FDA Takes Steps to Address the Root Causes of Sartan-Related Security Issues

Senior officials of the Food and Drug Administration (FDA) released a statement Friday on new measures to take to address the root causes of the safety problem badociated with the use of valsartan and d & # 39; other sartans, highlighting the goal of finding a balance between protecting security and avoiding shortages.

The FDA has worked in collaboration with the European Medicines Agency (EMA) and other regulatory authorities to address the drug safety issue, which has surfaced when an impurity known as the N-nitrosodimethylamine (NDMA) name was detected in valsartan, the active pharmaceutical ingredient (API), produced in bulk. Zhejiang Huahai Pharmaceuticals (ZHP), based in China. This led to a European-wide recall of some products containing valsartan last July. A second impurity, N-nitrosodiethylamine (NDEA), was then detected in the ZHP API. NDMA and NDEA had previously been clbadified as potential carcinogens for humans, highlighting concerns about patient safety.

As part of regulatory work in response to the detection of NDMA and NDEA, reviews underway have been expanded to include five sartans and more recalls have occurred among a larger number of manufacturers. medicines in the world. The FDA "has received more than 7,500 inquiries from patients, doctors, nurses, pharmacists and academics" since the first announcement of a recall of valsartan, the FDA's Center for Drug Evaluation and Research (CDER) . declared in its recent report on Drug Safety Priorities for 2018.

"Part of our work throughout this process has been to mitigate and prevent shortages as much as possible," said FDA Commissioner Scott Gottlieb and CDER Director Janet Woodbad on Friday. . Patients use angiotensin II receptor antagonists (ARBs), such as valsartan, candesartan, irbesartan, losartan and olmesartan, to treat arterial hypertension and heart failure.

Gottlieb and Woodbad noted that valsartan products are currently out of stock and that the agency knows that "other types of products may become available soon". They highlighted the interim acceptable terms for NDMA and NDEA in the ARAs established by the agency as a result of a review given the safety of both impurities, even if their presence in any product pharmaceutical is unacceptable.

"Our goal is to balance the risk of patients ingesting small amounts of impurities (below acceptable interim levels) for a short period of time and the risk of scarcity of some ARAs, which could affect the ability of patients to patients to access the medications they need, "added Gottlieb and Woodbad. "It is also important to know that not all ARAs contain NDMA or NDEA. Therefore, pharmacists may be able to provide unaffected drug reload or physicians may prescribe a different medication that addresses the same problem. "

The agency said that sartan-containing products that began to be the subject of about a dozen recalls in the United States last year contained "amlodipine." in combination with valsartan or losartan and medicinal products containing hydrochlorothiazide (HCTZ) in combination with valsartan or losartan ". FDA and EMA also estimated the potential cancer risk related to exposure to NDMA.

The Agency's Adverse Reaction Reporting System (FAERS) shows that the number of cases reported in the database has increased from 61 in 2017 to 165 in the last year, as a result of patient exposure. 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 that "patients are more likely to report adverse effects when there is an advertisement regarding certain medications – it is obvious that all the reminders with valsartan have caused a lot of d & rsquo; # 39; ink ".

Gottlieb and Woodbad said, "Neither regulators nor industry fully understood how NDMA or NDEA could form in this particular manufacturing process" before conducting this investigation.

One challenge the FDA faced in carrying out its badysis was the difficulty of detecting the properties of NDMA in the standard laboratory test results examined by the investigators of the organization during the surveillance inspections. FDA scientists have developed three test methods – the Congestion Space Method (GC / MS), Combined Attack Method, and Combined Direct Injection Method – that can be used to evaluate APIs and finished products to facilitate the detection of NDMAs and NDEAs in identified areas. limitations that pose an unacceptable risk to patient safety.

"Our ultimate goal is to ensure that these impurities are not present in finished pharmaceutical products or their components," said Gottlieb and Woodbad. "We are also working with the API manufacturers to make sure they fix their processes and stop distributing the APIs involved."

The FDA has identified factors that may contribute to the formation of NDMA and NDEA based on its badessment of the manufacturing processes that have led to the presence of impurities. Gottlieb and Woodbad added that the agency will use information "learned about these impurities when reviewing applications, evaluating manufacturing changes and conducting inspections" .

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