Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: REX Medical Ltd, Unit 18/273 Neilson Street, Onehunga, Auckland 1061, PO Box 18-119, Glen Innes 1743, AUCKLAND Ph (09) 574 6060 Fax (09) 574 6070
Pharmacotherapeutic group: Anti-inflammatory and Anti-rheumatic products, Non-steroids, Oxicams
ATC code: M01AC06
Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, which has shown anti-inflammatory, analgesic and antipyretic properties in animals. Meloxicam showed potent anti-inflammatory activity in all standard models of inflammation. A common mechanism for the above effects may exist in the ability of meloxicam to inhibit the biosynthesis of prostaglandins, known mediators of inflammation.
Comparison of the ulcerogenic dose and the anti-inflammatory effective dose in the rat adjuvant arthritis model confirmed a superior therapeutic margin in animals over standard NSAIDs. In vivo, meloxicam inhibited prostaglandin biosynthesis more potently at the site of inflammation than in the gastric mucosa or the kidney.
These differences are thought to be related to a selective inhibition of COX-2 relative to COX-1 and it is believed that COX-2 inhibition provides the therapeutic effects of NSAIDs whereas inhibition of constitutive COX-1 may be responsible for gastric and renal side effects.
The COX-2 selectivity of meloxicam has been confirmed both in vitro and ex vivo in a number of test systems. In the human whole blood assay, meloxicam has been shown in vitro to inhibit COX-2 selectively. Meloxicam (7.5mg and 15mg) demonstrated a greater inhibition of COX-2 ex vivo, as demonstrated by a greater inhibition of lipopolysaccharide-stimulated PGE2 production (COX-2) as compared with thromboxane production in clotting blood (COX-1). These effects were dose-dependent. Meloxicam has been demonstrated to have no effect on either platelet aggregation or bleeding time at recommended doses ex vivo, while indomethacin, diclofenac, ibuprofen and naproxen significantly inhibited platelet aggregation and prolonged bleeding.
In clinical trials, gastro-intestinal adverse events overall were reported less frequently with meloxicam 7.5mg and 15mg than with the NSAIDs with which it has been compared, due predominantly to a lower reporting incidence of events such as dyspepsia, vomiting, nausea and abdominal pain. There is no single study powered adequately to detect statistically differences in the incidence of clinically significant upper gastro-intestinal perforation, obstruction, or bleeds between meloxicam and other NSAIDs. A pooled analysis has been conducted involving patients treated with meloxicam in 35 clinical trials in the indications osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Exposure to meloxicam in these trials ranged from 3 weeks to one year (most patients were enrolled in one-month studies). Almost all patients participated in trials that permitted enrolment of patients with a prior history of gastro-intestinal perforation, ulcer or bleed. The incidence of clinically significant upper gastro-intestinal perforation, obstruction, or bleed (POB) was assessed retrospectively following independent blinded review of cases. Results are shown in the following table.
Cumulative risk of POBs for meloxicam 7.5mg and 15mg from clinical trials compared to diclofenac and piroxicam (Kaplan-Meier estimates):
| TREATMENT Daily dose | Interval (days) | Patients at interval midpoint | POBs within interval | Risk (%) | 95% confidence interval |
|---|---|---|---|---|---|
| Meloxicam 7.5mg | 1 - <30 | 9636 | 2 | 0.02 | 0.00 – 0.05 |
| 30 - <91 | 551 | 1 | 0.05 | 0.00 – 0.13 | |
| Meloxicam 15mg | 1 - <30 | 2785 | 3 | 0.12 | 0.00 – 0.25 |
| 30 - <91 | 1683 | 5 | 0.40 | 0.12 – 0.69 | |
| 91 - <182 | 1090 | 1 | 0.50 | 0.16 – 0.83 | |
| 182 - <365 | 642 | 0 | 0.50 | ||
| Diclofenac 100mg | 1 - <30 | 5110 | 7 | 0.14 | 0.04 – 0.24 |
| 30 - <91 | 493 | 2 | 0.55 | 0.00 – 1.13 | |
| Piroxicam 20mg | 1 - <30 | 5071 | 10 | 0.20 | 0.07 – 0.32 |
| 30 - <91 | 532 | 6 | 1.11 | 0.35 – 1.86 |
Meloxicam is well absorbed from the gastrointestinal tract, which is reflected by a high absolute bioavailability of 89% following oral administration.
Following single dose administration of meloxicam, mean maximum plasma concentrations are achieved within 5-6 hours for the tablets.
With multiple dosing, steady state conditions were reached within 3 to 5 days. Once daily dosing leads to drug plasma concentrations with a relatively small peak-trough fluctuation in the range of 0.4 – 1.0 ฮผg/mL for 7.5 mg doses and 0.8 – 2.0 ยตg/mL for 15mg doses, respectively (Cmin and Cmax at steady state, respectively). Maximum plasma concentrations of meloxicam at steady state, are achieved within five hours for the tablet.
