Drug Injury Watch

Januvia, Onglyza, Other Diabetes Drugs In DPP-4 Inhibitor Class Significantly Increase Risk Of Crohn's Disease (CD)

But Same Medical Study Finds That DPP-4 Inhibitors Do Not Increase Risk Of Inflammatory Bowel Disease (IBD)

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Back in March 2018 we wrote this report, "Januvia, Onglyza, And Certain Other Diabetes Drugs Linked To Inflammatory Bowel Disease (IBD)", which was about a study published by The BMJ medical journal about the use of dipeptidyl peptidase-4 (DPP-4) inhibitors for treatment of type 2 diabetes being associated with increased risk for IBD.

Now, about a year later, the medical journal Annals of Pharmacotherapy has published an article, "Dipeptidyl Peptidase-4 Inhibitors and Inflammatory Bowel Disease Risk: A Meta-analysis", which concludes that DPP-4 inhibitors do not appear to increase the risk of developing IBD -- but goes on to point out that these drugs, such as Januvia and Onglyza, increase the risk of Crohn's disease (CD).

The following diabetes medicines are in the DPP-4 inhibitor class of drugs:

Januvia (sitagliptin)
Janumet (sitagliptin / metformin HCl)
Janumet XR (sitagliptin / metformin HCl)
Tradjenta (linagliptin)
Jentadueto (linagliptin / metformin HCl)
Glyxambi (empagliflozin / linagliptin)
Onglyza (saxagliptin)
Kombiglyze XR (saxagliptin and metformin)
Qtern (dapagliflozin and saxagliptin)
Nesina (alogliptin)
Kazano (alogliptin and metformin)
Oseni (alogliptin and pioglitazone)

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From the Abstract for this new Annals of Pharmacotherapy article, published on January 30, 2019, we get the following:

• Objective: This meta-analysis aims to elucidate the risk for [inflammatory bowel disease (IBD)] with DPP-4 inhibitor therapy.
• Results: A total of 16 individual studies evaluating a total of 198 404 patients were included for analysis. Studies ranged from 52 weeks through 5 years. In the primary random-effects analysis, DPP-4 inhibitor exposure resulted in a nonsignificant increase in the risk of [inflammatory bowel disease (IBD)] (RR = 1.52; 95% CI = 0.72 to 3.24; I2 = 54.2%).... DPP-4 inhibitor use significantly increased the risk of [Crohn's disease (CD)] (RR = 2.47; 95% CI = 1.36 to 4.48)....
• Conclusion and Relevance: Based on a conservative random-effects analysis, DPP-4 inhibitors do not appear to increase the risk of developing inflammatory bowel disease. However, long-term postmarketing surveillance is warranted.

In summary, this recent study found that the DPP-4 inhibitor class of drugs is not associated with IBD; however, DPP-4 inhibitor diabetes drugs, such as Januvia and Onglyza, increase the risk of Crohn's disease (CD).

Be assured that we will continue to monitor the safety profile of these DPP-4 diabetes drugs.

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A French Medical Study Provides More Support For Apparent Link Between Benicar With Chronic Severe Diarrhea And Substantial Weight Loss Side Effects

Researchers Found An Almost 10-Times Increased Risk Of Severe Intestinal Malabsorption Associated With Benicar After 2-Years Use Compared To Some Other Blood Pressure Medications

(Posted by Tom Lamb at DrugInjuryWatch.com)

We continue to hear about patients who have been diagnosed with sprue-like enteropathy or intestinal malabsorption while using Benicar, Azor, Tribenzor, or Benicar HCT, and we have written previously about the still-emerging Benicar drug injury litigation.

In May 2014 the medical journal Gastroenterology published an article, "Severe Malabsorption Associated With Olmesartan: A French Nationwide Cohort Study", which provides some insight concerning the association between Benicar and a side effect that is often initially mistaken for celiac disease.

