Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Alpex Pharma (UK) Limited, Warren Plantation Church End, Haynes, Bedford, MK45 3RJ, UK Contact address: PO BOX 849, Bedford, MK45 9EG
Pharmacotherapeutic group: Non steroidal anti-inflammatory agents, 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 NSAID, its precise mechanism of action remains unknown. However, there is at least one common mode of action shared by all NSAID (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 89% following oral administration (capsule). Tablets, oral suspension and capsules were shown to be bioequivalent.
Following single dose administration of meloxicam, mean maximum plasma concentrations 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, respectively). 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.
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. Inter-individual 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 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 is about 20 hours. Total plasma clearance amounts on average 8 mL/min.
Meloxicam demonstrates linear pharmacokinetics in the therapeutic dose range of 7.5 mg 15 mg following per oral or intramuscular administration.
Neither hepatic, nor mild nor moderate renal insufficiency has 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 (see section 4.2).
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 NSAID: 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 resorptions) 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). Foetotoxic 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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