番茄社区

In August, we reported on what initially appeared to be a limited problem affecting certain lots of drugs containing valsartan, an angiotensin receptor blocker (ARB). Since then, however, manufacturers' troubles with this and similar drugs have mushroomed. In this article, we review what happened after those initial reports.

ARB recalls starting in Europe this summer reverberated around the world due to the finding of unacceptable levels of N-Nitrosodimethylamine (NDMA), a probable potential carcinogen, in valsartan -- apparently a manufacturing byproduct. But is this an isolated issue of manufacturers cutting corners or has the cancer problem for these drugs been brewing for years?

"As background, the presence of NDMA and N-Nitrosodimethylamine (NDEA) in valsartan tablets is an industry-wide issue," according to a statement from Mylan, maker of over 100 lots of valsartan that were among the affected in subsequent waves of recalls.

The recalls have been so extensive that the FDA released a statement last week that it is tolerating impurities that would expose individuals on maximal doses to less than 96 ng/day NDMA and 26.5 ng/day NDEA “for a short period of time to avoid a possible shortage of ARBs.”

In July, the agency estimated the risk as one additional case of cancer for every 8,000 people taking the highest dose of recalled valsartan (320 mg) containing NDMA. The new “acceptable intake” limits for NDMA and NDEA were calculated as daily exposures that would result a .

A Glitch in Manufacturing?

When concern extended to the presence of NDEA, another potential carcinogen similar to NDMA, the FDA published methods of detecting both compounds in active pharmaceutical ingredients (APIs) and finished drug products. More lots of generic ARB -- including irbesartan (Avapro) and losartan (Cozaar) -- subsequently fell under voluntary recall after companies implemented the FDA protocol.

After a of the facility, all products from Zhejiang Huahai Pharmaceuticals -- maker of the valsartan API first implicated in the recalls -- were placed on import alert in late September, meaning they were no longer legally allowed to enter the U.S.

FDA published its to the Chinese manufacturer in late November, chiding it for not doing its due diligence when faced with quality complaints from customers and failure to adequately assess the potential impact of using a new solvent in 2011 to increase product yield and lower production costs.

It appeared that the new solvent was to blame for the carcinogenic impurities found.

"NDMA appears to be generated during the formation of the tetrazole ring by reaction of dimethylamine (which may be present as an impurity or degradant in the solvent dimethylformamide [DMF]) and sodium nitrite under acidic conditions (where nitrous acid is formed)," according to the European Medicines Agency.

Carcinogens Take Cancer Issue Back Full-Circle

All the while, the brand names have escaped the ARB recalls, perhaps due to better manufacturing processes.

A Boehringer Ingelheim spokesperson told 番茄社区 that the company makes its telmisartan products Micardis, Micardis HCT, and Twynsta in Malgrat, Spain, in a process that does not form NDMA or NDEA.

Similarly, the olmesartan API used in Daiichi Sankyo products (Benicar, Benicar HCT, Azor, Tribenzor) has tested negative or NDMA and NDEA contamination, according to work done in external and company laboratories, a representative said in a statement.

Yet the cancer issue with ARBs is not just a story of these impurities.

In 2010, telmisartan was tied to an increase in a patient's risk of developing a new cancer in a meta-analysis by Ilke Sipahi, MD, of Acibadem Maslak Hospital in Istanbul, Turkey, and colleagues. He told 番茄社区 that he has stopped prescribing ARBs for hypertension ever since -- now only giving sacubitril/valsartan (Entresto) for heart failure given the known mortality benefit of that drug.

After Sipahi's study, FDA followed up with its own investigation and determined that the cancer concerns were unfounded.

Yet internal FDA documents show that Thomas Marciniak, a medical team leader at the agency, disagreed with that meta-analysis -- ultimately, he sent a memo to senior officials saying: "The FDA needs to inform patients and physicians about the ARB lung-cancer risks. ."

"I am surprised to see that no action was taken by the agency after this document was made public," Sipahi said.

Options for Hypertensive Patients

"Since July of this year, we get a news alert almost every week that some ARBs have carcinogenic nitrosamines in them, and we have no idea when these recalls will stop. As you know, these nitrosamines that they find in ARBs are especially related to lung cancer, and lung cancer was the one that was increased in randomized controlled trials," Sipahi said.

The recalls are making some patients nervous, but there's no generalized panic yet, said Howard Weintraub, MD, of New York University School of Medicine in New York, who noted that he has started giving more patients olmesartan (Benicar) and azilsartan (Edarbi) instead.

Nevertheless, the concern about cancer adds fire to the old debate: ARBs or angiotensin-converting enzyme (ACE) inhibitors for hypertension?

Weintraub continues to have "a great deal of confidence" in ARBs, he said. "The literature would support that they are probably just as good on an outcome basis as ACE inhibitors and certainly lower blood pressure as well if not better. When multiple drug classes are compared, the ARBs have the lowest side effect profile."

On the flip side, ARBs "have carcinogenic potential, and moreover they do not provide any protection against myocardial infarction, unlike most other antihypertensives," Sipahi countered.

Even so, ACE inhibitors were linked to an compared to ARBs after 5 years of use in a recent BMJ study.

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