Meloxicam Intravenous Injection

Abstract

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Keywords

Drug Information Formulary Management/P & T Pain Management

Pharmacy and Therapeutics Review

Generic Name: MELOXICAM INTRAVENOUS INJECTION

Proprietary Name: Anjeso (Baudax Bio, Inc)

Approval Rating: 3S

Therapeutic Class: Nonsteroidal Anti-Inflammatory Drugs

Similar Drugs: Ketorolac Injection

Sound-/Look-Alike Names: Ancef, Anoro Ellipta

Indications

Meloxicam intravenous (IV) injection is approved by the Food and Drug Administration (FDA) for the management of moderate to severe pain in adults, for use alone or in combination with non-nonsteroidal anti-inflammatory drug (NSAID) analgesics.¹ Meloxicam IV is associated with a delayed onset of analgesia and is not recommended for use when rapid onset of analgesia is required.¹

See Table 1 for a comparison of the injectable formulations of the NSAIDs ketorolac and meloxicam.^1,2

Table 1.

Comparison of Injectable Ketorolac and Meloxicam.^1,2

	Meloxicam	Ketorolac
Brand name (manufacturer)	Anjeso (Baudax Bio)	(Various)
Generic availability	No	Yes
Route(s) of administration	IV	IM, IV
Indication	Moderate to severe pain in adults, for use alone or in combination with non-NSAID analgesics	Short-term management of moderately severe acute pain in adults who require analgesia at the opioid level, usually in a postoperative setting
Dosage	30 mg once daily, administered by IV bolus injection over 15 seconds	Single-dose treatment: IM injection given slowly and deeply into the muscle: Patients <65 years: 1 dose of 60 mgPatients ≥65 years, renally impaired, and/or weighing <50 kg: 1 dose of 30 mg IV bolus given over no less than 15 seconds: Patients <65 years: 1 dose of 30 mg Patients ≥65 years, renally impaired, and/or weighing <50 kg: 1 dose of 15 mg Multiple-dose treatment (IV or IM): Patients <65 years: 30 mg every 6 hours (maximum daily dose, 120 mg) Patients ≥65 years, renally impaired patients, and patients weighing <50 kg: 15 mg every 6 hours (maximum daily dose, 60 mg)
Maximum duration of therapy	Shortest duration possible	5 days^a

Including oral ketorolac tromethamine therapy, which is used as continuation treatment, if necessary, following initial therapy with IV or IM ketorolac tromethamine.

Clinical Pharmacology

Meloxicam IV is an NSAID with analgesic, anti-inflammatory, and antipyretic properties. Its mechanism of action is thought to involve the inhibition of cyclooxygenase (COX-1 and COX-2).¹

The effects of IV meloxicam and ketorolac on platelet function have been evaluated using various tests. The collagen with adenosine diphosphate test (sensitive to thrombocytopathies) showed no differences in closure time for meloxicam- or ketorolac-treated samples and untreated control. The collagen with epinephrine test (sensitive to aspirin-induced platelet abnormalities) showed no difference in closure time between any meloxicam concentration and untreated control, while ketorolac was associated with longer closure times versus untreated control and versus meloxicam at several concentrations.³

Meloxicam IV has no clinically significant effect on the QTc interval.¹

Pharmacokinetics

A single-dose of meloxicam 30 mg administered IV in healthy volunteers produced a peak plasma concentration of 5642.9 ng/mL, a time to peak concentration of 0.12 hours, an area under the curve (AUC_inf) of 107 508.7 ng•hour/mL, and a half-life of 23.3 hours. Oral administration of meloxicam 15 mg produced values of 1221 ng/mL, 6.57 hours, 53 998.8 ng•hour/mL, and 26.4 hours, respectively. Following multiple dosing, meloxicam 30 mg IV resulted in predictable accumulation (slightly higher than 2-fold) without a change in terminal elimination half-life.¹

Following administration of meloxicam IV, apparent volume of distribution during the terminal elimination phase is 9.63 L.¹ Meloxicam protein binding is extensive (99.4%) and primarily to albumin.^1,4

