FOOD AND DRUG ADMINISTRATION
DIVISION OF ANTI-INFLAMMATORY, ANALGESIC AND OPHTHALMIC DRUG PRODUCTS -- HFD-550
Medical Officer Review
NDA 21-042 (capsules) and NDA 21-052 (oral solution)
S 007 (Gastrointestinal Safety)
Submission date (letter): June 29, 2000
Submission type: supplement NDA
End of Review date: March 30, 2001
Reviewer: Maria Lourdes Villalba, MD.
Drug name: VIOXX (Rofecoxib)
Applicant: Merck Research Laboratories
Pharmacologic category: NSAID (COX-2 inhibitor)
Proposed indications: Management of acute pain, dysmenorrhea and signs and symptoms of osteoarthritis.
Dosage form and route: Oral capsule, 12.5, 25 mg and 50 mg
Oral solution 12.5 mg/5ml and 25 mg/5ml
Project Manager: Sandra Folkendt
Related Reviews: Stats: Qian Li, Ph.D;
GI safety: Lawrence Goldkind, M.D.;
CV safety: Shari Targum, M.D.
Original NDA 21-042 reviews.
IND 46,894 (Rofecoxib).
OPDRA safety reviews
Orig NDA # 21042s007
HFD-550/Statistics/SLin/QLi Maria Lourdes Villalba, M.D. (M.O).
Lawrence Goldkind, M.D., Team Leader, DAIAODP
NDA # 21-042 & 21-052, s007 – VIOXX GI safety
Table of contents
Section I. Executive Summary
Section II. Review
1.2 Studies 089 and 090
2. Data from original NDA
2.1 Study 058
2.2 Phase II/III OA studies
3. Post-marketing data
Section III. Conclusions
Section IV. Recommendations for Regulatory Action
NDA 21-042/052, s007 -VIOXX Gastrointestinal Safety
In order to adequately interpret the cardiovascular and overall safety results in the VIGOR study and provide adequate labeling information, review of the complete report of study 102 (ADVANTAGE) is necessary. A review of the safety database from the ADVANTAGE trial will allow for further global safety assessment of rofecoxib at currently labeled chronic doses and in subjects requiring cardioprotective doses of aspirin.
The applicant should be informed that labeling changes cannot be made until review of safety database from the ADVANTAGE study is complete.
2. Summary of findings
2.1 Data sources:
NDA 20-042/052 supplement 007 included three new studies (088c, 085, 090), and two studies from the original NDA (study 058 and 069). Additionally, data submitted to IND # 46,894 and post-marketing data were reviewed.
Study 088c (VIGOR) was a 8,000-patient study comparing rofecoxib 50 mg daily to naproxen 500 mg BID (median exposure was 9 months). The study excluded patients who were taking or were candidates for taking low dose aspirin (ASA). Studies 085, 090 and 058 were 6-week efficacy studies of rofecoxib 12.5 and 25 mg daily that allowed concomitant use of low dose ASA. Study 069 was a pooled analysis of GI events in the entire phase II/III osteoarthritis program. Except for study 058, all studies included in study 069 also excluded the use of low dose ASA.
As part of the IND# 46,894 (rofecoxib), the applicant conducted a 12-week 5,500-patient safety study (# 102 or "ADVANTAGE"), comparing rofecoxib 25 mg daily and naproxen 500 mg BID in a population that did not exclude the use of low dose ASA. This study was completed in March 2000, however, the complete study report has not been submitted to the FDA for review. The FDA medical reviewers have requested that the complete report of study 102, be submitted for review.
2.2.1. GI safety
The cumulative incidence of PUB’s was 1.8% and 3.9% (median exposure of 9 months) for rofecoxib and naproxen, respectively. Of note, this cumulative rate is very close to the 2 – 4% rate presented in the WARNING section of the NSAID template for patients treated for one year. The cumulative incidence of complicated PUB’s was 0.5 % and 1.2 % in the rofecoxib and naproxen groups, respectively.
