A Comprehensive Monograph on Rabeprazole: Pharmacology, Clinical Efficacy, and Therapeutic Profile

Section 1: Introduction and Drug Identification

1.1. Overview and Classification

Rabeprazole is a second-generation proton pump inhibitor (PPI), a class of potent antisecretory agents used extensively in the management of acid-related disorders of the upper gastrointestinal tract.[1] Chemically, it is classified as a substituted benzimidazole, a structural characteristic shared by all members of the PPI class.[3] Its primary therapeutic function is to reduce the production of gastric acid, making it a cornerstone therapy for conditions such as gastroesophageal reflux disease (GERD), peptic ulcer disease (including gastric and duodenal ulcers), and pathological hypersecretory states like Zollinger-Ellison syndrome.[1]

The mechanism of action of rabeprazole involves the selective and irreversible inhibition of the gastric hydrogen-potassium adenosine triphosphatase (H+/K+-ATPase) enzyme system, commonly referred to as the proton pump.[1] This enzyme represents the final step in the pathway of gastric acid secretion by parietal cells. By blocking this pump, rabeprazole effectively suppresses both basal and stimulated acid production, independent of the stimulus.[2] Unlike older classes of acid-suppressing medications, rabeprazole does not exhibit anticholinergic or histamine H2-receptor antagonist properties, targeting the acid secretion pathway more directly and potently.[1]

Rabeprazole is administered as an inactive prodrug, which requires conversion to its active form within the highly acidic environment of the parietal cell secretory canaliculus.[1] This site-specific activation ensures that its inhibitory action is localized to the target enzyme, contributing to its favorable safety and efficacy profile. The drug is marketed globally under various brand names, most notably Aciphex® in the United States and Pariet® in other regions.[1]

1.2. Chemical and Physical Properties

A thorough understanding of rabeprazole's chemical and physical properties is fundamental to appreciating its formulation, stability, and biological activity.

The systematic chemical name for rabeprazole is (RS)-2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole.[7] It is also commonly referred to by its IUPAC name, 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.[8] Throughout its development and in scientific literature, it has been identified by various synonyms and codes, including LY-307640, E3810, and CS-1363.[1]

Rabeprazole's molecular formula is C18​H21​N3​O3​S, corresponding to an average molecular weight of approximately 359.44 g/mol.[8] It exists as a solid, with a color ranging from light brown to very dark brown, and has a defined melting point of 99-100 °C, at which it undergoes decomposition.[9] The stability of rabeprazole is highly dependent on pH. It is characterized as being rapidly degraded in acidic media but is significantly more stable under neutral or alkaline conditions.[10] This inherent acid lability is a critical chemical characteristic that directly dictates its pharmaceutical formulation. To prevent premature degradation by stomach acid and ensure its delivery to the site of absorption in the small intestine, rabeprazole must be formulated in enteric-coated, delayed-release dosage forms.[11]

The molecule's ionization potential, or pKa, is a key determinant of its pharmacodynamic behavior. While a predicted pKa of 9.57 has been reported, likely corresponding to the benzimidazole ring, a more functionally significant pKa value of approximately 5.0 is associated with its pyridine ring.[5] This specific pKa value is central to its mechanism of action, as it allows the molecule to become protonated and activated within the acidic environment of the parietal cell canaliculus, a crucial step for its conversion from an inactive prodrug to its active, pump-inhibiting form. This property distinguishes it from other PPIs and contributes to its rapid onset of action.

Rabeprazole is slightly soluble in dimethyl sulfoxide (DMSO) and methanol, while its sodium salt form, which is used in pharmaceutical preparations, is very soluble in water and methanol.[10] It is also described as hygroscopic, meaning it readily absorbs moisture from the atmosphere, a property that requires consideration during manufacturing and storage.[10]

Table 1: Chemical and Physical Properties of Rabeprazole

Property	Value	Source(s)
Chemical Name	(RS)-2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole	7
Synonyms	Aciphex, Pariet, LY-307640, E3810	1
CAS Number	117976-89-3	8
DrugBank ID	DB01129	1
Molecular Formula	C18​H21​N3​O3​S	8
Molecular Weight	359.44 g/mol (Average)	8
Appearance	Solid; Light Brown to Very Dark Brown	10
Melting Point	99-100 °C (with decomposition)	9
Solubility	Slightly soluble in DMSO, Methanol; Sodium salt is very soluble in water	10
Stability	Hygroscopic; Unstable in acid, stable in alkaline conditions	10
pKa (Pyridine Ring)	~5.0	5
BCS Class	1, 3	10
InChIKey	YREYEVIYCVEVJK-UHFFFAOYSA-N	9

1.3. Related Substances and Impurities

The manufacturing and quality control of rabeprazole involves monitoring for a range of related substances. These include its pharmaceutically used sodium salt (CAS 117976-90-6), its individual enantiomers such as the R-Isomer, key metabolites like Rabeprazole Sulfide (EP Impurity B) and Rabeprazole Sulfone, and various other process-related impurities and degradation products.[7] The identification and control of these substances are mandated by pharmacopeial standards (e.g., European Pharmacopoeia, EP) and are essential for ensuring the purity, safety, and consistency of the final drug product. The list of known impurities includes compounds such as Rabeprazole N-Oxide, various chloro analogs, and carboxylic acid derivatives, which are used as reference standards in analytical testing.[7]

Section 2: Clinical Pharmacology

2.1. Mechanism of Action

Rabeprazole exerts its therapeutic effect through a highly specific and potent mechanism of action centered on the inhibition of the final step of gastric acid production.[1] As a member of the proton pump inhibitor class, it targets the gastric

H+/K+-ATPase, an enzyme exclusively found on the secretory surface of the gastric parietal cells.[1] This enzyme functions as a proton pump, actively exchanging potassium ions (

K+) from the gastric lumen for hydrogen ions (H+) from within the parietal cell, which are then secreted as hydrochloric acid (HCl).[15]

The process begins with the oral administration of rabeprazole as an inactive prodrug, formulated to protect it from the acidic environment of the stomach.[2] After passing through the stomach and being absorbed in the small intestine, rabeprazole enters the systemic circulation and is delivered to the parietal cells. Due to its lipophilic nature and weak base properties, it freely crosses the parietal cell membrane and accumulates in the highly acidic secretory canaliculi, where the pH can be less than 2.[3]

