Bupivacaine And Meloxicam

FDA Drug Information • Also known as: Zynrelef

Brand Names: Zynrelef
Drug Class: Amide Local Anesthetic [EPC], Nonsteroidal Anti-inflammatory Drug [EPC]
Route: INFILTRATION
Dosage Form: SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed 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 ( 5.1 ) ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ) 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 ( 5.2 ) Cardiovascular Thrombotic 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 [see Warnings and Precautions (5.1) ] . ZYNRELEF is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1) ] . Gastrointestinal Bleeding, Ulceration, and Perforation 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 [see Warnings and Precautions (5.2) ] .

Description

11 DESCRIPTION ZYNRELEF (bupivacaine and meloxicam) extended-release solution, for soft tissue or periarticular instillation use, contains bupivacaine, an amide local anesthetic, and meloxicam, a nonsteroidal anti-inflammatory drug (NSAID). 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 C 18 H 28 N 2 O. The molecular weight of bupivacaine is 288.4. Bupivacaine is sparingly soluble in water and freely soluble in alcohol. Bupivacaine has a log P ow of 1.82 and a pKa of 8.1. Bupivacaine has the following structural formula: Chemical Structure 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)-2 H -1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C 14 H 13 N 3 O 4 S 2 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). Chemical Structure

What Is Bupivacaine And Meloxicam Used For?

1 INDICATIONS AND USAGE ZYNRELEF is indicated in adults for postsurgical analgesia for up to 72 hours after: soft tissue surgical procedures orthopedic surgical procedures – foot and ankle procedures – other orthopedic surgical procedures (e.g., total joint arthroplasty) in which direct exposure to articular cartilage is avoided [see Warnings and Precautions (5.10) ] ZYNRELEF is indicated in adults for postsurgical analgesia for up to 72 hours after: soft tissue surgical procedures orthopedic surgical procedures – foot and ankle procedures – other orthopedic surgical procedures (e.g., total joint arthroplasty) in which direct exposure to articular cartilage is avoided [see Warnings and Precautions (5.10) ] 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 ( 1 ). 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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION ZYNRELEF is intended for single-dose administration only ( 2.1 ). Administer ZYNRELEF via instillation only. The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF ( 2.1 ). ZYNRELEF should only be prepared and administered with the components provided in the ZYNRELEF kit ( 2.1 ). ZYNRELEF is applied without a needle into the surgical site following final irrigation and suction and prior to suturing ( 2.1 ). – The recommended dose of ZYNRELEF is up to a maximum dose of 400 mg/12 mg (14 mL) ( 2.4 ). See Full Prescribing Information for important preparation and administration instructions, dose selection, and compatibility considerations ( 2.2 , 2.3 , 2.4 , 2.5 ). 2.1 Important Dosage and Administration Information ADMINISTER ZYNRELEF VIA INSTILLATION ONLY. ZYNRELEF should not be administered via the following routes. – Epidural – Intrathecal – Intravascular – Intra-articular [see Warnings and Precautions (5.10) , Nonclinical Toxicology (13.2) ] – Regional nerve blocks – Pre-incisional or pre-procedural locoregional anesthetic techniques. 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 (5.11) ] . 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 or vial access needle, 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 or vial access needle, Luer lock applicator, and syringe(s) during drug withdrawal and administration. ZYNRELEF is applied without a needle into the surgical site after placement of implant(s) (if applicable), following...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with bupivacaine HCl or meloxicam and are discussed in greater detail in other sections of the labeling: Cardiovascular System Reactions [see Warnings and Precautions (5.1 , 5.4) ] Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2) ] Dose-Related Toxicity [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.5) ] Hypertension [see Warnings and Precautions (5.6) ] Heart Failure and Edema [see Warnings and Precautions (5.7) ] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.8) ] Anaphylactic Reactions [see Warnings and Precautions (5.9) ] Chondrolysis [see Warnings and Precautions (5.11) ] Methemoglobinemia [see Warnings and Precautions (5.12) ] Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.13) ] Serious Skin Reactions [see Warnings and Precautions (5.14) ] Drug Reaction with Eosinophilia and Systemic Toxicity (DRESS) [see Warnings and Precautions (5.15) ] Fetal Toxicity [see Warnings and Precautions (5.16) ] Hematologic Toxicity [see Warnings and Precautions (5.17) ] Most common adverse reactions (incidence ≥5%) are: Soft tissue procedures: vomiting ( 6.1 ). Orthopedic procedures: constipation and headache ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Heron Therapeutics, Inc. at 1-844-437-6611 and www.ZYNRELEF.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 1627 patients undergoing various surgical procedures across 14 clinical studies including 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, of whom 1183 received ZYNRELEF by instillation. Patients treated with ZYNRELEF ranged in age from 18 to 85 years (median age 51 years), with 53.0% female, 82.1% White, 13.7% African-American, and 4.3% all other races. Common Adverse Reactions The safety of ZYNRELEF has been evaluated in 1064 patients who received ZYNRELEF in single doses up to 400 mg/12 mg via instillation into the surgical site, including 533 patients undergoing a soft tissue surgical procedure (herniorrhaphy, abdominoplasty, augmentation mammoplasty, or Cesarean section) and 531 patients undergoing an orthopedic surgical procedure (bunionectomy, total knee arthroplasty, total shoulder arthroplasty, or lumbar spinal surgery). The most common adverse reactions (incidence greater than or equal to 5% and higher than placebo) following ZYNRELEF administration among patients undergoing soft tissue procedures was vomiting and among patients undergoing orthopedic procedures were constipation and headache. The safety of ZYNRELEF as part of a scheduled, non-opioid multimodal analgesic regimen including 1 or more other NSAIDs has been evaluated in a total of 473 patients undergoing soft tissue procedures or orthopedic procedures. NSAIDs included ibuprofen, ketorolac, and celecoxib. In these studies, the most common adverse reactions (incidence of greater than or equal to 2%) potentially associated with NSAIDs were pruritus and postoperative anemia. Rare but clinically serious NSAID-related adverse events, including peptic ulcer hemorrhage, gastritis requiring hospitalization, hematemesis and melena, gastrointestinal hemorrhage, and increased hepatic enzymes, were observed in subjects with predisposing risk factors (i.e., concomitant comorbidities and/or on concomitant medications such as anticoagulant and/or antiplatelet medications) that increased...

