An Expert Report on Dexlansoprazole (DB05351)

Executive Summary

Dexlansoprazole is a second-generation proton pump inhibitor (PPI) that represents a significant pharmaceutical refinement in the management of acid-related gastrointestinal disorders.[1] Chemically, it is the pure (R)-(+)-enantiomer of lansoprazole, a characteristic that contributes to its distinct pharmacokinetic profile.[3] The medication is primarily indicated for the healing of all grades of erosive esophagitis (EE), the maintenance of healed EE, and the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) in adults and adolescents aged 12 years and older.[4]

The defining feature of dexlansoprazole is its innovative Dual Delayed-Release (DDR) formulation. This technology incorporates two distinct types of enteric-coated granules within a single capsule, engineered to release the active drug at different pH levels and times within the small intestine.[3] This results in a unique bimodal plasma concentration profile with two peaks, one at 1-2 hours and a second at 4-5 hours post-administration.[2] The clinical consequence of this extended-release profile is a prolonged duration of acid suppression over a 24-hour period, which addresses key limitations of earlier PPIs, such as nocturnal acid breakthrough and the need for strict meal-dependent dosing.[8] This allows for the convenience of administration without regard to food, a factor that can improve patient adherence and real-world effectiveness.[6]

Clinically, while dexlansoprazole demonstrates robust efficacy in healing EE, its superiority over other potent PPIs like esomeprazole in this indication is not consistently established.[11] Its primary clinical advantages appear to lie in symptom control, particularly in patients with NERD, and in managing nocturnal heartburn due to its prolonged pharmacodynamic effect.[8]

The safety profile of dexlansoprazole is consistent with the PPI class. Common adverse effects include diarrhea, abdominal pain, and nausea.[3] It carries the established warnings for long-term PPI use, including an increased risk of

Clostridioides difficile-associated diarrhea, osteoporosis-related bone fractures, hypomagnesemia, and vitamin B12 deficiency.[13] A significant contraindication is its co-administration with rilpivirine-containing antiretroviral products, as the elevated gastric pH can severely compromise rilpivirine absorption and efficacy.[15]

In summary, dexlansoprazole is a valuable therapeutic agent within the PPI armamentarium. It is not a universally superior option for all patients with acid-related disorders, but its unique DDR formulation provides a distinct clinical niche for patients who experience significant nocturnal symptoms or for whom adherence to pre-meal dosing regimens is a challenge.

Introduction and Therapeutic Context

Acid-related disorders, most notably gastroesophageal reflux disease (GERD), represent a significant global health issue, affecting a substantial portion of the population and imposing a considerable burden on quality of life and healthcare resources.[4] GERD is characterized by the reflux of stomach contents into the esophagus, leading to troublesome symptoms like heartburn and, in more severe cases, complications such as erosive esophagitis (EE), esophageal strictures, and Barrett's esophagus.[18] The underlying pathophysiology involves excessive or prolonged exposure of the esophageal mucosa to gastric acid.

The management of these conditions has evolved significantly, with therapeutic strategies primarily focused on reducing intragastric acidity. Proton pump inhibitors (PPIs) have emerged as the cornerstone of therapy, demonstrating superior efficacy over previous drug classes like H2-receptor antagonists.[3] PPIs exert their effect by targeting the final step in the acid production pathway: the H+/K+-ATPase enzyme, or "proton pump," located in the gastric parietal cells.[1]

Dexlansoprazole is classified as a new-generation, or second-generation, PPI, developed to address specific limitations inherent in earlier agents like omeprazole, pantoprazole, and its parent compound, lansoprazole.[1] Chemically, dexlansoprazole is the dextrorotatory, or (R)-(+)-enantiomer, of lansoprazole, which is a racemic mixture of both its (R)-(+) and (S)-(-)-enantiomers.[2] This stereochemical purity contributes to a more predictable and favorable pharmacokinetic profile.[3]

The primary clinical rationale for the development of dexlansoprazole was to overcome challenges associated with first-generation PPIs. These limitations include a relatively short plasma half-life, which can lead to incomplete control of acid secretion over a 24-hour period—a phenomenon particularly problematic at night (nocturnal acid breakthrough).[2] Furthermore, the efficacy of most older PPIs is dependent on administration 30-60 minutes before a meal to ensure the drug is present in the bloodstream when the proton pumps are maximally stimulated by food. This strict dosing regimen is often a significant barrier to patient adherence, with studies indicating that up to 40% of patients may not take their PPI as directed, leading to suboptimal therapeutic outcomes.[7] Dexlansoprazole was engineered with an innovative Dual Delayed-Release (DDR) technology, a novel formulation designed specifically to provide a prolonged plasma concentration profile, enabling sustained acid suppression and offering the convenience of dosing independent of meal times.[1]

Chemical Profile and Pharmaceutical Formulation

Chemical Identity and Physicochemical Properties

Dexlansoprazole is a small molecule drug belonging to the substituted benzimidazole class of compounds.[2] Its definitive chemical identity is established through its International Union of Pure and Applied Chemistry (IUPAC) name:

2-methylsulfinyl]-1H-benzimidazole.[1] As a sulfoxide, its stereochemistry is a critical feature; it is the purified (R)-(+)-enantiomer of lansoprazole, a distinction that is fundamental to its pharmacokinetic behavior.[3] The compound is typically supplied as a white to light yellow or beige powder or crystal.[21] For research and manufacturing purposes, it is recommended to be stored under refrigerated conditions (e.g., 0-10°C or 2-8°C) and protected from air and heat.[21] A comprehensive list of its technical identifiers is provided in Table 3.1.

