Explore a world of 72-hour postoperative pain relief

Postoperative pain relief data

ZYNRELEF patients experienced superior pain relief through 72 hours—when pain is most severe—compared to patients receiving the current standard of care, bupivacaine HCl solution, making ZYNRELEF the first and only product to demonstrate superiority over bupivacaine HCl solution in Phase 3 studies. In addition to data collected during the EPOCH 1 Bunionectomy study and the EPOCH 2 Herniorrhaphy study, ZYNRELEF demonstrated 72 hours of pain relief in the EPOCH Total Knee Arthroplasty study.1-5

After the successful completion of the initial studies, ZYNRELEF was used as the foundation of a scheduled non-opioid multimodal regimen to further reduce postoperative pain and increase the number of patients requiring no opioids in EPOCH 1 Single-Arm Follow-On, EPOCH 2 Single-Arm Follow-On, and EPOCH TKA Single-Arm Follow-On. These follow-on studies were open-label, and were conducted without a control group as superiority to placebo and standard-of-care bupivacaine HCl solution had already been established in the initial studies.6-8

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.

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Bunionectomy

72 Hours of Pain Relief
Greater Pain Reduction
Reduced Severe Pain

72 hours of pain relief1,3,7

ZYNRELEF patients reported greater pain relief in the 0-8– and 0-12–hour periods, when bupivacaine is effective.3
AUC0-8 vs Bupivacaine: P = .048a
AUC0-12 vs Bupivacaine: P < .001b

Even excluding the first 24 hours from analysis, ZYNRELEF patients had lower pain intensity through 72 hours.3
AUC24-72 vs Bupivacaine: P = .007a

When ZYNRELEF was used with a scheduled regimen of oral over-the-counter analgesics, mean pain scores stayed in the mild range for the full 72-hour observation period.7

EPOCH 1 Bunionectomy Study: Did not include the scheduled analgesic regimen

Saline Placebo (n = 100)
Bupivacaine HCI Solution 50 mg (n = 155)
ZYNRELEF 60 mg/1.8 mg (n = 157)

EPOCH 1 Single-Arm Follow-On Study

ZYNRELEF up to 60 mg/1.8 mg + OTC (n = 31)

AUC0-72 vs Placebo: P < .001

AUC0-72 vs Bupivacaine HCl Solution: P < .001

aAnalysis not prespecified; nominal P value not controlled for multiplicity.

bNominal P value not controlled for multiplicity.

NRS: Numeric Rating Scale.

AUC: area under the curve.

OTC: over-the-counter. EPOCH 1 Single-Arm Follow-On provided a non-opioid OTC regimen of oral ibuprofen and acetaminophen.

EPOCH 1 Study Design
Follow-On Study Design

Herniorrhaphy

72 Hours of Pain Relief
Greater Pain Reduction
Reduced Severe Pain

72 Hours of pain relief1,4,6

ZYNRELEF patients reported greater pain relief in the 0-8– and 0-12–hour periods, when bupivacaine is effective.4
AUC0-8 vs Bupivacaine: P = .04a
AUC0-12 vs Bupivacaine: P < .001b

Even excluding the first 24 hours from analysis, ZYNRELEF patients had significantly lower pain intensity through 72 hours.4
AUC24-72 vs Bupivacaine: P ≤ .001a

When ZYNRELEF was used with a scheduled regimen of oral over-the-counter analgesics, mean pain scores stayed in the mild range for the full 72-hour observation period.6

EPOCH 2 Herniorrhaphy Study: Did not include the scheduled analgesic regimen

Saline Placebo (n = 82)
Bupivacaine HCI Solution 75 mg (n = 172)
ZYNRELEF 300 mg /9 mg (n = 164)

EPOCH 2 Single-Arm Follow-On Study

ZYNRELEF 300 mg/9 mg + OTC (n = 33)

AUC0-72 vs Placebo: P < .001

AUC0-72 vs Bupivacaine HCl Solution: P < .001

aAnalysis not prespecified; nominal P value not controlled for multiplicity.

bNominal P value not controlled for multiplicity.

Note: EPOCH 2 Single-Arm Follow-On study results reflect reported pain intensity at rest; EPOCH 2 results reflect reported pain intensity with activity (after sitting up from a resting position).

NRS: Numeric Rating Scale.

OTC: over-the-counter. EPOCH 2 Single-Arm Follow-On provided a non-opioid OTC regimen of oral ibuprofen and acetaminophen.

EPOCH 2 Study Design
Follow-On Study Design

Total knee arthroplasty

Primary and Key Secondary
Area Under the Curve
Reduced Severe Pain
Pain Reduction

EPOCH TKA: Greater pain reduction with ZYNRELEF versus bupivacaine HCl solution5

ZYNRELEF significantly lowered pain vs bupivacaine HCl at 0- to 48-hours and 0- to 72-hours, without adjusting for opioids. ZYNRELEF significantly lowered pain vs bupivacaine HCl at 0- to 48-hours and 0- to 72-hours, without adjusting for opioids.

Patients treated with ZYNRELEF required fewer opioids than those treated with bupivacaine HCl solution or saline placebo

EPOCH TKA: Primary analysis and sensitivity analysis were performed5

Sensitivity analysis: ZYNRELEF patients needed less rescue opioid medication to reach lower pain scores for 48 and 72 hours. Sensitivity analysis: ZYNRELEF patients needed less rescue opioid medication to reach lower pain scores for 48 and 72 hours.

In the primary analysis, ZYNRELEF demonstrated statistically superior pain reduction through 48 and 72 hours versus placebob

In the sensitivity analysis, ZYNRELEF demonstrated greater pain reduction through 48 and 72 hours versus placeboc

aNominal P value not controlled for multiplicity.

bPain scores reported adjusting for opioid rescue medication use.

cAs reported without adjustment for opioid rescue medication use.

AUC: area under the curve.

NRS: Numeric Rating Scale of pain intensity score.

EPOCH TKA Study Design
Follow-On Study Design

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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. Svensson I, Sjöström B, Haljamäe H. Assessment of pain experiences after elective surgery. J Pain Symptom Manage. 2000;20(3):193-201. doi:10.1016/S0885-3924(00)00174-3. 3. 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. 4. 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. 5. 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. 6. 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. 7. 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. 8. 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. 9. Data on file. Study HTX-011-301. San Diego, CA: Heron Therapeutics Inc; 2018. 10. Data on file. Study HTX-011-302. San Diego, CA: Heron Therapeutics Inc; 2018.