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ZynrelefTM Heron Therapeutics

November 2, 2021

Dear RAPID Response:

To the Editor:

Zynrelef<sup>TM</sup> Heron Therapeutics

ZynrelefTM Heron Therapeutics

Recently, the U.S. Food and Drug Administration (FDA) approved a new drug for the treatment of postoperative pain after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty. This medication is a combination product consisting of bupivacaine and meloxicam (ZynrelefTM Heron Therapeutics). In an effort to familiarize myself with this new product I reviewed the package insert1, but when I came to the section on Management of Local Anesthetic Overdose, I was surprised to see that the recommended treatment for seizures was a barbiturate or benzodiazepine and the treatment for circulatory depression was intravenous fluids or a vasopressor. Nowhere in this section was the use of lipid emulsion therapy (e.g. Intralipids) mentioned.

Lipid emulsion therapy has rapidly become the standard of care for severe local anesthesia systemic toxicity2. The fact that it is not even mentioned as a treatment for bupivacaine overdose is an oversight that must be corrected. If a problem developed after the use of this drug the package insert is one resource the treating perioperative clinician might rely on. Therefore, the use of Lipid emulsion therapy must be included in this FDA document as a treatment for local anesthesia systemic toxicity.



  1. ZYNRELEF™ prescribing information. Access data Food and Drug Administration web site. Accessed July 20, 2021.
  2. American Society of Regional Anesthesia (ASRA). Checklist for Treatment of Local Anesthetic Systemic Toxicity. ASRA website. Updated November 1, 2020. Accessed July 20, 2021.


In Response:

We appreciate your concern for patient safety, specifically regarding the optimal treatment of local anesthetic systemic toxicity (LAST).

ZYNRELEF (HTX-011) is an extended-release solution of bupivacaine and low-dose meloxicam1. ZYNRELEF, unlike most other formulations of local anesthetics, is applied without a needle into the surgical site where the active ingredients are released over 72 hours. Application without a needle eliminates the inherent risk of inadvertent intravascular injection that could lead to systemic toxicity, and the controlled release from the ZYNRELEF polymer results in mean bupivacaine Cmax levels from the highest approved dose (400 mg bupivacaine/12 mg meloxicam) of 695 ng/mL, which is well below the commonly accepted threshold of 2,000 ng/mL for bupivacaine-related neurotoxicity and 4,000 ng/mL for cardiac toxicity2.

The efficacy and safety of ZYNRELEF for the approved indications was demonstrated during the ZYNRELEF clinical development program, and the approval and labeling for ZYNRELEF followed the 505(b)(2) regulatory process. In the 505(b)(2) process, the information for warnings and precautions relied on the prescribing information of the reference product, bupivacaine HCl (Marcaine™)3. Although lipid emulsion therapy has been recommended to treat LAST since 20104, it’s use is not included in the Marcaine label and as a result, all FDA-approved bupivacaine products that utilized the 505(b)(2) regulatory approval process (ie, Exparel, Xaracoll, and Posimir) do not contain recommendations for the use of lipid emulsion therapy for the treatment of LAST5-7.

Standard industry practice is to ensure agreement and collaboration with the FDA throughout the drug development process to ensure the product is safe, effective, and of high quality to support its approval. The FDA also ensures appropriate and adequate product labeling that both protects and informs patients and physicians on effective and safe use of the product. Heron therefore considers that the existing recommendations on the safe and appropriate use of ZYNRELEF are reflected within the FDA approved labeling statements, and that the ZYNRELEF labeling is in line with all other bupivacaine containing, FDA-approved local anesthetics.



  1. ZYNRELEF (bupivacaine and meloxicam) Extended-Release Solution [Full Prescribing Information]. Heron Therapeutics, Inc. San Diego, CA.
  2. Feldman HS, Arthur GR, Covino BG. Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog. Anesth Analg. 1989;69(6):794-801.
  3. Marcaine™ (bupivacaine hydrochloride) injection, USP [Full Prescribing Information]. Hospira, Inc. Lake Forest, IL.
  4. Neal JM, Woodward CM, Harrison TK. The American Society of Regional Anesthesia and Pain Medicine Checklist for Managing Local Anesthetic Systemic Toxicity: 2017 Version. Reg Anesth Pain Med 2018;43(2):150-153.
  5. EXPAREL® (Bupivacaine Liposome Injectable Suspension) [Full Prescribing Information]. Pacira Pharmaceuticals, Inc. San Diego, CA.
  6. POSIMIR® (bupivacaine solution) for infiltration use [Full Prescribing Information]. DURECT Corporation. Cupertino, CA.
  7. XARACOLL® (bupivacaine hydrochloride) implant [Full Prescribing Information]. Innocoll Pharmaceuticals Limited. Athlone, Ireland.

The information provided is for safety-related educational purposes only, and does not constitute medical or legal advice. Individual or group responses are only commentary, provided for purposes of education or discussion, and are neither statements of advice nor the opinions of APSF. It is not the intention of APSF to provide specific medical or legal advice or to endorse any specific views or recommendations in response to the inquiries posted. In no event shall APSF be responsible or liable, directly or indirectly, for any damage or loss caused or alleged to be caused by or in connection with the reliance on any such information.