Table 3.1: Chemical and Physical Identifiers of Dexlansoprazole

Identifier Type	Value	Source Snippet(s)
IUPAC Name	2-methylsulfinyl]-1H-benzimidazole	1
DrugBank ID	DB05351	2
CAS Number	138530-94-6	3
PubChem CID	9578005	1
Molecular Formula	C16​H14​F3​N3​O2​S	3
Molecular Weight	369.36 g/mol	23
InChI	InChI=1S/C16H14F3N3O2S/c1-10-13(20-7-6-14(10)24-9-16(17,18,19)8-25(23)15-21-11-4-2-3-5-12(11)22-15/h2-7H,8-9H2,1H3,(H,21,22)/t25-/m1/s1	1
InChIKey	MJIHNNLFOKEZEW-RUZDIDTESA-N	1
SMILES	CC1=C(C=CN=C1C(=O)C2=NC3=CC=CC=C3N2)OCC(F)(F)F	1
Drug Class	Proton Pump Inhibitor (PPI), Small Molecule	2
Appearance	White to light yellow/beige powder or crystal	21

The Dual Delayed-Release (DDR) Formulation

The unique clinical profile of dexlansoprazole is inextricably linked to its advanced pharmaceutical formulation, known as Dual Delayed-Release (DDR) technology.[1] This formulation was not developed as a mere novelty but as a targeted, engineered solution to address well-documented clinical challenges that limited the real-world efficacy of first-generation PPIs. These challenges included the short plasma half-life of older drugs, which often resulted in inadequate control of stomach acid during the night (nocturnal acid breakthrough), and the cumbersome requirement for pre-meal dosing, a major contributor to patient non-adherence and subsequent treatment failure.[2]

The DDR system is contained within a single capsule that holds two pharmacologically distinct types of enteric-coated granules.[3] The mechanism relies on pH-dependent dissolution, which ensures the drug is released sequentially as it travels through the gastrointestinal tract:

1. First Release: Approximately 25% of the total dose is contained in granules with an enteric coating designed to dissolve at a pH of 5.5. This release occurs in the proximal duodenum, shortly after the capsule contents pass from the stomach. This initial release results in the first peak in plasma concentration, which occurs approximately 1 to 2 hours after administration.[6] This provides rapid onset of acid suppression, similar to conventional PPIs.
2. Second Release: The remaining 75% of the dose is contained in a second set of granules. These have a different enteric coating that is more robust and designed to dissolve at a higher pH of 6.75. This release occurs more distally in the small intestine. This delayed release is responsible for a second, later peak in plasma concentration, occurring approximately 4 to 5 hours after administration.[2]

The explicit purpose of this bimodal release is to extend the plasma drug concentration-time curve, thereby prolonging the duration of effective acid suppression over a full 24-hour dosing interval.[2] By maintaining therapeutic plasma levels for a longer period, especially in the latter half of the dosing interval, the DDR formulation directly targets nocturnal acid production.[8] Furthermore, this design ensures that an effective concentration of the drug is available to inhibit proton pumps that become active later in the day, independent of a large morning meal. This pharmacokinetic profile is the basis for its FDA-approved administration without regard to food, a significant advantage that simplifies the treatment regimen and directly addresses a primary cause of non-adherence and therapeutic failure in chronic GERD management.[6]

Clinical Pharmacology

Mechanism of Action

Dexlansoprazole is a potent member of the Proton Pump Inhibitor (PPI) class of medications.[1] Its therapeutic effect is achieved through the targeted and irreversible inhibition of the final common pathway of gastric acid secretion. Like other PPIs, dexlansoprazole is administered as an inactive prodrug.[26] After absorption, it is selectively concentrated in the highly acidic environment of the secretory canaliculi of gastric parietal cells.

Within this acidic compartment, dexlansoprazole undergoes a proton-catalyzed chemical rearrangement, converting it into its active form, a reactive tetracyclic sulfenamide.[26] This active metabolite then forms a stable, covalent disulfide bond with specific cysteine residues on the alpha subunit of the H+/K+-ATPase enzyme system—the proton pump.[1] The primary molecular targets are the Potassium-transporting ATPase alpha chain 1 and its associated beta subunit.[2]

This covalent binding permanently inactivates the individual enzyme, preventing it from pumping hydrogen ions (H+) from the cytoplasm of the parietal cell into the gastric lumen in exchange for potassium ions (K+).[2] By blocking this final step in the acid production pathway, dexlansoprazole profoundly suppresses both basal (fasting) and stimulated (e.g., meal-induced) gastric acid secretion, leading to a significant increase in intragastric pH.[2] Acid secretion can only resume after the synthesis of new H+/K+-ATPase enzyme molecules, a process that takes time, thus contributing to the prolonged duration of action of a single daily dose.

Pharmacodynamics

The pharmacodynamic effects of dexlansoprazole are a direct consequence of its mechanism of action and are characterized by sustained acid suppression. Clinical studies measuring intragastric pH have quantified this effect. In a head-to-head, single-dose crossover study, dexlansoprazole 60 mg demonstrated superior acid control compared to esomeprazole 40 mg. Over a 24-hour period, dexlansoprazole achieved a mean percentage of time with intragastric pH > 4 of 58%, compared to 48% for esomeprazole. The mean 24-hour pH was also significantly higher with dexlansoprazole (4.3 vs. 3.7).[8]

Critically, the analysis revealed that this difference was most pronounced during the second half of the dosing interval (>12–24 hours post-dose), where dexlansoprazole maintained a mean time with pH > 4 of 60% versus 42% for esomeprazole.[8] This finding provides a clear pharmacodynamic basis for the clinical observation that dexlansoprazole is particularly effective at controlling nocturnal acid breakthrough, directly linking its unique DDR formulation to a tangible physiological outcome.

As with all PPIs, the profound reduction in gastric acid (hypochlorhydria) leads to secondary physiological responses. The body compensates for the reduced acidity by increasing the secretion of the hormone gastrin from G-cells. This sustained hypergastrinemia can lead to enterochromaffin-like (ECL) cell hyperplasia.[2] Consequently, serum levels of both gastrin and Chromogranin A (CgA)—a marker used in the diagnosis of neuroendocrine tumors—become elevated. This can lead to false-positive results in diagnostic investigations for such tumors. To avoid misdiagnosis, it is recommended to temporarily discontinue dexlansoprazole therapy at least 14 days before assessing CgA levels and 30 days before assessing gastrin levels.[2] Additionally, upon cessation of long-term therapy, a rebound acid hypersecretion effect can occur, which is a class effect of PPIs.[2]

Pharmacokinetics (A.D.M.E.)

