AHFS Class:

• Reversible COX-1/COX-2 Inhibitors 28:08.04.04

Generic Name(s):

• Meloxicam

Meloxicam is a nonsteroidal anti-inflammatory agent (NSAIA) exhibiting analgesic, antipyretic, and anti-inflammatory actions1,2,3,4,5,6,7,8,9,10 that has been referred to as a “preferential” rather than “selective” COX-2 inhibitor.5,6,10

Meloxicam is used orally for anti-inflammatory and analgesic effects in the symptomatic treatment of osteoarthritis or rheumatoid arthritis in adults and for the management of the signs and symptoms of pauciarticular or polyarticular course juvenile rheumatoid arthritis.1,31,32 Meloxicam also is used parenterally for the relief of moderate to severe pain.35

The potential benefits and risks of meloxicam therapy as well as alternative therapies should be considered prior to initiating meloxicam therapy.1 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1

Osteoarthritis

Meloxicam is used orally in the symptomatic treatment of osteoarthritis in adults.1,31 Efficacy for the management of the signs and symptoms of osteoarthritis (e.g., pain, stiffness, quality of life) of the knee or hip has been established in controlled studies of 4 weeks' to 6 months' duration in adults.1,11,12,13,14,15 Efficacy of 7.5 or 15 mg once daily (as tablets) was comparable to that of piroxicam 20 mg daily or 100 mg daily of conventional or extended-release diclofenac.1,12,13,14,15 Efficacy of meloxicam 5 or 10 mg once daily (as capsules) for the management of pain associated with osteoarthritis of the knee or hip was established in a 12-week placebo-controlled study.31,36 Both the 5- and 10-mg daily dosages of meloxicam were superior to placebo for relieving osteoarthritis pain; the proportion of meloxicam-treated patients achieving various percentage reductions in pain intensity from baseline to week 12 was similar for the 5- and 10-mg daily dosages.31 Meloxicam has not been compared with celecoxib in patients with osteoarthritis. For additional information on the management of osteoarthritis, see Uses: Osteoarthritis, in Celecoxib 28:08.04.08.

Rheumatoid Arthritis in Adults

Meloxicam is used orally for the management of the signs and symptoms of rheumatoid arthritis in adults.1,18,19 In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction.22

Efficacy of meloxicam for the management of rheumatoid arthritis was established in a placebo-controlled, double-blind study of 12 weeks' duration; the primary measure of clinical response in this study was the American College of Rheumatology criteria for a 20% improvement (ACR 20 response) in measures of disease activity.1 An ACR 20 response is achieved if the patient experiences a 20% improvement in the number of tender and swollen joints and a 20% or greater improvement in at least 3 of the following criteria: patient pain assessment, patient global assessment, physician global assessment, patient self-assessed disability, or laboratory measures of disease activity (i.e., erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP] level).21 In this study, meloxicam 7.5 or 15 mg daily was substantially more effective than placebo as evaluated by ACR 20 response; the 22. 5-mg daily dosage provided no additional benefit compared with 15 mg daily.1

For additional information on the management of rheumatoid arthritis, see Uses: Rheumatoid Arthritis in Adults, in Celecoxib 28:08.04.08.

Juvenile Arthritis

Meloxicam is used orally for the management of the signs and symptoms of pauciarticular or polyarticular course juvenile rheumatoid arthritis.1,23,32 Efficacy of meloxicam was established in 2 double-blind, active-controlled studies of 12 weeks' duration in pediatric patients 2-16 years of a response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30; a composite of parent and investigator assessments, number of active joints, number of joints with limited range of motion, disability index, and ESR).1,23 Results of these studies indicate that meloxicam is as effective as naproxen in the treatment of juvenile rheumatoid arthritis.1 In one study, response rates (ACR pediatric 30 criteria) of 77, 76, or 74% were achieved at 12 months in children receiving meloxicam 0.125 mg/kg daily, meloxicam 0.25 mg/kg daily, or naproxen 10 mg/kg daily, respectively.23

Pain

Meloxicam is used parenterally for the relief of moderate to severe pain, either alone or in combination with non-NSAIA analgesics.35 Because of delayed onset of analgesia, use of parenteral meloxicam alone is not recommended when rapid onset of analgesia is required.35

