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.

2.1 Important Dosage and Administration Information

• 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 (5.10)].
• The safety of concomitant administration of ZYNRELEF and other NSAID medications has not been evaluated. If additional NSAID medication is indicated in the post-operative period, monitor patients for signs and symptoms of NSAID toxicity [see Clinical Pharmacology (12.3)].
• 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, 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, Luer lock applicator, and syringe(s) during drug withdrawal and administration.
• ZYNRELEF is applied without a needle into the surgical site 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.
• ZYNRELEF should not be administered via the following routes.–Epidural–Intrathecal–Intravascular or intra-articular–Regional nerve blocks–Pre-incisional or pre-procedural locoregional anesthetic techniques.

2.2 Preparation Instructions

1. 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.
2. Prepare vial for filling of syringe(s) by attaching vented vial spike. Prepare syringe by filling with air then attach to vented vial spike.
3. Invert to allow product to fill the vial neck and push air into vial. Withdraw dose of ZYNRELEF into syringe. (The dose volume takes into account the potential residual volume in the components.)
   

   Nominal Dose of Bupivacaine / Meloxicam (mg/mg)	Number of Syringes and LLAs* Per Dose	Volume to be Withdrawn (mL)
   * LLA: Luer lock cone-shaped applicator
   60 / 1.8	1	2.3 (using 3 mL syringe provided)
   200 / 6	1	7 (using 12 mL syringe provided)
   300 / 9	1	10.5 (using 12 mL syringe provided)
   400 / 12	2	14 (using two 12 mL syringes provided, 7 mL ZYNRELEF per syringe)

4. Repeat steps 1-3 for more than one syringe.
5. Prepare product immediately prior to use and apply syringe tip cap 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.

1. Using the Luer lock cone-shaped applicator attached to the syringe, apply ZYNRELEF to the tissues within the surgical site as follows:

   a.

   For foot and ankle surgical procedures, apply ZYNRELEF to the proximal and distal ends (i.e., beyond the boney repair) of the wound.

   b.

   For small-to-medium open abdominal surgical procedures, close the peritoneum (if applicable), then apply ZYNRELEF above and below the fascial repair.

   c.

   For lower extremity total joint arthroplasty surgical procedures, apply ZYNRELEF directly to the joint capsule, the anteromedial tissues and periosteum, and the anterolateral tissues and periosteum after placement of the components.

2. 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.
3. 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 foot and ankle 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 (14.1)].
• For small-to-medium open abdominal 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 (14.2)].
• For lower extremity total joint arthroplasty surgical procedures, such as total knee arthroplasty: up to 14 mL to deliver 400 mg of bupivacaine and 12 mg of meloxicam [see Clinical Studies (14.3)].

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, and syringe tip caps.
• Surgical mesh materials, including polypropylene (Prolene®), Gore-tex, and polyester.
• Silicone membranes.
• Bone cement.
• Metal alloys used in surgical implants.

5.1 Cardiovascular (CV) Thrombotic Events with NSAID Use

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. The risk of these events following single-dose local application of ZYNRELEF is uncertain.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, do not exceed the recommended dose. Physicians and patients should remain alert for the development of such events following treatment with ZYNRELEF, even in the absence of previous CV symptoms. Inform patients about the signs and symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation with NSAID Use

NSAIDs, including meloxicam in ZYNRELEF, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

5.3 Dose-Related Toxicity

The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. The toxic effects of local anesthetics are additive. Avoid additional local anesthetic administration within 96 hours following ZYNRELEF instillation. If additional local anesthetic administration with ZYNRELEF cannot be avoided based on clinical need, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after administration of ZYNRELEF.

Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death.

5.4 Risk of Use in Patients with Impaired Cardiovascular Function

Patients with impaired cardiovascular function (e.g., hypotension, heart block) may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by ZYNRELEF. Monitor patients closely for blood pressure, heart rate, and ECG changes.

5.5 Hepatotoxicity

5.6 Hypertension

NSAIDs, including meloxicam in ZYNRELEF, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) after administration of ZYNRELEF.

5.7 Heart Failure and Edema

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. The risk of these events following single-dose local application of ZYNRELEF is uncertain.

Avoid the use of ZYNRELEF in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ZYNRELEF is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.8 Renal Toxicity and Hyperkalemia

5.9 Anaphylactic Reactions

5.10 Chondrolysis

Limit exposure to articular cartilage due to the potential risk of chondrolysis.

Intra-articular infusions of local anesthetics, following arthroscopic and other surgical procedures is an unapproved use, and there have been post marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of glenohumeral chondrolysis have been described in pediatric patients and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are associated with chondrolysis. The time of onset of symptoms, such as joint pain, stiffness, and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who have experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

5.11 Methemoglobinemia

Cases of methemoglobinemia have been reported in association with local anesthetic use.

Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue any oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

5.12 Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include: chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NSAIDs are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When ZYNRELEF is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for exacerbation of asthma symptoms.

5.13 Serious Skin Reactions

NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions.

ZYNRELEF is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

5.14 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ZYNRELEF. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, evaluate the patient immediately and treat as clinically indicated.

5.15 Fetal Toxicity

5.16 Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with ZYNRELEF has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including meloxicam, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

5.17 Masking of Inflammation and Fever

The pharmacological activity of ZYNRELEF in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

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 1067 patients undergoing various surgical procedures across 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. Patients treated with ZYNRELEF ranged in age from 18 to 85 years (median age 47 years), with 61.8% female, 78.9% White, 16.0% African-American, and 5.1% all other races.

Among 504 patients who received ZYNRELEF in single doses of 60 mg/1.8 mg to 400 mg/12 mg via instillation into the surgical site, the most common adverse reactions (incidence greater than or equal to 10% and higher than saline placebo) following ZYNRELEF administration were constipation, vomiting, and headache.

7.1 Bupivacaine Drug Interactions

In clinical studies, other local anesthetics (including ropivacaine and lidocaine) have been administered before, during, or after application of ZYNRELEF without evidence of local anesthetic systemic toxicity. Administration of ZYNRELEF with other formulations of local anesthetics, including bupivacaine liposome injectable suspension, has not been studied [see Warnings and Precautions (5.3)].

The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. If co-administration cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.1), Warnings and Precautions (5.1) and Overdosage (10)].

Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics (Table 5).

7.2 Meloxicam Drug Interactions

See Table 6 for clinically significant drug interactions with meloxicam.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness of ZYNRELEF in pediatric patients has not been established.

8.5 Geriatric Use

Of the total number of patients undergoing various surgical procedures who were exposed to ZYNRELEF in clinical studies (N=1067), 136 patients (12.7%) were ≥ 65 years old, while 30 (2.8%) were ≥75 years old. No overall differences in safety or efficacy were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions, although the applicability of this to a single administration of low-dose meloxicam in ZYNRELEF is uncertain [see Warnings and Precautions (5.1, 5.2, 5.8)].

In clinical studies, differences in various pharmacokinetic parameters have been observed with bupivacaine HCl between elderly and younger patients. Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to bupivacaine may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in ZYNRELEF dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. Consider reducing the dose of ZYNRELEF for elderly patients.

8.6 Hepatic Impairment

Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity.

Because meloxicam is primarily metabolized in the liver and hepatotoxicity may occur, monitor patients with hepatic impairment for signs and symptoms of worsening disease. Meloxicam has not been adequately studied in patients with severe hepatic impairment.

No dose adjustment of ZYNRELEF is necessary in patients with mild to moderate hepatic impairment. ZYNRELEF should only be used in patients with severe hepatic impairment if the benefits are expected to outweigh the risks; monitor patients for signs of worsening liver function. Consider increased monitoring for local anesthetic systemic toxicity in subjects with moderate to severe hepatic disease [see Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Because bupivacaine and meloxicam and their metabolites are excreted by the kidney, the risk of toxic reactions to these drugs may be greater in patients with impaired renal function. This should be considered when performing dose selection of ZYNRELEF. Consider reducing the dose of ZYNRELEF for patients with mild to moderate renal impairment.

Patients with severe renal disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Patients with severe renal impairment have not been studied. The use of ZYNRELEF in patients with severe renal impairment is not recommended. Meloxicam is not dialyzable. When using ZYNRELEF in patients on hemodialysis do not exceed maximum recommended dose or use with other meloxicam-containing products [see Clinical Pharmacology (12.3)].

8.8 Poor Metabolizers of CYP2C9 Substrates

In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin or phenytoin), consider dose reduction, as these patients may have abnormally high plasma levels of meloxicam due to reduced metabolic clearance. Monitor these patients for adverse effects.

10.1 Bupivacaine

10.2 Meloxicam

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.2, 5.6, 5.8)]. There is limited experience with meloxicam overdosage. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment, call a poison control center (1-800-222-1222).

