ORTHOPEDIC SURGERY
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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.
Efficacy in total knee arthroplasty
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.1
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.1
37% of TKA patients experienced no severe pain through 72 hours when treated with ZYNRELEF plus a non-opioid MMA regimen.2
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.3
More opioid-free patients
The mean consumption of opioids in the EPOCH TKA Single-Arm Follow-On study was 1 to 2 pills of oxycodone 10 mg per day through 72 hours (25 MME).3
39% of TKA patients received no opioid discharge prescription and had no callbacks through day 11 of recovery when treated with ZYNRELEF and a non-opioid MMA regimen.3
Efficacy in bunionectomy
Greater pain reduction
Bunionectomy patients treated with ZYNRELEF showed an 18% reduction in pain intensity compared to those treated with bupivacaine HCl solution.5
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.5
More opioid-free patients
29% of bunionectomy patients treated with ZYNRELEF required no opioids in the first 72 hours following surgery, compared with 11% of patients treated with bupivacaine HCl solution.4,5
Of bunionectomy patients treated with ZYNRELEF who were opioid-free at 72 hours, 82% remained opioid-free through day 28.5
When bunionectomy patients treated with ZYNRELEF also received a scheduled, non-opioid, multimodal regimen of over-the-counter oral acetaminophen and ibuprofen, 77% required no opioids through 72 hours.6
Of bunionectomy patients receiving ZYNRELEF plus the scheduled, non-opioid, multimodal regimen who were opioid free at 72 hours, 100% remained opioid-free through 28 days.6
Resources for you
Adding ZYNRELEF to formulary
Interested in seeing ZYNRELEF added to your institution’s formulary? Contact a Heron representative today to find out more information about becoming a champion for the next generation of postoperative pain management.
EPOCH 1 Bunionectomy Study Design
- The Phase 3, randomized, double-blind, multicenter EPOCH 1 trial shows how ZYNRELEF performed in patients who underwent unilateral bunionectomy with osteotomy with a lidocaine Mayo block. This trial compared ZYNRELEF not only to placebo but also to the standard of care, bupivacaine HCl solution. Of the 412 total patients in the intent-to-treat population, the mean patient age was 47 years (range, 18-77 years). Patients were predominantly female (86%).
- During surgery, intravenous fentanyl (≤4 μg/kg) was permitted for intraoperative pain control. No other opioids, analgesics, or anti-inflammatory agents (except study drug) were permitted intraoperatively, unless needed to treat an adverse event, for pretreatment prior to needle placement, or to decrease venous irritation.
- Per protocol, patients were to receive rescue medication only upon request for pain control during the 72-hour postoperative observation period. Medication was not permitted for pain prophylaxis. Upon request, patients requiring postoperative rescue medication could receive oral immediate-release oxycodone (≤10 mg within a 4-hour period as needed), intravenous morphine (≤10 mg within a 2-hour period as needed), and/or oral acetaminophen (≤1 g in a 6-hour period). For patients administered any acetaminophen-containing product, the total daily dose could not exceed 4 g. No other analgesic agents, including NSAIDs, were permitted during the 72-hour postoperative observation period.
- Following the 72-hour period, there were 10-day and 28-day follow-ups to assess opioid use over that period, as captured by patient diaries. Conservatively, opioid use was imputed to patients if on any day they missed a diary entry.
- Patients rated pain intensity on the 0-to-10 Numeric Rating Scale (NRS) of pain, and missing scores were imputed by carrying forward the last nonmissing postdose value. Pain scores were then analyzed with adjustment for the analgesic duration of rescue medications.
- Hierarchically tested endpoints were as follows:
- Primary: pain intensity area under the curve through 72 hours (AUC0-72) versus placebo
- First key secondary: pain intensity (AUC0-72) versus bupivacaine HCl solution
- Second key secondary: mean total opioid use (0-72 hours) versus placebo
- Third key secondary: proportion opioid-free (0-72 hours) versus bupivacaine HCl solution
- Fourth key secondary: mean total opioid use (0-72 hours) versus bupivacaine HCl solution
- Additional prespecified secondary endpoints (not controlled for multiple hypothesis testing) included:
- Pain intensity AUC0-12
- Pain intensity AUC0-24
- Pain intensity AUC0-48
- Proportion with any severe pain (NRS ≥7) through 72 hours
- Proportion opioid-free (0-72 hours) versus placebo
- Post hoc analyses included:
- Pain intensity AUC0-8
- Pain intensity AUC24-72
- Proportion opioid-free and without severe pain (NRS <7) through 72 hours
- Adverse events that emerged during this study were recorded through a safety follow-up visit on day 42. Patients who reported multiple events within a preferred term were counted only once for that preferred term. Opioid-related events were categorized by prespecified preferred terms as opioid related regardless of whether a patient actually received an opioid.