Meloxicam is extensively metabolized in the liver to inactive metabolites.^1,4 The main metabolic enzyme is CYP2C9, and CYP3A4 plays a minor role.¹

Meloxicam is excreted predominantly as its metabolites.⁴ Traces of the unchanged parent compound are excreted in urine (0.2%) and feces (1.6%). Administration of cholestyramine following a single IV meloxicam dose can decrease meloxicam’s AUC by 50%.¹

No meaningful changes in meloxicam IV pharmacokinetics were observed based on age, gender, or race.¹

The impact of hepatic impairment on meloxicam IV pharmacokinetics has not been fully evaluated. Following a single 15 mg oral dose of meloxicam in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, no marked difference in plasma concentrations or protein binding were observed compared with healthy volunteers. Patients with severe hepatic impairment have not been adequately evaluated.¹

Mild renal impairment in elderly subjects resulted in a minor change in peak plasma concentrations and AUC of meloxicam IV; no dosage adjustments are necessary in patients with mild renal impairment. Use of meloxicam IV in patients with moderate to severe renal impairment has not been adequately studied and is not recommended. Use is contraindicated in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion.¹

Comparative Efficacy

Indication: Management of Moderate to Severe Pain

Guidelines

Guideline: Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council

Reference: American Pain Society.⁵

Comments: Postoperative pain management should be tailored to the individual and the surgical procedure involved, with adequate follow-up assessment and adjustments as needed. Multimodal analgesia, or the use of a variety of analgesic medications and techniques possibly combined with nonpharmacological interventions, should be considered. Oral administration of opioids is recommended over IV administration for postoperative analgesia when the oral route is possible. The guideline panel recommends that the intramuscular route be avoided during administration of analgesics for the management of postoperative pain. IV patient-controlled analgesia (PCA) can be used when the parenteral route is needed; however, basal infusion of opioids with IV PCA in opioid-naïve adults is discouraged. Instead, acetaminophen and/or NSAIDs are recommended as part of multimodal analgesia for management of postoperative pain in patients without contraindications.

Studies

Drug: Meloxicam IV vs Placebo

Reference: Gottlieb et al⁶

Study Design: Phase 2, randomized, double-blind, placebo-controlled, single-center study

Study Funding: Recro Pharma, Inc

Patients: Fifty-nine adults with a bunion and scheduled to undergo primary, unilateral, first metatarsal osteotomy and internal fixation (without collateral procedures). A standardized anesthesia regimen (continuous popliteal sciatic nerve block and local anesthesia, with IV midazolam and propofol for sedation) was used during the surgery. On the first postoperative day and following cessation of a popliteal sciatic nerve block and discontinuation of other pain management measures (topical ice and ketorolac and/or morphine), patients had to have moderate to severe pain on a 4-point Likert scale and a score of 4 or higher on the 11-point numeric pain rating scale (NPRS). Exclusion criteria included known hypersensitivity to aspirin, NSAIDs, or any of the peri- or postoperative medications used in the study; active GI bleeding or a history of peptic ulcer disease; known bleeding disorders affecting coagulation; evidence of respiratory insufficiency, hypotension, or bradycardia; a history of migraine, frequent headaches, seizures, or significant renal, hepatic, cardiovascular, metabolic, neurologic, or psychiatric disease; a history of alcohol or drug abuse, hepatitis B or C, or HIV infection; body mass index (BMI) greater than 35 kg/m²; and pregnancy or breastfeeding. Patients were also excluded if they required treatment with opioids long-term (longer than 30 consecutive days in the past year); antiepileptics; antidepressants; neuroleptics; systemic or intra-articular corticosteroids (within 6 weeks prior to the study); sedative/hypnotic drugs; warfarin; lithium; combinations of furosemide with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker; analgesics other than those prespecified for postoperative rescue use; prophylactic antiemetics; epidural or spinal anesthetics; and/or pre-, intra-, or postoperative corticosteroids. Mean patient age was 47.2 years (range, 18-72 years); 81.4% of patients were women; and 50.8% were black or African American and 47.5% were white. Mean duration of surgery was 0.792 hours, baseline NPRS score was 7.593, and time to first dose of study medication was 17.933 hours.

