Immediate-release Esomeprazole Research Articles

Impact of concomitant low-dose aspirin on the safety and tolerability of naproxen and esomeprazole magnesium delayed-release tablets in patients requiring chronic nonsteroidal anti-inflammatory drug therapy: an analysis from 5 Phase III studies

Patients receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) and concomitant low-dose aspirin (LDA) are at increased risk of gastrointestinal (GI) toxicity. A fixed-dose combination of enteric-coated (EC) naproxen and immediate-release esomeprazole magnesium (NAP/ESO) has been designed to deliver a proton-pump inhibitor followed by an NSAID in a single tablet. To examine safety data from 5 Phase III studies of NAP/ESO in LDA users (≤ 325 mg daily, administered at any time during the study), and LDA non-users, data were analyzed from 6-month studies assessing NAP/ESO versus EC naproxen in patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis (n = 2), 3-month studies assessing NAP/ESO vs celecoxib or placebo in patients with knee osteoarthritis (n = 2), and a 12-month, open-label, safety study of NAP/ESO (n = 1). In an analysis of two studies, incidences of endoscopically confirmed gastric ulcers (GUs) and duodenal ulcers (DUs) were summarized by LDA subgroups. In the pooled analysis from all five studies, incidences of treatment-emergent adverse events (AEs) (including prespecified NSAID-associated upper GI AEs and cardiovascular AEs), serious AEs, and AE-related discontinuations were stratified by LDA subgroups. Overall, 2,317 patients received treatment; 1,157 patients received NAP/ESO and, of these, 298 received LDA. The cumulative incidence of GUs and DUs in the two studies with 6-month follow-up was lower for NAP/ESO vs EC naproxen in both LDA subgroups [GUs: 3.0 vs 27.9%, respectively, for LDA users, 6.4 vs 22.4%, respectively, for LDA non-users (both P < 0.001); DUs: 1.0 vs 5.8% for LDA users, 0.6 vs 5.3% for LDA non-users]. The incidence of erosive gastritis was lower in NAP/ESO- vs EC naproxen-treated patients for both LDA users [18.2 vs 36.5%, respectively (P = 0.004)] and LDA non-users [19.8 vs 38.5%, respectively (P < 0.001)]. Among LDA users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 16.1%; EC naproxen, 31.7%; celecoxib, 22.1%; placebo, 23.2%. Among LDA non-users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 20. %; EC naproxen, 36.6%; celecoxib, 18.5%; placebo, 18.9%. For LDA users, incidences of cardiovascular AEs were: NAP/ESO, 3.0%; EC naproxen, 1.0%; celecoxib, 0%; placebo, 0%. For LDA non-users, incidences of cardiovascular AEs were: NAP/ESO, 1.0%; EC naproxen, 0.6%; celecoxib, 0.3%; placebo, 0%. NAP/ESO appears to be well-tolerated in patients receiving concomitant LDA. For LDA users, AE incidence was less than that observed for EC naproxen. For most AE categories, incidences were similar among NAP/ESO, celecoxib and placebo groups. The safety of NAP/ESO appeared similar regardless of LDA use.

Impact of a Fixed-Dose Combination of Naproxen and Esomeprazole Magnesium on Serum Thromboxane B 2 Inhibition by Low-Dose Aspirin Over 5 Days in Healthy Adults: A Phase I, Randomized, Double-Blind, Placebo-Controlled, Noninferiority Trial

