Summary Basis of Decision for Prexige

3.3.1 Pharmacodynamics

Ex vivo COX-2 selectivity was evaluated in healthy subjects following single oral administration of lumiracoxib (25-800 mg). The percent inhibition of PGE₂ formation was measured as a marker of COX-2 inhibition and the percent inhibition of formation of TxB₂ as a marker of COX-1 inhibition. Following lumiracoxib treatment, there was substantial dose-dependent ex vivo inhibition of PGE₂ formation. Ex vivo inhibition of TxB₂ was highly variable and there was no dose-dependent trend in the data. Thus lumiracoxib remains highly selective even at concentrations near or at the C_max following a single dose as high as 800 mg. As no accumulation is expected, this selectivity is expected to be maintained under multiple oral administrations.

In order to confirm the selectivity of lumiracoxib in vivo, additional studies with multiple doses for up to nine days were conducted in which lumiracoxib was compared with naproxen and indomethacin as non-selective COX-2 inhibitors. Naproxen (500 mg) inhibited both PGE₂ as well as TxB₂ but while lumiracoxib (800 mg) inhibited formation of PGE₂ to the same extent, it had only a small effect on TxB₂ formation. Indomethacin (50 mg) provided a strong and sustained inhibition of TxB₂ (>80% compared to placebo) while the effect of 200 or 400 mg lumiracoxib was not different from that of placebo. These data confirm the selectivity of lumiracoxib at clinically relevant doses and at higher doses of up to 800 mg, and at plasma concentrations in excess of 25,000 ng/mL.

The effect of seven days of treatment with lumiracoxib (200 and 400 mg) on the production of several eicosanoids was studied in vivo in normotensive, salt-depleted, volume replete, healthy subjects. Lumiracoxib had no significant effect on thromboxane excretion. Systemic and renal prostacyclin production as measured by urinary excretion of 6-keto-PGF_1-á was significantly decreased by lumiracoxib, however the inhibitory effect was transient. Compared to placebo, maximum inhibition (25 to 40%) was achieved at 2 to 4 hours post-dose. After reaching the nadir, the effect of lumiracoxib began to diminish so that by hours 12 to 24 post-dose 6-keto-PGF_1-á excretion was at or near that observed in the placebo group. The data are consistent with previous published studies demonstrating that part of prostacyclin production is under the control of COX-2 activation. Renal PGE₂ production was significantly decreased to an equal degree, approximately 45-50%. The inhibitory effect was transient.

In a parallel group study in rheumatoid arthritis (RA) patients, the effect of lumiracoxib (800 and 1200 mg) and naproxen (500 mg) on platelet aggregation was investigated. Both lumiracoxib and naproxen appeared to have no substantial effect on ADP (adenosine diphosphate) and collagen-induced platelet aggregation.

The effect of multiple-dose treatment with lumiracoxib, naproxen, and placebo on GI mucosa was studied by endoscopy in healthy volunteers in a parallel group and crossover studies. Both studies included measurements of inhibition of TxB₂ in blood and the crossover study incorporated investigations of small intestine permeability (small and large bowel permeability by ⁵¹Cr-EDTA absorption) and PGE₂ measurement in gastric biopsies. No erosions were detected in the subjects treated with lumiracoxib at 200 mg or 800 mg and in this respect lumiracoxib was found to be statistically significantly different from naproxen and not different from placebo. Consistent with these findings, lumiracoxib was not different from placebo in terms of gastric permeability. There was a small effect on gastric PGE₂ inhibition by lumiracoxib compared to placebo. These are the expected findings of a selective COX-2 NSAID compared to naproxen.