Intervention: Patients were randomized (1:1:1) to receive meloxicam 30 mg, meloxicam 60 mg, or placebo as an IV bolus injection over 15 to 30 seconds on postoperative day 1. The second IV dose of study medication was administered 24 hours after the first dose, with the option of a third dose prior to discharge from the study center (after the initial 48 hours) at the discretion of the investigator and the subject. Assessments for adverse events and pain intensity were conducted prior to and at 0.25, 0.5, 0.75, 1, and 2 hours after the first dose; thereafter, pain was assessed every 2 hours until hour 48, and also assessed within 5 minutes before administration of each dose of rescue medication (oral oxycodone 5 mg administered up to every 2 hours as needed). Subjects were discharged after the 48-hour evaluations. All randomized patients received at least 1 dose of the study medication, 96.6% received 2 doses, and 50.8% received a third dose after the 48-hour assessment.

Results

Primary End Point(s)

Estimated effect size for summed pain intensity difference at 48 hours (SPID₄₈) was 1.15 (95% CI, 0.51-1.79) for meloxicam 30 mg and 1.01 for meloxicam 60 mg (P ≤ .01 for both vs placebo). Pain reduction was significantly greater with both doses of meloxicam IV compared to placebo (P ≤ .05) based on SPID at all specific time points (6 hours [SPID₆], 12 hours [SPID₁₂], 24 hours [SPID₂₄], and for the intervals 12 to 24 hours [SPID_12-24], 12-48 hours [SPID_12-48], and 24-48 hours [SPID_24-48]).

Statistically significant decreases in pain from baseline (ie, negative pain intensity difference [PID] values) were detected as early as 15 minutes after the first dose of meloxicam IV: mean PID was −1.5 with meloxicam 30 mg (P < .05 vs baseline) and −0.7 with meloxicam 60 mg (P < .05 vs baseline).

Mean change in pain intensity score from baseline at all assessments was less than zero (ie, pain level was lower than at baseline) with both doses of meloxicam IV; mean changes at the 48-hour assessment were −4.6 with meloxicam 30 mg and −4.3 with meloxicam 60 mg (both P < .001 vs baseline). In the placebo group, mean PID at 0.25 hours was −0.1; thereafter, pain intensity changes were above zero until the 20-hour assessment, with no significant difference from baseline detected until hour 28.

Secondary End Point(s)

Proportion of patients with 30% or higher overall reduction in pain from baseline within the first 24 hours after study drug administration was 50% with meloxicam 30 mg (P ≤ .05 vs placebo), 40% with meloxicam 60 mg (P ≤ .05 vs placebo), and 10.5% with placebo.

Proportion of patients with 50% or higher overall reduction in pain from baseline within the first 24 hours after study drug administration was 30% with meloxicam 30 mg (P ≤ .05 vs placebo), 20% with meloxicam 60 mg, and 0% with placebo.

Patient global assessment (PGA) of pain control at 24 and 48 hours after first dose of study drug (5-point scale; 0 = poor, 1 = fair, 2 = good, 3 = very good, 4 = excellent): No statistically significant differences were observed among the 3 treatment groups at either time point; however, more patients in the meloxicam groups reported “good” or better pain control.

Rescue medication was required by at least 90% of patients in all 3 groups within the first 24 hours of receiving the initial dose of study medication. The need for rescue medication was lower in all 3 groups during the second 24-hour period (hours 24-48): 55% in the meloxicam 30 mg group, 52.6% in the meloxicam 60 mg group, and 77.8% in the placebo group.

Median time to administration of the first dose of rescue analgesia was 3.1 hours in the meloxicam 60 mg group and 1.57 hours in the placebo group (P < .05); there was no significant difference between the meloxicam 30 mg group and the placebo group.

Mean number of rescue analgesia doses was 8.2 with meloxicam 30 mg, 6.9 with meloxicam 60 mg, and 11.1 with placebo.