Background Low-dose aspirin (LDA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are often used concomitantly; however, some NSAIDs may interfere with LDA antiplatelet activity. Objective We evaluated the impact of coadministered enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg (fixed-dose combination) on LDA-mediated platelet cyclooxygenase (COX)-1 inhibition. Methods In this Phase I, single-center, double-blind, placebo-controlled study, healthy volunteers (50–75 years) received enteric-coated LDA 81 mg once daily (QD) on days 1 to 5 (open-label), then enteric-coated LDA 81 mg QD plus either naproxen/esomeprazole magnesium or placebo twice daily (BID) on days 6 to 10 (randomized). Serum thromboxane B 2 (TXB 2) inhibition from baseline to day 11 was the primary end point. The primary analysis excluded volunteers with ≤95% inhibition at day 6. Assay sensitivity and noninferiority of naproxen/esomeprazole magnesium versus placebo were concluded if the 90% CI lower limit for percent inhibition of TXB 2 was >90.0% in both treatment groups (prespecified criterion). Tolerability was a secondary end point. Results Overall, 42 volunteers were enrolled, 40 randomized, and 32 included in the primary pharmacodynamic analysis (day 6 TXB 2 inhibition ≥95%). Most volunteers (86%) were white, and 57% were female. Mean age was 60 (7) years, and mean body mass index was 26.4 (2.6) kg/m 2. Day 11 mean serum TXB 2 inhibition was 99.1% (90% CI, 98.7–99.6) in the LDA plus placebo group (n = 18) versus 99.6% (90% CI, 99.4–99.8) in the LDA plus naproxen/esomeprazole magnesium group (n = 14). Noninferiority of naproxen/esomeprazole magnesium versus placebo was established (CI lower limit >90.0%). Adverse event (AE) incidence was 40% (n = 8/20) in the LDA plus placebo group and 15% (n = 3/20) in the LDA plus naproxen/esomeprazole magnesium group. No serious AEs or discontinuations due to AEs were observed. Conclusions This pilot investigation suggests that LDA coadministered with naproxen/esomeprazole magnesium is noninferior to LDA alone for platelet COX-1 inhibition, as measured by serum TXB 2 concentration, in healthy volunteers. ClinicalTrials.gov identifier: NCT01094483

A fixed-dose combination of naproxen and esomeprazole magnesium has comparable upper gastrointestinal tolerability to celecoxib in patients with osteoarthritis of the knee: Results from two randomized, parallel-group, placebo-controlled trials

Background. Non-steroidal anti-inflammatory drugs are associated with poor upper gastrointestinal (UGI) tolerability and increased ulcer risk, but patient adherence to gastroprotective co-therapy is frequently inadequate. A fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg was evaluated: efficacy is reported by Hochberg et al. (Curr Med Res Opin 2011;27:1243–53); tolerability findings are reported here.Patients and methods. In two 12-week double-blind, placebo-controlled, multicenter, phase III studies (PN400-307 and PN400-309), patients aged ≥ 50 years with symptomatic knee osteoarthritis randomly (2:2:1) received naproxen/esomeprazole magnesium BID, celecoxib 200 mg QD, or placebo. Tolerability end-points included: modified Severity of Dyspepsia Assessment (mSODA); heartburn severity; and UGI adverse events (AEs).Results. Overall, 619 (PN400-307) and 615 (PN400-309) patients were randomized; mSODA scores improved (baseline to week 12) in each group, with no significant treatment differences between naproxen/esomeprazole magnesium and celecoxib (95% CIs: PN400-307: –0.4, 1.9; PN400-309: –1.8, 0.6). Naproxen/esomeprazole magnesium-treated patients reported significantly more heartburn-free days versus celecoxib (95% CIs: PN400-307: 2.1, 12.7; PN400-309: 2.5, 13.4). UGI AE incidence (PN400-307: 17.3%; PN400-309: 20.3%) was similar between treatment groups. UGI AEs resulted in few discontinuations (< 4%, either study).Conclusions. Naproxen/esomeprazole magnesium has comparable UGI tolerability to celecoxib in patients with osteoarthritis.

Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials

Objective:To demonstrate that a fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg has comparable efficacy to celecoxib for knee osteoarthritis.Research design and methods:Two randomized, double-blind, parallel-group, placebo-controlled, multicenter phase III studies (PN400-307 and PN400-309) enrolled patients aged ≥50 years with symptomatic knee osteoarthritis. Following an osteoarthritis flare, patients received naproxen/esomeprazole magnesium twice daily, celecoxib 200 mg once daily, or placebo for 12 weeks.Clinical trial registration:NCT00664560 and NCT00665431.Main outcome measures:Three co-primary efficacy endpoints were mean change from baseline to week 12 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain and function subscales, and Patient Global Assessment of osteoarthritis using a visual analog scale (PGA-VAS).Results:In Study 307, 619 patients were randomized and 614 treated. In Study 309, 615 patients were randomized and 610 treated. Both naproxen/esomeprazole magnesium and celecoxib were associated with improvements (least squares mean change from baseline to week 12) in WOMAC pain (Study 307: −42.0 and −41.8, respectively; Study 309: −44.2 and −42.9, respectively), WOMAC function (Study 307: −36.4 and −36.3, respectively; Study 309: −38.9 and −36.8, respectively), and PGA-VAS (Study 307: 21.2 and 21.6, respectively; Study 309: 29.0 and 25.6, respectively). A prespecified non-inferiority margin of 10 mm between naproxen/esomeprazole magnesium and celecoxib was satisfied for each co-primary endpoint at week 12 in both studies. Significant improvements were observed with naproxen/esomeprazole magnesium versus placebo in both studies (p < 0.05). Celecoxib was significantly different from placebo in Study 307 (p < 0.05); however, the improvements were not significant in Study 309. Acetaminophen use and patient expectation of receiving active treatment (80% probability) may have contributed to a high placebo response observed.Conclusions:Naproxen/esomeprazole magnesium has comparable efficacy to celecoxib for the management of pain associated with osteoarthritis of the knee over 12 weeks.

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

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.

Safety aspects and rational use of a naproxen + esomeprazole combination in the treatment of rheumatoid disease

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for reduction of pain and inflammation, particularly in the setting of rheumatologic disorders. While effective, they are associated with risks, including nephrotoxicity, gastrointestinal inflammation, peptic ulcer disease, and worsened cardiovascular outcomes. After development of cyclo-oxygenase 2 inhibitors to minimize gastrointestinal complications, early use revealed increased cardiovascular event rate risk, and retrospective analysis of traditional NSAIDs revealed similar concerns, with the exception of naproxen. PN400 is a fixed-dose combination formulation designed to provide sequential delivery of a nonenteric-coated, immediate-release esomeprazole 20 mg mantle followed by an enteric-coated naproxen 500 mg core. This review summarizes the pharmacokinetics, benefits, safety, and tolerability of PN400. Phase I trials demonstrated pharmacokinetics consistent with its formulation, and at different esomeprazole combination doses, PN400 containing esomeprazole 20 mg was the lowest dose that still resulted in substantial sustained increases of gastric pH > 4. In two Phase III trials (Study 301 and Study 302), PN400 resulted in a significant reduction in gastric ulcers relative to enteric-coated naproxen (4.1% to 23.1% in Study 301, 7.1% to 24.3% in Study 302). Discontinuation due to NSAID-associated upper gastrointestinal adverse events or duodenal ulcers was significantly less in PN400 patients (3.2% to 12%, P < 0.001, in Study 301; 4.8% to 11.9%, P = 0.009, in Study 302). Two subjective patient indices were utilized to assess tolerability, ie, the Severity of Dyspepsia Assessment (SODA) and Overall Treatment Evaluation of Dyspepsia (OTE-DP). Patients with PN400 had significantly better upper gastrointestinal tolerability compared with those treated with enteric-coated naproxen in terms of SODA scores, proportion of heartburn-free patients, and OTE-DP response. While no formal recommendations are available at this time for use of this new combination medication, it will likely become an important treatment option with application for many patients.

