Meloxicam:a selective COX-2 inhibitor non-steroidal anti-inflammatory drug

Drug Evaluation

Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis

Meloxicam:a selective COX-2 inhibitor

non-steroidal anti-inflammatory drug

Manfred Schattenkirchner

Meloxicam is a new non-steroidal anti-inflammatory drug(NSAID) that selectively inhibits the inducible isoform of thecyclo-oxygenase (COX)-2 enzyme. This enzyme has a majorrole in mediating the inflammatory response, while synthesis ofprostaglandins required for normal physiological functioning ofthe stomach and kidneys is under the control of the constitutiveisoform, COX-1. Other NSAIDs in clinical use show varyingdegrees of selectivity towards COX-1. Only meloxicam and(albeit to a lesser extent) nimesulide could be described asselective for COX-2. In comparative trials of patients with osteo-and rheumatoid arthritis, meloxicam has been found to be atleast as effective as other NSAIDs, but with a greatly reducedincidence of gastrointestinal side-effects. There is no evidencethat meloxicam causes any deterioration in renal function inpatients with moderate degrees of renal failure, and no evidenceof drug accumulation with continued use. Meloxicam’s half-lifeof 20 h makes it ideal for once daily administration, and it is99% converted to inactive metabolites prior to excretion. Noclinically significant drug interactions have been detected, mak-ing it suitable for use in patients with co-existing pathology.Meloxicam’s safety and tolerability make it a significant advancein the treatment of rheumatic disease.

Keywords: cyclo-oxygenase 2, inflammation, meloxicam, non-steroidalanti-inflammatory drug, prostaglandin, rheumatic disease

Exp. Opin. Invest. Drugs (1997) 6(3):321-334

1. Introduction

Non steroidal anti-inflammatory drugs (NSAIDs) arethe mainstay of treatment for a wide range of rheumaticdiseases, and their efficacy is now established beyondquestion. These agents inhibit the formation of pro-staglandins (PGs), essential mediators in the inflamma-tory response. Their mechanism of action was firstproposed by Vane [1] in 1971, and has since beenfurther elucidated (see below). NSAIDs inhibit the

cyclo-oxygenase (COX) enzyme, which cyclisesarachidonic acid and adds the 15-hydroperoxy group,to form PGG2 [2]. This is then further converted toPGH2 and other prostanoids.

PGs have a wide range of physiological functions. Aswell as their role in the inflammatory response, theyhave both thrombotic and antithrombotic actions, fa-cilitate renal function, and protect the gastric mucosa(Table 1). Agents that inhibit PG synthesis disturb

3213211997 © Ashley Publicat ions Ltd. ISSN 1354-37841997 © Ashley Publicat ions Ltd. ISSN 1354-3784

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these physiological actions as well as the inflammatoryactions; the high incidence of unwanted side-effectsappears inseparable from the therapeutic (anti-inflam-matory) effect. A variety of preparations have beendeveloped to try and minimise these side-effects, inparticular gastric irritation.

Gastrointestinal intolerance of NSAIDs is extremelycommon. Studies indicate that the prevalence of suchsymptoms is approximately 30% [3,4]. Symptoms mayrange in severity from occasional heartburn or indiges-tion to daily dyspepsia that cannot be relieved byantacids or H2-blockers [3]. Although usually describedas ‘troublesome’, such symptoms can have a majorimpact on the quality of life. In some studies, 10% ormore of patients withdrew from their planned treat-ment regimens because of gastrointestinal symptomsthat they found unacceptable [4]. An even greater causefor concern is the 1% of patients who experiencesevere gastrointestinal haemorrhage or perforationwhen taking these drugs [4]; less than half of thesepatients have had prior warning in the form of dys-pepsia. Fries [5] estimates that, among patients takingNSAIDs for the treatment of rheumatoid arthritis, therisk of death or hospitalisation for a gastrointestinalevent is 1.3 - 1.6% in any 12 month period; becausethe average duration of disease is 21 years or more,this translates to a lifetime risk of about 1 in 3.

In the kidney, inhibition of PG synthesis may causeretention of water and electrolytes, hyperkalaemia,and renal tubular necrosis [2]. Idiosyncratic reactionsto NSAIDs are also known to occur, including intersti-tial nephritis and renal papillary necrosis. The use ofNSAIDs may therefore cause acute renal failure, pre-cipitate a patient into heart failure, or aggravate hyper-tension.