Efficacy and safety of IV meloxicam (30 mg once daily for 2 days starting on the day after surgery, with an optional third dose just prior to discharge) were evaluated in 2 randomized, double-blind, placebo-controlled trials (NCT02675907, NCT02678286) in adults with moderate to severe postoperative pain following bunionectomy or abdominoplasty.33,34,35 Mean baseline pain intensity, as measured on an 11-point numeric scale (with higher scores indicating more intense pain), was 6.8-7.3.35 A difference in the summed pain intensity difference (i.e., the difference between current pain and pain at baseline, multiplied by the interval between ratings and adjusted to account for any rescue analgesics) between the meloxicam and placebo groups was observed in both studies over the first 48 hours of treatment and in one of the studies (abdominoplasty study) over the first 24 hours.33,34,35 A generally consistent separation in pain scores between patients receiving meloxicam and those receiving placebo was observed in both studies from time of onset of pain relief through most of the dosing interval, with narrowing of the difference in pain scores between the meloxicam and placebo groups observed at the end of the first 24-hour dosing interval.33,35 In the bunionectomy study, 49-50% of patients receiving either meloxicam or placebo received rescue analgesic within 2 hours of receiving the initial study dose, while in the abdominoplasty study, 78% of patients receiving either meloxicam or placebo received rescue analgesic within 3 hours of receiving the initial study dose.35 The median time to first use of rescue analgesic (2 hours in patients who underwent bunionectomy, 1 hour in those who underwent abdominoplasty) occurred before the median time to meaningful pain relief in both studies (2 hours in the bunionectomy study, 3 hours in the abdominoplasty study).35

Other Uses

Meloxicam also has been used in the management of ankylosing spondylitis†.10

General

The potential benefits and risks of meloxicam therapy as well as alternative therapies should be considered prior to initiating meloxicam therapy.1

Administration

Meloxicam is administered orally for the management of rheumatoid arthritis, osteoarthritis, and juvenile rheumatoid arthritis and by IV injection for analgesia.1,31,35

Meloxicam is administered orally once daily without regard to meals.1,31

Meloxicam injection is for IV use only.35 The drug should be administered by direct (“bolus”) IV injection over 15 seconds.35 To reduce the risk of renal toxicity, patients must be well hydrated prior to administration.35 The injection should be visually inspected for particulate matter and discoloration prior to administration, and should be discarded if either is present.35

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1 Dosage of meloxicam must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.1

Osteoarthritis, Rheumatoid Arthritis, and Juvenile Arthritis

Meloxicam capsules are not bioequivalent to other oral formulations of the drug and therefore should not be interchanged at similar dosages for other oral meloxicam preparations.31 (See Description.)

The initial and maintenance dosage of meloxicam for the management of osteoarthritis or rheumatoid arthritis in adults is 7.5 mg once daily (as tablets).1 Titration to a maximum dosage of 15 mg once daily may provide additional benefit.1 Higher dosages (e.g., 22.5 mg daily or greater) were associated with increased adverse GI effects, and the manufacturer recommends that the dosage of meloxicam not exceed 15 mg daily.1

Alternatively, for the management of osteoarthritis pain in adults, meloxicam may be initiated at a dosage of 5 mg once daily (as capsules).31 Dosage may be increased to 10 mg once daily in patients who require additional analgesia.31 The maximum recommended dosage is 10 mg once daily.31

For the symptomatic management of juvenile rheumatoid arthritis, the recommended dosage of meloxicam is 0.125 mg/kg (maximum 7.5 mg) once daily; however, an oral suspension of the drug is no longer commercially available in the US, and meloxicam tablets should be used only in pediatric patients who weigh 60 kg or more.1,32 In pediatric patients weighing 60 kg or more, the recommended dosage of meloxicam for the treatment of juvenile rheumatoid arthritis is 7.5 mg once daily (as tablets).1 Higher dosages evaluated in clinical studies were not associated with additional benefit.1,23

Pain

For relief of moderate to severe pain in adults, the recommended IV dosage of meloxicam is 30 mg once daily.35 Analgesic response should be monitored.35 Because the median time to meaningful pain relief was 2-3 hours after IV meloxicam administration in clinical trials, patients receiving IV meloxicam may require a non-NSAIA analgesic with a rapid onset of effect (e.g., upon emergence from anesthesia, upon resolution of local or regional anesthetic blocks).35 In addition, some patients may not experience adequate analgesia for the entire 24-hour dosing interval and may require supplemental use of a short-acting, non-NSAIA, immediate-release analgesic.35 (See Pain under Uses.)

