bupivacaine/meloxicam (Rx)

Brand and Other Names:Zynrelef
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Dosing & Uses

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Dosage Forms & Strengths

Bupivacaine/meloxicam

extended-release solution for soft-tissue or periarticular instillation

  • 60mg/1.8mg as 2.3-mL single-dose vial
  • 200mg/6mg as 7-mL single-dose vial
  • 300mg/9mg as 10.5-mL single-dose vial
  • 400mg/12mg as 14-mL single-dose vial
  • Concentration: (29.25mg/0.88mg)/mL
  • Kit contains: 5 vented vial spikes, 10 Luer lock applicators, 10 sterile 3-mL Luer lock syringes, 8 sterile 12-mL Luer lock syringes

Postoperative Analgesia

Indicated as a single dose for postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy, or total knee arthroplasty

Bunionectomy

  • Up to 2.3 mL (bupivacaine 60 mg/meloxicam 1.8 mg); apply to proximal and distal ends (ie, beyond the boney repair) of the wound

Open inguinal herniorrhaphy

  • Up to 10.5 mL (bupivacaine 300 mg/meloxicam 9 mg); apply above and below the fascial repair

Total knee arthroplasty

  • Up to 14 mL (bupivacaine 400 mg/meloxicam 12 mg); apply directly to posterior capsule, the anteromedial tissues and periosteum, and the anterolateral tissues and periosteum after cementation of the components

Dosage Modifications

Renal impairment

  • Mild-to-moderate: Consider reducing dose
  • Severe: Not studied and not recommended
  • Hemodialysis: Meloxicam is not dialyzable; do not exceed maximum recommended meloxicam dose or use with other meloxicam-containing products

Hepatic impairment

  • Mild-to-moderate: No dosage adjustment required
  • Severe: Only use if benefits outweigh the risks; monitor for signs of worsening liver function

Poor CYP2C9 metabolizers

  • Consider dose reduction in patients who are known or suspected poor CYP2C9 metabolizers

Dosing Considerations

Avoid additional use of other local anesthetics within 96 hr following administration

Limitations of use

  • Safety and efficacy not established in highly vascular surgeries (eg, intrathoracic, large multilevel spinal, and head and neck procedures)

Safety and efficacy not established

Consider dose reduction, particularly in those with reduced renal or hepatic function

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Interactions

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            Adverse Effects

            >10%

            Bunionectomy

            • Dizziness (22%)
            • Incision site edema (17%)
            • Headache (14%)
            • Incision site erythema (13%)
            • Herniorrhaphy H4
            • Headache (13%)

            Total knee arthroplasty

            • Nausea (50%)
            • Vomiting (26%)
            • Constipation (24%)
            • Hypertension (19%)
            • Pyrexia (14%)

            1-10%

            Bunionectomy

            • Bradycardia (8%)
            • Impaired healing (6%)
            • Muscle twitching (6%)
            • Incision site cellulitis (4%)
            • Wound dehiscence (4%)
            • Incision site infection (3%)

            Herniorrhaphy

            • Bradycardia (9%)
            • Dysgeusia (9%)
            • Skin odor abnormal (8%)

            Total knee arthroplasty

            • Leukocytosis (7%)
            • Pruritus (7%)
            • Headache (7%)
            • Headache (7%)
            • Anemia (5%)
            • Hyperhidrosis (5%)
            • Hypotension (5%)
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            Warnings

            Black Box Warnings

            Cardiovascular risk

            • Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal
            • Risk may increase with duration of use
            • Patients with existing cardiovascular disease or risk factors for such disease may be at greater risk
            • The risk of these events following single-dose local application of bupivacaine/meloxicam is uncertain
            • Contraindicated in setting of coronary artery bypass graft (CABG) surgery

            Gastrointestinal risk

            • NSAIDs increase risk of serious GI adverse events, including bleeding, ulceration, and gastric or intestinal perforation, which can be fatal
            • GI adverse events may occur at any time during use and without warning symptoms
            • Geriatric patients and those with prior history of peptic ulcer disease and/or GI bleeding are at greater risk

