficacy and some of the safety data. In the future, it’d be nice to see some pediatric dosing information as well,” said voting committee member Jeffrey L. Galinkin, MD, professor of anesthesiology and pediatrics, University of Colorado, AMC, and medical safety officer, CPC Clinical Research, University of Colorado, both in Aurora.
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