Special Populations

Renal Impairment

No dosage adjustment of oral meloxicam is necessary in patients with mild to moderate renal impairment.1,31 Use in patients with severe renal impairment is not recommended.1,31 If meloxicam is used in patients undergoing hemodialysis, the maximum recommended dosage is 5 mg once daily (as capsules) or 7.5 mg once daily (as tablets); additional doses are not required following dialysis.1,31 (See Renal Impairment under Cautions.)

Use of IV meloxicam is not recommended in patients with moderate to severe renal impairment and is contraindicated in patients with moderate to severe renal impairment who are at risk for renal failure because of hypovolemia.35 (See Renal Impairment under Cautions.)

Hepatic Impairment

No dosage adjustment of oral meloxicam is necessary in patients with mild to moderate hepatic impairment.1,31 Patients with severe hepatic impairment have not been adequately studied.1,31 (See Hepatic Impairment under Cautions.)

IV meloxicam has not been studied in patients with hepatic impairment.35

Geriatric Patients

If anticipated benefits of meloxicam outweigh the potential risks, the manufacturers of oral meloxicam state that the drug should be initiated in geriatric patients at the low end of the dosage range.1,31 (See Geriatric Use under Cautions.)

CYP2C9 Poor or Intermediate Metabolizers

The manufacturer of IV meloxicam states that dosage reduction should be considered in patients who are known or suspected cytochrome P-450 isoenzyme 2C9 (CYP2C9) poor metabolizers.35

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that use of meloxicam should be avoided in patients who are CYP2C9 poor metabolizers.520 In patients who are CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1, meloxicam should be initiated at a dosage that is 50% of the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to a dosage that is 50% of the maximum recommended dosage.520 Dosage should not be increased until steady-state concentrations are attained (at least 7 days following the initial dose).520 Patients who are poor metabolizers should receive an alternative agent that is not metabolized by CYP2C9 or is not substantially affected by CYP2C9 genetic variants in vivo; alternatively, an NSAIA that is metabolized by CYP2C9 but has a shorter half-life could be considered.520 These alternatives also may be considered for intermediate metabolizers with an AS of 1.520 Intermediate metabolizers with an AS of 1.5 may receive dosages recommended for normal metabolizers.520 (See Pharmacogenomic Considerations under Cautions.)

Contraindications

Meloxicam is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to meloxicam or any ingredient in the formulation; those with a history of asthma, urticaria, or other allergic-type reaction precipitated by aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs); and in the setting of coronary artery bypass graft (CABG) surgery.508 In addition, parenteral meloxicam is contraindicated in patients with moderate to severe renal impairment who are at risk for renal failure because of hypovolemia.35

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500,502,508

Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500,501,502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.500,502,505,506,508 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.500,502,506,508

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.505,508 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).500,508,511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.508,511 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Meloxicam should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if meloxicam is used in such patients, the patient should be monitored for cardiac ischemia.508

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following CABG surgery, the incidence of myocardial infarction and stroke was increased.508 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.508

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.26,27,28,30,500,501,502,503,506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

To minimize the potential risk of adverse cardiovascular events, NSAIAs should be used at the lowest effective dosage and for the shortest possible duration of therapy.1,500,508 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.1,500,508

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,24,502,508

GI Effects

Serious, sometimes fatal, adverse GI effects (e.g., bleeding, ulceration, perforation of the esophagus, stomach, or small or large intestine) can occur with or without warning symptoms in patients receiving NSAIAs.1 The risk for GI bleeding is increased more than tenfold in patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs compared with patients without these risk factors.1 Other risk factors for GI bleeding include concomitant use of oral corticosteroids, antiplatelet agents (e.g., aspirin), anticoagulants, or selective serotonin-reuptake inhibitors (SSRIs); longer duration of NSAIA therapy (however, short-term therapy is not without risk); smoking; alcohol use; older a poor general health status; and advanced liver disease and/or coagulopathy.1 Most spontaneous reports of fatal adverse GI effects involve geriatric or debilitated patients.1 The frequency of NSAIA-associated upper GI ulcers, gross bleeding, or perforation is approximately 1% in patients receiving NSAIAs for 3-6 months and 2-4% at one year.1 In some clinical studies, meloxicam was associated with a lower incidence of adverse GI effects compared with other NSAIAs (e.g., diclofenac, naproxen, piroxicam).16,17

