# FOOD AND DRUG ADMINISTRATION

DIVISION OF ANTI-INFLAMMATORY, ANALGESIC AND OPHTHALMIC DRUG PRODUCTS
\-- HFD-550

Medical Officer Review

# VIOXX 

(Rofecoxib)

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/Div File

HFD-550/PM/Folkendt
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

HFD-550/Statistics/SLin/QLi Maria Lourdes Villalba, M.D. (M.O).

HFD-550/MO/Goldkind

> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Lawrence Goldkind, M.D., Team Leader, DAIAODP

+---------------------------------------------------------------+------+
| ####### NDA \# 21-042 & 21-052, s007 -- VIOXX GI safety       | #    |
|                                                               | #### |
| ####### Table of contents                                     | ###  |
|                                                               | Page |
+---------------------------------------------------------------+------+
| **Section I. Executive Summary**                              | 5    |
|                                                               |      |
| #  Section II. Review                                         | 9    |
|                                                               |      |
| ######### Background                                          | 10   |
|                                                               |      |
| ######### General background                                  | 11   |
|                                                               |      |
| 1.  Administrative history                                    | 12   |
|                                                               |      |
| 2.  Financial disclosure information                          | 13   |
|                                                               |      |
| 3.  Relevant issues in this application                       | 14   |
|                                                               |      |
| ######### Data reviewed in this submission                    | 14   |
|                                                               |      |
| 1.  New studies                                               | 14   |
|                                                               |      |
|     1.  VIGOR study                                           | 15   |
|                                                               |      |
| > 1.1.1.1 Disposition                                         | 15   |
|                                                               |      |
| 2.  Demographics                                              | 16   |
|                                                               |      |
| 3.  Exposure                                                  | 16   |
|                                                               |      |
| 4.  Safety results                                            | 16   |
|                                                               |      |
|     1.  Deaths                                                | 20   |
|                                                               |      |
|     2.  Serious adverse events                                | 37   |
|                                                               |      |
|     3.  Dropouts due to adverse events                        | 39   |
|                                                               |      |
|     4.  Pre-specified NSAID related adverse events            | 40   |
|                                                               |      |
|     5.  Hospitalizations                                      | 42   |
|                                                               |      |
|     6.  Most common adverse events                            | 42   |
|                                                               |      |
|     7.  Laboratory adverse events                             | 47   |
|                                                               |      |
|     8.  Vital signs                                           | 48   |
|                                                               |      |
|     9.  Adverse events in Methotrexate users                  | 49   |
|                                                               |      |
|     10. Use of concomitant medications                        | 50   |
|                                                               |      |
| 5.  Efficacy                                                  | 51   |
|                                                               |      |
| 6.  VIGOR Summary of findings                                 | 52   |
|                                                               |      |
| > 1.2 Studies 089 and 090                                     | 53   |
|                                                               |      |
| 3.  Study 102                                                 | 57   |
|                                                               |      |
| 2\. Data from original NDA                                    | 57   |
|                                                               |      |
| > 2.1 Study 058                                               | 57   |
| >                                                             |      |
| > 2.2 Phase II/III OA studies                                 | 58   |
|                                                               |      |
| # 3. Post-marketing data                                      | 61   |
|                                                               |      |
| **Section III. Conclusions**                                  | 64   |
|                                                               |      |
| **Section IV. Recommendations for Regulatory Action**         |      |
+---------------------------------------------------------------+------+
| #                                                             | #    |
+---------------------------------------------------------------+------+
| #                                                             |      |
+---------------------------------------------------------------+------+

# NDA 21-042/052, s007 - VIOXX Gastrointestinal Safety

# 

#  Executive summary

1.  **[Recommendations for Regulatory Action]{.underline}: Approvable.**

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 ]{.underline}**

**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.  **Conclusions**

**2.2.1. GI safety**

1.  The sponsor demonstrated a statistically significant reduction in
    PUBs and complicated PUB's, associated with the use of rofecoxib
    compared to naproxen in this population of patients not considered
    by their physicians to have an indication for cardiovascular
    prophylaxis with low dose ASA.

> **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.

2.  The post-marketing safety profile of rofecoxib is similar to other
    NSAIDs, including the risk of GI bleeding. From May 1999 to October
    2000, the FDA post-marketing AER system received 37 unduplicated
    reports of death due to gastrointestinal complications associated
    with the use of rofecoxib. Despite a substantial risk reduction
    compared to naproxen in the VIGOR study, the risk of serious GI
    complications associated with rofecoxib is still a concern. Risk
    factors associated with serious GI complications are similar to
    those associated with conventional NSAIDs: age, prior history of
    ulcer disease, concomitant use of ASA, coumadin or other
    antiplatelet agents, and corticosteroids.