Continuous treatment for longer periods (e.g. six months) did not point to any changes in pharmacokinetics compared to steady state pharmacokinetics after two weeks of oral treatment with 15 mg meloxicam/day. Any differences after treatment longer than six months are thus rather unlikely.
Meloxicam is very strongly bound to plasma proteins, essentially albumin (99%). Meloxicam penetrates into synovial fluid to give concentrations approximately half of those in plasma. Volume of distribution is low, on average 11 L. Interindividual variation is the order of 30-40%.
Meloxicam undergoes extensive hepatic biotransformation. Four different metabolites of meloxicam were identified in urine, which are all pharmacodynamically inactive. The major metabolite, 5'-carboxymeloxicam (60% of dose), is formed by oxidation of an intermediate metabolite 5'-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP 2C9 plays an important role in this metabolic pathway, with a minor contribution from the CYP 3A4 isoenzyme. The patient’s peroxidase activity is probably responsible for the other two metabolites, which account for 16% and 4% of the administered dose respectively.
Meloxicam is excreted predominantly in the form of metabolites, and occurs to equal extent in urine and faeces. Less than 5% of the daily dose is excreted unchanged in faeces, while only traces of the parent compound are excreted in urine. The mean elimination half-life is about 20 hours. Total plasma clearance amounts on average to 8mL/min.
Meloxicam demonstrates linear pharmacokinetics in the therapeutic dose range of 7.5 mg to 15 mg following per oral or intramuscular administration.
Neither hepatic insufficiency, nor mild to moderate renal insufficiency have a substantial effect on meloxicam pharmacokinetics. In terminal renal failure, the increase in the volume of distribution may result in higher free meloxicam concentrations, and a daily dose of 7.5 mg must not be exceeded.
Mean plasma clearance at steady state in elderly subjects was slightly lower than that reported for younger subjects.
In a study of 36 children, kinetic measurements were made in 18 children at doses of 0.25mg/kg BW. Maximum plasma concentration Cmax (34%) as well as AUC0โ (-28%) tended to be lower in the younger age group (aged 2 to 6 years, n=7) as compared to the older age group (7 to 14 years, n=11) while weight normalised clearance appeared to be higher in the younger age group. A historical comparison with adults revealed that plasma concentrations were at least similar for older children and adults. Plasma elimination half-lives (13h) were similar for both groups and tended to be shorter than in adults (15-20h).
An extensive toxicological program confirmed that meloxicam has an acceptable safety profile.
Oral LD50 values ranged from about 98 mg/kg in female rats up to >800 mg/kg in minipigs. Intravenous values ranged from about 52 mg/kg in rats to 100 – 200 mg/kg in minipigs. Main signs of toxicity included reduced motor activity, anaemia, and cyanosis. Most deaths occurred as a consequence of gastric ulcers and subsequent perforation leading to peritonitis.
Repeated dose toxicity studies in rats and minipigs showed characteristic changes reported with other NSAIDs e.g. gastrointestinal ulceration and erosions, and in the long term studies, renal papillary necrosis. Gastrointestinal side effects were observed at oral doses of 1mg/kg and higher in rats, and of 3 mg/kg and above in minipigs. After intravenous administration doses of 0.4 mg/kg in rats and 9 mg/kg in minipigs caused gastrointestinal lesions. Renal papillary necrosis occurred only in rats at doses of 0.6 mg/kg or higher after lifetime exposure to meloxicam.
Studies of toxicity on reproduction in rats and rabbits did not reveal teratogenicity up to oral doses of 4 mg/kg in rats and 80 mg/kg in rabbits. Oral reproductive studies in the rat have shown a decrease of ovulations and inhibition of implantations and embryotoxic effects (increase of resorptions) at maternotoxic dose levels at 1 mg/kg and higher.
The affected dose levels exceeded the clinical dose (7.5 – 15 mg) by a factor of 10 to 5-fold on an mg/kg dose basis (75 kg person). Fetotoxic effects at the end of gestation, shared by all prostaglandin synthesis inhibitors, have been described. Nonclinical studies indicate that meloxicam can be found in the milk of nursing rats.
Meloxicam was not mutagenic in the Ames test, the host-mediated assay, and a mammalian gene mutation assay (V79/HPRT), nor is it clastogenic in the chromosomal aberration assay in human lymphocytes and the mouse bone marrow micronucleus test.
Carcinogenicity studies in rats and mice did not show a carcinogenic potential up to dose levels of 0.8 mg/kg in rats and 8 mg/kg in mice. In these studies, meloxicam was chondro-neutral, i.e. it did not damage the articular cartilage following long-term exposure.
Meloxicam did not induce immunogenic reactions in tests on mice and guinea pigs. In several tests, meloxicam proved to be less phototoxic than older NSAIDs but similar in this respect to both piroxicam and tenoxicam.
In local tolerance studies; meloxicam was well tolerated by all tested routes of administration; intravenous, intramuscular, rectal, dermal, and ocular administration.
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