The effects of seven days treatment with lumiracoxib (200 and 400 mg), rofecoxib (25 mg), indomethacin (50 mg) or placebo on renal function were studied in normotensive, salt-depleted, volume replete healthy subjects; a model sensitive to the inhibition of prostanoids. On the first day of treatment, lumiracoxib resulted in a significant 18% reduction in glomerular filtration rate compared to placebo. Consistent with renal adaptation to lumiracoxib treatment, this effect was not detectable after seven days of dosing. Compared to the placebo treatment group, the lumiracoxib and rofecoxib groups resulted in a significantly decreased sodium, chloride, potassium, and water urinary excretion during the first six hours of the dosing interval. This effect decreased during the 6 to 12 hours interval and was not observed during the latter part of the dosing interval (12-24 hours post-dose). Endogenous lithium clearance measured up to six hours post-dose was significantly reduced by both lumiracoxib and rofecoxib treatment. There was no consistent dose-response effect between the two lumiracoxib dose cohorts based on the pharmacodynamic variables measured in this study. These findings indicate that both classes of NSAIDs carry the potential risk of increase volume retention, oedema and hyperkalaemia. However, over the course of this study, the changes in renal physiology in healthy individuals were not accompanied by any clinical signs of salt and water retention. In comparison with placebo, none of the treatments had an effect on mean diastolic and systolic blood pressure or body weight. Edema was not observed. Patients with illnesses (the targeted population) may react differently as compared to healthy individuals.

3.3.2 Pharmacokinetics

Absorption

Absorption of lumiracoxib was rapid with a median t_max of 2.3 hours. The mean plasma half-life of lumiracoxib was 3.98±1.37 hours after oral administration; the shorter half-life (2.17±0.34 h) observed after intravenous dosing is probably underestimated. Mean plasma clearance was 7.7±1.5 L/h. Based on a blood to plasma ratio of ~0.5, the mean blood clearance is estimated to be ~15 L/h which is roughly 16% of hepatic blood flow (about 90 L/h). The volume of distribution at steady state (V_ss) was 9.0±1.7 L.

The relative bioavailability of lumiracoxib was studied in 11 healthy subjects in a crossover study in which lumiracoxib (100 mg) was delivered to specific sites of the GI tract: stomach, proximal small bowel, distal small bowel and colon. The relative bioavailability compared to the reference release site of the stomach was consistently high in all regions. The t_max and C_max were lower for the stomach compared to the small bowel, presumably due to gastric emptying and dissolution effects. Mean absolute bioavailability of lumiracoxib was 74.0±8.6%.

Three studies were conducted to examine the effect of food on the bioavailability of lumiracoxib. All three studies were of a randomized crossover design in which healthy subjects received 2 x 100 mg lumiracoxib capsules, a 200 mg lumiracoxib tablet, or a 400 mg lumiracoxib tablet (65% drug load) under fasting conditions and after a high fat breakfast (FDA recommended high fat meal). While slight changes in AUC, C_max, and t_max were observed in the three studies, data suggest that lumiracoxib may be taken without regard to the timing of meals.

Distribution

The steady state pharmacokinetics (PK) of lumiracoxib were characterized over nine days in healthy subjects, over 28 and 91 days in osteoarthritis (OA) and rheumatoid arthritis (RA) patients. Following repeated oral administration of lumiracoxib to healthy subjects, both C_max and AUC_T did not exhibit significant change from Day 1 through the last day of dosing. In addition, there was no evidence for a rise in trough plasma concentrations collected throughout the multiple dose administration period. In OA/RA patients, there was no evidence for accumulation from the first dose (Day 0) compared to doses on days 28 or 91. Doses as high as 1200 mg orally in RA patients also did not result in accumulation. Thus, the pharmacokinetics of lumiracoxib are time-independent and no accumulation or auto-induction is observed.

Binding of lumiracoxib to plasma proteins was high (≥98%, almost exclusively to albumin) and independent of concentration over the 0.1 to 100 µg/mL test range. Plasma protein binding of lumiracoxib ex vivo in normal volunteers and patients with end stage renal disease requiring hemodialysis was analyzed. The mean bound percent of lumiracoxib was 98% in both patients with renal failure and in normal subjects.