This acidic environment is the key to rabeprazole's activation. The low pH triggers a two-step protonation of the rabeprazole molecule, leading to a rapid chemical rearrangement that converts it into its active form, a reactive tetracyclic sulfenamide.[2] This activated sulfenamide is then able to form a stable, covalent disulfide bond with specific cysteine residues on the alpha-subunit of the

H+/K+-ATPase enzyme, with Cys813 being a primary binding site.[4]

This covalent binding is irreversible and effectively inactivates the proton pump, preventing it from transporting hydrogen ions into the gastric lumen.[1] Consequently, the final step of acid secretion is blocked, leading to a profound and sustained reduction in gastric acidity. The duration of this acid suppression is significantly longer than the drug's presence in the plasma, as the restoration of acid secretion is dependent on the de novo synthesis of new proton pump enzymes by the parietal cells, a process that can take over 24 hours.[5] This irreversible, targeted inhibition explains the high efficacy of rabeprazole in treating acid-related disorders.

2.2. Pharmacodynamics

The pharmacodynamic profile of rabeprazole is distinguished by several features that provide a potential clinical advantage over other PPIs, particularly first-generation agents. These features include a rapid onset of action, potent and sustained acid suppression, and a unique mucoprotective effect.

A key pharmacodynamic differentiator for rabeprazole is its rapid onset of action, which is a direct consequence of its chemical structure. Rabeprazole possesses a pKa of approximately 5.0, which is the highest among the older generation of PPIs that includes omeprazole, lansoprazole, and pantoprazole.[5] A higher pKa means the drug can be activated at a less acidic pH. This allows for a much faster conversion to its active sulfenamide form within the parietal cell canaliculus compared to other PPIs.[14] In vitro studies have demonstrated that rabeprazole achieves near-maximal proton pump inhibition within just 5 minutes of exposure, whereas other PPIs can take 30 to 50 minutes to reach similar levels of inhibition.[14] This translates clinically to a more rapid acid-suppressing effect, providing faster symptom relief for patients, often from the first day of treatment.[14]

The acid suppression achieved by rabeprazole is both potent and durable. A standard oral dose of 20 mg has been shown to inhibit basal acid secretion by 86% and meal-stimulated acid secretion by 95% after the first dose.[3] This potent effect dramatically alters the gastric pH environment, increasing the percentage of a 24-hour period that the intragastric pH remains above 3 from a baseline of 10% to 65%.[3] Maintaining an intragastric pH above 4 is considered crucial for the healing of erosive esophagitis, and rabeprazole has demonstrated a superior ability to achieve this endpoint compared to older PPIs, particularly during the initial days of therapy.[14]

Beyond its primary role as an acid suppressant, rabeprazole exhibits a unique pharmacodynamic property not observed with other PPIs: the ability to stimulate gastric mucus and mucin production. Clinical studies have shown that rabeprazole administration significantly increases the content and viscosity of gastric mucin, a key component of the protective mucosal barrier.[14] This effect has been observed both under basal conditions and in response to acid-related challenges, such as co-administration with nonsteroidal anti-inflammatory drugs (NSAIDs) like naproxen.[17] This mucoprotective action may offer a complementary therapeutic benefit, enhancing the defense of the gastrointestinal mucosa against acid and other irritants. This property could be particularly relevant in preventing mucosal injury, such as that induced by NSAID or low-dose aspirin therapy.

2.3. Pharmacokinetics (ADME)

The pharmacokinetic profile of rabeprazole—its absorption, distribution, metabolism, and excretion (ADME)—is characterized by rapid absorption, high protein binding, a short plasma half-life, and a unique metabolic pathway that confers clinical advantages.

Absorption: Rabeprazole is administered orally in an enteric-coated, delayed-release formulation to protect the acid-labile drug from degradation in the stomach.[14] Following oral administration, it is rapidly absorbed from the proximal small intestine. Peak plasma concentrations (

Cmax​) are typically achieved between 2 and 5 hours (Tmax​) after dosing.[1] The absolute bioavailability of a 20 mg oral dose is approximately 52%, indicating substantial first-pass metabolism.[1] The pharmacokinetics are linear over a dose range of 10 to 80 mg, with

Cmax​ and the area under the plasma concentration-time curve (AUC) increasing proportionally with the dose.[14] Co-administration with food may delay the time to peak concentration (

Tmax​) but does not have a clinically significant impact on the overall extent of absorption (AUC), allowing the drug to be taken with or without food for most indications.[14]

Distribution: Once absorbed, rabeprazole is extensively distributed and is highly bound to human plasma proteins, with binding reported to be between 96.3% and 97.5%.[1] Its volume of distribution is estimated to be 0.34 L/kg, indicating distribution into various tissues, including the gastric mucosa.[14]

Metabolism and Pharmacogenomics: Rabeprazole undergoes extensive metabolism, primarily in the liver. A crucial and distinguishing feature of its metabolism is that the principal pathway is a non-enzymatic reduction to form its main metabolite, rabeprazole-thioether.[14] The cytochrome P450 (CYP) enzyme system plays a comparatively minor role. The isoenzymes CYP2C19 and CYP3A4 are involved in the formation of lesser metabolites, specifically demethylated rabeprazole and rabeprazole-sulfone, respectively.[14]

This predominantly non-enzymatic metabolic clearance has significant clinical and pharmacogenomic implications. Other PPIs, such as omeprazole and lansoprazole, are heavily metabolized by CYP2C19, an enzyme known for significant genetic polymorphisms in the population. These polymorphisms lead to different metabolizer phenotypes (poor, intermediate, and extensive), causing wide inter-individual variability in drug exposure and clinical effect. Because rabeprazole's clearance is less dependent on this polymorphic pathway, its pharmacokinetics are more consistent and predictable across the general population, regardless of a patient's CYP2C19 genotype.[14] This results in a more uniform acid-suppressing effect and a lower potential for clinically significant drug-drug interactions mediated by CYP2C19 inhibition.