To minimize the risk of adverse GI effects, NSAIAs should be used at the lowest effective dosage for the shortest duration necessary.1 Use of more than one NSAIA at a time should be avoided.1 (See Nonsteroidal Anti-inflammatory Agents under Interactions.) Use of NSAIAs should be avoided in patients at higher risk for GI toxicity unless expected benefits outweigh the increased risk of bleeding; alternate therapies other than an NSAIA should be considered in high-risk patients and those with active GI bleeding.1 Patients receiving NSAIAs should be monitored for GI ulceration and bleeding; even closer monitoring for GI bleeding is recommended in those receiving concomitant low-dose aspirin for cardiac prophylaxis.1 If a serious adverse GI event is suspected, evaluation of the patient should be initiated promptly and meloxicam should be discontinued until serious adverse GI events have been ruled out.1

Other Warnings and Precautions

Hepatic Effects

Borderline elevations of one or more liver function tests may occur in up to 15% of patients treated with NSAIAs, including meloxicam; meaningful (3 times the upper limit of normal) elevations of serum ALT or AST concentration have been reported in approximately 1% of patients receiving other NSAIAs.1 Severe, sometimes fatal, reactions (e.g., fulminant hepatitis, liver necrosis, hepatic failure) have been reported rarely in patients receiving NSAIAs.1 If clinical signs and symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur, meloxicam should be discontinued immediately and the patient should be evaluated.1

Hypertension

Use of NSAIAs, including meloxicam, can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events.1 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.1,508 Blood pressure should be monitored closely during initiation of meloxicam therapy and throughout therapy.1

Heart Failure and Edema

Data from observational studies indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.500,504,507,508 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.500,504,508 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.500,501,508 Fluid retention and edema also have been observed in some patients receiving NSAIAs.508 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat these conditions (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).508 (See Drug Interactions.)

The manufacturer states that meloxicam should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if meloxicam is used in such patients, the patient should be monitored for worsening heart failure.508 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507

Renal Effects

Renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury may occur with long-term administration of NSAIAs.1 Overt renal decompensation may occur in patients dependent on renal prostaglandins for maintenance of renal perfusion.1 Patients at particular risk include those with heart failure, hepatic or renal dysfunction, dehydration, or hypovolemia; those receiving a diuretic, ACE inhibitor, or angiotensin II antagonist; and geriatric patients.1,20 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1

Fluid depletion should be corrected prior to initiating meloxicam, and renal function should be monitored during therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.1

Hyperkalemia

Hyperkalemia has been reported in patients receiving NSAIAs, even in some patients without renal impairment; in such patients, the effect has been attributed to a hyporenin-hypoaldosterone state.1

Sensitivity Reactions

Sensitivity reactions, including anaphylactic reactions, are possible in patients with or without prior exposure to meloxicam.1 Immediate medical intervention and drug discontinuance are required if anaphylaxis occurs.1 Cross-sensitivity may exist with other NSAIAs.1 Meloxicam should be avoided in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); patients with asthma but without known aspirin sensitivity should be monitored for changes in manifestations of asthma.1 (See Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.)

