Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Ellison syndrome. It may also be used in combination with other medications to treat Helicobacter pylori. Effectiveness is similar to other proton pump inhibitors (PPIs). It is taken by mouth.
Common side effects include constipation, feeling weak, and throat inflammation. Serious side effects may include osteoporosis, low blood magnesium, Clostridioides difficile infection, and pneumonia. Use in pregnancy and breastfeeding is of unclear safety. It works by blocking H+/K+-ATPase in the parietal cells of the stomach.
Rabeprazole was patented in 1986, and approved for medical use in 1997. It is available as a generic medication. In 2017, it was the 288th most commonly prescribed medication in the United States, with more than 1million prescriptions.
Medical uses
Rabeprazole, like other proton pump inhibitors such as omeprazole, is used for the purposes of gastric acid suppression. This effect is beneficial for the treatment and prevention of conditions in which gastric acid directly worsens symptoms, such as duodenal and gastric ulcers. In the setting of gastroesophageal reflux disease (GERD), whose pathophysiology is characterized by prolonged exposure to gastric acid in the esophagus (often due to changes in stomach and/or esophagus anatomy, such as those induced by abdominal obesity), acid suppression can provide symptomatic relief. Acid suppression is also useful when gastric production of acid is increased, including rare conditions with excess gastric acid secretion (hypersecretory conditions) like Zollinger–Ellison syndrome (ZES), multiple endocrine neoplasia type 1 (MEN-1), and systemic mastocytosis. In an open-label, industry-sponsored, non-controlled study of high-dose rabeprazole for the treatment of ZES and idiopathic gastric acid hypersecretion (IGAH), including patients with MEN-1 and GERD, rabeprazole induced and maintained suppression of basal acid output over a 24 month period. Only one patient withdrew from the study due to an elevation in creatine phosphokinase judged to be possibly due to rabeprazole, while rabeprazole was otherwise well-tolerated in this population. There are no clinical trials to date that have studied the precise use of rabeprazole, or any PPI, for the treatment of acid-related complaints due to systemic mastocytosis, but acid suppressing medications such as PPIs and H2 receptor antagonists are routinely used to counter the histamine-mediated acid secretion found in this disorder.
Rabeprazole is also useful alongside antibiotic therapy for the treatment of the pathogen Helicobacter pylori, which otherwise thrives in acidic environments. In the original studies that gave rise to its approval for the eradication of H. pylori, rabeprazole was studied in combination with amoxicillin and clarithromycin. This triple therapy was studied at the specific doses of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily for 7 days, which is a higher dose of rabeprazole than what is used for the treatment of simple GERD (20 mg once daily). The higher dose is thought to provide more consistent elevation of pH in the stomach, leading to better eradication of H. pylori, congruent with the dosing strategies of other PPIs for this indication. Notably, H. pylori eradication with antibiotics and rabeprazole was also shown to prevent development of second gastric cancer in a randomized trial in high-risk South Korean patients with early stomach cancer treated by endoscopy.
Thus, rabeprazole is US Food and Drug Administration (FDA) approved for the treatment of symptomatic GERD in adolescents and adults, healing duodenal ulcers in adults, eradication of Helicobacter pylori, and pathologic hypersecretory conditions.
Available forms Rabeprazole is available in 10 and 20 mg, delayed-release tablets (pictured below). Rabeprazole-based products, like other proton pump inhibitor products, have to be formulated in delayed-release tablets to protect the active medication from being degraded by the acid of the stomach before being absorbed.
Specific populations Pediatrics Rabeprazole's only pediatric indication is for the treatment of symptomatic GERD in adolescents (12 years-old and up).
Pregnancy The FDA originally labeled rabeprazole as a pregnancy category B drug (meaning that in vivo research failed to demonstrate a fetal hazard, though human studies are lacking), but it was reclassified as a pregnancy category C drug (meaning that in vivo research has shown a fetal hazard, though the benefit of use may outweigh the risk) in 2014. This was after the publishing of an in vivo study that detected changes in bone morphology in rats treated with esomeprazole. In these rats, the following observations were noted:
shortened femurs, decreased width and thickness of cortical bone, decreased thickness of the tibial growth plate, and minimal to mild bone marrow hypocellularity occurred at doses equal to or greater than 3.4 times the daily maximum recommended human dose (MRHD); decreased survival, decreased birth weight, and an increase in neurobehavioral delays occurred at doses equal to or greater than 16.8 times the daily MRHD; physeal dysplasia of the femur occurred at doses equal to or greater than 33.6 times the daily MRHD.
In vivo studies on rabbits with rabeprazole doses of up to 50 mg/kg/day (about 13 times the normal human drug exposure of rabeprazole at 20 mg) failed to show evidence of fetal harm.
Lactation It is expected that rabeprazole will be secreted into human breast milk, though the clinical impact of this is still unknown. Avoiding rabeprazole during breastfeeding confers to lowest possible risk.
Geriatrics Advanced age does not appear to clinically impact rabeprazole's metabolism. However, elevations in the maximum plasma concentration and the total drug exposure (area under the curve, AUC) have occurred.