Plasma protein binding of lumiracoxib was also studied ex vivo in patients with moderate hepatic impairment. The mean bound percent of lumiracoxib was 98% in both patients with moderate hepatic impairment and in normal subjects. There is no evidence that binding in synovial fluid differs from binding to plasma proteins. Human plasma protein binding of lumiracoxib and its major metabolites was investigated at a concentration of 100 µg/mL. Lumiracoxib and 4'-hydroxy-lumiracoxib, were found to have comparably high plasma protein binding with bound percents of 99.6-99.7% and 99.5%, respectively. Protein binding of 4'-hydroxy-5-carboxy-lumiracoxib and 5-carboxy-lumiracoxib was slightly lower at 97.5-98.0% and 96.5-97.0%, respectively.

Metabolism

Following oral administration of lumiracoxib to healthy subjects, lumiracoxib was subject to only a modest first-pass effect with unchanged drug accounting for most (80-90%) of the drug-related material during the first 2.5 h post dose. The metabolite 4'-hydroxy-lumiracoxib was shown to be similar in potency and selectivity to lumiracoxib in assays of inhibition of thromboxane B₂ and prostaglandin E₂ production in whole blood, and therefore may have similar COX-2 inhibitory activity in humans in vivo. The relatively low concentrations of this metabolite in both plasma and synovial fluid with respect to lumiracoxib however, suggest that it is unlikely to contribute significantly to efficacy.

Excretion

Following oral administration of 400 mg [¹⁴C]-lumiracoxib to healthy subjects, a mean of 54% of the radioactive dose was recovered in urine and a mean of 43% was recovered in feces. Means of 3.3% and 2.0% of the dose were recovered as unchanged lumiracoxib in urine and feces, respectively. Renal clearance was determined following doses of 25-800 mg to healthy subjects and was found to be typically between 0.05-0.2 L/h. Lumiracoxib is thus mainly cleared by metabolism.

Sub-Population Pharmacokinetics

PK data from subjects included in 16 studies were used in an analysis of the influence of demographic factors (age, gender, race, and body weight) on the PK of lumiracoxib. No clinically relevant treatment effects were noted with respect to any of these factors.

In an open-label study, eight subjects with end stage renal disease (ESRD) and eight matched healthy controls each received an oral dose of 200 mg lumiracoxib. The AUC of lumiracoxib in ESRD patients was about 27% lower than in healthy subjects, and neither AUC nor C_max appeared to be influenced by dialysis. Treatment with lumiracoxib is not recommended in patients with advanced renal disease.

The PK of lumiracoxib was also examined in patients with moderate hepatic impairment. AUC was increased by only 1%, therefore no dose adjustment is required in patients with mild to moderate hepatic impairment. The impact of severe hepatic impairment has not been assessed.

As lumiracoxib is cleared principally by metabolism catalyzed by CYP2C9, there exists a possibility of a group of poor metabolizers in the general population, with consequent potential for increased exposure and possible loss of COX-2 selectivity. This has been studied in vitro and in vivo. No correlation between the CYP2C9 genotype and exposure to lumiracoxib was observed. The data support the use of lumiracoxib in the general population without concern for loss of COX-2 selectivity in patients who possess CYP2C9 genotypes which bear a potential for lower clearance of drugs mainly metabolized by CYP2C9.

With respect to drug-drug interactions, lumiracoxib appears to have a low potential for interactions with compounds cleared by cytochrome P450. Interactions of clinical significance resulting from plasma protein binding effects of lumiracoxib on other drugs or by effects of co-administered drugs on lumiracoxib are not anticipated. No significant effect on the PK of lumiracoxib was noted when taken concomitantly with omeprazole or antacids, and lumiracoxib was not found to influence treatment with methotrexate or oral contraceptives.

