Sperling Prostate Center

Update: Voluntary Recall of Extended Release Metformin

NOTE: The following is an update to a blog I posted in early 2020.

Metformin red flag, December 2019

I have occasionally reported on studies that link a possible preventive effect against prostate cancer (PCa) with the common diabetes drug, metformin. In February 2020 I notified readers that the FDA had issued a Dec. 2019 alert about a dangerous contaminant in some metformin products:

The FDA is investigating whether metformin in the U.S. market contains NDMA, and whether it is above the acceptable daily intake limit of 96 nanograms. The agency will also work with companies to test samples of metformin sold in the U.S. and will recommend recalls as appropriate if high levels of NDMA are found. If as part of our investigation, metformin drugs are recalled, the FDA will provide timely updates to patients and health care professionals.[i]

NDMA

N-Nitrosodimethylamine (NDMA) is part of a group of compounds called nitrosamines. NDMA can cause liver damage, and is known to cause cancer in lab animals. It is an unintended byproduct formed during chemical processes used to treat drinking water with chlorine, and during other processes used to cure meat, fish and tobacco. Thus, it can be found at very low levels in many (but not all) of these products.

What is a safe exposure level? No one knows. NDMA as an extremely dangerous substance subject to strict reporting requirements by facilities that produce, store or use it in significant quantities.[ii] However, no federal standard has been set for drinking water.[iii] In California, a state with stringent environmental standards, the allowable drinking water level is 10 ng/L; in Ontario, Canada it is 9 ng/L.

The FDA has set 96 ng/L as the upper safe limit for the presence of NDMA in pharmaceuticals, a number considerably higher than the drinking water standards cited above. That might seem like the agency is not johnny-on-the-spot with its safeguard function as a watchdog. However, the FDA has been actively sniffing out NDMA in surprising locations. In April 2020, the FDA ordered all ranitidine medications (brand name Zantac) immediately withdrawn from the market because it had detected the cancer-causing NDMA in several brand name and generic heartburn medications.[iv] The FDA also investigated certain blood pressure and heart failure medicines call Angiotensin II Receptor Blockers, and recommended numerous recalls for unacceptable nitrosamine levels.[v]

The latest news on NDMA in metformin

Since I last wrote on this topic in Feb. 2020, the agency has continued its testing and investigation into the presence of NDMA in metformin. Up till the end of May 2020, the FDA had not recommended metformin recalls in the U.S. because they had not found any immediate release (IR) metformin samples with NDMA levels that exceed the agency’s acceptable daily intake—and as of this writing, it’s still the case. However, on May 28 they issued a statement that they had discovered NDMA levels “…above the agency’s acceptable intake limit in several lots of the extended-release (ER) formulation of metformin… The agency is in contact with five firms to recommend they voluntarily recall their products.”[vi]

Then, on July 13, the FDA published a list of several companies that voluntarily recalled numerous packaged lots of metformin ER.[vii] At the same time, they recommended that diabetics taking metformin avoid the dangers of going off their medications by continuing to take them until their doctor or pharmacist provides a safe alternative. The FDA also encourages healthcare professionals to continue prescribing metformin to their diabetic patients as appropriate.

The bottom line is that no formulations of immediate release metformin have been found to contain NDMA, so those preparations remain on the market. As for metformin and PCa, a recent review of literature that queried “…the mechanisms of action, biological effects, epidemiological evidence, and research advances of [metformin] with respect to PCa…” found that the drug may have a future role against PCa due to “numerous mechanisms of action…to decrease or repress the growth, proliferation, and differentiation of PCa cells.”[viii] I remain optimistic about metformin as a weapon in the arsenal against PCa.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

[i] Statement issued by Janet Woodcock, MD. Dec. 5, 2019. https://www.fda.gov/news-events/press-announcements/statement-janet-woodcock-md-director-fdas-center-drug-evaluation-and-research-impurities-found
[ii] Chemicals in Your Community: A Guide to the Emergency Planning and Community Right-to-Know Act. U.S. Government Printing Office: 1988 516-002/80246.
[iii] “Technical Fact Sheet – N-Nitroso-dimethylamine (NDMA).” Environmental Protection Agency, Jan. 2014. https://www.epa.gov/sites/production/files/2014-03/documents/ffrrofactsheet_contaminant_ndma_january2014_final.pdf
[iv] Ries, Julia. “FDA Orders Zantac Taken Off Store Shelves Due to Cancer-Causing Chemical.” Healthline, Apr. 1, 2020. https://www.healthline.com/health-news/fda-warns-zantac-may-have-carcinogen
[v] Statement issued by Janet Woodcock, MD. Director, Center for Drug Evaluation and Research. Sep. 13, 2019.
[vi] https://www.fda.gov/news-events/press-announcements/fda-alerts-patients-and-health-care-professionals-nitrosamine-impurity-findings-certain-metformin
[vii] https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin
[viii] Zaidi S, Gandhi J, Joshi G, Smith N, Khan SA. The anticancer potential of metformin on prostate cancer. Prostate Cancer Prostatic Dis. 2019 Sep;22(3):351-361.

About Dr. Dan Sperling

Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.

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