Bupivacaine

Bupivacaine is a white to off-white crystalline powder, crystals, or granules. The chemical name for bupivacaine is (±)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide, and its empirical formula is C18H28N2O. The molecular weight of bupivacaine is 288.4. Bupivacaine is sparingly soluble in water and freely soluble in alcohol. Bupivacaine has a log Pow of 1.82 and a pKa of 8.1. Bupivacaine has the following structural formula:

Meloxicam

Meloxicam is a pale yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2. Meloxicam is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula:

ZYNRELEF is a sterile, clear, pale yellow to yellow, viscous liquid provided in single-dose vials (10 mL or 20 mL) for instillation into the surgical site. Each mL of the solution contains active ingredients bupivacaine 29.25 mg and meloxicam 0.88 mg; and inactive ingredients tri(ethylene glycol) poly(orthoester) (730 mg), triacetin (293 mg), dimethyl sulfoxide (117 mg), and maleic acid (0.59 mg).

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The instillation of ZYNRELEF into the surgical site results in systemic plasma levels of bupivacaine and meloxicam for up to the duration as described in Table 7. Systemic plasma levels of bupivacaine or meloxicam following application of ZYNRELEF do not correlate with local efficacy.

12.5 Pharmacogenomics

CYP2C9 activity is reduced in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from three published reports showed that meloxicam AUC was substantially higher in individuals with reduced CYP2C9 activity, particularly in poor metabolizers (e.g., *3/*3), compared to normal metabolizers (*1/*1). The frequency of CYP2C9 poor metabolizer genotypes varies based on racial/ethnic background but is generally present in <5% of the population.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

The maximum recommended human dose (MRHD) of ZYNRELEF is 400 mg and 12 mg of bupivacaine and meloxicam, respectively.

14.1 Study 1

In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical trial (NCT03295721), 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. The mean patient age was 47 years (range 18 to 77) and patients were predominantly female (86%). 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. 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 significant reduction in pain intensity compared to those treated with either bupivacaine HCl or saline placebo for up to 72 hours (Figure 1). 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%).

Figure 1. Mean Pain Intensity with Activity Over 72 Hours for STUDY 1 (Bunionectomy)

Based on similarities in surgical site characteristics, such as anatomic location, tissue type, length and depth of surgical area, and vascularity, between bunionectomy and other foot and ankle surgical procedures, the pharmacokinetic profile and effectiveness of ZYNRELEF are not expected to be clinically significantly different when ZYNRELEF is administered at the same dose.

14.2 Study 2

In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical trial (NCT03237481), 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. The mean patient age was 49 years (range 18 to 83) and patients were predominantly male (94%). 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, which 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 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 (Figure 2). 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).

Figure 2. Mean Pain Intensity with Activity Over 72 Hours for STUDY 2 (Herniorrhaphy)

Based on similarities in surgical site characteristics, such as anatomic location, tissue type, length and depth of surgical area, and vascularity, between open inguinal herniorrhaphy and other small-to-medium open abdominal surgical procedures, the pharmacokinetic profile and effectiveness of ZYNRELEF are not expected to be clinically significantly different when ZYNRELEF is administered at the same dose.

14.3 Study 3

In this multicenter, double-blind, parallel-group, active- and placebo-controlled clinical study (NCT03015532), 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. The mean age was 62 years (range 33 to 85) and 51% of patients were female.

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 (10 mg oxycodone orally every 4 hours, and/or 10-15 mg morphine IV every 2 hours). 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 (Figure 3). 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.

Figure 3. Mean Pain Intensity at Rest Over 72 Hours for STUDY 3 (Total Knee Arthroplasty)

Based on similarities in surgical site characteristics, such as anatomic location, tissue type, length and depth of surgical area, and vascularity, between total knee arthroplasty and other lower extremity total joint arthroplasty surgical procedures, the pharmacokinetic profile and effectiveness of ZYNRELEF are not expected to be clinically significantly different when ZYNRELEF is administered at the same dose.

Storage

Store ZYNRELEF kits at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture and light.

If ZYNRELEF vials are removed from the kit, store them at controlled room temperature. Protect from light during storage.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Warnings and Precautions (5.9)].

Serious Skin Reactions, including DRESS

Advise patients to contact their healthcare provider as soon as possible if they develop any type of rash or fever [see Warnings and Precautions (5.13, 5.14)].

Methemoglobinemia

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.11)].

Fetal Toxicity

Inform pregnant women of the risk of the premature closing of the fetal ductus arteriosus if ZYNRELEF or other NSAIDs are used starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with ZYNRELEF is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios because meloxicam can be detected in plasma beyond 48 hours after administration [see Warnings and Precautions (5.15) and Use in Specific Populations (8.1)].

Temporary Loss of Sensation Near the Surgical Site

Inform patients in advance that ZYNRELEF can cause temporary loss of sensation near the surgical site.

Use of NSAIDs

Inform patients of the increased risk of gastrointestinal toxicity if an NSAID or salicylate (e.g., diflunisal, salsalate) is used in the postoperative period following administration of ZYNRELEF [see Drug Interactions (7)].