Correlation of Two Patient-Reported Outcomes to Assess Dyspepsia: Patients Listening to Their Gut Feeling: 2010 Presidential Poster

Purpose: Results from two identical 6-month, multicenter, randomized, double-blind, parallel-group, controlled, Phase 3 studies, involving H. pylori-negative patients aged ≥50 yrs or 18-49 yrs with a history of ulcer, have shown a reduced incidence of endoscopic gastric ulcers and improved upper gastrointestinal (UGI) tolerability (including patient-reported outcomes [PROs]) with a fixed-dose combination of enteric-coated (EC) naproxen 500 mg and immediate-release esomeprazole 20 mg vs. EC naproxen 500 mg (Goldstein, et al. Aliment Pharmacol Ther 2010; in press). PRO assessments of dyspepsia included the Severity Of Dyspepsia Assessment (SODA; a validated 17-question tool measuring domains of pain intensity, non-pain symptoms, and satisfaction with a 7-day recall period) and the Overall Treatment Evaluation of Dyspepsia (OTE-DP; a short tool that assesses change in upper abdominal pain and/or discomfort as better, worse, or same since start of treatment). The aim of this analysis was to determine if a correlation exists between the SODA and OTE-DP findings. Methods: In this combined post-hoc analysis, a Spearman's correlation coefficient (CC) was used to evaluate the relationship between the three SODA domains (assessed at baseline and Months 1, 3, and 6) and OTE-DP outcomes (assessed at Month 6). Correlations were derived using mean change in SODA score from baseline to Month 6 (or last visit) and OTE-DP scores at Month 6 using a 15-point scale (same=0; better=1 to 7; worse=-1 to -7); no treatment effect was considered.Results: A total of 861 patients were randomized (Study 301, n=438; Study 302, n=423); of these, 735 (Study 301, n=378; Study 302, n=357) with both SODA and OTE-DP scores were included in this analysis. Both SODA and OTE-DP scores trended in the same direction; a moderate yet significant treatment-independent correlation was observed between each of the three SODA domain scores and OTE-DP scores (table). Conclusion: In conclusion, OTE-DP outcomes appear to correlate consistently with SODA scores for the evaluation of NSAID-associated dyspepsia in each of these studies. The combined data provide a stronger estimate of the correlation magnitude. Based on these findings, OTE-DP may provide a valid and simpler tool than SODA for the practicing physician to measure dyspepsia, and may offer an alternative to SODA in trials evaluating the UGI tolerability of NSAIDs. Disclosure: Dr Goldstein - consultant, speakers bureau, advisory committee member, independent contractor, research/educational grants: AstraZeneca; consultant, independent contractor, research grant: POZEN. Dr Datto - Employee: AstraZeneca Ms Hwang: Employee: AstraZeneca These studies were sponsored by POZEN Inc. Medical writing support was provided by James Sampayo of Complete Medical Communications, funded by AstraZeneca.

Rational use of nonsteroidal anti-inflammatory drugs and proton pump inhibitors in combination for rheumatic diseases

Correspondence: wolfgang w Bolten Division of Rheumatology, Klaus-Miehlke Klinik, Leibnizstrasse 23, 65191 wiesbaden, Germany Tel +49 611 575811 Fax +49 611 575888 email wbolten@em.uni-frankfurt.de Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are successfully used to alleviate pain and inflammation in rheumatic diseases. In an appreciable percentage of cases, the use of systemic NSAIDs is associated with adverse lesions of the gastrointestinal (GI) mucosa up to life-threatening perforations, ulcers, and bleeding. Reliable warning signals mostly do not arise. Therefore, it is important to take preventive measures to reduce the GI risk. One established method is to assign cyclooxygenase 2 (COX-2)-specific inhibitors (coxibs) instead of traditional NSAIDs (tNSAIDs). Coxibs spare in part the endogenous gastroprotective mechanisms. Another reliable choice to improve the GI safety is the comedication of proton pump inhibitors (PPIs) to suppress gastric acid. A fixed NSAID/PPI combination ensures expected protective effects by improving patients’ PPI adherence and physicians’ PPI prescription persistence. A fixed combination of enteric-coated naproxen and immediate-release esomeprazole has just been approved by the US Food and Drug Administration. PPI combinations with aspirin, other tNSAIDs, and coxibs are desirable. Patients in all risk groups, even patients at low risk of GI adverse events, benefit from concomitant protective measures. Moreover, the literature suggests that NSAID/PPI combinations are cost effective, including for patients in low-GIrisk groups. Pricing of fixed NSAID/PPI combinations will play a pivotal role for their broad acceptance in the future.