Comments: Safety and efficacy analyses were conducted in the intention-to-treat (ITT) population. If rescue medication was given, subsequent data points were handled using a last observation carried forward method (in which the pain intensity score obtained before the first dose of rescue medication was carried forward to replace all pain intensity scores obtained after the rescue dose) and a 2-hour windowed last observation carried forward method (in which the pain intensity score obtained before each dose of rescue medication was carried forward to replace the pain intensity score collected in the following 2-hour window). The study was completed by 57 patients; 1 patient in the meloxicam 60 mg group withdrew, and 1 in the placebo group was withdrawn by the investigators.

Similar results were observed in another bunionectomy study comparing meloxicam IV 30 mg and placebo.⁷

Limitations: The study was conducted at only 1 center in the United States and had a small sample size. The length of hospital stay may not reflect the current standard of care for this type of surgery.

Reference: Singla et al⁸

Study Design: Phase 3, randomized, double-blind, placebo-controlled, multicenter study

Study Funding: Recro Pharma, Inc

Patients: A total of 219 adults undergoing abdominoplasty without collateral procedures. The surgical technique was standardized across all study sites. The anesthetic regimen used during the surgery included fentanyl and propofol, with or without volatile anesthetics or muscle relaxants. No local anesthetics were used. Immediate postoperative pain was treated with fentanyl 25 µg IV as needed. Patients had to have moderate or severe pain on a 4-point categorical pain rating scale and a score of 4 or greater on an 11-point NPRS within 3 hours of the end of surgery (last suture) on day 1; have an ability to answer questions, follow commands, and participate in pain assessment evaluations; be undergoing a surgical procedure lasting 3 hours or less; and have no significant deviations from surgical protocol, anesthetic protocol, or specified pretreatment analgesic regimen. Exclusion criteria included pregnancy or breastfeeding; BMI of 35 kg/m² or higher; evidence of respiratory insufficiency, clinically significant hypotension, bradycardia, or other significant abnormalities; need for more extensive surgical procedures (eg, liposuction, dissection above the umbilicus); allergy to meloxicam or other NSAIDs; elevated aminotransferases; history of HIV, hepatitis B, or hepatitis C; significant renal, hepatic, cardiovascular, metabolic, neurologic, or psychiatric conditions; history of migraine (within the past 12 months); myocardial infarction (MI) or coronary artery bypass graft (CABG) surgery within 12 months; active or recent bleeding (within 6 months); GI ulceration or bleeding; and a known bleeding disorder or use of agents affecting coagulation. Mean patient age was 40 years; 98.2% of patients were women; 63% were white and 33.3% were black or African American; and 39.7% were Hispanic or Latino. Mean baseline BMI was 26.7 kg/m², surgery duration was 1.366 hours, time from end of surgery to first dose of study medication was 0.854 hours, and baseline pain intensity score was approximately 7.3.

Intervention: Patients were randomized (1:1) to treatment with meloxicam 30 mg or placebo as an IV bolus injection over 15 to 30 seconds every 24 hours for up to 3 doses. Patients who had inadequate pain relief could receive rescue medication (oral oxycodone 5 mg) after the first study drug administration, then every 2 hours as needed. The third dose of study drug could be given at 48 hours (prior to discharge) at the discretion of the investigator. All patients received at least 1 dose of the study medication; 87.1% received a third dose of meloxicam IV and 78.9% received a third dose of placebo after the 48-hour assessment. Analgesic medications other than those prespecified for postoperative use (eg, opioids, acetaminophen, NSAIDs [other than aspirin for cardiovascular indications]) were prohibited during the treatment period.

Results

Primary End Point(s)

Pain intensity reduction was significantly greater with meloxicam IV compared to placebo based on SPID₂₄: Least squares (LS) mean reduction in SPID₂₄ was -4262.1 with meloxicam IV and -3535.7 with placebo (P = .0145).

Secondary End Point(s)

A statistically significant effect on pain intensity reduction was observed with meloxicam IV versus placebo for SPID₁₂ (−1763.8 with meloxicam IV vs 1471.1 with placebo; P = .0434), SPID₄₈ (−10 600 with meloxicam IV vs −8828.2 with placebo; P = .004), and SPID_24-48 (−6337.8 with meloxicam IV vs −5293.5 with placebo; P = .0028), but not for SPID₆ (−607 with meloxicam IV vs −510.9 with placebo; P = .1841).

