Source: Υπουργείο Υγείας (CY) Revision Year: 2020 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: Non steroidal anti-inflammatory agent, Oxicams
ATC Code: M01AC06
Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam family, with anti- inflammatory, analgesic and antipyretic properties.
The anti-inflammatory activity of meloxicam has been proven in classical models of inflammation. As with other NSAIDs, its precise mechanism of action remains unknown. However, there is at least one common mode of action shared by all NSAIDs (including meloxicam): inhibition of the biosynthesis of prostaglandins, known inflammation mediators.
Meloxicam is well absorbed from the gastrointestinal tract, which is reflected by a high absolute bioavailability of about 90% following oral administration (capsule). Tablets, oral suspension and capsules were shown to be bioequivalent.
Following single dose administration of meloxicam, median maximum plasma concentrations are achieved within 2 hours for the suspension and within 5-6 hours with solid oral dosage forms (capsules and 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 µg/ml for 7.5 mg doses and 0.8-2.0 µg/ml for 15 mg doses, respectively (Cmin and Cmax at steady state, correspondingly). Mean maximum plasma concentrations of meloxicam, at steady state, are achieved within five to six hours for the tablet, capsule and the oral suspension, respectively.
Extent of absorption for meloxicam following oral administration is not altered by concomitant food intake or the use of inorganic antacids.
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 after i.m. or i.v. administration, and shows interindividual variation in the order of 7-20%. The volume of distribution following administration of multiple oral doses of meloxicam (7.5 to 15 mg) is about 16 L with coefficients of variation ranging from 11 to 32%.
Meloxicam undergoes extensive hepatic biotransformation. Four different metabolites of meloxicam were identified in urine, which are all pharmacodynamic 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 extents 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 varies between 13 and 25 hours after oral, i.m. and i.v. administration. Total plasma clearance amounts about 7-12 mL/min following single doses orally, intravenously or rectally administered.
Meloxicam demonstrates linear pharmacokinetics in the therapeutic dose range of 7.5 mg to 15 mg following per oral or intramuscular administration.
Neither hepatic, nor mild to moderate renal insufficiency has a substantial effect on meloxicam pharmacokinetics.
Subjects with moderate renal impairment had significant higher total drug clearance. A reduced protein binding is observed in patients with terminal renal failure. 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 (see section 4.2).
Elderly male subjects exhibited similar mean pharmacokinetic parameters compared to those of young male subjects. Elderly female patients showed higher AUC-values and longer elimination half-lives compared to those of young subjects of both genders. Mean plasma clearance at steady state in elderly subjects was slightly lower than that reported for younger subjects.
The toxicological profile of meloxicam has been found in preclinical studies to be identical to that of other NSAIDs: gastrointestinal ulcers and erosions; renal papillary necrosis at high doses during chronic administration in two animal species.
Oral reproductive studies in the rat have shown a decrease of ovulations and inhibition of implantations and embryotoxic effects (increase of resorption) at maternotoxic dose levels at 1 mg/kg and higher. 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.
The affected dose levels exceeded the clinical dose (7.5-15 mg) by a factor of 10 to 5-fold on a mg/kg dose basis (75 kg person). Fetotoxic effects at the end of gestation, shared by all prostaglandin synthesis inhibitors, have been described. No evidence has been found of any mutagenic effect, either in vitro or in vivo. No carcinogenic risk has been found in the rat and mouse at doses far higher than those used clinically.
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