As sartans continued to struggle, the problem expanded in 2019
In March, we reported that a new generic valsartan (Diovan) hit the market to help the angiotensin receptor blocker (ARB) shortage caused by waves of recalls. In this follow-up, we take a look at the developments in the nitrosamine impurity problem that are now affecting other classes of drugs.
Since the summer of 2018, numerous lots of generic ARBs -- namely valsartan, losartan, and irbesartan -- have been recalled for containing the probable carcinogenic impurities N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA).
A generic valsartan from Alkem Laboratories was approved in March after a priority review from the FDA. It was supposed to alleviate concerns of a shortage of these blood pressure-lowering drugs.
At the time of the new generic's approval, however, N-nitroso-N-methyl-4-aminobutyric acid (NMBA) had just been been found to be an impurity of interest to the agency. This known environmental contaminant, found in water and foods, is also a potential carcinogen.
The FDA estimated that if 8,000 people took the highest valsartan dose (320 mg) containing NDMA from the recalled batches daily for 4 years, there may be one additional case of cancer over their lifetimes.
This risk was higher than that for NDEA, where it would take 18,000 people taking highest-dose valsartan containing NDEA from recalled batches over the same period to get one case of cancer, according to agency estimates.
After the FDA shared two testing methods to detect NDMA, NDEA, and NMBA in ARBs, unacceptable amounts of NMBA were found in losartan products.
This resulted in further expansions of voluntary recalls throughout the spring and summer on losartan products from companies such as Torrent Pharmaceuticals, Teva Pharmaceuticals, Vivimed Life Sciences, and Macleods Pharmaceuticals.
Through the fall, FDA officials inspected manufacturing plants and issued warning letters to the Indian company Torrent Pharmaceuticals and U.S. manufacturer Mylan for violations of current good manufacturing practice in the making of valsartan and losartan in India.
Ranitidine Affected, Too
"Now that we know some of the root causes of the nitrosamine impurity problem, we're using these findings to inform our evaluation of medicines other than ARBs. We are testing samples of other drugs with similar manufacturing processes," according to an FDA statement in August.
Indeed, by mid-September the FDA was already alerting patients and health care professionals of NDMA found in samples of the antacid drug ranitidine (Zantac), though only at levels "barely" exceeding what is found in common foods.
"Although many of these levels of NDMA observed through FDA testing are much lower than the levels some third-party scientists first claimed, some levels still exceed what the FDA considers acceptable for these medicines," a statement said in November.
Starting in late September, lots of prescription and over-the-counter ranitidine underwent voluntary recall because of NDMA contamination. Affected products include those from GlaxoSmithKline, Novartis, Sandoz, Apotex, Perrigo Company, Novitium Pharma, Lannett Company, Aurobindo, Amneal, Glenmark Pharmaceuticals, Dr. Reddy's Laboratories, and Sanofi.
So far, the FDA announced that its tests of alternative antacids such as famotidine (Pepcid), cimetidine (Tagamet), esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec) have shown no NDMA.
Manufacturers have also been asked by FDA officials to test the antacid nizatidine (Axid) and recall their products with NDMA above the acceptable intake level of 96 nanograms per day, or 0.32 ppm. In December, the agency ruled that makers of ranitidine and nizatidine products should first test for NDMA before releasing them for consumer use.
Metformin is the latest drug to be tentatively affected by the nitrosamine contamination issue.
In early December, the Singapore government recalled three metformin drugs due to NDMA found above the acceptable level.
The FDA responded swiftly in a statement: "Based on the information we have available, the levels of NDMA seen outside the U.S. are within the range that is naturally occurring in some foods and in water. While we are aware that some regulatory agencies outside the U.S. may be recalling some metformin drugs, there are no metformin recalls affecting the U.S. market at this time."
Testing by the agency is, nevertheless, underway.
The European Medicines Agency made a similar announcement.
"At this point, there are no data indicating that EU metformin medicines are affected. Authorities in the EU are in the process of working with companies to test EU medicines and will provide further updates as more information becomes available," the agency said in a press release.
Read the original article on Medpage Today: The Year Nitrosamine Contamination Went Beyond ARBs