PID from baseline was numerically lower with meloxicam IV than with placebo at every time point after 30 minutes. The meloxicam IV group showed a statistically significant difference in time to perceptible pain relief compared to placebo (median of 0.76 hours with meloxicam IV and 1.28 hours with placebo; P = .005); however, there was no statistically significant difference between the 2 groups for time to meaningful pain relief, which was approximately 3 hours in both groups.

Proportion of patients with 30% or greater overall reduction in pain from baseline within the first 24 hours after study drug administration was 71.8% with meloxicam IV and 56.9% with placebo (P = .0178).

Proportion of patients with 50% or greater overall reduction in pain from baseline within the first 24 hours after study drug administration was 28.2% with meloxicam IV and 18.3% with placebo (P = .0788).

PGA of pain control: A statistically significant difference favoring meloxicam IV over placebo was observed at 48 hours (P = .0027) but not at 24 hours. The proportion of patients reporting “good” or better pain control on PGA was numerically better for those treated with meloxicam IV compared to placebo at hour 24 (84.3% vs 67.3%) and at hour 48 (88.8% vs 83.4%).

At least 1 dose of rescue medication was used within the first 24 hours by 88.2% of patients in the meloxicam IV group and 89.9% of those in the placebo group (P = .6559). There was also no significant difference between the time to first dose of rescue medication (2.6 vs 2.45 hours, respectively); however, during hours 24 to 48, fewer patients in the meloxicam IV group required rescue analgesia (55.6% vs 75.7%; P = .0014). The number of rescue doses per subject was also significantly lower in the meloxicam IV group than in the placebo group: 3.66 versus 4.38 during hours 0 to 24 (P = .0275), 1.75 versus 2.72 during hours 24 to 48 (P = .0009), and 5.38 versus 7.07 during hours 0 to 48 (P = .0027).

Comments: The study was conducted at 4 sites in the United States. The primary efficacy analysis was conducted in the ITT population.

Limitations: The study was conducted at only 4 centers in the United States and had a small sample size. The length of hospital stay may not reflect the current standard of care for this type of surgery. Administration of analgesia was delayed until pain reached the threshold of moderate to severe.

A pooled analysis of the safety of meloxicam IV for treatment of moderate to severe acute pain (conducted in 2018) consisted of 1426 adults with moderate to severe postoperative pain and treated with at least 1 dose of IV meloxicam (5-60 mg) or placebo in 4 phase 2 studies and 3 phase 3 studies. In trials monitoring opioid use, meloxicam IV was often associated with reduced postoperative rescue opioid use. According to the pooled data, treatment-emergent adverse events occurred in 47% of meloxicam IV-treated patients and 57% of placebo-treated subjects. The most common adverse events across treatment groups included nausea, headache, vomiting, and dizziness.⁹

Several other studies evaluating meloxicam IV use are not described in the prescribing information but demonstrated adequate postoperative pain relief and decreased need for opioid analgesics in dental impaction surgery, open abdominal hysterectomy, major elective surgery, and orthopedic surgery.^10-13

Contraindications, Warnings, and Precautions

Contraindications

Meloxicam IV is contraindicated in patients with known hypersensitivity reactions to meloxicam or to any component of the formulation (povidone, sodium deoxycholate [deoxycholic acid], sucrose, and water for injection); in patients with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; in the setting of CABG surgery; and in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion.¹

Warnings and Precautions

The warnings and precautions associated with meloxicam IV are similar to those of injectable ketorolac (see Table 2).

Table 2.

