The role of dexlansoprazole modified-release in the management of gastroesophageal reflux disease

Abstract

Dexlansoprazole modified-release (MR) is the R-enantiomer of lansoprazole and is currently the only proton-pump inhibitor (PPI) with a novel dual delayed release (DDR) formulation. Overall, dexlansoprazole MR demonstrates a similar safety and side-effect profile as lansoprazole. Dexlansoprazole MR has been shown to be highly efficacious in healing erosive esophagitis, maintaining healed esophageal mucosa in patients with erosive esophagitis and controlling symptoms of patients with nonerosive reflux disease (NERD). Recent studies have also demonstrated that dexlansoprazole MR is highly effective in improving nocturnal heartburn, gastroesophageal reflux disease (GERD) related sleep disturbances and bothersome regurgitation. Dexlansoprazole MR is well tolerated and can be taken without regard to food.

Introduction

Gastroesophageal reflux disease (GERD) is a common condition with a prevalence of 10–20% in the Western world and an annual incidence of 0.38–0.45%.¹ The range of GERD prevalence estimate is 18.1–27.8% in North America and 8.8–25.9% in Europe.² In the United States (US), 20% of the population experience GERD-related symptoms weekly and 7% daily.^1,3 Several studies have demonstrated that patients with GERD have reduced health-related quality of life and work productivity. GERD is the most common outpatient gastroenterology diagnosis in the US with a concomitant significant economic burden.

There are three GERD phenotypes, where the most prevalent is nonerosive reflux disease (60–70%), followed by erosive esophagitis (30%) and Barrett’s esophagus (6–12%).^4,5

During the last three decades, the mainstay of GERD treatment has been acid suppression. Multiple studies have demonstrated that proton-pump inhibitors (PPIs) provide superior therapeutic efficacy in the management of GERD than other antireflux medications such as histamine 2 receptor antagonists.⁶

Overall, PPIs demonstrate an unsurpassed rates of symptomatic relief and healing of esophageal inflammation as well as significant improvement in health-related quality of life in patients with erosive esophagitis.^7,8 However, despite these pharmacological advantages of current PPIs, there are still many areas of unmet need in GERD. It has been reported that approximately 10–15% of adult patients with erosive esophagitis will continue to demonstrate some level of esophageal inflammation after 8 weeks of treatment. These patients usually demonstrate moderate-to-severe esophageal inflammation (Los Angeles grades C and D) at baseline (prior treatment) and comprise approximately 25–30% of all erosive esophagitis patients.⁸ Of all patients who healed their erosive esophagitis after 8 weeks of treatment and subsequently received maintenance treatment, 15–23% with Los Angeles grades A and B and 24–41% with grades C and D relapse within 6 months.⁹ Moreover, in adult patients with nonerosive reflux disease (NERD), up to 40% remain symptomatic while on once-daily PPI.⁸ Consequently, up to 35.4% of patients and 34.8% of physicians are not fully satisfied with the outcome of PPI treatment.⁹ Furthermore, PPIs demonstrate a limited therapeutic value in controlling atypical or extraesophageal manifestations of GERD, ameliorating postprandial heartburn, relieving nighttime heartburn and improving acid control in patients with Barrett’s esophagus.¹⁰ Importantly, PPIs have to be taken prior to a meal and thus do not offer a flexible treatment schedule.

Dexlansoprazole MR (modified-release) is the seventh PPI to be introduced into the US market. Unlike the other six PPIs, which have a delayed release formulation, dexlansoprazole has a dual delayed release (DDR) technology which was designed to prolong the plasma concentration time profile in order to improve symptoms control and esophageal mucosal healing, using a once-daily dose.¹¹ The US Food and Drug Administration approved the drug on 30 January, 2009 for once-daily treatment of erosive esophagitis healing, maintaining healed erosive esophagitis and symptom control in NERD.

The following review includes all the studies that have been published thus far on the clinical value of dexlansoprazole MR and summarizes our current knowledge about the value of dexlansoprazole MR in clinical practice.