From the Abstract for this medical journal article about that French Benicar study:

Introduction: Several cases of severe sprue-like enteropathy have been reported in patients treated with [Benicar (Olmesartan medoxomil)], an angiotensin II receptor blocker (ARB) approved for the treatment of hypertension. The association has been questioned: in the ROADMAP phase 3-trial, the rate of diarrhea was similar in patients who received [Benicar (olmesartan)] and placebo. The objective of this study was to assess in a large, nation-wide patient cohort, the risk of severe intestinal malabsorption associated with [Benicar (olmesartan)], compared with ARBs other than [Benicar (olmesartan)] or ACEIs.

Results: 4,546,680 patients summing up to 9,010,303 person-years were included. 218 events were observed. Compared with ACEI, the adjusted rate ratio of severe intestinal malabsorption associated with [Benicar (olmesartan)] was 2.27 (95% confidence interval 1.59-3.23, p<0.0001). This adjusted rate ratio varied with treatment duration: less than 1 year RR =0.87 (95% CI 0.47- 1.6, p=0.64), between 1 and 2 years RR = 3.20 (1.58-6.46, p=0.001), 2 years or more RR= 9.53 (4.46-20.3, p<0.0001). Compared with other ARBs, the rate ratio of severe intestinal malabsorption associated with [Benicar (olmesartan)] intake was 3.0 (95% CI 2.1-4.33, p<0.0001). The risk of severe intestinal malabsorption was not significantly different between patients who were prescribed ARBs other than olmesartan and ACEIs.

Conclusion: [Benicar (olmesartan)] was associated with an increased risk of severe intestinal malabsorption. The increased risk appears after one year of treatment and reaches 9.53 after 2 years of [Benicar (olmesartan)]. ARBs other than [Benicar (olmesartan)] were not associated with an increased risk of severe intestinal malabsorption.

Our law firm is investigating these Benicar sprue-like enteropathy cases -- involving chronic severe diarrhea and substantial weight loss -- as possible products liability lawsuits against the responsible drug company, Daiichi Sankyo, Inc.

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July 2014 Boxed Warning For Linzess: Irritable Bowel Syndrome / Constipation Drug May Be Unsafe And Cause Diarrhea In Children

FDA Drug Alert Warns That Linzess Should Not Be Used In Children Under Age 6 And Neither Safety Nor Efficacy Established For Those Under 18 Years Old

 

(Posted by Tom Lamb at DrugInjuryWatch.com)
 

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UPDATE: "Synergy Petitions FDA to Update Linzess Labeling" (FDA News, 3/2/18)

In a citizen’s petition to the FDA, Synergy Pharmaceuticals urged the FDA to require a revision of the approved package insert of Ironwood Pharmaceutical’s irritable bowel syndrome medication Linzess (linaclotide).

Synergy claimed the Linzess package insert fails to provide adequate information for its use because the incidences of adverse effects in its clinical trials are unclear or misrepresented....

 (3/2/18)

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Linzess (linaclotide) was approved by the FDA in 2012 for irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation.  It is from Forest Pharmaceuticals, Inc., who has advertisements for this relatively new drug on television and in magazines.

As announced by the FDA by means of an August 15, 2014 MedWatch Safety Information email alert, in July 2014 there were several major label changes made to the following sections of the Linzess Prescribing Information (accessed 8/18/14):

-- Boxed Warning; 
-- Contraindications (4);
-- Warnings and Precautions, Pediatric Risk (5.1); and,
-- Warnings and Precautions, Diarrhea.

The new Linzess "Black-Box" Warning states:

WARNING: PEDIATRIC RISK

• LINZESS is contraindicated … in nonclinical studies, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration in young juvenile mice. …The safety and efficacy of LINZESS has not been established in pediatric patients under 18 years of age

 

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And here is another one of the rather alarming label changes for Linzess made by the FDA and Forest Pharmaceuticals in July 2014:

WARNINGS AND PRECAUTIONS

Pediatric Risk

• LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop significant diarrhea and its potentially serious consequences…

The bottom line is that starting last month Linzess should not be prescribed to children less than 6 years old because it may harm them.

And as for older children up to age 18, it appears there is no certainty that Linzess is either a safe drug or an effective drug.

There is no indication that Forest has sent a so-called "Dear Doctor" letter to health care providers about these several important major label changes to the effect that Linzess is not a safe IBS and chronic constipation drug for young children.

