Industry fears sales ban as NDMA risk in metformin rekindled

The U.S.-based Valisure claims “High levels of NDMA detected in some metformin”

Private research firm warned of risk in ranitidine and nizatidine last year

Pharmaceutical companies “Korean regulator should level actions with the U.S. and Europe”

The risk of impurity found in metformin could resurface due to another warning from the U.S.-based private research firm.

 

The pharmaceutical industry’s concern deepens as the same research firm that warned about ranitidine risk last year published the metformin analytic data.

 

Already pharmaceutical companies fear global health authorities would order a complete sales ban on metformin after they collect and probe the products.

 

◆ Valisure “16 out of 38 metformin batches showed NDMA exceeding acceptable level” According to industry sources on Mar.

 

3, Valisure, a private research institute based in the U.S., has detectd cancerous N-nitrosodimenthylamine (NDMA) exceeding acceptable level of daily intake in some metformin products, which used in the U.S.

 

as antidiabetic drugs.

 

Valisure investigated NDMA in 38 metformin production batches manufactured by 22 pharmaceutical companies, following the liquid chromatography-mass spectrometry (LC-MS) protocol.

 

Apparently, Valisure has found NDMA exceeding acceptable level of daily intake in 16 batches from 11 companies.

 

One of the batches had NDMA content level 16.5 times higher than the acceptable daily intake level of 96 ng.

 

Valisure has requested the U.S.

 

Food and Drug Administration (FDA) to recall the metformin products containing levels of NDMA in excess of the daily acceptable intake limit.

 

Valisure’s list of metformin production batch found containing NDMA exceeding the acceptable level of daily intake (96 ng) (Source: Valisure Citizen Petition on Metformin)

The analytic findings from the firm contrast from the statement issued a month ago by FDA.

 

On Feb.

 

3, the U.S.

 

health regulator informed their analysis on 10 metformin products distributed in the U.S.

 

market found two products with low level of NDMA content, which the regulator recommended not to use.

 

◆ Industry tenses up as Valisure warned of risk of ranitidine and nizatidine last year The pharmaceutical industry is keenly watching the private research firm, because Valisure first warned of impurity found in ranitidine last year.

 

Housed in New Haven, CT, Valisure operates online pharmacies in 38 states in the U.S.

 

and regularly publishes analytic findings regarding pharmaceutical safety.

 

Interestingly, Valisure’s metformin impurity risk warning is similar to the actions taken for ranitidine impurity risk.

 

FDA issued a statement last year announcing the presence of low levels of NDMA in ranitidine drugs like Zantac, but did not mention a specific plan to recall the product.

 

Since then, Valisure disclosed their own investigation showing high levels of NDMA in ranitidine drugs including Zantac, and requested FDA to recall the products.

 

As a result, majority of ranitidine drugs were detected with unacceptable level of NDMA and the drugs were recalled in the U.S.

 

and Europe.

 

Valisure also urged FDA to initiate investigation on nizatidine by presenting findings of NDMA in the drug.

 

Korea’s Ministry of Food and Drug Safety (MFDS) also decided to ban sales and recall 13 nizatidine products in last November due to the presence of excessive level of NDMA.

 

Such development of the decisions by global health regulators is the reason the pharmaceutical companies are tensed up about MFDS’ actions following the metformin analysis.

 

The risk of NDMA in metformin was first raised from Singapore.

 

On Dec.

 

4 last year, Singapore’s Health Sciences Authority (HSA) recalled three items out of 46 metformin-containing drugs they have tested.

 

The result confirmed high levels of NDMA exceeding the acceptable daily intake level.

 

MFDS is currently probing NDMA in metformin active ingredient and finished products.

 

Although it has already been three months since the Singaporean health regulator spoke of the risk in metformin, the Korean ministry has not yet revealed the investigation outcome.

 

In last December, MFDS had pharmaceutical companies to submit record of using metformin.

 

And on Jan.

 

15, the ministry presented NDMA testing methodology for metformin.

 

The ministry is still probing NDMA contamination in collected active metformin ingredients.

 

Over a month has passed since FDA has presented the interim result of metformin-NDMA investigation, but the Korean health regulator has not even mentioned of a next step.

 

Three days after the news of Zantac detected with NDMA in the U.S., MFDS announced interim test result of NDMA level in Zantac on last Sept.

 

16 and said the impurity has not been detected.

 

But for the ranitidine issue, the Korean government ordered sales ban on the product in a mere of 10 days.

 

MFDS official stated, “Currently an inspection on contamination in metformin is ongoing.” The ministry is reviewing NDMA contamination in over 900 metformin samples.

 

◆ Pharmaceutical companies anxious of stringent actions like ranitidine or valsartan risk Clearly, the pharmaceutical industry is edgy on the MFDS-confirmed level of NDMA in metformin from Korea and their response, because Korean regulator’s action on NDMA-detected drug so far has been more stringent than that of the U.S.

 

or European regulators.

 

MFDS has banned sales of finished product that used the controversial active ingredient at least once since January of 2015.

 

Many of the products were probably banned from the market even if the controversial active ingredient was not used recently.

 

In the U.S., only the products using active ingredient from Zhejiang Huahai Pharmaceutical were recalled by batches.

 

An order of complete sales ban on the product was never given.

 

The level of action taken by European health regulator was on par.

 

While every ranitidine product was banned in Korea, pharmaceutical companies voluntarily recalled the products by batches in the U.S.

 

and Europe.

 

Whereas 13 nizatidine products were banned from sales in Korea, Japan only recalled a number of the products and the U.S.

 

and Europe have not given a recall order.

 

The Korean regulator has decide to recall specific batches of nizatidine with high levels of NDMA, but those products were temporarily banned from sales until the recall was completed.

 

Valisure pointed out the level of NDMA in metformin varies depending on each batch, although they were manufactured by a same company.

 

They argued the pharmaceutical substance could be the unstable factor.

 

The MFDS’ decision to weed out ranitidine products was made because ‘ranitidine has an unstable quality, therefore, it is always exposed to the risk of generating NDMA.’ A tremendous chaos in the whole of pharmaceutical industry would be inevitable if the ministry is to take actions as stringent as before when it finds high levels of NDMA in some of metformin.

 

According to pharmaceutical market research firm UBIST, pharmaceuticals with metformin generated 473.2 billion won last year from outpatient prescription.

 

The market continues to grow as the volume has doubled since 2014.

 

Pharmaceutical companies argue the Korean regulator should take similar level of actions as the U.S.

 

or Europe, even if they find high levels of NDMA in some of metformin available in Korea.

 

Especially because a research was published claiming NDMA found in valsartan and ranitidine would not be harmful to human body.

 

In last December, MFDS stated, “Reviewing individual dose and administration period of patients actually taking finished product containing valsartan manufactured from Huahai Pharmaceutical with NDMA, the possibility of causing cancer was low enough to ignore.” FDA also issued a statement last November, “The risk of causing cancer by NDMA detected in ranitidine is close to the risk exposed from having barbecued meat or smoked meat.” A pharmaceutical company insider urged, “Regardless of unconfirmed harm of pharmaceuticals detected with NDMA, the produces were banned from sales and recalled.

 

Accordingly, pharmaceutical companies had to endure immense loss and the public’s apprehension has deepened.

 

On products with impurities found in the future, the Korean government should order a batch-basis recall like the U.S.

 

and European government have.”