More Questions and Answers: Impurities Found in Certain Angiotensin II Receptor Blocker (ARB) products
Examples of ARBs include the drugs valsartan, losartan, irbesartan, candesartan, eprosartan, olmesartan, and telmisartan.
Beginning in June 2018, FDA learned that some generic versions of the prescription drug valsartan contained unexpected impurities that posed a safety concern.
The impurities in ARB medications, N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) are probable human carcinogens (cancer-causing), and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) is a potential human carcinogen.
Most medicines found to contain these impurities above the interim acceptable intake limits have been recalled and are no longer available in the U.S. market.
The agency is not objecting to some losartan medicines with NMBA levels above the daily acceptable intake limit, but below 9.82 parts per million remaining on the market.
Our investigation and testing activities are ongoing.
We have posted a list of ARB medicines on the FDA website for healthcare professionals and patients to monitor.
We suggest health care professionals check regularly for updates.
Our investigation and testing activities are ongoing, and we continue updating the lists of recalled ARBs as new information becomes available.
Our ongoing investigation has determined that these impurities may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the starting materials, intermediates or finished active pharmaceutical ingredient (API).
The presence of these impurities in other processes may also be caused when current good manufacturing processes (CGMPs) are not appropriately followed.
We are testing samples of other ARBs to help inform the ongoing investigation.
We encourage patients who take an ARB to regularly check online for updates to our lists of ARB medicines affected by the recall or to see if any other medicines have been affected.
Patients should continue taking their current medicine until a doctor or pharmacist gives them a replacement.
We will continue to work with manufacturers to ensure affected medicines are quickly removed from the market. FDA has also posted a list of ARBs that are currently available, along with information regarding the status of FDA’s assessment for those medications.
NDMA was the first impurity discovered, and FDA pharmacologists, toxicologists and chemists have taken measures to assess its risk.
Our scientists estimate that if 8,000 people took the highest daily valsartan dose (320 mg) that contained NDMA for four years (the amount of time we believed the affected products had been on the U.S. market), there may be one additional case of cancer beyond the average cancer rate among Americans.
Most patients who were exposed to the impurity through the use of affected valsartan received less exposure than in the scenario described above.
Since there are many manufacturers of valsartan and sources can vary whenever a patient refills a prescription, it is very likely that a patient using valsartan for four years would not have always received one of the relatively few affected medicines that contained these impurities.
We are still seeking to similarly quantify the risk to patients from NDEA and will communicate our findings as soon as possible.
We review information on impurity testing provided in drug applications and when inspecting manufacturing facilities.
Manufacturers are required to test for impurities that may be introduced or developed during their manufacturing processes.
We review that information in drug applications, including requests to change the manufacturing process.
We employ organic chemists to review applications and referenced information to look for steps – and manufacturing changes – where these risks could be introduced.
We also inspect manufacturing facilities around the world, and in routine current good manufacturing practices inspections we can review a manufacturer’s records regarding impurity testing.
However, the review of records depends on manufacturers conducting appropriate tests that are capable of detecting the impurity.
Tests are selected based on assessments of what impurities may develop based on the manufacturing process.
In other words, it needs to be recognized that there is a risk of an impurity occurring to know that it should be tested for.
Before we undertook this analysis, neither regulators nor industry fully understood how the nitrosamines could form during the manufacturing process.
We are working with manufacturers to recall medicines with nitrosamine impurities above the interim acceptable intake levels that present an unnecessary risk to patients.
We will update our website if any other medicines are recalled due to these impurities.
We are also working with makers of API to ensure they remediate their manufacturing processes and their API does not contain these impurities.
Though the number of affected products has grown since July 2018, there is still sufficient supply of unaffected products available.
Other medications may also be suitable as replacements for ARBs.
Patients who need to switch medications because of the recall should consult with their doctors to determine the best alternative therapy.
We routinely post updates on the investigation, including lists of recalled ARBs as well as our assessment of ARBs that are still on the market, on our website as new information becomes available.
We are working very closely with global regulatory agencies, including the European Medicines Agency and Health Canada.
Our task force overseeing this investigation exchanges information with regulatory counterparts around the world, including inspection findings, laboratory test methods and results, and our scientific assessment of the problem’s cause and its risk to patients.
Not every manufacturing site produces valsartan, irbesartan, or losartan for all countries, but we believe sharing this information is vital to advancing our ongoing investigations.
It enables us to address emerging issues quickly to benefit U.S. patients.
This includes monitoring actions other regulators are taking as part of their investigations.
FDA's website contains the most current information about the affected products.
Please send us questions or comments by email to druginfo@FDA.hhs.gov or by phone to 855-543-3784.
Patients and health care professionals should report any unexpected adverse event with ARB-containing products to the FDA’s MedWatch program to help the agency better understand the scope of the problem:
- Complete and submit the report online at www.FDA.gov/medwatch/report.htm or
- Download and complete the appropriate form, then submit it via fax at 1-800-FDA-0178.