After valsartan recall, study offers 'modest reassurance' on short-term cancer risk

In the wake of a worldwide recall, patients prescribed several common drugs that contain valsartan must be w...

Posted: Sep 13, 2018 8:04 AM
Updated: Sep 13, 2018 8:04 AM

In the wake of a worldwide recall, patients prescribed several common drugs that contain valsartan must be wondering exactly how much of a cancer risk their medication may have posed.

Now, an expedited study suggests that there is no markedly increased short-term risk of overall cancer among users of valsartan contaminated with the impurity, N-nitrosodimethylamine or NDMA. However, more research is needed to assess long-term risk.

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The study was published in the medical journal BMJ on Wednesday.

Certain products containing the valsartan ingredient, used to treat high blood pressure and heart failure, were recalled in July by the US Food and Drug Administration and other agencies around the world due to an "impurity" in the drug that poses a potential cancer risk.

That impurity, NDMA, has been classified as a probable human carcinogen, based on lab test results. It may have contaminated certain valsartan batches since 2012.

As of now, the long-term risks posed by NDMA found in certain valsartan-containing drugs remain somewhat unknown, and the amount of NDMA consumed plays a role in that risk.

In an assessment in July, FDA scientists estimated that if 8,000 people took the highest valsartan dose, at 320 milligrams, from the recalled batches daily for four years, there may be one additional case of cancer over the lifetimes of these 8,000 people.

Valsartan is off patent and is used as a component of other generic medicines, but not all medicines containing the ingredient are involved in the recent recall.

The researchers noted in the new study that the NDMA contamination, which exceeded regular exposure limits, was specific to drug products manufactured by Zhejiang Huahai Pharmaceuticals in Linhai, China. The contamination seemed to be related to a change in the manufacturing process that was implemented in 2012, according to the researchers.

The specific medicines included in the FDA voluntary recall are valsartan from Major Pharmacuticals, Solco Healthcare and Teva Pharmaceuticals Industries, as well as valsartan/hydrochlorothiazide from Solco and Teva.

The full recall list was updated last month.

A 'non-significant' increase in cancer risk

The new study involved health data on 5,150 Danish patients who filled a valsartan prescription between 2012 and 2018. The data came from four nationwide registries in Denmark: the Danish Cancer Registry, the National Prescription Registry, the National Patient Register, and the Civil Registration System.

The researchers tracked each patient's exposure to NDMA contamination based on which valsartan drug products they used, as recorded in the National Prescription Registry. The researchers then compared cancer occurrence among the patients who had been exposed to the NDMA contamination versus those who had not been exposed.

The researchers found that over an average of 4.6 years, exposure to valsartan products potentially contaminated with NDMA showed no association with overall cancer risk compared with exposure to valsartan products unlikely to be contaminated.

When the researchers analyzed associations with specific types of cancer, there were increased risks seen for colorectal and uterine cancer, but those risks were not statistically significant. So the researchers remain uncertain whether there could be risk associated with specific cancer types.

In general, "the estimate for our primary outcome suggests a negligible and statistically non-significant increase in cancer risk of 9%," the researchers wrote in the study.

The study had some limitations, including that the findings only pertain to short-term early cancer risk after exposure to NDMA, which means that more research is needed to explore long-term total cancer risk. Also, the actual NDMA content of each individual valsartan tablet was not included in the data since such information was not made available.

"At most, our findings suggest that the levels of NDMA exposure achieved through valsartan products do not translate into a substantially increased short term cancer risk. Furthermore, the fact that our study evaluates a potential safety concern holds some implications about how to interpret the results," the researchers wrote in the study.

'I don't think it means that patients are completely out of the woods'

Dr. Erin Michos, an associate professor and associate director of preventive cardiology at Johns Hopkins Medicine, called the study "well-done" but noted that more research is needed over a longer period of time to substantially evaluate true cancer risk.

"It provides some modest reassurance for the short-term, but the absence of a signal for cancer excess isn't really all that surprising to me, because it's just too soon for something like cancer," said Michos, who was not involved in the study.

"There hasn't been long enough follow-up to really see a signal. So while I'm reassured that they didn't find one, I don't think it means that patients are completely out of the woods," she said, adding that she plans to inform her own patients about the new study.

"Now that this study is coming out, I'm going to share it with my patients. I think that many of them are worried, and although this data by no means dispels all fears -- because it's not a long enough follow-up -- I think it will give them at least some short-term reassurance," she said. "While this is concerning, the attributable risk of cancer from this exposure, if any, is anticipated to be very low."

Rita Banzi and Vittorio Bertele, of the Mario Negri Institute for Pharmacological Research in Italy, co-authored an editorial that accompanied the new study in the journal BMJ on Wednesday.

In the editorial, they noted how the study was planned, conducted, analyzed and published all within three months from when regulatory authorities were notified of the contamination issue.

"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," Banzi and Bertele wrote.

"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," they wrote.

All in all, Michos said that the fact a contaminant was found in valsartan to begin with was "a violation of all of our trust."

"It makes us all wonder about the safety. The public wants their medicines to be safe. So this whole incident raises questions about other products that are made in China, and whether they're up to standards," Michos said.

"This contaminant started way back in 2012, so why did it take six years to come to light?" she asked. "Public safety is our number-one priority and so I'm not making light of this at all."

If you are worried that your drug could be on the recall list, talk with your doctor or pharmacist before changing any routine with your medicine. Because not all valsartan drugs are involved in the recall, they might be able to switch you to a version of the drug made by another company.

If you know your drug is on the recall list, the FDA suggests you continue taking it until your doctor or pharmacist provides a replacement.

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