Excretion: Following metabolism, the metabolites of rabeprazole are eliminated primarily through the kidneys. Approximately 90% of an administered dose is excreted in the urine, mainly as thioether carboxylic acid, glucuronide, and mercapturic acid metabolites.[1] The remaining 10% is excreted in the feces.[14] The plasma elimination half-life (

t1/2​) of rabeprazole is short, ranging from 1 to 2 hours.[1] Despite this short half-life, significant drug accumulation does not occur with repeated daily dosing.[19] The prolonged pharmacodynamic effect is due to the irreversible nature of the proton pump inhibition, not the sustained presence of the drug in the plasma.

Table 2: Key Pharmacokinetic Parameters of Rabeprazole

Parameter	Value	Clinical Notes
Bioavailability	~52%	Subject to significant first-pass metabolism.
Tmax​ (Time to Peak Plasma Concentration)	2–5 hours	Food can delay Tmax​ but does not significantly affect overall exposure (AUC).
Plasma Protein Binding	96.3–97.5%	Highly bound, primarily to albumin.
Volume of Distribution	~0.34 L/kg	Distributes into tissues including gastric mucosa.
Primary Metabolic Pathway	Non-enzymatic reduction	Forms rabeprazole-thioether; a key differentiator from other PPIs.
Key Enzymes (Minor Pathway)	CYP2C19, CYP3A4	Less dependence on these enzymes leads to more predictable pharmacokinetics.
Elimination Half-life (t1/2​)	1–2 hours	Short plasma half-life contrasts with long duration of acid suppression.
Route of Excretion	~90% renal (as metabolites), ~10% fecal	No dosage adjustment needed for renal impairment.

Section 3: Clinical Applications and Dosing

3.1. FDA-Approved Indications

Rabeprazole is approved by the U.S. Food and Drug Administration (FDA) for a range of acid-related gastrointestinal conditions in adult and pediatric populations. The specific indications vary by patient age and the formulation used.[13]

Indications in Adults:

• Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD): For the short-term (4 to 8 weeks) treatment and symptomatic relief of endoscopically diagnosed erosive or ulcerative GERD. An additional 8-week course may be considered for patients who have not healed.[20]
• Maintenance of Healing of Erosive or Ulcerative GERD: For maintaining healing and reducing the relapse rate of heartburn symptoms in patients with previously healed erosive GERD. Controlled studies for this indication extend up to 12 months.[20]
• Treatment of Symptomatic GERD: For the treatment of daytime and nighttime heartburn and other symptoms associated with GERD for up to 4 weeks.[20]
• Healing of Duodenal Ulcers: For the short-term (up to 4 weeks) treatment and symptomatic relief of active duodenal ulcers.[20]
• Helicobacter pylori Eradication: As part of a three-drug regimen with amoxicillin and clarithromycin for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or a history within the past 5 years) to eradicate the bacterium and reduce the risk of ulcer recurrence.[20]
• Pathological Hypersecretory Conditions: For the long-term treatment of conditions involving gastric acid hypersecretion, most notably Zollinger-Ellison syndrome.[20]

Indications in Adolescents (12 Years of Age and Older):

• Treatment of Symptomatic GERD: For the short-term (up to 8 weeks) treatment of symptomatic GERD.[20]

Indications in Pediatric Patients (1 to 11 Years of Age):

• Treatment of GERD: For the treatment of GERD for up to 12 weeks, using the specific Aciphex® Sprinkle™ delayed-release capsule formulation.[20]

The approval of the Aciphex® Sprinkle™ formulation was a significant development, addressing the clinical challenge of administering acid-suppressive therapy to young children who are unable to swallow tablets. This dedicated pediatric formulation, supported by clinical trial data, provides a safe, effective, and reliable dosing option for pediatric GERD, thereby expanding rabeprazole's clinical utility into a previously underserved patient population.[22]

3.2. Dosage and Administration

The appropriate dosage and administration of rabeprazole depend on the specific indication, patient age, and formulation. Adherence to these guidelines is crucial for achieving optimal therapeutic outcomes.[11]

Available Formulations:

• Delayed-Release Tablets: 20 mg (e.g., Aciphex®).[12]
• Delayed-Release Sprinkle Capsules: 5 mg and 10 mg (e.g., Aciphex Sprinkle™).[12]

Administration Instructions:

• Tablets: Must be swallowed whole. Patients should be instructed not to chew, crush, or split the tablets, as this would disrupt the enteric coating and lead to drug degradation by stomach acid.[12]
• Sprinkle Capsules: The capsules should be opened and the entire contents (granules) sprinkled onto a small amount of soft food (such as applesauce, yogurt, or baby food) or into a small amount of liquid (such as apple juice or infant formula). The mixture should be at or below room temperature and consumed within 15 minutes of preparation. The granules themselves should not be chewed or crushed.[6]

Timing with Food: The instructions for taking rabeprazole with respect to meals are nuanced and indication-specific, reflecting efforts to optimize pharmacodynamics for different clinical goals.

• For the healing of duodenal ulcers and the eradication of H. pylori, rabeprazole should be taken with or after a meal.[11] For duodenal ulcers, this timing ensures the drug is present when meal-stimulated acid secretion is maximal. For H. pylori eradication, taking the medication with food can improve the tolerability and potentially the absorption of the co-administered antibiotics (amoxicillin and clarithromycin), which is critical for the success of the regimen.
• For all other indications, rabeprazole can be taken with or without food, as the primary goal is consistent 24-hour acid suppression, which is not significantly affected by food intake.[11]

Table 3: FDA-Approved Indications and Dosing Regimens for Rabeprazole

Indication	Patient Population	Recommended Dose	Duration of Therapy	Administration Notes
Healing of Erosive/Ulcerative GERD	Adults	20 mg once daily	4 to 8 weeks	May be taken with or without food. An additional 8-week course may be considered.
Maintenance of GERD Healing	Adults	20 mg once daily	Up to 12 months (in controlled studies)	May be taken with or without food.
Treatment of Symptomatic GERD	Adults	20 mg once daily	Up to 4 weeks	May be taken with or without food.
Healing of Duodenal Ulcers	Adults	20 mg once daily	Up to 4 weeks	Must be taken after the morning meal.
H. pylori Eradication	Adults	20 mg twice daily (with Amoxicillin 1000 mg twice daily and Clarithromycin 500 mg twice daily)	7 days	Must be taken with morning and evening meals.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison)	Adults	Starting dose 60 mg once daily; titrate to patient needs (up to 100 mg once daily or 60 mg twice daily)	Long-term, as clinically indicated	May be taken with or without food.
Treatment of Symptomatic GERD	Adolescents (≥12 years)	20 mg once daily	Up to 8 weeks	May be taken with or without food.
Treatment of GERD (Sprinkle Formulation)	Pediatrics (1-11 years)	<15 kg: 5 mg once daily; ≥15 kg: 10 mg once daily	Up to 12 weeks	Take 30 minutes before a meal. Sprinkle on soft food or liquid.

