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FDA Statement

FDA Statement on the agency’s list of known nitrosamine-free valsartan and ARB class medicines, as part of agency’s ongoing efforts to resolve ongoing safety issue

For Immediate Release:
Statement From:
Scott Gottlieb, M.D.

Since we announced our investigation of impurities found in drugs known as angiotensin II receptor blockers (ARBs), used to treat high blood pressure and heart failure, we’ve been working to thoroughly understand how this issue arose, how we could address and mitigate exposure to this unnecessary risk to patients, and what we could do to prevent these types of impurities from reoccurring in future medications. We know that the discovery of these genotoxic impurities, called nitrosamines, is alarming to patients who expect their products to be free from these types of impurities. And while we’ve concluded through our risk assessments that the maximum possible exposure to nitrosamines (which are also known environmental contaminants and found in water and foods, including meats, dairy products and vegetables) in ARB medicines appears to be small, their presence in drug products is not acceptable.

Our response to this issue has been comprehensive and constant – an internal working group led by a multidisciplinary team of chemists, toxicologists, physicians, pharmacists, communication specialists, investigators and analytical laboratory staff from across the FDA and in collaboration with global regulators. We’ve remained steadfast in making sure we minimize risks to patients who rely on these medications, ensure access to safe ARBs or acceptable alternative therapies, and ensure affected medications are removed from the U.S. supply chain. Although we still have more work to do, we’re making significant advances in our efforts to protect patients from unnecessary exposure to these impurities.

Today, for the first time since the first nitrosamine impurity was discovered last summer, we’re announcing that we so far have identified 40 ARB medications where our assessment concluded they do not contain any known nitrosamine impurities, with the expectation that this number will increase. Our goal is for this information to help health care providers as they consider acceptable treatment options for their patients. Our assessment takes into consideration testing for impurities conducted by the FDA’s laboratories, an evaluation of the manufacturing process used by multiple manufacturers of the active pharmaceutical ingredient (API) found in ARB medicines, as well as other information available to the agency from manufacturers and international regulators. We’ll continue to update this list of nitrosamine-free ARBs as we become aware of additional information and as we progress in our assessments of other ARB medications.

We’re also continuing to work with manufacturers to swiftly remove medications from the market if they contain a nitrosamine impurity at levels higher than the interim acceptable intake limits. Removing the affected medications from the market has led to shortages, and since then we’ve been working to mitigate and prevent shortages as often as possible. Currently, valsartan products are in shortage, and we know that other types of products have the potential to fall into shortage soon. In anticipation, the agency is not objecting to temporary distribution of specific lots of losartan that contain impurities above the interim acceptable intake limit, for a short period of time. After careful evaluation of safety data and consideration of the benefits and risks to patients, we think it’s critical that patients have access to these drugs while impurity-free losartan is manufactured. Our scientists feel that this will not have a meaningful increased risk for cancer over the time it should take to get impurity-free losartan to market. The agency expects many companies will be able to manufacture losartan without nitrosamine impurities and replenish the U.S. supply in approximately six months. We want to reassure patients that we strongly believe the risks, such as stroke, of abruptly discontinuing these important medicines far outweighs the low risk associated with continuing the medications with these impurities.

In addition to the 40 medications listed above, the list also includes other products on the market that remain under evaluation. For these ARBs, although our overall determination is still pending, at this time nitrosamine impurities either have not been detected or are below the interim acceptable intake limits, and the medications can still be distributed.

We’ll keep working with manufacturers to eliminate these impurities from the drug supply, but we recognize that we also need to ensure patients who need ARBs have access now.

We’re also providing an update regarding steps we have taken to engage drug product and API manufacturers to address nitrosamine impurities in their medications. We recently sent manufacturers and applicants a letter to inform them about factors that can contribute to the formation of nitrosamine impurities during manufacturing (which we understand may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the drug’s API) and to reiterate steps they should take to ensure these impurities are not present in any ARB in the future. In addition to these risks, our letter emphasizes the possibility of contaminated raw materials, including and especially solvents and catalysts (particularly when these are reused). Manufacturers should determine whether the raw materials they use to make drugs were recycled, meaning previously used, even if it is not disclosed by their supplier. We also urge manufacturers to be vigilant and ensure that materials they receive from their suppliers are free of nitrosamines, including when they consider new suppliers.

Patients should continue taking their medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option --even if they learn that their ARB medicine is recalled. The risk associated with abruptly discontinuing the use of these important medicines far outweighs the low risk that our scientists estimate to be associated with continuing the medicine until the patient’s doctor or pharmacist provides a safe replacement or a different treatment option. We’re closely monitoring the supply of ARBs and will communicate any drug shortages promptly to the public. Today’s news, of the certainty and broad number of nitrosamine-free ARB medicines, is another positive step. Health care practitioners should familiarize themselves with alternative medicines that can be used to treat hypertension, heart failure or renal disease in case of shortages.

Despite the very low risks associated with the use of affected ARBs, we fully recognize that these medications can be made without nitrosamine impurities and are working with manufacturers to reach that goal. We’ll continue to prioritize our investigation into this ongoing issue, and we’ll provide additional updates to consumers, health care providers and industry on our investigation and assessments to ensure patient safety. We’ll continue to improve our science and standards for detecting and preventing the development of genotoxic impurities during the drug manufacturing process, and this will remain an area of intense focus in the months ahead.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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