Pharmacological characteristics

Dexlansoprazole is the R-enantiomer of lansoprazole, which constitutes more than 80% of the circulating drug after administration of oral lansoprazole.¹² The drug has a lower clearance time and a 5-fold greater systemic exposure than the S-enantiomer of lansoprazole.¹²

Dexlansoprazole MR (Dexilant™, TAK-390MR, Takeda Global Research & Development Center, Inc., Deerfield, IL, USA) is a modified-release formulation of dexlansoprazole that has a unique DDR technology to deliver the drug in two discrete phases. The dexlansoprazole MR capsule contains two types of granules each with a coating that dissolves at a different pH level. The coating of one type of granules is sensitive to pH 5.5 and consequently the granules are released at the proximal duodenum. The coating of the other type of granules is sensitive to pH 6.8 and thus the granules are released at the distal ileum. Overall, 25% of the drug is released in the proximal duodenum and the other 75% in the distal ileum. As a result, administration of dexlansoprazole MR results in a dual-peak time–concentration profile as opposed to the single peak seen with regular delayed release PPIs. With only a once-a-day drug administration, the therapeutic plasma levels are markedly extended over time allowing inhibition of newly formed or active proton pumps following the initial PPI effect. Importantly, consumption of dexlansoprazole does not appear to be meal dependent. The medication can be taken before, after or during a meal with no significant alteration in the effect of the drug on intragastric pH.¹³

Overall, dexlansoprazole MR demonstrates a unique pharmacodynamic profile which likely translates to improved clinical efficacy in GERD patients.^14,15

Erosive esophagitis

There are two pivotal randomized controlled trials that assessed the efficacy and safety of dexlansoprazole MR in healing erosive esophagitis.^15,16 A total of 4092 patients with erosive esophagitis were randomized to receive dexlansoprazole MR 60 mg, dexlansoprazole MR 90 mg, or lansoprazole 30 mg once daily. Week 8 healing was assessed using a closed-testing procedure (first for non-inferiority then superiority versus lansoprazole). Secondary clinical endpoints included week 4 healing and week 8 healing in patients with moderate-to-severe erosive esophagitis (Los Angeles grades C and D), who comprised 30% of the study participants. In addition, symptoms control and drug tolerability were evaluated. Statistical assessment was performed using both life table and crude rate analyses.

Dexlansoprazole MR (30 mg and 60 mg) was non-inferior to lansoprazole 30 mg once daily. However, dexlansoprazole MR 60 mg was superior to lansoprazole 30 mg in one trial (85% versus 79% healing rates, respectively, p < 0.05) and dexlansoprazole MR 90 mg was superior to lansoprazole 30 mg in healing rates after 8 weeks of treatment in both trials (86% versus 79% and 90% versus 85%; respectively, p < 0.05). Integrated data from these two trials demonstrated that dexlansoprazole MR 90 mg was significantly better than lansoprazole 30 mg in patients with moderate-to-severe erosive esophagitis, which resulted in a therapeutic gain of 8%. This therapeutic gain suggests that an additional 25–30% of patients with moderate-to-severe erosive esophagitis, who were not healed with lansoprazole after 8 weeks of treatment, may be healed with dexlansoprazole MR 90 mg. The number needed to treat in order to prevent one treatment failure was 13 for patients with moderate-to-severe erosive esophagitis and 17 for patients with all grades of erosive esophagitis.

Both dexlansoprazole MR 60 mg and 90 mg were highly efficacious in relieving GERD-related symptoms, although not statistically better than the rate achieved in patients receiving lansoprazole 30 mg/day. More than 80% of the participants in all three treatment groups reported sustained resolution of heartburn (i.e. 7 consecutive heartburn-free days). Both dexlansoprazole MR doses were well tolerated with no dose-dependent adverse events and with a side-effect profile similar to that of lansoprazole 30 mg once daily.

In a post hoc analysis of the aforementioned phase III trial, response to treatment with lansoprazole 30 mg or dexlansoprazole MR 60 mg was greater with an increase in body mass index (BMI).¹⁷ Within each treated arm, patients with the highest BMI category (⩾30) demonstrated better symptom response rate compared with patients with the lowest BMI category (<25).

When comparing the median frequency of 24-h heartburn-free days in the different BMI categories, treatment with dexlansoprazole 60 mg led to significantly higher frequencies compared with lansoprazole 30 mg (84.8% versus 81.81%, p = 0.022), at the highest BMI category but not at lower BMI categories.

