Data Summary
Olmesartan medoxomil is an angiotensin II receptor blocker (ARB) that was approved on April 25, 2002, for the treatment of hypertension, alone or with other antihypertensive agents. The current olmesartan drug labels include diarrhea in the Adverse Reactions section.
FDA evaluated adverse event reports received by FDA’s Adverse Event Reporting System (FAERS), published literature case series,3-4 information from FDA’s Mini-Sentinel pilot of the Sentinel Initiative, and information from the CMS Medicare database. FDA’s evaluation found clear evidence of an association between olmesartan and sprue-like enteropathy.
FDA identified 23 serious cases in FAERS presenting as late-onset diarrhea with significant weight loss and, in some cases, with intestinal villous atrophy on biopsy. All patients improved clinically after discontinuation of olmesartan, and a positive rechallenge was seen in 10 of the cases.
In June 2012, Mayo Clinic researchers published a case series of sprue-like enteropathy associated with olmesartan in 22 patients whose clinical presentation was similar to that of the FAERS cases: Patients in the Mayo Clinic case series developed diarrhea, weight loss, and villous atrophy while on olmesartan, and drug discontinuation resulted in clinical improvement.3 Â Eighteen patients had follow-up intestinal biopsies histologically demonstrating recovery or improvement of the duodenum after discontinuation of olmesartan.
In May 2013, an article describing patients with villous atrophy and negative serologies for celiac disease reported that some patients without definitive etiologies for villous atrophy were characterized as having unclassified sprue. Some of these patients were later found to have villous atrophy associated with olmesartan use.4
The signal of sprue-like enteropathy with olmesartan was further investigated for a possible ARB class effect using active surveillance data. Â Mini-Sentinel and CMS Medicare data were assessed for celiac disease (as a marker for enteropathy and other gastrointestinal symptoms) after exposure to ARBs. Mini-Sentinel and CMS Medicare assessments of ICD-9 codes for celiac disease showed that at a 2-year minimum exposure, which correlates with the long latency observed in literature and case reports, olmesartan users had a higher rate of celiac disease diagnoses in claims and administrative data than users of other ARBs. Interpretation is limited by the small number of events observed at longer exposure periods and the uncertainty about the validity of codes for celiac disease, but these results support other data in suggesting a lack of a class effect.
Although the mechanism for olmesartan-associated sprue-like enteropathy is uncertain, the long latency before onset of symptoms, findings of lymphocytic or collagenous colitis, and high association with HLA-DQ2/8 suggest a localized delayed hypersensitivity or cell-mediated immune response to the pro-drug olmesartan medoxomil. Rubio-Tapia et al., suggest that ARB-mediated inhibition of TGF-β, an important mediator of gut homeostasis, is a possible mechanism for olmesartan-associated sprue-like enteropathy, although it is unclear why this effect is not observed with other ARBs.3