# Presentation: 227243

## Joint Meeting of the Arthritis and Drug Safety and Risk Management Advisory Committees

- February 16-18, 2005

## Leonard M. Baum, RPh

- Vice President, Regulatory Affairs
- Bayer HealthCare
- Consumer Care Division

## Agenda

- Regulatory Overview
- Naproxen
- ADAPT Trial
- Safety Evaluation
- Clinical Pharmacology
- Clinical Studies
- Postmarketing Surveillance
- Observational Studies
- Conclusions

## Roche/Bayer Presenters and Responders

- _Presenters:_** **
**Leonard M. Baum, RPh**
- Vice President, Regulatory Affairs
- Bayer HealthCare
**Martin H. Huber, M.D.**
- Vice President, Global Head Drug Safety Risk Management
- Hoffmann La-Roche Inc.
- _Responders:_
**Susan Sacks, Ph.D.****	****	**
- Global Head, Epidemiology
- Hoffmann La-Roche Inc.
**Bharat Thakrar, Ph.D.**
- Senior Epidemiologist
- Hoffmann La-Roche Inc.

**Ernst Weidmann, M.D.**
- Head, Global Safety
- Bayer HealthCare
**Steve Zlotnick, Pharm.D**.
- Director, Medical Affairs
- Bayer HealthCare

## Outside Experts

**Kay Brune, M.D.**
- Professor and Chairman
- Department of Experimental and Clinical Pharmacology and Toxicology
- Friedrich-Alexander University Erlangen - Nuremberg
**Ian  M. Gralnek, M.D., MSHS**
- Assistant Professor of Medicine, Division of Digestive Diseases
- David Geffen School of Medicine at UCLA

## Regulatory Overview 

- Naproxen available in the United States since 1976
- Prescription currently marketed by multiple manufacturers for the treatment of RA, OA, ankylosing spondylitis, gout, juvenile RA, dysmenorrhea, tendinitis, bursitis, and pain
- Aleve (OTC) approved in 1994** **
- Currently marketed by Bayer HealthCare for temporary relief of minor aches and pains, and for the temporary reduction of fever
- Multiple generic versions

## Naproxen

- Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), belongs to the chemical class propionic acid derivatives
- Naproxen has anti-inflammatory, analgesic and antipyretic properties
- Naproxen known to inhibit platelet aggregation
- The major differences between members of the NSAID class are potency and pharmacokinetics

## Classes of NSAIDS

***Salicylic acid derivatives***
- Aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal
***Para-aminophenol derivatives***
- Acetaminophen
***Indole and indene acetic acids***
- Indomethacin, sulindac
***Heteroaryl acetic acids***
- Tolmetin, diclofenac, ketorolac
***Propionic acids***
- _Naproxen_, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin
***Anthranilic acids (fenamates)***
- Mefenamic acid, meclofenamic acid
***Enolic acids***
- Oxicams (piroxicam, meloxicam)
***Alkanones***
- Nabumetone
***Coxibs***
- Celecoxib, valdecoxib, rofecoxib (withdrawn)

*Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10**th** edition*

## Relevance of Naproxen Data

- The safety profile for naproxen is well known
- Naproxen is a reference drug for many analgesic clinical trials
- Naproxen and other non-selective NSAIDs, are important treatment options for a broad range of patients and conditions

## Naproxen Exposure Data (Rx and OTC)

**courses of therapy (2 tab x 10 days)*

## The ADAPT Trial

- NIH sponsored study
- Bayer provided naproxen sodium for investigational use
- Study Design
- Naproxen sodium 220 mg bid
- Celecoxib 200 mg bid
- Placebo
- Patient Population
- 2400 patients, age 70 years or older, for prevention of Alzheimer’s disease
- Study Duration
- Began in 2001, planned for 7 years, suspended after 3 years

*Sources: NIH News Dec 20, 2004; Washingtonpost.com Feb 1, 2005, written by Woloshin S et al.*

## Publicly Reported Events Leading to the Suspension of ADAPT 

- DSMB review on Dec. 10, 2004 did not recommend stopping the study
- The APC study was suspended due to indications of an increase in cardiovascular and cerebrovascular risk of celecoxib vs. placebo (Dec. 17, 2004)
- NIA announced ADAPT trial suspension (Dec. 20, 2004)
- Information released to public by study group, were based on preliminary findings, not through peer-reviewed journals

*Sources: Celebrex News Release Dec 17, 2004; NIH News Dec 20, 2004; *
*Washingtonpost.com Feb 1, 2005, written by Woloshin S et al.*

## Summary

- Naproxen is a non-selective COX-1 / COX-2 inhibitor
- Widely used
- Established safety profile
- Reference standard
- Unadjudicated preliminary findings of ADAPT needs to be looked at in context of the wide body of data on naproxen

## Martin H. Huber, MD

- Global Head, Drug Safety
- Hoffmann-La Roche Inc.

