Adverse Effects of Anti-Inflammatory Drugs:

Transcription

1 Non-Steroidal anti-inflammatory drug (NSAIDs) are widely used to provide effective anti-inflammatory and analgesic therapy for patients with arthritis. However, they are associated with a high incidence of gastrointestinal (GI) side effects, which can reduce patient compliance and discourage physicians from prescribing them (Giercksky et al., 1989, Larkai et al., 1989, Fries, 1991, Garcia Rodriguez and Jick, 1994). The most common (GI) adverse effects include dyspepsia, nausea and abdominal pain, which are seldom serious and occur at a similar frequency with many standard NSAIDs, including piroxicam, diclofenac and naproxen (Brogden et al., 1984, Giercksky et al., 1989). Adverse Effects of Anti-Inflammatory Drugs: Serious adverse effects include upper (GI) perforations, ulcerations and bleedings (PUBs), which frequently require hospitalization; the overall risk of hospitalization or death due to an NSAID - related (GI) effect has been estimated to be 0.4 % / year for patients with osteoarthritis (OA) and 1.3 % / year for those with rheumatoid arthritis (RA) (Fries, 1991). Such figures would suggest~ 2600 deaths / year in the USA from (RA) and 3200 from (OA) (Fries, 1991). Risk factors for such events include age, past ulcer history, NSAID dosage and corticosteroid use (Fries, 1991, Bateman, 1994, Garcia Rodriguez and Jick, 1994). In addition, patients taking NSAIDs frequently experience symptomatic (GI) side effects are a 1

2 poor guide to ulceration and should be regarded as a separated drugrelated problem. Therefore, there is a need for a NSAID with improved (GI) tolerability which nevertheless retains the efficacy of its class. It has been recognized since 1971 that both the efficacy and the toxicity of NSAIDs result from their inhibition of prostaglandin (PG) biosynthesis, mediated by cyclooxygenase (COX) enzyme (Vane, 1971), which exist as two distinct isoforms that are structurally and functionally distinct (Wong and Richards, 1991, Xie et al., 1991, Masferrer et al., 1992). The (GI) side effects of NSAIDs are thought to be due to inhibition of COX-1, the constitutive isoform, which has cytoprotective effects in the (GI) tract and kidney (Whittle et al., 1980, Hawkey et al., 1998). Anti-inflammatory actions, however, are mediated through inhibition of COX-2, which is induced in response to pro-inflammatory and other stimuli (Kujubu et al., 1991, Jones et al., 1993). This discovery has led to the hypothesis that selective inhibition of COX-2 will reduce the potential for (GI) toxicity without compromising the therapeutic efficacy (Vane, 1994, Hawkey et al., 1998). Selective COX-2 Anti-Inflammatory: The NSAID, Meloxicam, has shown preferential activity (Churchill et al., 1996, Engelhardt et al., 1996) in its ability to inhibit COX-2 compared to COX-1, assessed in various assays including lipopolysaccharide-simulated whole-blood monocyte production of PGE2 and whole blood platelet thromboxane production (Churchill et al., 1996, Engelhardt et al., 1996, Pairet and Engelhardt, 1996). In the 2

3 human whole blood assay, various NSAIDs, including ibuprofen, naproxen, indomethacin and piroxicam, were non-selective (Patrignani et al., 1996). Meloxicam was approximately ~ 10 fold more potent against COX-2 than COX-1 (Patrignani et al., 1996). Exvivo in clinical studies in humans have shown similar preferential selectivity (Stichtenoth et al., 1996). Clinical studies have shown that Meloxicam is effective therapy for (OA) and (RA), at a daily doses of 7.5 mg and 15 mg, respectively. A global analysis of over 5000 patients treated with both doses of Meloxicam over a variable time has suggested a favourable (GI) tolerability profile in studies involving comparisons with diclofenac, piroxicam and naproxen (Distel et al., 1996). Meloxicam [4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)- 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, UH-AC 62 XX; Boehringer Ingelheim], an oxicam derivative, is a non - steroidal drug of the acidic enolcarboxamide class (cf. Figure 1), has antiinflammatory, analgetic, and antipyretic therapeutic effects (Busch et al., 1998, Hanft et al., 2001, Martindale, 2005, Fahmy, 2006, Kürti et al., 2011, Boehringer, 2014). 3