Source: Synthesized from [6]

3.3. Use in Special Populations

The pharmacokinetic profile of rabeprazole allows for its use without dose adjustment in several special populations.

• Geriatric Population: No dosage adjustment is necessary for elderly patients. However, clinical monitoring is prudent as some studies suggest elderly patients may be more sensitive to the effects of the medication.[6]
• Renal Impairment: The pharmacokinetics of rabeprazole are not significantly altered by renal dysfunction. Therefore, no dosage adjustment is required for patients with any degree of renal impairment, including those on maintenance hemodialysis.[19]
• Hepatic Impairment: For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), no dosage adjustment is needed. However, due to a lack of clinical data and a potential for increased exposure, caution should be exercised when prescribing rabeprazole to patients with severe hepatic disease (Child-Pugh Class C).[19]
• Pediatric Population: The safety and efficacy of rabeprazole for the treatment of GERD have been established in children aged 1 year and older.[20] The use of the Aciphex® Sprinkle™ formulation is indicated for children 1 to 11 years of age. For adolescents 12 years and older, the 20 mg delayed-release tablet is used.[20] The use of rabeprazole is not recommended in children younger than 1 year of age, as studies did not demonstrate efficacy in this group.[6] For indications other than GERD, the safety and efficacy of rabeprazole in pediatric patients have not been established.[6]

Section 4: Safety Profile and Tolerability

4.1. Adverse Reactions

Rabeprazole is generally well-tolerated. The most common adverse reactions observed in clinical trials, occurring at a rate of 2% or greater and more frequently than placebo, are typically mild to moderate in severity. These include headache, pharyngitis (sore throat), abdominal pain, diarrhea, flatulence, nausea, vomiting, constipation, and infection.[20]

While rare, serious adverse events have been reported during postmarketing surveillance. These include hematologic disorders (agranulocytosis, pancytopenia, thrombocytopenia), severe hepatotoxicity (hepatic encephalopathy, jaundice), musculoskeletal events (rhabdomyolysis), severe hypersensitivity reactions (anaphylaxis, angioedema), and life-threatening dermatologic conditions such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).[20] The occurrence of such events necessitates immediate discontinuation of the drug and appropriate medical intervention.

4.2. Warnings and Precautions

The prescribing information for rabeprazole includes several important warnings and precautions. The majority of these are class-effect warnings applicable to all PPIs, stemming from the physiological consequences of long-term, profound gastric acid suppression rather than a toxicity unique to the rabeprazole molecule itself. Adherence to the principle of using the lowest effective dose for the shortest duration appropriate to the condition being treated is the primary strategy for mitigating these risks.

• Presence of Gastric Malignancy: A symptomatic response to rabeprazole therapy does not exclude the presence of an underlying gastric malignancy. Patients presenting with alarm symptoms (e.g., dysphagia, weight loss, recurrent vomiting) or those who do not respond adequately to therapy should undergo further investigation to rule out cancer.[13]
• Clostridium difficile-Associated Diarrhea (CDAD): PPI use, especially in hospitalized patients, is associated with an increased risk of CDAD. This diagnosis should be considered in any patient on PPI therapy who develops persistent diarrhea that does not improve. If CDAD is confirmed, PPI therapy should be reassessed.[21]
• Bone Fracture: Multiple observational studies have suggested that long-term (typically one year or longer) or high-dose PPI therapy is associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine.[12] Patients should be managed according to established guidelines for bone health.
• Hypomagnesemia: Prolonged treatment with PPIs (usually for more than one year) can lead to hypomagnesemia, which can be serious and may manifest as tetany, seizures, or cardiac arrhythmias. In some cases, the condition may be difficult to correct, requiring magnesium supplementation and discontinuation of the PPI. Periodic monitoring of serum magnesium levels should be considered for patients on long-term therapy or those taking concomitant medications like diuretics or digoxin that can also lower magnesium levels.[6]
• Cyanocobalamin (Vitamin B-12) Deficiency: Chronic acid suppression for three years or longer can impair the absorption of dietary vitamin B-12. This risk should be considered in patients on long-term PPI therapy who develop clinical symptoms consistent with B-12 deficiency.[21]
• Acute Tubulointerstitial Nephritis (TIN): This form of acute kidney injury has been observed in patients taking PPIs. It is considered an idiopathic hypersensitivity reaction and can occur at any point during therapy. It may present with non-specific symptoms or signs of renal dysfunction. If TIN is suspected, rabeprazole should be discontinued immediately.[21]
• Cutaneous and Systemic Lupus Erythematosus (CLE/SLE): PPIs have been associated with new onset or exacerbation of existing autoimmune conditions, including CLE and SLE. If a patient develops characteristic lesions or systemic symptoms, discontinuation of the PPI and referral to a specialist should be considered.[21]
• Fundic Gland Polyps: The risk of developing fundic gland polyps, which are benign growths in the stomach, increases with long-term PPI use, particularly beyond one year. These are typically discovered on endoscopy and are another reason to limit therapy to the shortest effective duration.[21]
• Carcinogenicity: In long-term animal carcinogenicity studies, rats treated with high doses of rabeprazole developed gastric neuroendocrine (carcinoid) tumors.[32] This is a known class effect of PPIs, believed to be a secondary consequence of drug-induced hypergastrinemia resulting from profound and prolonged acid suppression. While the clinical relevance of this finding in humans remains a subject of debate, it reinforces the importance of using PPIs only when indicated and for the minimum duration necessary.