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.35 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.35 Symptoms may resemble those of an acute viral infection.35 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.35 If such signs or symptoms develop, meloxicam should be discontinued and the patient evaluated immediately.35

Dermatologic Reactions

Serious, potentially fatal, skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving meloxicam.1 These serious skin reactions may occur without warning.1 Meloxicam should be discontinued at the first appearance of rash or any other sign of hypersensitivity.1

Hematologic Effects

Anemia has been reported, principally in patients receiving long-term (e.g., 6 months' duration) therapy with meloxicam.1 Anemia may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.1 If signs and/or symptoms of anemia occur during therapy with meloxicam, hemoglobin concentration or hematocrit should be determined.1 Notable effects on platelets or bleeding times do not appear to occur.2,3,8,9

NSAIAs may increase the risk of bleeding.1 Patients with certain coexisting conditions (e.g., coagulation disorders) or receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk; such patients should be monitored for bleeding.1

Pharmacogenomic Considerations

In patients with the cytochrome P-450 isoenzyme 2C9 (CYP2C9) poor metabolizer phenotype, metabolism of meloxicam may be decreased substantially; the half-life of meloxicam is prolonged and higher plasma concentrations of the drug may increase the likelihood and/or severity of adverse effects.520 Metabolism of meloxicam may be moderately reduced in CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1 and mildly reduced in those with an AS of 1.5.520 Higher plasma concentrations of the drug in intermediate metabolizers with an AS of 1 may increase the likelihood of adverse effects.520 The presence of other factors affecting clearance of the drug (e.g., hepatic impairment, advanced age) also may increase the risk of adverse effects in intermediate metabolizers.520 (See CYP2C9 Poor or Intermediate Metabolizers under Dosage and Administration and also see Description.) The Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs should be consulted for additional information on interpretation of CYP2C9 genotype testing.520

Other Precautions

NSAIAs may mask certain signs of infection; NSAIAs cannot be used as a substitute for corticosteroid therapy nor used to treat adrenal insufficiency.1

Consideration should be given to obtaining a complete blood cell count and chemistry profile periodically during long-term use.1

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.35,1200 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.35,1200 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.35,1200 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.35,1200

Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.1202

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.35,1200 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.35,1200 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.35,1200 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.35,1200 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.35,1200 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.35 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.35 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.35

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.35 In animal studies, inhibitors of prostaglandin synthesis, such as meloxicam, were associated with increased pre- and post-implantation losses.35 Prostaglandins also have an important role in fetal kidney development.35 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.35

Embryofetal deaths and an increased incidence of septal heart defects have been observed with meloxicam in animal reproduction studies.35

The effects of meloxicam on labor and delivery are unknown.35 In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, increased the incidence of dystocia, delayed parturition, and decreased pup survival.35

Lactation

Meloxicam is distributed into milk in rats.1 It is not known whether meloxicam distributes into human milk, affects milk production, or affects nursing infants.1

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for meloxicam and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Fertility

Use of NSAIAs, including meloxicam, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.1 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1

Meloxicam also may impair fertility in men.35 Administration of meloxicam to male rats for 35 days at dosages of 0.3 times the maximum recommended human dosage resulted in decreased sperm count and motility and histopathologic evidence of testicular degeneration; it is not known whether these effects on fertility are reversible, and the clinical relevance of the findings is unknown.35

Pediatric Use

Safety and efficacy of oral meloxicam have not been established in children younger than 2 years of age.1,32 Safety and efficacy of oral meloxicam have been established in pediatric patients 2-17 years of age with juvenile rheumatoid arthritis.1,32 The manufacturers state that safety and efficacy of meloxicam capsules and parenteral meloxicam have not been established in pediatric patients.31,35

Geriatric Use

Geriatric patients receiving NSAIAs are at increased risk for serious adverse cardiovascular, GI, and renal effects.1 Although results from clinical studies of meloxicam revealed no overall differences in efficacy or safety of the drug between geriatric patients and younger individuals, most of the spontaneous reports of fatal adverse GI effects with NSAIAs have been in geriatric or debilitated individuals.1,31,35 If anticipated benefits of meloxicam outweigh the potential risks, the drug should be initiated at the low end of the dosing range and the patient should be monitored for adverse effects.1

Hepatic Impairment

Oral meloxicam has not been adequately studied in patients with severe hepatic impairment.1,31 Because meloxicam is extensively metabolized in the liver and may cause hepatotoxicity, the drug should be used with caution in patients with hepatic impairment.1 If anticipated benefits of meloxicam outweigh the potential risks in patients with severe hepatic impairment, the patient should be monitored for signs of worsening liver function.31 Plasma concentrations of orally administered meloxicam are not substantially altered in patients with mild to moderate hepatic impairment, and the manufacturers of oral meloxicam state that dosage adjustment is not required in these patients.1,31