The pharmacokinetic profile of dexlansoprazole is largely defined by its enantiomeric purity and its unique Dual Delayed-Release (DDR) formulation.

• Absorption: The DDR formulation results in a distinctive bimodal plasma concentration-time profile. The first peak concentration (Tmax​) occurs 1 to 2 hours after administration, with a second, higher peak occurring within 4 to 5 hours.[1] This profile ensures that drug is available for absorption over an extended period. The mean maximum plasma concentration ( Cmax​) and the area under the concentration-time curve (AUC) increase in a dose-proportional manner. While food can have a variable effect on pharmacokinetic parameters, it is not considered clinically significant, which is the basis for the recommendation that dexlansoprazole can be administered without regard to meal timing.[1]
• Distribution: Following multiple doses, the apparent volume of distribution (Vz​/F) in patients with symptomatic GERD is approximately 40 L. Dexlansoprazole is highly bound to plasma proteins, with a binding percentage of 96% to 99% that remains constant across a wide range of concentrations.[1]
• Metabolism: Dexlansoprazole is extensively metabolized in the liver to inactive metabolites, with no parent drug being recovered in the urine.[1] The metabolic pathways are complex, involving oxidation, reduction, and subsequent conjugation reactions (sulfation, glucuronidation, and glutathione conjugation).[1] The primary oxidative pathways are mediated by the cytochrome P450 enzyme system. Hydroxylation is primarily carried out by CYP2C19, while oxidation to the sulfone metabolite is mediated by CYP3A4.[1]
• Excretion: The inactive metabolites of dexlansoprazole are cleared from the body via both renal and fecal routes. Following administration of a radiolabeled dose, approximately 50.7% of the administered radioactivity is excreted in the urine and 47.6% is found in the feces.[1] The terminal elimination half-life ( t1/2​) is relatively short, at approximately 1 to 2 hours, which underscores the importance of the DDR formulation in extending the drug's pharmacodynamic effect well beyond its plasma half-life.[1] The apparent clearance (CL/F) is in the range of 11.4 to 11.6 L/hour.[1] Due to its high protein binding and extensive metabolism, dexlansoprazole is not expected to be removed from circulation by hemodialysis.[2]

Table 4.3: Summary of Dexlansoprazole Pharmacokinetic Parameters

Parameter	Value	Comment/Source Snippet(s)
Tmax​ (Peak 1)	1-2 hours	First release from DDR formulation 1
Tmax​ (Peak 2)	4-5 hours	Second release from DDR formulation 1
Cmax​ (60 mg)	1397 ng/mL (51% CV)	Mean value in healthy adults 1
AUC (60 mg)	6529 ng·h/mL (60% CV)	Mean value in healthy adults 1
Half-life (t1/2​)	1-2 hours	1
Volume of Distribution (Vz​/F)	40 L	In symptomatic GERD patients 1
Plasma Protein Binding	96-99%	Concentration-independent 1
Clearance (CL/F)	11.4-11.6 L/hour	1
Major Metabolic Enzymes	CYP2C19, CYP3A4	1
Excretion Routes	Urine (~51%), Feces (~48%)	Excretion of inactive metabolites 1

Pharmacogenomics

The metabolism of dexlansoprazole is significantly influenced by genetic variations in the CYP2C19 enzyme, which is known to be polymorphic.[2] This leads to distinct patient subgroups, or phenotypes, based on their metabolic capacity:

• Extensive Metabolizers (EMs): Individuals with two fully functional alleles (e.g., *1/*1).
• Intermediate Metabolizers (IMs): Individuals with one functional and one non-functional allele (e.g., *1/*2).
• Poor Metabolizers (PMs): Individuals with two non-functional alleles (e.g., *2/*2).[2]

This genetic variability has a profound impact on the systemic exposure to dexlansoprazole. Studies in Japanese subjects, a population with a higher prevalence of PM phenotypes, have shown that compared to EMs, IMs have up to two-fold higher mean Cmax​ and AUC values. In PMs, the difference is even more dramatic, with mean Cmax​ up to four times higher and mean AUC up to twelve times higher.[29] In PMs, the metabolic burden shifts away from the deficient CYP2C19 pathway towards the CYP3A4 pathway, resulting in dexlansoprazole sulfone becoming the major circulating plasma metabolite, whereas 5-hydroxy dexlansoprazole is the primary metabolite in EMs and IMs.[2]

Despite this substantial pharmacokinetic variability, current FDA labeling and standard clinical practice do not mandate genotype-guided dosing for dexlansoprazole.[5] This apparent paradox suggests that the drug possesses a very wide therapeutic index for its approved indications. The lack of a required dose adjustment implies that even at the lower drug exposures seen in extensive metabolizers, the dose is sufficient to achieve the necessary level of acid suppression for clinical efficacy. Conversely, the significantly higher exposures in poor metabolizers do not typically lead to an unacceptable increase in toxicity, at least for the approved short- to medium-term treatment durations. This "forgiving" pharmacokinetic-pharmacodynamic relationship is a key clinical attribute. However, it also raises important considerations for nuanced clinical practice. This variability could become more clinically relevant in the context of very long-term therapy, in patients with multiple risk factors for PPI-related adverse events, or during co-administration of drugs with a narrow therapeutic index that are also metabolized by CYP2C19, such as tacrolimus, where changes in exposure can have critical consequences.