One wonders whether this July 2014 FDA / Forest Linzess label change might have come too late for some pediatric patients who used Linzess and then suffered "significant diarrhea and its potentially serious consequences".

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DrugInjuryLaw.com: Current Legal And Medical Information About Prescription Drug Side Effects  (All website content by attorney Tom Lamb)

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When Someone Using Benicar Is Diagnosed With Celiac Disease They May Have, Instead, Developed Drug Induced Sprue-Like Enteropathy Or Intestinal Malabsorption

This Severe Diarrhea Side Effect Is Caused By Olmesartan, Which Is Also Found In Azor, Tribenzor, And Benicar HCT Blood Pressure Medications

(Posted by Tom Lamb at DrugInjuryWatch.com)

Back in May 2014 we made reference to this medical article, "A Review of Current Evidence of Olmesartan Medoxomil Mimicking Symptoms of Celiac Disease", published online by the Journal of Pharmacy Practice, in our post entitled Benicar (Olmesartan) Associated With Sprue-Like Enteropathy, Which Is A Chronic / Severe Diarrhea Condition That Can Be Misdiagnosed As Celiac Disease.

More recently, in June 2014, on the Family Practice News Digital Network, we found this news report, "Olmesartan can cause celiac disease mimicker".

The antihypertensive agent olmesartan is associated with increased risk of a severe sprue-like enteropathy, as highlighted in a nationwide French cohort study.

This olmesartan-related illness is characterized by villous atrophy, severe chronic diarrhea, and weight loss, with negative serology for celiac disease.

The hospitalization rate for this disorder is time dependent. The risk doesn’t increase significantly until after the first year on therapy but climbs steeply thereafter, Dr. Myriam Mezzarobba reported at the annual Digestive Disease Week.

Importantly, angiotensin receptor blockers other than olmesartan (Benicar) were not associated with an increased risk of severe intestinal malabsorption in the French study. Neither were ACE inhibitors, added Dr. Mezzarobba of the French National Health Insurance Fund, Paris.

This article points out that many of the patients who developed this Benicar side effect and were hospitalized are given the discharge diagnosis of intestinal malabsorption instead of sprue-like enteropathy.  Both of these medical conditions, however, are notable for chronic and severe diarrhea with substantial weight loss.

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Returning to the June 2014 news report, we get this additional insightful information:

Session discussant Dr. Benjamin Lebwohl stressed that the French study holds a key lesson for gastroenterologists everywhere.

"Lest we become very aggressive in our case finding for celiac disease – and many of us are now looking more closely for this disease – we need to remember that villous atrophy is not always due to celiac disease," said Dr. Lebwohl, a gastroenterologist at Columbia University, New York.

He characterized the association between olmesartan and severe intestinal malabsorption found in the French national study as "robust," adding: "Importantly, this risk was not an acute risk. It increased over time. This is not an acute drug reaction, this is something that can develop at any point, even years after starting olmesartan."

Our firm continues to hear from patients who have been diagnosed with sprue-like enteropathy or intestinal malabsorption while using Benicar, Azor, Tribenzor, or Benicar HCT, and we are investigating those cases as possible products liability lawsuits against the drug company.

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DrugInjuryLaw.com: Current Legal And Medical Information About Prescription Drug Side Effects  (All website content by attorney Tom Lamb)

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Benicar (Olmesartan) Associated With Sprue-Like Enteropathy, Which Is A Chronic / Severe Diarrhea Condition That Can Be Misdiagnosed As Celiac Disease

This Diarrhea With Weight Loss Is Also A Side Effect Of Benicar HCT, Azor, And Tribenzor -- Other Blood Pressure Medicines Containing Olmesartan

(Posted by Tom Lamb at DrugInjuryWatch.com)

An association between the serious side effect sprue-like enteropathy and the oral angiotensin-receptor blockers (ARBs) Benicar, Benicar HCT, Azor, and Tribenzor and has been getting increased attention in the medical literature.

As pointed out by the FDA in July 2013 when it issued this MedWatch alert, "FDA Drug Safety Communication: FDA approves label changes to include intestinal problems (sprue-like enteropathy) linked to blood pressure medicine olmesartan medoxomil", severe and chronic diarrhea with substantial weight loss has been reported in patients taking Benicar and the other related drugs months to years after they first started using these blood pressure pills.

