What is Benicar?
Benicar (Olmesartan medoximil) is an angiotensin receptor blocker (ARB) used to reduce high blood pressure in patients with hypertension (1). ARBs, also known as “sartans”, are a group of molecules used to control blood pressure in patients who are intolerant to conventional ACE-inhibitor therapy. Just like the other sartans, Benicar acts by blocking angiotensin II AT1 receptors. These receptors are responsible for a vasoconstricting effect, and thus, when blocked, relax vessels reducing blood pressure (2). Benicar (Olmetec in Europe) is often used in association with several other drugs for the treatment of hypertension. These drugs include: Hydrochlorothiazide (Benicar HCT), Amlodipine (Azor), or both (Tribenzor). Benicar was approved by the U.S. Food and Drugs Administration (FDA) on April 25, 2002, after a short clinical trial of just three months (3).
Benicar Side Effects – Benicar Diarrhea and Benicar Enteropathy
Diarrhea is included among the various Benicar side effects together with other adverse reactions such as dizziness, vomiting or rash that are common for all ARBs. However, Benicar diarrhea as well as the other gastrointestinal problems caused by this medication, seem to be much more severe than its similar counterparts. This form of unexplained chronic diarrhea and enteropathy significantly affects a patient’s health, up to the point of preventing the intestine from properly absorb nutrients from digested food. Long-term consequences of these Benicar intestinal problems do, in fact, include substantial weight loss (usually around 20 kilograms) and malnutrition (4, 5, 6).
This type of Benicar diarrhea is somewhat similar to the symptoms showed by people affected by Celiac Disease (CD). Probably the most significative symptoms are Benicar villous atrophy and mucosal inflammation, two conditions that greatly reduce the ability of the small intestine to absorb adequate amounts of nutrients. However, Celiac Disease is also characterized by a specific immune response such as positive antibody testing and symptomatic response to a gluten-free diet. Benicar enteropathy is not affected by any dietary restrictions, nor it does present any immunological or histological findings except for a typical subepithelial collagen deposition called “sprue” (5). As shown in a first clinical study submitted by the Mayo Clinic in 2012, the only improvement was seen when patients stopped taking Benicar (6).
One year later, in 2013, another study published in the American Journal of Gastroenterology found evidence of an association between Benicar and an unclassified sprue-like enteropathy. These Benicar gastrointestinal problems were so severe that some patients lost almost 60 kilograms and required hospitalization, negatively impacting their health and requiring several years to fully recover. Later that same year, the FDA issued an investigation panel to evaluate Benicar safety and found convincing evidence that correlates this medication with sprue-like enteropathy after a 2-year minimum exposure. The short 3-months long clinical trial that granted approval to Benicar was insufficient to adequately evaluate its risks (7). In April 2014, the FDA approved a change to Benicar label to include a warning about the risk of concerning Benicar intestinal problems (4). Similarly, even the Agenzia Italiana del Farmaco (AIFA), the Italian agency equivalent of the FDA, issued an analogous warning about Benicar dangers and Benicar gastrointestinal risks (8).
A large retrospective study published in 2014 in the Journal of Pharmacy Practice, reviewed the current Pubmed literature and found consistent evidence showing that Benicar side effects accounted for 22% of previously unclassified sprue cases (9). Although a potential mechanism mediated by the inhibition of the TGF-β action on the intestine has been suggested, no final answer has yet been found. This mechanism is, in fact, common for all the other sartans, although Benicar (olmesartan) is the only one that causes gastrointestinal problems of this magnitude (4). Other mechanisms have been suggested, and research showed that Benicar could be responsible for an immuno-mediated response of the intestinal epithelial cells that leads to clinical effects which are very similar to those of gluten in the gut of a subject affected by celiac disease (10).
Additional Benicar Dangers – Benicar during pregnancy and Benicar cardiovascular death risk
Benicar dangers are not limited to just gastrointestinal issues, however. Other than the numerous additional Benicar side effects that make this medication stand out among the other sartans, the FDA issued a black label to warn about its danger. The “black box warning” is the most ominous admonition issued by FDA, and in this case, exhorts patients to show the highest degree of caution using Benicar during pregnancy. Due to the high risk of fetal toxicity, pregnant women should immediately stop taking Benicar as it can “cause injury of death to the developing fetus.”(3, 11)
However, that’s not the only additional Benicar danger. During the last few years, several large clinical trials highlighted Benicar’s controversial role in increasing cardiovascular mortality in diabetic subjects taking high doses of this drug. FDA issued a safety review after the results of the ROADMAP trial found an unexpected five-fold increase in the risk of Benicar cardiovascular death in patients with type 2 diabetes. Although another clinical trial, the ORIENT one also showed similar results, a wider review of other studies led the FDA regulators not to recommend against using Benicar in diabetic patients. FDA announced that they found “no clear evidence of increased cardiovascular risks” associated with the use of Benicar in diabetic patients. Although FDA’s final decision was in favor of Benicar’s safety, the controversial results coming from the various studies still raise numerous concerns among doctors and patients (12, 13, 14).