4 Figure (1). Meloxicam chemical Structure. Pharmacological Action of Meloxicam: It is indicated for short term symptomatic treatment of exacerbations of osteoarthritis as well as long term symptomatic treatment of rheumatoid arthritis or ankylosing spondylitis. Meloxicam is also frequently used to treat rheumatoid arthritis, osteoarthritis and other joint diseases (Hanft et al., 2001, Ambrus et al., 2009). Besides its main therapeutic application as an antiinflammatory and strong analgetic agent, it is also emerging as a promising drug for the treatment of Alzheimer s disease and cancer (Luger et al., 1996, Furst, 1998, Goldman et al., 1998, Tsubouchi et al., 2000, Ambrus et al., 2009). Studies of Meloxicam treatment of animals with adjuvant arthritis revealed marked amelioration of the symptoms of bone and cartilage destruction i.e. anti-arthritic activity, anti-inflammatory activity and at the same time less gastric and local tissue irritation as compared to NSAIDs available prior to its development (Stei and Püschner, 1994, Engelhardt et al., 1995, Engelhardt et al., 1996 a, Busch et al., 1998, Hasan et al., 2009). 4

5 Meloxicam is a relatively well-permeable drug, with a permeability coefficient determined on the Caco-2 cell model from an apical to a basolateral site of PA to B =17.6± cm/s, and it has low solubility and a low dissolution rate, which are limiting factors for its absorption rate (bioavailability 89% after its dissolution (Del Tacca et al., 2002)). Its maximum peak plasma concentration is reached 3 7 hrs following the administration of an oral suspension, and after 5 9 hrs for tablets (Liang et al., 2000, Hanft et al., 2001). To achieve adequate pharmacodynamic properties such as rapid onset of the drug effect, fast dissolution is important for this type of drug (Ambrus et al., 2009). Meloxicam has a high intrinsic activity combined with a low ulcerogenic potential (i.e. a high therapeutic index) (Engelhardt et al., 1996 b). The therapeutic index of Meloxicam is higher than that of other NSAIDs, including piroxicam, diclofenac, and indomethacin (Engelhardt et al., 1996 b). Meloxicam is a commonly applied NSAID, because it does not cause aspirin like hypersensitivity reaction (Bavbek et al., 2006). The single oral dose of Meloxicam is mg (Noble and Balfour, 1996). The favorable side effect profile and the low quantity of a single dose make this NSAID suitable for administration via alternative pathways, e.g. intranasally. This may result in novel opportunities for the easing of pain, which affects the region of the head (Kürti et al., 2011). Mechanism of Action of Meloxicam: Meloxicam generally accepted mechanism of action through preferentially inhibits cyclooxygenase-2, which is induced by 5

6 inflammatory stimuli in pathophysiological conditions, rather than cyclooxygenase-1, which is responsible for physiological processes, e.g. in the stomach, as consistently demonstrated in a number of models (Churchill et al., 1996, Pairet and Engelhardt, 1996, Engelhardt et al., 1996 a). Despite the structural relationship to other NSAIDs (Woolf and Radulovic, 1989, Olkkola et al., 1994), the introduction of the methyl group in the thiazolyl moiety of Meloxicam has facilitated the formation of metabolites (Schmid et al., 1995) that undergo fast elimination, leading to a shorter t1/2, in comparison with piroxicam and tenoxicam (Busch et al., 1998). Physico-chemical Properties of Meloxicam: Meloxicam is a pale yellow powder, practically insoluble in water; slightly soluble in acetone; soluble in dimethyl formamide; very slightly soluble in ethanol (96%) and in methanol (Martindale, 2005). It has a molecular weight of and its empirical formula is C14H13N3O4S2 (Merck, 1996, BritishPharmacopia, 2006, USP-32, 2009). Meloxicam is an acidic drug (pka, 1.1 and 4.2), practically insoluble in water at physiological ph (12 µg/ml) and has a zwitterionic property with two pka values (pka1 =1.09, pka2 =4.18) (Luger et al., 1996). The percentage of ionized drug and the solubility increase with increasing ph (Gao et al., 2006) until the highest solubility reported is reached in ph 10 phosphate buffer solution (Luger et al., 1996), decreasing ph leads to an increase in the ratio of non-ionized to ionized drug combined with a decrease in solubility (Luger et al., 1996). 6