EPOCH 1 Single-Arm Follow-On Study Design
- In this Phase 2, open-label follow-on study to EPOCH 1, an individualized dose of ZYNRELEF (up to 60 mg/1.8 mg) was used as the foundation of a scheduled multimodal analgesic regimen in 31 patients who underwent unilateral bunionectomy with osteotomy with a lidocaine Mayo block. Compared to historical data from EPOCH 1, ZYNRELEF with a scheduled multimodal postoperative analgesic regimen was evaluated for reduction in mean pain intensity and the need for postoperative opioids in patients. This trial measured mean pain intensity through 72 hours post surgery and the proportion of patients who were opioid-free through 72 hours and remained opioid-free through the 28-day recovery period. The mean patient age was 49 years (range, 21-70 years), and patients were predominantly female (94%).
- During surgery, intravenous fentanyl (≤4 μg/kg) was permitted for intraoperative pain control. No other opioids, analgesics, or anti-inflammatory agents (except ZYNRELEF) were permitted intraoperatively, unless needed to treat an adverse event, for pretreatment prior to needle placement, or to decrease venous irritation.
- Per protocol, patients were to receive opioid rescue medication only upon request for pain control during the 72-hour postoperative observation period. Rescue medication was not permitted for pain prophylaxis. Upon request, patients requiring postoperative rescue medication could receive oral immediate-release oxycodone (≤10 mg within a 4-hour period as needed) and/or intravenous morphine (≤10 mg within a 2-hour period as needed).
- Following surgery, patients were to receive a scheduled multimodal postoperative analgesic regimen with oral ibuprofen and acetaminophen. Once patients were able to tolerate oral intake in the postoperative anesthesia care unit, they received 600 mg oral ibuprofen every 6 hours. Three hours after the first dose of ibuprofen, they started 1 g oral acetaminophen every 6 hours, alternating the 2 medications so that an analgesic was administered every 3 hours until the 72-hour inpatient postoperative period was complete. Besides oral ibuprofen, oral acetaminophen, and the rescue medications, no other analgesic agents were permitted during the 72-hour postoperative observation period.
- Following the 72-hour period, there were 7-day and 28-day follow-ups to assess opioid use over that period, as captured by patient diaries. Conservatively, opioid use was imputed to patients if on any day they missed a diary entry.
- Patients rated pain intensity on the 0-to-10 Numeric Rating Scale (NRS) of pain, and missing scores were imputed by carrying forward the last nonmissing postdose value. Pain scores were then analyzed with adjustment for the analgesic duration of rescue medications.
- Adverse events that emerged during this study were recorded through a safety follow-up visit on day 42. Patients who reported multiple events within a preferred term were counted only once for that preferred term. Opioid-related events were categorized by prespecified preferred terms as opioid related regardless of whether a patient actually received an opioid.
EPOCH TKA Study Design
- This Phase 2b, randomized, double-blind, multicenter trial shows how periarticular application of ZYNRELEF performed in patients who underwent primary unilateral total knee arthroplasty under general anesthesia. This trial compared ZYNRELEF, with and without ropivacaine, not only to placebo but also to the standard of care, bupivacaine HCl solution. Of the 222 total patients in the intent-to-treat (ITT) population, the mean patient age was 62 years (range, 33-85 years). A comparable number of male and female patients comprised the ITT population (51% female).
- Just prior to surgery, patients were to receive 150 mg oral pregabalin and intravenous acetaminophen (≤1 g within a 6-hour window). During surgery, intravenous fentanyl (≤4 μg/kg) was permitted for intraoperative pain control, and all patients were to receive an additional 75 μg intravenous fentanyl just prior to the end of surgery. No other opioids, analgesics, or anti-inflammatory agents (except study drug, including ropivacaine in a subset of ZYNRELEF patients) were permitted intraoperatively, unless needed to treat an adverse event, for pretreatment prior to needle placement, or to decrease venous irritation. Between study drug administration and hospital discharge, patients were to receive aspirin (325 mg twice daily) to prevent deep vein thrombosis (as well as tranexamic acid for antifibrinolysis).
- Per protocol, patients were to receive rescue medication only upon request for pain control during the 72-hour postoperative observation period. Medication was not permitted for pain prophylaxis. Patients requiring postoperative rescue medication could receive oral immediate-release oxycodone (≤10 mg within any 4-hour period as needed) and/or intravenous morphine (≤15 mg within the first 2 hours after surgery as needed and, thereafter, ≤10 mg within a 2-hour period as needed). Non-opioid analgesics were not permitted during the 72-hour postoperative observation period.
- Following the 72-hour period, there were 10-day and 28-day follow-ups to assess opioid use over that period, as captured by patient diaries. Conservatively, opioid use was imputed to patients if on any day they missed a diary entry.
- Patients rated pain intensity on the 0-to-10 Numeric Rating Scale (NRS) of pain, and missing scores were imputed by carrying forward the last nonmissing postdose value. Pain scores were then analyzed both with adjustment for the analgesic duration of rescue medications (primary and key secondary endpoints) and without adjustment (sensitivity analysis and additional secondary endpoints).
