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Boxes of Zantac on a market shelf
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Almost a year after online pharmacy Valisure notified the U.S. Food and Drug Administration (FDA) that it had found unsafe levels of a carcinogen in Zantac (ranitidine) samples tested, the FDA has requested that all ranitidine products be pulled from the market immediately.  The recall includes all prescription and over-the-counter versions of drugs.

The agency took this action after learning that N-nitrosodimethylamine (NDMA) or the “impurity,” as they call it, can increase over time and when the drug is exposed to higher than room temperatures, such as those that may occur during transport or when sitting in a warm car.

FDA Finds NDMA in Ranitidine Increases During Storage and With Time

The FDA, in requesting this recall, is responding to testing and evaluation prompted by information from third-party laboratories.  On January 2, 2020, Emery Pharma, one of the independent labs the FDA refers to, sent a citizen’s petition to the FDA requesting the agency recall all lots of ranitidine.  Emery’s tests revealed that while stable at room temperature, the ranitidine molecule could become unstable at temperatures of about 158 degrees Fahrenheit, resulting in increased and unsafe levels of NDMA, a probable human carcinogen.

Ramin Janafi, Ph.D., President and CEO of Emery Pharma, noted that the drug was “very likely” exposed to elevated temperatures during shipment and storage, particularly in the southern states in the U.S., and suggested that in addition to a recall, the FDA should require the product be shipped in temperature-controlled trucks and stored under refrigeration.

The FDA noted in its recent announcement that it has confirmed that NDMA levels increase even under normal storage conditions, and increases significantly when stored at high temperatures, “including temperatures the product may be exposed to during distribution and handling by consumers.”  The FDA also found that the older a ranitidine product is, or the longer the length of time since it was manufactured, the greater the level of NDMA.

Because of these findings, the FDA is sending letters to all manufacturers requesting they withdraw their products form the market.  Consumers are advised to stop taking the drug, to avoid buying more, and to consider other similar products instead.  Patients taking prescription ranitidine should talk to their doctors about alternatives.

Valisure Reported the Presence of NDMA in Zantac Last June

Valisure sent a citizen’s petition to the FDA in September 2019 asking the agency to take this action then.  CEO David Light and Chief Scientific Officer Kaury Kucera, Ph.D., requested that the FDA “request a recall and suspend sales of ranitidine from the U.S. market” due to the presence of NDMA.

Valisure found NDMA in Zantac during routine testing and informed the FDA that according to their results, the carcinogen was not an impurity, but a result of the instability of the ranitidine molecule itself: “The ranitidine molecule contains both a nitrite and a dimethylamine (“DMA”) group which are well known to combine to form NDMA.”

The FDA questioned Valisure’s results, however.  The testing method Valisure used employed heat, which the FDA noted could artificially increase levels of NDMA.  The agency conducted it’s own tests and found lower levels than Valisure did, but still confirmed that the levels were higher than the FDA’s recommended safe limit of 96 nanograms per day.

Because of these findings, the FDA warned patients and healthcare providers about the risk in September 2019 and encouraged manufacturers to conduct their own tests on their products.  Many of those manufacturers recalled their medicines after receiving the FDA’s request, including brand name Zantac manufacturer Sanofi, which recalled the drug in October 2019.  Some forms of generic ranitidine, however, remained on the market.

Where Does the NDMA Come From?

All ranitidine products will soon be off the market, but the FDA has yet to say clearly where the NDMA is coming from.

Valisure has continued to assert that the NDMA is not an “impurity” in Zantac, as the FDA has termed it.  Valisure’s tests suggested that ranitidine could “react with itself” under standard conditions resembling those that occur during digestion to produce NDMA at levels higher than the acceptable daily intake.

The pharmacy also pointed to other evidence showing that ranitidine could form NDMA during digestion, including a 2016 study that reported urinary levels of NDMA 400-fold from 110 to 47,600 ng after ranitidine intake, while total N-nitrosamines increased 5-fold.

The FDA conducted its own laboratory tests, however, and which did not find that Zantac formed NDMA within the digestive system.  Janet Woodcock, M.D., Director for the FDA’s Center for Drug Evaluation and Research, said in a statement, “We also conducted tests that simulate what happens to ranitidine after it has been exposed to acid in the stomach with a normal diet and results of these tests indicate that NDMA is not formed through this process.”  She added that the FDA must still test the drugs in the human body “to fully understand if ranitidine forms NDMA.”

Meanwhile, many people who took Zantac for years and were then diagnosed with cancer have filed Zantac lawsuits in court.  Due to the rising number of cases and the common questions of fact, the U.S. Judicial Panel of Multidistrict Litigation (JPML) recently ordered all federally filed Zantac lawsuits to be centralized in the U.S. District Court for the Southern District of Florida.

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