            Contraindications

            Known hypersensitivity (eg, anaphylactic reactions, serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components

            History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; severe, sometimes fatal, anaphylactic reactions to NSAIDs reported

            Patients undergoing obstetrical paracervical block anesthesia; use of bupivacaine in this technique has resulted in fetal bradycardia and death

            Patients undergoing coronary artery bypass graft (CABG) surgery

            Cautions

            Hepatotoxicity

            • Amide-type local anesthetics (eg, bupivacaine) are metabolized by the liver; use cautiously with hepatic impairment
            • Increased ALT/AST ≥3x ULN reported (rarely) with NSAID use; rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure, reported
            • Inform patients of warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms); if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash), promptly evaluate the patient

            Bupivacaine

            • Prevent dose-related toxicity by assuring proper dose and correct technique
            • Chondrolysis reported with intra-articular infusion of local anesthetics

            Meloxicam

            • Anaphylaxis and aspirin-sensitive asthma
              • May cause anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma
              • A subpopulation of patients with asthma may have aspirin-sensitive asthma including severe, potentially fatal bronchospasm; these patients also may may have intolerance to other NSAIDs
              • These patients may also be intolerant to other NSAIDs; when used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for exacerbation of asthma symptoms
            • Cardiovascular events
              • Cardiovascular thrombotic events reported with NSAID use
              • Avoid use post myocardial infarction unless benefits outweigh risk; contraindicated in first 10-14 days following CABG
              • Avoid use with severe heart failure unless benefits outweigh risk of worsening heart failure
              • Fluid retention and edema observed in some patients taking NSAIDs
            • Hypertension
              • NSAIDs may impair response to loop and thiazide diuretics; monitor blood pressure
              • May lead to new-onset hypertension or exacerbate existing hypertension
            • GI bleeding, ulceration, and perforation
              • Anemia reported in NSAID-treated patients; this may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis
              • Monitor hemoglobin or hematocrit if signs or symptoms of anemia occur
            • Renal toxicity and hyperkalemia
              • Long-term administration of NSAIDs has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury
              • Increases in serum potassium concentration, including hyperkalemia, reported with NSAIDs, even in some patients without renal impairment
              • NSAIDs may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation; patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly; these effects are reversible upon discontinuation of the NSAID
              • Meloxicam may hasten progression of renal dysfunction in patients with preexisting renal disease; because some meloxicam metabolites are excreted by the kidney, monitor patients for signs of worsening renal function; correct volume status in dehydrated or hypovolemic patients prior to initiating therapy
            • Skin reactions
              • NSAIDs can cause serious adverse reactions (eg, exfoliative dermatitis, Stevens-Johnson Syndrome [SJS], toxic epidermal necrolysis [TEN], eosinophilia and systemic symptoms [DRESS] syndrome), which can be fatal
              • These serious events may occur without warning; inform patients about signs and symptoms of serious skin reactions
              • 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; disorder is variable in its presentation, other organ systems not noted here may be involved; 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
            • Methemoglobinemia
              • 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 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 severity of signs and symptoms, patients may respond to supportive care, ie, oxygen therapy, hydration; a more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen
            • Masking of inflammation and fever
              • May reduce utility of diagnostic signs in detecting infection by reducing inflammation and fever
            • Fetal toxicity
              • NSAIDs may cause premature closure of fetal ductus arteriosus, oligohydramnios, and neonatal renal impairment