When indirect comparison of randomized controlled trials of dexlansoprazole and esomeprazole was performed, there was no statistical difference between the two medications in erosive esophagitis healing.¹⁸

Maintenance of erosive esophagitis healing

Approximately 90% of the patients with healed erosive esophagitis, who are not maintained on antireflux medication will relapse within 6 months after discontinuation of treatment.⁹ In addition, symptomatic relapse occurs in about 85% of the erosive esophagitis patients within 12 months after drug cessation.¹⁹ The aforementioned studies emphasized the importance of long term maintenance treatment in patients who receive acute treatment to heal erosive esophagitis.

Patients from the two previously mentioned erosive esophagitis healing trials were offered to participate in two randomized placebo-controlled studies that evaluated maintenance of healed erosive esophagitis over a period of 6 months. Both studies had a similar design.^15,20

In the first trial, 445 patients with healed erosive esophagitis were randomized to dexlansoprazole MR 30 mg, 60 mg or placebo once daily for 6 months.¹⁵ Dexlansoprazole MR 30 mg and 60 mg were superior to placebo for maintaining healed erosive esophagitis (p < 0.0025). Using life table analysis, maintenance rates were 75%, 83%, and 27% for dexlansoprazole 30 mg, 60 mg and placebo, respectively. Crude maintenance rates were expectedly lower at 66%, 66% and 14%, respectively. Dexlansoprazole MR controlled heartburn (median of 91–96% for 24-h heartburn-free days and 96–99% for heartburn-free nights). The other study included 451 patients with healed erosive esophagitis who were randomized to dexlansoprazole MR 60 mg, 90 mg or placebo.²⁰ Both dexlansoprazole 60 mg and 90 mg were superior to placebo for maintaining healing of erosive esophagitis (p < 0.0025). Maintenance rates were 87%, 82% and 26%, respectively, using life table analysis and 66%, 65.1% and 14% using crude rate analysis. In addition, both doses were superior to placebo for the percentage of 24-h heartburn-free days (96%, 94% and 19%, respectively) and nights (98%, 97% and 50% respectively). Both doses of dexlansoprazole MR, were well tolerated with diarrhea, flatulence, gastritis, abdominal pain and upper respiratory tract infection more common in dexlansoprazole MR than placebo, but were not dose related.

In another study, indirect comparison between dexlansoprazole MR (30 mg, 60 mg, and 90 mg) and esomeprazole [Nexium^®, Cambridge, UK (20 mg and 40 mg)], revealed no significant differences between any doses of dexlansoprazole MR and any dose of esomeprazole in maintaining healed erosive esophagitis after 6 months treatment.¹⁸

NERD

NERD is the most common phenotypic presentation of GERD. One study evaluated the efficacy and safety of dexlansoprazole MR in controlling symptoms in patients with NERD. This was a 4-week, double-blind, placebo-controlled trial.²¹ A total of 947 NERD patients were randomized to receive dexlansoprazole MR 30 mg, 60 mg or placebo once daily. All enrolled patients had to have heartburn for at least 6 months and normal esophageal mucosa on upper endoscopy. During the 7-day run-in period patients had to have at least 4 days with heartburn symptoms. Dexlansoprazole MR 30 mg and 60 mg provided a significantly better median percentages of 24-hour heartburn-free days compared with placebo (54.9% and 50.0% versus 17%, respectively; p < 0.00001). The percentage of nights without heartburn was also significantly greater in patients receiving dexlansoprazole MR 60 mg and 30 mg than placebo (80.8% and 76.9% versus 51.7%, respectively p > 0.00001). Heartburn relief was achieved as early as day 3 of treatment with dexlansoprazole MR and was maintained throughout the 4-week treatment period.

Dexlansoprazole MR also reduced symptom severity and improved quality of life. There were no statistically significant differences between dexlansoprazole MR 30 mg and 60 mg in any of the clinical endpoints. Percentages of patients experiencing treatment-emergent adverse events were similar among the different treatment groups.

In an indirect comparison of randomized controlled trials of dexlansoprazole MR versus esomeprazole,¹⁸ dexlansoprazole MR 30 mg was more effective than esomeprazole 20 mg or 40 mg [risk ratio (RR): 2.01, 95% confidence interval (CI): 1.15–33.51; RR:2.17, 95% CI: 1.39–3.38, respectively] in symptomatic control of heartburn at 4 weeks in patients with NERD.

