ZYNRELEF

ZYNRELEF is an FDA-registered drug product whose active ingredient is BUPIVACAINE AND MELOXICAM. It is labelled by Heron Therapeutics, Inc. taken by infiltration and marketed as a human prescription drug product. Identifiers on file: NDC 47426-501, application NDA211988, label effective 20260420. This page reproduces the FDA-approved label text so you can check what a product is, who makes it and how it is supplied before discussing it with a pharmacist or prescriber.

Across FDA labelling, products containing BUPIVACAINE AND MELOXICAM are most often described in connection with: surgical procedures, zynrelef indicated, postsurgical analgesia, soft tissue, total joint, direct exposure, articular cartilage, avoided see. Wording differs between labels, and the full indications section on this page takes precedence when it is present.

1 INDICATIONS AND USAGE ZYNRELEF is indicated in adults for postsurgical analgesia for up to 72 hours after: soft tissue surgical procedures orthopedic surgical procedures – foot and ankle procedures – other orthopedic surgical procedures (e.g., total joint arthroplasty) in which direct exposure to articular cartilage is avoided [see Warnings and Precautions (5.10) ] ZYNRELEF is indicated in adults for postsurgical analgesia for up to 72 hours after: soft tissue surgical procedures orthopedic surgical procedures – foot and ankle procedures – other orthopedic surgical procedures (e.g., total joint arthroplasty) in which direct exposure to articular cartilage is avoided [see Warnings and Precautions (5.10) ] Limitations of Use Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large 4 or more level spinal, and head and neck procedures ( 1 ). Limitations of Use Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large 4 or more level spinal, and head and neck procedures.

