Indication and limitations of use
ZYNRELEF is indicated in adults for instillation to produce postsurgical analgesia for up to 72 hours after soft tissue and orthopedic procedures including foot and ankle, and other procedures in which direct exposure to articular cartilage is avoided.
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.
Understanding the unique formulation of ZYNRELEF
ZYNRELEF is the first and only product to demonstrate superiority over bupivacaine HCl solution through 72 hours in Phase 3 studies.1-3 The unique formulation of ZYNRELEF combines the local anesthetic bupivacaine with a low dose of the NSAID meloxicam.1
Meloxicam and inflammation
Meloxicam is a potent NSAID with a long half-life that has demonstrated synergistic activity with bupivacaine in ZYNRELEF. The meloxicam in ZYNRELEF works to normalize the acidity levels at the surgical site by lowering the concentration of hydrogen ions in the environment, thereby potentiating the analgesic efficacy of bupivacaine through 72 hours.4
ZYNRELEF’s Biochronomer® polymer enables consistently regulated delivery of both active ingredients for 72 hours after surgery. Once released by the Biochronomer polymer, the low dose of meloxicam works to moderate inflammation without impeding the natural healing process.4
Release rates of active ingredients5,a:
- 0 to 24 hours: approximately 52% of bupivacaine and approximately 44% of meloxicam
- 0 to 48 hours: approximately 81% of bupivacaine and approximately 81% of meloxicam
- 0 to 72 hours: approximately 93% of bupivacaine and approximately 95% of meloxicam
aReflects in vitro release rates of active ingredients.
Greater pain reduction
TKA patients treated with ZYNRELEF showed a 23% reduction in pain intensity in the first 72 hours following surgery compared to those treated with placebo.6
In the sensitivity analysis, which is not adjusted for the use of opioid rescue medication and therefore reflects the level of pain the patient is actually experiencing, TKA patients treated with ZYNRELEF showed a 38% reduction in pain intensity in the first 72 hours following surgery compared to those treated with placebo.6
37% of TKA patients experienced no severe pain through 72 hours when treated with ZYNRELEF plus a non-opioid MMA regimen.7
When treated with ZYNRELEF plus a non-opioid MMA regimen, the majority of patients rated their pain control as “good” or “excellent”: 88% on day 1 of recovery, 90% on day 2 of recovery, and 100% on day 3 of recovery.8
Bunionectomy patients treated with ZYNRELEF showed an 18% reduction in pain intensity compared to those treated with bupivacaine HCl solution.1,2
46% of bunionectomy patients treated with ZYNRELEF experienced no severe pain in the first 72 hours—a 90% increase over patients treated with bupivacaine HCl solution.2
ZYNRELEF and coadministration
Mixing ZYNRELEF with bupivacaine is not required to achieve efficacy. Moreover, the product cannot be mixed with water, saline, or other local anesthetics or it will become very viscous and difficult to administer.1
Other local anesthetics can be administered before ZYNRELEF without causing release of the active ingredients all at once. The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF.1
ZYNRELEF was well tolerated when used concomitantly with aspirin, ropivacaine, and acetaminophen.6,9-11 In cohorts receiving ketorolac, celecoxib, or ibuprofen in addition to ZYNRELEF, no increase in NSAID-related toxicity was seen.7,9,10,12
In Phase 2 studies of ZYNRELEF with a scheduled non-opioid MMA regimen, the most common gastrointestinal-related TEAE was nausea, and there were no serious gastrointestinal TEAEs. There were few TEAEs in cardiac disorders, vascular disorders, or renal and urinary disorders system organ classes, and none were serious. One subject had a TEAE associated with abnormal liver function tests (mild transaminases increased), which resolved.13,14
Adding ZYNRELEF to formulary
Need more information about getting ZYNRELEF added to your institution’s formulary? Contact a Heron representative today to find out more about becoming a champion for the next generation of postoperative pain management.
Important Safety Information and Indication
Indication
ZYNRELEF is indicated in adults for instillation to produce postsurgical analgesia for up to 72 hours after soft tissue and orthopedic procedures including foot and ankle, and other procedures in which direct exposure to articular cartilage is avoided.
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.
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 a 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 CABG.
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.
Risk of Joint Cartilage Necrosis and Degeneration with Unapproved Intra-articular Use: Animal studies evaluating the effects of ZYNRELEF following intra-articular administration in the knee joint demonstrated cartilage necrosis and degeneration.
Chondrolysis: Limit exposure to articular cartilage due to the potential risk of chondrolysis.
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 effects.
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 ≥5%) in controlled clinical trials with ZYNRELEF are soft tissue procedures: vomiting and orthopedic procedures: constipation 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 instillation to produce postsurgical analgesia for up to 72 hours after soft tissue and orthopedic procedures including foot and ankle, and other procedures in which direct exposure to articular cartilage is avoided.
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.
Please see full Prescribing Information, including Boxed Warning.
References: 1. ZYNRELEF [package insert]. San Diego, CA: Heron Therapeutics Inc; 2024. 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. Ottoboni T, Quart B, Pawasauskas J, Dasta JF, Pollack 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. 5. Data on file. Summary of biopharmaceutic studies and associated analytical methods. San Diego, CA: Heron Therapeutics Inc; 2018. 6. 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. 7. 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. 8. Data on file. Study HTX-011-306. San Diego, CA: Heron Therapeutics Inc; 2019. 9. 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. 10. 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. 11. 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. 12. Data on file. HTX-011 safety update. San Diego, CA: Heron Therapeutics Inc; 2019. 13. Data on file. Study HTX-011-215. San Diego, CA: Heron Therapeutics Inc; 2019. 14. Data on file. Study HTX-011-218. San Diego, CA: Heron Therapeutics Inc; 2019.