What should health care professionals know?
- The FDA has determined the recalled lots of valsartan, irbesartan, and losartan products pose an unnecessary risk to patients. The agency recommends that pharmacists provide a replacement product not affected by the recall or prescribers consider other available treatment options for their patient’s medical condition.
- Lists of valsartan and irbesartan products affected by the recall are available on the FDA website for healthcare professionals and patients to monitor. To date, there is one affected lot of losartan product: Sandoz Inc. losartan potassium hydrochlorothiazide, 100 mg/25 mg tablets, NDC 0781-5207-10, Lot number JB8912; Exp. Date 06/2020. The FDA suggests health care professionals check regularly for updates.
- Samples can also be affected and part of the recall. Be certain to check samples to ensure affected products are not given to patients.
The term “ARB” is used to describe drugs in the angiotensin II receptor blocker (ARB) class. ARBs are also called “sartans,” a term derived from a portion of their names that they all share. Examples of ARBs include the drugs candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. ARBs are commonly used to treat high blood pressure and heart failure.
Beginning in late June 2018, the FDA found that some generic versions of the prescription drug valsartan contained unexpected impurities that posed a safety concern. The impurities in these products, N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) are probable human carcinogens (cancer-causing). NDMA was the first impurity to be discovered in some valsartan products. During our investigation of valsartan products, the agency learned of a second impurity, NDEA. Upon testing that now includes other ARBs, NDEA has also been found in some irbesartan and losartan products. All products found to contain these impurities have been recalled and are no longer available in the U.S. market. Our investigation and testing activities are ongoing.
We have posted a list of valsartan products affected by the recall and a separate list of irbesartan products affected by the recall on the FDA’s website for health care professionals and patients to monitor. To date, there is one affected lot of losartan product: Sandoz Inc.’s losartan potassium hydrochlorothiazide, 100 mg/25 mg tablets, NDC 0781-5207-10, Lot number JB8912; Exp. Date 06/2020. Our investigation and testing activities are ongoing, and we will be updating the lists as new information develops.
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The FDA’s 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 the FDA’s current good manufacturing processes (CGMPs) are not appropriately followed.
What should patients know?
- Not all lots of valsartan, irbesartan and losartan products are affected and being recalled. Other ARBs including candesartan, eprosartan, olmesartan and telmisartan have not been affected by a recall.
- Continue taking your current medicine until a doctor or pharmacist gives a replacement.
- If you are taking any medication containing an ARB, compare the information on your prescription bottle with this valsartan list and this irbesartan list to determine if your current medicine has been recalled. If you take an ARB with losartan, ensure it is not this affected product: Sandoz Inc. losartan potassium hydrochlorothiazide, 100 mg/25 mg tablets, NDC 0781-5207-10, Lot number JB8912; Exp. Date 06/2020. If you are not certain, contact your pharmacist.
- If you have medicine included in a recall, contact your pharmacist. The pharmacist may be able to provide you with an unaffected ARB made by another company. If not, contact your doctor immediately to discuss other treatment options.
The FDA is 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 valsartan and irbesartan products affected by the recall or to see if any other products besides the one currently known lot of losartan product have been affected. Patients should continue taking their current medicine until a doctor or pharmacist gives a replacement. The FDA will continue to work with manufacturers to ensure all affected products are quickly removed from the market.
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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 API and finish drug product, 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 drug products 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.
The FDA reviews information on impurity testing provided in product 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 product 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. The FDA also inspects manufacturing facilities across 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 NDMA or NDEA could form during this process.
The FDA is working with manufacturers to recall affected products. Lists of valsartan and irbesartan products affected by the recall are available on the FDA website for healthcare professionals and patients to monitor. To date, there is one affected lot of losartan product: Sandoz Inc. losartan potassium hydrochlorothiazide, 100 mg/25 mg tablets, NDC 0781-5207-10, Lot number JB8912; Exp. Date 06/2020. We will update our website if any other products 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.
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The number of affected products has grown since the FDA’s initial findings, however, there is still sufficient supply of unaffected products available. Other medications may also be suitable as replacements. Patients who need to switch medications because of the recall should consult with their doctors to determine the best alternative therapy.
The FDA has identified factors in manufacturing processes that may contribute to the formation of NDMA and NDEA. As part of our investigation, we are working to ensure that other manufacturing conditions do not contribute to NDMA, NDEA, or related impurities in finished drug products. We will use the information we have learned about these impurities when reviewing applications, assessing manufacturing changes, and conducting inspections. Manufacturers using processes at risk for formation of these impurities will be required to test for them to ensure that the resulting drug product is safe for patients.
The FDA routinely posts updates on the investigation and the affected products on our website as new information becomes available.
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The FDA is working very closely with global regulatory agencies, including the European Medicines Agency and Health Canada. The FDA’s 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 impact on 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.
The FDA website contains the most current information about the affected products. Please send us questions or comments by email to [email protected] or by phone to 855-543-3784.
Consumers and health care professionals should report any adverse reactions with valsartan-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.
Posted: November 2018
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