4.3. Drug-Drug Interactions

Rabeprazole has the potential to interact with other drugs through two primary mechanisms: alteration of gastric pH and effects on drug-metabolizing enzymes.

The most common interactions are pharmacodynamic, arising from rabeprazole's primary effect of increasing intragastric pH. This can alter the absorption of drugs whose bioavailability is pH-dependent. The absorption of drugs that require an acidic environment for dissolution and absorption, such as the antifungal ketoconazole, certain antiretrovirals like atazanavir, iron salts, and some tyrosine kinase inhibitors like erlotinib, may be significantly reduced.[3] Conversely, the absorption of drugs like digoxin may be increased, potentially leading to toxicity.[20]

Pharmacokinetic interactions involving metabolic pathways are less common with rabeprazole compared to other PPIs, a direct result of its primary non-enzymatic clearance. However, some clinically important interactions exist.

• Warfarin: Although initial studies showed no significant interaction, postmarketing reports have described increases in INR and prothrombin time in patients receiving concomitant warfarin and a PPI. Close monitoring of these parameters is recommended when initiating or discontinuing rabeprazole in patients on warfarin.[21]
• Methotrexate: Concomitant use of PPIs with high-dose methotrexate can elevate and prolong serum levels of methotrexate and its active metabolite, increasing the risk of toxicity. A temporary withdrawal of rabeprazole may be necessary during high-dose methotrexate administration.[21]
• Clopidogrel: A significant interaction of concern with the PPI class is the potential inhibition of CYP2C19, the enzyme responsible for activating the antiplatelet prodrug clopidogrel. Inhibition of this enzyme can reduce the effectiveness of clopidogrel and increase the risk of major adverse cardiovascular events (MACEs). Because rabeprazole's metabolism is largely independent of CYP2C19, it has a lower potential to interfere with clopidogrel activation compared to strong CYP2C19 inhibitors like omeprazole and esomeprazole. A meta-analysis of studies investigating this interaction found that rabeprazole was associated with the lowest risk of increasing MACEs when used with clopidogrel, making it a theoretically and evidentially safer choice in this clinical scenario.[14]

Table 4: Clinically Significant Drug Interactions with Rabeprazole

Interacting Drug/Class	Mechanism of Interaction	Clinical Effect	Management Recommendation
Antiretrovirals (e.g., Atazanavir, Rilpivirine)	Increased gastric pH	Decreased absorption and plasma levels of the antiretroviral, potentially leading to loss of virologic response.	Concomitant use with rilpivirine is contraindicated. Concomitant use with atazanavir is not recommended.
Azole Antifungals (e.g., Ketoconazole, Itraconazole)	Increased gastric pH	Decreased absorption and therapeutic effect of the antifungal.	Avoid concomitant use. If necessary, monitor for lack of efficacy. Consider administering with an acidic beverage (e.g., cola).
Iron Salts	Increased gastric pH	Decreased absorption of oral iron supplements.	Monitor iron levels. Separate administration times if possible.
Digoxin	Increased gastric pH	Increased absorption and plasma levels of digoxin, leading to potential toxicity.	Monitor digoxin levels and for signs of toxicity when initiating or discontinuing rabeprazole.
Warfarin	Potential inhibition of metabolism (CYP2C19/3A4)	Increased INR and prothrombin time, leading to increased risk of bleeding.	Monitor INR and prothrombin time closely, especially during initiation and discontinuation of therapy.
Methotrexate (high-dose)	Decreased renal clearance (mechanism unclear)	Elevated and prolonged serum levels of methotrexate, increasing risk of toxicity.	Consider temporary withdrawal of rabeprazole during high-dose methotrexate therapy.
Clopidogrel	Minimal inhibition of CYP2C19	Lower potential to inhibit clopidogrel activation compared to other PPIs. Considered a safer option in this context.	No dose adjustment of clopidogrel is necessary. Rabeprazole may be a preferred PPI in patients on dual antiplatelet therapy.

Source: Synthesized from [3]

Section 5: Comparative Analysis and Clinical Context

5.1. Efficacy vs. Other Proton Pump Inhibitors

The selection of a specific PPI often involves consideration of comparative efficacy, speed of symptom relief, and patient-specific factors. While many large-scale meta-analyses conclude that standard doses of different PPIs have comparable efficacy in healing erosive esophagitis over an 8-week period, a more granular examination of the evidence reveals nuanced differences.[34]

In terms of esophagitis healing rates, some studies have shown potential advantages for newer agents. A study focused on elderly patients found that after 8 weeks of treatment, rabeprazole (94.6% healing rate) and pantoprazole (93.5%) were significantly more effective than omeprazole (75.0%).[34] Other meta-analyses have reported that esomeprazole 40 mg provides statistically superior healing rates at both 4 and 8 weeks compared to omeprazole 20 mg and lansoprazole 30 mg.[36] These findings suggest that while broad equivalence is often cited, certain PPIs may offer an edge in specific populations or when compared to the first-generation agent, omeprazole.

Regarding symptom relief, the speed of onset is a clinically important parameter. Evidence suggests that esomeprazole may provide faster relief from heartburn in the first few days of treatment compared to omeprazole, lansoprazole, and pantoprazole.[36] Similarly, the study in elderly patients demonstrated that rabeprazole and pantoprazole were superior to both omeprazole and lansoprazole in improving symptoms of heartburn, acid regurgitation, and epigastric pain.[34] This rapid and consistent symptom control may be linked to rabeprazole's unique pharmacodynamic and pharmacokinetic properties, such as its high pKa and predictable metabolism.

An interesting dimension of comparison comes from real-world patient-reported outcomes. On the consumer drug information website Drugs.com, rabeprazole (with an average rating of 8.2 out of 10) and its brand name Aciphex (9.1 out of 10) consistently receive higher satisfaction ratings from users compared to esomeprazole (6.1), omeprazole (6.9), and lansoprazole (6.6).[38] While not a substitute for rigorous clinical trial data, these ratings may reflect patient perceptions of factors like speed of relief, consistency of effect, and tolerability, which are not always fully captured by traditional trial endpoints like 8-week healing rates. This discrepancy suggests that the "equivalence" seen in some clinical trials may not fully translate to therapeutic interchangeability for every patient.

