FDA Takes Steps to Address Root Causes of Sartan Safety Issues

Regulatory NewsRegulatory News | 25 January 2019 |  By 

 Top officials at the US Food and Drug Administration (FDA) issued a statement Friday on new steps to address the root causes of the safety issue related to the use of valsartan and other sartans, stressing the goal of striking a balance between protecting safety and avoiding shortages.
FDA has worked in collaboration with the European Medicines Agency (EMA) and other regulators to address the drug safety issue, which surfaced when an impurity known as N-nitrosodimethylamine (NDMA) was detected in the active pharmaceutical ingredient (API) valsartan produced in bulk by China-based Zhejiang Huahai Pharmaceuticals (ZHP). This led to a European-wide recall of certain valsartan-containing products last July. A second impurity—N-nitrosodiethylamine (NDEA)—was later detected in ZHP’s API. NDMA and NDEA had been previously classified as probable human carcinogens, underscoring patient safety concerns.
As part of the regulators’ work in response to the detection of NDMA and NDEA, ongoing reviews have extended to include five sartans and more recalls have occurred from more drug manufacturers worldwide. FDA “has received more than 7,500 inquiries from patients, physicians, nurses, pharmacists and academicians” since the first news of a valsartan recall, FDA’s Center for Drug Evaluation and Research (CDER) stated in its recent report on 2018 drug safety priorities.
“Part of our work throughout this process has been to mitigate and prevent shortages, where possible,” FDA Commissioner Scott Gottlieb and CDER Director Janet Woodcock said in a joint statement Friday. Patients rely on angiotensin II receptor blockers (ARBs), such as valsartan, candesartan, irbesartan, losartan and olmesartan, to treat high blood pressure and heart failure.
Gottlieb and Woodcock noted that valsartan products are currently in shortage and the agency knows “that other types of products may fall into shortage soon.” They pointed to the interim acceptable limits for NDMA and NDEA in ARBs that the agency established based on a review of safety data for both impurities, though their presence in any drug product is unacceptable.
“Our goal is to balance the risk of patients ingesting low levels of the impurities (below the interim acceptable levels) for a short period of time with the risk that there is a shortage of certain ARBs, which may impact patients’ ability to access the medicine they need,” Gottlieb and Woodcock added. “It also is important to know not all ARBs contain NDMA or NDEA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.”
The agency clarified that the sartan-containing products that began being subject to about a dozen recalls in the US last year contained “amlodipine in combination with valsartan or losartan and medications containing hydrochlorothiazide (HCTZ) in combination with valsartan or losartan.” FDA and EMA also estimated potential risk of cancer from exposure to NDMA.
The agency’s Adverse Event Reporting System (FAERS) shows that cases reported to the database increased from just 61 in 2017 to 165 last year, following patients’ exposure to amlodipine and valsartan, valsartan and HCTZ, or amlodipine, valsartan and HCTZ.


Erin Fox, director of drug information at the University of Utah Health Care, explained to Focus that she thinks “patients are more likely to report adverse effects when there is publicity about certain drugs—certainly all of the recalls with valsartan have had a lot of press.”
Gottlieb and Woodcock noted: “Neither regulators nor industry fully understood how NDMA or NDEA could form during this particular manufacturing process” prior to conducting this investigation.
A challenge FDA faced with the undertaking of its analysis relates to the difficulty in detecting NDMA’s properties in standard laboratory testing results reviewed by agency investigators during surveillance inspections. FDA scientists developed three testing methods—the (GC/MS) headspace method, the combined headspace method and the combined direct injection method—that can be used for evaluating APIs and finished drug products to aid in the detection of NDMA and NDEA within the identified limits that pose an unacceptable risk to patient safety.
“Our ultimate goal is to ensure that these impurities are not present in finished drug products, or their components,” Gottlieb and Woodcock said. “We’re also working with API makers to ensure that they fix their processes and cease distribution of affected API.”
FDA identified factors that could contribute to the formation of NDMA and NDEA based on its evaluation of manufacturing processes that led to the presence of the impurities. Gottlieb and Woodcock added that the agency will use the information it “has learned about these impurities when reviewing applications, assessing manufacturing changes and conducting inspections.”


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