[6] 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),[17] 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.

[23] 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.

[24] 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[25]).

[28] Gastrin is an endogenous human hormone that stimulates gastric acid secretion and regulating the growth of certain cells in the stomach.

[29] 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.

[2] 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.

[30] Prolonged elevated serum gastrin has been shown to cause rat ECL cells to form carcinoid tumors.

[29] 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.

[31] The studies included in the meta-analysis did not differentiate between rabeprazole and other PPIs,[32][33][34][35] so it is unclear if the potential risk may differ across the PPI class.

[11] These include Stevens-Johnson syndrome (a serious disease characterized by skin rash and risk of organ failure), serious blood cell abnormalities, coma, and death.

[36] A rare, though less understood, side effect of the PPI class is the risk of myopathy and rhabdomyolysis, a syndrome of striated muscle destruction.

[38] The mechanism of PPI-induced osteoporosis and fractures is unclear, but hypotheses include hypocalcemia and hypomagnesemia, hyperparathyroidism, and B12 deficiency (inducing neurological deficits and subsequent falls).

[39] In opposition to the calcium malabsorption hypothesis, rabeprazole prevented reductions in bone mineral density akin to the effect of minodronic acid in a study of gastrectomized rats.

[45] One hypothesis for this association is that PPI-induced acid suppression fosters the growth of aerobic bacteria in the stomach, which can be transferred to the lungs by microaspiration, promoting colonization and subsequent pneumonia.

[44] In line with the stomach acid suppression hypothesis for bacterial overgrowth, PPIs have also been associated with Clostridioides difficile infections.

[45] However, as these meta-analyses have pooled PPIs together, it is unknown whether the risk of infection differs significantly between rabeprazole and other members of the PPI class.

[45] Rabeprazole was identified as the causative agent in a case report of collagenous colitis, inducing chronic, watery diarrhea.

[51] The first reported case of rabeprazole-induced acute interstital nephritis occurred in a 62 year-old female in Australia, prescribed rabeprazole for complaints of dyspepsia due to suspected GERD.

[52] The mechanism for PPI-induced acute interstital nephritis has not been elucidated, though an immune-related hypothesis has been posited on the basis of extra-renal toxicity consistent with an immunologic, hypersensitivity reaction.

[38] In one case, rhabdomyolysis developed in a 50 year-old patient 2 weeks after starting both rabeprazole and domperidone, a prokinetic and antiemetic agent,[53] which resolved after discontinuation of both drugs.

[38] Per the French imputability method of causality assessment, it was determined that rabeprazole was a "plausible" cause of the rhabdomyolysis, noting that domperidone was started concurrently.

[3] However, the acid-suppression effects of rabeprazole, like other PPIs, may interfere with the absorption of drugs that require acid, such as ketoconazole and digoxin.

However, because this is thought to be mediated by the effect of omeprazole and esomeprazole on CYP2C19, the enzyme that activates clopidogrel, this drug interaction is not expected to occur as strongly with rabeprazole.

However, whether the effect of omeprazole and esomeprazole on clopidogrel's metabolism actually leads to poor clinical outcomes is still a matter of intense debate among healthcare professionals.

[11] After being activated by gastric (stomach) acid to a reactive sulfenamide intermediate,[56] rabeprazole permanently binds the cysteine residues, forming covalent, disulfide bonds.

The pKa (the pH at which 50% of the drug becomes positively charged) of rabeprazole is around 5.0, meaning that it doesn't take a lot of acid to activate it.

While this theoretically translates into a faster onset of action for rabeprazole's acid-inhibiting effect, the clinical implications of this fact have yet to be elucidated.

[11] Theoretically, a high pKa should correlate with off-target activation of the PPI (possibly inducing side effects), though the clinical relevance of this has also yet to be elucidated.

Rabeprazole's bioavailability is approximately 52%, meaning that 52% of orally administered dose is expected to enter systemic circulation (the bloodstream).

[2] It takes about 3.5 hours for rabeprazole to reach the maximum concentration in human plasma after a single orally administered dose.