7 The aqueous solubility of Meloxicam at various ph values is compared with the other NSAIDs, the results indicate that Meloxicam is a weak acidic drug (Meloxicam has pka values of 1.1 and 4.2), when dissolved in acid dissolution medium the solubility is poor (Chiou et al., 2007). Pka: 4.08 in water; 4.24 ± 0.01 in water / ethanol (1:1); 4.63 ± 0.03 in water / ethanol (1:4) (Merck, 1996). Meloxicam suitable for pharmaceutical purposes can be isolated by crystallization from non-polar organic solvents as tetrahydrofuran (THF). The structure of Meloxicam obtained in this mannar is characterized by a tautomeric arrangement of the protons. However, under physiologic conditions (ph 7.4), the anion form of Meloxicam is the predominant structure. It has been suggested that under aqueous conditions, in addition to the anion form, zwitterions forms may also exist. For the zwitterionic forms, two prototropic forms (enolate and amidate) are possible and one of them (amidate) may exhibit mesomeric stabilization. It has also been speculated that Meloxicam might crystallize in different prototropic forms depending upon the polarity of the solvent or the ph value. Meloxicam may exist in the zwitterions form in polar solvents but exclusively in the enolic form in non-polar solvents such as THF. Indeed, piroxicam forms zwitterions in polar solvent (Tsai et al., 1993). Finally additional molecular species such as the cation form of Meloxicam may be present under acidic conditions. However, a recent study (Tsai et al., 1993) reported one pka value and one tautomeric form for Meloxicam only (enol form) and explicitly three classes of compounds; (i) Acetyl salicylic acid (ASA), (ii) other NSAIDs and (iii) Meloxicam and diclofenac. (ASA) is highly soluble 7

8 in aqueous solution, even under highly acidic conditions, thus a considerable proportion of (ASA) will be present in the non-ionized form in the acidic gastric juice of the stomach. These non-ionized molecules can easily penetrate through lipid membranes into the mucosal cells of the stomach wall, where the higher intracellular ph leads to ionization and trapping is thought to be a major factor in the development of direct local damage to the gastric mucosa, resulting in the ulceration and bleeding associated with (ASA) (Price and Fletcher, 1990). The solubility of piroxicam, tenoxicam and Meloxicam is increased at very low ph, indicating there may be a second ionization constant. In order to determine the relationship between the dissolution rate and the oral absorption, the dissolution profiles of Meloxicam as well as its ethanolamine salts were evaluated at ph 1.2 and 6.8. The dissolution rates of Meloxicam and its ethanolamine salts were similarly very slow at ph 1.2 resulting in less than 10% dissolution in 12 hrs and thus, it may not be meaningful to compare the dissolution rates at ph 1.2. Based on the small volume of gastric fluids and short residence time in the stomach, Meloxicam and its ethanolamine salts should be dissolved and absorbed mainly in the intestine. Therefore, the dissolution profiles were also examined at ph 6.8. On the contrary to those at ph 1.2, ethanolamine salt formation significantly enhanced the dissolution rate of Meloxicam at ph 6.8. Meloxicam diethanolamine salt exhibited the highest dissolution rate at ph 6.8 followed by the monoethanolamine salt and triethanolamine salt. Accordingly, the faster dissolution of Meloxicam via ethanolamine salt formation at ph 6.8 appeared to be correlated well with more 8

9 rapid absorption (shorter Tmax) of Meloxicam in rats (Han and Choi, 2007). The ultraviolet (UV)- visible spectrum ( nm) of Meloxicam in acidic (0.1 N HCL), alkaline (0.1 N NaOH) and neutral (methanol) solvent systems are evaluated. The maximum ultraviolet absorption of Meloxicam was found at 345, 362 and 356 nm in acidic (0.1 N HCl), alkaline (0.1 N NaOH) and neutral (methanol) solvent systems, respectively. The obtained spectra and maximum absorption wavelength for Meloxicam in acidic and alkaline solvent system was compared with the reference spectra of Meloxicam. In another study the (UV) spectrum of Meloxicam in 100 mm borate buffer (ph 8.5) has two maximum absorption band at 205 and 363 nm. The light absorption, in the range of a % w/v solution in methanol exhibits a maximum at 354 nm. the absorbance at 354 nm is about 0.8 (BritishPharmacopia, 2006). The melting point of authentic Meloxicam is 254 ºC (dec) (Merck, 1996). Meloxicam has a lethal dose 50 (LD50) in rats, mouse and rabbits (mg/kg): ~ 83.5, 470, 320 orally, respectively (Pfizer, 2012). Bioavailability of Meloxicam: Meloxicam is almost completely absorbed when given parenterally, orally or rectally with an absolute bioavailability (F) of 89% (Türck et al., 1997, Davies and Skjodt, 1999). The absolute bioavailability (F) was 89% (Türck et al., 1995) for oral capsules after a single 30 mg dose. Maximum Meloxicam 9

