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Meloxicam (Mobic) for relief of osteoarthritis symptoms

October 1, 2000

Meloxicam (Mobic) for relief of osteoarthritis symptoms

By Joy Lee, PharmD candidate
Medical University of South Carolina
Charleston

Indications:
Meloxicam, manufactured by Boehringer Ingelheim in Ridgefield, CT, is indicated for relief of the signs and symptoms of osteoarthritis.1

Pharmacology:
Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that exerts its action by blocking cyclooxygenase (COX-1 and -2), which prevents the synthesis of several prostaglandins. Prostaglandins are responsible in part for the development of pain and inflammation in a variety of medical disorders.2 Meloxicam demonstrates anti-inflammatory, analgesic, and antipyretic effects.3

NSAIDs can cause gastrointestinal side effects due to a variety of mechanisms related to direct topical or systemic effects.4,5 The two COX isoforms, COX-1 and COX-2, have led to the discovery that the mechanisms for NSAID efficacy and toxicity can be separated by producing NSAIDs that are more specific. COX-2 is the major isoenzyme involved in inflammatory pain conditions. Meloxicam is an enolic acid NSAID and is more selective for COX-2 than older NSAIDs. However, unlike celecoxib, meloxicam is not categorized as a COX-2 inhibitor.1

Pharmacokinetics:

Meloxicam concentrations peak two hours after intramuscular (IM) administration and five to 11 hours after oral administration. Oral bioavailability is approximately 95%. The volume of distribution is 10 to 15 L. Meloxicam is about 99% bound to serum protein. The liver metabolizes meloxicam to inactive metabolites. The cytochrome P450 2C isoenzymes, especially CYP2C9, are responsible for most of the drug's metabolism.

Meloxicam is excreted unchanged (0.25%) in the urine. The elimination half-life is about 15 hours after IV administration and about 20 hours after IM administration. Following oral administration, the elimination half-life is 13.2 to 24 hours. The systemic clearance is 8.6 to 11.5 mL/min following IV administration and 8.51 mL/min following IM administration.1

Pharmacokinetic differences between young adult and elderly patients are not significant enough to warrant dose adjustment. Older women often have higher plasma concentrations (47%) than young women, but a change in dose has not been recommended. The dose of meloxicam does not require adjustment in patients with mild (CrCl 41 to 60 mL/min) to moderate (CrCl 20 to 40 mL/min) renal impairment. Meloxicam has not been studied in patients with severe renal impairment and should not be used in those patients. Hemodialysis does not remove meloxicam.1,3

Selected clinical trials:

C. Hawkey and colleagues conducted a trial to compare meloxicam and diclofenac.4 A double-blind, prospective randomized trial evaluating 9,323 patients with symptomatic osteoarthritis over 28 days, it was designed to compare the tolerability, safety, and efficacy of the two agents. Four thousand six hundred thirty-five patients received meloxicam 7.5 mg by mouth daily; 4,688 patients received diclofenac 100 mg sustained release (SR) by mouth daily.4

Tolerability was assessed by the patient and physician using a four-point verbal rating scale (VRS). Adverse events were reported by patients and physicians. Using a visual analogue scale (VAS), the patients rated their pain on active movement and at rest. Measurements were taken at the start and end of the study. Global efficacy was assessed using a VRS (1 = good, 2 = satisfactory, 3 = unsatisfactory, 4 = bad). The patients assessed the change in their arthritic condition using a four-point VRS (1 = improved, 2 = satisfactory, 3 = unsatisfactory, 4 = bad). Changes in patient status during the trial also were assessed (1 = improved, 2 = unchanged, 3 = deteriorated). Withdrawals due to lack of efficacy were taken into consideration.4

Twenty-seven percent (n = 2,517) of patients receiving meloxicam reported adverse effects, compared with 32% of patients on diclofenac (n = 2,983) (p < 0.001). Thirteen percent (n=1,211) of patients taking meloxicam experienced GI adverse events vs. 19% (n = 1,771) of patients taking diclofenac (p < 0.001).4

Both treatments were similarly effective in reducing pain on active movement of joints affected by OA and pain at rest.4 The reasons for withdrawal from study for patients on meloxicam (n = 4,635) were as follows: adverse events, 5.48% (n = 254); lack of efficacy 1.73% (n = 80).

The reasons for withdrawal for patients on diclofenac (n = 4,688) were as follows: adverse events, 7.96% (n = 373); lack of efficacy 1.05% (n = 49). This trial confirms the results of earlier studies showing that meloxicam has a superior GI tolerability profile (13% of patients experiencing GI adverse events vs. 19% of patients on diclofenac) compared with other NSAIDs (p < 0.001).4

Dequeker and colleagues conducted the Safety and Efficacy Large-Scale Evaluation of COX-inhibiting Therapies Trial (SELECT) in osteoarthritis.6 SELECT was a prospective, randomized, double-blind, double-dummy trial conducted in 12 countries. This study compared two regimens:

  • meloxicam 7.5 mg by mouth once daily for 28 days;
  • piroxicam 20 mg by mouth once daily for 28 days.