IV meloxicam has not been studied in patients with hepatic impairment.35

Renal Impairment

The renal effects of meloxicam may hasten the progression of renal dysfunction in patients with preexisting renal disease.1 Because some metabolites of the drug are excreted by the kidneys, patients with preexisting renal disease should be monitored for signs of worsening renal function.1

In patients with mild or moderate renal impairment, total plasma concentrations of meloxicam decrease and total clearance increases with the degree of renal impairment, while exposure to the free (unbound) drug is similar across all patient groups.1 The higher meloxicam clearance in patients with renal impairment may be due to an increased fraction of unbound meloxicam being available for hepatic metabolism and subsequent excretion.1 Dosage adjustment of oral meloxicam is not necessary in patients with mild to moderate renal impairment.1,31

Oral meloxicam has not been adequately studied in patients with severe renal impairment and use in such patients is not recommended.1,31 If meloxicam must be used in patients with advanced renal disease, renal function should be closely monitored.1

Meloxicam is not removed by dialysis.1,31 Following single-dose administration, peak plasma concentrations of unbound meloxicam were higher in patients with renal failure requiring chronic hemodialysis (free fraction 1%) than in healthy individuals (free fraction 0.3%).1,31 (See Renal Impairment under Dosage and Administration.)

Pharmacokinetics of IV meloxicam in geriatric patients with mild renal impairment are similar to those in young healthy individuals.35 IV meloxicam has not been studied in patients with moderate or severe renal impairment, and use in such patients is not recommended.35 IV meloxicam is contraindicated in patients with moderate to severe renal impairment who are at risk for renal failure because of hypovolemia.35

Common Adverse Effects

Adverse effects occurring in 2% or more of adults receiving oral meloxicam include dyspepsia, headache, nausea, diarrhea, upper respiratory tract infection, abdominal pain or discomfort, dizziness, edema, flatulence, influenza-like illness, musculoskeletal and connective tissue signs and symptoms (back pain, muscle spasms, musculoskeletal pain), and rash.1,31 Adverse effects occurring in 2% or more of patients receiving IV meloxicam, with or without rescue opiate analgesics, for postoperative pain and more frequently than with placebo include constipation, increased γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP) concentrations, and anemia.35

The most common adverse effects reported in pediatric patients receiving oral meloxicam include abdominal pain, vomiting, diarrhea, headache, and pyrexia.1

Drugs Affecting Hepatic Microsomal Enzymes

Meloxicam is extensively metabolized by cytochrome P-450 (CYP) isoenzyme 2C9, with minor contribution by CYP3A4.1 Concomitant use of CYP2C9 inhibitors (e.g., amiodarone, fluconazole) may result in increased plasma concentrations of meloxicam.35 Reduction of meloxicam dosage should be considered, and the patient should be monitored for adverse effects.35

Antacids

The manufacturer states that meloxicam tablets can be administered without regard to antacid administration since studies indicate that pharmacokinetic interactions are unlikely.1

Anticoagulants

Anticoagulants, such as warfarin, and nonsteroidal anti-inflammatory agents (NSAIAs) have synergistic effects on bleeding.1 Concomitant use of meloxicam and anticoagulants is associated with a higher risk of serious bleeding compared with use of either agent alone.1 In healthy individuals receiving warfarin (international normalized ratio [INR] 1.2-1.8), meloxicam did not alter warfarin pharmacokinetics or average prothrombin time; however, INR increased from 1.5 to 2.1 in one individual.1 Caution is advised if meloxicam is used concomitantly with warfarin.1 Patients receiving such concomitant therapy should be monitored appropriately for signs of bleeding.1

Because reduced CYP2C9 function is associated with an increased risk of major bleeding or supratherapeutic INRs in patients receiving concomitant therapy with warfarin (a CYP2C9 substrate) and NSAIAs, some experts state that concomitant use of warfarin and NSAIAs should be avoided in patients who are CYP2C9 intermediate or poor metabolizers.520

Antihypertensive Agents

Concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents may reduce the blood pressure response to the antihypertensive agent.1 Therefore, blood pressure should be monitored to ensure that target blood pressure is achieved.1