10 plasma concentrations (Cmax) were achieved after 5-6 hrs (Tmax) when administered after breakfast (Türck et al., 1996). The (Cmax) occurred later (Tmax was doubled) when Meloxicam was administered in a fasted state. During chronic therapy for osteoarthritis or rheumatoid arthritis it is generally more common to administer NSAIDs after a meal, thus the (Tmax,ss) value of 5-6 hrs for Meloxicam is probably the clinically more relevant value. Very similar values were found after rectal administration (Türck et al., 1995). Absorption after intramuscular injection is faster than after oral administration, with (Cmax) occurring after hrs (Narjes et al., 1996). Ninety percent of the (Cmax) is achieved after 0.87 hr (Narjes et al., 1996). Pharmacokinetics of Meloxicam: The pharmacokinetics of Meloxicam are linear over the entire dose range ( mg) and remain unchanged from single to multiple dosing conditions, total Meloxicam clearance found to be 7-8 ml/min with an elimination half-life around 20 hours (Türck et al., 1997). Although several pharmacokinetic studies of Meloxicam have been published, only few have been focused on bioequivalence (Türck et al., 1997, Dasandi et al., 2002, Marcelín Jiménez et al., 2005, Rigato et al., 2006, Gschwend et al., 2007). Mean plasma concentration-time profiles at steady state from individual volunteers show multiple concentration peaks (Türck et al., 1996), which indicate a continual absorption for several hours after the (Cmax) has been attained. This results in a 50% increase in apparent clearance (Busch et al., 1995). This suggests Meloxicam undergoes gastrointestinal recycling and may account for why the 10

11 drug does not undergo faster elimination. In the case of possible Meloxicam overdose, the standard measures of gastric evacuation and general supportive measures should be used as there is no known antidote (Boehringer, 2014). It has been shown in clinical trial that cholestyramine or charcoal (Laufen and Leitold, 1986), eliciting a faster elimination of the drug. 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 μg/ml for 7.5 mg doses and μg/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 (DataSheet, 2013). The absorption of Meloxicam is independent of dose over the range mg, leading to dose-linear increases in Meloxicam plasma concentrations (Türck et al., 1995). This enables easy dose titration in those patients requiring higher or lower doses than normal. 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 per-oral treatment with 15 mg Meloxicam/day. Any differences after treatment longer than six months are thus rather unlikely (DataSheet, 2013). Meloxicam is very strongly bound to plasma proteins essentially albumin, being >99% bound (Türck et al., 1995). The 11

12 binding is consistent over the concentration range encountered in clinical practice. At therapeutic concentration, this high protein binding results in a restricted volume of distribution (Vd) of 10-15L (Türck et al., 1995), which is similar to that reported for other NSAIDs (Verbeeck et al., 1983). Animal experiments suggest that Meloxicam is predominantly distributed to highly perfused (albumin rich) compartments such as the blood, liver, kidney, etc. (Busch et al., 1998). The (Vd) equates approximately with the extracellular space, although Meloxicam readily penetrates other tissues. For example, 40-45% of the accompanying steady-state Meloxicam plasma concentrations are found in synovial fluid, slightly lower concentrations being observed in the adjacent tissues (Degner et al., 1994). Inflamed tissue is characterized by extravasation and probably, decreased ph values, compared with non-inflamed tissue. Such conditions are ideally suited to 'trap' a NSAID from the circulation. Indeed, high concentrations of Meloxicam in inflamed tissue have been observed in animal models (Busch and Engelhardt, 1989). Meloxicam is almost exclusively eliminated by metabolic degradation. The drug undergoes roughly equal renal and faecal elimination, with <0.25% excreted unchanged in urine and 1.6% of the parent compound present in the faeces. The latter may also represent a small amount of unabsorbed drug (Schmid et al., 1994). Meloxicam undergoes extensive hepatic biotransformation. In vitro studies suggest that it metabolized primarily by cytochrome P450, particularly by CYP2C9 and to a minor extent by CYP3A4. 12