            Drug interaction overview

            • Other local anesthetics
              • If unable to avoid coadministration, monitor for neurologic and cardiovascular adverse effects
              • Toxic effects of local anesthetics are additive; avoid additional local anesthetic within 96 hr after bupivacaine/meloxicam administration
            • Drug-associated methemoglobinemia
              • Avoid coadministration of bupivacaine with other drugs that increase risk of methemoglobinemia
              • Examples of such drugs include nitrates/nitrites (eg, nitric oxide, nitroglycerin, nitroprusside, nitrous oxide); other local anesthetic; certain antineoplastic agents (eg, cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase); certain antibiotics (eg, dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides); antimalarials (eg, chloroquine, primaquine); anticonvulsants (eg, phenobarbital, phenytoin, sodium valproate); and other drugs (eg, acetaminophen, metoclopramide, quinine, sulfasalazine)
            • Drugs interfering with hemostasis
              • Monitor if coadministered
              • Coadministration of NSAIDs with anticoagulants (eg, warfarin), antiplatelet agents (eg, aspirin), or drugs that inhibit serotonin (eg, SSRIs, SNRIs) may increases risk of bleeding
            • Aspirin
              • Monitor for signs and symptoms of GI bleeding
              • Coadministration of NSAIDs and aspirin associated with increased incidence of GI adverse effects compared with when an NSAID is used alone
            • ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers
              • Monitor blood pressure, volume, renal function
              • NSAIDs may decrease antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers
              • Coadministration of NSAIDs with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure, particularly in patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment
            • Effect of NSAIDS on selected drugs
              • Monitor serum levels (if applicable) and adverse effects
              • Digoxin: Coadministration may increase digoxin serum levels
              • Lithium: Coadministration may increase plasma lithium levels
              • Methotrexate: Coadministration may increase risk for methotrexate toxicity (eg, neutropenia, thrombocytopenia, renal dysfunction)
              • Cyclosporine: Coadministration may increase cyclosporine-associated nephrotoxicity
              • Pemetrexed: Coadministration may increase risk of pemetrexed-associated myelosuppression, renal, and GI toxicity
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            Pregnancy & Lactation

            Pregnancy

            Data are unavailable on use of bupivacaine/meloxicam in pregnant females to evaluate drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes; however, data are available on the individual components

            Bupivacaine

            • There are no studies conducted with pregnant females
            • Animal studies
              • Embryofetal deaths were observed with SC administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg; SC administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD
              • Advise pregnant females of the potential risks to a fetus

            Meloxicam

            • Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive
            • Fetal toxicity
              • Avoid use of NSAIDs in pregnant women at about 30 weeks' gestation and later; NSAIDs increase risk of premature closure of fetal ductus arteriosus at approximately this gestational age
              • Use of NSAIDs at about 20 weeks' gestation or later in pregnancy may also cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment
              • These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation
              • Oligohydramnios is often, but not always, reversible with treatment discontinuation; complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation
              • In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required
              • If NSAID treatment is necessary between about 20 and 30 weeks' gestation, limit use to the lowest effective dose and shortest duration possible
              • Consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours; discontinue drug if oligohydramnios occurs and follow up according to clinical practice
            • Animal studies
              • Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization
              • Administration of prostaglandin synthesis inhibitors, such as meloxicam, resulted in increased preimplantation and postimplantation loss

            Infertility

            • Females
              • Based on the mechanism of action, prostaglandin-mediated NSAIDs may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women
              • Animal studies have shown prostaglandin synthesis inhibitors may disrupt prostaglandin-mediated follicular rupture required for ovulation
              • Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation
              • Consider withdrawal/avoidance of NSAIDs in women who have difficulties conceiving or who are undergoing infertility investigation
            • Males
              • Male rats given meloxicam PO for 35 days had decreased sperm count and motility, and histopathological evidence of testicular degeneration at 0.8 times the MRHD based on BSA comparison

            Lactation

            Data are unavailable on whether drug is present in human milk, or on the effects on breastfed infants, or on milk production

            Animal data

            • Meloxicam is present in milk of lactating rats at concentrations higher than those in plasma
            • Bupivacaine and meloxicam detected in milk of lactating pigs, but only bupivacaine was detected in plasma of piglets

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Bupivacaine: Local amide anesthetic; blocks generation and conduction of nerve impulses presumably by increasing the electrical excitation threshold in the nerve, by slowing nerve impulse propagation, and by reducing the rate of action potential rise

            Meloxicam: Member of oxicam class; inhibits synthesis of prostaglandins in body tissues by inhibiting at least 2 cyclooxygenase (COX) isoenzymes, COX-1 and COX-2