Clinical Efficacy and Therapeutic Applications

FDA-Approved Indications

Dexlansoprazole has been rigorously evaluated in numerous phase 3 clinical trials and is approved by the U.S. Food and Drug Administration (FDA) for several specific indications in adults and adolescents.[5]

• Healing of Erosive Esophagitis (EE): Dexlansoprazole is indicated for the short-term treatment (up to 8 weeks) of all grades of EE in patients 12 years of age and older.[2] Clinical trials have demonstrated its high efficacy for this purpose. In two large 8-week studies involving adults with EE, 85% to 88% of patients treated with dexlansoprazole achieved complete mucosal healing.[31] A study in adolescents (ages 12-17) with EE showed a healing rate of 88% after 8 weeks of treatment.[31]
• Maintenance of Healed Erosive Esophagitis and Heartburn Relief: Following successful healing of EE, dexlansoprazole is indicated for maintenance therapy to prevent recurrence and relieve associated heartburn. The approved duration is up to 6 months in adults and up to 16 weeks in adolescents (ages 12-17).[2] In a pivotal maintenance trial in adults, 66.4% of patients receiving dexlansoprazole remained in remission (healed) after 6 months, compared to only 14.3% of patients who received a placebo.[31]
• Treatment of Symptomatic Non-Erosive Gastroesophageal Reflux Disease (NERD): Dexlansoprazole is indicated for the treatment of heartburn associated with NERD for a duration of 4 weeks in patients 12 years of age and older.[2] In a 4-week clinical trial of adults with a history of symptomatic NERD, patients treated with dexlansoprazole experienced heartburn-free days for a median of 54.9% of the study period, a significant improvement over the 18.5% observed in the placebo group.[31]

Off-Label and Investigational Uses

While dexlansoprazole has specific FDA-approved indications, clinicians may use it for other conditions based on its mechanism of action, a practice known as off-label use.

• Gastritis: The use of dexlansoprazole for gastritis (inflammation of the stomach lining) is not an FDA-approved indication. However, because gastritis symptoms can be driven by gastric acid, it may be used off-label in certain cases to manage the condition.[31]
• Other Acid-Related Conditions: While not explicitly listed as approved indications, the powerful acid-suppressive effects of dexlansoprazole make it a plausible treatment option for other conditions where PPIs are standard of care, such as prophylaxis against NSAID-associated gastric ulcers or management of hypersecretory conditions like Zollinger-Ellison syndrome. Its use in patients with Barrett's Esophagus is also common in clinical practice to minimize acid exposure to the metaplastic tissue, although this is not a distinct FDA indication.[19]

Comparative Efficacy Analysis

A critical aspect of positioning dexlansoprazole in therapy is understanding its efficacy relative to other commonly prescribed PPIs. The evidence suggests a nuanced picture where dexlansoprazole's advantages are specific to certain indications and patient profiles, rather than demonstrating universal superiority.

• Versus Lansoprazole: As the pure R-enantiomer, dexlansoprazole provides a three- to five-fold greater area under the plasma concentration-time curve (AUC) compared to the S-enantiomer contained within racemic lansoprazole.[3] This translates to greater systemic drug exposure. In clinical trials for the healing of EE, dexlansoprazole showed numerically higher healing rates than lansoprazole, although the difference did not achieve statistical significance in all studies.[6]
• Versus Esomeprazole: This comparison is particularly relevant as both are considered second-generation, enantiomer-pure PPIs.
• For NERD: Indirect comparison meta-analyses have suggested that dexlansoprazole 30 mg provides a more significant treatment effect for heartburn symptom control at 4 weeks compared to both esomeprazole 20 mg and 40 mg.[12]
• For Healing of EE: The same indirect comparisons found no statistically significant differences in the rates of esophageal healing between the two drugs.[12]
• For Acid Control: A direct head-to-head pharmacodynamic study provided key insights. A single dose of dexlansoprazole 60 mg resulted in superior 24-hour intragastric pH control compared to esomeprazole 40 mg, an effect driven primarily by better acid suppression in the 12-24 hour post-dose interval.[8]
• Versus Other PPIs (Omeprazole, Pantoprazole): A comprehensive network meta-analysis found that standard-dose esomeprazole 40 mg demonstrated superiority over other PPIs, including omeprazole, in both mucosal healing and heartburn relief.[11] Notably, the same analysis found that dexlansoprazole 60 mg was associated with significantly more all-cause discontinuations compared to omeprazole 20 mg, pantoprazole 40 mg, and lansoprazole 30 mg, suggesting potential differences in tolerability in some patient populations.[11]

This body of evidence does not support the conclusion that dexlansoprazole is the most potent or effective PPI for all indications, particularly for the anatomical healing of severe EE, where esomeprazole has a strong evidence base. Instead, the data points to a specific clinical niche for dexlansoprazole. Its unique pharmacokinetic profile, derived from the DDR formulation, translates directly into superior 24-hour pharmacodynamic acid control. This makes it an excellent choice for managing symptoms, especially nocturnal heartburn and GERD-related sleep disturbances, and for treating NERD, where symptom control is the primary goal. Furthermore, its meal-independent dosing offers a significant convenience and adherence advantage. Therefore, the rational prescribing choice is not based on a hierarchy of universal efficacy, but on matching the drug's specific profile—prolonged symptom control and dosing flexibility—to the individual patient's clinical needs and lifestyle.

Table 5.3: Comparative Efficacy of Dexlansoprazole vs. Other PPIs in Key Clinical Endpoints

Clinical Endpoint	Comparator Drug(s)	Dexlansoprazole Finding	Source Snippet(s)
Healing of Erosive Esophagitis (8 weeks)	Lansoprazole, Esomeprazole	Effective, but not consistently superior to comparators in healing rates.	6
Maintenance of Healed EE	Placebo	Significantly superior to placebo in maintaining healing.	31
Symptom Control in NERD (4 weeks)	Esomeprazole (20 mg, 40 mg)	Indirect comparisons suggest superiority over esomeprazole for heartburn relief.	12
24-hour Intragastric pH Control	Esomeprazole (40 mg)	Head-to-head study showed superior 24-hour pH control, driven by better suppression at 12-24 hours post-dose.	8
Overall Acceptability / Discontinuation	Omeprazole, Pantoprazole, Lansoprazole	One network meta-analysis found significantly higher all-cause discontinuation rates for dexlansoprazole 60 mg.	11

Dosage, Formulations, and Administration

Available Formulations and Strengths

Dexlansoprazole is marketed by Takeda Pharmaceuticals under the brand name DEXILANT and is available in two distinct oral formulations.[1]