Healthy volunteers were pre-treated with multiple-doses of fluconazole, then concomitantly administered lumiracoxib. The modest effect of fluconazole on lumiracoxib pharmacokinetics may suggest that under conditions of inhibition of CYP2C9, an alternative route of clearance is available for lumiracoxib, likely via an alternative metabolic pathway. As lumiracoxib may form an acyl glucuronide directly, this seems to be a likely alternative pathway, however other mechanisms cannot be excluded.

In a parallel group study, healthy subjects were treated with warfarin, warfarin and lumiracoxib, or warfarin and placebo administered concomitantly for five days. This study suggests that the PK of substrates less sensitive to CYP2C9 inhibition than warfarin are unlikely to be affected by co-administration with lumiracoxib. On the basis of the pharmacodynamic (PD) analysis in this study, additional monitoring of anticoagulant activity should be conducted in patients receiving warfarin, particularly in the first few days after initiating or changing lumiracoxib therapy. This admonition regarding testing patients on anticoagulants is generic to all selective COX-2 NSAIDs. Bleeding problems (some fatal) were reported in some patients in post-marketing reports.

3.3.3 Clinical Efficacy

The efficacy of 100 mg lumiracoxib once daily (o.d.) in the treatment of the signs and symptoms of knee OA was evaluated in two new double-blind, phase III placebo- and active-controlled OA studies (Study 2360, n=1551, and Study 2361, n=1684) comparing the efficacy and safety of 100 mg lumiracoxib o.d.) to that of placebo and 200 mg celecoxib o.d. for 13 weeks, followed by extension phases of 52 weeks. Study 2360 was extended to 52 weeks as an open-label, long-term efficacy/safety study in patients treated with 100 mg lumiracoxib o.d., while Study 2361 was extended to 52 weeks as an active-controlled efficacy/safety study in patients treated with 100 mg lumiracoxib o.d. or 200 mg celecoxib o.d.

Three co-primary efficacy variables were used in the two pivotal trials: OA pain intensity at 13 weeks in the target joint in the last 24 hours, the patient's global assessment of disease activity at 13 weeks, and the total score of the Western Ontario and McMaster Universities (WOMAC) questionnaire at 13 weeks. Key secondary variables were also evaluated; the OMERACT-OARSI response, and other common secondary variables (PASS and MPCI).

Data from the two major efficacy studies showed superior efficacy of 100 mg lumiracoxib o.d. to placebo and comparable efficacy to 200 mg celecoxib o.d. at 13 weeks for all three co-primary variables.

Treatment with 100 mg lumiracoxib o.d. resulted in improvement throughout the 52-week time points in overall pain, patient and physician global assessments, OA-specific pain (e.g., walking, stair climbing, resting, standing upright), stiffness (in the morning and later in the day), and functional physical measures of OA (as quantified by the WOMAC questionnaire or the AUSCAN Hand Osteoarthritis Index).

3.3.4 Clinical Safety

The relevant safety data for lumiracoxib was presented in three separate safety datasets. In each dataset, clinical studies were grouped based on similarities in the study design, patient population, and exposure. Dataset 1 represented pooled safety data from 13 short-term OA studies of up to 13 weeks exposure, dataset 2 represented pooled safety data from three long-term OA studies of up to one year exposure, and dataset 9 represented pooled safety data from 23 combined short and long-term OA and RA studies of up to one year exposure. All three datasets included safety data from patients taking 100 mg lumiracoxib o.d. as well as higher doses. In datasets 1 and 9, the safety of lumiracoxib was compared to that of different selective COX-2 inhibitors, non-selective NSAIDs, and placebo. In dataset 2, the safety of lumiracoxib at doses of 100, 200, and 400 mg o.d. was compared to that of 200 mg celecoxib o.d. with no placebo comparison.

Safety data also included results from a large GI outcome study (TARGET); an international, double-blind, phase III study conducted to further investigate the GI safety of lumiracoxib. In the TARGET study, 18,325 OA patients were randomized to receive treatment with 400 mg lumiracoxib o.d. (a supra-therapeutic dose, four-times the maximum recommended chronic daily dose), 500 mg naproxen twice daily (b.i.d.) or 800 mg ibuprofen three times daily (t.i.d.) for one year. TARGET was prospectively designed to include patients who were taking low-dose aspirin (75-100 mg daily) for primary or secondary prevention of coronary heart disease.