2 DOSAGE AND ADMINISTRATION ZYNRELEF is intended for single-dose administration only ( 2.1 ). Administer ZYNRELEF via instillation only. The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF ( 2.1 ). ZYNRELEF should only be prepared and administered with the components provided in the ZYNRELEF kit ( 2.1 ). ZYNRELEF is applied without a needle into the surgical site following final irrigation and suction and prior to suturing ( 2.1 ). – The recommended dose of ZYNRELEF is up to a maximum dose of 400 mg/12 mg (14 mL) ( 2.4 ). See Full Prescribing Information for important preparation and administration instructions, dose selection, and compatibility considerations ( 2.2 , 2.3 , 2.4 , 2.5 ). 2.1 Important Dosage and Administration Information ADMINISTER ZYNRELEF VIA INSTILLATION ONLY. ZYNRELEF should not be administered via the following routes. – Epidural – Intrathecal – Intravascular – Intra-articular [see Warnings and Precautions (5.10) , Nonclinical Toxicology (13.2) ] – Regional nerve blocks – Pre-incisional or pre-procedural locoregional anesthetic techniques. ZYNRELEF is intended for single-dose administration only. As there is a potential risk of severe, life-threatening adverse reactions associated with the administration of bupivacaine, ZYNRELEF should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurologic or cardiac toxicity [see Overdosage (10) ] . The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. Avoid intravascular administration of ZYNRELEF. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amide-containing products. Limit exposure to articular cartilage due to the potential risk of chondrolysis [see Warnings and Precautions (5.11) ] . ZYNRELEF is a viscous solution supplied as a kit consisting of a single-dose glass vial, and the following sterile components: Luer lock syringe(s), a vented vial spike or vial access needle, Luer lock cone-shaped applicator(s), and syringe tip cap(s). ZYNRELEF should only be prepared and administered with the components provided in the ZYNRELEF kit. See the ZYNRELEF Instructions for Use included in the kit for complete administration instructions with illustrations. The contents of the ZYNRELEF vial are sterile. The vial exterior is not sterile. Follow your facility's standard operating procedures regarding aseptic drug preparation. Each ZYNRELEF vial contains overfill to compensate for residual amounts that remain in the vial, vented vial spike or vial access needle, Luer lock applicator, and syringe(s) during drug withdrawal and administration. ZYNRELEF is applied without a needle into the surgical site after placement of implant(s) (if applicable), following final irrigation and suctioning, and prior to suturing of each layer, when multiple tissue layers are involved. When ZYNRELEF comes in contact with moisture in the tissues, it becomes more viscous, allowing it to stay in place. ZYNRELEF does not degrade sutures. When tying knots with monofilament sutures, contact with ZYNRELEF may cause knots to loosen or untie due to the viscosity of ZYNRELEF. In vitro studies showed an increase in elasticity with monofilament sutures exposed to ZYNRELEF with unknown clinical significance. Minimize administration of ZYNRELEF near the incision line and wipe off excess ZYNRELEF from the skin prior to suturing. Three (3) or more knots ending in a multi-throw knot (e.g., a Surgeon's knot) are recommended with monofilament sutures. Braided or barbed sutures are recommended, especially for closure of deeper layers. Image 2.2 Preparation Instructions See the ZYNRELEF Instructions for Use included in the kit for complete administration instructions with illustrations. ZYNRELEF is a clear, pale yellow to yellow, viscous liquid. Visually inspect the ZYNRELEF vial for particulate matter and discoloration. Obtain a new vial if particulate matter or discoloration is observed. Prepare vial for filling of syringe(s) by attaching vented vial spike or vial access needle. Syringe attachment for product withdrawal: For vented vial spike, fill syringe with air prior to attaching syringe. Attach syringe to vented vial spike, invert vial and syringe to allow product to fill the vial neck, then push air into vented vial spike prior to withdrawing ZYNRELEF from vial. For vial access needle, do not fill syringe with air prior to attaching syringe. Attach syringe to vial access needle, then invert vial and syringe to allow product to fill the vial neck prior to withdrawing ZYNRELEF from vial. Withdraw dose of ZYNRELEF into syringe. (The dose volume takes into account the potential residual volume in the components.). Withdrawal time using the vial access needle is faster than the vented vial spike. Nominal Dose of Bupivacaine / Meloxicam Number of Syringes and LLAs LLA: Luer lock cone-shaped applicator Per Dose Volume to be Withdrawn 60 mg/ 1.8 mg 1 2.3 mL (using 3 mL syringe provided) 200 mg / 6 mg 1 7 mL (using 12 mL syringe provided) 300 mg/ 9 mg 1 10.5 mL (using 12 mL syringe provided) 400 mg/ 12 mg 2 14 mL (using two 12 mL syringes provided, 7 mL ZYNRELEF per syringe) Repeat steps 1-3 for more than one syringe. Prepare product immediately prior to use and apply syringe tip cap if needed until product delivery. 2.3 Administration Instructions Before administration, remove the syringe tip cap and attach the Luer lock cone-shaped applicator to the syringe. Using the Luer lock cone-shaped applicator attached to the syringe, apply ZYNRELEF to the tissues within the surgical site as follows: For soft tissue procedures, apply ZYNRELEF into the wound prior to closure of each layer within the surgical space. – For abdominal procedures, apply after closure of the peritoneum (if applicable) and avoid administration below the peritoneum. In general for orthopedic procedures, apply ZYNRELEF into the wound and on the periosteum from the proximal to the distal ends of the wound (i.e., beyond the boney repair). – For total joint arthroplasty, apply ZYNRELEF directly into the joint capsule, onto the periosteum, and the antero-, medial-, and lateral tissues (if applicable), after placement of the component(s). – For spinal procedures, apply ZYNRELEF after closure of the paraspinal musculature and again after closure of the subcutaneous fascia. ZYNRELEF must not be applied to the dura or spinal cord. Only apply ZYNRELEF to the tissue layers below the skin incision and not directly onto the subdermal layer or the skin. Minimize administration of ZYNRELEF near the incision line. Use only the amount necessary to coat the tissues, such that ZYNRELEF does not leak from the surgical wound after closure. Wipe off excess ZYNRELEF from the skin prior to or during closure of the wound. 2.4 Dosing Instructions As a general guidance in selecting the proper dosing of ZYNRELEF, the following examples of dosing are provided: 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 [see Clinical Studies (14) ] ; – abdominoplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14) ] ; – Cesarean section: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14) ] ; – augmentation mammoplasty: up to 7 mL per side to deliver total of 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14) ] . For orthopedic surgical procedures, such as: – bunionectomy: up to 2.3 mL to deliver 60 mg of bupivacaine and 1.8 mg of meloxicam [see Clinical Studies (14) ] ; – total knee arthroplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14) ] ; – total shoulder arthroplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14) ] ; – 1- to 3-level spinal surgery: up to 7 mL to deliver 200 mg bupivacaine and 6 mg meloxicam [see Clinical Studies (14) ] . 2.5 Compatibility Considerations Do not dilute ZYNRELEF. ZYNRELEF is a nonaqueous solution. It cannot be mixed with water, saline, or other local anesthetics as the product will become more viscous and difficult to administer. When a topical antiseptic such as povidone iodine (e.g., Betadine ® ) is applied, the site should be allowed to dry before a local anesthetic, including ZYNRELEF, is administered into the site. When administered in recommended doses and concentrations, ZYNRELEF does not ordinarily produce irritation or tissue damage. ZYNRELEF is compatible with: All components of the ZYNRELEF kit, including syringes, Luer lock cone-shaped applicator, vented vial spike, vial access needle, and syringe tip caps. Surgical mesh materials, including polypropylene (Prolene ® ), Gore-tex, and polyester. Silicone membranes. Bone cement. Metal alloys used in surgical implants.