• DEXILANT Delayed-Release Capsules: This is the primary formulation and is available in two strengths:
• 30 mg: An opaque capsule with a blue and gray body, imprinted with "TAP" and "30".[5]
• 60 mg: An opaque, blue capsule, imprinted with "TAP" and "60".[5]
• DEXILANT SoluTab Delayed-Release Orally Disintegrating Tablets: Approved in 2016, this formulation was developed as an alternative for patients who have difficulty swallowing capsules.[15]
• 30 mg: This is the only available strength for the SoluTab. It is designed to be placed on the tongue, where it disintegrates, and the resulting microgranules are swallowed without chewing or the need for water.[15]

It is critical to note that the formulations are not directly interchangeable on a milligram basis for all indications. Specifically, the prescribing information warns that two 30 mg DEXILANT SoluTab are not interchangeable with one 60 mg DEXILANT capsule.[10]

Dosing Regimens by Indication

The recommended dosage of dexlansoprazole varies by indication and patient age, as outlined in the FDA-approved labeling. The principle of using the lowest effective dose for the shortest appropriate duration should always be applied.[13]

Table 6.2: FDA-Approved Dosing Regimens for Dexlansoprazole

Indication	Patient Population	Recommended Dosage	Duration
Healing of Erosive Esophagitis (EE)	Adults & Adolescents (≥12 years)	60 mg once daily	Up to 8 weeks
Maintenance of Healed EE & Heartburn Relief	Adults	30 mg once daily	Up to 6 months*
Maintenance of Healed EE & Heartburn Relief	Adolescents (12-17 years)	30 mg once daily	Up to 16 weeks*
Symptomatic Non-Erosive GERD	Adults & Adolescents (≥12 years)	30 mg once daily	4 weeks
*Controlled studies did not extend beyond these specified durations.4

Administration Guidelines

Proper administration is key to ensuring the efficacy of dexlansoprazole, with different rules applying to each formulation.

• DEXILANT Capsules:
• Can be taken without regard to food or the timing of meals.[5]
• Capsules must be swallowed whole and should not be chewed.[10]
• DEXILANT SoluTab:
• Must be taken at least 30 minutes before a meal.[10]
• The tablet should not be broken or cut. It should be placed on the tongue to disintegrate and then swallowed.[15]
• Alternative Administration for Capsules: For patients unable to swallow the capsules whole, the following methods are approved:

1. With Applesauce: Open the capsule and sprinkle the intact granules onto one tablespoon of applesauce. The mixture must be swallowed immediately without chewing the granules. The mixture should not be stored for later use.[27]
2. Via Oral Syringe: Open the capsule and empty the granules into a container with 20 mL of water. Withdraw the entire mixture into an oral syringe. Swirl the syringe gently and administer the contents into the mouth immediately. Refill the syringe with 10 mL of water, swirl, and administer to ensure all granules are delivered. Repeat the 10 mL water rinse a second time.[13]
3. Via Nasogastric (NG) Tube (≥16 French): Follow the same procedure as for the oral syringe, but instead inject the mixture through the NG tube into the stomach. Flush the tube twice with 10 mL of water after administration.[13]

• Missed Dose: If a patient misses a dose, they should take it as soon as they remember. However, if it is nearly time for the next scheduled dose, the missed dose should be skipped to avoid taking a double dose. The patient should then return to their regular dosing schedule.[4]

Comprehensive Safety and Tolerability Profile

Adverse Reactions

The safety profile of dexlansoprazole has been characterized through extensive clinical trials and post-marketing surveillance. In general, it is well-tolerated, with a side effect profile largely consistent with the PPI class.

• Most Common Adverse Reactions: In controlled clinical trials, the most frequently reported adverse reactions (occurring in ≥2% of patients) were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).[3]
• Less Common and Other Reported Reactions: Other adverse effects reported, with incidence not always known, include headache, gas, mouth pain, sore throat, stuffy nose, blurred vision, decreased interest in sexual intercourse, and erectile dysfunction.[4] At higher doses (e.g., 60 mg twice daily), nonserious reactions such as hot flashes, contusion, and oropharyngeal pain have been observed.[2]
• Serious Adverse Reactions: Although rare, serious adverse events can occur and require immediate medical attention. These include:
• Hypersensitivity Reactions: Anaphylaxis and other severe allergic reactions (hives, difficulty breathing, swelling of the face, lips, tongue, or throat) are possible.[4]
• Renal Effects: Acute tubulointerstitial nephritis (TIN), a form of acute kidney injury, has been reported.[4]
• Severe Cutaneous Adverse Reactions (SCARs): This includes life-threatening conditions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS).[16]
• Gastrointestinal Infections: An increased risk of severe diarrhea related to Clostridioides difficile infection.[13]
• Autoimmune Conditions: New onset or exacerbation of cutaneous and systemic lupus erythematosus.[14]
• Long-Term Effects: These are discussed in detail in the warnings section and include bone fractures, fundic gland polyps, hypomagnesemia, and vitamin B12 deficiency.[4]
• Drug-Induced Liver Injury (DILI): Based on FDA-approved labeling analysis, dexlansoprazole is categorized as having "Less-DILI-Concern" with a severity grade of 4, indicating a relatively low risk of severe liver injury.[1]

Table 7.1: Summary of Adverse Reactions (Common and Serious)

System Organ Class	Adverse Reaction	Reported Incidence/Comment	Source Snippet(s)
Gastrointestinal	Diarrhea	4.8% (most common)	3
	Abdominal Pain	4.0%	3
	Nausea	2.9%	3
	C. difficile-Associated Diarrhea	Serious; risk increased with PPI use	13
	Fundic Gland Polyps	Serious; risk with long-term use (>1 year)	14
Respiratory	Upper Respiratory Tract Infection	1.9%	3
Musculoskeletal	Bone Fracture (hip, wrist, spine)	Serious; risk with long-term/high-dose use	4
Renal and Urinary	Acute Tubulointerstitial Nephritis (TIN)	Serious; hypersensitivity reaction	4
Metabolism	Hypomagnesemia	Serious; risk with prolonged use (>3 months)	14
	Vitamin B12 Deficiency	Serious; risk with long-term use (>3 years)	4
Immune System	Anaphylaxis/Hypersensitivity	Serious; requires immediate medical attention	4
	Cutaneous/Systemic Lupus Erythematosus	Serious; new onset or exacerbation	16
Skin	Severe Cutaneous Adverse Reactions (SJS/TEN)	Serious; life-threatening	16