            Absorption

            Peak plasma time

            • Bunionectomy
              • Bupivacaine: 3 hr
              • Meloxicam: 18 hr
            • Herniorrhaphy
              • Bupivacaine: 18 hr
              • Meloxicam: 54 hr
            • Total knee arthroplasty
              • Bupivacaine: 21 hr
              • Meloxicam: 36 hr

            Peak plasma concentration

            • Systemic plasma levels of bupivacaine or meloxicam following application do not correlate with local efficacy
            • Bunionectomy
              • Bupivacaine: 54 ng/mL
              • Meloxicam: 26 ng/mL
            • Herniorrhaphy
              • Bupivacaine: 271 ng/mL
              • Meloxicam: 225 ng/mL
            • Total knee arthroplasty
              • Bupivacaine: 695 ng/mL
              • Meloxicam: 275 ng/mL

            AUC

            • Bunionectomy
              • Bupivacaine: 1,718 hng/mL
              • Meloxicam: 2,079 hng/mL
            • Herniorrhaphy
              • Bupivacaine: 15,524 hng/mL
              • Meloxicam: Not reported
            • Total knee arthroplasty
              • Bupivacaine: 38,173 hng/mL
              • Meloxicam: 19,525 hng/mL

            Distribution

            After bupivacaine and meloxicam have been released and are absorbed systemically, their distribution is expected to be as other bupivacaine formulations or meloxicam oral formulation

            Bupivacaine

            • Depending on route of administration, distribution to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain

            Meloxicam

            • Protein bound: 99.4%; primarily to albumin
            • Vd: ~10 L

            Metabolism

            Bupivacaine

            • Metabolized primarily by the liver via conjugation with glucuronic acid
            • Metabolites: ~5% converted to the major metabolite, pipecolylxylidine

            Meloxicam

            • Metabolized in liver by CYP2C9 (major) and CYP3A4 (minor)
            • Metabolites (inactive): 5'-Carboxy meloxicam, 5'-hydroxymethyl meloxicam

            Elimination

            Half-life

            • Bupivacaine: 14-15 hr
            • Meloxicam: 22-25 hr

            Excretion

            • Bupivacaine: Mainly excreted by kidneys; 6% unchanged in urine
            • Meloxicam: Predominately excreted as metabolites equally between urine and feces

            Pharmacogenomics

            CYP2C9 activity reduced in individuals with genetic variants (eg, CYP2C9*2 and CYP2C9*3 polymorphisms)

            Limited data found meloxicam

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            Administration

            Incompatibilities

            Bupivacaine/meloxicam is a nonaqueous solution; do not mix with water, saline, or other local anesthetics as the product will become more viscous and difficult to administer

            Topical antiseptic, such as povidone iodine (eg, Betadine); allow antiseptic to dry before local anesthetic administered into site

            When administered in recommended doses and concentrations, does not ordinarily produce irritation or tissue damage

            Compatibilities

            Compatible with all components in the kit, including syringes, Luer lock applicators, 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

            Soft Tissue or Periarticular Instillation

            Follow instructions in kit and only use supplied syringes and applicators

            Apply solution 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 bupivacaine/meloxicam comes in contact with moisture in tissues, it becomes more viscous, allowing it to stay in place

            Does not degrade sutures; when using monofilament sutures, ≥3 knots recommended; contact with bupivacaine/meloxicam may cause a single knot to loosen or untie

            DO NOT administer by following routes: Epidural, intrathecal, intravascular or intra-articular, regional nerve blocks, preincisional or preprocedural locoregional anesthetic techniques

            Only apply to tissue layers below the skin incision and not directly onto subdermal layer or the skin

            Use only amount necessary to coat the tissues, such that bupivacaine/meloxicam does not leak from surgical wound after closure

            Potential risk of severe, life-threatening neurological or cardiac toxicity associated with bupivacaine; administer in setting where trained personnel and equipment are available

            Storage

            Store kit in carton at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Protect from moisture and light

            If vial removed from kit, store at controlled room temperature and protect from light

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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