FDA NewsPerspective

FDA advisory committee does not support Exparel indication for use as postoperative analgesia

The Anesthetic and Analgesic Drug Products Advisory Committee voted 6 to 4 that the data submitted in the supplemental new drug application for Exparel (bupivacaine liposomal injectable suspension) does not support approval of an additional indication for nerve block use as postoperative analgesia.

“We remain confident that the data from our clinical program provides all of the necessary information to support expansion of the current Exparel label for infiltration to also include use as a nerve block for regional analgesia,” Dave Stack, chairman and chief executive officer at Pacira Pharmaceuticals, said in a company press release. “We look forward to working with the FDA to address any outstanding questions as we move through the [supplemental NDA] review process toward our ultimate goal of offering additional flexibility in the way Exparel can be administered so that clinicians and patients alike have increased opportunity to realize the benefits of long-lasting non-opioid pain control.”

More data needed

Despite the number of studies submitted by Pacira Pharmaceuticals in the application, most of the committee believed there was not enough data provided, due in part to small patient numbers and a high amount of opioid use. Suggestions were made by some committee members that future studies should include a comparator arm instead of the use of placebo, specifically when it comes to stating whether bupivacaine liposomal injectable suspension is opiate-sparring.

“If you are going to talk about opiate-sparring, you are not going to want to compare that to the placebo,” Gregory Terman, MD, PhD, professor, department of anesthesiology and pain medicine at the University of Washington and temporary voting member of the committee, said. “I am not sure too many people would think placebo causes a lot of opiate-sparring. There you really do need an active comparator and the fact that, despite recommendations for active comparators, that has not been what the sponsor has done except with investigator-initiated studies. I am not sure that opioid-sparring was the plan at all.”

Jeffrey L. Galinkin , MD, FAAP, a voting member of the committee, said establishing a post-marketing registry will be important to distinguish if bupivacaine liposomal injectable suspension continues to have a higher incidence of systemic toxicity compared with other local anesthetics.

However, David S. Craig, PharmD, a voting member, questioned the other panelists about why they thought other studies were needed.

“The active comparator studies would be nice and if you look at most of the active comparator studies there is no difference between Exparel and active comparator in many of the regular-release bupivacaines,” Craig said. “That is a specific issue clinicians can help to digest and to understand whether they need to use it in their practice[s] or not. That is not the question. The question is: do we need more data to support this expanded indication? My opinion, no.”

Concerns about current use

Also mentioned during the discussion was concern that bupivacaine liposomal injectable suspension is already in use for the indication sought by Pacira Pharmaceuticals, despite its unapproved status. Laura D. Porter, MD, a patient representative with a vote as a temporary member, noted her surgeon used bupivacaine liposomal injectable suspension outside of a clinical trial when she underwent knee replacement in 2016.

“One of the issues that I have is the fact it is being used already for this and it is not approved,” Porter said.

She added, “Let’s say that we do not approve the relabeling. Are doctors still going to use it?”

The Prescription Drug User Fee Act or PDUFA date for FDA to complete its review of Pacira Pharmaceutical’s supplemental NDA for bupivacaine liposomal injectable suspension is April 6, 2018. – by Casey Tingle

Reference:

https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm591101.htm

http://investor.pacira.com/phoenix.zhtml?c=220759&p=irol-newsArticle&ID=2332847

The Anesthetic and Analgesic Drug Products Advisory Committee voted 6 to 4 that the data submitted in the supplemental new drug application for Exparel (bupivacaine liposomal injectable suspension) does not support approval of an additional indication for nerve block use as postoperative analgesia.

“We remain confident that the data from our clinical program provides all of the necessary information to support expansion of the current Exparel label for infiltration to also include use as a nerve block for regional analgesia,” Dave Stack, chairman and chief executive officer at Pacira Pharmaceuticals, said in a company press release. “We look forward to working with the FDA to address any outstanding questions as we move through the [supplemental NDA] review process toward our ultimate goal of offering additional flexibility in the way Exparel can be administered so that clinicians and patients alike have increased opportunity to realize the benefits of long-lasting non-opioid pain control.”

More data needed

Despite the number of studies submitted by Pacira Pharmaceuticals in the application, most of the committee believed there was not enough data provided, due in part to small patient numbers and a high amount of opioid use. Suggestions were made by some committee members that future studies should include a comparator arm instead of the use of placebo, specifically when it comes to stating whether bupivacaine liposomal injectable suspension is opiate-sparring.

“If you are going to talk about opiate-sparring, you are not going to want to compare that to the placebo,” Gregory Terman, MD, PhD, professor, department of anesthesiology and pain medicine at the University of Washington and temporary voting member of the committee, said. “I am not sure too many people would think placebo causes a lot of opiate-sparring. There you really do need an active comparator and the fact that, despite recommendations for active comparators, that has not been what the sponsor has done except with investigator-initiated studies. I am not sure that opioid-sparring was the plan at all.”

Jeffrey L. Galinkin , MD, FAAP, a voting member of the committee, said establishing a post-marketing registry will be important to distinguish if bupivacaine liposomal injectable suspension continues to have a higher incidence of systemic toxicity compared with other local anesthetics.

However, David S. Craig, PharmD, a voting member, questioned the other panelists about why they thought other studies were needed.

“The active comparator studies would be nice and if you look at most of the active comparator studies there is no difference between Exparel and active comparator in many of the regular-release bupivacaines,” Craig said. “That is a specific issue clinicians can help to digest and to understand whether they need to use it in their practice[s] or not. That is not the question. The question is: do we need more data to support this expanded indication? My opinion, no.”

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Concerns about current use

Also mentioned during the discussion was concern that bupivacaine liposomal injectable suspension is already in use for the indication sought by Pacira Pharmaceuticals, despite its unapproved status. Laura D. Porter, MD, a patient representative with a vote as a temporary member, noted her surgeon used bupivacaine liposomal injectable suspension outside of a clinical trial when she underwent knee replacement in 2016.

“One of the issues that I have is the fact it is being used already for this and it is not approved,” Porter said.

She added, “Let’s say that we do not approve the relabeling. Are doctors still going to use it?”

The Prescription Drug User Fee Act or PDUFA date for FDA to complete its review of Pacira Pharmaceutical’s supplemental NDA for bupivacaine liposomal injectable suspension is April 6, 2018. – by Casey Tingle

Reference:

https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm591101.htm

http://investor.pacira.com/phoenix.zhtml?c=220759&p=irol-newsArticle&ID=2332847

    Perspective
    David C. Ring

    David C. Ring

    Long-acting anesthetics can give people a break from postoperative pain, allowing them to get home and settled-in more comfortably. But, when the anesthetic wears off, it can be an unpleasant surprise as the holiday from the pain ends. It can feel like something is wrong, which can make the pain more intense. Because the amount of opioids used in the first few days would a priori be expected to be less, that is not a good measure of success. The total amount of opioids used is also not a good outcome measure because the use of opioids is so variable between patients and in different countries. We need some global measure of satisfaction with pain relief over the entire recovery experience to try to gauge the value of long-acting anesthetics. Given the growing evidence that mindset and circumstances, such as high self-efficacy, peace of mind, support, distraction, return to meaningful activities, are the best pain relievers, we need to be careful not to reinforce a passive and external sense of pain relief by focusing singularly on medications.

    • David C. Ring, MD, PhD
    • Orthopedics Today Editorial Board Member

    Disclosures: Ring reports he is retained by a law firm regarding a suit of Texas counties v. Purdue Pharma LP.