Furthermore, studies have shown that for patients with an incomplete response to standard once-daily (QD) therapy, increasing the dosing frequency to twice-daily (BID) can improve outcomes. A meta-analysis found that BID PPI therapy resulted in higher esophageal healing rates at 8 weeks compared to QD therapy, a finding that was specifically demonstrated for rabeprazole 20 mg BID versus 20 mg QD.[40]

Table 5: Comparative Efficacy of PPIs in Erosive Esophagitis (8-Week Healing Rates)

PPI and Dose	8-Week Healing Rate (%)	Notes on Efficacy and Symptom Relief
Rabeprazole 20 mg	~81-95%	Found to be superior to omeprazole in elderly patients for healing and symptom relief.34 High patient satisfaction ratings.38
Omeprazole 20 mg	~75-87%	Often used as the comparator. Found to be less effective than other PPIs in some studies, particularly in the elderly.34
Esomeprazole 40 mg	~90-94%	Meta-analyses show superiority over omeprazole and lansoprazole for healing rates and may offer faster heartburn relief.36
Lansoprazole 30 mg	~82-93%	Generally considered equivalent to omeprazole but may be less effective than rabeprazole and pantoprazole for symptom relief in the elderly.34
Pantoprazole 40 mg	~83-94%	Found to be superior to omeprazole in elderly patients for healing and demonstrated better symptom control than omeprazole and lansoprazole.34

Note: Healing rates are approximate ranges synthesized from multiple sources and can vary based on study population and esophagitis severity.

Source: Synthesized from 34

5.2. Key Clinical Trial Evidence

Beyond standard GERD treatment, the clinical development of rabeprazole has successfully established its efficacy in more specialized and preventative therapeutic areas, differentiating it from competitors and extending its clinical value.

• Functional Dyspepsia: The SAMURAI study, a large, multicenter, randomized, placebo-controlled trial conducted in Japan, investigated the use of rabeprazole in patients with functional dyspepsia diagnosed by Rome III criteria. The trial found that a 20 mg once-daily dose of rabeprazole provided significantly greater satisfactory symptom relief compared to placebo. Interestingly, this effect was not observed with the 10 mg or 40 mg doses, suggesting a specific therapeutic window for this indication. The benefit was independent of H. pylori status, establishing rabeprazole 20 mg as an effective treatment option for this challenging condition.[42]
• Intermittent Maintenance Therapy: For patients with symptomatic, non-erosive GERD (sGERD), long-term management is often a clinical challenge. A double-blind, placebo-controlled study evaluated an intermittent, on-demand treatment strategy. Patients who achieved initial symptom control were randomized to receive 7- to 14-day courses of rabeprazole 20 mg or placebo whenever symptoms recurred. The results showed that the rabeprazole group had a significantly higher percentage of heartburn-free days and fewer discontinuations due to treatment failure, demonstrating that intermittent rabeprazole is an effective maintenance strategy for sGERD.[43]
• Prophylaxis of Aspirin-Induced Ulcers: The widespread use of low-dose aspirin (LDA) for cardiovascular protection has led to an increase in gastrointestinal complications. The PLANETARIUM study was a long-term trial (up to 76 weeks) that assessed the efficacy of rabeprazole in preventing peptic ulcer recurrence in patients on chronic LDA therapy. The study concluded that both low-dose rabeprazole 5 mg and standard-dose 10 mg once daily were highly effective and well-tolerated for long-term prophylaxis, with cumulative ulcer recurrence rates of only 3.7% and 2.2%, respectively.[44] This provides strong evidence for rabeprazole's role in a crucial preventative medicine context.
• Nocturnal Acid Breakthrough (NAB): A significant limitation of standard PPI therapy is NAB, where intragastric pH drops for sustained periods overnight, leading to nighttime symptoms. To address this, a dual delayed-release (DDR) formulation of rabeprazole was developed. A real-world observational study of this formulation (HERCULES study) demonstrated significant improvements in heartburn severity, a reduction in night-time awakenings, and high patient satisfaction, confirming its effectiveness in managing NAB and improving overall GERD control.[45]

Section 6: Manufacturing, Regulatory Status, and Future Directions

6.1. Formulations, Brand Names, and Manufacturers

Rabeprazole is available globally in various formulations and under numerous brand names. The original branded products in the United States are Aciphex® (delayed-release tablets) and Aciphex Sprinkle™ (delayed-release capsules), initially marketed by Eisai Inc. and later by Waylis Therapeutics.[22] A prominent international brand name is Pariet®.[1]

Following the patent expiry, the market for rabeprazole expanded significantly. The first generic versions of the 20 mg delayed-release tablet were approved by the FDA in November 2013.[49] Today, a large number of pharmaceutical companies manufacture and market generic rabeprazole sodium, including major firms such as Aurobindo Pharma, Dr. Reddy's Laboratories, Lannett Company, Mylan (now Viatris), and Teva Pharmaceuticals.[47] This has increased the accessibility and affordability of the medication. The availability of numerous international brands reflects its widespread use worldwide.

Table 6: Selected International Brand Names for Rabeprazole

Brand Name	Brand Name	Brand Name	Brand Name
Acera	Finix	Pariet	Rabeone
Aciphex	Gastech	Pepcia	Rabep
Anslag	Happi	Prabex	Rabez
Barole	Helirab	Praber	Rafron
Bepra	Neutracaine	Puloros	Staycool
Cyra	Noflux	R-Cid	Veloz
Eurorapi	Ontime	Rabec	Zibepar

Source: A representative list synthesized from [5]

6.2. Regulatory History

The regulatory journey of rabeprazole in the United States highlights a typical lifecycle for a successful pharmaceutical product, from initial approval to indication expansion and eventual generic competition.

