Frequently Asked Questions

ZYNRELEF formulation and Biochronomer® technology

What is an extended-release dual-acting local anesthetic (DALA)?

ZYNRELEF is the first and only extended-release dual-acting local anesthetic.1-4 Its unique formulation combines the local anesthetic bupivacaine with a low dose of the NSAID meloxicam and was designed to overcome the challenges of inflammation at the surgical site. The meloxicam inhibits inflammation, normalizing pH at the surgical site and potentiating the effects of bupivacaine.1,5

Learn more about the dual-acting mechanism of action of ZYNRELEF.

How does ZYNRELEF differ from other long-acting local anesthetics already on the market and other alternatives to postoperative opioids?

  • MOA: The dual-acting formulation of ZYNRELEF combines the local anesthetic bupivacaine with a low dose of meloxicam that is thought to enable ZYNRELEF to overcome tissue inflammation and the resulting acidosis. This allows more bupivacaine to penetrate the nerve cell and provide pain relief.1,5
  • Formulation: ZYNRELEF uses Biochronomer polymer technology to diffuse pharmacological agents over a period of 72 hours.1,5
  • Administration: ZYNRELEF is delivered via a single, needle-free application into the surgical site.1

There have been no head-to-head studies of ZYNRELEF versus other available extended-release products or local anesthetic “cocktails” that combine bupivacaine with other medications. ZYNRELEF was tested against standard-of-care (SOC) bupivacaine HCl solution.1-3

Learn more about the dual-acting mechanism of action of ZYNRELEF.

Is ZYNRELEF just another form of liposomal bupivacaine?

No. ZYNRELEF is the first and only extended-release dual-acting local anesthetic (DALA).1-4 It is also the only local anesthetic considered by FDA to be extended-release, based on superiority to bupivacaine through 72 hours.1 It combines bupivacaine with a low dose of meloxicam and is designed to overcome the challenges of inflammation at the surgical site, which creates an acidic environment that would otherwise make it difficult for bupivacaine to penetrate the nerve cell membrane and reach the intended site of action.1,5,6 ZYNRELEF uses proprietary Biochronomer® controlled-diffusion technology, a polymer that allows for delivery of the active ingredients over the course of 72 hours after surgery, providing sustained pain relief.1,5

Learn more about the dual-acting mechanism of action of ZYNRELEF.

Why was meloxicam selected for ZYNRELEF?

The inflammatory process associated with surgical incision creates an acidic environment that makes it difficult for local anesthetics to penetrate the nerve cell membrane and reach the intended site of action.6 Meloxicam is a potent NSAID with a long half-life, and it was selected specifically for its anti-inflammatory mechanism of action.1,7 The physicochemical properties allow it to be formulated into the polymer and have the intended release rates.7 The meloxicam in ZYNRELEF is thought to overcome the challenge of tissue acidosis caused by inflammation at the surgical site, normalizing pH at the surgical site in order to potentiate the analgesic effect of bupivacaine.1,5

Learn more about the dual-acting mechanism of action of ZYNRELEF.

How much of the bupivacaine is released immediately as opposed to over time?

The active ingredients in ZYNRELEF are released using a proprietary Biochronomer controlled-diffusion technology.1,5

  • Within the first 24 hours, 52% of bupivacaine and 44% of meloxicam8,a
  • Within the first 48 hours, 81% of bupivacaine and 81% of meloxicam8,a
  • By 72 hours, 93% of bupivacaine and 95% of meloxicam8,a

aReflects in vitro release rates of active ingredients.

Graph: curve of bupivacaine 400 mg release rate from ZYNRELEF over 72 hours.
Graph: curve of meloxicam 12 mg release rate from ZYNRELEF over 72 hours.
Learn more about the dual-acting mechanism of action of ZYNRELEF.

Why does ZYNRELEF combine bupivacaine with the NSAID meloxicam?

The inflammatory process associated with surgery creates an acidic environment that makes it difficult for local anesthetics to penetrate the nerve cell membrane and reach the intended site of action.6 Meloxicam is a potent NSAID with a long half-life, and was selected specifically for its anti-inflammatory mechanism of action.1,7 It is thought to work synergistically to reduce local inflammation, thereby potentiating the analgesic efficacy of bupivacaine.1

Learn more about the dual-acting mechanism of action of ZYNRELEF.

