Frequently Asked Questions

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

• 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

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

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

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 meloxicam^8,a
• Within the first 48 hours, 81% of bupivacaine and 81% of meloxicam^8,a
• By 72 hours, 93% of bupivacaine and 95% of meloxicam^8,a

^aReflects in vitro release rates of active ingredients.

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

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

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.

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

ZYNRELEF pricing as of January 1, 2024. 340B prices update quarterly. Confirm current pricing with your Heron representative.

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). Product should be used at room temperature.¹

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

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)

As a general guidance in selecting the proper dosing of ZYNRELEF, the following examples of dosing are provided¹:

• For soft tissue surgical procedures, such as:
• Open inguinal herniorrhaphy: up to 10.5 mL to deliver 300 mg of bupivacaine and 9 mg of meloxicam
• Abdominoplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam
• Cesarean section: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam
• Augmentation mammoplasty: up to 7 mL per side to deliver total of 400 mg of bupivacaine and 12 mg of meloxicam

• For orthopedic surgical procedures, such as:
• Bunionectomy: up to 2.3 mL to deliver 60 mg of bupivacaine and 1.8 mg of meloxicam
• Total knee arthroplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam
• Total shoulder arthroplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam
• 1- to 3-level spinal surgery: up to 7 mL to deliver 200 mg bupivacaine and 6 mg meloxicam

Limit exposure to articular cartilage due to the potential risk of chondrolysis.

Note: Not all procedures listed under each vial size require full contents to cover affected tissues.

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

The extraction site of a laparoscopic procedure is a small-to-medium open wound, which means that with the approval of the recent sNDA in December 2021, ZYNRELEF is now indicated for laparoscopic procedures. When applying ZYNRELEF during a laparoscopic procedure, ZYNRELEF can be placed onto the fascia of the trocar and extraction sites. It should not be applied directly to the peritoneum. Prior to application, it is recommended to add a stitch within each port site to keep the product in place on pain-generating tissues.¹

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

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

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

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

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

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.

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. 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

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

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.

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

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

Yes, generic bupivacaine HCl solution or ropivacaine as a nerve block may be used. However, ZYNRELEF has not been studied using 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 ingredients^8,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.

ZYNRELEF has been studied in multiple surgical models, including bunionectomy, herniorrhaphy, and total knee arthroplasty.¹