In standard clinical trials, lumiracoxib was evaluated for safety in approximately 18,500 patients combined, including approximately 15,850 patients with OA and 2,650 patients with RA. Of those, approximately 1,850 OA patients were treated with 100 mg lumiracoxib o.d. for 3 months, and approximately 750 patients were treated with 100 mg lumiracoxib o.d. for one year.

Compared to the other NSAID comparators used in the clinical program for the study of lumiracoxib, the following safety conclusions could be drawn:

1) A superior gastrointestinal safety profile relative to non-selective NSAIDs
GI toxicity leading to ulcers, perforations, and bleeding is one of the major health risks associated with NSAID therapy and accounts for significant mortality and morbidity. An enhanced GI safety profile for lumiracoxib compared to non-selective NSAIDs was clearly demonstrated in all clinical safety datasets. GI AEs and ulcers were reported much less frequently with lumiracoxib than with non-selective NSAIDs. In long-term OA studies, GI adverse events (AEs) and ulcers were also less frequently reported with 100 mg lumiracoxib o.d. (the indicated dose in the current submission) compared to 200 mg celecoxib o.d. (the only other COX-2 selective inhibitor currently authorised in Canada).

A superior GI safety profile for lumiracoxib compared to non-selective NSAIDs was also demonstrated in the TARGET study. A highly statistically significant 79% reduction in complicated ulcers [perforations, obstructions, bleeds (POBs)] of the upper GI tract was demonstrated with the use of a four-fold supra-therapeutic dose of 400 mg lumiracoxib o.d. dose vs. the use of naproxen and ibuprofen in patients not taking low-dose ASA. A highly significant 66% reduction in POBs in favor of lumiracoxib vs. the combined non-selective NSAIDs was also seen in the overall study population (including patients taking low-dose aspirin). Furthermore, the risk of upper GI tract (UGIT) ulcer complications and/or symptomatic ulcers [perforations, ulcers, and bleeds (PUBs)] was significantly lower with lumiracoxib vs. non-selective NSAIDs in patients not taking low-dose ASA and in the overall study population. In the TARGET study, the GI benefit of lumiracoxib versus non-selective NSAIDs was decreased when low-dose ASA treatment was added. Consequently, the reduction in serious GI adverse events was not statistically significant for lumiracoxib compared to non-selective NSAIDs in patients taking both lumiracoxib and low-dose ASA. However, both for POBs and PUBs, there was a consistent numerical advantage for lumiracoxib compared to either non-selective NSAIDs in the subgroup of patients taking ASA simultaneously with lumiracoxib.

2) Fewer hypertensive adverse events compared to other NSAIDs
In the TARGET study, the incidence rates of increases in mean systolic or diastolic blood pressure were significantly less with a four-fold supra-therapeutic dose of 400 mg lumiracoxib o.d. compared to ibuprofen or naproxen. Furthermore, there was a significantly lower incidence rate of de novo or aggravated hypertensive AEs with lumiracoxib compared to ibuprofen.

Hypertension was also less frequently reported with 100 mg lumiracoxib o.d. compared to 200 mg celecoxib o.d. in long-term OA studies. In combined short and long-term OA/RA studies, hypertension was reported with a similar frequency for both 100 mg lumiracoxib o.d. and 200 mg celecoxib o.d., but was reported with a lower frequency for 100 mg lumiracoxib o.d. compared to non-selective NSAIDs.

In the one-year OA studies with lumiracoxib at a daily dose of 100 mg, hypertension and edema were observed in 3.3% and 2.6% of patients, respectively. In the TARGET study, the rates of hypertension in the overall patient population taking 400 mg lumiracoxib o.d. and common therapeutic doses of naproxen and ibuprofen were 5.1%, 5.6%, and 7.2%, respectively. These differences were not statistically significant, except for lumiracoxib vs. ibuprofen. The corresponding rates for edema were 3.6%, 3.1%, and 4.3%, respectively.