13 Four different metabolites of Meloxicam (AF-UH 1 SE, UH-AC 110 SE, BIBO 8032 and DS-AC 2 SE) were identified in urine (Schmid et al., 1994), which are all pharmacodynamically inactive (Schmid et al., 1994). 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). The patient's peroxidase activity is probably responsible for the other two metabolites, which account for 16% and 4% of the administered dose, respectively (Türck et al., 1996). Oral Meloxicam has a total clearance of l/hr (Türck et al., 1996), Meloxicam excretion is predominantly in the form of metabolites and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled 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 (DrugBank, 2005, DataSheet, 2013). The mean elimination half-life is about 20 hours (Türck et al., 1995). Total plasma clearance amounts on average to 8 ml/min ( 8.8 ml/min [Healthy Male Adults (Fed) oral 7.5 mg tablets], 9.9 ml/min [Eldery Male (Fed) oral 15 mg capsules], 5.1 ml/min [Eldery Female (Fed) oral 15 mg capsules], 19 ml/min [Renal Failure (Fasted) oral 15 mg capsules], 11 ml/min [Hepatic Insufficiency (Fasted) oral 15 mg capsules]) (DrugBank, 2005, DataSheet, 2013). 13

14 Meloxicam steady-state plasma concentrations are achieved within 3-5 days. In common with most other NSAIDs, a considerable variation between subjects ( inter individual coefficient of variation 30%) has been observed. In comparison with other NSAIDs of the same class, Meloxicam has a relatively short elimination half-life of ~20 hrs. This value allows a once-a-day dosage without the need for a slow release formulation. The values for piroxicam are ~53 hrs (Hobbs, 1986) and for tenoxicam hrs (Nilsen, 1994). Additionally, steady state is achieved within 3-5days with Meloxicam whereas 1-2 weeks is necessary for the other NSAIDs. NSAIDs with a short elimination half-life, such as diclofenac (t½, 1-2 hrs (Willis et al., 1979)) need a slow release formulation for a once-daily regimen. The performance of slow release formulations may be influenced by the concomitant intake of food. Diclofenac is a well known example for which quite different concentration-time profiles are seen with and without food (Scheidel et al., 1994). Such food effects are more rare with compounds with a longer elimination half-life. With multiple dosing, steady state concentrations were reached by Day 5. A second Meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling (RxList, 2012). Meloxicam demonstrates linear pharmacokinetics in the therapeutic dose range of 7.5 mg to 15 mg following per-oral or intramuscular administration (DataSheet, 2013). The concomitant administration of food as well as other agents is known to affect the absorption, as well as elimination, of NSAIDs. Thus several pharmacokinetic interaction trials involving 14

15 Meloxicam have been undertaken which demonstrated the lack of clinically relevant interactions with high-fat food (Türck et al., 1995), P-acetyldigoxin (Degner et al., 1995), methotrexate (Hübner et al., 1997), cimetidine (Busch et al., 1996), antacids (Busch et al., 1996), acetylsalicylic acid (Busch et al., 1996) or furosemide (Muller et al., 1995). Recent data also indicate that there is no relevant interaction with warfarin. The usual daily per-oral dose of Meloxicam is 7.5 and 15 mg taken as a single dose. The maximum recommended daily dose for adults is 15 mg, while the maximum recommended dose for adolescents is 0.25 mg/kg. As a dosage for use in children not yet been established, usage should be restricted to adolescents and adults. In dialysis patients with severe renal failure, the dose should not exceed 7.5 mg/day. No dose reduction in patients with mild to moderate renal or hepatic impairment (Boehringer, 2014). The total daily amount should be taken as a single dose, with water or another liquid, during a meal. Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis (Boehringer, 2014). In the treatment of rheumatoid arthritis and ankylosing spondylitis, Meloxicam is given by mouth in a usual dose of 15 mg daily as a single dose. Those with an increased risk of adverse reactions should be started on 7.5 mg daily. A dose of 7.5 mg daily is recommended for long-term treatment in the elderly. In the treatment 15

