Updated July 6, 2020 (New recalls and finding of “DMF” carcinogen)

In June, five companies announced recalls of lots of metformin, including Amneal, Apotex, Lupin, Marksans, and Teva. On July 3, 2020, Granules India also recalled their metformin ER product.  Recall announcements from the individual companies:

The recalls were prompted by a Citizen Petition Valisure filed with the with the Food and Drug Administration (FDA) on March 2, 2020. In the petition, Valisure urged FDA to request recalls for the identified lots of metformin consistent with FDA’s mandate to ensure the safety of the drug supply in America. Valisure’s analysis of 22 companies selling metformin and a total of 38 batches revealed 16 batches and 11 companies where NDMA levels were detected above the 96 nanograms (ng) daily acceptable intake limit. Several batches contained over 10 times the daily acceptable intake limit and there was significant variability from batch to batch, even within a single company.

Valisure has recently detected a second probable human carcinogen in metformin tablets called N,N-Dimethylformamide (“DMF”). In many cases, levels of DMF in metformin drug products tested exceed the high levels found in valsartan drug products Valisure reported June 13, 2019 and can expose patients to DMF in the order of milligrams per week. These findings of DMF in metformin are in agreement with the recent FDA statement posted July 2, 2020 on metformin  where the “interfering substance” is DMF. More detail in Valisure’s letter linked below.

 

As stated in our FDA Citizen Petition from June 13, 2019, DMF is a chemical that was reclassified in 2018 as a Group 2A probable human carcinogen by the World Health Organization (“WHO”) and International Association for Research of Cancer (“IARC”).  DMF is classified by the FDA as a Class 2 solvent and is commonly used in the production of pharmaceutical active ingredients.  According to the FDA, Class 2 solvents “should be limited in pharmaceutical products because of their inherent toxicity.”  Valisure notes that the WHO and IARC reclassified DMF to Group 2A probable human carcinogen status in 2018, while the most recent revision of the FDA regulation of residual solvents is dated June 2017. Thus, Valisure requests an expeditious review of DMF in drug products and that the FDA take action to significantly lower the acceptable daily intake limit for DMF.

Also, as our petition stated, the California Environmental Protection Agency had expressed concern regarding the permeation-enhancing activity of DMF whereby it “may act as an escort to facilitate the easy entry of either endogenous or exogenous carcinogens.” This means DMF might amplify the activity of other carcinogens and potentially increase the toxicity of even low levels of NDMA.

Additionally, on May 27, 2020, in a first-of-its-kind study, Valisure posted the results from their testing of crowdsourced samples of metformin. The study was posted to medRxiv.org,the preprint server for health sciences. The study’s objective was to test for NDMA in tablets of metformin that were sent directly from individuals around the United States to Valisure’s laboratory. The intention of this study was to evaluate the prevalence of contamination in metformin with the least possible bias by sourcing direct from individuals. Therefore, a direct-to-consumer crowdsourcing study was conducted and resulted in the evaluation of 128 samples of metformin medication from individuals located in 30 states.

The study summarizes the results in its abstract: “42% of all medication samples contained detectable levels of NDMA and, when scaled to maximum daily tablet dose, 36% of all medication samples contained NDMA levels exceeding the FDA daily acceptable intake limit. The highest NDMA detection from the tested samples was 1565 ng per tablet, which, when commonly taken four times a day, is 65 times the United States Food and Drug Administration (FDA) acceptable daily intake limit.  Results underscore the need for immediate product recalls of tainted medications and an overall investigation of metformin manufacturing practices.”

Metformin is an oral diabetes medicine that helps control blood sugar levels in adults and adolescents with type 2 diabetes. More than 30 million people in the United States have diabetes, of which 90 to 95% are type 2. Metformin is the fourth-most prescribed drug in the U.S. with approximately 80 million prescriptions written in 2019.

“The presence of this carcinogen in metformin where multiple tablets can be taken daily and often for a lifetime diabetic condition, makes this finding particularly concerning,” said Deanna Akinbajo, PharmD, MPH, Chief Pharmacist of Valisure. “Furthermore, the increased prevalence of diabetes in adolescents and young adults strongly underscores the need for quick action to protect patients.”

The carcinogenic nature of nitrosamines, and specifically NDMA, has been extensively studied by the scientific community since the 1960s. The World Health Organization (WHO) and the International Agency for Research on Cancer (IARC) have classified NDMA as a Group 2A compound thereby defining it as “probably carcinogenic to humans.” FDA currently recognizes the danger of this compound and, as a result, has set strict daily acceptable intake limits and advised companies to recall medications like valsartan, losartan, and ranitidine that did not meet this standard.

Media Coverage:

Bloomberg: https://www.bloomberg.com/news/articles/2020-05-27/fda-finds-carcinogen-in-some-versions-of-popular-diabetes-drug

Wall Street Journal: https://www.wsj.com/articles/fda-asks-five-companies-to-recall-diabetes-drug-metformin-11590771735

FiercePharma: https://www.fiercepharma.com/manufacturing/fda-recommends-metformin-recalls-for-5-drugmakers-after-carcinogen-contamination

Becker’s Hospital Review: https://www.beckershospitalreview.com/pharmacy/5-drugmakers-have-recalled-metformin-products-after-fda-warning.html