Can I coadminister ZYNRELEF with other local anesthetics?

Due to the novel properties of the Biochronomer technology, lidocaine and other local anesthetics can be administered before ZYNRELEF without causing ZYNRELEF to “dump” the active ingredients all at once. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. ZYNRELEF should be applied as is, without diluting or mixing with water, saline, or other local anesthetics. No mixing with bupivacaine is required to achieve efficacy with ZYNRELEF.1

Learn more about the dual-acting mechanism of action of ZYNRELEF.

ZYNRELEF ordering, storage, preparation, dosing, and administration

What are the recommended storage conditions for the ZYNRELEF kit and/or vial?

ZYNRELEF is room temperature stable for 36 months.9 The vial should be stored at a controlled room temperature (20°C to 25°C; 68°F to 77°F). Temperature excursions are permitted within 15°C to 30°C (59°F to 86°F).1

Learn more about ZYNRELEF dosing and administration.

Can the kit be stored in our automated dispensing system?

Yes. ZYNRELEF is room temperature stable,1 and the kit will fit into automated dispensing systems.

Learn more about ZYNRELEF dosing and administration.

What vial sizes are available for ZYNRELEF?

ZYNRELEF is available in 2 different vial amounts:1

  • 14 mL (containing 400 mg of bupivacaine and 12 mg of meloxicam)
  • 7 mL (containing 200 mg of bupivacaine and 6 mg of meloxicam)
Learn more about ZYNRELEF dosing and administration.

Which vial size should be used for which surgeries?

The type of surgical procedure and amount of affected tissues that could result in pain generation will determine the vial size of ZYNRELEF needed. For example, for bunionectomy, a smaller procedure, up to 60 mg from the 7-mL vial size would be appropriate. For TKA, up to 400 mg from the 14-mL vial size would be appropriate; 400 mg is the maximum dose.1

Learn more about ZYNRELEF dosing and administration.

If the surgical wound is large, will ZYNRELEF cover the entire area?

ZYNRELEF spreads easily and covers a large area. The 14-mL dose volume is sufficient to cover total knee arthroplasty (TKA), a large surgical procedure.1

Learn more about ZYNRELEF dosing and administration.

How is ZYNRELEF applied when performing a surgery laparoscopically?

At this time, ZYNRELEF is not indicated for use laparoscopically. Heron is planning future studies for laparoscopic surgery.

Learn more about ZYNRELEF dosing and administration.

If ZYNRELEF is not injected, how does it reach the nerve cells?

The active ingredients of ZYNRELEF diffuse throughout the affected tissue at the surgical site. Meloxicam is thought to potentiate the effect of bupivacaine by facilitating penetration into the nerve cell at the intended site of action so that the bupivacaine can block pain signals to the brain.1,5,6

Learn more about ZYNRELEF dosing and administration.

Do I need to mix ZYNRELEF with bupivacaine or dilute with saline to prevent an analgesic gap after administration?

ZYNRELEF is a viscous formulation and does not require volume expansion to achieve efficacy. Therefore, the product should not be mixed with water, saline, or other local anesthetics. However, other local anesthetics such as lidocaine can be administered before ZYNRELEF without causing release of the active ingredients all at once.1

Learn more about ZYNRELEF dosing and administration.

How much does ZYNRELEF cost?

Heron offers 340B pricing to eligible institutions, which allows purchases at a minimum discount of 23.1%. ZYNRELEF is available through full-line wholesalers and specialty distributors; prime vendor discounts apply. GPO and sub-WAC pricing are also available. In addition, reimbursement for ZYNRELEF may offset the cost of the product for many patients.

ZYNRELEF pricing table: 14-mL WAC = $267.50; 14-mL 340B = $203.57; 7-mL WAC = $135.50; 7-mL 340B = $103.12.

GPO: group purchasing organization. WAC: wholesaler acquisition cost.

ZYNRELEF pricing as of May 12, 2021. Confirm current pricing with your Heron representative.

Learn more about pricing and reimbursement for ZYNRELEF.

ZYNRELEF safety information

Can ZYNRELEF be used with other NSAIDs?

