The toxicological profile of Movalis 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.
Absorption
Movalis 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 Movalis, 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 Movalis at steady state, are achieved within five to six hours for the tablet, capsule and the oral suspension, respectively. Extent of absorption for Movalis following oral administration is not altered by concomitant food intake.
Distribution
Movalis is very strongly bound to plasma proteins, essentially albumin (99%). Movalis 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%.
Biotransformation
Movalis undergoes extensive hepatic biotransformation. Four different metabolites of Movalis were identified in urine, which are all pharmacodynamically inactive. The major metabolite, 5'-carboxyMovalis (60% of dose), is formed by oxidation of an intermediate metabolite 5'- hydroxymethylMovalis, 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. Elimination
Movalis 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. Linearity/non-linearity
Movalis demonstrates linear pharmacokinetics in the therapeutic dose range of 7.5 mg 15 mg following per oral or intramuscular administration.
Special populations
Hepatic/renal insufficiency:
Neither hepatic, nor mild nor moderate renal insufficiency has a substantial effect on Movalis pharmacokinetics. In terminal renal failure, the increase in the volume of distribution may result in higher free Movalis concentrations, and a daily dose of 7.5 mg must not be exceeded.
Elderly:
Mean plasma clearance at steady state in elderly subjects was slightly lower than that reported for younger subjects.
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