• August 19, 1999: The U.S. FDA granted initial approval for Aciphex® (rabeprazole sodium) 20 mg delayed-release tablets under New Drug Application (NDA) 020973, sponsored by Eisai Inc. The initial indications were for the healing of erosive GERD and duodenal ulcers.[48]
• November 8, 2002: The FDA approved supplemental NDAs for additional indications, including the use of rabeprazole in a triple-therapy regimen for the eradication of Helicobacter pylori.[52]
• March 26, 2013: A significant milestone was achieved with the FDA approval of Aciphex Sprinkle™ delayed-release capsules in 5 mg and 10 mg strengths. This approval was specifically for the treatment of GERD in children aged 1 to 11 years, addressing a key unmet need in pediatric gastroenterology.[22]
• November 8, 2013: The FDA approved the first Abbreviated New Drug Applications (ANDAs) for generic rabeprazole sodium 20 mg delayed-release tablets, opening the market to competition and increasing patient access.[49]

6.3. Future Directions and Emerging Research

The future of rabeprazole, as a mature drug, is focused less on the discovery of entirely new therapeutic applications and more on the optimization of its delivery and the refinement of its use in specific, high-need patient populations.

A primary area of ongoing innovation is the development of novel formulations. Standard PPIs can have limitations, particularly in controlling nocturnal acid breakthrough (NAB), which affects a substantial portion of GERD patients. The creation of dual delayed-release (DDR) formulations, such as Happi ER, represents a significant step forward. These formulations contain two types of enteric-coated granules—one that releases rabeprazole in the proximal small intestine for immediate effect, and another that releases it more distally for a sustained effect. This approach is designed to prolong the plasma concentration of the drug, providing more consistent 24-hour acid control and specifically targeting the overnight period to reduce NAB.[45] Clinical evidence suggests this technology is effective and improves patient satisfaction, indicating a clear future direction for branded PPI therapy.

Another key area is the expansion of prophylactic use. With an aging population and the increasing use of antiplatelet agents like low-dose aspirin (LDA) for cardiovascular disease prevention, the incidence of drug-induced gastroduodenal injury is a growing public health concern. Long-term clinical trials, such as the PLANETARIUM study, have provided robust evidence that low-dose rabeprazole (5 mg and 10 mg) is safe and effective for the long-term prevention of peptic ulcer recurrence in these high-risk patients.[44] This positions rabeprazole as a key agent in gastroprotective strategies, a role that is likely to expand as clinical guidelines evolve to recommend routine PPI co-prescription in this large patient group.

Finally, while the long-term safety of all PPIs remains an area of active research and debate, future studies may seek to determine if rabeprazole's unique pharmacological profile offers any advantages. For instance, its minimal impact on the CYP2C19 enzyme already makes it a preferred agent for patients on clopidogrel.[33] Further research could explore whether its distinct mucin-enhancing properties translate into a better long-term safety profile with respect to mucosal health, although this remains a topic for future investigation. The overarching trend is a move towards more precise and personalized application of rabeprazole, leveraging its established efficacy and unique properties to optimize outcomes in well-defined clinical scenarios.

