Bupivacaine and meloxicam
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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) ] .
Amide Local Anesthetic, Nonsteroidal Anti-inflammatory Drug
Dosing in kidney impairment
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 ] .
Dosing in liver impairment
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 , and Clinical Pharmacology ] .
Preparation and administration
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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 , Nonclinical Toxicology ] – 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 ] .
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 ] . 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 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 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.
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Preparation Instructions See the ZYNRELEF Instructions for Use included in the kit for complete administration instructions with illustrations. 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.
Prepare vial for filling of syringe(s) by attaching vented vial spike or vial access needle. Syringe attachment for product withdrawal: For vented vial spike, fill syringe with air prior to attaching syringe. Attach syringe to vented vial spike, invert vial and syringe to allow product to fill the vial neck, then push air into vented vial spike prior to withdrawing ZYNRELEF from vial.
For vial access needle, do not fill syringe with air prior to attaching syringe. Attach syringe to vial access needle, then invert vial and syringe to allow product to fill the vial neck prior to withdrawing ZYNRELEF from vial. Withdraw dose of ZYNRELEF into syringe. (The dose volume takes into account the potential residual volume in the components.).
Withdrawal time using the vial access needle is faster than the vented vial spike. [See table below.] Repeat steps 1-3 for more than one syringe. Prepare product immediately prior to use and apply syringe tip cap if needed until product delivery.
Administration Instructions Before administration, remove the syringe tip cap and attach the Luer lock cone-shaped applicator to the syringe. Using the Luer lock cone-shaped applicator attached to the syringe, apply ZYNRELEF to the tissues within the surgical site as follows: For soft tissue procedures, apply ZYNRELEF into the wound prior to closure of each layer within the surgical space. – For abdominal procedures, apply after closure of the peritoneum (if applicable) and avoid administration below the peritoneum.
In general for orthopedic procedures, apply ZYNRELEF into the wound and on the periosteum from the proximal to the distal ends of the wound (i.e., beyond the boney repair). – For total joint arthroplasty, apply ZYNRELEF directly into the joint capsule, onto the periosteum, and the antero-, medial-, and lateral tissues (if applicable), after placement of the component(s). – For spinal procedures, apply ZYNRELEF after closure of the paraspinal musculature and again after closure of the subcutaneous fascia.
ZYNRELEF must not be applied to the dura or spinal cord. 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. 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.
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, vial access needle, and syringe tip caps. Surgical mesh materials, including polypropylene (Prolene ® ), Gore-tex, and polyester.
Silicone membranes. Bone cement. Metal alloys used in surgical implants.
| Nominal Dose of Bupivacaine / Meloxicam | Number of Syringes and LLAsLLA: Luer lock cone-shaped applicator Per Dose | Volume to be Withdrawn |
|---|---|---|
| 60 mg/ 1.8 mg | 1 | 2.3 mL (using 3 mL syringe provided) |
| 200 mg / 6 mg | 1 | 7 mL (using 12 mL syringe provided) |
| 300 mg/ 9 mg | 1 | 10.5 mL (using 12 mL syringe provided) |
| 400 mg/ 12 mg | 2 | 14 mL (using two 12 mL syringes provided, 7 mL ZYNRELEF per syringe) |
Drug interactions
Check bupivacaine and meloxicam against a medication listLabel text (14 paragraphs)
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 cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of ZYNRELEF with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.17)] .
Aspirin Clinical Impact: In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ] . Intervention: If aspirin is indicated in the postoperative period, monitor patients for signs and symptoms of GI bleeding [see Clinical Pharmacology (12.3) ] . ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of ZYNRELEF and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of ZYNRELEF and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ] .
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs have reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect.
Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Intervention: During concomitant use of ZYNRELEF with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Digoxin Clinical Impact: The concomitant use of NSAIDS with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of ZYNRELEF and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance.
The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3) ] . Intervention: Monitor patients on lithium for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of ZYNRELEF and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine Clinical Impact: Concomitant use of NSAIDs and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of ZYNRELEF and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity [see Warnings and Precautions (5.2) ] . Intervention: If additional NSAID or salicylate medication is indicated in the postoperative period, monitor patients for signs and symptoms of GI toxicity [see Clinical Pharmacology (12.3) ] .
Pemetrexed Clinical Impact: Concomitant use of NSAIDs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of ZYNRELEF and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.
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 lactation
Pregnancy
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 oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.8 and 8 times, respectively, the meloxicam dose level of 12 mg at the MRHD of ZYNRELEF.
Increased incidence of septal heart defects was observed in rabbits treated throughout embryogenesis with meloxicam…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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