FDA, EMA Valsartan Update, New Data on Cancer Risk

Megan Brooks

September 13, 2018

UPDATED SEPTEMBER 14, 2018 // The US Food and Drug Administration (FDA) has announced their latest testing has shown a second substance, N-nitrosodiethylamine (NDEA), in three  lots of Torrent Pharmaceuticals' recalled valsartan drug products.

These Torrent products were included in the company's recall on August 23.

Valsartan is an angiotensin II receptor antagonist used to treat hypertension and heart failure. This past July, some valsartan products manufactured by the Chinese company Zhejiang Huahai Pharmaceuticals were found to be contaminated with N-nitrosodimethylamine (NDMA), a potential carcinogen, which led US and European regulators to pull all affected valsartan products from the market.

In a statement issued September 13, the FDA said it is continuing to test all products that contain valsartan for NDEA and related impurities.

"If the agency finds NDEA in products that have not been recalled, the FDA will work with companies to ensure all affected products are removed from the market. The agency is also evaluating the risks NDEA in these products poses to patients," the agency writes. "The FDA expects to complete this risk analysis in the coming days and will continue to provide updates to the public as new information becomes available."  

"As we continue to investigate the root cause of the impurities found in products that contain valsartan, our scientists are testing these products to better understand these impurities and to ensure they're not present in other products," added FDA Commissioner Scott Gottlieb, MD. "We're also taking steps to make sure we're providing stringent oversight of manufacturing processes to reduce the likelihood that impurities could be introduced into other products," he said.

Gottlieb pledged to keep the public informed as the agency expands their investigation. "We'll also continue to work with global regulatory agencies to learn as much as we can about how these impurities came about and how they may affect patients' health around the globe," he said.

In a statement also issued September 13, the European Medicines Agency (EMA) said it is also assessing the effects of NDEA detected in valsartan made by Zhejiang Huahai using its previous manufacturing process. "Both NDEA and NDMA belong to the class of nitrosamines and are classified as probable human carcinogens (substances that could cause cancer)," the agency writes.

Data on levels of NDEA are currently "very limited," the statement notes, "and EMA will provide further information on whether its presence impacts the risk assessment once more information becomes available.

"Although the review covers all valsartan medicines, the immediate focus has been on medicines containing the active substance manufactured by Zhejiang Huahai and Zhejiang Tianyu  where unacceptable levels of NDMA have been confirmed," the agency writes. "EU authorities have now carried out inspections of the manufacturing sites of both companies in China and will consider the findings."

The EMA included an updated calculation of cancer risk, noting that the lifetime risk for cancer is considered low and reiterating this previous estimate of one case in 5000 adults taking the highest dose every day from July 2012 to July 2018.   

"EMA's risk assessment is based on the average levels of NDMA in the active substance produced by Zhejiang Huahai since 2012 (when the company changed its manufacturing process) and on the assumption that all the NDMA is transferred to the final product," the statement notes.

"Patients who have taken treatments with lower doses or for shorter lengths of time will be at a lower risk," they write. The risk will also be lower for patients taking valsartan produced by another company, Zhejiang Tianyu, which had smaller amounts of NDMA than valsartan produced by Zhejiang Huahai.

"The low risk estimate is to some extent supported by a Danish study which tracked patients who had taken medicines containing valsartan from Zhejiang Huahai over the past 6 years. However, the authors note that patients were followed up for a relatively short period (4.6 years on average)," they write.

Expedited Cancer Assessment

The updates come the same day as publication of that Danish study, an expedited assessment of cancer risk associated with exposure to valsartan contaminated with NDMA that provides some reassurance, finding no increase in overall cancer risk among users of these products, at least in the short term.

"This is the first study to quantify the potential consequences of this contamination with regards to cancer risk," Kasper Kristensen, MD, Department of Public Health, Clinical Pharmacology and Pharmacy, University of Southern Denmark, Odense, told theheart.org | Medscape Cardiology.

"We think the most important message is one of reassurance," said Kristensen, who also cautioned that the limitations of the study need to be considered.

"We were only able to assess short-term cancer risk because of the limited follow-up time. Thus, we do not know whether long-term cancer risk is affected," said Kristensen. "Further, due to limited statistical precision we were not able to confidently assess risk for individual cancers (as opposed to the composite outcome of all cancers)."

The study was published online September 13 in the BMJ.  

Using data from Danish health registries, investigators identified all 5150 adults with no prior cancer who filled a valsartan prescription between January 1, 2012, and June 30, 2018.

During a median follow-up of 4.6 years, there were 104 new cancer diagnoses among NDMA-unexposed and 198 among NDMA-exposed adults. In adjusted analysis, there was no increased risk for overall cancer in patients using NDMA-contaminated valsartan products compared with patients using noncontaminated valsartan products, with no evidence of a dose-response relationship.

For single cancer outcomes, a slightly increased risk was observed for colorectal and uterine cancer, "although with wide confidence intervals that included the null," the investigators note.

They acknowledge that "uncertainty persists about single cancer outcomes, and studies with longer follow-up are needed to assess long term cancer risk."

Table. Cancer Risk With Use of Potentially NMDA-Tainted Valsartan

Cancer Type Adjusted Hazard Ratio (95% Confidence Interval) No. of Events
All cancer 1.09 (0.85 - 1.41) 302
Colorectal 1.46 (0.79 - 2.73) 51
Pancreatic 0.71 (0.21 - 2.44) 12
Lung 0.94 (0.47 - 1.91) 39
Melanoma 1.34 (0.46 - 3.85) 17
Breast 0.85 (0.42 - 1.73) 36
Uterine 1.81 (0.55 - 5.90) 15
Prostate 1.33 (0.68 - 2.62) 47
Kidney 1.00 (0.22 - 4.65) 8
Bladder 0.66 (0.15 - 2.89 8


The main strength of the study, say the investigators, is the use of high-quality nationwide registries, leaving little potential for selection bias, while the limited median follow-up time is the main weakness.

It's worth noting, they say, that this analysis was completed and submitted for publication within 7 weeks after the finding of NDMA in valsartan products was announced publicly. The paper was published after a fast-track peer review process spanning only 3 weeks from submission to publication.

Writing in a BMJ editorial, Rita Banzi and Vittorio Bertele' from the Center for Drug Regulatory Policies, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, say "This study alone cannot dispel doubts about the potential risk for patients in the longer term, but it helps inform decision-making around this episode."  

They note that in a preliminary assessment of the possible risk to patients of taking NDMA-tainted valsartan, the EMA estimated that there might be one extra case of cancer for every 5000 patients using the highest valsartan dose (320 mg) every day for 7 years.  

The editorialists say the Danish cohort covers about "one fifth of the person years of exposure required to confirm the EMA estimation. Therefore, patients exposed to this impurity need continued monitoring."

The study had no specific funding. The authors and editorial writers have declared no relevant conflicts of interest.

BMJ. Published online September 13, 2018. Full text, Editorial

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