However, it is clear that NSAIDs vary in their toxicity.A number of epidemiological studies have been un-dertaken, and from them some clear points emerge.All users of NSAIDs have an increased risk of gastro-intestinal bleeding and/or perforation, and this effect

is dose-related but not related to duration of use. Themost important predictor of gastrointestinal adverseeffects is a history of previous upper gastrointestinalbleeding and perforation [6]. Other risk factors identi-fied [5] include age, use of prednisone, antacid orH2-receptor blocker, and disability. Estimates of therelative toxicity between the most and the least toxicdrugs range from 2 - 3 times [7], to 8 times [6], to ashigh as 10 times or more [8]. All these studies useddifferent methodologies and direct comparisons arenot possible, but ketoprofen and azapropazone areconsistently recognised as carrying a high risk, withpiroxicam and indomethacin also giving substantialcause for concern. By contrast, ibuprofen is consis-tently reported in these studies as one of the safestNSAIDs. However, ibuprofen is often used at lowdosage, and a recent meta-analysis looking morecarefully at the effect of dose concluded that highdoses of ibuprofen carry a similar risk to other NSAIDssuch as naproxen and indomethacin [9]. The apparentsafety benefits of ibuprofen are only seen when it isused at low (analgesic) dosage. However, patients withosteoarthritis, rheumatoid arthritis, and other inflam-matory conditions are likely to require high (anti-in-flammatory) doses of these agents; for them, ibuprofenoffers no safety advantage.

Recognition that NSAIDs vary in their potential tocause gastrointestinal disturbance has led to efforts todevelop agents combining the recognised efficacy ofthese drugs with improved tolerability. Much work hasfocused on the selective inhibition of the COX-2isoform, an inducible isoform of COX responsible formediating the inflammatory response. Meloxicam(Boehringer Ingelheim), a new NSAID which is alreadymarketed in several countries, shows marked selectiv-ity towards COX-2 in preference to the constitutiveisoform of the enzyme, COX-1. Other potential selec-tive inhibitors of COX-2 are in development, includingSC-58125, SC-58635 (Celecoxib; Searle Monsanto), NS-398 (Taisho Pharmaceutical Co.), and L-745,337, DSFand MK966 (Merck Frosst).

Table 1: Principal functions of prostaglandins.

Site of action Role

Prostacyclin (PGI2) Stomach Cytoprotective at gastric mucosa

Kidney Excretion of water and electrolytes

Blood vessels i) Antithrombogenic: maintains a non-thrombogenic barrier between blood and vessel wallii)Vasodilator

Prostaglandins(largely PGE2)

Stomach As above

Kidney As above

Injured tissue Mediates the inflammatory response

Thromboxane A2 Platelets Promotes platelet aggregation in response to vessel injury

322 Meloxicam: a selective COX-2 inhibitor non-steroidal anti-inflammatory drug - Schattenkirchner

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1997) 6(3)

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2. Mechanism of action of NSAIDs:new discoveries

In 1972, Flower and Vane postulated the existence ofdifferent COX isoforms on the basis of their discoverythat COX preparations made from the brain were moresensitive to paracetamol than those from the spleen[10]. Immunological studies also pointed to the exist-ence of two distinct forms of COX [11,12]. The exist-ence of two separate isoforms was confirmed in theearly 1990s, when molecular biology techniques al-lowed the identification of an alternative mRNA spe-cies, coding for a distinctly different COX [13,14]. Thisnewly discovered enzyme was named COX-2, and itdiffers from COX-1 in a number of important respects.Although the two isoforms have the same molecularweight (71 kDa), they share only 60% homology oftheir amino acids. They are found in different locationsin the cell, with COX-1 mainly in the cytoplasm orendoplasmic reticulum, and COX-2 at perinuclear sitesand on the endoplasmic reticulum.

The two COX isoforms have quite different functions.COX-1 has been described as a constitutive ‘house-keeping’ enzyme [15]. It has an important role inproducing prostanoids required for physiological func-tioning of the stomach and the kidney. The activitylevels of COX-1 remain relatively constant, whereasCOX-2 expression is increased by a factor of up to 80during the inflammatory process [16-19]. It wouldtherefore appear that COX-2 is an inducible enzymeand is involved in the synthesis of those PGs respon-sible for mediating the inflammatory process. NSAIDsthat inhibit both forms of COX exert their unwantedside-effects through inhibition of COX-1, and theiranti-inflammatory actions through inhibition of COX-2.However, there is some evidence that COX-1 may alsohave a role in inflammation [2], and the optimalselectivity of an agent for each isoform is currentlyunknown. The crystal structures of COX-1 [20] andCOX-2 [21] have now been fully elucidated, and revealdifferences in the conformations of the NSAID bindingsites, which may be important in determining drugselectivity.

The relative selectivity of an NSAID for each isoformis described by the COX-2/COX-1 ratio. This is calcu-lated from the IC50 values of the drug for both typesof enzyme (that is, the concentration of drug whichinhibits PG synthesis by 50%) [2]. A ratio lower than 1indicates relative selectivity for COX-2, whereas a ratiohigher than 1 indicates relative COX-1 selectivity. Avariety of experimental models to assess NSAID activityagainst each COX isoform have been described [22-32].These may be broadly divided into models usingcell-free enzyme preparations, microsomal fractions,cell fragments, intact cells, and whole human blood,

and have been used to examine the activity of agentsagainst both animal and human enzymes (Tables 2and 3).

Direct comparisons between the results obtained usingdifferent models are not possible as both absolute IC50

values and the COX-2/COX-1 ratio vary greatly be-tween models. For example, nabumetone is selectivefor COX-2 in a model using murine enzyme in microso-mal membranes [33], but fails to show this effect inmodels using human enzymes in cells or microsomalassays [22,25] or in ex vivo human blood cells [27].Proper assessment of selectivity for either isoformtherefore demands that results are obtained from as-says performed on several different models. Althoughabsolute values may vary, the rank order of COX-2/COX-1 ratios is generally similar when a range ofcompounds are examined by several methods.