Post hoc analyses of phase III trial data, assessed the impact of BMI on baseline heartburn symptoms severity and frequency as well as response to PPI therapy in patients with NERD and erosive esophagitis.¹⁷ A total of 621 NERD patients were stratified by BMI (<25, 25 to <30 and >30 kg/m). NERD patients received either dexlansoprazole MR 30 mg or placebo daily for 4 weeks. In NERD patients, baseline heartburn severity increased with higher BMI, but did not reach statistical significance. Treatment with dexlansoprazole MR 30 mg in NERD patients with higher BMI resulted in lower heartburn symptom severity, and higher percentage of 24-h heartburn-free days compared with patients with the lowest BMI. However, the trend did not reach statistical significance.

Refractory GERD

Thus far, only one study evaluated the value of dexlansoprazole MR in GERD patients who failed PPI once daily.²² The final analysis of the study included 142 GERD patients. All patients who were included in the study required double-dose PPI to fully control their symptoms. This was a single-blinded, multicenter study. After a 6-week screening period patients were switched to dexlansoprazole MR 30 mg plus placebo for an additional 6-week period. The authors demonstrated that after switching, heartburn remained well controlled in 88% of the patients. Furthermore, the patients were able to maintain their GERD-related symptom severity and quality of life after the switch. Table 1 depicts the percentage of patients in each PPI group who were able to switch to dexlansoprazole MR 30 mg with full control of their GERD-related symptoms.

Table 1.

Percentage of patients who remained symptomatically well controlled after stepping down to dexlansoprazole MR 30 mg once daily from a prior double-dose PPI.

Prior PPI	Percentage of patients who remained well controlled %
Esomeprazole	84.0
Lansoprazole	85.7
Omeprazole	88.1
Pantoprazole	100.0
Rabeprazole	87.5

PPI, proton-pump inhibitor.

Nighttime heartburn and sleep disturbances

Nocturnal symptoms and sleep disturbances are very common in patients with GERD. Studies have reported that up to 50% of patients with GERD suffer from nocturnal symptoms.^23,24 In addition, many patients with nighttime GERD report GERD-related sleep disturbances resulting in poor quality of sleep.²³ A prospective, randomized, double-blind, placebo-controlled study that included 305 patients with three or more nights of moderate-to-severe heartburn per week, evaluated the effect of dexlansoprazole MR 30 mg on nocturnal symptoms over a 4-week period.²⁵ Patients were randomized to two treatment arms that included dexlansoprazole MR 30 mg or placebo. Patients randomized to dexlansoprazole MR were significantly better compared with placebo in controlling nocturnal GERD-related symptoms. Overall, patients receiving dexlansoprazole MR 30 mg experienced 73.1% heartburn-free nights compared with 35.7% in those receiving placebo (p < 0.0001). Furthermore a greater percentage of patients in the dexlansoprazole MR group (47.5%) had relief of nocturnal heartburn symptoms over the last week of the study period when compared with the placebo group (19.6%; p < 0.001). Moreover, dexlansoprazole MR was significantly better than placebo in controlling GERD-related sleep disturbances (69.7% versus 47.9%, respectively; p < 0.001), which led to significantly greater improvement in sleep quality, work productivity and nocturnal symptom severity.

Regurgitation

In a post hoc analysis, the authors evaluated the impact of dexlansoprazole on heartburn versus regurgitation in patients with either NERD or erosive esophagitis.²⁶ The study included 661 NERD patients, who received either dexlansoprazole MR 30 mg, 60 mg or placebo using a randomized, double-blind 4-week trial and 1909 erosive esophagitis (EE) patients who received dexlansoprazole MR 60 mg or lansoprazole 30 mg in two 8-week, randomized, blinded trials. Assessment of symptom severity was done at baseline, at week 2 and 4 of the NERD study and at week 4 and 8 of both EE trials, using the Patient Assessment of Upper Gastrointestinal Symptom Severity questionnaire (PAGI-SYM). NERD patients receiving dexlansoprazole MR 30 mg and 60 mg experienced significantly greater improvements in symptom severity for both heartburn and regurgitation compared with placebo. This was noted at weeks 2 and 4 in heartburn and regurgitation subscales of PAGI-SYM scores. The authors concluded that dexlansoprazole MR appears to be effective in improving both heartburn and regurgitation in both EE and NERD patients and this improvement is maintained throughout the duration of treatment.

