Bupivacaine-Meloxicam

Bupivacaine-Meloxicam is a combination medicine used in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after foot and ankle, small-to-medium open abdominal, and lower extremity total joint arthroplasty surgical procedures.

• Bupivacaine-Meloxicam is available under the following different brand names: Zynrelef

Common side effects of Bupivacaine-Meloxicam include:

• weakness,
• long-lasting numbness or tingling,
• restlessness,
• drowsiness,
• tremors,
• headache,
• blurred vision,
• fast or slow heartbeats,
• breathing problems,
• chills or shivering,
• back pain,
• nausea, and
• vomiting

Serious side effects of Bupivacaine-Meloxicam include:

• hives,
• difficulty breathing,
• swelling of the face, lips, tongue, or throat,
• red rash,
• itching,
• sneezing,
• severe dizziness,
• vomiting,
• anxiety,
• restlessness,
• confusion,
• drowsiness,
• lightheadedness,
• ringing in the ears,
• problems with speech or vision,
• metallic taste in the mouth,
• numbness or tingling around the mouth,
• muscle twitching,
• tremors,
• seizures,
• weak or shallow breathing,
• slow or fast heart rate,
• gasping,
• feeling unusually hot,
• weak pulse,
• little or no urination,
• headache, and
• skin that looks pale, gray, or blue-colored

Rare side effects of Bupivacaine-Meloxicam include:

• none

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out. 

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Extended-release solution for soft-tissue or periarticular instillation

• 60 mg/1.8 mg as 2.3-mL single-dose vial
• 200 mg/6 mg as 7-mL single-dose vial
• 300 mg/9 mg as 10.5-mL single-dose vial
• 400 mg/12 mg as 14-mL single-dose vial
• Concentration: (29.25 mg/0.88 mg)/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

Adult dosage

• Foot and ankle surgical procedures (e.g., bunionectomy)
• Up to 2.3 mL (bupivacaine 60 mg-Meloxicam 1.8 mg); apply to proximal and distal ends (i.e., beyond the boney repair) of the wound
• Small-to-medium open abdominal procedures (open inguinal herniorrhaphy)
• Up to 10.5 mL (bupivacaine 300 mg-Meloxicam 9 mg); apply above and below the fascial repair
• Lower extremity total joint arthroplasty surgical procedures (e.g., total knee arthroplasty)
• Up to 14 mL (bupivacaine 400 mg-Meloxicam 12 mg); apply directly to the posterior capsule, the anteromedial tissues and periosteum, and the anterolateral tissues and periosteum after cementation of the components

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Bupivacaine-Meloxicam has severe interactions with the following drug:
• sodium polystyrene sulfonate
• Bupivacaine-Meloxicam has serious interactions with the following drugs:
  • aminolevulinic acid oral
  • aminolevulinic acid topical
  • apixaban
  • benazepril
  • bupivacaine implant
  • captopril
  • enalapril
  • fosinopril
  • ketorolac
  • ketorolac intranasal
  • lisinopril
  • methotrexate
  • methyl aminolevulinate
  • moexipril
  • pemetrexed
  • perindopril
  • ponesimod
  • quinapril
• Bupivacaine-Meloxicam has moderate interactions with at least 240 other drugs.
• Bupivacaine-Meloxicam has minor interactions with at least 51 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Known hypersensitivity (eg, anaphylactic reactions, serious skin reactions) to any local anesthetic agent of the amide type, NSAIDs, or 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
• For patients undergoing obstetrical paracervical block anesthesia; the use of bupivacaine in this technique has resulted in fetal bradycardia and death
• Patients undergoing coronary artery bypass graft (CABG) surgery

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Bupivacaine-Meloxicam?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Bupivacaine-Meloxicam?”

Cautions

• Hepatotoxicity
• Amide-type local anesthetics (eg, bupivacaine) are metabolized by the liver; use cautiously with hepatic impairment
• Increased ALT/AST more than 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
  • Limit exposure to articular cartilage due to the potential risk of chondrolysis
  • Chondrolysis reported with an intra-articular infusion of local anesthetics; intra-articular infusions of local anesthetics, following arthroscopic and other surgical procedures is an unapproved use
• 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 have an 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 the benefits outweigh the risk of worsening heart failure
  • Fluid retention and edema were 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 injuries
  • Increases in serum potassium concentration, including hyperkalemia, were 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 the 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 before 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 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 signs and symptoms, patients may respond to supportive care, ie, oxygen therapy, and hydration; a more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen
• Masking of inflammation and fever
  • May reduce the 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 the risk of methemoglobinemia
    • Examples of such drugs include nitrates/nitrites (e.g., nitric oxide, nitroglycerin, nitroprusside, nitrous oxide); other local anesthetics; certain antineoplastic agents (e.g., cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase); certain antibiotics (e.g., dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides); antimalarials (e.g., chloroquine, primaquine); anticonvulsants (e.g., phenobarbital, phenytoin, sodium valproate); and other drugs (e.g., 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 increase the risk of bleeding
  • Aspirin
    • Monitor for signs and symptoms of GI bleeding
    • Coadministration of NSAIDs and aspirin is associated with an 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, and renal function
    • NSAIDs may decrease the 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 the risk for methotrexate toxicity (eg, neutropenia, thrombocytopenia, renal dysfunction)
    • Cyclosporine: Coadministration may increase cyclosporine-associated nephrotoxicity
    • Pemetrexed: Coadministration may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity

Pregnancy and Lactation

• Data are unavailable on the 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 on pregnant females
• 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 the use of NSAIDs in pregnant women at about 30 weeks gestation and later; NSAIDs increase the 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
• Infertility
  • Females
    • Based on the mechanism of action, prostaglandin-mediated NSAIDs may delay or prevent the 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 orally 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 the drug is present in human milk, on the effects on breastfed infants, or milk production