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The most recent medical article we have seen on this still emerging drug safety issue was published online by the Journal of Pharmacy Practice in late March 2014.  From the Abstract for "A Review of Current Evidence of Olmesartan Medoxomil Mimicking Symptoms of Celiac Disease" we get this information:

Objective: To review the evidence of an association between [Benicar, Benicar HCT, Azor, and Tribenzor (olmesartan medoxomil)] and symptoms mimicking celiac disease....

Data Sources: Literature was searched in PubMed (1965-November 2013) using the key words or MeSH terms olmesartan, enteropathy, celiac disease, sprue, and diarrhea.

Data Synthesis: There have been recent implications of [Benicar, Benicar HCT, Azor, and Tribenzor (olmesartan medoxomil)] being linked to symptoms mimicking celiac disease. Investigators first identified the association in 22 patients who presented with presumed refractory celiac disease. Upon further evaluation, it was discovered that these symptoms improved when [Benicar, Benicar HCT, Azor, or Tribenzor (olmesartan medoxomil)] was discontinued. In response to this report, additional case studies have been published.

Conclusions: There is growing evidence supporting the association between [Benicar, Benicar HCT, Azor, and Tribenzor (olmesartan medoxomil)] and sprue-like symptoms; however, further research is warranted. These symptoms can be life threatening and clinicians should be aware of the potential association.

For more information you can take a look at our previous articles:

• Benicar-Induced Enteropathy: Recently Found / New Possible Cause Of Villous Atrophy: Symptoms And Diagnosis
• Blood Pressure Drug Benicar Causes Serious Intestinal Side Effects Such As Chronic And Severe Diarrhea Months Or Years After Starting Drug

Of course, we are continuing to monitor this drug safety issue concerning Benicar, Benicar HCT, Azor, and Tribenzor.

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Benicar-Induced Enteropathy: Recently Found / New Possible Cause Of Villous Atrophy: Symptoms And Diagnosis

Chronic Or Severe Diarrhea With Damage To The Intestinal Villi And Malabsorption Indicate Sprue-Like Enteropathy

(Posted by Tom Lamb at DrugInjuryWatch.com)

An association between the oral angiotensin-receptor blocker (ARB) Benicar (olmesartan) and the serious side effect sprue-like enteropathy has been noted in the medical literature and flagged by the FDA as we reported back in August with this article, "Blood Pressure Drug Benicar Causes Serious Intestinal Side Effects Such As Chronic And Severe Diarrhea Months Or Years After Starting Drug".

We point out that the July 2013 FDA Drug Safety Communication about Benicar also applies to Benicar HCT, Azor, and Tribenzor, which are other high blood pressure, or hypertension medications from the drug company Daiichi Sankyo.

An article from the January 2014 edition of the Pharmacy and Therapeutics (P&T®) medical journal includes an article, "Olmesartan and Drug-Induced Enteropathy" (PDF format), which provides some valuable information concerning the symptoms and diagnosis of this recently found Benicar side effect.  From that article:

• Most often, diarrhea as a side effect of medications occurs independently of damage to the intestinal mucosa. However, when villous involvement and malabsorption are present, the damage is defined as sprue-like enteropathy.
• Symptoms of sprue-like enteropathy include severe, chronic diarrhea with substantial weight loss, as well as abdominal pain, fatigue, bloating, nausea, vomiting, and anemia.
• [Benicar (olmesartan)]-induced enteropathy can develop months to years after the initiation of therapy and, in severe cases, can lead to hospitalization.

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• Patients 57 to 81 years of age, irrespective of gender, have experienced weight loss of up to [88 lbs. (40 kg)] while taking [Benicar].
• In patients without celiac disease or other likely causes, a thorough review of their medications should be performed to rule out drugs associated with villous atrophy.
  Besides [Benicar (olmesartan)], these agents include [Imuran (azathioprine)], [CellCept (mycophenolate)], methotrexate, neomycin, and [Colcrys (colchicine)].
• Although the mechanism precipitating this adverse effect remains uncertain, it is essential to consider [Benicar (olmesartan)]-associated enteropathy in patients with biopsy-proven villous atrophy when no other cause can be found.