Warnings, Precautions, and Long-Term Safety

The use of dexlansoprazole, particularly over long periods, carries several important warnings that are characteristic of the PPI class. Clinicians should adhere to the principle of using the lowest effective dose for the shortest duration appropriate for the condition being treated.[13]

• Clostridioides difficile-Associated Diarrhea (CDAD): Observational studies suggest that PPI therapy is associated with an increased risk of CDAD, especially in hospitalized patients. This diagnosis should be considered for any patient on a PPI who develops persistent diarrhea that does not improve.[13]
• Bone Fracture: Multiple observational studies have linked long-term (a year or longer) and/or high-dose (multiple daily doses) PPI therapy to an increased risk of osteoporosis-related fractures of the hip, wrist, or spine.[4] Patients at risk for osteoporosis should be managed according to established guidelines.
• Cutaneous and Systemic Lupus Erythematosus (CLE/SLE): PPIs have been associated with both new onset and exacerbation of these autoimmune diseases. If a patient develops characteristic lesions or systemic symptoms like arthralgia, discontinuation of dexlansoprazole should be considered.[14]
• Cyanocobalamin (Vitamin B12) Deficiency: Daily treatment with any acid-suppressing medication for a long period (e.g., longer than 3 years) can lead to malabsorption of vitamin B12 due to drug-induced hypo- or achlorhydria. This diagnosis should be considered if clinical symptoms of deficiency are observed.[4]
• Hypomagnesemia: Symptomatic and asymptomatic hypomagnesemia has been reported in patients treated with PPIs for prolonged periods (at least 3 months, but in most cases after a year of therapy). This can lead to serious adverse events including tetany, arrhythmias, and seizures. In some cases, magnesium supplementation alone is not sufficient, and the PPI must be discontinued. Clinicians may consider monitoring magnesium levels prior to initiation and periodically during long-term treatment.[14]
• Acute Tubulointerstitial Nephritis (TIN): This serious kidney problem has been observed in patients taking PPIs. It can occur at any point during therapy and is generally attributed to an idiopathic hypersensitivity reaction. Patients may present with non-specific symptoms or signs of renal dysfunction. Dexlansoprazole should be discontinued if TIN develops.[4]
• Fundic Gland Polyps: Long-term use (especially over one year) of PPIs increases the risk of developing fundic gland polyps, which are typically benign growths in the stomach.[14]
• Gastric Malignancy: A symptomatic response to dexlansoprazole therapy does not rule out the presence of an underlying gastric malignancy.[13]

Contraindications

There are two absolute contraindications for the use of dexlansoprazole:

1. Known Hypersensitivity: Dexlansoprazole is contraindicated in patients with a known history of hypersensitivity to dexlansoprazole, any of its components, or other substituted benzimidazoles. Serious reactions, including anaphylaxis, have been reported.[13]
2. Concomitant Use with Rilpivirine: PPIs are contraindicated for use with rilpivirine-containing products (e.g., Complera, Edurant, Odefsey). The increase in gastric pH caused by dexlansoprazole significantly reduces the absorption of rilpivirine, which can lead to a loss of virologic response and potential development of resistance.[15]

Overdosage

There have been no reports of significant overdosage with dexlansoprazole in the literature. Single doses up to 300 mg and multiple daily doses of 120 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice-daily doses of 60 mg. In the event of over-exposure, treatment should be symptomatic and supportive. As dexlansoprazole is extensively protein-bound and metabolized, it is not expected to be removed from circulation by hemodialysis.[2]

Significant Drug-Drug Interactions

Dexlansoprazole is subject to a number of clinically significant drug-drug interactions, primarily driven by its effects on gastric pH and its metabolism via the cytochrome P450 system. An estimated 159 drugs are known to interact with dexlansoprazole, with 19 classified as major interactions.[37]

Pharmacokinetic Interactions

• Drugs with pH-Dependent Absorption: By raising intragastric pH, dexlansoprazole can alter the absorption of other orally administered drugs.
• Decreased Absorption: The bioavailability of drugs that require an acidic environment for absorption may be significantly reduced. This includes certain antifungal agents (e.g., ketoconazole, itraconazole), antiretrovirals (e.g., atazanavir, nelfinavir), and some tyrosine kinase inhibitors (e.g., erlotinib). This can lead to loss of efficacy of the co-administered drug.[16]
• Increased Absorption: Conversely, the absorption of drugs like digoxin may be increased, potentially raising the risk of toxicity. Monitoring of digoxin levels may be necessary.[39]
• Metabolic Interactions (CYP450 System): Dexlansoprazole is metabolized by CYP2C19 and CYP3A4, making it susceptible to interactions with inhibitors and inducers of these enzymes.[2]
• CYP2C19/CYP3A4 Inducers: Strong inducers such as rifampin and St. John's wort can accelerate the metabolism of dexlansoprazole, leading to lower plasma concentrations and potentially reduced therapeutic effect.[19]
• CYP2C19/CYP3A4 Inhibitors: Co-administration with inhibitors (e.g., voriconazole) could increase systemic exposure to dexlansoprazole.
• As a Substrate/Inhibitor: Dexlansoprazole itself can affect the metabolism of other drugs.
• Tacrolimus: Dexlansoprazole can increase the whole blood concentrations of tacrolimus, a CYP3A4 substrate with a narrow therapeutic window. Close monitoring of tacrolimus levels is recommended, especially in transplant patients.[15]
• Warfarin: While there is a theoretical potential for interaction, a dedicated study found that dexlansoprazole did not significantly affect the pharmacokinetics of warfarin enantiomers or its anticoagulant pharmacodynamics.[19] However, caution and monitoring of INR are still prudent.
• Clopidogrel: This is a class-wide concern for PPIs. Clopidogrel is a prodrug that requires activation by CYP2C19. By competing for this enzyme, PPIs may reduce the formation of the active metabolite of clopidogrel, thereby diminishing its antiplatelet effect.[16]