Comparison of the Contraindications, Warnings, and Precautions Associated With Injectable Ketorolac and Meloxicam.^1,2

	Meloxicam	Ketorolac
Boxed warning
Cardiovascular risk	X
GI risk	X
Contraindications
Hypersensitivity to drug or other product components	X	X
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs	X	X
CABG surgery	X	X
Renal insufficiency, moderate to severe	X	X
Risk for renal failure due to volume depletion		X
Active peptic ulcer disease, recent GI bleeding or perforation, and history of peptic ulcer disease or GI bleeding		X
Prophylactic analgesic before any major surgery		X
Labor and delivery		X
Suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, and those at high risk of bleeding		X
Current use of aspirin or NSAID therapy (cumulative risk of NSAID-related adverse events)		X
Concomitant use of probenecid therapy		X
Concomitant use of pentoxifylline therapy		X
Neuraxial (epidural or intrathecal) administration		X
Warnings and precautions
Cardiovascular thrombotic events	X	X
Status post CABG surgery (increased risk of MI and stroke)	X	X
Post MI (increased risk of reinfarction, cardiovascular-related death, all-cause mortality)	X	X
GI effects (eg, risk of ulceration, bleeding, and perforation)	X	X
Heart failure and edema	X	X
Hepatotoxicity	X	X
Hypertension	X	X
Renal toxicity	X	X
Hyperkalemia	X
Anaphylactic reactions	X	X
Exacerbation of asthma related to aspirin sensitivity	X	X
Serious skin reactions	X	X
Premature closure of fetal ductus arteriosus	X	X
Hematologic toxicity (eg, anemia, bleeding)	X	X
Masking of inflammation and fever	X
Pregnancy	No adequate and well-controlled studies; avoid use in the third trimester	No adequate and well-controlled studies; use caution
Breastfeeding	Use caution	Use caution
Pediatric patients	Safety and efficacy not established	Safety and efficacy in patients <17 years not established

Meloxicam IV labeling includes a boxed warning regarding the risk of serious cardiovascular and GI events with use of NSAIDs.¹

Use of NSAIDs is associated with an increased risk of cardiovascular thrombotic events (eg, MI, stroke). Evidence regarding concurrent use of aspirin to mitigate this risk has been inconsistent; concurrent use of aspirin is associated with an increase in risk for serious GI events.¹

Two previous studies of another COX-2–selective NSAID for the treatment of pain following CABG surgery showed an increased incidence of MI and stroke. The use of NSAIDs in the setting of CABG is contraindicated for this reason.¹

Based on observational studies in the Danish National Registry, patients treated with NSAIDs in the post MI period may be an increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of NSAID treatment following MI. Therefore, meloxicam should be avoided in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent cardiovascular thrombotic events. If meloxicam is used in patients with a recent MI, monitor for signs of cardiac ischemia.¹

Treatment with NSAIDs, including meloxicam, can increase the risk of adverse GI effects (eg, inflammation; ulceration; bleeding; and perforation of the esophagus, stomach, or small or large intestine). These adverse events can occur at any time, with or without warning symptoms, in patients treated with meloxicam IV. The risk is increased in patients with a history of peptic ulcer disease and/or GI bleeding; other factors include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. The risk of GI bleeding is also increased in patients with advanced liver disease and/or coagulopathy.¹

Elevations in liver enzymes (eg, ALT, AST) have been reported in about 1% of patients treated with NSAIDs in clinical trials. Rare but sometimes fatal cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure, have been reported. Patients should be warned of this risk and informed of warning signs and symptoms (eg, nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).¹

New or worsening hypertension can occur during NSAID therapy, including with meloxicam IV. Hypertensive patients taking ACE inhibitors, thiazides, or loop diuretics may have impaired response to these therapies while taking NSAIDs.¹

There is an increased risk of heart failure with NSAID use, based on meta-analysis results; a Danish National Registry study of patients with heart failure showed NSAID use increased the risk of MI, hospitalization for heart failure, and death. In addition, fluid retention and edema can occur with NSAID therapy. The therapeutic effects of treatments used to treat these medical conditions (eg, diuretics, ACE inhibitors, angiotensin receptor blockers) may be blunted by meloxicam use. Therefore, meloxicam should be avoided in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If meloxicam is used in patients with severe heart failure, monitor for signs of worsening heart failure.¹

Renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury can occur during NSAID therapy, especially during long-term administration. Renal toxicity has also occurred in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID 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, or liver dysfunction, as well as those taking diuretics and ACE inhibitors or angiotensin receptor blockers and elderly patients. Volume status should be corrected in patients with dehydration or hypovolemia prior to initiation of meloxicam IV therapy. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.¹