The target population for anti-inflammatory drugs includes a substantial number of patients who will need low dose ASA for cardiovascular prophylaxis. Adequate data on the safety of the chronic co-use of rofecoxib and low dose ASA do not exist. Studies that allowed the concomitant use of rofecoxib and low dose ASA were of short duration and not powered to detect differences in serious GI and CV events. Therefore, the exclusion of patients using low dose ASA is a serious limitation to the generalizability of the findings of the VIGOR study.
Different NSAIDs are associated with different risk of developing serious GI events. The only non-selective NSAID comparator included in this study was naproxen. Therefore, claims of GI superiority could be only be made in comparison to naproxen, not to all NSAIDs.
In view of the cardiovascular findings the sponsor conducted a subgroup analysis of patients identified as potential candidates for cardiovascular prophylaxis with low dose ASA by retrospective chart review in this study. This post-hoc analysis showed that the risk of developing a CV/thrombotic event was 14.3% and 2.9% per 100 patients years, for rofecoxib and naproxen, respectively) (RR= 4.89; 95% C.I. 1.41, 16.88; p= 0.012). For those patients in whom neither prospective physician assessment nor retrospective chart review suggested need for low dose ASA use, the risk of developing a CV/thrombotic event was 1.2% and 0.6% per 100 patient years, for rofecoxib and naproxen, respectively. (RR= 1.88; 95% C.I. 1.03, 3.45; p=0.041). Twelve of the twenty MI in the rofecoxib group and all four MI in the naproxen group were in patients who were not candidates for prophylactic aspirin, based on the sponsor’s post hoc chart review.
prophylactic low dose ASA, however, outstanding issues are:
There are no adequate data available to answer these questions. The sponsor proposes that studies 085, 090 and 058 support the safety of the concomitant use of rofecoxib and ASA. Each of these three studies was designed as an efficacy trial and neither the size (less than 1000 patients on rofecoxib taking into account all three studies) nor the duration (6 weeks) was adequate to detect significant differences in serious GI or CV events. A total of 161 patients were exposed to rofecoxib and aspirin. The dose of rofecoxib used in 085 and 090 was one fourth of the dose used in the VIGOR study.
2.2.3. Overall safety in the VIGOR study
This risk reduction in relevant GI events did not translate into an overall safety
benefit of rofecoxib over naproxen. GI safety must be assessed within the overall
safety profile of a drug. Evaluation of safety by routine parameters showed no
advantage of rofecoxib over naproxen:
Rofecoxib 50 mg
Naproxen 1000 mg
b. Serious AEs
c. Dropouts due to AEs
d. Serious lab AEs
e. Dropouts due to lab AEs
378 ( 9.3)
643 ( 15.9)
315 ( 7.8)
Body systems with the highest rate of SAE’s were the Cardiovascular (2.5 and 1.1% for rofecoxib and naproxen, respectively – crude rates -) and Digestive systems (1.2 and 2.4% for rofecoxib and naproxen, respectively – crude rates -).
Other than GI and CV, the safety profile of rofecoxib and naproxen showed a similar pattern and was consistent with that of the NSAID class, although the number of non-GI NSAID-related (liver, renal, HTN and edema-related) AE’s were consistently higher in the rofecoxib group. Safety profiles must be carefully analyzed based on events of comparable severity and seriousness. In the VIGOR study the potential advantage of decreasing the rate of complicated PUB’s was counterbalanced by the increased rate of developing serious non-GI events (particularly cardiovascular events).
It is of note that this study employed rofecoxib 50 mg/day, a dose twice the highest recommended dose for chronic use in OA. However, 50 mg/day is the dose approved for the treatment of acute pain and post-marketing data indicate that some patients take the 50 mg dose for more than a few days. Additionally, a superior organ-specific GI safety profile may be interpreted by some as enhanced overall safety, encouraging the "dose-creep" phenomenon. Therefore, the VIOXX label should reflect the overall safety data generated in this study.