Works cited

1. Rabeprazole: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 30, 2025, https://go.drugbank.com/drugs/DB01129
2. go.drugbank.com, accessed July 30, 2025, https://go.drugbank.com/drugs/DB01129#:~:text=Rabeprazole%20is%20an%20antiulcer%20drug,and%20stimulated%20gastric%20acid%20secretion.
3. Rabeprazole sodium - accessdata.fda.gov, accessed July 30, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/078964Orig1s000lbl.pdf
4. Pharmacokinetics and Pharmacodynamics of the Proton Pump Inhibitors, accessed July 30, 2025, https://www.jnmjournal.org/journal/view.html?doi=10.5056/jnm.2013.19.1.25
5. Rabeprazole - Wikipedia, accessed July 30, 2025, https://en.wikipedia.org/wiki/Rabeprazole
6. Rabeprazole (oral route) - Side effects & dosage - Mayo Clinic, accessed July 30, 2025, https://www.mayoclinic.org/drugs-supplements/rabeprazole-oral-route/description/drg-20066981
7. Rabeprazole | CAS No- 117976-89-3 | Simson Pharma Limited, accessed July 30, 2025, https://www.simsonpharma.com/product/rabeprazole
8. Rabeprazole | CAS 117976-89-3 | SCBT - Santa Cruz Biotechnology, accessed July 30, 2025, https://www.scbt.com/p/rabeprazole-117976-89-3
9. Rabeprazole - CAS Common Chemistry, accessed July 30, 2025, https://commonchemistry.cas.org/detail?ref=117976-89-3
10. Rabeprazole | 117976-89-3 - ChemicalBook, accessed July 30, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3680731.htm
11. Aciphex (Rabeprazole Sodium): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed July 30, 2025, https://www.rxlist.com/aciphex-drug.htm
12. Rabeprazole Uses, Side Effects & Warnings - Drugs.com, accessed July 30, 2025, https://www.drugs.com/mtm/rabeprazole.html
13. aciphex delayed-release tablets - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed July 30, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/020973s043lbl.pdf
14. A review of rabeprazole in the treatment of acid-related diseases ..., accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2386363/
15. What is the mechanism of Rabeprazole Sodium? - Patsnap Synapse, accessed July 30, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-rabeprazole-sodium
16. Rabeprazole: a review of its use in acid-related gastrointestinal disorders - PubMed, accessed July 30, 2025, https://pubmed.ncbi.nlm.nih.gov/10551440/
17. Rabeprazole: The Unique PPIs - ClinicSearch, accessed July 30, 2025, https://clinicsearchonline.org/article/rabeprazole-the-unique-ppis
18. Rabeprazole: pharmacokinetics and pharmacokinetic drug interactions - PubMed, accessed July 30, 2025, https://pubmed.ncbi.nlm.nih.gov/12369444/
19. Review article: the pharmacokinetics of rabeprazole in health and disease - PubMed, accessed July 30, 2025, https://pubmed.ncbi.nlm.nih.gov/10491724/
20. ACIPHEX®(rabeprazole sodium) Label - accessdata.fda.gov, accessed July 30, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020973s035204736s005lbl.pdf
21. Rabeprazole Sodium - FDA Drug Approval Details - MedPath, accessed July 30, 2025, https://trial.medpath.com/drug/approvals/fda/000fa9a888c56a2b
22. FDA Approves ACIPHEX® Sprinkle™ (Rabeprazole Sodium) For Use in Children Ages 1 to 11 - Media Center - Eisai, accessed July 30, 2025, https://media-us.eisai.com/2013-03-26-FDA-Approves-ACIPHEX-Sprinkle-Rabeprazole-Sodium-For-Use-in-Children-Ages-1-to-11
23. Is Rabeprazole A Safe Treatment for Gastroesophageal Reflux Disease in Children Ages 1-16 years? - DigitalCommons@PCOM, accessed July 30, 2025, https://digitalcommons.pcom.edu/cgi/viewcontent.cgi?article=1204&context=pa_systematic_reviews
24. Pediatric Focused Safety Review Aciphex Sprinkle (rabeprazole) - FDA, accessed July 30, 2025, https://www.fda.gov/media/96811/download
25. Rabeprazole: MedlinePlus Drug Information, accessed July 30, 2025, https://medlineplus.gov/druginfo/meds/a699060.html
26. Rabeprazole: Side Effects, Dosage, Uses, and More - Healthline, accessed July 30, 2025, https://www.healthline.com/health/drugs/rabeprazole-oral-tablet
27. Rabeprazole (AcipHex): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed July 30, 2025, https://www.webmd.com/drugs/2/drug-17504/rabeprazole-oral/details
28. Rabeprazole Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 30, 2025, https://www.drugs.com/sfx/rabeprazole-side-effects.html
29. What are the side effects of Rabeprazole (proton pump inhibitor)? - Dr.Oracle AI, accessed July 30, 2025, https://www.droracle.ai/articles/95025/side-effect-of-rabeprazole
30. www.nhs.uk, accessed July 30, 2025, https://www.nhs.uk/medicines/rabeprazole/side-effects-of-rabeprazole/#:~:text=Long%20term%20side%20effects&text=Taking%20rabeprazole%20for%20more%20than,ulcers%20and%20pins%20and%20needles
31. Common questions about rabeprazole - NHS, accessed July 30, 2025, https://www.nhs.uk/medicines/rabeprazole/common-questions-about-rabeprazole/
32. Rabeprazole and its salts - OEHHA, accessed July 30, 2025, https://oehha.ca.gov/sites/default/files/media/downloads/crnr/070910rabeprazole.pdf
33. A network meta-analysis: evaluating the efficacy and safety of concurrent proton pump inhibitors and clopidogrel therapy in post-PCI patients - Frontiers, accessed July 30, 2025, https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1385318/full
34. Comparison of four proton pump inhibitors for the short-term ..., accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4611579/
35. Meta‐analysis: comparing the efficacy of proton pump inhibitors in short‐term use, accessed July 30, 2025, https://www.periodicos.capes.gov.br/index.php/acervo/buscador.html?task=detalhes&id=W2028184021
36. Comparative study of omeprazole, lansoprazole, pantoprazole and esomeprazole for symptom relief in patients with reflux esophagitis - PMC, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2653397/
37. Comparative effectiveness and acceptability of the FDA-licensed proton pump inhibitors for erosive esophagitis: A PRISMA-compliant network meta-analysis - PMC, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5626283/
38. Lansoprazole vs Rabeprazole Comparison - Drugs.com, accessed July 30, 2025, https://www.drugs.com/compare/lansoprazole-vs-rabeprazole
39. Esomeprazole vs Rabeprazole Comparison - Drugs.com, accessed July 30, 2025, https://www.drugs.com/compare/esomeprazole-vs-rabeprazole
40. A Meta-Analysis and Systematic Review of the Efficacy of Twice Daily PPIs versus Once Daily for Treatment of Gastroesophageal Reflux Disease - PMC, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5585660/
41. (PDF) A Meta-Analysis and Systematic Review of the Efficacy of Twice Daily PPIs versus Once Daily for Treatment of Gastroesophageal Reflux Disease - ResearchGate, accessed July 30, 2025, https://www.researchgate.net/publication/319241506_A_Meta-Analysis_and_Systematic_Review_of_the_Efficacy_of_Twice_Daily_PPIs_versus_Once_Daily_for_Treatment_of_Gastroesophageal_Reflux_Disease
42. Randomised clinical trial: rabeprazole improves symptoms in patients with functional dyspepsia in Japan - PubMed, accessed July 30, 2025, https://pubmed.ncbi.nlm.nih.gov/23957383/
43. Clinical trial: maintenance intermittent therapy with rabeprazole 20 mg in patients with symptomatic gastro-oesophageal reflux disease - a double-blind, placebo-controlled, randomized study - PubMed, accessed July 30, 2025, https://pubmed.ncbi.nlm.nih.gov/20132154/
44. Long-term efficacy and safety of rabeprazole in patients taking low-dose aspirin with a history of peptic ulcers: a phase 2/3, randomized, parallel-group, multicenter, extension clinical trial - PubMed Central, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4454079/
45. Real-world-evidence, prospective-observational study to evaluate ..., accessed July 30, 2025, https://www.wjgnet.com/2150-5349/full/v16/i1/103898.htm
46. Real-world-evidence, prospective-observational study to evaluate safety and effectiveness of rabeprazole dual-delayed-release capsules in patients with gastroesophageal reflux disease - PMC, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11907338/
47. Generic Aciphex Availability - Drugs.com, accessed July 30, 2025, https://www.drugs.com/availability/generic-aciphex.html
48. Drug Approval Package: Aciphex Delayed Release (Rabeprazole Sodium) NDA# 020973, accessed July 30, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20973_Aciphex.cfm
49. FDA approves first rabeprazole generics for treatment of GERD, accessed July 30, 2025, https://www.gabionline.net/generics/news/FDA-approves-first-rabeprazole-generics-for-treatment-of-GERD
50. Rabeprazole Delayed-Release Tablets 20 mg - 90/Bottle - Aurobindo Pharma USA, accessed July 30, 2025, https://www.aurobindousa.com/products/rabeprazole-dr-tabs-20-mg-90/
51. Rabeprazole Sodium Tablets - Lannett Company, accessed July 30, 2025, https://www.lannett.com/products/rabeprazole-sodium/
52. Drug Approval Package: Aciphex (Rabeprazole Sodium) NDA #020973/S-13, 021456, accessed July 30, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/021456_aciphex.cfm
53. Rabeprazole Sodium - FDA Approval - MedPath, accessed July 30, 2025, https://trial.medpath.com/drug/approvals/fda/e6f11a7efc2242ed