September 19, 2018
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Recalled valsartan products may not increase cancer risk

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Valsartan products that were contaminated with N-nitrosodimethylamine, an impurity that has been classified as a probable human carcinogen that led to recalls of several drug products by the FDA, did not markedly increase the short-term overall risk for cancer, according to a study published in The BMJ.

As Cardiology Today previously reported, the FDA is currently investigating all valsartan products for the impurity and related impurities, in addition to working with companies that produce the products with the impurities to ensure that the products are removed from the market.

Danish health care data

Anton Pottegård, PhD, associate professor at University of Southern Denmark in Odense and head of research at the hospital pharmacy at Odense University Hospital in Denmark, and colleagues analyzed data of 5,150 patients aged at least 40 years from nationwide Danish health care registries who were free from cancer and filled a prescription for valsartan between 2012 and June 2018.

Researchers categorized 128 unique valsartan products as the following:

probably contaminated with N-nitrosodimethylamine (18%), as they were manufactured with an active ingredient from Zhejiang Huahai Pharmaceuticals;

possibly contaminated (26%), as they contained the active ingredient from Zhejiang Huahai Pharmaceuticals and other companies; and

unlikely to be contaminated (55%), which did not contain the active ingredient from Zhejiang Huahai Pharmaceuticals.

The primary outcome was a composite of all cancers except nonmelanoma skin cancer.

Follow-up was conducted until death, a cancer outcome, migration or June 30, 2018, whichever came first. A 1-year lag time from a patient’s first prescription was applied due to the unlikelihood that less than 1-year exposure to N-nitrosodimethylamine would affect a patient’s risk for a cancer diagnosis.

Patients unexposed to N-nitrosodimethylamine (n = 3,625) contributed 7,344 person-years of follow-up and those ever exposed to N-nitrosodimethylamine (n = 3,450) contributed 11,920 person-years of follow-up.

Exposure to contaminated products

During a median follow-up of 4.6 years, there were 104 cancer outcomes in the unexposed group and 198 in the exposed group. Exposure to valsartan products that were either probably or possibly contaminated with N-nitrosodimethylamine was not associated with cancer vs. products unlikely to be contaminated (adjusted HR = 1.09; 95% CI, 0.85-1.41). There was no evidence of a dose-response relationship (P = .7).

When single cancer outcomes were assessed, patients in the exposed group had a numerically higher risk for colorectal cancer (HR = 1.46; 95% CI, 0.79-2.73) and uterine cancer (HR = 1.81; 95% CI, 0.55-5.9), although these and other cancer outcomes did not reach statistical significance.

Results were similar after stratification by age and sex.

“In addition to knowledge about the risks associated with exposure to [N-nitrosodimethylamine], the present study provides proof-of-concept for such processes, which hold great promise for the use of pharmacoepidemiological input in the regulatory assessment of future public health crises,” Pottegård and colleagues wrote.

“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,” Rita Banzi, PhD, and Vittorio Bertele, MD, of the Center for Drug Regulatory Policies in Milan, wrote in a related editorial. “It also illustrates the usefulness of national registries for examining the relations between risk factors and health problems and how research can give a prompt response whenever public health concerns emerge.” – by Darlene Dobkowski

Disclosures: The authors, Banzi and Bertele report no relevant financial disclosures.