Pharmacodynamic Interactions

• Methotrexate (MTX): Concomitant use of PPIs with methotrexate, particularly at high doses, has been shown to elevate and prolong the serum concentrations of MTX and/or its metabolite, hydroxymethotrexate. This is thought to be due to competitive inhibition of renal elimination and can lead to methotrexate toxicity. A temporary withdrawal of dexlansoprazole therapy should be considered during high-dose methotrexate administration.[15]

Interference with Diagnostic Tests

• Chromogranin A (CgA): Drug-induced decreases in gastric acidity lead to a secondary increase in CgA levels, which can cause false-positive results in diagnostic tests for neuroendocrine tumors. Therapy should be stopped at least 14 days before assessing CgA levels.[2]
• Tetrahydrocannabinol (THC): There have been reports of false-positive urine screening tests for THC in patients receiving PPIs.[2]
• Secretin Stimulation Test: Dexlansoprazole may interfere with the results of this test, which is used to diagnose gastrinomas.[2]

Table 8.0: Clinically Significant Drug-Drug Interactions with Dexlansoprazole

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence & Management	Source Snippet(s)
Rilpivirine	Increased gastric pH reduces rilpivirine absorption.	Loss of virologic response and potential for resistance. Co-administration is contraindicated.	15
Atazanavir / Nelfinavir	Increased gastric pH reduces absorption of these antiretrovirals.	Sub-therapeutic drug levels and loss of efficacy. Avoid concomitant use.	16
Ketoconazole / Itraconazole	Increased gastric pH reduces absorption of these antifungals.	Reduced antifungal efficacy. Avoid concomitant use.	39
Tacrolimus	Dexlansoprazole may inhibit CYP3A4-mediated metabolism of tacrolimus.	Increased tacrolimus concentrations and risk of toxicity. Monitor tacrolimus blood levels closely and adjust dose as needed.	15
Methotrexate (high-dose)	Inhibition of renal elimination of methotrexate.	Elevated and prolonged methotrexate levels, increasing risk of toxicity. Consider temporary withdrawal of dexlansoprazole.	15
Warfarin	Potential inhibition of CYP2C19-mediated metabolism.	Potential for increased INR and bleeding risk. Monitor INR, although one study showed no significant effect.	19
Digoxin	Increased gastric pH may increase digoxin absorption.	Increased risk of digoxin toxicity. Monitor digoxin levels.	39
CYP2C19/3A4 Inducers (Rifampin, St. John's Wort)	Induction of dexlansoprazole metabolism.	Decreased plasma concentration and potential loss of dexlansoprazole efficacy. Avoid concomitant use.	19

Use in Specific Populations

The use of dexlansoprazole requires careful consideration in certain patient populations, with specific recommendations for dosage adjustments or avoidance based on age and organ function.

Pediatric and Geriatric Use

• Pediatrics:
• Dexlansoprazole is FDA-approved for the treatment of EE and symptomatic NERD in adolescents 12 years of age and older. Efficacy and safety in this age group have been established in clinical trials, with dosing recommendations mirroring those for adults for the respective indications and durations.[4]
• The safety and effectiveness of dexlansoprazole in children younger than 12 years of age have not been established.[42]
• Critically, the use of DEXILANT is not recommended in children younger than 2 years of age. This recommendation is based on concerns about an increased risk for heart problems, such as heart valve thickening, in this vulnerable population.[4]
• Geriatrics:
• Clinical studies have not identified significant differences in the overall safety or effectiveness of dexlansoprazole between elderly and younger patients.[4]
• Pharmacokinetic analyses show that while the terminal elimination half-life is longer and the systemic exposure (AUC) is approximately 35% higher in geriatric subjects, these differences are not considered to be clinically relevant.[42]
• Therefore, no dosage adjustment is necessary for elderly patients based on age alone.[42] However, it is important to note that elderly patients (age ≥50) may be more susceptible to the long-term risks associated with PPIs, such as osteoporosis-related fractures, and should be treated with the lowest effective dose for the appropriate duration.[4]

Hepatic and Renal Impairment

• Renal Impairment:
• Dexlansoprazole is extensively metabolized by the liver into inactive metabolites, and virtually no parent drug is recovered in the urine. As such, the pharmacokinetics of the drug are not expected to be altered by renal impairment.[5]
• Studies have not been conducted specifically in patients with renal impairment, but based on its metabolic profile, no dosage adjustment is required for patients with any degree of renal impairment.[5]
• Hepatic Impairment:
• The liver is the primary site of dexlansoprazole metabolism, and hepatic function significantly impacts drug exposure.
• Mild Hepatic Impairment (Child-Pugh Class A): No dosage adjustment is necessary.[5]
• Moderate Hepatic Impairment (Child-Pugh Class B): In patients with moderate liver disease, the systemic exposure (AUC) to dexlansoprazole is approximately doubled compared to subjects with normal hepatic function. Therefore, a dosage reduction is recommended. For the healing of EE, the dose should be limited to 30 mg once daily for up to 8 weeks. Caution is advised.[4]
• Severe Hepatic Impairment (Child-Pugh Class C): Dexlansoprazole has not been studied in this population. Due to the expected significant increase in drug exposure, use is not recommended.[5]