Table 2: Models used to determine COX-1 and COX-2inhibition.

Model Authors Ref.

Pure enzyme preparation Mitchell et al.Ogino et al.

[23][29]

Microsomal fraction Churchill et al. [25]

Cells Laneuville et al.Mitchell et al.Churchill et al.O’Neill et al.Pairet et al.

[22][23][25][26][31]

Intact cells Mitchell et al.Engelhardt et al.

[23][24]

Whole blood Patrignani et al.Glaser et al.Patrignani et al.Panara et al.

[27][28][31][32]

Table 3: Enzyme preparations used in studies of COX-1 andCOX-2 inhibition.

Enzyme source Authors Ref.

Animal Mitchell et al.Engelhardt et al.Ogino et al.Pairet et al.

[23][24][29][30]

Human Laneuville et al.Churchill et al.O’Neill et al.Patrignani et al.Glaser et al.Patrignani et al.Panara et al.

[22][25][26][27][28][31][32]

Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis - Drug Evaluation 323


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3. COX-2 selectivity of meloxicam:pharmacology and Phase I studies

3.1 In vitro animal studies

Meloxicam has been extensively compared with otherNSAIDs in a number of models. An intact cell modelused macrophages from guinea-pig peritoneum, eitherin their unstimulated (normal) state to examine COX-1activity, or following stimulation of an inflammatoryresponse by lipopolysaccharide (LPS) extracted fromS. typhimurium (i.e., following induction of COX-2)[24]. Assays were performed on the stimulated cellsboth during the induction phase and after an intervalof 6 h, thereby examining the efficacy of the agentsunder test during COX-2 induction and followingcompletion of the induction process, when COX-2expression is at its peak.

Meloxicam had the lowest COX-2/COX-1 ratio (i.e.,greatest selectivity for COX-2) of any of the substancesunder test. Diclofenac was approximately equipotentagainst COX-1 and COX-2, and all the other NSAIDstested were selective for COX-1. In unstimulated cells(COX-1), the most potent agents were indomethacinand diclofenac, followed by piroxicam, meloxicam,flurbiprofen and tenoxicam. However, during stimula-tion of COX-2 induction by LPS, meloxicam was morepotent than indomethacin by a factor of 3, piroxicamby a factor of 92, tenoxicam by a factor of 170, andflurbiprofen by a factor of 3500. The COX-2/COX-1ratios indicate that meloxicam is the only one of theseagents that could be described as selective for COX-2(Table 4).

Further investigations have been performed usingcell-free enzyme preparations. In an assay using COX-1 derived from sheep seminal vesicle and COX-2derived from sheep placenta [29], the ability of meloxi-cam to inhibit conversion of arachidonic acid to PGswas compared with that of indomethacin, piroxicam,and an agent in development, NS-398. In this system,indomethacin selectively inhibited COX-1 (COX-2/COX-1 ratio 3.626) and piroxicam inhibited bothisoforms to approximately the same degree (COX-1/COX-2 ratio 0.716). Meloxicam was approximately20 times more active against COX-2 than COX-1 (ratio0.053), and NS-398 showed very strong selectivity forCOX-2, with no activity against COX-1 even at concen-trations of 100 µM.

The activities of meloxicam, the 4′ isomer of meloxi-cam, and piroxicam were further compared againstCOX-1 derived from bovine aortic endothelial cells andCOX-2 derived from mouse and guinea-pig peritonealmacrophages, in which an inflammatory response hadbeen stimulated with endotoxin [30]. COX-2/COX-1ratios for meloxicam were reported as 0.2 with guinea-

pig macrophages and 0.8 with mouse macrophages.These ratios compare with 30 and 133, respectively,for 4′-meloxicam, and 71 and 250 for piroxicam. Thisstudy was particularly interesting in that it demon-strated that minor structural variations in the moleculesignificantly affect its biological activity (the methylsubstitution on the thiazole group is located at the 4position in 4′-meloxicam, rather than the usual 5position).

3.2 In vivo animal studies

Further studies [34] have been performed to examinethe action of meloxicam and other NSAIDs (piroxicam,tenoxicam, tenidap, diclofenac, naproxen, and flur-biprofen) in live animal models. The effect on COX-2activity in inflamed tissues (rat pleurisy and mouseperitonitis) was examined, as well as COX-1 activity inthe stomach, kidney and blood. Meloxicam was apotent inhibitor of PGE2 synthesis in inflamed tissues,being twice as potent as tenoxicam in rat pleurisy andin the same order of magnitude as piroxicam, althoughmeloxicam had a steeper dose-response curve. Inaddition, in mouse peritonitis, meloxicam was ap-proximately twice as active as piroxicam and morethan 10 times as active as diclofenac or naproxen.

