Revision Year: 2022 Publisher: Alphapharm Pty Ltd trading as Viatris, Level 1, 30 The Bond, 30-34 Hickson Road, Millers Point NSW 2000 www.viatris.com.au Phone: 1800 274 276
Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, which has shown antiinflammatory, analgesic and antipyretic properties in animals. Meloxicam showed 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, by inhibition of cyclooxygenase (COX).
Comparison of the ulcerogenic dose and the anti-inflammatory effective dose in rat adjuvant arthritis model confirmed a greater therapeutic margin in animals over other NSAIDs (piroxicam, diclofenac, naproxen, flurbiprofen). In rats, meloxicam showed greater inhibitory effect on prostaglandin biosynthesis at the site of inflammation than in the gastric mucosa or the kidney.
Selective inhibition of the cyclooxygenase-2 (COX-2) isoenzyme, relative to COX-1, by meloxicam has been demonstrated in vitro on various cell systems: guinea pig macrophages, bovine aortic endothelial cells (for testing of COX-1 activity), mouse macrophages (for testing for COX-2 activity) and human recombinant enzymes expressed in cos-cells and in human whole blood.
The efficacy of meloxicam in treating the symptoms of osteoarthritis and rheumatoid arthritis has been confirmed in several clinical trials.
Two clinical studies of six months duration were performed in patients with osteoarthritis of the hip or knee. In the first study, the efficacy of meloxicam 15 mg (n=306) and piroxicam 20 mg (n=149) were found to be comparable, using as efficacy endpoints improvement in overall pain, pain on movement, global efficacy, change in duration of inactivity and change in quality of life score. In the second study, the efficacy of meloxicam 7.5 mg (n=169) was found to be comparable to that of diclofenac 100 mg SR (n=167) using similar endpoints.
Once daily dosing of meloxicam 7.5 mg (n=153) and 15 mg (n=156) showed a consistently more efficacious response than placebo (n=155) in a 12-week trial in patients with osteoarthritis of the knee or hip. Efficacy was measured by global assessment of disease activity, global assessment of pain and arthritic condition, as measured by the WOMAC (Western Ontario and McMaster University) Osteoarthritis Index. Both doses of meloxicam were also shown to be comparable to diclofenac 50 mg twice daily (bid) (n=152) with regard to efficacy, with a lower incidence of gastrointestinal (GI) adverse events when compared to diclofenac.
Two large scale, randomised, active-controlled clinical studies of four weeks duration were conducted in patients with osteoarthritis of the hand, hip, knee or spine. In the first study (MELISSA), the effects of meloxicam 7.5 mg (n=4,635) were compared against the effects of diclofenac 100 mg SR (n=4,688). In the second study (SELECT), the effects of meloxicam 7.5 mg (n=4,320) were compared against the effects of piroxicam 20 mg (n=4,336). The results from both studies indicated that meloxicam 7.5 mg was as efficacious as diclofenac 100 mg SR and piroxicam 20 mg in the treatment of symptomatic osteoarthritis.
The use of meloxicam for the symptomatic treatment of rheumatoid arthritis was evaluated in a double-blind controlled trial involving 894 patients treated for 12 weeks. Meloxicam (7.5 mg, 15 mg and 22.5 mg daily) was compared to placebo, with diclofenac (75 mg twice daily) compared to placebo to establish trial sensitivity. The primary endpoints were number of painful or tender joints; number of swollen joints; investigator’s global assessment of disease activity; patient’s global assessment of disease activity and patient’s assessment of pain. For all five primary endpoints, the meloxicam 7.5 mg group was significantly better than placebo for both mean on trial and last observation. The meloxicam 15 mg group was significantly better for three of five primary endpoints, excluding painful and swollen joints. In patients who had flared at baseline tender joints, the meloxicam 15 mg group differed almost significantly from the placebo group (p<0.05 not met due to the lower number of patients).
A second trial also investigated the use of meloxicam for the symptomatic treatment of rheumatoid arthritis. This double-blind placebo-controlled trial used three doses of meloxicam (7.5 mg, 15 mg and 22.5 mg daily), in patients with rheumatoid arthritis over a 12-week period. A total of 898 patients were treated with meloxicam. The primary endpoint in this study was the American College of Rheumatology (20%) response criterion (ACR20) response rate, a composite measure of clinical, laboratory and functional measures of rheumatoid arthritis response. For this parameter, all three doses of meloxicam were more effective than placebo for the duration of the study. For the endpoints that comprised the ACR20 criteria, each of the meloxicam groups was superior to placebo at all visits except for C-reactive protein. Efficacy reached a plateau at the meloxicam 15 mg dose (see Table 4). The overall incidence and severity of adverse events was similar among all three meloxicam groups.