The maximum amount of meloxicam in ZYNRELEF is 12 mg released over 3 days.1

Heron Therapeutics, Inc, has investigated the use of ZYNRELEF as part of a multimodal analgesic strategy. In cohorts receiving ketorolac, celecoxib, or ibuprofen in addition to ZYNRELEF, no increase in NSAID-related toxicity was seen.10-14

Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. Following administration of ZYNRELEF, if additional NSAID medication is indicated in the postoperative period, monitor patients for signs and symptoms of NSAID-related GI adverse reactions.1

Were there any issues of local anesthetic systemic toxicity (LAST) seen in the trials with ZYNRELEF?

In the ZYNRELEF clinical development program, there was no evidence of LAST based on a review of potential LAST-related treatment-emergent adverse events (TEAEs), vital signs, ECGs, and bupivacaine plasma concentrations.14,15

As part of the clinical research program for ZYNRELEF, a summary of LAST assessment questionnaire results was generated, showing the number and percentage of subjects with any potential signs or symptoms of LAST, with a breakdown of each sign or symptom overall and by each visit.15-17 The proportion of patients treated with ZYNRELEF who had a potential LAST-related TEAE was lower than that of standard bupivacaine and similar to that of placebo (ie, subjects with no exposure to bupivacaine). Additionally, despite the extended release of bupivacaine from ZYNRELEF over 3 days, the incidences of potential LAST-related TEAEs with a rapid onset (within 1 hour after study drug administration) were similar across all treatment groups. The incidences of potential LAST-related TEAEs with a delayed onset (between 1 to 72 hours after study drug administration) in the ZYNRELEF group were lower than the standard bupivacaine group and similar to placebo group.15

View the ZYNRELEF full Prescribing Information for more LAST-related warnings and precautions.

What is the risk of GI bleeding or perforation with ZYNRELEF?

NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

No events of gastrointestinal bleeding or perforation that were reported in any of the clinical trials were related to treatment with ZYNRELEF.11,14,15,18-21 Even in cohorts receiving ketorolac, celecoxib, or ibuprofen in addition to ZYNRELEF, no increase in NSAID-related toxicity was seen with this one-time low dose of meloxicam released over 3 days.10,11,13,14

Following administration of ZYNRELEF, if additional NSAID medication is indicated in the postoperative period, monitor patients for signs and symptoms of NSAID-related GI adverse reactions.1

Is there a risk of the NSAID meloxicam in ZYNRELEF causing renal impairment?

The highest recommended dose of ZYNRELEF contains 400 mg bupivacaine and a low dose (12 mg) of meloxicam, released over 72 hours.1

Only subjects with a creatinine clearance of >30 mL/min were considered eligible to participate. Therefore, there is no data on patients with severe renal impairment.16-20, 22-26

Bupivacaine and meloxicam and their metabolites are excreted by the kidney. No dose adjustment of ZYNRELEF is necessary in patients with mild to moderate renal impairment.1 Patients with renal disease, especially those with severe renal disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Patients with severe renal impairment have not been studied. The use of ZYNRELEF in patients with severe renal impairment is not recommended. Meloxicam is not dialyzable. When using ZYNRELEF in patients on hemodialysis do not exceed maximum recommended dose or use with other meloxicam-containing products.1

Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZYNRELEF in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function.1

Was any increase in infection rates observed in patients treated with ZYNRELEF?

In adequate and well-controlled trials, patients treated with ZYNRELEF did not experience increased rates of infection.15

What happens if someone accidentally injects the polymer? What precautions are in place to ensure that this doesn’t happen?

Do not inject ZYNRELEF.

The polymer in ZYNRELEF has a high viscosity1 that renders it extremely difficult to push through even a large hypodermic needle. While this practical barrier does not remove the risk of attaching a needle to the syringe, it greatly reduces the risk of someone trying to administer ZYNRELEF as an injection, and the in-market packaging will include pronounced warnings against the use of any Luer lock attachment other than the provided applicator.

Visit the Resource Center for cards and videos that can help you administer ZYNRELEF.

Is ZYNRELEF compatible with prosthetics and implantables (eg, titanium, plastics, and ceramics)?

Compatibility with ZYNRELEF was tested with Prolene® mesh, silicone membranes, bone cement, and metal alloys used in surgical implants. ZYNRELEF is also compatible with all components of the ZYNRELEF kit, including syringes, Luer lock cone-shaped applicator, vented vial spike, and syringe tip caps.1

See more safety information for ZYNRELEF.

Can ZYNRELEF be used as a nerve block for anesthesia?

