One manufacturer of Metformin, a medication prescribed to people suffering from type 2 diabetes, has issued a recall on extended release tablets and the federal government is asking other manufacturers to recall the medication.
Apotex Corp is recalling all lots of Metformin Hydrochloride Extended-Release Tablets, USP 500mg. Apotex was notified by the U.S. Food and Drug Administration (FDA) that one lot was tested and showed levels of a carcinogen, N-Nitrosodimethylamine, in excess of the acceptable daily intake limit. The manufacturer has extended the recall to all lots of Metformin Hydrochloride Extended-Release Tablets in the US. Apotex stopped selling this product in the US in February 2019, and there remains only limited product on the market. To date, Apotex has not received any reports of adverse events related to use of the product.
N-Nitrosodimethylamine (NDMA) is classified as a probable human carcinogen, a substance that could cause cancer. NDMA is a known environmental contaminant found in water and foods, including meats, dairy products, and vegetables.
Metformin Hydrochloride Extended-Release Tablets, USP is a prescription oral product indicated as an adjunct to diet and exercise to improve blood sugar control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. The affected Metformin Hydrochloride Extended-Release Tablets, USP can be identified by NDC numbers stated on the product label.
|Product||Strength||Pack Size||NDC Number|
|Metformin Hydrochloride Extended-Release Tablets, USP||500mg||100’s Bottle||60505-0260-1|
The tablets were distributed nationwide. Apotex is notifying wholesalers and arranging for return of all recalled product.
Customers who purchased the product directly from Apotex can call Inmar Rx Solutions at 1-888-985-9014 (option 1) (9 a.m.–5 p.m., Monday through Friday) to arrange for their return.
Consumers with questions can contact Apotex Corp. by phone at 1-800-706-5575 (8:30 a.m.–5 p.m., Monday through Friday) or email UScustomerservice@Apotex.com. Consumers should contact their physician or healthcare provider if they have experienced any problems that may be related to taking or using this drug.
Adverse reactions or quality problems experienced with the use of this product may be reported to the FDA’s MedWatch Adverse Event Reporting program either online, by regular mail or by fax.
- Complete and submit the report Online
- Regular Mail or Fax: Download form or call 1- 800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
The FDA announced Friday that testing revealed NDMA in several lots of the extended-release formulation of metformin. The agency has contacted five firms to recommend they recall their products. Company recall notices will be posted on FDA’s website. There are additional manufacturers of the metformin ER formulation that supply a significant portion of the U.S. market, and their products are not being recalled. The FDA is continuing to work closely with manufacturers to ensure appropriate testing. Assessments are underway to determine whether metformin ER recalls will result in shortages and the agency will work closely with manufacturers to prevent or reduce any impact of shortages.
Patients are advised to continue taking metformin tablets, even if they have been recalled, until they consult with their health care provider who can prescribe a replacement. Patients with type 2 diabetes could face dangerous health risks if they stop taking their prescribed metformin. The FDA recommends that health care professionals continue to prescribe metformin when clinically appropriate; FDA testing has not shown NDMA in immediate release metformin products (the most commonly prescribed type of metformin).
The FDA is working with manufacturers to identify the source of the NDMA impurity. At this time, the elevated levels of NDMA have been found in some finished-dose tablets of the ER formulation but have not been detected NDMA in samples of the metformin active pharmaceutical ingredient.
The agency is also asking all manufacturers of extended release metformin to test each batch before it is released into the U.S. market.
In late 2019, the FDA announced it had become aware of NDMA in some metformin products in other countries. The agency immediately began testing to determine whether the metformin in the U.S. was at risk, as part of the 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.
Recently, the FDA became aware of reports of higher levels of NDMA in certain ER formulations of metformin via a citizen petition filed by a private laboratory. FDA testing of the same metformin lots confirmed unacceptable NDMA levels in some, but not all, of those lots. In other instances, our laboratory detected NDMA in lots that the private laboratory did not. The agency also found that the levels of NDMA, when present, were generally lower than reported by the private laboratory. Given FDA scientists’ deep experience quantifying these impurities in drugs, the agency is confident in the reliability of the FDA’s testing method and results and will continue to take action based on the latest scientific information. The results have also been consistent with the findings of other regulatory agencies’ laboratories around the world.
NDMA is a common contaminant found in water and foods including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of NDMA. The FDA and the international scientific community do not expect it to cause harm when ingested at low levels. The FDA’s acceptable intake limit for NDMA in drug formulations is 96 nanograms per day. The FDA does not expect nitrosamines to cause harm when ingested at or below the acceptable intake limit levels (such low levels of nitrosamines are present in foods in low levels and ingested as part of usual diets) even over a long period of time (such as a 70-year lifespan). Nitrosamine impurities may increase the risk of cancer if people are exposed to them at above-acceptable levels over long periods of time, but we do not anticipate that shorter-term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer. We are working to ensure medicines on the U.S. market do not exceed the acceptable intake limit.
The FDA has previously investigated the presence of nitrosamines in the U.S. drug supply, beginning with the blood pressure and heart failure medicines called angiotensin II receptor blockers (ARBs) and then heartburn medicines, ranitidine and nizatidine, as well as diabetes medication, metformin and other medicines. In April 2020, the agency requested manufacturers withdraw all prescription and over-the-counter ranitidine drug products from the market because of test results showing that NDMA in some ranitidine products increases over time and, when stored at higher than room temperatures, may result in consumer exposure to unacceptable levels of this impurity.
There are multiple reasons for the presence of NDMA in drugs. The FDA has previously found that the source of NDMA can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines including NDMA, can be formed.
The FDA is taking a systematic approach to identify medicines with nitrosamines above the acceptable intake limit and remove them from the market. Improved technology enables the detection of even trace amounts of impurities in drug products and may be the reason why more products have been found to have low levels of NDMA. Today, better testing methods exist, and the FDA better understands the specific manufacturing steps that may increase the risk of nitrosamine formation. The FDA works closely with international drug regulatory agencies, who have also been testing drug products for NDMA and are collaborating to investigate the sources of these impurities.
For more information about drug recalls, visit https://www.fda.gov/drugs/drug-safety-and-availability/drug-recalls.
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