Table 4. Analysis of ACR 20 Response Rate for Evaluable Patients at 12-weeks:
| p-value# | ||||||
|---|---|---|---|---|---|---|
| Study Phase | Treatment | Total | Responder1* N (%) | Placebo | Meloxicam 7.5 mg | Meloxicam 15 mg |
| Week 12 | Placebo | 292 | 97 (33.2) | |||
| Meloxicam 7.5 mg | 306 | 138 (45.1) | 0.0008 | |||
| Meloxicam 15 mg | 293 | 158 (53.9) | 0.0000 | 0.0439 | ||
1 The primary efficacy end-point was the ACR 20. A responder was a patient with a response defined as: ≥20% improvement in both tender joint count and swollen joint count and at least three of the following: ≥20% improvement in: patient pain assessment; patient global (overall) assessment; physician global (overall) assessment; the modified health assessment questionnaire; C-reactive protein.
* Early terminations were considered as non-responders from the termination date.
# Obtained from Cochran-Mantel-Haenszel test stratified by centre.
The data from both studies indicate that meloxicam is effective and safe for the treatment of patients with rheumatoid arthritis.
Meloxicam is well absorbed from the gastrointestinal tract following oral administration (absolute bioavailability: 89%). Once daily dosing leads to mean drug plasma concentrations with a relatively narrow Cmaxss – Cminss window in the range of 0.3 to 1.0 µg/mL for 7.5 mg doses or 0.7 to 1.9 µg/mL for 15 mg doses. However, values outside of this range have been encountered (Cmin and Cmax at steady-state respectively). The absorption is not altered by concomitant food intake. Maximum plasma concentrations were regularly achieved between 5 to 6 hours following tablet administration, irrespective of concomitant food consumption. Drug concentrations are dose-proportional for oral 7.5 mg and 15 mg doses, respectively. Steady-state conditions are achieved in 3 to 5 days.
Volume of distribution is low (on average, 16 L). The volume of distribution following administration of multiple oral doses of meloxicam (7.5 to 15 mg) ranged from 10.1 L to 17.0 L (CV 24.6 to 39.9%). In plasma, more than 99% is bound to plasma proteins. Meloxicam penetrates well into synovial fluid to give concentrations approximately half those in plasma.
Meloxicam is eliminated almost entirely by hepatic metabolism: two thirds by cytochrome (CYP) P450 enzymes (CYP 2C9 two thirds and CYP 3A4 one third) and one third by other pathways, such as peroxidase oxidation. Meloxicam is almost completely metabolised to four pharmacologically inactive metabolites. The major metabolite, 5'-carboxymeloxicam (60% of dose), from CYP 2C9 mediated metabolism, 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 excretion is predominantly in the form of metabolites and occurs to equal extents in the faeces and urine. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and faeces (1.6%). The extent of the urinary excretion was confirmed for unlabelled multiple 7.5 mg doses: 0.5%, 6% and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively.
There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of colestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. Meloxicam is eliminated from the body with a mean elimination half-life of 20 hours. Total plasma clearance ranged from 7 to 9 mL/min following multiple oral doses of meloxicam.
Following a single 15 mg dose of meloxicam, there was no marked difference in plasma concentrations in subjects with mild (Child-Pugh Class I) and moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic insufficiency. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied.
Meloxicam pharmacokinetics has been investigated in subjects with different degrees of renal insufficiency. Mild renal insufficiency does not have any substantial effect on meloxicam pharmacokinetics. Total drug plasma concentrations decreased with the degree of renal impairment, while free AUC values were similar. Total clearance of meloxicam increased in these patients, probably due to the increase in free fraction, leading to an increased metabolic clearance. Subjects with moderate renal impairment had higher total drug clearance. (Total clearance – no impairment: mean 4.80 mL/min (CV 34.3), median 4.44 mL/min; moderate impairment: mean 8.02 mL/min (CV 46.2), median 6.94 mL/min).
There is no need for dose adjustment in patients with mild to moderate renal failure (creatinine clearance greater than 25 mL/min). Patients with severe renal insufficiency have not been adequately studied. The use of meloxicam in patients with severe renal impairment is not recommended (see Section 4.3 CONTRAINDICATIONS and Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). A reduced protein binding was observed in patients with end stage renal disease on haemodialysis (see Section 4.2 DOSE AND METHOD OF ADMINISTRATION).
Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic haemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Haemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after haemodialysis. Meloxicam is not dialysable.
Clearance is decreased in the elderly. In clinical studies, steady state pharmacokinetics in the elderly (mean age 67) did not differ significantly from those in a younger population (mean age 50), however elderly females had a higher systemic exposure to meloxicam than did elderly males.
Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs. 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or tmax across genders.
Meloxicam did not demonstrate genotoxic potential in assays for gene mutation in vitro and chromosomal damage in vitro and in vivo.
Two-year dietary studies showed no evidence for carcinogenic activity at meloxicam doses up to 0.8 mg/kg/day (approximately half of the highest human dose at 15 mg/day for a 50 kg person based on bodysurface-area [BSA]) in rats and up to 8 mg/kg/day (2.2 times the highest human dose based on BSA) in mice. In rats, the highest dose used was nephrotoxic, while the highest dose used in mice was subtoxic.
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