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Safety in Lactation: Local anaesthesia

25 September 2020Local anaesthetics are generally considered to be compatible with breastfeeding. They are used in a variety of clinical situations (surgery including Caesarean sections, labour and…
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New Medicines

ZynrelefPostoperative pain

Information

Zynrelef
New formulation
Heron Therapeutics
Heron Therapeutics

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Launched
Jul 21NICE decides this product is not suitable for a Technology Appraisal because the benefits of the technology cannot be adequately quantified within the Technology Appraisal methods framework. The possibility of an evidence summary will be explored [11].
Jul 21Heron Therapeutics announces U.S. commercial launch and availability of Zynrelef [10].
Jul 21Anticipate 2022 launch if company awaiting NICE TA before launch [9].
May 21US FDA approves Zynrelef (bupivacaine and meloxicam) for soft tissue or periarticular installation in adults to produce postsurgical analgesia for up to 72 hours after a bunionectomy, open inguinal herniorrhaphy, and total knee arthroplasty [8].
Sep 20Approved in EU for the treatment of somatic postoperative pain from small- to medium-sized surgical wounds in adults. Heron expect to make Zynrelef available to patients in the EU during 2021 [7].
Jul 20Recommended for EU approval by CHMP - the full indication is "for treatment of somatic postoperative pain from small- to medium-sized surgical wounds in adults (see section 5.1). It is proposed that the medicine is administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity." [5]
Jun 20Heron Therapeutics receives a complete response letter from US FDA. In the CRL, FDA states it is unable to approve the NDA in its present form based on the need for additional non-clinical information [6].
Oct 19Resubmitted NDA filing accepted by the FDA [4].
Apr 19EU filing accepted by the EMA. The EMA will review the application via centralised procedure. The eligibility to the centralised procedure for bupivacaine/meloxicam was based on its meeting criteria of a medicinal product constituting a significant scientific innovation. The MAA submission was supported by data from the 7 completed PII and PIII studies [2].
Apr 19FDA issues a complete response letter (CRL) to Heron Therapeutics regarding the New Drug Application (NDA) for bupivacaine/meloxicam for management of post-operative pain. The CRL stated that the US FDA was unable to approve the NDA and requested the company for additional Chemistry Manufacturing and Controls (CMC) and non-clinical information. In review of the NDA, the agency did not identified any issue related to clinical efficacy and safety data. The US FDA did not request any further clinical data from the company. Heron plans to schedule a meeting with the FDA to resolve issues outlined in the CRL [2].
Dec 18Granted priority review in the US [2].
Oct 18Filed in US. The NDA filing is based on the results of 7 completed clinical studies in 5 bony and soft tissue surgical procedures that included over 1,000 patients who received HTX 011 [2].

Category

HTX-011 is a fixed-dose combination of the local anaesthetic bupivacaine with the nonsteroidal anti-inflammatory drug (NSAID) meloxicam, in a long-acting, extended-release formulation.
Almost 60% of patients experience severe pain in the postoperative period, with a marked negative impact on health related quality of life [1].
Postoperative pain
Infiltration

Further information

Yes

Trial or other data

Oct 19Positive topline results from multicentre PIIIb open-label single-arm, postoperative pain management study in 51 pts undergoing total knee arthroplasty (TKA) surgery. HTX-011 + scheduled postoperative oral acetaminophen and celecoxib. In this study, mean pain scores remained in the mild range through 72 hours post-surgery. Median consumption of opioids was 4-to-5 pills of oxycodone (22.5 morphine milligram equivalents) through 72 hours and 75% of pts were discharged without opioids. HTX-011 + oral analgesic regimen was well tolerated and there were no deaths, serious adverse events or premature discontinuations due to adverse events.[3]
Aug 19Results of PIII EPOCH 2 study (n=418) published in Hernia. HTX-011 reduced mean pain intensity by 23% versus placebo (primary endpoint; p < 0.001) and by 21% versus bupivacaine HCl (p < 0.001) with significant reductions in the number of patients experiencing severe pain. Opioid consumption over 72 h was reduced by 38% versus placebo (p < 0.001) and 25% versus bupivacaine HCl (p = 0.024). Overall, 51% of HTX-011 subjects were opioid-free through 72 h (versus 22% for placebo [p < 0.001] and 40% for bupivacaine HCl [p = 0.049]). HTX-011 was generally well-tolerated with fewer opioid-related adverse events reported compared to the bupivacaine HCl and placebo and no evidence of local anesthetic systemic toxicity [13].
May 19May 19: Results of PIII EPOCH 1 study (n=412) were published in BMJ Regional Anaesthesia and Pain Medicine Journal. The results for the primary and all four key secondary endpoints were statistically significant in favour of HTX-011. HTX-011 demonstrated superior, sustained pain reduction through 72 hours, significantly reduced opioid consumption and resulted in significantly more opioid-free subjects compared with saline placebo and bupivacaine HCl. Safety was similar across groups with fewer opioid-related adverse events observed in the HTX-011 group [12].
May 19Heron Therapeutics announces that the EPOCH 1 study achieved both primary and key secondary endpoint [2].
Mar 18Top-line data from the two PIII EPOCH 1 and EPOCH 2 trials released. The results from the these trials will support the NDA [2].
Mar 18PIII EPOCH 1 study to evaluate the analgesic efficacy and safety of bupivacaine/meloxicam administered via local administration into the surgical site in subjects undergoing bunionectomy completes (NCT03295721; HTX011-301). The randomised, double-blind, saline placebo- and active-controlled trial enrolled 412 patients in the US [2].
Jan 18PIII EPOCH 2 trial designed to evaluate the efficacy and safety of bupivacaine/meloxicam, applied locally to the surgical site, for postoperative analgesia in patients undergoing unilateral open inguinal herniorrhaphy completes (HTX-011-302; NCT03237481). The primary endpoints were the difference in mean area under the curve (AUC) of pain intensity scores through 72 hours compared with placebo. The randomised, saline placebo and active controlled trial enrolled 418 patients in the US and Belgium [2].

Evidence based evaluations