FDA Drug Safety Communication: Ongoing Safety Review of Benicar and Cardiovascular Events

Safety Announcement 

Additional Information for Patients 

Additional Information for Healthcare Professionals 

Data Summary

 

Safety Announcement 

[06-11-2010] The U.S. Food and Drug Administration (FDA) is evaluating data from two clinical trials in which patients with type 2 diabetes taking the blood pressure medication, Benicar (olmesartan)* had a higher rate of death from a cardiovascular cause compared to patients taking a placebo.

FDA's review is ongoing and the Agency has not concluded that Benicar increases the risk of death. FDA currently believes that the benefits of Benicar in patients with high blood pressure continue to outweigh its potential risks.

The Agency plans to review the primary data from the two studies of concern, ROADMAP and ORIENT, and is considering additional ways to assess the cardiovascular effects of Benicar.

ROADMAP and ORIENT are both long-term clinical trials. In both trials, patients with type 2 diabetes were given either Benicar or placebo to determine if treatment with Benicar would slow the progression of kidney disease. An unexpected finding observed in both trials was a greater number of deaths from a cardiovascular cause (heart attack, sudden death, or stroke) in the Benicar-treated patients compared to placebo (see Data Summary below).

Benicar (also known as olmesartan) is in the class of drugs called angiotensin II receptor blockers (ARBs). These drugs and a closely related group of drugs called angiotensin-converting enzyme inhibitors (ACEIs) have been evaluated in many studies involving thousands of patients at high-risk for cardiovascular events, such as patients who had a previous heart attack or had heart failure. No increased risk of cardiovascular-related death has been reported in these trials and, in fact, some of these studies indicate ARBs and ACEIs are useful as treatments for certain patients at high-risk for cardiovascular events.

This communication is in keeping with FDA's commitment to inform the public about its ongoing safety review of drugs. The Agency will update the public when this review is complete. 

*Benicar (olmesartan) is also sold in combination with hydrocholorothiazide as Benicar HCT for the treatment of high blood pressure.

 

Additional Information for Patients

  • FDA has not concluded that Benicar increases the risk of death. The Agency is reviewing this safety concern and will update the public when additional information is available.
  • FDA believes the benefits of Benicar in patients with high blood pressure continue to outweigh the potential risks.
  • Do not stop your treatment with Benicar unless told to do so by your healthcare professional.
  • Talk to your healthcare professional if you have concerns about Benicar.
  • Report any side effects from the use of Benicar to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.

 

Additional Information for Healthcare Professionals 

  • FDA has not concluded that Benicar increases the risk of death. The Agency is reviewing information related to the safety concern and will update the public when additional information is available.
  • FDA believes the benefits of Benicar in patients with high blood pressure continue to outweigh the potential risks.
  • In the ROADMAP and ORIENT trials, there were a greater number of cardiovascular-related deaths in the Benicar group compared to the placebo group.
  • Additional information about ROADMAP and ORIENT can be found at clinicaltrials.gov.
  • Other controlled clinical trials evaluating Benicar and other angiotensin II receptor blockers have not suggested an increased risk of cardiovascular-related death.
  • Follow the recommendations in the drug label when prescribing Benicar.
  • Report adverse events involving Benicar to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of this page.

 

Data Summary

The Randomized Olmesartan and Diabetes Microalbuminuria Prevention Study (ROADMAP) was a randomized, double-blind, placebo-controlled, multicenter trial conducted in Europe. The trial included 4,447 patients with type 2 diabetes and at least one additional cardiovascular risk factor, but without overt evidence of nephropathy. Patients were randomized to receive either 40 mg of olmesartan or placebo daily. Patients were permitted to receive other antihypertensive medications, but not ACEIs or ARBs.

 

The primary objective was to evaluate whether olmesartan could delay the onset of microalbuminuria. The majority of patients had 3 to 5 cardiovascular risk factors and 80% of patients were using other antihypertensives. The mean duration of exposure to olmesartan was 39 months.

 

The Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) was a randomized, double-blind, placebo-controlled, multicenter trial conducted in Japan and Hong Kong. Patients (n= 566) with type 2 diabetes and overt nephropathy were randomized to receive olmesartan 10 mg to 40 mg or placebo daily. Patients were permitted to take additional antihypertensives including ACEIs, but excluding ARBs. The primary composite endpoint was the time to first event of doubling of serum creatinine, end stage renal disease, and all cause death.

 

An unexpected finding in both trials was an increased number of cardiovascular deaths in the patients receiving olmesartan compared to placebo. The incidence of major cardiovascular events are summarized in tables 1 and 2 below.

 

Table1. Summary of findings from the ROADMAP trial

Outcome Olmesartan (n=2,232) Placebo (n=2,215)
Total cardiovascular deaths 15 3
Sudden cardiac death 7 1
Fatal myocardial infarction 5 0
Death during or post PTCA or CABG 1 0
Fatal Stroke 2 2
All deaths 26 15
>Non-fatal Stroke 14 8
>Non-fatal MI 17 26

 

Table 2. Summary of findings from the ORIENT trial

Outcome Olmesartan (n=282) Placebo (n=284)
Total cardiovascular deaths 10 3
Sudden cardiac death 5 2
Fatal myocardial infarction 1 1
Cardiovascular death of unknown cause 1 0
Fatal Stroke 3 0
All deaths 19 20
>Non-fatal Stroke 8 11
>Non-fatal MI 3 7

In considering the results of these trials, it is important to remember that numerous clinical trials with olmesartan as well as trials with other ARBs have not suggested an increased risk of cardiovascular-related death.

 

To evaluate the possible association with olmesartan and increased cardiovascular-related death, FDA plans to review the primary data from the two trials and the total clinical trial data on olmesartan. Also, the Agency will evaluate additional ways to understand the findings from ROADMAP and ORIENT, in light of information supporting the use of ARBs and ACEIs in certain patients at high risk for cardiovascular events.

 

    

Posted: June 2010


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