Participants were recruited from general practice and had OA affecting the hip, knee, hand, or vertebral spine. The primary endpoints of this trial were the incidence of adverse events (especially those involving the gastrointestinal tract) and efficacy. Endpoints were assessed using reports of adverse effects and a VAS for assessment of pain reduction on movement.6

Fewer adverse effects were reported by patients taking meloxicam (22.5%, n = 972) than by those taking piroxicam (27.9%, n = 1,210)(p < 0.001). Specifically, gastrointestinal adverse events occurred in 10.3% (n = 445) of patients on meloxicam and in 15.4% (n = 665) of patients taking piroxicam (p < 0.001).6 Efficacy of the two drugs was similar according to the VAS, which assessed reduction in pain on active movement.

The average pain reduction with meloxicam was 47% and 45% with piroxicam. Seventy-five patients (1.7%) on meloxicam and 68 patients (1.6%) on piroxicam withdrew from the study due to lack of efficacy.6

Participation requirements

Lipscomb and colleagues conducted a double-blind, placebo-controlled study comparing the effects of meloxicam, piroxicam, and placebo on esophageal, gastric, and duodenal mucosal injury, mucosal blood flow, and prostaglandin production.7 Lipscomb’s study compared three regimens:

  • meloxicam, 15 mg by mouth, daily for 28 days;
  • piroxicam, 20 mg by mouth, daily for 28 days;
  • placebo, by mouth, daily for 28 days.

Participants were required to be healthy, between 18 and 50 years of age, with no history of gastrointestinal disease or NSAID consumption within the previous four weeks. The primary endpoints of this trial were mucosal damage, mucosal blood flow, and mucosal prostaglandin E2 concentrations. Mucosal damage and blood flow were measured using gastroscopy; biopsies were taken from mucosa in the esophagus, gastric body, antrum, and duodenal bulb. Those samples were assessed for histology and prostaglandin E2 content.

The researchers used a complex method of determining prostaglandin E2 concentrations. Mucosal specimens were frozen after biopsy and sent to TNO Nutrition and the Food Research Institute in the Netherlands. The samples were homogenized and centrifuged for a second assay run.7

Assessments were made on days No. 1, 7, and 28 of therapy. Significant macroscopic gastric mucosal damage occurred within 24 hours of the first dose of piroxicam. The damage score increased from 0 to 2.5 on day No. 1, was at 2 on day No. 7, and was 0 at day No. 28 (p = 0.02). Seven subjects sustained acute injury; damage was resolved by the end of the study for six of these seven patients.

In the meloxicam and placebo groups, no significant macroscopic gastric damage was observed. Seven subjects using placebo and five using meloxicam sustained minor damage to the gastric mucosa. Piroxicam caused more acute gastric damage than did meloxicam; patients on piroxicam had a score of 2.5 on the modified Lanza grading scale for gastric mucosal damage, and patients on meloxicam scored a 0.1 (p = 0.06).

Mucosal blood flow was similar at the start of the study for all three groups, and no significant changes occurred during the study. No changes in gastric mucosal prostaglandin concentration were observed. No serious adverse events occurred during the study; however, 73% of participants on meloxicam, 71% of participants on piroxicam, and 67% of participants on placebo experienced at least one adverse event. Nausea and dyspepsia were the most commonly reported adverse effects.7

This study supports that meloxicam causes less acute damage to the upper gastrointestinal tract than piroxicam does and that meloxicam is comparable to placebo.7

Adverse reactions:

Piroxicam has been studied in more than 13,000 patients. Patients taking meloxicam have reported edema (up to 5%), malaise/flu-like symptoms (up to 5%), headache and dizziness (up to 8%), abdominal pain (up to 3%), dyspepsia (5%), nausea (4%), flatulence (3%), diarrhea (3% to 8%), and rash (up to 3%).1,3 Patients have developed elevated liver enzymes. However, the same effect was seen with placebo. Reductions in platelet count, hemoglobin, and hematocrit have been reported, as have elevations in creatinine, uric acid, and urea. Proteinuria, hematuria, and leukocyturia have been reported.2

Pregnancy/lactation:

Meloxicam is categorized under pregnancy category C; D in the third trimester. That means there are no adequate and well-controlled studies in pregnant women and, in the third trimester, positive evidence of human fetal risk exists, but benefits in certain situations may outweigh the risks. Meloxicam, as well as other NSAIDs, should be avoided in late pregnancy to avoid the risk of premature closure of the ductus arteriosus.3

Contraindications:

Meloxicam is contraindicated in patients who have hypersensitivity to meloxicam or any of its components, aspirin, or other NSAIDs. Patients who have experienced asthma, urticaria, or allergic-type reactions after taking NSAIDs or aspirin should avoid meloxicam. Severe, though rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in these patients.3

Warnings:

Serious gastrointestinal toxicity (such as inflammation, ulceration, bleeding, perforation of the stomach, small intestine, or large intestine) can occur at any time, with or without warning signs in patients taking NSAIDs. Minor upper gastrointestinal problems are common and also may occur at any time while a patient is taking an NSAID. Patients and physicians should remain alert for symptoms of ulceration and bleeding.