Helicobacter pylori eradication

Dexlansoprazole MR is not indicated for eradication of Helicobacter pylori (H. pylori) infection. However, because of the pharmacokinetics (PK) and pharmacodynamics (PD) of the medication, several trials evaluated its value in H. pylori eradication. In one study that was discontinued prematurely, the authors evaluated the eradication rate of amoxicillin 1 gr and dexlansoprazole 120 mg, both given twice daily for 14 days.²⁷ After recruiting 13 participants into the study, the authors had to discontinue further enrollment due to a very low eradication rate (53.8%). Interestingly, a super-high dose of dexlansoprazole (240 mg) was used in this study but still without much success.

In another study from Thailand, the authors used levofloxacin-dexlansoprazole MR-based quadruple therapy.²⁸ Patients infected with H. pylori were randomized to receive either 7 or 13 days of levofloxacin 500 mg qd, dexlansoprazole MR 60 mg bid, clarithromycin 1000 mg qd and bismuth subsalicylate 1048 mg bid). Eradication rate was assessed with a 13c urea breath test at least 4-weeks after treatment. Intention-to-treat analysis revealed 84% and 96% eradication rate for the 7 and 14-day regimens, respectively (almost reaching statistical significance).

A study also compared H. pylori eradication rates between rabeprazole-based triple therapy (rabeprazole 20 mg bid, clarithromycin 500 mg bid and amoxicillin 1 gr bid) versus dexlansoprazole MR-based triple therapy (dexlansoprazole MR 60 mg qd, clarithromycin 500 mg bid and amoxicillin 1 gr bid) given over a period of 7 days.²⁹ H. pylori eradication was assessed 6-week after cessation of treatment. Both regimens achieved similar eradication rates (dexlansoprazole MR 83.3%, rabeprazole 81.6%) by using intention-to-treat analysis. However, the authors concluded that the dexlansoprazole MR-based regimen provides several advantages over the rabeprazole-based regimen, including better compliance (once versus twice a day) and reduced cost.

Side effects

Overall, dexlansoprazole MR is well tolerated with very few side effects. Moreover in one study, fewer patients receiving dexlansoprazole MR discontinued therapy because of adverse events, when compared with placebo (p < 0.05).³⁰ Studies have also demonstrated that dexlansoprazole MR has a side-effect profile that is comparable with lansoprazole.

The safety profile of dexlansoprazole was evaluated in six controlled trials that included data from 4270 patients. In general, dexlansoprazole MR had fewer adverse events per 100 patient months compared with the lansoprazole and placebo groups (15.64–18.75 versus 21.06 and 24.49, respectively; p = NS).³⁰

The most commonly reported treatment-emergent adverse events related to dexlansoprazole (with a frequency of >2%) were nausea, diarrhea, abdominal pain, flatulence, vomiting and upper respiratory tract infections.³⁰ Diarrhea was the most common adverse event leading to discontinuation of dexlansoprazole MR therapy in 0.7% of the patients. No changes in the cardiac rhythm or in QT interval were detected in healthy volunteers who received a single dose of dexlansoprazole MR 90 mg or 300 mg.³¹ No histologic findings of concern were noted on gastric biopsies of patients receiving dexlansoprazole MR.

Chronic PPI use has been associated with a variety of complications, including gastroenteritis, osteoporosis with bone fracture, Clostridium difficile colitis, pneumonia, small bowel bacterial overgrowth, hypomagnesaemia, chronic kidney disease, ischemic heart disease, dementia and others. These complications have been suggested to be a class effect and thus it is expected that dexlansoprazole MR may pose similar risks to other PPIs. However, because the drug has been on the market for a relatively limited period of time, dexlansoprazole MR is not mentioned in many of the studies reporting complications due to long term PPI treatment.