3) No statistically significant increase in cardiovascular risk relative to other currently authorised NSAIDs
No increase in the risk of myocardial infarction (MI), cardiovascular (CV) death, or stroke was observed with lumiracoxib compared to placebo in short-term OA studies (up to 13 weeks). Fewer CV ischemic events were reported with 100 mg lumiracoxib o.d. compared to 200 mg celecoxib o.d. in both short and long-term (up to one year) OA studies.

In the TARGET study, the treatment groups demonstrated no significant differences in the total number of patients with confirmed or probable cardio- and cerebro-vascular severe adverse events (SAEs). The incidence of the APTC (Anti-Platelet Trialists' Collaboration) composite CV endpoint (including the incidence of clinical or silent MI, stroke, and CV death) with a four-fold supra-therapeutic dose of 400 mg lumiracoxib o.d. was not statistically significantly different from that with the non-selective NSAIDs naproxen and ibuprofen. For patients with pre-existing CV risks or those taking low dose aspirin, the risks of CV events with lumiracoxib were no greater than those with naproxen or ibuprofen. The incidence of MI was similar for lumiracoxib and ibuprofen whether the patients were receiving low-dose aspirin or not. An increase in the incidence of MI was observed for lumiracoxib when compared to naproxen in patients not receiving low-dose aspirin. However, this increase in the incidence of MI did not reach statistical significance and was not seen in patients receiving low-dose aspirin.

Both the long-term OA studies and the TARGET study were conducted for only one year and hence, the CV risk associated with the long-term use of lumiracoxib for more than one year, is still undetermined.

4) No increase in edema or hematological risk relative to other NSAIDs
Edema was less frequently reported with 100 mg lumiracoxib o.d. compared to non-selective NSAIDs in short-term OA studies. In long-term OA studies, the incidence of edema was similar for the two COX-2 selective inhibitors lumiracoxib (100 mg o.d.) and celecoxib (200 mg o.d.). In combined short- and long-term OA/RA studies, edema was reported less with 100 mg lumiracoxib o.d. and other selective COX-2 inhibitors compared to non-selective NSAIDs. In the TARGET study, edema was reported with similar frequencies in both naproxen and lumiracoxib patients but was slightly less frequent in patients treated with 400 mg lumiracoxib o.d. compared to patients treated with 800 mg ibuprofen t.i.d.

In short-term OA studies, less frequent decreases in hemoglobin, hematocrit, neutrophils, and lymphocytes were reported with lumiracoxib compared to non-selective NSAIDs. The percentage of patients with hematological abnormalities was slightly lower for 100 mg lumiracoxib o.d. compared to 200 mg celecoxib o.d. in long-term OA studies.

5) No increase in serious skin adverse reactions compared to other NSAIDs and no new safety concerns
There was no incidence of serious skin adverse reactions in pre-approval clinical studies with lumiracoxib, but a few cases of serious skin reaction have been reported with lumiracoxib in the post-marketing experience. No additional risks or new types of safety problems have been identified, other than those already known and labelled as drug class effects of NSAIDs or COX-2 inhibitors.

6) An increased risk of liver abnormalities compared to other NSAIDs
Elevations in liver enzymes are a drug class effect for NSAIDs which can signal more serious liver problems. Hepatic toxicity, as indicated by elevations in liver transaminases ALT and/or AST, was noted more frequently with lumiracoxib compared to other NSAIDs in some clinical trials (long term studies at 200 and 400 mg o.d. lumiracoxib). In long-term pooled OA studies, notable elevations in ALT and alkaline phosphatase were slightly more frequent with 100 mg lumiracoxib o.d. compared to 200 mg celecoxib o.d. Increases in hepatic function enzymes were also more frequent with 200 and 400 mg lumiracoxib o.d. compared to 100 mg lumiracoxib o.d. and 200 mg celecoxib o.d. In the combined short- and long-term OA/RA studies, notable elevations and shifts from normal to high post-baseline ALT values were more frequent with all lumiracoxib doses (with a dose related trend) than with non-selective NSAIDs, other COX-2 inhibitors, or placebo.