ZYNRELEF is not indicated for nerve block, as Heron Therapeutics, Inc, is focused on administration by needle-free instillation into the surgical site.1

Can a block still be used when administering ZYNRELEF?

Yes, generic bupivacaine HCl solution or ropivacaine as a nerve block may be used. However, ZYNRELEF has not been studied using paracervical block anesthesia and is contraindicated for use in patients undergoing obstetrical paracervical block anesthesia. It also should not be used in obstetrical procedures prior to delivery. Nerve blocks using longer-acting local anesthetics (liposomal bupivacaine) are not necessary because ZYNRELEF provides up to 72 hours of analgesia.1

The patient’s total exposure to local anesthetics must be considered before application of ZYNRELEF, as well as during the first 72 hours that follow application. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF.1

Release rates of the active ingredients8,a:

  • Within the first 24 hours, 52% of bupivacaine and 44% of meloxicam has been released
  • Within the first 48 hours, 81% of bupivacaine and 81% of meloxicam has been released
  • By 72 hours, 93% of bupivacaine and 95% of meloxicam has been released

aReflect in vitro release rates of active ingredients.

View the ZYNRELEF full Prescribing Information to see the full list of warnings and precautions.

In what surgical models has ZYNRELEF been studied?

ZYNRELEF has been studied in multiple surgical models and is indicated for use in bunionectomy, open inguinal herniorrhaphy, and total knee arthroplasty.1

Learn more about the efficacy of ZYNRELEF.

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Important Safety Information and Indication

Indication

ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures.

Important Safety Information

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
  • ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
  • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Contraindications

ZYNRELEF is contraindicated in patients with known hypersensitivity (eg, anaphylactic reactions and serious skin reactions) to any amide local anesthetic, NSAIDs, or other components of ZYNRELEF; with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (severe, sometimes fatal, anaphylactic reactions to NSAIDS have been reported in such patients); undergoing obstetrical paracervical block anesthesia; or undergoing coronary artery bypass graft (CABG) surgery.

Warnings and Precautions

Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after application of ZYNRELEF. When using ZYNRELEF with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours.

Hepatotoxicity: If abnormal liver tests persist or worsen, perform a clinical evaluation of the patient.

Hypertension: Patients taking some antihypertensive medication may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure.

Heart Failure and Edema: Avoid use of ZYNRELEF in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure.

Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZYNRELEF in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal failure.

Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs.

Methemoglobinemia: Cases have been reported with local anesthetic use.

Serious Skin Reactions: NSAIDs, including meloxicam, can cause serious skin adverse reactions. If symptoms present, evaluate clinically.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): If symptoms are present, evaluate clinically.

Fetal Toxicity: Due to the risk of oligohydramnios/fetal renal dysfunction and premature closure of the ductus arteriosus with NSAIDS, limit use of ZYNRELEF between about 20 to 30 weeks gestation, and avoid use after about 30 weeks.

Hematologic Toxicity: Monitor hemoglobin and hematocrit in patients with any signs or symptoms of anemia.

Drug Interactions

Drugs That Interfere with Hemostasis: Monitor patients for bleeding who are using ZYNRELEF with drugs that interfere with hemostasis (eg, warfarin, aspirin, SSRIs/SNRIs). 

ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers: Use with ZYNRELEF may diminish the antihypertensive effect of these drugs. Monitor blood pressure.

ACE Inhibitors and ARBs: Use with ZYNRELEF in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function.

Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effect.

Use in Specific Populations

Infertility: NSAIDs are associated with reversible infertility. Consider avoidance of ZYNRELEF in women who have difficulties conceiving.

Severe Hepatic Impairment: Only use if benefits are expected to outweigh risks; monitor for signs of worsening liver function.

Severe Renal Impairment: Not recommended.

Adverse Reactions

Most common adverse reactions (incidence ≥10%) in controlled clinical trials with ZYNRELEF are constipation, vomiting, and headache.

Report side effects to Heron at 1-844-437-6611 or to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indication

ZYNRELEF is indicated in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty.

Limitations of Use: Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures.

Please see full Prescribing Information, including Boxed Warning.

