VIOXX 50 mg

4047

Total number of events Cumulative Rate^†

17

29

45

0.46%

0.82%

1.81%*

Naproxen1000 mg

4029

Total number of events Cumulative Rate^†

9

15

19

0.23%

0.43%

0.60%

¹Confirmed by blinded adjudication committee, ²Number of patients remaining after 4 months were 3405 and 3395 for VIOXX and naproxen respectively, ³Number of patients remaining after 8 months were 2806 and 2798 for VIOXX and naproxen respectively, ⁴Number of patients remaining were 531 and 514 for VIOXX and naproxen respectively.

† Kaplan-Meier cumulative rate.

* p-value <0.002 for the overall relative risk compared to naproxen by Cox proportional hazard model

For cardiovascular data from 2 long-term placebo-controlled studies, see PRECAUTIONS, Cardiovascular Effects.

The VIGOR study described above compared clinically relevant outcomes. Several studies summarized below have utilized scheduled endoscopic evaluations to assess the occurrence of asymptomatic ulcers in individual patients taking VIOXX or a comparative agent. The results of outcomes studies, such as VIGOR, are more clinically relevant than the results of endoscopy studies (see CLINICAL STUDIES, Special Studies, VIGOR).

Two identical (U.S. and Multinational) endoscopy studies in a total of 1516 patients were conducted to compare the percentage of patients who developed endoscopically detectable gastroduodenal ulcers with VIOXX 25 mg daily or 50 mg daily, ibuprofen 2400 mg daily, or placebo. Entry criteria for these studies permitted enrollment of patients with active Helicobacter pylori infection, baseline gastroduodenal erosions, prior history of an upper gastrointestinal perforation, ulcer, or bleed (PUB), and/or age ≥65 years. However, patients receiving aspirin (including low-dose aspirin for cardiovascular prophylaxis) were not enrolled in these studies. Patients who were 50 years of age and older with osteoarthritis and who had no ulcers at baseline were evaluated by endoscopy after weeks 6, 12, and 24 of treatment. The placebo-treatment group was discontinued at week 16 by design.

Treatment with VIOXX 25 mg daily or 50 mg daily was associated with a significantly lower percentage of patients with endoscopic gastroduodenal ulcers than treatment with ibuprofen 2400 mg daily. See Figures 3 and 4 for the results of these studies.

Life-Table Cumulative Incidence Rate of Gastroduodenal Ulcers ≥ 3 mm** (Intention-to-Treat)

^† p < 0.001 versus ibuprofen 2400 mg

** Results of analyses using a ≥ 5mm gastroduodenal ulcer endpoint were consistent.

*** The primary endpoint was the cumulative incidence of gastroduodenal ulcer at 12 weeks.

Life-Table Cumulative Incidence Rate of Gastroduodenal Ulcers ≥ 3 mm** (Intention-to-Treat)

† p < 0.001 versus ibuprofen 2400 mg

** Results of analyses using a ≥ 5mm gastroduodenal ulcer endpoint were consistent.

*** The primary endpoint was the cumulative incidence of gastroduodenal ulcer at 12 weeks.

In a similarly designed 12-week endoscopy study in RA patients treated with VIOXX 50 mg once daily (twice the highest dose recommended for chronic use in OA and RA) or naproxen 1000 mg daily (common therapeutic dose), treatment with VIOXX was associated with a significantly lower percentage of patients with endoscopic gastroduodenal ulcers than treatment with naproxen.

A similarly designed 12-week endoscopy study was conducted in OA patients treated with low-dose enteric coated aspirin 81 mg daily, low-dose enteric coated aspirin 81 mg plus VIOXX 25 mg daily, ibuprofen 2400 mg daily, or placebo. There was no difference in the cumulative incidence of endoscopic gastroduodenal ulcers in patients taking low-dose aspirin plus VIOXX 25 mg as compared to those taking ibuprofen 2400 mg daily alone. Patients taking low-dose aspirin plus ibuprofen were not studied. (See PRECAUTIONS, Drug Interactions, Aspirin.)

Serious clinically significant upper GI bleeding has been observed in patients receiving VIOXX in controlled trials, albeit infrequently (see WARNINGS, Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation).

Occult fecal blood loss associated with VIOXX 25 mg daily, VIOXX 50 mg daily, ibuprofen 2400 mg per day, and placebo was evaluated in a study utilizing ⁵¹Cr-tagged red blood cells in 67 healthy males. After 4 weeks of treatment with VIOXX 25 mg daily or VIOXX 50 mg daily, the increase in the amount of fecal blood loss was not statistically significant compared with placebo-treated subjects. In contrast, ibuprofen 2400 mg per day produced a statistically significant increase in fecal blood loss as compared with placebo-treated subjects and VIOXX-treated subjects. The clinical relevance of this finding is unknown.

Multiple doses of VIOXX 12.5, 25, and up to 375 mg administered daily up to 12 days had no effect on bleeding time relative to placebo. There was no inhibition of ex vivo arachidonic acid- or collagen-induced platelet aggregation with 12.5, 25, and 50 mg of VIOXX.

Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis. (See PRECAUTIONS, Cardiovascular Effects.)

In a 12-week, double-blind active-controlled, non-inferiority study, 310 patients, 2 years to 17 years of age with pauciarticular or polyarticular course JRA, received the following treatments: lower-dose VIOXX 0.3 mg/kg (to a maximum of 12.5 mg) once daily in patients ≥ 2 years to ≤ 11 years of age or VIOXX 12.5 mg once daily in patients ≥ 12 years to ≤ 17 years of age; higher-dose VIOXX 0.6 mg/kg (to a maximum of 25 mg) once daily in patients ≥ 2 years to ≤ 11 years of age or VIOXX 25 mg once daily in patients ≥ 12 years to ≤ 17 years of age; NSAID comparator targeted to an effective dose in patients

≥ 2 years to ≤ 17 years of age. The response rates were based upon the JRA Definition of Improvement ≥ 30% (JRA DOI 30) criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI 30 response rates were 55% in both the VIOXX 0.6 mg/kg (to a maximum of 25 mg) and NSAID comparator treatment groups achieving the non-inferiority criterion. A single non-inferiority trial is not sufficient to support a conclusion of equivalence.

In a 52-week open-label extension to the 12-week study, 160 patients received VIOXX 0.6 mg/kg to a maximum of 25 mg once daily (patients ≥ 2 years to ≤ 11 years of age) or 25 mg once daily (patients ≥ 12 years to ≤ 17 years of age) and 67 patients ≥ 2 years to ≤ 17 years of age received NSAID comparator targeted to an effective dose. There were no unexpected safety findings.

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