16 of acute exacerbations of osteoarthritis the usual daily dose of Meloxicam by mouth is 7.5 mg, increased if necessary to a maximum of 15 mg daily given as a single dose (Martindale, 2005, Boehringer, 2014). Meloxicam may be given by rectal suppository in doses similar to those used orally but use should be limited to the shortest time possible. Meloxicam Side Effects: Between September 1996, when Meloxicam was first marketed in the UK, and mid June 1998 the UK Committee on Safety of Medicines had received a total of 773 reports of 1339 suspected adverse reactions for Meloxicam (ControlAgency, 1998 ). Of all the reactions 41% were gastrointestinal and of these 18% involved gastrointestinal perforation, ulceration and/or bleeding; the mean age of the patients involved was 64 years. Although most patients recovered after withdrawal of Meloxicam and/or treatment, 5 died. A total of 193 reactions involved the skin, the most common being pruritus, rash, and urticaria. There were also reports of angioedema (25 reports), photosensitivity (12 reports), and bullous dermatoses, including erythema multiforme and Stevens Johnson syndrome (5 reports). No patients died from skin reactions and most recovered after Meloxicam was withdrawn. Other frequently reported reactions were neurological (mostly headache), cardiovascular (oedema and palpitations), dizziness, flushing, and fatigue. A prescription event monitoring study has also analyzed events reported with Meloxicam use (Martin et al., 2000). In a cohort of 19,087 patients who had received Meloxicam sometime between December 1996 and March 16

17 1997, 203 patients had experienced 252 events considered to be suspected adverse reactions. The majority of reactions were not serious or were labelled side-effects of Meloxicam. Rare, serious suspected adverse reactions included 2 reports of thrombocytopenia and 1 each of interstitial nephritis and idiosyncratic liver abnormality. The most frequent gastrointestinal event was dyspepsia; other more serious gastrointestinal events occurring during Meloxicam exposure included upper gastrointestinal bleeding (33 reports) and peptic ulcer (19 reports). However it was considered that the incidence of gastrointestinal disturbance was low in the absence of gastrointestinal risk factors. Adverse drug reactions reported during the first year of marketing of Meloxicam to the Swedish Medical Products Agency suggested a similar safety profile to other NSAIDs (Anonymous, 1998). Of the 15 reports, 6 were for gastrointestinal disturbances and 5 involved skin reactions (Martindale, 2005). It has been proposed that preferential inhibitors of cyclooxygenase-2, such as Meloxicam, might produce fewer adverse effects than other NSAIDs but there has been little convincing evidence that the risk of severe gastrointestinal events is lower with Meloxicam than with other NSAIDs at equi-effective doses. Two recent large multicentre studies (Dequeker et al., 1998, Hawkey et al., 1998) have reported a lower incidence of gastrointestinal adverse effects with Meloxicam than with non-selective cyclo-oxygenase inhibitors (diclofenac (Hawkey et al., 1998) or piroxicam (Dequeker et al., 1998)) but in one of these (Hawkey et al., 1998) the dose of Meloxicam given also appeared to be less effective than the reference drug (Martindale, 2005). 17

18 clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment. The most commonly-observed adverse events of Meloxicam are gastrointestinal in nature. Peptic ulcers, perforation or (GI) bleeding, sometimes fatal, particularly in elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, excerbation of colitis and crohn's disease have been reported following adminstration. Less frequently, gastritis has been observed (Boehringer, 2014). Meloxicam should be avoided in severe hepatic impairment, in bleeding disorders, and in patients with renal failure unless receiving dialysis. Rectal use should be avoided in patients with a history of proctitis, haemorrhoids, or rectal bleeding. The pharmacokinetics of Meloxicam were not substantially altered in patients with a creatinine clearance of 41 to 60 ml/min compared with those with normal renal function (Boulton Jones et al., 1997). In those with a creatinine clearance of 20 to 40 ml/minute, total plasma-meloxicam concentrations were lower but Meloxicam free fractions were higher. Such free Meloxicam concentrations were similar to the other groups. On the basis of these results, it was suggested that it was not necessary to reduce Meloxicam doses in 18

19 patients with a creatinine clearance greater than 20 ml/min (Martindale, 2005). 19