In the TARGET study, 400 mg lumiracoxib o.d., a four-fold supra-therapeutic dose, was more hepatotoxic than the non-selective NSAID comparators naproxen and ibuprofen. ALT/AST elevations were seen in 2.6% of patients treated with Prexige compared to 0.6% of patients treated with NSAIDs. Six patients treated with 400 mg lumiracoxib o.d. had adjudicated serious hepatic AEs (significant elevations in liver function parameters accompanied by a concomitant increase in bilirubin). There were no instances of hepatic failure. After study medication withdrawal all of the patients fully recovered.

In general, lumiracoxib at a four-fold supra-therapeutic dose of 400 mg o.d. induced a higher frequency of adverse liver reactions compared to the 100 mg o.d. lumiracoxib dose and 200 mg celecoxib o.d. At 12 months, the percentage of patients with ALT >3 x ULN was 0.9% for the lumiracoxib 100 mg o.d. and 0.4% for celecoxib 200 mg o.d. groups and 2.6% and 2.2% for lumiracoxib 200 mg o.d. and 400 mg o.d., respectively (supra-therapeutic doses). For AST, the percentage of patients with notable abnormalities tended to be slightly higher in the lumiracoxib 200 mg o.d. group.

7) An increased potential for kidney dysfunction
Decreased renal function is a drug class effect for NSAIDs. Renal toxicity, as indicated by elevations in serum creatinine and decreases in creatinine clearance, was observed more frequently with lumiracoxib compared to some NSAIDs in the clinical studies. In short-term OA studies, elevations in serum creatinine were similar for 100 mg lumiracoxib o.d. and non-selective NSAIDs, but were higher for 100 mg lumiracoxib o.d. compared to 200 mg celecoxib o.d. In both short- and long-term OA/RA studies, the incidence of serum creatinine elevation >35.36 µmol/L above baseline was higher for 100 mg lumiracoxib o.d. compared to 200 mg celecoxib o.d. and displayed dose-dependent increases with increasing doses of lumiracoxib. More frequent increases in serum creatinine >35.36 µmol/L above baseline and more frequent decreases in creatinine clearance <81 mL/min, as well as similar decreases in creatinine clearance <30 mL/min (0.3% lumiracoxib 100 mg o.d. vs. 0.3% celecoxib 200 mg o.d.), were noted for 100 mg lumiracoxib o.d. compared to 200 mg celecoxib o.d. in combined short- and long-term OA/RA studies. In some clinical studies, decreased creatinine clearance and hyperkalemia were observed more frequently with 100 mg lumiracoxib o.d., whereas increased creatinine, BUN, and potassium values were more common in the All NSAIDs group. Mean increases from baseline creatinine levels tended to be lower in the lumiracoxib groups and highest in the All NSAID group.

In the TARGET study, although there was no statistically significant difference in the incidence of major renal events between the treatment groups, the increases in serum creatinine ≥100% above baseline were statistically significantly less frequent with naproxen compared to lumiracoxib, but there was no significant difference between lumiracoxib and ibuprofen. Increases in serum creatinine  100% and/or urine protein >3g/L, which were defined as major renal events in the study, were more frequent with 400 mg lumiracoxib o.d., a four-fold supra-therapeutic dose, compared to 500 mg naproxen b.i.d. or 800 mg ibuprofen t.i.d. Increases in serum creatinine >35.36 µmol/L above baseline were also more frequent with lumiracoxib compared to the two non-selective NSAIDs, and the difference was statistically significant for lumiracoxib vs. naproxen but not for lumiracoxib vs. ibuprofen.