Clinical trial: evaluation of gastric acid suppression with three doses of immediate‐release esomeprazole in the fixed‐dose combination of PN 400 (naproxen/esomeprazole magnesium) compared with naproxen 500 mg and enteric‐coated esomeprazole 20 mg: a randomized, open‐label, Phase I study in healthy volunteers

PN 400 is a fixed-dose combination formulated to provide sequential delivery of immediate-release (IR) esomeprazole and enteric-coated (EC) naproxen. To evaluate gastric acid suppression with three doses of esomeprazole in PN 400 compared with EC esomeprazole 20 mg. In this Phase I, randomized, open-label study, 28 healthy adults received PN 400 b.d. (naproxen 500 mg plus esomeprazole 10, 20 and 30 mg) and non-EC naproxen 500 mg b.d. plus EC esomeprazole 20 mg o.d., each for 9 days in a crossover fashion. The primary endpoint was percentage of time on day 9 that intragastric pH was >4.0; secondary endpoints included pharmacokinetics and safety. Day 9 percentage of time where intragastric pH was >4.0 was 76.5%, 71.4%, 40.9% and 56.9% [corrected] for PN 400 containing 30, 20 and 10 mg esomeprazole, and naproxen plus esomeprazole 20 mg respectively. This was significantly greater for PN 400 containing 30 and 20 mg esomeprazole vs. naproxen plus esomeprazole 20 mg (95% CI: 13.0-26.0 and 7.8-20.7 respectively). The pharmacokinetics of PN 400 were consistent with its formulation. No serious adverse events occurred. PN 400 containing 20 mg esomeprazole was the lowest dose to achieve gastric acid suppression comparable to EC esomeprazole 20 mg and was selected for further evaluation.

Clinical trial: the incidence of NSAID‐associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric‐coated naproxen alone

Gastroprotective co-therapy may reduce the risk of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers, but adherence is suboptimal. To compare the incidence of gastric ulcers with PN 400 [enteric-coated (EC) naproxen 500 mg and immediate-release esomeprazole 20 mg], or EC naproxen. Two randomized, double-blind, multicentre studies (PN400-301, PN400-302). Patients [stratified by low-dose aspirin (< or =325 mg) use] aged > or =50 years or 18-49 years with a history of ulcer, received PN 400 BID (301, n = 218; 302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210) for 6 months. The primary endpoint was the cumulative incidence of endoscopic gastric ulcers. The cumulative incidence of gastric ulcers was significantly lower with PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs. 24.3%, P < 0.001). PN 400 was associated with a lower combined incidence of gastric ulcers vs. EC naproxen in low-dose aspirin users (n = 201) (3.0% vs. 28.4%, P < 0.001) and non-users (n = 653) (6.4% vs. 22.2%, P < 0.001). The incidence of, and discontinuations due to, upper gastrointestinal (UGI) AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01, both studies). PN 400 significantly reduces the incidence of gastric ulcers, regardless of low-dose aspirin use, in at-risk patients, and is associated with improved UGI tolerability relative to EC naproxen (ClinicalTrials.gov, NCT00527782).

T1972 Pharmacokinetics of Naproxen and Esomeprazole in PN400, a Single-Tablet, Multilayer Formulation of Enteric-Coated Naproxen Coupled with Immediate-Release Esomeprazole

T1972 Pharmacokinetics of Naproxen and Esomeprazole in PN400, a Single-Tablet, Multilayer Formulation of Enteric-Coated Naproxen Coupled with Immediate-Release Esomeprazole