In summary, while medical doctors should first exclude other causes of sprue-like enteropathy, i.e., differential diagnosis, it is important that doctors know Benicar can be a cause of this chronic or severe diarrhea condition which can result in a weight loss of 40 pounds to 90 pounds, or even more. 

Likewise patients taking Benicar should be aware of the various symptoms that may be related to sprue-like enteropathy and, if those occur, report them to the prescribing doctor or one of their other physicians.

Meanwhile, some Benicar drug injury lawsuits have been filed against the drug company Daiichi Sankyo for their alleged failure to adequately or timely warn doctors and patients about the apparent link between Benicar and sprue-like enteropathy.

In fact, my law firm is currently in the process of investigating a few possible Benicar lawsuits, including one involving an unfortunate death.

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DrugInjuryLaw.com: Legal Information And News About Prescription Drug Side Effects  (All website content by attorney Tom Lamb)

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Blood Pressure Drug Benicar Causes Serious Intestinal Side Effects Such As Chronic And Severe Diarrhea Months Or Years After Starting Drug

Olmesartan-associated Sprue-like Enteropathy FDA Warning Also Applies To Benicar HCT, Azor, And Tribenzor From Drug Company Daiichi Sankyo

(Posted by Tom Lamb at DrugInjuryWatch.com)

The FDA has found clear evidence of an association between the blood pressure drug Benicar (olmesartan) and a serious intestinal condition known as sprue-like enteropathy, which is characterized by severe diarrhea or diarrhea that does not go away and, often, significant weight loss.

It is important to note that some patients developed this serious intestinal side effect enteropathy, which can require hospitalization, months to years after first starting to take Benicar.

From a July 3, 2013 MedPage Today news report, "FDA Adds GI Warning to Benicar Label":

The connection between sprue-like enteropathy and [Benicar (olmesartan)] was first reported in June 2012 by Mayo Clinic researchers who, from 2008-2010, had seen 22 patients with symptoms suggestive of celiac disease but antibody blood tests that did not support the diagnosis.

Later in October 2012, researchers at the American College of Gastroenterology meeting noted that [Benicar (olmesartan)], an angiotensin II receptor blocker, or ARB, had been linked to another 40 such cases of sprue-like enteropathy.

"We believe it is the tip of the iceberg," said Margot Herman, MD, at the GI meeting.

Symptoms of sprue-like enteropathy include severe, chronic diarrhea with substantial weight loss.

The 22 initial patients reported by the Mayo Clinic were on average 69 years old and had a duration of diarrheal illness for an average of 19 months.

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In early July 2013 this FDA Drug Safety Communication was issued, "FDA approves label changes to include intestinal problems (sprue-like enteropathy) linked to blood pressure medicine olmesartan medoxomil [(e.g., Benicar, Benicar HCT, Azor, and Tribenzor)]". It began by informing that the FDA has approved changes to the labels of these drugs in include the fact that these drugs can cause serious intestinal problems.

The Warnings and Precautions part of the July 2013 revised Benicar Prescribing Information, or drug label, sets forth this new warning about these serious intestinal side effects:

5.5  Sprue-like Enteropathy

Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Benicar in cases where no other etiology is identified.

Previously the Daiichi Sankyo drug labels for Benicar, Benicar HCT, Azor, and Tribenzor included a mention of diarrhea in the Adverse Reactions section.

According to the July FDA Drug Safety Communication about Benicar and similar blood pressure medications containing the same active ingredient:

In 2012, a total of approximately 10.6 million prescriptions were dispensed, and approximately 1.9 million patients received a dispensed prescription for olmesartan-containing products from U.S. outpatient retail pharmacies. 

Further, it states that the FDA will continue to evaluate the safety of olmesartan-containing products such as Benicar, Benicar HCT, Azor, and Tribenzor.

As regards legal cases, we are investigating some Benicar-related enteropathy reports from patients as drug injury claims against the pharmaceutical company Daiichi Sankyo.

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DrugInjuryLaw.com: Legal Information And News About Prescription Drug Side Effects  (All website content by attorney Tom Lamb)

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