Trepoxicam-7.5 (Page 4 of 5)

12.3 Pharmacokinetics

12.3 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. 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 Cmax was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. 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.

Meloxicam oral suspension doses of 7.5 mg/5 mL and 15 mg/10 mL have been found to be bioequivalent to meloxicam 7.5 mg and 15 mg capsules, respectively. Meloxicam capsules have been shown to be bioequivalent to MOBIC tablets.

Table 3 Single Dose and Steady-State Pharmacokinetic Parameters for Oral 7.5 mg and 15 mg Meloxicam (Mean and % CV)1

		Steady State	Steady State	Steady State	Single Dose	Single Dose
Pharmacokinetic Parameters (% CV)		Healthy male adults (Fed)2	Elderly males (Fed)2	Elderly females (Fed)2	Renal failure (Fasted)	Hepatic insufficiency (Fasted)
		7.5 mg3 tablets	15 mg capsules	15 mg capsules	15 mg capsules	15 mg capsules
N		18	5	8	12	12
Cmax	[µg/mL]	1.05(20)	2.3 (59)	3.2 (24)	0.59 (36)	0.84 (29)
tmax	[h]	4.9 (8)	5 (12)	6 (27)	4 (65)	10 (87)
t1/2	[h]	20.1(29)	21 (34)	24 (34)	18 (46)	16 (29)
CL/f	[mL/min]	8.8 (29)	9.9 (76)	5.1 (22)	19 (43)	11 (44)
Vz/f4	[L]	14.7(32)	15 (42)	10 (30)	26 (44)	14 (29)

(2.2)]. The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively. In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients. The pharmacokinetics of MOBIC in pediatric patients under 2 years of age have not been investigated. Geriatric Elderly males (³65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females (³65 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. 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. Hepatic Impairment Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in patients with mild (Child- Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Renal Impairment Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of MOBIC in subjects with severe renal impairment is not recommended [see Warnings and Precautions (5.6) and Use in Specific Populations (8.7)]. 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 [see Dosage and Administration (2.1), Warnings and Precautions (5.6), and Use in Specific Populations (8.7)]. Drug Interactions Aspirin: When MOBIC is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known [see Drug Interactions (7.2)]. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Lithium: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg QD every day as compared to subjects receiving lithium alone [see Drug Interactions (7.4)]. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites [see Drug Interactions (7.5)]. Warfarin: The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [see Drug Interactions (7.7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.5- and 2.6-fold, respectively, the maximum recommended human daily dose based on body surface area comparison). Mutagenesis: Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility: Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/ kg/day in females (up to 5.8- and 3.2-fold greater, respectively, than the maximum recommended human daily dose based on body surface area comparison).