In contrast to other agents, doses of meloxicam suffi-cient to inhibit PGE2 synthesis did not affect leuk-otriene (LT) B4 concentrations in the inflammatoryexudate in the mouse or rat. LTB4 is an inflammatoryproduct of the lipooxygenase enzyme, and its concen-tration has been observed to rise after treatment withother NSAIDs. The failure of meloxicam to exhibit thiseffect may have favourable implications, reducing thechances of drug-induced bronchospasm.

The effect of NSAIDs on physiological PG synthesismediated by COX-1 was also examined. Meloxicamwas the least potent inhibitor of gastric PGE2 synthesis,whereas flurbiprofen was the most potent. In thekidneys, meloxicam inhibited PGE2 formation to a

Table 4: COX-2/COX-1 ratios of NSAIDs in guinea-pigperitoneal macrophages.

Compound COX-2/COX-1 ratio

Meloxicam 0.33

Piroxicam 33

Tenoxicam 15

Tenidap 122

Diclofenac 2.2

Indomethacin 30

Flurbiprofen 317



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similar extent to diclofenac, but less than tenoxicam,tenidap, and piroxicam. Finally, an assay of thrombox-ane B2 (the stable metabolite of thromboxane A2)concentrations in rat serum after coagulation of theblood showed that meloxicam inhibited its synthesisto a similar degree to indomethacin and tenidap, butsubstantially less than piroxicam or tenoxicam.

Taken together, these results show that meloxicam isa potent inhibitor of PG synthesis under inflammatoryconditions (COX-2 inhibition) in rodent species, but isa weak inhibitor under normal physiological condi-tions (COX-1 inhibition). Piroxicam showed similaranti-inflammatory activity, but was also a more potentinhibitor of physiological PG synthesis.

3.3 Human in vitro results

The COX inhibition profiles of meloxicam and otherNSAIDs against human enzymes have been examinedusing a microsomal assay system [25]. The genes forhuman COX-1 or COX-2 were transfected into insectcells, and microsomes prepared from the insect cellswere assayed for PGE2 levels in the presence of variousNSAIDs. In this model, meloxicam was considerablymore active against COX-2 than COX-1, with a COX-2/COX-1 ratio of 0.013. Nimesulide, with a COX-2/COX-1 ratio of 0.2, was the only other comparatorto show COX-2 selectivity. Diclofenac showed nearlyequal activity against both COX isoforms, but ibupro-fen, naproxen, indomethacin and 6-MNA (the activemetabolite of nabumetone) preferentially inhibitedCOX-1 (Figure 1).

Human COX isoforms were further investigated usinga whole cell preparation of cos cells transfected witheither COX-1 or COX-2 [25]. Meloxicam demonstratedclear COX-2 selectivity, with a 14-fold difference be-

tween IC50 values for COX -1 and COX-2. Nimesulideshowed only a 4-fold difference between COX-1 andCOX-2 IC50 values. Piroxicam and diclofenac wereequipotent against both COX isoforms in this system,while ibuprofen, naproxen, 6-MNA (the active meta-bolite of nabumetone), indomethacin, and aspirinwere all selective inhibitors of COX-1.

A third model for the investigation of inhibition ofhuman COX has been developed using whole bloodwithdrawn from healthy volunteers [27]. In the normal(unstimulated) state, COX-1 is present in both humanmonocytes and platelets. Stimulation with LPS inducesCOX-2 synthesis in monocytes; COX-2 is found in theperinuclear area of the cell, and platelets, which haveno nucleus, do not express it. Platelet COX-1 can beirreversibly inhibited by pre-treatment with aspirin,rendering it possible to measure monocyte COX activ-ity alone. Using this model to assess COX-2 activity,and platelets themselves as a measure of COX-1 activ-ity, meloxicam has a COX-2/COX-1 ratio of 0.09 [35],i.e., selectivity for COX-2 (see Figure 2). This com-pares with COX-2/COX-1 ratios of 0.51 for in-domethacin, 0.67 for 6-MNA, 6 for (R)-indobufen, and23.3 for (S)-indobufen using the same model [27].Meloxicam is therefore more selective for COX-2 thanthe other agents examined in this study, but it retainssome activity against COX-1. Its relative activity againstthe two isoforms was approximately 10 times greateragainst COX-2 in an ex vivo study, whereas SC-58125,L-745,337 and NS-398 were all more than 150 times aspotent against COX-2 than against COX-1 [31]. Theseresults were repeated in vitro in an assay usingheparinised whole blood, when L-745,337 and NS-398inhibited COX-2 at concentrations < 1% of thoserequired to achieve comparable inhibition of COX-1[32].

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Figure 1: Selectivity of NSAIDs against human recombinant COX-2 and COX-1 in a microsomal assay system.



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3.4 Phase I studies in man

In vivo data from healthy human volunteers haveshown that meloxicam selectively inhibits COX-2 asmeasured with respect to platelet function and renalPG synthesis. This is reflected in an improved safetyprofile in human volunteers compared with otherNSAIDs.