Drug interactions

Dexlansoprazole MR is extensively metabolized in the liver by oxidation and reduction, followed by conjugation with sulphates, glucoronate and glutathione to inactive metabolites, through the cytochrome P450 (CYP) enzymatic system. Drug interaction studies demonstrated that dexlansoprazole MR and lansoprazole have the potential to inhibit the activity of CYP3A, CYP2C19, and, in the case of dexlansoprazole MR, also the potential to induce the human hepatic CYP1A. Concomitant use of dexlansoprazole MR and medications that inhibit the CYP2C19 isoenzyme can potentially increase the systemic exposure of dexlansoprazole. In contrast, CYP2C19 and CYP3A4-inducers like rifampicin can potentially reduce the plasma concentration of dexlansoprazole. However, there is currently, no evidence that concomitant administration of dexlansoprazole MR with diazepam, phenytoin, warfarin, or theophylline affects the PK of these drugs.³¹

Dexlansoprazole MR, as with any other medication that alters gastric pH, may interfere with the absorption of mediations in which bioavailability depends upon acidic gastric pH.

Dexlansoprazole MR should not be coadministered with atazanavir, an HIV protease inhibitor, due to decreased bioavailability. Other medications that should be avoided include ketoconazole, itraconazole, erlotinib, ampicillin esters, iron salts, and mycophenolate mofetil (MMF) primarily due to reduced gastric absorption because of increased intragastric pH. On the other hand, the absorption of digoxin can increase with the concomitant use of dexlansoprazole MR, so serum level monitoring of digoxin on a regular basis is recommended. Coadministration of dexlansoprazole MR and tacrolimus may also increase tacrolimus blood concentration.

In patients who require warfarin in addition to dexlansoprazole MR, their international normalized ratio (INR) and prothrombin time (PT) should be followed closely. This is more a cautionary recommendation because evidence for significant alteration in INR/PT due to concomitant use has been rarely reported.

There are conflicting data as to whether PPIs have the potential to reduce the effectiveness of clopidogrel. Clopidogrel is a prodrug that requires metabolism by hepatic CYP enzymes, including CYP2C19, to become an active metabolite that blocks platelet P2Y₁₂ adenosine diphosphate receptors.

Given the fact that PPIs inhibit CYP2C19, there has been a concern that the conversion of clopidogrel to its active metabolite is interrupted by the coadministration of a PPI. Another concern is that the elevation of intragastric pH caused by PPI consumption may decrease the absorption of clopidogrel.

A randomized, open-label, two-period, crossover study evaluated the effects of PPIs (including dexlansoprazole) on the PK and PD of clopidogrel as well as the inhibition of platelet function using three distinct platelet function assays. The study also assessed the frequency of patients who would be categorized as at risk for ischemic or thrombotic events after percutaneous coronary intervention was performed. The study demonstrated that rapid absorption of clopidogrel is unaffected by any of the PPIs studied including dexlansoprazole, lansoprazole, omeprazole and esomeprazole. All PPIs decreased the peak plasma concentrations of clopidogrel, but esomeprazole and omeprazole did so to a greater degree than lansoprazole and dexlansoprazole MR. The area under the curve for the clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole MR or lansoprazole. Moreover, esomeprazole, but not dexlansoprazole MR or lansoprazole, significantly reduced the effect of clopidogrel on the vasodilator-stimulated phosphoprotein platelet reactivity index. The authors concluded that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole MR or lansoprazole rather than esomeprazole or omeprazole.

However, despite the aforementioned results, it is important to remember that PK and PD interactions based solely on ex vivo platelet function testing have not been reliably correlated with clinical outcomes. Thus, it is recommended to be cautious, when treating patients concomitantly with a PPI and clopidogrel.

Summary

Dexlansoprazole MR’s unique formulation and PK profile may result in improved clinical efficacy in patients with GERD. While comparative trials with many of the currently available PPIs are still lacking and unlikely to be pursued in the future, dexlansoprazole has certain pharmacological features that can markedly improve compliance and adherence.

Presently, dexlansoprazole MR is indicated for the healing of erosive esophagitis (60 mg qd) for up to 8 weeks, maintenance of erosive esophagitis healing (30 mg qd) for up to 6 months and relief of symptoms of NERD patients (30 mg qd) for up to 4 weeks. However, dexlansoprazole MR has also been shown to be beneficial in patients with nocturnal GERD-related symptoms, sleep disturbances due to GERD, acid regurgitation, eradication of H. pylori and heartburn relief in obese patients.

The drug is well tolerated with a safety profile that at least is similar to that of lansoprazole. However, the prevalence of complications due to chronic use is still unknown, because of the short time since the drug has been released into the market. In addition, some studies have suggested less drug interactions when compared with other PPIs. In the US, the use of the drug has been limited by its cost and insurance reimbursement.