## Safety Evaluation

- Clinical Pharmacology
- Clinical Studies
- Post-Marketing Safety Surveillance
- Post-Marketing Clinical Studies
- Observational Studies

## Pharmacological Difference between Naproxen and COX-2 Inhibitors

- Naproxen is a non-selective COX-1 /COX-2 inhibitor
- Naproxen is known to inhibit platelet aggregation and thus, is not expected to have an increased risk of myocardial infarction

## Clinical Trials and Post-Marketing Surveillance

- Clinical trials in the prescription and OTC naproxen NDAs did not provide any evidence of an increased risk of myocardial infarction or stroke
- A review of postmarketing surveillance data showed no signal for MI or cerebrovascular accident with exposures to prescription naproxen of more than 110,000,000 patients
- A review OTC postmarketing surveillance data did not identify a signal for MI or CVA with an estimate of 550,000,000 courses of therapy

## Proportional Reporting Rate (PRR)

| Event | PRR | Significance (P value) |
| --- | --- | --- |
| Ischemic coronary artery disorders (high-level term) | 0.16 | <0.05 |
| MI (preferred terms) | 0.18 | <0.05
 |
| CNS hemorrhages and cerebrovascular accidents (high level term) | 0.16 | < 0.05 |

*Source: Evans S et al. Pharmacoepidemiology and Drug Safety 2001; 10: 483-86*

## Post-Marketing Clinical Trials

**VIGOR**
- Randomized RA patients ≥ 50 yo (or ≥ 40 yo and receiving long-term glucocorticoid therapy) into either rofecoxib 50mg qd (N=4,047) or naproxen 500mg bid (N=4,029)
- Overall rate of cardiovascular events reported in association with naproxen is consistent with that expected in this population
- MI: Rofecoxib (0.4%) vs. naproxen (0.1%)
- Ischemic cerebrovascular events: 0.2% in both arms

*Source: Bombardier C et al. NEJM 2000; 343:1520-8*

## Post-Marketing Clinical Trials

**TARGET**
- Randomized OA patients ≥ 50 yo into either lumiracoxib 400mg qd (N=9,156), naproxen 500mg bid (N=4,754) or ibuprofen 800mg tid (N=4,415)
- Naproxen arm showed lower rates for cerebrovascular events and MI:
- Stroke: Lumiracoxib (0.34%) vs. naproxen (0.25%)
- Ischemic stroke: Lumiracoxib (0.32%) vs. naproxen (0.23%)
- Hemorrhagic stroke: 0.02% in both arms
- Acute MI: Lumiracoxib (0.38%) vs. naproxen (0.23%)

*Source: Farkouh ME et al. Lancet 2004; 364: 675-84*

## Post-Marketing Clinical Trials

**TARGET (cont.)**
- Rate of MI events was lower for naproxen than ibuprofen, using lumiracoxib as the reference point for both studies

| Event* | Lumiracoxib | Ibuprofen |
| --- | --- | --- |
| CV death | 0.18% | 0.23% |
| All MI | 0.11% | 0.16% |
| Stroke | 0.18% | 0.20% |

*Source: Farkouh ME et al. Lancet 2004; 364: 675-84*

- * Given in percent of patients with confirmed or probable cardiovascular and cerebrovascular events

|  | Lumiracoxib | Naproxen |
| --- | --- | --- |
|  | 0.23% | 0.17% |
|  | 0.38% | 0.21% |
|  | 0.34% | 0.25% |

## Additional Post-Marketing Clinical Trials

**Alzheimer’s Trial**
- Randomized mild to moderate AD patients (mean age: 74 yo) into either rofecoxib 25mg qd, naproxen sodium 220mg bid, or placebo

*Source: Aisen PS et al. JAMA 2003; 289: 2819-26*

| Events | Placebo
(n=111) | Naproxen 
(N=118) | Rofecoxib 
(N=122) |
| --- | --- | --- | --- |
| Death | 1 | 1 | 2 |
| MI | 1 | 0 | 3 |
| Stroke/TIA | 1 | 3 | 3 |

## Trials with Celecoxib	

- Pooled analysis of  41 celecoxib clinical trials (White et al)
- 2271 naproxen patients
- 1 non-fatal stroke
- 1 fatal stroke
- 2 non-fatal MIs
- Naproxen (relative to celecoxib): 4/393 (1.01 per 100 patient years)
- Celecoxib (relative to NSAIDs): 56/4,969 (1.13 per 100 patient years)
- Placebo (relative to celecoxib): 3/200 (1.5 per 100 patient years)
- There is no evidence of an increased risk of MI or stroke compared to either celecoxib or placebo

- Source: White et al. Am J Cardiology 2003; 92: 411-18

## Observational Studies	

- Case control studies and retrospective cohort studies can be performed in a shorter period of time
- Opportunity to detect/evaluate relatively infrequent events
- Reflect “real world” use of the drug
- More heterogeneous populations
- Concomitant medications, concurrent illnesses
- Value of observational studies increases when these studies are done in multiple populations

*Source: Strom B, Pharmacoepidemiology 2000; Wiley and Sons*

## Summary of observational studies of naproxen and MI

***Source: Juni et al. Lancet 2004;364:2021-29***

## Sensitivity Analysis of Observational Studies

- Meta-analysis included multiple studies from same databases
- Performed analysis including only one study from GPRD and one study from Tennessee Medicaid
- Excluded Jick, Watson, Schlienger studies with GPRD and Ray (Lancet 2002, 359:118-23) study with Tennessee Medicaid
- Resulting pooled RR : 0.87 (0.72-1.03)
- No material change in conclusions of Juni et al.

## Summary

- A review of the observational studies shows no increased risk of MI with naproxen
- A review of the postmarketing surveillance data shows no signal for MI or cerebrovascular events
- The published clinical trials do not provide evidence of an increased risk of MI or cerebrovascular events
- Unadjudicated preliminary findings of ADAPT are inconsistent with the known data and pharmacologic properties of naproxen

## Conclusions

- The vast majority of data collected for over 30 years indicates no signal for naproxen and myocardial infarction or cerebrovascular accidents.
- Naproxen Rx and Aleve OTC remain safe and effective
- Naproxen remains an important treatment option for patients