3.  Data provided by the sponsor do not support removal of the NSAID
    class GI WARNING section from the VIOXX label.

    2.  **Cardiovascular safety**

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1.  **The cumulative rate for serious CV/thrombotic events was 1.8%
    (n= 45) and 0.6% (n= 19)** in the rofecoxib and naproxen groups
    respectively over the 9-month period. The relative risk of
    developing serious CV/thrombotic events was more than twice in the
    rofecoxib group as compared to the naproxen group (RR= 2.37; 95% C.I
    1.39, 4.06; p= 0.0016, based on risk per 100 patient years). The
    difference was mainly due to the difference in the number of
    myocardial infarction (MI): 20 in rofecoxib and 4 in naproxen (crude
    rate 0.5 % and 0.1% for rofecoxib and naproxen, respectively) (RR=
    5.0; 95% C.I. 1.72, 14.3, based on risk per 100 patient years).

In view of the cardiovascular findings the sponsor conducted a subgroup
analysis of patients identified as [potential]{.underline} 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.

2.  The sponsor has suggested a possible cardio-protective effect of
    naproxen as the sole explanation for the cardiovascular findings in
    this study. Several issues are raised by this suggestion:

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a.  Inhibition of endothelial prostacyclin synthesis (a potent
    vasodilator and anti-platelet agent) by selective COX-2 inhibitors
    has been demonstrated in pre-clinical studies. The potential effect
    of unopposed thromboxane A2 production (due to lack of effect on
    platelet COX-1) has raised concern over a possible pro-thrombotic
    effect of selective COX-2 inhibitors.

b.  There are no placebo-controlled studies of naproxen in the
    prevention of cardiovascular thrombotic events.

c.  The effect size of naproxen in this study (58% decrease risk of
    serious CV thrombotic events as compared to rofecoxib over a 9-month
    period) exceeds that reported in the literature for an anti-platelet
    agent in a primary or secondary prevention setting (review Table
    14).

d.  Other studies (085, 090 and 102) suggest a trend of excess of MI in
    the rofecoxib group as compared to the active comparators.

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3.  The sponsor recommends that patients with known cardiovascular risk
    should be on

prophylactic low dose ASA, however, outstanding issues are:

a.  Whether the addition of low dose ASA will abolish the GI advantage
    of rofecoxib over naproxen.

b.  Whether any of the differences in cardiovascular findings seen
    between rofecoxib and naproxen groups will be prevented by low dose
    ASA

c.  Whether patients at no risk of cardiovascular disease (by standard
    risk factors) taking rofecoxib should be on low dose ASA.

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.

4.  In addition to the CV/thrombotic events, rofecoxib had a higher
    incidence of discontinuations due to HTN-related events \[n= 28
    (0.7%)\] as compared to naproxen \[n= 6 (0.2%)\] and a higher
    incidence of CHF-related events \[n= 19 (0.5%)\] as compared to
    naproxen \[n= 9 (0.2%)\]. More patients in the rofecoxib group
    required additional cardiovascular medication as compared to the
    naproxen group.

5.  Study 102 was a 5,500-patient study that compared rofecoxib (25
    mg/day) and naproxen (1000 mg/day) for 12 weeks and allowed the use
    of low dose ASA. This large database contains valuable information
    about the concomitant use of rofecoxib and low dose ASA as well as
    the overall safety of rofecoxib compared to naproxen at a dose
    labeled for chronic use.

**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    |
|                         |                     |                     |
|                         | N=4047 (%)          | N=4029 (%)          |
+-------------------------+---------------------+---------------------+
| a\. Deaths              | 22 (0.5)            | 15 (0.4)            |
|                         |                     |                     |
| b\. Serious AEs         | 378 ( 9.3)          | 315 ( 7.8)          |
|                         |                     |                     |
| c\. Dropouts due to AEs | 643 ( 15.9)         | 635 (15.8)          |
|                         |                     |                     |
| d\. Serious lab AEs     | 3 (0.1)             | 0 (0)               |
|                         |                     |                     |
| e\. Dropouts due to lab | 22 (0.5)            | 12 (0.3)            |
| AEs                     |                     |                     |
|                         | 338 (8.4)           | 263 (6.6)           |
| f\. Hospitalizations    |                     |                     |
+-------------------------+---------------------+---------------------+

> 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.