Drug Interactions

7 DRUG INTERACTIONS Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking ZYNRELEF with drugs that interfere with hemostasis ( 7.2 ). ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers : Concomitant use with ZYNRELEF may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7.2 ). ACE Inhibitors and ARBs : Concomitant 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 ( 7.2 ). Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effect ( 7.2 ). 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). Table 5. Examples of Drugs Associated with Methemoglobinemia Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.2 Meloxicam Drug Interactions See Table 6 for clinically significant drug interactions with meloxicam. Table 6. Clinically Significant Drug Interactions with Meloxicam Drugs that Interfere with Hemostasis Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and...

Contraindications

4 CONTRAINDICATIONS ZYNRELEF is contraindicated in: Patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components of ZYNRELEF [see Warnings and Precautions (5.9 , 5.14) ] . Patients with a 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 [see Warnings and Precautions (5.9) ] . Patients undergoing obstetrical paracervical block anesthesia. The use of bupivacaine in this technique has resulted in fetal bradycardia and death [see Use in Specific Populations (8.1) ] . Patients undergoing coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1) ] . ZYNRELEF is contraindicated for: Patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components of ZYNRELEF ( 4 ) Patients with a 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 ( 4 ) Patients undergoing obstetrical paracervical block anesthesia ( 4 ) Patients undergoing coronary artery bypass graft (CABG) surgery ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary There are no available human data on use of ZYNRELEF in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. However, there are available data on the individual components of ZYNRELEF, bupivacaine and meloxicam. Bupivacaine The available data on bupivacaine use in pregnant women for epidural anesthesia (excluding paracervical block) are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are no adequate and well-controlled studies with bupivacaine in pregnant women. In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at a comparable bupivacaine dose level of 400 mg at the maximum recommended human dose (MRHD) of ZYNRELEF. Decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning) at a comparable bupivacaine dose to the MRHD ( see Data ). Based on animal data, pregnant women should be advised of the potential risks to a fetus. Meloxicam Use of NSAIDs, including ZYNRELEF, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ZYNRELEF use between about 20 and 30 weeks of gestation and avoid ZYNRELEF use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations , Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ZYNRELEF, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to...

