Mobic Structural Formula and Composition

Mobic Information

Mobic Structural Formula and Composition

Each yellow tablet contains meloxicam 7.5 mg for oral administration. It is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1, 1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the structural formula illustrated to the right.

Meloxicam is a yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2.

Mobic is available as a tablet for oral administration containing 7.5 mg meloxicam.

The inactive ingredients in Mobic include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium citrate dihydrate.

Clinical Pharmacology: Mechanism of Action

Meloxicam is a nonsteroidal anti-inflammatory drug (Anti-Inflammatory Drugs">NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of meloxicam, like that of other Anti-Inflammatory Drugs">NSAIDs, may be related to prostaglandin synthetase (cyclooxygenase) inhibition.

Pharmacokinetics: Absorption

The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Meloxicam capsules have been shown to be bioequivalent to Mobic tablets. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg.

After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean C_max was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. The rate or extent of absorption was not affected by multiple dose administration, suggesting linear pharmacokinetics.

With multiple dosing, steady state conditions were reached by day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting gastrointestinal recirculation.

Food and Antacid Effects

Drug intake after a high fat breakfast (75 g of fat) did not affect extent of absorption of meloxicam capsules, but led to 22% higher C_max values. Mean C_max values were achieved between five and six hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Mobic tablets can be administered without regard to timing of meals and antacids.

Distribution

The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~ 99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~ 99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam.

Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.

Metabolism

Meloxicam is almost completely metabolized to four pharmacologically inactive metabolites. The major metabolite, 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism was formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that cytochrome P-450 2C9 plays an important role in this metabolic pathway with a minor contribution of the CYP 3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively.

Excretion

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. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%.

The mean elimination half-life (t_1/2) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min.

Special Populations: Pediatric

The pharmacokinetics of Mobic in pediatric patients under 18 years of age have not been investigated.

Special Populations: Geriatric

Elderly males (≤ 65 years of age) exhibited meloxicam plasma concentrations and steady state pharmacokinetics similar to young males. Elderly females (≤ 65 years of age) had a 47% higher AUCss and 32% higher Cmax ss as compared to younger females (≤ 55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients.

Special Populations: Gender

Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg Mobic, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs. 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders.

Special Populations: Hepatic Insufficiency

Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in subjects with mild (Child-Pugh Class I) and moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic insufficiency. No dose adjustment is necessary in mild to moderate hepatic insufficiency. Patients with severe hepatic impairment

(Child-Pugh Class III) have not been adequately studied.

Renal Insufficiency

Meloxicam pharmacokinetics have been investigated in subjects with different degrees of renal insufficiency. Total drug plasma concentrations decreased with the degree of renal impairment while free AUC values were similar. Total clearance of meloxicam increased in these patients probably due to the increase in free fraction leading to an increased metabolic clearance. There is no need for dose adjustment in patients with mild to moderate renal failure (CrCL >15 mL/min). Patients with severe renal insufficiency have not been adequately studied. The use of Mobic in subjects with severe renal impairment is not recommended (see Warnings, Advanced Renal Disease).

Hemodialysis

Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.

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