Japanese ancestry In a study on rabeprazole's pharmacokinetics, the AUC was elevated by approximately 50–60% in men of Japanese ancestry compared to men in the United States. See the pharmacogenetics section below for a pharmacogenetic explanation of these findings.
Kidney or liver problems In people that have kidney or liver problems, these problems do not appear to affect rabeprazole's metabolism in a clinically meaningful way. This includes individuals on dialysis for kidney problems. Severe liver problems like cirrhosis of the liver do affect rabeprazole's elimination half-life, but not to a degree of dangerous accumulation. In a review of patients taking rabeprazole while having end-stage kidney disease and mild-to-moderate severity, chronic compensated cirrhosis of the liver, the alteration in rabeprazole's metabolism was not clinically meaningful.
Contraindications Rabeprazole is contraindicated in the following populations and situations: people with a known hypersensitivity to rabeprazole, substituted benzimidazoles (which are chemically similar to rabeprazole, like omeprazole), or any other component of the capsule formulation (e.g. certain dyes) concurrent use of rilpivirine, a medication used to treat HIV infection
Hypersensitivity Syndrome An allergy to a PPI like rabeprazole may take the form of type I hypersensitivity or delayed hypersensitivity reactions. A selective (pattern C—see below for a discussion of cross-reactivity patterns) type I hypersensitivity reaction to rabeprazole resulting in anaphylaxis has been reported, as well as several whole group hypersentivities.
Cross-reactivity Hypersensitivity to PPIs can take the form of whole group hypersensitivity, pattern A, B, or C. Whole group hypersentivity occurs when a person is cross-reactive to all PPIs; that is, all PPIs will induce the allergy. In pattern A, a person may be allergic to omeprazole, esomeprazole, and pantoprazole, but not to lansoprazole and rabeprazole. This is thought to be due to the structural similarities between omeprazole, esomeprazole, and pantoprazole, contrasted with lansoprazole and rabeprazole. Pattern B is the opposite, reflecting people that are allergic to lansoprazole and rabeprazole, but not to omeprazole, esomeprazole, and pantoprazole. Pattern C, in the context of rabeprazole, would reflect a person that is allergic to only rabeprazole, but not to other PPIs (omeprazole, esomeprazole, pantoprazole, and lansoprazole).
Rilpivirine Rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV, is contraindicated with all PPIs because of their acid-suppressing effect. PPIs suppress acid, thereby raising the pH of (alkalizing) the stomach's contents. Rilpivirine is best absorbed under acidic conditions. Therefore, rabeprazole would be expected to decrease the absorption of rilpivirine, decrease the concentration of rilpivirine in the blood, and possibly lead to therapeutic failure and induce resistance of the HIV virus to rilpivirine and/or cross-resistance with other NNRTIs.
Adverse effects In general, rabeprazole is fairly well tolerated, even with up to five years of continuous use (the duration of follow-up in a pharmacovigilance clinical trial). The side effect profile is similar to that of omeprazole. The side effect profile is similar to that of omeprazole and other commonly used PPIs. The most common side effects include headache, nausea, and diarrhea. Rare side effects include rashes, flu-like symptoms, and infections (including by the gastrointestinal pathogen Clostridioides difficile). Rare instances of rabeprazole-induced liver injury (also known as hepatotoxicity) have been reported. Characteristic proton-pump inhibitor hepatotoxicity occurs within the first 4 weeks of starting the medication.
Gastrin is an endogenous human hormone that stimulates gastric acid secretion and regulating the growth of certain cells in the stomach. Enterochromafin-like (ECL) cells, responsible for stimulating gastric acid secretion by the release of histamine in the stomach, respond to prolonged gastrin exposure by growing and proliferating. Rabeprazole is associated with elevated serum gastrin levels (hypergastrinemia), which occurs through inhibiting the negative feedback of stomach acid on gastrin secretion by G cells in the antrum of the stomach. The elevation in serum gastrin levels are thought to be dependent upon the degree of rabeprazole's CYP2C19 metabolism. Rabeprazole is not as significantly metabolized by CYP2C19 compared to other medications in the same class, like omeprazole. Hypergastrinemia has been posited as a potential source of rabeprazole-induced neuropsychiatric symptoms (e.g. dizziness, numbness, and tremor), though more research is needed to clarify the effect and mechanism.
Prolonged elevated serum gastrin has been shown to cause rat ECL cells to form carcinoid tumors. According to a 2013 meta-analysis of observational studies, the use of acid-suppressing drugs (including PPIs like rabeprazole, but also histamine receptor 2 antagonists) may be associated with the development of gastric cancer. The studies included in the meta-analysis did not differentiate between rabeprazole and other PPIs, so it is unclear if the potential risk may differ across the PPI class.
Acid suppression via rabeprazole can decrease the absorption of vitamin B12 and magnesium, leading to deficiency. A case of rabeprazole-induced iron deficiency anemia has been reported. Theoretically, rabeprazole could induce an iron deficiency anemia by reducing the dietary absorption of iron, which requires acid for bioavailability.