Hyperkalemia may occur during NSAID therapy, including in patients without renal impairment.¹

Anaphylactic reactions have occurred with meloxicam therapy in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma.¹

Patients with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in patients with aspirin-sensitive asthma, meloxicam IV is contraindicated in patients with this type of aspirin sensitivity. If meloxicam is used in a patient with preexisting asthma (without known aspirin sensitivity), monitor for changes in the signs and symptoms of asthma.¹

NSAIDs, including meloxicam IV, can cause serious skin reactions (eg, exfoliative dermatitis, Stevens-Johnson Syndrome, toxic epidermal necrolysis). Meloxicam should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.¹

Meloxicam can cause premature closure of fetal ductus arteriosus. Use during pregnancy should be avoided starting at 30 weeks’ gestation (third trimester).¹

Anemia can occur with NSAID therapy, possibly due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. In the case of signs or symptoms of anemia, monitor hemoglobin or hematocrit.¹

The risk of bleeding events may be increased in with use of NSAIDs, including meloxicam IV. Comorbid conditions (eg, coagulation disorders) or concomitant use of warfarin, other anticoagulants, antiplatelet agents (eg, aspirin), SSRIs, or serotonin norepinephrine reuptake inhibitors (SNRIs) may increase bleeding risk.¹

The pharmacologic activity of meloxicam IV can mask signs of infection (eg, inflammation and/or fever).¹

Use of NSAIDs, including meloxicam IV, in pregnant women during the third trimester increases the risk of premature closure of the fetal ductus arteriosus. Meloxicam IV should be avoided during pregnancy starting at 30 weeks’ gestation. There are no adequate and well-controlled studies of meloxicam in pregnant women; data from observational studies regarding potential embryo-fetal risks of NSAID use during the first 2 trimesters are inconclusive.¹

There are no studies on the effects of meloxicam during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibited prostaglandin synthesis, caused delayed parturition, and increased the incidence of stillbirth.¹

There are no data regarding the presence of meloxicam IV or its metabolites in human milk or its effects on breastfeeding infants or milk production. Caution is advised.¹

Safety and efficacy of meloxicam IV have not been established in pediatric patients.¹

Use in elderly patients may be associated with an increased risk of NSAID-related serious cardiovascular, GI, and/or renal adverse reactions.¹

See Table 2 for a comparison of the contraindications, warnings, and precautions associated with the injectable formulations of ketorolac and meloxicam.^1,2

Adverse Reactions

The most common adverse reactions associated with meloxicam (incidence at least 2% and occurring at a greater frequency than with placebo) in controlled clinical trials included constipation (7.6% vs 6.1% with placebo), gamma-glutamyltransferase increased (2.8% vs 1.5% with placebo), and anemia (2.4% vs 1% with placebo).¹

Other adverse reactions (incidence less than 2%) reported with meloxicam in clinical trials included asthenia, back pain, edema, fatigue, hyperthermia, infusion-site reactions (including pain, pruritus, phlebitis, and thrombosis), muscle spasms, noncardiac chest pain, pyrexia, vaginal discharge, weight decrease, disturbance in attention, migraine, presyncope, somnolence, syncope, abdominal discomfort, abdominal distension, abdominal pain, diarrhea, dry mouth, epigastric discomfort, flatulence, frequent bowel movements, gastritis, gastroesophageal reflux, GI pain, rectal hemorrhage, tachycardia, increased bleeding time, neutropenia, thrombocytosis, cellulitis, gastroenteritis, urinary tract infection, vulval abscess, abnormal liver function test, hypokalemia, hypomagnesemia, incision-site hemorrhage, incision-site rash, wound dehiscence, wound hematoma, confusion, hallucination, insomnia, dyspnea, epistaxis, hypoxia, oropharyngeal pain, contact dermatitis, ecchymosis, rash, pollakiuria, and urinary retention.¹

Drug Interactions

Drug interactions with meloxicam are similar to those reported with other NSAIDs.