The effects of therapeutic doses of meloxicam (7.5 mgonce daily) and indomethacin (25 mg three timesdaily), a non-selective COX inhibitor, on platelet func-tion and renal synthesis of PGE2 have been assessed[36]. Following the addition of arachidonic acid (aprecursor of PG) to platelet-rich plasma, indomethacincaused significant inhibition (compared to pre-treat-ment) of both platelet aggregation and thromboxaneB2 formation, whereas meloxicam had no significanteffect on either. Meloxicam also had no significanteffect on urinary excretion of PGE2, whereas in-domethacin reduced its excretion by 43% (p < 0.05).

In view of the concerns about gastrointestinal toxicityof NSAIDs, a placebo-controlled double-blind trial hasbeen performed to compare the effects of meloxicam7.5 mg and 15 mg with piroxicam 20 mg on thegastrointestinal tract [37]. A combination of oesophago-gastro-duodenal endoscopy and faecal blood lossmeasurement was employed to ensure that the condi-tion of the entire gastrointestinal tract was assessed.The piroxicam group had a significant increase infaecal blood loss, but this was not seen with eithermeloxicam group. Meloxicam 7.5 mg caused nochange in endoscopic appearance of the upper GItract, whereas piroxicam 20 mg caused a significantincrease in the endoscopic score relative to baseline,placebo and to meloxicam 7.5 mg. Meloxicam 15 mg

caused no substantial change in endoscopic appear-ance relative to placebo (Figure 3). Severe adverseevents occurred significantly more frequently amongpiroxicam subjects than in any other group, and theincidence of endoscopically detected ulceration wassignificantly higher in this group. Altogether, 6 out of12 subjects in the piroxicam group developed en-doscopically detected ulceration during the course ofthe study, whereas only one subject taking meloxicam15 mg did so. No severe adverse events were recordedamong any meloxicam 7.5 mg subjects. This studydemonstrated an improved safety profile for meloxi-cam compared with piroxicam, and this was particu-larly marked in the incidence of upper gastrointestinalulcers developing during the course of the study.

In clinical practice, many patients who require treat-ment with NSAIDs are elderly and may have co-exist-ing pathology. In particular, poor renal function maygive cause for concern, both in case of accumulationof the drug as a result of reduced excretion and in caseof further impairment as a result of NSAID treatment.An open study of 28 days’ treatment with meloxicam15 mg in patients (mean age 70 years) with rheumaticdisease and mild renal impairment (creatinine clear-ance 25 - 60 ml/min) [38] has provided very encour-aging results. There were no significant changes increatinine clearance over the course of the study, andno rise in the concentration of serum creatinine, ureaor potassium at any time during the study. Troughlevels of meloxicam, recorded at intervals throughoutthe study, failed to show any evidence of accumula-tion. Adverse events were recorded in 5% of patients(predominantly gastrointestinal), but 96% of patientsassessed meloxicam as ‘well’ or ‘very well’ tolerated.

Figure 2: Activity of meloxicam against COX-2 and COX-1 in whole blood samples from human volunteers.The percentage inhibition of COX-1 and COX-2 at Cmean (steady state) is shown.



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4. Pharmacokinetics and metabolism ofmeloxicam

4.1 Absorption and distribution

Meloxicam is well absorbed from the gastrointestinaltract, with 89% bioavailability after a single oral dose[39]. Maximum plasma concentrations are reachedfaster when meloxicam is taken with food (5 - 6 h)than when fasting [40]. The half-life in man is approxi-mately 20 h [39], making it ideal for once-daily admini-stration. A steady-state plasma concentration isreached within 3 - 5 days, comparing favourably withNSAIDs with a long half-life, which require 1 - 2 weeksto reach steady-state.

In common with other NSAIDs, meloxicam is highlyprotein bound to albumin (> 99%) [39], resulting in arestricted volume of distribution that equates to theextracellular space. It readily penetrates other tissues,such as synovial fluid, and animal models show that itis present in high concentrations in inflamed tissue [41].

4.2 Metabolism

Only very small quantities of meloxicam are excretedunchanged in the urine and faeces [42]. Elimination isalmost entirely by metabolic degradation, largely me-diated by cytochrome P450 2C. The principal reactionsare oxidation of the methyl group of the thiazolylmoiety, and cleavage of the thiazine ring system [43].The resulting metabolites have no biological activity.

4.3 Effect of concurrent disease or age

No difference has been observed in the pharmacoki-netics of meloxicam between young and elderly malepatients, although elderly (> 65 years) female patientshad a higher plasma concentration than younger fe-males [44]. However, this is not associated with anincreased number of adverse events and adjustment ofthe dose is not recommended.

There is no evidence of altered pharmacokinetics inmild to moderate renal dysfunction or hepatic insuffi-ciency [45,46]. The total plasma concentration ofmeloxicam is lower in patients with renal failure, butthis is compensated for by an increase in the free(unbound) fraction. Free Cmax values tended to behigher in these patients, and it is recommended thatthe lower dose of 7.5 mg daily should be used inend-stage renal failure.

4.4 Drug interactions

Many patients taking NSAIDs are elderly and may betaking other medication. However, no drug interac-tions of clinical significance have been demonstratedwith digoxin [47], methotrexate [48], cimetidine [49],antacids [49], furosemide [50] or warfarin [51].