References: 1. ZYNRELEF [package insert]. San Diego, CA: Heron Therapeutics Inc; 2021. 2. Viscusi E, Gimbel JS, Pollack RA, Hu J, Lee G-C. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in bunionectomy: Phase III results from the randomized EPOCH 1 study. Reg Anesth Pain Med. 2019;44(7):700-706. doi:10.1136/rapm-2019-100531. 3. Viscusi E, Minkowitz H, Winkle P, Ramamoorthy S, Hu J, Singla N. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the Phase 3 EPOCH 2 study. Hernia. 2019;23(6):1071-1080. doi:10.1007/s10029-019-02023-6. 4. Lachiewicz PF, Lee G-C, Pollak R, Leiman D, Hu J, Sah A. HTX-011 reduced pain and opioid use after primary total knee arthroplasty: results of a randomized Phase 2b trial. J Arthroplasty. 2020;35(10):2843-2851. doi:10.1016/j.arth.2020.05.044. 5. Ottoboni T, Quart B, Pawasauskas J, Dasta JF, Pollak RA, Viscusi ER. Mechanism of action of HTX-011: a novel, extended-release, dual-acting local anesthetic formulation for postoperative pain. Reg Anesth Pain Med. 2020;45(2):117-123. doi:10.1136/rapm-2019-100714. 6. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006;53(3):98-109. doi:10.2344/0003-3006(2006)53[98:EOLAP]2.0.CO;2. 7. Data on file. Written pharmacology summary. San Diego, CA: Heron Therapeutics Inc; 2017. 8. Data on file. Summary of biopharmaceutic studies and associated analytical methods. San Diego, CA: Heron Therapeutics Inc; 2018. 9. Roca R; Center for Drug Evaluation and Research. NDA approval letter: NDA 211988 (Zynrelef). Silver Spring, MD: US Food and Drug Administration; May 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/211988Orig1s000ltr.pdf. Accessed May 13, 2021. 10. Singla N, Winkle P, Bertoch T, Hu J, Beaton A, Redan J. Opioid-free recovery after herniorrhaphy with HTX-011 as the foundation of a multimodal analgesic regimen. Surgery. 2020;168(5):915-920. doi:10.1016/j.surg.2020.06.036. 11. Pollak R, Cai D, Gan TJ. Opioid-free recovery from bunionectomy with HTX-011, a dual-acting local anesthetic combining bupivacaine and meloxicam, as the foundation of non-opioid multimodal analgesia [published online January 19, 2021]. J Am Podiatr Med Assoc. 2021:20-204. doi:10.7547/20-204. 12. Fanikos J, Minkowitz H, Reinhorn M, Quart B. HTX-011 as the foundation of a non-opioid, multimodal analgesic regimen reduces the need for opioids following herniorrhaphy in a real-world study. Poster presented at: American Society of Health-System Pharmacists 2019 Midyear Clinical Meeting & Exhibition; December 9, 2019; Las Vegas, NV. 13. Hacker S. Postoperative pain management of total knee arthroplasty using HTX-011 with multimodal analgesia: results from a Phase 3b open-label study. Poster presented at: Orthopedics Today Hawaii 2020; January 12-16, 2020; Koloa, HI. 14. Data on file. HTX-011 safety update. San Diego, CA: Heron Therapeutics Inc; 2019. 15. Data on file. HTX-011 integrated summary of safety. San Diego, CA: Heron Therapeutics Inc; 2018. 16. Data on file. Study HTX-011-302. San Diego, CA: Heron Therapeutics Inc; 2018. 17. Data on file. Study HTX-011-301. San Diego, CA: Heron Therapeutics Inc; 2018. 18. Data on file. Study HTX-011-C2016-208. San Diego, CA: Heron Therapeutics Inc; 2017. 19. Data on file. Study HTX-011-C2015-202. San Diego, CA: Heron Therapeutics Inc; 2018. 20. Data on file. Study HTX-011-C2015-203. 21. Data on file. Study HTX-011-306. San Diego, CA: Heron Therapeutics Inc; 2019. 22. Data on file. Study HTX-011-209. San Diego, CA: Heron Therapeutics Inc; 2018. 23. Data on file. Study HTX-011-215. San Diego, CA: Heron Therapeutics Inc; 2019. 24. Data on file. Study HTX-011-218. San Diego, CA: Heron Therapeutics Inc; 2019. San Diego, CA: Heron Therapeutics Inc; 2018. 25. Data on file. Study HTX-011-211. San Diego, CA: Heron Therapeutics Inc; 2018.  26. Data on file. Study HTX-011-220. San Diego, CA: Heron Therapeutics Inc; 2019.