Another Nitrosamine Impurity Found In Valsartan; ‘Low’ Cancer Risk Seen

Zhejiang Huahai has detected a second probable carcinogen in valsartan API it manufactured. Meanwhile risk analysis suggests cancer risk from the first probable carcinogen is low, at least so far.

Discovery of a second nitrosamine impurity that is probably carcinogenic has raised new concerns about the safety of valsartan, a commonly prescribed blood pressure and heart failure medication, even as additional study suggests the cancer risk from the first impurity is low.

US FDA and the European Medicines Agency both reported Sept. 13 that Zhejiang Huahai Pharmaceuticals Co. Ltd. has detected the second impurity, N-nitrosodiethylamine (NDEA), in valsartan API it made before switching to a new manufacturing process in 2012.

The first impurity found, N-nitrosodimethylamine (NDMA), is associated with the manufacturing process the firm started using in 2012. (Also see "As Recalls Multiply, EU Agency Studies How To Rid Chinese Firm’s Valsartan API Of Probable Carcinogen" - Pink Sheet, 20 Jul, 2018.)

Authorities have found NDMA in valsartan API from some other sources, but generally at lower levels.

Since the discovery of NDEA in older valsartan API, FDA has been retesting all valsartan API and drug products that are marketed or have been recalled in the US. So far it has found NDEA in three recalled lots of valsartan that Torrent Pharmaceuticals manufactured with API from Zhejiang Huahai.

Based on the latest test results from Zhejiang Huahai, EMA estimates that the lifetime cancer risk from the first impurity found, NDMA, is one in 5,000 for adults who took 320 mg/d of valsartan for the entire six years that the firm used its new API manufacturing process.

EMA says the one in 5,000 risk level “is considered low.”

However, it’s still 20 times higher than the theoretical one in 100,000 excess lifetime cancer risk that the International Council on Harmonization’s M7 (R1) guideline on mutagenic impurities uses for a threshold of toxicological concern. And ICH M7 says to go lower still for certain high potency mutagenic carcinogens, including N-nitroso- compounds like NDMA and NDEA.

Proof-of-Concept for Pharmacovigilance?

Nevertheless, the BMJ, formerly the British Medical Journal, on Sept. 12 published the results of a Danish nationwide cohort study on the risk of cancer from use of NDMA-contaminated valsartan.

The study focused on 5,150 Danish patients with no history of cancer who had been using valsartan at least since 2012 or who later started using it. The cohort’s median exposure was 4.6 years.

The study did not find any substantially increased short-term cancer risk. However, results suggested a higher, but statistically insignificant increased risk of colorectal and uterine cancer that might bear further study. And the study was unable to address long-term cancer risk. For these reasons, the researchers concluded further study was warranted to assess long term cancer risk.

An editorial accompanying the study report said the study, which took three months from start to finish, demonstrates the potential of registries in addressing safety concerns. Even though the study used data from four nationwide Danish registries, it covered only one fifth of the cohort years required to confirm EMA’s risk estimate. Results of active pharmacovigilance research at the European level could have helped clarify the impact on valsartan safety, the journal opined. “Had the Danish study extended to a larger European population, we might already have a conclusive answer.”

A related opinion piece by the study authors said they view it as “a proof-of-concept study in that expedited pharmacoepidemiologic assessment is possible and has its place in such urgent public health matters.”

From the editors of the Gold Sheet.