5. Clinical efficacy of meloxicam inosteoarthritis

The efficacy of meloxicam in osteoarthritis of the hipand knee has been investigated in a number of clinicaltrials; the results are summarised here. Taken together,these trials indicate that meloxicam is well tolerated in

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Figure 3: Mean total endoscopic scores in subjects taking meloxicam, 7.5 mg or 15 mg, or piroxicam 20 mg daily for 28 days.The gastric and duodenal mucosa were rated using the Lanza scoring system, and the oesophageal score determined as follows:Normal = 0, erythema = 1, < 3 erosions = 2, > 3 erosions or ulcer = 3. The total score was then calculated by adding together theoesophageal score and the four gastro-duodenal scores (fundus/corpus/antrum/bulbus).



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the treatment of osteoarthritis and has an efficacysimilar to that of other well-established NSAIDs.

A three-week placebo-controlled trial of oral meloxi-cam 7.5 mg or 15 mg in patients with painfulosteoarthritis of the knee demonstrated its efficacy inthis condition [52]. Patients were randomly allocatedto receive once daily doses of meloxicam 7.5 mg (n =140), 15 mg (n = 134), or placebo (n = 137). Efficacywas assessed using a 100 mm visual analogue scale.Meloxicam in doses of either 7.5 mg or 15 mg wasfound to be significantly more effective than placebo,and was well tolerated, with an adverse event ratesimilar to that of placebo.

A six-week trial comparing meloxicam 15 mg dailywith piroxicam 20 mg daily, for the treatment ofosteoarthritis of the hip, found no significant di fferencebetween the two in relieving pain on movement [53].Both patient groups reported a similar reduction in thetotal index of severity (comprising scores for painassessment, maximum walking distance, and routineactivities). Gastrointestinal adverse events were re-corded in 20.9% of the meloxicam group and 22.8% ofthe piroxicam group, but only one patient (out of totalof 129) in the meloxicam group suffered a severegastrointestinal event, compared to three patients (outof a total of 127) in the piroxicam group. Similarfindings were made in a longer study lasting for sixmonths [54], in which patients with osteoarthritis of thehip or knee recorded no significant differences inefficacy between meloxicam 15 mg daily and piroxi-cam 20 mg daily. However, the incidence of gastroin-testinal adverse events was lower in the meloxicamgroup (24.2% vs. 30.2%), and the time to first occur-rence was longer (mean 163 days vs. 144 days).

A six-week study comparing meloxicam 15 mg dailywith diclofenac slow release 100 mg daily inosteoarthritis indicated a slight superiority for meloxi-cam in respect of pain in movement, pain at rest, andglobal efficacy [55]. However, the incidence of gastro-intestinal adverse events showed marked variancebetween the two groups, with an incidence of 26.2%in diclofenac patients compared with only 16.4% inmeloxicam patients. The efficacy of meloxicam com-pared with diclofenac was further confirmed by asix-month study in which patients took a lower dose,7.5 mg, of meloxicam or diclofenac slow release 100mg daily [56]. Once again, there was no significantdifference in any of the efficacy parameters betweenthe two groups (Figure 4), apart from the median doseof paracetamol (taken for additional pain relief), whichwas lower in meloxicam patients. Adverse events(mainly gastrointestinal and respiratory) were milderand tended to appear at a later stage in those patientstaking meloxicam. Severe adverse events were more

frequent in the diclofenac group (22% vs. 15.8%). Anumber of significant abnormalities in laboratory pa-rameters were detected in diclofenac patients (reducedhaemoglobin and white cell count, increased urea, andaltered liver function tests) whereas only minorchanges (judged to be clinically irrelevant) were foundin meloxicam patients. Altogether, 18.7% of the di-clofenac patients had to withdraw from the trial be-cause of adverse events, compared to 12.4% of themeloxicam patients.

6. Clinical efficacy of meloxicam inrheumatoid arthritis

Trials in patients with rheumatoid arthritis have alsodemonstrated that meloxicam is as effective as otherNSAIDs, with the additional benefit of a superior safetyprofile. Once-daily doses of meloxicam 7.5 mg or 15mg are both significantly more effective than placeboin reducing disease activity [57]. Over the course ofthree weeks, no significant differences in safety profilewere found between either dose of active drug orplacebo. When meloxicam 15 mg daily was comparedwith piroxicam 20 mg daily over three weeks [58], therewas no significant difference in the efficacy parametersbetween the two groups (Figure 5). Differences wereobserved in the tolerability of the two treatment re-gimes, with more gastrointestinal adverse events in thepiroxicam group (14% vs. 11%). Global tolerability ofmeloxicam was assessed as better than that of piroxi-cam by both patients and physicians.