Overdosage

10 OVERDOSAGE No data are available with regard to overdose of ZYNRELEF. Findings related to the individual active substances are listed below. 10.1 Bupivacaine Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution [see ( Warnings and Precautions (5.3) and Adverse Reactions (6) ] . Following administration of ZYNRELEF (400 mg/12 mg) by instillation, a highest individual maximum plasma concentration (C max ) of bupivacaine of 1830 ng/mL was reported. No apparent bupivacaine-related systemic toxicity was observed. Signs and symptoms of overdose include CNS symptoms (dizziness, sensory and visual disturbances, and eventually convulsions) and cardiovascular effects (that range from hypertension and tachycardia to myocardial depression, hypotension, bradycardia, and asystole). Plasma levels of bupivacaine associated with toxicity can vary. Although concentrations of 2,000 to 4,000 ng/mL have been reported to elicit early subjective CNS symptoms of bupivacaine toxicity, symptoms of toxicity have been reported at levels as low as 800 ng/mL. Management of Local Anesthetic Overdose At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments...

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING ZYNRELEF ® (bupivacaine and meloxicam) extended-release solution is a clear, pale-yellow to yellow viscous liquid available in 4 presentations. Each single-dose glass vial is filled with a solution of 29.25 mg/mL bupivacaine and 0.88 mg/mL meloxicam. Each presentation described below is supplied in the ZYNRELEF kit containing a vial (packaged in an individual carton) along with sterile, individually packaged components for administration. Product Presentation (Kit Supplied with Vial Access Needle) Vial Access Needle Provided Luer Lock Syringe(s) Provided Luer Lock Applicator(s) Provided Syringe Tip Cap(s) Provided NDC Bupivacaine/Meloxicam Net Quantity Volume Each ZYNRELEF vial contains overfill to compensate for residual amounts that remain in the vial, vial access needle, Luer lock applicator, and syringe(s) during drug withdrawal and administration 47426-501-02 400 mg/12 mg 14 mL 1 × 20 mL 2 × 12 mL 2 2 47426-502-02 300 mg/9 mg 10.5 mL 1 × 20 mL 1 × 12 mL 1 1 47426-503-01 200 mg/6 mg 7 mL 1 × 10 mL 1 × 12 mL 1 1 47426-504-01 60 mg/1.8 mg 2.3 mL 1 × 10 mL 1 × 3 mL 1 1 Product Presentation (Kit Supplied with Vented Vial Spike) Vented Vial Spike Provided Luer Lock Syringe(s) Provided Luer Lock Applicator(s) Provided Syringe Tip Cap(s) Provided NDC Bupivacaine/Meloxicam Net Quantity Volume 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 47426-301-02 400 mg/12 mg 14 mL 1 2 × 12 mL 2 2 47426-302-02 300 mg/9 mg 10.5 mL 1 1 × 12 mL 1 1 47426-303-01 200 mg/6 mg 7 mL 1 1 × 12 mL 1 1 47426-304-01 60 mg/1.8 mg 2.3 mL 1 1 × 3 mL 1 1 The following replacement components are individually supplied separate from the kit: Carton containing 5 vented vial spikes Carton containing 10 Luer lock applicators Carton containing 10 sterile 3 mL Luer lock syringes Carton containing 8 sterile 12 mL Luer lock...

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.