NSAIDs should be prescribed with extreme caution in patients with a history of ulcer disease or gastrointestinal bleeding. To minimize the potential risk for an adverse gastrointestinal event, the lowest effective dose should be used for the shortest possible duration.3

Similar to other NSAIDs, anaphylactoid reactions have occurred in patients without prior exposure to meloxicam. Patients with the aspirin triad (such as asthma, rhinitis [with or without nasal polyps], and severe, potentially fatal bronchospasm) should not be given meloxicam. Patients should be educated to seek emergency help when an anaphylactoid reaction occurs.3

Dosage and administration:

The usual starting dose of meloxicam is 7.5 mg given orally once daily for the treatment of arthritis. The lowest dose of meloxicam should be sought for each patient. Some patients may benefit from a dose increased to 15 mg once daily. The maximum recommended daily dose of meloxicam is 15 mg. Meloxicam can be taken without regard to timing of antacids or meals.3

Drug interactions:

The half-life of meloxicam is decreased by cholestyramine, and the clearance is increased. Coadministration should be avoided. Meloxicam does not have a significant effect on the pharmacokinetics of furosemide, digoxin, methotrexate, or warfarin. Antacids (such as aluminum and magnesium hydroxide), cimetidine, and aspirin have minimal or no effect on pharmacokinetics; no dosage adjustment is required.3 The effects of ACE inhibitors may be diminished by NSAID co-administration. Patients should avoid concurrent use of corticosteroids, hydralazine, lithium, and thiazide diuretics with meloxicam.8

Drug-food interactions:

Ethanol may enhance gastric mucosal irritation when used by patients taking meloxicam. Administration of meloxicam after a high fat breakfast (75 g of fat) did not affect extent of absorption. No interaction was detected with concomitant administration of antacids.

Dosage forms:

Meloxicam is available as a biconvex, yellow, round, uncoated tablet containing 7.5 mg of the drug. On one side of the tablet, the Boehringer Ingelheim logo is impressed; the other side is engraved with the letter M.3

Potential for medication errors:

Piroxicam sounds similar to meloxicam. Names that sound similar to Mobic include Mavik (trandolapril), Moban (molindrone HCl), Mobidin (magnesium salicylate), and Modicon (ethinyl estradiol/ norethindrone).

Discussion:

An estimated 15.8 million adults in the United States, or approximately 12% of those between ages 25 and 74, have signs and symptoms of osteoarthritis, a disease causing cartilage breakdown in the joints, resulting in pain and stiffness.5 Meloxicam has been studied in more than 13,000 patients in clinical trials and has been shown to be effective in relieving osteoarthritis symptoms with a gastrointestinal adverse effect profile similar to placebo.2

Several agents appear on hospital formularies for the treatment of osteoarthritis, including choline magnesium salicylate, diclofenac, ibuprofen, aspirin, naprosyn, acetaminophen, celecoxib, and rofecoxib. Meloxicam has been directly compared with diclofenac and piroxicam in clinical trials, which support that meloxicam has comparable efficacy and reduced gastrointestinal adverse effects.4,6,7 However, it has not been compared with choline magnesium salicylate, acetaminophen, ibuprofen, aspirin, naprosyn, celocoxib, or rofecoxib.

Celecoxib and rofecoxib are NSAIDs that are selective for COX-2 and may cause less bleeding and gastrointestinal toxicity than traditional NSAIDs. Meloxicam is an NSAID that has been shown to cause fewer gastrointestinal side effects and exhibit comparable efficacy to other NSAIDs. Nevertheless, further trials need to be conducted comparing the safety and efficacy of meloxicam and other NSAIDs.

References

  1. Burnham TH, ed. Drug Facts and Comparisons. St. Louis; Wolters Kluwer Co.; 2000.
  2. Gelman CR, Rumack BH, Hutchison TA, eds. Drugdex System. Englewood, CO: Micromedex Inc.; August 2000.
  3. Mobic package insert. Ridgefield, CT: Boehringer Ingelheim; 2000.
  4. Hawkey C, Kahan A, Steinbruck K, et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. Br J Rheumatology 1998; 37:937-945.
  5. DiPiro JT, ed. Pharmacotherapy: A Pathophysiologic Approach. 4th ed. Stamford, CT: McGraw-Hill Professional Publishing; 1999.
  6. Dequeker J, Hawkey C, Kahan A, et al. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: Results of the safety and efficacy large-scale evaluation of COX-inhibiting therapies (SELECT) trial in osteoarthritis. Br J Rheumatology 1998; 37:946-951.
  7. Lipscomb GR, Wallis N, Armstrong G, Rees WD. Gastrointestinal tolerability of meloxicam and piroxicam: A double-blind placebo-controlled study. Br J Clin Pharmacol 1998; 46:133-147.
  8. Meloxicam [serial on-line] Lexi-Comp [cited 2000 July 7]; 1(1). Available from www.lexi.com/html/chapter/ mono/hf080330.htm.