General Information

Zynrelef contains bupivacaine, an amide local anesthetic, and meloxicam, a nonsteroidal anti-inflammatory drug (NSAID).

Zynrelef is specifically 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. Zynrelef is also approved for use in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after foot and ankle, small-to-medium open abdominal, and lower extremity total joint arthroplasty surgical procedures.

Zynrelef is supplied as an extended-release solution, for soft tissue or periarticular instillation use. Zynrelef is intended for single-dose administration only. The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of Zynrelef.  Zynrelef should only be prepared and administered with the components provided in the Zynrelef kit. Zynrelef is applied without a needle into the surgical site following final irrigation and suction and prior to suturing. The recommended doses of Zynrelef are as follows:

• Bunionectomy: up to 2.3 mL to deliver 60 mg/1.8 mg
• Open inguinal herniorrhaphy: up to 10.5 mL to deliver 300 mg/9 mg
• Total knee arthroplasty: up to 14 mL to deliver 400 mg/12 mg 

Mechanism of Action

Zynrelef is a fixed-dose combination of bupivacaine and meloxicam.

Bupivacaine: Local anesthetics block the generation and the conduction of nerve impulses presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

Meloxicam: The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Side Effects

Adverse effects associated with the use of Zynrelef may include, but are not limited to, the following:

• constipation
• vomiting
• headache

The Zynrelef drug label comes with the following Black Box Warning: 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. 

Clinical Trial Results

Study 1:

In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical trial, 412 patients undergoing unilateral simple bunionectomy with a lidocaine Mayo block were randomized to 1 of the following 3 treatment groups in a 3:3:2 ratio (respectively): Zynrelef 60 mg/1.8 mg, bupivacaine HCl 50 mg, or saline placebo. Zynrelef was applied directly into the surgical site, using the cone-shaped applicator, at the end of the procedure, after final irrigation and suction but prior to closure. Bupivacaine HCl and saline placebo were administered by injection and instillation, respectively. Pain intensity was rated by patients using an 11-point numeric rating scale (NRS) out to 72 hours post-dose. Postoperatively, there was no scheduled pain medication regimen; however, patients were allowed rescue medication as needed, and included oxycodone 10 mg orally every 4 hours, morphine 10 mg IV every 2 hours, and/or acetaminophen 1000 mg orally every 6 hours. The primary endpoint was the mean area under the curve (AUC) of the NRS pain intensity scores (cumulative pain scores) with activity over the 72-hour period for the Zynrelef treatment group compared to the saline placebo treatment group. Patients treated with Zynrelef demonstrated a significant reduction in pain intensity compared to those treated with either bupivacaine HCl or saline placebo for up to 72 hours. A significant proportion of patients treated with Zynrelef did not receive opioid analgesia (29%) over 72 hours compared to those treated with either bupivacaine HCl (11%) or saline placebo (2%).

Study 2:

In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical trial, 418 patients undergoing unilateral open inguinal herniorrhaphy with mesh under general anesthesia were randomized to 1 of the following 3 treatment groups in a 2:2:1 ratio (respectively): Zynrelef 300 mg/9 mg, bupivacaine HCl 75 mg, or saline placebo. Zynrelef was applied directly into the surgical site, using the cone-shaped applicator, at the end of the procedure, following irrigation and suction of each fascial layer but prior to closure. Bupivacaine HCl and saline placebo were administered by injection and instillation, respectively. Pain intensity was rated by patients using an 11-point NRS out to 72 hours post-dose. Postoperatively, there was no scheduled pain medication regimen; however, patients were allowed rescue medication as needed. The primary endpoint was the mean AUC of the NRS pain intensity scores (cumulative pain scores) with activity over the 72-hour period for the Zynrelef treatment group compared to the saline placebo treatment group. Secondary endpoints included mean AUC of NRS pain intensity scores over the 72-hour period for the Zynrelef treatment group compared to the bupivacaine HCl treatment group, proportion of patients who did not receive opioid analgesia, and total opioid consumption. Patients treated with Zynrelef demonstrated a statistically significant reduction in pain intensity compared to those treated with either bupivacaine HCl or saline placebo for up to 72 hours. A significant proportion of patients treated with Zynrelef did not receive opioid analgesia (51%) over 72 hours compared to those treated with either bupivacaine HCl (40%) or saline placebo (22%). A significant reduction in total opioid consumption over 72 hours was also observed for patients treated with Zynrelef (median consumption 0 mg) compared to those treated with either bupivacaine HCl (7.3 mg) or saline placebo (11.3 mg).

Study 3:

In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical study, 222 patients undergoing primary unilateral total knee arthroplasty under general anesthesia were randomized to one of the following treatment groups in a 1:1:1:1 ratio: Zynrelef 400 mg/12 mg, Zynrelef 400 mg/12 mg plus ropivacaine 50 mg (injected into the posterior capsule), bupivacaine HCl 125 mg, or saline placebo. Zynrelef was administered, using the cone-shaped applicator, onto the posterior capsule, the anteromedial tissues and periosteum, and the anterolateral tissues and periosteum after cementation of the components. Preoperatively, patients were administered pregabalin 150 mg as a single oral dose and acetaminophen up to 1 g IV. Pain intensity was rated by the patients using an 11-point NRS out to 72 hours post-dose. Postoperatively, there was no scheduled pain medication regimen, and patients were allowed only opioid rescue medication as needed. The primary endpoint was the AUC of the NRS pain intensity scores (cumulative pain scores) at rest collected over the first 48 hours. Patients treated with Zynrelef demonstrated a significant reduction in pain intensity compared to patients treated with saline placebo for the first 48-hour and 72-hour postoperative periods. There were two patients who did not receive opioid analgesia over 72 hours; one in the Zynrelef 400 mg/12 mg + ropivacaine treatment group and one in the bupivacaine HCl treatment group.