Concomitant use of meloxicam with ACE inhibitors or angiotensin II receptor antagonists in geriatric patients or patients with volume depletion or renal impairment may result in reversible deterioration of renal function, including possible acute renal failure; such patients should be monitored for signs of worsening renal function.1 Patients receiving concomitant therapy with meloxicam and ACE inhibitors or angiotensin II receptor antagonists should be adequately hydrated, and renal function should be assessed when concomitant therapy is initiated and periodically thereafter.1

Bile Acid Sequestrants

When meloxicam was administered following 4 days of pretreatment with cholestyramine, meloxicam clearance was increased by 50%, half-life was decreased from 19.2 hours to 12.5 hours, and area under the concentration-time curve (AUC) was decreased by 35%.1 These findings suggest a recirculation pathway for meloxicam in the GI tract.1 The clinical importance of this interaction has not been established.1

Cimetidine

Pharmacokinetic interactions between cimetidine and meloxicam are unlikely.1

Cyclosporine

Concomitant use of meloxicam and cyclosporine may increase cyclosporine-associated nephrotoxicity.1 Patients should be monitored for signs of worsening renal function.1

Digoxin

Pharmacokinetic interactions between digoxin and meloxicam are unlikely.1

Diuretics

NSAIAs reduce the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients.1 This effect has been attributed to NSAIA inhibition of renal prostaglandin synthesis.1 Although studies with meloxicam have not demonstrated a reduction in the natriuretic effect of furosemide or an effect of meloxicam on the pharmacokinetics or pharmacodynamics of furosemide, patients receiving concomitant therapy with meloxicam and diuretics should be monitored for signs of worsening renal function and for adequacy of diuretic and antihypertensive effects.1

Lithium

NSAIAs can decrease renal clearance of lithium by approximately 20% and increase mean trough lithium concentrations by about 15%.1 This effect has been attributed to NSAIA inhibition of renal prostaglandin synthesis.1 In healthy individuals, concomitant administration of meloxicam (15 mg daily) with lithium carbonate (804-1072 mg twice daily) increased lithium exposure by about 21% compared with administration of lithium alone.1 Patients receiving lithium and meloxicam concomitantly should be monitored closely for signs of lithium toxicity.1

Methotrexate

Concomitant use of NSAIAs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).1 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Methotrexate 10:00.) Although no pharmacokinetic interaction was observed in a study of 13 adults with arthritis receiving concomitant methotrexate (weekly) and meloxicam, patients receiving the drugs concomitantly should be monitored for methotrexate toxicity.1

Nonsteroidal Anti-inflammatory Agents

In controlled clinical trials, concomitant use of NSAIAs and analgesic dosages of aspirin did not produce any greater therapeutic effect than use of NSAIAs alone.1 However, concomitant use of aspirin and an NSAIA increases the risk for serious adverse GI events.1 Because of the potential for increased adverse effects, concomitant use of meloxicam with other NSAIAs or with low or analgesic dosages of aspirin generally is not recommended.1

Patients receiving meloxicam should be advised not to take low-dose aspirin without consulting their clinician.1 Meloxicam is not a substitute for low-dose aspirin for cardioprophylaxis, and patients receiving antiplatelet agents such as aspirin concomitantly with meloxicam should be monitored closely for bleeding.1 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.24,502,508

Concomitant administration of aspirin (1 g 3 times daily) and meloxicam in healthy individuals increased the AUC and peak concentration of meloxicam by 10 and 24%, respectively; the clinical importance of this interaction is not known.1 When NSAIAs were administered with aspirin, protein binding of the NSAIA was reduced but clearance of the free (unbound) NSAIA was not altered.1

Pemetrexed

Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.37 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.1 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.1,37 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant meloxicam and pemetrexed therapy.1 Concomitant use of meloxicam and pemetrexed is not recommended in patients with creatinine clearance less than 45 mL/minute.1

Serotonin-reuptake Inhibitors

Serotonin release by platelets plays an important role in hemostasis.1 Results of case-control and epidemiologic cohort studies indicate that concomitant use of NSAIAs and drugs that interfere with serotonin reuptake may potentiate the risk of bleeding beyond that associated with an NSAIA alone.1 Patients receiving concomitant therapy with meloxicam and selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) should be monitored for signs of bleeding.1