Meloxicam 7.5 mg once daily has also been comparedwith naproxen 750 mg daily (500 mg in the morningand 250 mg in the evening) for the treatment ofrheumatoid arthritis over a period of six months [59].No significant difference could be found between thetwo drugs in respect of any of the primary efficacyvariables assessed, or for eight out of ten of thesecondary efficacy variables. When compared withbaseline values, there was a statistically significantimprovement in all the secondary end-points at 26weeks in the meloxicam group, and in nine out of tenin the naproxen group. Striking differences betweenthe two groups were observed in respect of safety andtolerability, with only 0.36 gastrointestinal adverseevents per meloxicam patient, compared with 0.52 pernaproxen patient. This statistically significant differ-ence is reflected in the number of patients whodiscontinued treatment because of gastrointestinal ad-verse events: 6.0% in the meloxicam group vs. 12.2%in the naproxen group. Patients in the naproxen groupshowed a significant fall in mean haemoglobin, eryth-rocyte count and haematocrit during the course of thetrial, suggesting ongoing blood loss. This phenomenon



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was not observed in the meloxicam group. A rise inmean serum creatinine and urea values was observedin the naproxen group, suggesting inhibition of renalPG synthesis, whereas these values actually fell in themeloxicam group over the course of the trial.

7. Clinical efficacy of meloxicam in sciaticaand lumbago

The anti-inflammatory and analgesic actions of meloxi-cam have also been assessed in several studies of itsuse in acute sciatica and lumbago. These patients are

likely to need only a short course of NSAID (7 - 10days), but a rapid onset of action is essential to providerelief from severe pain. It is common practice to givethe first dose of drug parenterally, changing to oralforms for the remainder of the course. The intensityand speed of action of meloxicam 15 mg given eitherintramuscularly or orally have been assessed in pa-tients with acute sciatica [60]. There was no differencebetween the two groups in the mean time to pain relief,although those patients with muscle strength deficit(i.e., the most severely affected) had faster relief ofspontaneous pain intensity with intramuscular meloxi-cam. Maximum improvement in induced pain was

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slightly faster with intramuscular use, but in all otherrespects there was no significant difference betweenoral and intramuscular treatment. Both oral and intra-muscular meloxicam fulfilled the main requirement ofan agent in this indication, namely producing rapidand effective relief of pain. Local and overall tolerabil-ity of meloxicam was very high (approaching 100%)in both groups, as assessed by both physicians andpatients.

When compared with other NSAIDs in current use forthe treatment of acute lumbago, meloxicam (intramus-cular followed by oral) performed as well as piroxicam(intramuscular followed by oral) [61], and was signifi-cantly better than diclofenac (intramuscular followedby oral) when given intravenously and then orally [62].In both of these trials, meloxicam also had a clearadvantage in terms of gastrointestinal tolerability.

8. Safety and tolerability of meloxicam

An overview of the gastrointestinal safety and toler-ability of meloxicam has been provided by an analysiscompiling results over 6000 subjects [63]. Of these,4175 received meloxicam 7.5 or 15 mg daily, and 1473received equipotent doses of comparator drugs,namely piroxicam 20 mg, diclofenac slow release 100mg, or naproxen 750 or 1000 mg daily (the twonaproxen dosages were taken together for the pur-poses of this analysis). Gastrointestinal adverse eventswere most common in those patients taking naproxen,followed (in order of decreasing frequency) by thosetaking diclofenac, piroxicam, meloxicam 15 mg, andmeloxicam 7.5 mg. The frequency of gastrointestinal

adverse events for meloxicam was comparable toplacebo (Figure 6). In double-blind studies of osteo-and rheumatoid arthritis, both meloxicam doses had asignificantly better safety profile than all other NSAIDstested.

Both meloxicam doses were associated with signifi-cantly fewer severe adverse events than all otherNSAIDs tested. When specific types of adverse eventwere examined separately, meloxicam (either dose)was significantly superior to all other comparatorstested in respect of abdominal pain. For dyspepsia, thebest tolerated drug was meloxicam 7.5 mg, followed(in order) by meloxicam 15 mg, piroxicam, diclofenac,and naproxen. Meloxicam 7.5 mg was significantlybetter tolerated than diclofenac and naproxen in re-spect of all upper gastrointestinal events (pooled inci-dence of duodenal ulcer, dyspepsia, eructation,nausea, vomiting, gastric ulcer, haematemesis, andmelaena). Meloxicam 15 mg was also better in thisrespect than naproxen.

The most serious gastrointestinal adverse events aregrouped together under the acronym PUB (perfora-tion, ulceration and bleeding). It is generally acceptedthat the elderly (> 65 years) are most at risk ofdeveloping PUB, and this was reflected in this analysis,with the exception that no elderly patient takingmeloxicam 7.5 mg suffered a PUB. Although PUB wasmore common in elderly subjects taking meloxicam 15mg than in younger subjects, the increase in incidencewas less marked than that seen with the comparatorNSAIDs. The overall incidence of PUB was lowest inthe group treated with meloxicam 7.5 mg, and nextlowest in the meloxicam 15 mg group. Both doses of

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Figure 6: Percentage of patients with gastrointestinal adverse events after 30 and 180 days of treatment in a global analysis of all dou-ble-blind clinical studies in rheumatoid arthritis and osteoarthritis (treatment duration for placebo for 21 days).* p < 0.005 compared with meloxicam 7.5 mg (log rank test). # p < 0.05 compared with meloxicam 15 mg (log rank test).



