Regulatory Focus™ > News Articles > 2019 > 4 > EMA Urges Pioglitazone Manufacturers to Check for Nitrosamine Impurities

EMA Urges Pioglitazone Manufacturers to Check for Nitrosamine Impurities

Posted 26 April 2019 | By Zachary Brennan 

EMA Urges Pioglitazone Manufacturers to Check for Nitrosamine Impurities

The European Medicines Agency (EMA) on Friday called on companies using certain reagents to manufacture the diabetes medicine pioglitazone to test their products and check their processes to rule out the presence of nitrosamine impurities, in particular nitrosodimethylamine (NDMA).

“The request follows the detection of low levels of NDMA in a few batches of pioglitazone manufactured by Hetero Labs in India,” EMA said.

In the US, Hetero in March announced a recall of 87 lots of losartan potassium tablets (25 mg, 50 mg and 100 mg). The recalled losartan potassium tablets contain the impurity N-Nitroso-N-methyl-4-aminobutyric acid (NMBA), which is a known animal and potential human carcinogen, FDA said. 

EMA, meanwhile, previously conducted an EU-wide safety review, which set legally-binding limits for nitrosamine impurities in sartan blood pressure medicines. EMA said it’s working with national authorities and international partners to ensure manufacturers avoid or keep the presence of nitrosamine below the acceptable limits.

“Based on experience from the review of sartans, EMA is launching an exercise with experts from across the EU regulatory network to consider how to prevent such incidents in future and to see if their management can be improved, should they occur,” EMA said.

EMA and national authorities will also continue investigating the presence of impurities in angiotensin II receptor blockers (ARBs), including others such as N-nitrosoethylisopropylamine (EIPNA), N-nitrosodiisopropylamine (DIPNA) and NMBA.

EMA’s previous review of ARBs also estimated the highest possible cancer risk with these impurities.

“It concluded that if 100,000 patients took valsartan from Zhejiang Huahai (where the highest levels of impurities were found) every day for 6 years at the highest dose, there could be 22 extra cases of cancer due to NDMA over the lifetimes of those 100,000 patients. NDEA in these medicines could lead to 8 extra cases in 100,000 patients taking the medicine at the highest dose every day for 4 years,” EMA added.

Work on the recalls has been ongoing in the US, too, with FDA noting nearly 40 recalls of ARBs since last July. The latest from FDA includes Torrent Pharmaceuticals recalling an additional 104 lots of losartan potassium and losartan potassium/hydrochlorothiazide combination tablets, as they were made using ingredients from Hetero that contained NMBA.

In response to the finding of NMBA in Hetero ingredients, FDA in early March updated its interim list of acceptable intake of nitrosamine impurities in ARB products to include limits for NMDA at 96 nanograms per day. At that level, FDA says the impurity poses a 1:100,000 risk for developing cancer after 70 years of exposure at the daily acceptable limit.


© 2021 Regulatory Affairs Professionals Society.

Regulatory Focus newsletters

All the biggest regulatory news and happenings.