Long-term safety of naproxen and esomeprazole magnesium fixed-dose combination: phase III study in patients at risk for NSAID-associated gastric ulcers

Abstract

Objective:

To evaluate long-term safety of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg fixed-dose combination (FDC) in patients at risk of NSAID-associated upper gastrointestinal (UGI) ulcers.

Research design and methods:

In this open-label, multicenter, phase III study, Helicobacter pylori-negative patients aged ≥50 years or 18–49 years with history of uncomplicated ulcer within the past 5 years, who had osteoarthritis, rheumatoid arthritis, or other condition requiring daily NSAIDs for ≥12 months received naproxen/esomeprazole twice daily for 12 months.

Clinical trial registration:

NCT00527904.

Main outcome measures:

Adverse events (AEs), vital signs, physical examination, and laboratory tests. Subgroup analyses included age and low-dose aspirin (LDA) use. Predefined NSAID-associated UGI and cardiovascular AEs were analyzed.

Results:

Of 239 patients treated (safety population), 135 completed ≥348 treatment days (12-month completers). AE incidence was approximately 70%; dyspepsia, constipation, upper respiratory tract infection, nausea, back pain, and contusion were most frequent (≥5% patients, either population). Treatment-related AEs occurred in 28.0% and 23.7% of patients in the safety and 12-month completer populations, respectively; 18.8% of patients withdrew due to AEs (safety population). Few serious AEs and no deaths occurred. In the safety population, AE incidence was 71.4% and 76.9% in patients aged <65 years (n = 161) and ≥65 years (n = 78), respectively, and 67.6% and 75.8% in LDA users (n = 74) and non-users (n = 165), respectively. Predefined UGI and cardiovascular AEs were observed in 18.8% and 6.3% of patients, respectively, in the safety population, and 16.3% and 5.2%, respectively, in 12-month completers. Dyspepsia and hypertension were most common. Additional assessments showed no unexpected findings.

Conclusions:

Based on these outcome measures, long-term treatment with FDC naproxen/esomeprazole is not associated with any new safety issues, including predefined UGI and cardiovascular AEs, in patients requiring NSAID therapy who are at risk of UGI complications.

Key words::

• Drug combinations
• Drug safety
• Esomeprazole
• Long-term
• Naproxen
• NSAIDs
• Upper gastrointestinal

Transparency

Declaration of funding

This study was sponsored and conducted by POZEN Inc.

Declaration of financial relationships

M.S., L.E., and K.V. are employees of AstraZeneca. J.F. is an employee of POZEN Inc. with stock ownership. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

We thank Lynsey Stevenson, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca.