Five companies—Teva Pharmaceuticals USA, Lupin, Apotex, Anmeal Pharmaceuticals and Marksans Pharma—are voluntarily recalling in the US select lots of metformin extended-release formulations, a drug to treat Type 2 diabetes, due to evaluated levels of a nitrosamine impurity, N-nitrosodimethylamine (NDMA), a potential carcinogen.

The recalls follow an announcement by the US Food and Drug Administration (FDA) late last month (May 2020) that its laboratory testing had revealed elevated levels of NDM above the agency’s acceptable intake limit in several lots of products. The FDA said at the time that it was in contact with five firms to recommend to them to voluntarily recall select lots.

Teva is voluntarily recalling 14 lots of metformin hydrochloride extended-release tablets, USP 500-mg and 750-mg, 100- and 1,000 count bottles, in the US to the consumer level due to the detection of levels of NDMA in excess of the acceptable daily intake limit. The FDA’s acceptable intake limit for NDMA in drug formulations is 96 nanograms per day. The lots were distributed nationwide in the US as retail bottles of 100 tablets and 1.000 tablets to Teva’s direct customers between January 8, 2019 and May 27, 2020.

Lupin Pharmaceuticals, the US subsidiary of Lupin, a Mumbai, India-based pharmaceutical company, is voluntarily recalling one lot of metformin hydrochloride extended-release tablets USP (generic equivalent of Fortamet), 500-mg to the consumer level in the US due to the detection of levels in excess of the acceptable daily intake limit.

Apotex, a Toronto, Canada-headquartered generic-drug company, is expanding its previously announced retail level recall of metformin hydrochloride extended-release Tablets, USP 500-mg that was initiated on May 29, 2020 to the consumer level in the US to include all lots of the product in the US. Apotex said that the FDA had notified the company of one with NDMA above the acceptable daily limit and as a precautionary measure, the company decided to recall all lots. Apotex said it stopped selling this product in the US in February 2019, and there remains only limited product on the market. To date, Apotex says it has not received any reports of adverse events related to use of the product.

Amneal Pharmaceuticals, a Bridgewater, New Jersey-based generic-drug company, is voluntarily recalling all lots of metformin hydrochloride extended-release tablets, USP, 500-mg and 750-mg, within expiry to the consumer level in the US. Amneal was notified by the FDA that the agency’s testing of seven lots of metformin hydrochloride extended-release Tablets, USP, 500-mg and 750-mg, showed NDMA amounts above acceptable FDA levels. FDA recommended the recall of the seven tested lots. Amneal says it has agreed to this recall and has further decided to extend the recall to all lots within expiry of metformin hydrochloride extended-release tablets, USP, 500-mg and 750-mg out of an abundance of caution.

Marksans Pharma, a Mumbai, India-based pharmaceutical company, is voluntarily recalling one lot of metformin hydrochloride extended-release tablets, USP 500-mg, to the consumer level in the US due to detection of NDMA about acceptable daily limits. The product was distributed by Time-Cap Labs, Farmingdale, New York-based company nationwide in the US to wholesalers who further distributed to pharmacies.

The FDA’s investigation into nitrosamine impurities in metformin is part of ongoing investigations and company recalls due to nitrosamine impurities in other active pharmaceutical ingredients (APIs). In 2018, the FDA and the European Medicines Agency initiated investigations of nitrosamine impurities in certain “sartan”-containing APIs, used in anti-hypertensive and cardiovascular drugs, such as valsartan, candesartan, irbesartan, losartan, and olmesartan. They later broadened those investigations into prescription and over-the-counter forms of ranitidine, a H2 (histamine-2) blocker used to decrease the amount of acid created by the stomach.

In late 2019, the FDA announced it had become aware of NDMA in some metformin products in other countries. The agency began testing to determine whether the metformin in the US supply was at risk as part of its ongoing investigation into nitrosamine impurities across medication types. By February 2020, the agency had identified very low levels of NDMA in some samples, but at that time, no FDA-tested sample of metformin exceeded the acceptable intake limit for NDMA. Recently, the FDA says it became aware of reports of higher levels of NDMA in certain ER formulations of metformin via a citizen petition filed by a private laboratory, and the agency initiated further testing in metformin ER products.

Last month (May 2020), the agency said it had not detected NDMA levels above acceptable limits in immediate-release metformin products, which is the most commonly prescribed type of metformin.

Source: Teva, Lupin, Apotex, Amneal Pharmaceuticals, and Marksans Pharma (as reported on FDA website)