Benicar Lawsuits – the FDA Warnings and Daiichi Sankyo past issues
It won’t be the first time that Daiichi Sankyo is under the FDA’s radar for fraudulent or misleading behaviors, however. Daiichi Sankyo was already warned twice by FDA for producing misleading advertisement about their products. They received their first warning in 2007 because they failed to inform the public about the potential dangers and contraindications of their drug Evoxac (cevimeline hydrochloride). In the warning letter from the Department of Health and Human Services, the regulators accuse the pharmaceutical company in clear terms:
“These promotional materials are false or misleading because they present efficacy claims for Evoxac but fail to communicate information about the risks associated with its use.” (15)
After just a couple of years, in 2013 Daiichi Sankyo received another warning letter from the FDA, claiming they repeated a similarly fraudulent advertisement campaign for Benicar too:
“The promotional material is misleading because it makes unsubstantiated efficacy claims associated with Benicar and Benicar HCT. […] Promotional materials are misleading if they represent or suggest that a drug is more effective than has been demonstrated by substantial evidence or substantial clinical experience. ” (16)
This last letter is especially alarming, as Daiichi Sankyo is known for a terrible past that permanently stained its reputation: the Ranbaxy issue. In 2014, the newly acquired generic drugmaker company acquired by Daiichi was found guilty of felony charges caused by lack of manufacturing safety by the U.S. Department of Justice. The FDA issued a recall of over 500,000 bottles of Lipitor (atorvastatin), forcing the company to pay $500 million in fines to settle down the civil and criminal allegations. In April 2015, Daiichi Sankyo agreed to pay $39 million to settle down a whistleblower lawsuit that alleged the pharmaceutical company paid kickbacks to doctors and physicians to convince them prescribing various medications, including Benicar (17, 18, 19).
It’s unsurprising then that many patients who suffered long-term injuries caused by Benicar side effects are now filing dozen of Benicar lawsuits asking for compensation. As soon as the FDA released the new warning about Benicar intestinal problems, several Benicar attorneys determined that Daiichi Sankyo could be held liable for all the injuries caused to the patients who took this medication. In 2015 over 30 Benicar lawsuits have been consolidated in a Multidistrict Litigation in the U.S. District Court for the District of New Jersey.
Article written by Dr. Claudio Butticè, PharmD.
Last Updated: 01/28/2016
- Benicar® Full Prescribing Information. (Accessed January 2016)
- Izzo JL Jr, Neutel JM, Silfani T, Dubiel R, Walker F. Efficacy and safety of treating stage 2 systolic hypertension with olmesartan and olmesartan/HCTZ: results of an open-label titration study. J Clin Hypertens (Greenwich). 2007;9;36-44
- U.S. Food and Drugs Administration (FDA). Olmesartan (marketed as Benicar) Information. (Accessed January 2016).
- U.S. Food and Drugs Administration (FDA). FDA Drug Safety Communication: FDA approves label changes to include intestinal problems (sprue-like enteropathy) linked to blood pressure medicine olmesartan medoxomil. (Accessed January 2016).
- De Petris G, Caldero SG, Chen L, et al. (May 2014). “Histopathological changes in the gastrointestinal tract due to medications: an update for the surgical pathologist (part II of II)”. Int. J. Surg. Pathol. 22 (3): 202–11. doi:10.1177/1066896913502230
- Rubio-Tapia A, Herman ML, Ludvigsson JF, et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc 2012;87:732-8.
- DeGaetani M, Tennyson CA, Lebwohl B, et al. Villous atrophy and negative celiac serology: A diagnostic and therapeutic dilemma. Am J Gastroenterol 2013;108:647-53.
- Agenzia Italiana del Farmaco (AIFA). Olmesartan – Riassunto delle caratteristiche del prodotto. (Accessed January 2016)
- Sanford ML, Nagel AK. A Review of Current Evidence of Olmesartan Medoxomil Mimicking Symptoms of Celiac Disease. J Pharm Pract. 2014 Mar 28.
- Marietta, E. V., Nadeau, A. M., Cartee, A. K., Singh, I., Rishi, A., Choung, R. S., Wu, T.-T., Rubio-Tapia, A. and Murray, J. A. (2015), Immunopathogenesis of olmesartan-associated enteropathy. Alimentary Pharmacology & Therapeutics, 42: 1303–1314. doi: 10.1111/apt.13413
- Hünseler, C; Paneitz, A; Friedrich, D; Lindner, U; Oberthuer, A; Körber, F; Schmitt, K; Welzing, L; Müller, A; Herkenrath, P; Hoppe, B; Gortner, L; Roth, B; Kattner, E; Schaible, T (Jan 2011). “Angiotensin II receptor blocker induced fetopathy: 7 cases”. Klin Padiatr 223 (1): 10–4. doi:10.1055/s-0030-1269895
- Haller H, Ito S, Izzo JL, et al. Olmesartan for the delay or prevention of microalbuminuria in Type 2 Diabetes. N Engl J Med 2011; 364: 907-17.
- Imai E, Chan JC, Ito S, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia 2011; 54: 2978-86.
- Zhou EH, Gelperin K, Levenson MS, et al. Risk of acute myocardial infarction, stroke, or death in patients initiating olmesartan or other angiotensin receptor blockers – a cohort study using the Clinical Practice Research Datalink. Pharmacepidemiol Drug Saf 2014; 23: 340-7.
- U.S. Food and Drugs Administration (FDA). DEPARTMENT OF HEALTH & HUMAN SERVICES – Daiichi Sankyo Warning Letter 2007. (Accessed January 2016)
- U.S. Food and Drugs Administration (FDA). DEPARTMENT OF HEALTH & HUMAN SERVICES – Daiichi Sankyo Warning Letter 2013. (Accessed January 2016)
- Reuters. Ranbaxy pleads guilty, to pay $500 mln in settlement. http://in.reuters.com/article/ranbaxy-settlement-felony-usa-idINDEE94C0DA20130513 (Accessed January 2016)
- Forest Laboratories. (2014, March 31). Form 10-K. United States Securities and Exchange Commission. (Accessed January 2016)
- Forest Laboratories. (2014, February 6). Form 10-Q. United States Securities and Exchange Commission. (Accessed January 2016)