4 CONTRAINDICATIONS ZYNRELEF is contraindicated in: Patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components of ZYNRELEF [see Warnings and Precautions (5.9 , 5.14) ] . Patients with a 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 [see Warnings and Precautions (5.9) ] . Patients undergoing obstetrical paracervical block anesthesia. The use of bupivacaine in this technique has resulted in fetal bradycardia and death [see Use in Specific Populations (8.1) ] . Patients undergoing coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1) ] . ZYNRELEF is contraindicated for: Patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components of ZYNRELEF ( 4 ) Patients with a 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 ( 4 ) Patients undergoing obstetrical paracervical block anesthesia ( 4 ) Patients undergoing coronary artery bypass graft (CABG) surgery ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with bupivacaine HCl or meloxicam and are discussed in greater detail in other sections of the labeling: Cardiovascular System Reactions [see Warnings and Precautions (5.1 , 5.4) ] Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2) ] Dose-Related Toxicity [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.5) ] Hypertension [see Warnings and Precautions (5.6) ] Heart Failure and Edema [see Warnings and Precautions (5.7) ] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.8) ] Anaphylactic Reactions [see Warnings and Precautions (5.9) ] Chondrolysis [see Warnings and Precautions (5.11) ] Methemoglobinemia [see Warnings and Precautions (5.12) ] Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.13) ] Serious Skin Reactions [see Warnings and Precautions (5.14) ] Drug Reaction with Eosinophilia and Systemic Toxicity (DRESS) [see Warnings and Precautions (5.15) ] Fetal Toxicity [see Warnings and Precautions (5.16) ] Hematologic Toxicity [see Warnings and Precautions (5.17) ] Most common adverse reactions (incidence ≥5%) are: Soft tissue procedures: vomiting ( 6.1 ). Orthopedic procedures: constipation and headache ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Heron Therapeutics, Inc. at 1-844-437-6611 and www.ZYNRELEF.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of ZYNRELEF has been evaluated in a total of 1627 patients undergoing various surgical procedures across 14 clinical studies including 7 randomized, double-blind, bupivacaine- and placebo-controlled and saline placebo-controlled studies designed to investigate ZYNRELEF to reduce postoperative pain for 72 hours and the need for opioid analgesics, of whom 1183 received ZYNRELEF by instillation. Patients treated with ZYNRELEF ranged in age from 18 to 85 years (median age 51 years), with 53.0% female, 82.1% White, 13.7% African-American, and 4.3% all other races. Common Adverse Reactions The safety of ZYNRELEF has been evaluated in 1064 patients who received ZYNRELEF in single doses up to 400 mg/12 mg via instillation into the surgical site, including 533 patients undergoing a soft tissue surgical procedure (herniorrhaphy, abdominoplasty, augmentation mammoplasty, or Cesarean section) and 531 patients undergoing an orthopedic surgical procedure (bunionectomy, total knee arthroplasty, total shoulder arthroplasty, or lumbar spinal surgery). The most common adverse reactions (incidence greater than or equal to 5% and higher than placebo) following ZYNRELEF administration among patients undergoing soft tissue procedures was vomiting and among patients undergoing orthopedic procedures were constipation and headache. The safety of ZYNRELEF as part of a scheduled, non-opioid multimodal analgesic regimen including 1 or more other NSAIDs has been evaluated in a total of 473 patients undergoing soft tissue procedures or orthopedic procedures. NSAIDs included ibuprofen, ketorolac, and celecoxib. In these studies, the most common adverse reactions (incidence of greater than or equal to 2%) potentially associated with NSAIDs were pruritus and postoperative anemia. Rare but clinically serious NSAID-related adverse events, including peptic ulcer hemorrhage, gastritis requiring hospitalization, hematemesis and melena, gastrointestinal hemorrhage, and increased hepatic enzymes, were observed in subjects with predisposing risk factors (i.e., concomitant comorbidities and/or on concomitant medications such as anticoagulant and/or antiplatelet medications) that increased the risk for NSAID-related gastrointestinal toxicity. Adverse Reactions Reported in Phase 3 and 2b Placebo-controlled Trials Three randomized, bupivacaine-controlled and saline placebo-controlled studies were conducted in patients undergoing bunionectomy (STUDY 1, Table 1 and Table 2), open inguinal herniorrhaphy (STUDY 2, Table 3), and total knee arthroplasty (STUDY 3, Table 4). The bunionectomy procedures in STUDY 1 were performed under regional anesthesia, a lidocaine Mayo block, and intravenous sedation. The herniorrhaphy procedures in STUDY 2 were performed under general anesthesia. The total knee arthroplasty procedures in STUDY 3 were performed under either general or spinal anesthesia. Patients in STUDY 1 and STUDY 2 were allowed opioid rescue with intravenous (IV) morphine and oral oxycodone, and/or non-opioid rescue with oral acetaminophen. Patients in STUDY 3 were pretreated with oral pregabalin and acetaminophen, and allowed opioid rescue with IV morphine and oral oxycodone postoperatively. Table 1. Adverse Reactions with ZYNRELEF in Study 1 (Bunionectomy) Occurring with ≥5% Incidence and Higher than with Saline Placebo Preferred Term Saline Placebo (N=101), % Bupivacaine HCl 50 mg (N=154), % ZYNRELEF 60 mg/1.8 mg (N=157), % Dizziness 18 23 22 Incision site edema 13 14 17 Headache 10 13 14 Incision site erythema 8 12 13 Bradycardia 6 8 8 Impaired healing 1 4 6 Muscle twitching 5 5 6 In STUDY 1, bone healing was assessed by X-ray on Days 28 and 42. There was no clinically meaningful difference in bone healing between treatment groups. A total of 4 subjects had delayed bone healing: 1 in the ZYNRELEF group, 1 in the saline placebo group, and 2 in the bupivacaine HCl group. The incidence of local inflammatory adverse events was higher in the ZYNRELEF group than in either control group (Table 2). Table 2. Incidence of Local Inflammatory Adverse Events with ZYNRELEF in Study 1 (Bunionectomy) Occurring with ≥2% Incidence and Higher than with Saline Placebo Saline Placebo (N=101), % Bupivacaine HCl 50 mg (N=154), % ZYNRELEF 60 mg/1.8 mg (N=157), % Incision site edema 13 14 17 Incision site erythema 8 12 13 Impaired healing 1 4 6 Incision site cellulitis 1 1 4 Wound dehiscence 2 1 4 Incision site infection 0 1 3 Table 3. Adverse Reactions with ZYNRELEF in Study 2 (Herniorrhaphy) Occurring with ≥5% Incidence and Higher than with Saline Placebo Preferred Term Saline Placebo (N=82), % Bupivacaine HCl 75 mg (N=173), % ZYNRELEF 300 mg/9 mg (N=163), % Headache 12 14 13 Bradycardia 7 9 9 Dysgeusia 4 12 9 Skin odor abnormal All TEAEs of skin odor abnormal were recorded at a single site. 1 1 8 Table 4. Adverse Reactions with ZYNRELEF in Study 3 (Total Knee Arthroplasty) Occurring with ≥5% Incidence and Higher than with Saline Placebo Preferred Term Saline Placebo (N=53), % Bupivacaine HCl 125 mg (N=55), % ZYNRELEF 400 mg/12 mg (N=58), % Nausea 47 55 50 Constipation 23 33 24 Vomiting 19 27 26 Hypertension 15 13 19 Pyrexia 4 15 14 Leukocytosis 0 2 7 Pruritis 2 5 7 Headache 0 7 7 Anemia 2 0 5 Hyperhidrosis 4 0 5 Hypotension 4 2 5 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZYNRELEF or other products containing NSAIDs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. ZYNRELEF Injury, Poisoning, and Procedural Complications: Wound necrosis, Wound dehiscence. Surgical and Medical Procedures: Post-procedural drainage. NSAIDs Skin and Appendages: Exfoliative dermatitis, SJS, TEN, and FDE [see Warnings and Precautions (5.14) ] .

