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Ranitidine (Zantac) and NDMA, from the public record

By Kelsey research · Published

Ranitidine, sold under the brand name Zantac and as generics, is an H2 blocker that lowers stomach acid. It was sold over the counter for heartburn and by prescription for ulcers and reflux. Below is the dated FDA record on N-nitrosodimethylamine (NDMA), a nitrosamine impurity, in ranitidine products, from FDA's own pages and, for the existence of a court proceeding only, an order of the Judicial Panel on Multidistrict Litigation (JPML).

Chronology, September 2019 to April 2020

Date Event Date type Source
Sep 13, 2019 FDA announces that some ranitidine medicines, including some sold as Zantac, contain NDMA at low levels. It classifies NDMA as a probable human carcinogen. It states it is "not calling for individuals to stop taking ranitidine at this time." announced [1][2]
Sep 24 and 26, 2019 FDA announces voluntary recalls of ranitidine by Sandoz (prescription capsules) and by Apotex (over-the-counter tablets sold under store labels). announced [2]
Oct 2, 2019 FDA states that a third-party laboratory's higher-temperature method generated "very high levels of NDMA" from the test procedure. It recommends a method without elevated temperatures. Its own "early, limited testing" found "unacceptable levels of NDMA in samples of ranitidine." announced [2]
Oct 23, 2019 FDA posts a second testing method and announces further recalls, including all ranitidine tablets and capsules from Dr. Reddy's. announced [2]
Nov 1, 2019 FDA posts its laboratory results for NDMA in ranitidine. The current version of that page states that NDMA was present in all ranitidine and nizatidine samples tested, and that the levels are similar to those in foods such as grilled or smoked meats. published [2][3]
Dec 4, 2019 FDA asks manufacturers to test all lots before release. It reports that its scientists found ranitidine "does not form NDMA in typical stomach conditions," and that some evidence links nitrite and NDMA formation if ranitidine is also present. announced [2]
Feb 6, 2020 The JPML centralizes pending Zantac actions in the Southern District of Florida as MDL No. 2924. published [4]
Apr 1, 2020 FDA requests that manufacturers withdraw all prescription and over-the-counter ranitidine from the U.S. market immediately. announced [5]

FDA's limit of 96 nanograms of NDMA per day

From December 2019 onward, FDA's updates refer to an acceptable daily intake limit of 96 nanograms per day, or 0.32 parts per million for ranitidine.[2] FDA's laboratory page describes up to 0.096 micrograms per day as "considered reasonably safe for human ingestion based on lifetime exposure."[3] That page also lists NDMA levels by company, product and lot.

The reasons FDA gave on April 1, 2020

FDA said "the impurity in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity." It said new testing, prompted by third-party laboratory information, confirmed that NDMA levels increase "even under normal storage conditions," and that older products showed higher levels.[5]

Two statements in the same release bear on how to read it. The CDER director said: "We didn't observe unacceptable levels of NDMA in many of the samples that we tested. However, since we don't know how or for how long the product might have been stored, we decided that it should not be available to consumers and patients unless its quality can be assured." The release also said that in September 2019 the agency "did not have enough scientific evidence to recommend whether individuals should continue or stop taking ranitidine medicines."[5]

FDA said it was sending letters to all ranitidine manufacturers asking them to withdraw their products. It advised over-the-counter users to stop and dispose of their supply, and advised prescription users to talk with a health care professional first. It reported no NDMA to date in famotidine, cimetidine, esomeprazole, lansoprazole or omeprazole.[5] On April 16, 2020, FDA alerted the public to a voluntary recall of an Amneal nizatidine oral solution for the same impurity.[2]

What the record shows, and what it leaves open

FDA's position changed over about six and a half months. In September 2019 it reported low NDMA levels and did not advise patients to stop. In April 2020 it asked for withdrawal of every ranitidine product, and gave storage-related growth of NDMA as the reason. The word "request" matters. FDA's release describes letters asking manufacturers to withdraw. It does not describe a recall order.

On testing, within three weeks of the first alert, FDA stated that one outside method produced NDMA through heating, and it published its own methods. Its laboratory page reports NDMA in every sample it tested, at a range of levels. FDA's April 2020 rationale concerns the impurity rising with age and heat. It does not rest on a finding about any patient.

The record does not show whether anyone developed cancer from NDMA in ranitidine. FDA's statements concern an impurity, exposure levels and a limit set for lifetime intake. They contain no epidemiologic finding about ranitidine users. The FDA pages also do not show what any manufacturer knew, or when, about NDMA formation. The JPML order shows only that actions were centralized for pretrial proceedings. It decides nothing about any claim, and this page takes no position on any.

Sources

  1. FDA, Zantac (ranitidine): Safety Information, NDMA Found in Samples of Some Ranitidine Medicines, posted 09/13/2019. https://www.fda.gov/safety/medical-product-safety-information/zantac-ranitidine-safety-information-ndma-found-samples-some-ranitidine-medicines
  2. FDA, FDA Updates and Press Announcements on NDMA in Zantac (ranitidine), dated entries from 9/13/2019 to 4/16/2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine
  3. FDA, Laboratory Tests, Ranitidine. https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-ranitidine
  4. Judicial Panel on Multidistrict Litigation, Transfer Order, In re Zantac (Ranitidine) Products Liability Litigation, MDL No. 2924, Document 198, filed 02/06/20. https://www.jpml.uscourts.gov/sites/jpml/files/MDL-2924-Transfer%20Order-1-20.pdf
  5. FDA, press release, "FDA Requests Removal of All Ranitidine Products (Zantac) from the Market," April 1, 2020. https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market