Adults

Osteoarthritis and Rheumatoid Arthritis

The MOBIC Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with MOBIC 7.5 mg/day, 3,505 OA patients and 1351 RA patients treated with MOBIC 15 mg/day. MOBIC at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo and/or active-controlled osteoarthritis trials and 2363 of these patients were treated in ten placebo and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across MOBIC trials.

A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of MOBIC with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of MOBIC with placebo.

Table 2a depicts adverse events that occurred in ≥ 2% of the MOBIC treatment groups in a 12-week placebo and active-controlled osteoarthritis trial.

Table 2b depicts adverse events that occurred in ≥ 2% of the MOBIC treatment groups in two 12-week placebo controlled rheumatoid arthritis trials.

Table 2a Adverse Events (%) Occurring in ≥ 2% of MOBIC Patients in a 12-Week Osteoarthritis Placebo and Active-Controlled Trial

Table 2b Adverse Events (%) Occurring in ≥ 2% of MOBIC Patients in two 12-Week Rheumatoid Arthritis Placebo Controlled Trials

The adverse events that occurred with MOBIC in ≥ 2% of patients treated short-term (4-6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 3.

Table 3 Adverse Events (%) Occurring in ≥ 2% of MOBIC Patients in 4 to 6 Weeks and 6 Month Active-Controlled Osteoarthritis Trials

Higher doses of MOBIC (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore the daily dose of MOBIC should not exceed 15 mg.

Pediatrics

Pauciarticular and Polyarticular Course Juvenile Rheumatoid Arthritis (JRA)

Three hundred and eighty-seven patients with pauciarticular and polyarticular course JRA were exposed to MOBIC with doses ranging from 0.125 to 0.375 mg/kg per day in three clinical trials. These studies consisted of two 12-week multicenter, double-blind, randomized trials (one with a 12-week open-label extension and one with a 40-week extension) and one 1-year open-label PK study. The adverse events observed in these pediatric studies with MOBIC were similar in nature to the adult clinical trial experience, although there were differences in frequency. In particular, the following most common adverse events, abdominal pain, vomiting, diarrhea, headache, and pyrexia, were more common in the pediatric than in the adult trials. Rash was reported in seven (<2%) patients receiving MOBIC. No unexpected adverse events were identified during the course of the trials. The adverse events did not demonstrate an age or gender-specific subgroup effect.

The following is a list of adverse drug reactions occurring in < 2% of patients receiving MOBIC in clinical trials involving approximately 16,200 patients. Adverse reactions reported only in worldwide post-marketing experience or the literature are shown in italics and are considered rare (< 0.1%).

ACE-inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.

Aspirin

When MOBIC tablets/oral suspension is administered with aspirin (1000 mg TID) to healthy volunteers, it tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects.

Concomitant administration of low-dose aspirin with MOBIC tablets/oral suspension may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC tablets/oral suspension alone. MOBIC tablets/oral suspension is not a substitute for aspirin for cardiovascular prophylaxis.

Cholestyramine

Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t_½, 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 QID 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 β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.

Furosemide

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with Mobic® (meloxicam) tablets/oral suspension, patients should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.

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 BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC tablets/oral suspension. Patients on lithium treatment should be closely monitored for signs of lithium toxicity when MOBIC tablets/oral suspension is introduced, adjusted, or withdrawn.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with 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.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing Mobic® (meloxicam) tablets/oral suspension therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. 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 tablets/oral suspension with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.

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