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meloxicam showed a significant benefit in this respectwhen compared with piroxicam and naproxen (Fig-ure 7). Meloxicam 7.5 mg was also significantly supe-rior to diclofenac in respect of PUBs defined as serious,i.e., those requiring or prolonging hospitalisation, orjudged to be life-threatening or disabling.

These results therefore confirm the patterns seen inindividual clinical trials, in which meloxicam has con-sistently shown a better safety profile than comparatorNSAIDs. Although serious adverse events of NSAIDsare relatively uncommon, milder adverse events areextremely frequent and are a major cause of poorpatient compliance and discontinuation of therapy. Areflection of the superior tolerability of meloxicam isshown in the fact that discontinuation of treatment inthese trials was least common in patients takingmeloxicam 7.5 mg, followed by those taking meloxi-cam 15 mg. The difference between the number ofdiscontinuations was significant (p < 0.05) betweeneither dose of meloxicam compared with diclofenacor naproxen, and between meloxicam 7.5 mg andpiroxicam.

The selectivity of meloxicam for COX-2 predicts thatthis drug is likely to be associated with a lowerincidence of gastrointestinal adverse events thanNSAIDs which are selective for COX-1, and this analy-sis suggests that this is indeed the case.

8. Regulatory affairs

Meloxicam was first approved for the treatment ofosteoarthritis and rheumatoid arthritis in France in May1995. Under the European Union mutual recognitionprocedure, the CPMP subsequently approved its use

throughout the European Union. For the treatment ofosteoarthritis, the recommended dose is 7.5 mg oncedaily, increasing to 15 mg daily in severe cases; forrheumatoid arthritis, the recommended dose is 15 mgonce daily.

South Africa and many other countries worldwide havealso approved meloxicam for clinical use. Submissionsto the Japanese authorities and the US Food and DrugAdministration are in preparation.

9. Conclusions

The well-documented concerns over safety and toler-ability of NSAIDs have led to extensive efforts todevelop new agents with similar analgesic and anti-in-flammatory properties, but better safety profiles. Thediscovery that the COX enzyme exists in two distinctisoforms with different functions has made it possibleto develop new compounds which selectively inhibitCOX-2, the isoform responsible for mediating theinflammatory response. Meloxicam is the first of theseto become available for clinical use. When comparedwith existing NSAIDs, meloxicam is at least as effectiveas its comparators, but causes significantly fewer ad-verse reactions. The most likely explanation for thesefindings is the COX-2 selectivity of meloxicam, ena-bling it to inhibit the inflammatory response whilesparing PG synthesis in those sites where it is neededfor normal physiological functions, particularly thestomach and the kidneys.

These findings have important implications for patientswith rheumatic disease. Although the severe, poten-tially life-threatening adverse reactions (gastrointesti-nal PUB) are relatively uncommon, meloxicam has

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Figure 7: PUB with meloxicam and other NSAIDs.* p < 0.05 compared with meloxicam.



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demonstrated a significant safety advantage over otherNSAIDs. More common are the extremely widespreadmilder reactions, which are often unpleasant enoughadversely to affect quality of life and reduce patientcompliance. For these patients, meloxicam offers theprospect of effective symptom relief combined withgreatly enhanced tolerability.

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58. HUSKISSON EC, NARJES H, BLUHMKI E, DEGNER F: Com-parison of meloxicam 15 mg and piroxicam 20 mg in a3-week, double-blind trial in RA. Eighth APLAR Congressof Rheumatology (1996). Abstract 351.

59. WOJTULEWSKI JA, SCHATTENKIRCHNER M, BARCELÓ P etal.: A six-month double-blind trial to compare theefficacy and safety of meloxicam 7.5 mg daily andnaproxen 750 mg daily in patients with rheumatoidarthritis. Br. J. Rheumatol. (1996) 35(Suppl. 1):22-28.

60. AUVINET B, ZILLER R, APPELBOOM T, VÉLICITAT P: Com-parison of the onset and intensity of action of intramus-cular meloxicam and oral meloxicam in patients withacute sciatica. Clin. Ther. (1995) 17:1078-1090.

61. BOSCH H-C, HETTICH M, DEGNER FL: Efficacy and toler-ability of intramuscular and oral meloxicam: a compari-

son with piroxicam in acute lumbago. Rheumatol. Eur.(1996) 25(Suppl. 1):Abstract 431.

62. COLBERG K, HETTICH M, SIGMUND R, DEGNER FL: Theefficacy and tolerability of an 8-day administration ofintravenous and oral meloxicam: a comparison withintramuscular and oral diclofenac in patients with acutelumbago. Curr. Med. Res. Opin. (1996) 13:363-377.

63. DISTEL M, MUELLER C, BLUHMKI E: Global analysis ofgastrointestinal safety of a new NSAID, meloxicam.Inflammopharmacology (1996) 4:71-81.

Dr Manfred SchattenkirchnerMedizinische Poliklinik der Universität München, Pettenkoferstraße8A, 80336 München, Germany.



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Meloxicam:a selective COX-2 inhibitor non-steroidal anti-inflammatory drug