1 FDA recall record(s) match this product name or manufacturer. A match means the firm or product name appears in the enforcement report; confirm lot numbers and dates against the official FDA notice before acting.

What is ZYNRELEF used for?
1 INDICATIONS AND USAGE ZYNRELEF is indicated in adults for postsurgical analgesia for up to 72 hours after: soft tissue surgical procedures orthopedic surgical procedures – foot and ankle procedures – other orthopedic surgical procedures (e.g., total joint arthroplasty) in which direct exposure to articular cartilage is avoided [see Warnings and Precautions (5.10) ] ZYNRELEF is indicated in …

Who makes ZYNRELEF?
Heron Therapeutics, Inc. is the labeler of record for ZYNRELEF.

What form does ZYNRELEF come in?
administered by infiltration. Strengths and pack sizes vary by label, so compare the NDC on your pack with the identifier listed on this page.

Is ZYNRELEF prescription or over-the-counter?
The FDA label for this product is recorded as human prescription drug. Marketing status can differ between strengths and countries, so check the dispensing rules where you live.

Has ZYNRELEF been recalled?
1 FDA recall record(s) match this product name or manufacturer. Review the recall and safety notices section on this page and confirm lot numbers against the official FDA enforcement report.

Where does this information come from?
All content is reproduced from FDA Structured Product Labelling data via openFDA. It is provided for identification and reference only and is not medical advice.