Concomitant use of meloxicam with anticoagulants (eg, warfarin), antiplatelet agents (eg, aspirin), SSRIs, or SNRIs may increase the risk of bleeding.¹

Analgesic doses of aspirin and low-dose aspirin for cardiac prophylaxis may increase the risk of bleeding when used with meloxicam. Meloxicam is also not a substitute for low-dose aspirin for cardiovascular protection.¹

Concomitant use with other NSAIDs or salicylates (eg, diflunisal, salsalate) may increase the risk of GI toxicity.¹

NSAIDs may diminish the antihypertensive effect of ACE inhibitors, angiotensin receptor blockers, or beta-blockers (including propranolol). In addition, the combination of NSAIDS and these drugs may cause deterioration of renal function in patients who are elderly, volume depleted, or have preexisting renal impairment.¹

Use of NSAIDS with loop diuretics (eg, furosemide) or thiazide diuretics may reduce the natriuretic effect of the diuretic. While this effect has not been observed in studies with furosemide agents and meloxicam, patients should still be monitored for a decreased diuretic effect.¹

Use with lithium may result in elevated lithium plasma levels due to decreased lithium clearance.¹

Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (eg, neutropenia, thrombocytopenia, renal dysfunction).

Concomitant use of meloxicam IV may increase the risk of pemetrexed-related toxicities (eg, myelosuppression, renal and GI toxicity).¹

Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.¹

Concomitant use of CYP2C9 inhibitors (eg, amiodarone, fluconazole, sulphaphenazole) may increase the plasma levels of meloxicam due to reduced metabolic clearance.¹

Recommended Monitoring

Complete blood cell count and chemistry profile; occult blood loss; periodic liver function tests; renal function (urine output, serum urea nitrogen and creatinine); signs or symptoms of GI bleeding; blood pressure (baseline and periodically during therapy); and periodic ophthalmologic exam with long-term therapy.¹

Monitoring of renal function is recommended in patients with preexisting renal or hepatic impairment, heart failure, dehydration, or hypovolemia.¹

If anemia is suspected, monitor hemoglobin and/or hematocrit.¹

All patients should be monitored for signs of bleeding.¹

Dosing

The recommended meloxicam IV dose is 30 mg once daily. The injection should be given as an IV bolus over 15 seconds. Duration of treatment should be for the shortest period consistent with individual patient treatment goals. When initiating meloxicam IV, monitor patient analgesic response. If pain control is not adequate for the entire 24-hour dosing interval, a short-acting, non-NSAID, immediate-release analgesic should be used.¹

To reduce the risk of renal toxicity, it is important that the patient be well hydrated before the administration of meloxicam IV.¹

Meloxicam IV has not been studied in patients with hepatic impairment; no dosage adjustment is necessary in patients with mild to moderate hepatic impairment.¹

The pharmacokinetics of meloxicam IV were similar in patients with mild renal impairment and in healthy young subjects. Patients with moderate or severe renal impairment were not evaluated; meloxicam IV is not recommended for this population. Meloxicam IV is contraindicated in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion.¹

Poor metabolizers of CYP2C9 substrates may have higher than anticipated meloxicam plasma concentrations. A lower dose of meloxicam may be necessary to decrease the risk of dose-related adverse effects.¹

Product Availability and Storage

Meloxicam IV was approved by the FDA on February 20, 2020. Meloxicam IV is available as a 1 mL fill (30 mg/mL) in a single-dose 2 mL vial.¹

Store meloxicam IV vials at 15°C to 25°C (59°F-77°F), with excursions permitted between 4°C to 30°C (40°F-86°F). The vials should not be frozen and should be protected from light.¹

Drug Safety/REMS

No REMS is required for meloxicam IV.¹

Conclusion

Meloxicam IV is approved for the management of moderate to severe pain in adults, for use alone or in combination with non-NSAID analgesics. The time to meaningful pain relief after IV bolus administration is 2 to 3 hours; therefore, non-NSAID analgesics with rapid onset of effect may be needed, for example, upon anesthetic emergence or resolution of local or regional anesthetic blocks. In addition, some patients may not experience adequate analgesia for the entire 24-hour dosing interval and may require administration of a short-acting, non-NSAID, immediate-release analgesic. There are no head-to-head comparison studies with injectable ketorolac.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Danial E. Baker

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