Use in Pregnancy and Lactation

• Pregnancy:
• There are no adequate and well-controlled studies of dexlansoprazole use in pregnant women, and the available data is insufficient to inform a drug-related risk.[27] The US FDA has not assigned it a pregnancy category (the former A, B, C, D, X system is being phased out).[44]
• Animal reproduction studies using lansoprazole at doses higher than the maximum recommended human dose revealed some evidence of fetal harm, including effects on bone development and reduced body weight gain.[44]
• Given the lack of human data, dexlansoprazole should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.[27]
• Lactation:
• It is not known whether dexlansoprazole or its metabolites are excreted in human milk.[27] The racemic parent compound, lansoprazole, is excreted in the milk of lactating rats.[27]
• The potential effects on a nursing infant are unknown. While some sources suggest that the amount in breastmilk is unlikely to be harmful based on the safe use of lansoprazole in infants, this is an extrapolation, not direct evidence.[45]
• A clinical decision must be made to either discontinue breastfeeding or discontinue the drug, taking into account the importance of the medication to the mother's health.[27]

Table 9.0: Dosing Adjustments in Special Populations

Population	Condition	Recommendation	Rationale/Source Snippet(s)
Pediatrics	<2 years	Not Recommended	Potential risk of heart problems (e.g., heart valve thickening).
	2-11 years	Use and dose must be determined by a doctor; safety/efficacy not established.	4
	≥12 years	Standard adult dosing for approved indications.	5
Geriatrics	N/A	No dosage adjustment required.	Higher exposure is not clinically relevant. 42
Renal Impairment	Any degree	No dosage adjustment required.	Drug is hepatically metabolized; PK not altered by renal function. 5
Hepatic Impairment	Mild (Child-Pugh A)	No dosage adjustment required.	5
	Moderate (Child-Pugh B)	Reduce dose to 30 mg daily (for healing of EE).	Systemic exposure (AUC) is approximately doubled. 5
	Severe (Child-Pugh C)	Not Recommended	Drug has not been studied in this population. 5

Regulatory and Commercial History

Dexlansoprazole was developed by Takeda Pharmaceutical Company Limited and has a notable regulatory and commercial history in the United States.[1]

• Initial Approval and Brand Name: The New Drug Application (NDA) for TAK-390MR (the development code for dexlansoprazole modified release) was filed in January 2008. The U.S. Food and Drug Administration (FDA) granted its initial approval on January 30, 2009.[34] The drug was first launched under the brand name Kapidex.[3]
• Name Change to Dexilant: Following its launch, post-marketing surveillance revealed reports of dispensing errors due to name confusion between Kapidex and two other medications with very different uses: Casodex (bicalutamide, an antiandrogen for prostate cancer) and Kadian (morphine, an opioid analgesic). To mitigate this safety risk, Takeda received FDA approval for a name change. On March 4, 2010, the company announced that Kapidex would be marketed under the new trade name Dexilant.[3]
• New Formulation Approval: To provide an alternative for patients with dysphagia (difficulty swallowing), Takeda developed an orally disintegrating tablet formulation. Dexilant SoluTab was approved by the FDA on January 27, 2016.[15]
• Market Presence and Prescription Data: Dexlansoprazole is available in the U.S. by prescription only (℞-only).[3] It has established a significant presence in the PPI market. In 2022, it was the 186th most commonly prescribed medication in the United States, accounting for more than 2 million prescriptions.[3] Despite this, in some markets like Canada, it has been noted as the most expensive PPI available, which can be a factor in prescribing decisions.[3]

Expert Analysis and Clinical Recommendations

Dexlansoprazole represents a sophisticated evolution in proton pump inhibitor therapy, distinguished not by a fundamental change in mechanism but by a highly engineered pharmaceutical delivery system. A comprehensive analysis of its chemical, pharmacological, and clinical data reveals a clear and specific therapeutic niche.

The cornerstone of dexlansoprazole's value is its Dual Delayed-Release (DDR) formulation. This design directly addresses two of the most significant practical limitations of first-generation PPIs. First, by creating a prolonged plasma concentration profile with two distinct peaks, it provides more consistent acid suppression over a 24-hour period. The superior pharmacodynamic control in the latter half of the dosing interval (12-24 hours post-dose) makes it a particularly strong choice for patients whose quality of life is impacted by nocturnal acid breakthrough, including nighttime heartburn and GERD-related sleep disturbances. Second, the formulation's design allows for effective absorption and action independent of food intake. This liberates patients from the rigid and often-forgotten requirement to dose 30-60 minutes before a meal, a major source of non-adherence and real-world treatment failure.

Based on the available evidence, the ideal patient profiles for initiating or switching to dexlansoprazole include:

• Patients with Symptomatic NERD: Indirect meta-analyses suggest superior heartburn control compared to esomeprazole in this population, where symptom relief, rather than mucosal healing, is the primary therapeutic goal.
• Patients with Persistent Nocturnal Symptoms: Individuals who continue to experience nighttime reflux symptoms despite optimal dosing of a conventional PPI are prime candidates for dexlansoprazole.
• Patients with Adherence Challenges: For individuals whose lifestyles or cognitive status make adherence to strict pre-meal dosing schedules difficult, the flexibility of dexlansoprazole can translate directly into improved therapeutic outcomes.

Conversely, for the initial, rapid healing of severe erosive esophagitis (e.g., Los Angeles Grades C and D), the evidence does not consistently place dexlansoprazole as superior to other potent PPIs like esomeprazole. In these cases, clinical decisions should be guided by factors such as formulary access, cost, and physician experience. The choice of PPI should be an individualized one, carefully matching the drug's profile to the patient's specific clinical presentation and needs.

In line with modern gastroenterology guidelines, the principle of using the lowest effective dose for the shortest necessary duration must be applied to dexlansoprazole to mitigate the well-documented risks of long-term PPI therapy. For patients who require indefinite maintenance therapy (e.g., those with healed severe EE or Barrett's esophagus), a frank discussion about the potential risks (fractures, infections, micronutrient deficiencies) versus the benefits of continued acid suppression is a crucial part of shared decision-making. Periodic re-evaluation of the ongoing need for therapy is a cornerstone of responsible prescribing.

Looking forward, the therapeutic landscape for acid suppression is evolving with the advent of potassium-competitive acid blockers (P-CABs). Head-to-head clinical trials comparing the efficacy, long-term safety, and cost-effectiveness of dexlansoprazole against these newer agents will be essential to further define its precise and enduring place in the management of acid-related disorders.

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