- Hierarchically tested endpoints were as follows:
- First primary: pain intensity area under the curve through 48 hours (AUC0-48) for ZYNRELEF with ropivacaine versus placebo
- Second primary: pain intensity (AUC0-48) for ZYNRELEF versus placebo
- First key secondary: pain intensity (AUC0-72) for ZYNRELEF with ropivacaine versus placebo
- Second key secondary: pain intensity (AUC0-72) for ZYNRELEF versus placebo
- A prespecified sensitivity analysis (not controlled for multiple hypothesis testing) was performed on the primary and key secondary endpoints. Pain scores in this sensitivity analysis were analyzed without adjustment for the analgesic duration of rescue medications.
- Additional prespecified secondary endpoints (not controlled for multiple hypothesis testing) included:
- Pain intensity AUC0-48 versus bupivacaine HCl solution (no adjustment for rescue medications)
- Pain intensity AUC0-72 versus bupivacaine HCl solution (no adjustment for rescue medications)
- Adverse events that emerged during this study were recorded through a safety follow-up visit on day 28. Patients who reported multiple events within a preferred term were counted only once for that preferred term. Opioid-related events were categorized by prespecified preferred terms as opioid related regardless of whether a patient actually received an opioid.
EPOCH TKA Single-Arm Follow-On
- In this Phase 3b, open-label follow-on to the EPOCH TKA study, ZYNRELEF was used as the foundation of a scheduled multimodal analgesic regimen in 51 patients who underwent primary unilateral total knee arthroplasty under bupivacaine spinal anesthesia. Compared to historical data from EPOCH TKA, ZYNRELEF with a scheduled multimodal postoperative analgesic regimen was evaluated for reduction in mean pain intensity and the need for postoperative opioids. This trial measured mean pain intensity and mean total opioid use through 72 hours post surgery, as well as the proportion of patients who were opioid-free through 72 hours and remained opioid-free through day 11. The mean patient age was 65 years (range, 39-83 years), and patients were predominantly female (61%).
- On the day of surgery (day 1), patients were to receive 1 g oral acetaminophen, 200 mg oral celecoxib, and 300 mg oral pregabalin just before being taken to the operating room. During surgery, intravenous fentanyl (≤4 μg/kg) was permitted for intraoperative pain control. No other opioids, analgesics, or anti-inflammatory agents (except ZYNRELEF) were permitted intraoperatively, unless needed to treat an adverse event, for pretreatment prior to needle placement, or to decrease venous irritation. Between study drug administration and hospital discharge, patients were to receive aspirin (325 mg twice daily) to prevent deep vein thrombosis (as well as tranexamic acid for antifibrinolysis).
- Per protocol, patients were to receive opioid rescue medication only upon request for pain control during the 72-hour postoperative observation period. Rescue medication was not permitted for pain prophylaxis. Upon request, patients requiring postoperative rescue medication could receive oral immediate-release oxycodone (≤10 mg within a 4-hour period as needed), intravenous morphine (≤5 mg within a 4-hour period as needed), and/or intravenous hydromorphone (≤1 mg within a 4-hour period as needed).
- Following surgery, patients were to receive a scheduled multimodal postoperative analgesic regimen for 7 days. For the first 3 days, once patients were able to tolerate oral intake, they received 1 g oral acetaminophen every 8 hours and 200 mg oral celecoxib every 12 hours. For the next 4 days, patients received 600 mg oral ibuprofen every 6 hours. Three hours after the first dose of ibuprofen, they started 1 g oral acetaminophen every 6 hours, alternating the 2 medications so that an analgesic was administered every 3 hours. After the 4 days following discharge, patients could continue taking acetaminophen and/or ibuprofen (not to exceed the precedent regimen) as needed. Besides the scheduled multimodal analgesic regimen and permitted opioid rescue medications, no other analgesic agents were permitted through day 11.
- Following the 72-hour period, there was a day-11 follow-up to assess opioid use over the intervening period, as captured by patient diaries. Conservatively, opioid use was imputed to patients if on any day they missed a diary entry.
- Patients rated pain intensity on a 100-mm visual analog scale (VAS) and on the 0-to-10 Numeric Rating Scale (NRS) of pain, and missing data were imputed by carrying forward the last nonmissing postdose value. Pain scores were analyzed without adjustment for the analgesic duration of rescue medications.
- Adverse events that emerged during this study were recorded through a safety follow-up visit on day 29. Patients who reported multiple events within a preferred term were counted only once for that preferred term. Opioid-related events were categorized by prespecified preferred terms as opioid related regardless of whether a patient actually received an opioid.
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. 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. 2. 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. 3. Data on file. Study HTX-011-306. San Diego, CA: Heron Therapeutics Inc; 2019. 4. ZYNRELEF [package insert]. San Diego, CA: Heron Therapeutics Inc; 2024. 5. 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. 6. 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.