Description

Meloxicam, an oxicam derivative that is structurally related to piroxicam, is a nonsteroidal anti-inflammatory agent (NSAIA) exhibiting analgesic, antipyretic, and anti-inflammatory actions.1,2,3,4,5,6,7,8,9,10 In vitro and in vivo studies indicate that meloxicam inhibits the cyclooxygenase-2 (COX-2) isoform of prostaglandin endoperoxide synthase (prostaglandin G/H synthase [PGHS]) to a greater extent than the COX-1 isoform.2,3,5,6,8,10 However, meloxicam's COX-2 selectivity is dose dependent and is diminished at higher dosages.5,6,7,8,9 Therefore meloxicam sometimes has been referred to as a “preferential” rather than “selective” COX-2 inhibitor.5,6,10 For additional information on COX-1 and COX-2, see Pharmacology: Mechanism of Action, in Celecoxib 28:08.04.08.

Meloxicam 10-mg capsules and 15-mg tablets are not bioequivalent.31 Following administration under fasting conditions, the 33% lower dose of meloxicam in the 10-mg capsules resulted in 33% lower overall systemic exposure to the drug compared with the 15-mg tablets; peak plasma concentrations were comparable with the 10-mg capsules and the 15-mg tablets, and the median time to peak plasma concentration was 2 hours for meloxicam 5- or 10-mg capsules but 4 hours for the 15-mg tablets.31

At clinically relevant concentrations, meloxicam is extensively (approximately 99.4%) bound to plasma proteins, mainly to albumin.1 Protein binding decreases to approximately 99% in patients with renal disease.1 Following a single oral dose of meloxicam, concentrations of the drug in synovial fluid are 40-50% of plasma concentrations, but the free fraction is 2.5 times higher in synovial fluid than in plasma because of the lower albumin content of synovial fluid.1

Meloxicam is extensively metabolized to inactive metabolites in the liver, principally via the cytochrome P-450 (CYP) 2C9 isoenzyme, with minor contribution by CYP3A4.1,2,3,4,8,10 The drug and its metabolites are excreted in urine and feces, and meloxicam undergoes substantial biliary secretion and enterohepatic recirculation.1,2,3,4,8,10 Only trace amounts of an administered dose of meloxicam are excreted unchanged in urine or feces.1 The elimination half-life of meloxicam reportedly ranges from approximately 15-24 hours.1,31,35 Limited data indicate that meloxicam exposure is increased substantially in individuals with reduced CYP2C9 activity (e.g., CYP2C9*2 and CYP2C9*3 polymorphisms), particularly in poor metabolizers (e.g., individuals with the *3/*3 diplotype), compared with normal metabolizers.35

Advice to Patients

Importance of reading the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.1

Risk of serious cardiovascular toxicity (e.g., myocardial infarction, stroke).1,500,508 Importance of seeking immediate medical attention if signs and symptoms of serious cardiovascular toxicity (e.g., chest pain, dyspnea, weakness, slurring of speech) occur.1,500,508

Risk of GI ulceration or bleeding; importance of reporting any signs or symptoms of GI ulceration or bleeding (e.g., epigastric pain, dyspepsia, melena, hematemesis).1 Inform patients receiving concomitant low-dose aspirin of the increased risk of GI bleeding.1

Risk of hepatotoxicity; advise patients to discontinue taking meloxicam and immediately contact their clinician if signs or symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, flu-like symptoms) occur.1

Risk of serious skin reactions, drug reaction with eosinophilia and systemic symptoms (DRESS), and anaphylactic and other sensitivity reactions.1,35 Advise patients to discontinue taking meloxicam immediately if they develop any type of rash or fever and to promptly contact their clinician.35 Importance of seeking immediate medical attention if an anaphylactic reaction occurs.35

Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.1,508

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 Advise patients that concomitant use of other NSAIAs with meloxicam provides little or no increase in efficacy but increases risk of GI toxicity, and is not recommended.1 Advise patients not to use concomitant low-dose aspirin without consulting their clinician.1 Alert patients to the presence of NSAIAs in many OTC drugs.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of avoiding use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician and of avoiding use beginning at 30 weeks' gestation because of risk of premature closure of the fetal ductus arteriosus; advise pregnant women that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.35,1200 Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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