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Heartburn Over Heartburn Pills? Making Sense of the Zantac© (Ranitidine) Recall

Heartburn Over Heartburn Pills?  Making Sense of the Zantac© (Ranitidine) Recall

by Amy S. York, Esq.

Last fall, many heartburn sufferers were surprised when their local pharmacies started removing Zantac (ranitidine) and its generics from the shelves.  People who had taken these medications for decades suddenly were left wondering what was happening, how could they get their medication, why had it been removed, and what to do.  Some switched to other medications, some found other pharmacies that had not pulled the medication off their shelves, and some just found half-spent, older bottles shoved back behind the vitamin-C and Tylenol.

That early removal of product from store shelves was just a shot across the bow:  on April 1, 2020, the FDA announced that it was requesting all ranitidine products from the market and advised consumers to stop taking the medication immediately.[1]

This left most of us wondering:  What happened and why is it such a big deal?

Finding this answer was more difficult than I expected.  I found lots of websites making dramatic claims, but finding verifiable data proved harder.  With this blog, I hope to provide useful information with links to the source so that readers can dig deeper than the hype and understand just what happened – and why it really is a big deal.

NDMA, Cancer Risk, and the FDA’s Early Actions

In June 2019, an independent pharmacy conducted quality testing of ranitidine and “found dramatically high amounts of NDMA.”[2]  The independent pharmacy, Valisure Pharmacy based in Connecticut, filed a detailed petition with the FDA on September 13, 2019, requesting the agency to recall all ranitidine products.[3]  Valisure’s testing had shown that NDMA might be introduced through contamination in the manufacturing process but could also – alarmingly – be produced as ranitidine itself degrades over time, whether on the shelf or inside the human body.[4]  In other words, the NDMA problem wasn’t just a mistake in manufacturing; the drug itself was degrading into NDMA over time.

NDMA is a short-hand abbreviation for the chemical N-nitrosodimethylamine.[5]  It is no longer produced or commercially used in the United States except for research purposes.[6]  “It was formerly used in production of liquid rocket fuel, antioxidants, additives for lubricants and softeners for copolymers.”[7]  NDMA is classified as a B2 (probable human) carcinogen.[8]  It is “listed as a priority pollutant by the EPA.”[9]

At low levels, NDMA is not anticipated to be harmful.  The FDA maintains that “consuming up to 0.096 micrograms or 0.32 parts per million (ppm) of NDMA per day is considered reasonably safe for human ingestion based on lifetime exposure.”[10]  NDMA is commonly found in smoked or grilled meats and ground water as well as in cigarette smoke.[11]  The State of Texas, for instance, has determined that NDMA is concentrations of less than 0.018 micrograms per liter in ground water are acceptable.[12]

The FDA’s testing of about 45 batches of the drug across multiple manufacturers varied considerably, from a low of 0.03 ppm on the low end of three batches from Pharma Associates to 2.85 ppm in one batch from Novitium.[13]   To put it a different way, some of the ranitidine tested contained nearly 9 times the “safe” amount of NDMA in each dose.  Valisure’s results were much more alarming – showing NDMA levels at least 3,000 times higher than the “safe” limit.[14]  Valisure’s CEO, David Light, believes the difference between the Valisure results and the FDA results arise from differences in test methods.[15]  Regardless, the effects are cumulative:  the longer a person has been taking the drug, the more likely damage is to occur.[16]

According to the EPA, “[e]xposure to high levels of NDMA may cause liver damage in humans.”[17]  Potential symptoms of overexposure include headache, fever, nausea, vomiting, dizziness, jaundice, abdominal cramps, enlarged liver, and reduced function of liver, kidneys, and lungs.[18]  In animal experiments, NDMA exposure caused tumors of the liver, respiratory tract, kidney, and blood vessels.[19]

The dangers of NDMA are well known.  In 1989, the Agency for Toxic Substances and Disease Registry issued a public health statement that “[w]hen rats, mice, hamsters, and other animals ate food, drank water, or breathed air containing lower levels of NDMA for periods more than several weeks, liver cancer as well as non-cancerous liver damage occurred.”[20]  “The high level short-term and low level long-term exposures that caused non-cancerous liver damage and/or cancer in animals also usually resulted in internal bleeding and death.”[21]  “Mice that were fed NDMA during pregnancy had offspring that were born dead or died shortly after birth.”[22]  The agency was unaware at the time of reports of similar ill-effects occurring in humans but proposed that it “is reasonable to expect that exposure to NDMA by eating, drinking, or breathing could cause cancer in humans.”[23]  In short, the agency put people on notice that ingesting NDMA could lead to liver damage, liver cancer, internal bleeding, birthing issues, and death.

Researchers have continued to look into the effects of human ingestion of NDMA.  In a longitudinal study of rubber workers, for instance, a group of scientists at the Institute of Epidemiology and Social Medicine found that exposure to high levels of NDMA was related to a higher likelihood of death due to cancers of the esophagus, mouth, and pharynx.[24]  The World Health Organization has tentatively linked NDMA consumption to gastric or colorectal cancer.[25]  Other studies have been performed linking human NDMA ingestion to other cancers and conditions, including brain cancer, gastrointestinal cancer, prostate cancer, and rectal cancers .[26]

FDA Study Results and Second Zantac Recall

The FDA promptly responded to Valisure’s petition on September 13, 2019, issuing a statement suggesting that patients taking Ranitidine seek other medications.[27]  On September 24, 2019, the FDA announced a voluntary recall of 14 batches of the drug.[28]  It again suggested that patients consider other medications, but emphasized that not all batches of the product were under recall.[29]  Within the next few weeks, at least five more manufacturers joined in the voluntary recall, removing their products from store shelves.[30]  Within the following few months, a host of other manufacturers did as well.[31]

On April 1, 2020, the FDA announced that it was requesting manufacturers to withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately.[32]  It cautioned that although it did not find extremely high levels of NDMA in the samples it tested, “NDMA levels increase in ranitidine even under normal storage conditions, and NDMA has been found to increase significantly in samples stored at higher temperatures, including temperatures the product may be exposed to during distribution and handling by consumers.”[33]  Testing also “showed that the older a ranitidine product is, or the longer the length of time since it was manufactured, the greater the level of NDMA.”[34]

According to the FDA, ranitidine degraded into NDMA under normal conditions and warmer conditions sped up the rate of conversion.  In other words, the drug is inherently unstable and potentially unsafe.  Because the FDA could not be sure that the ranitidine supply was safe, it recommended that consumers immediately stop taking the drug and required manufacturers to pull their product from the shelves.[35]

What Happens Now?

If you took Zantac or other ranitidine drugs, especially for a longer period of time, you may want to consult with your doctor and have a physical.  Your physician can examine you and conduct testing to look at your organ function and overall health.  Ideally, your doctor is satisfied that you are in tip-top health!

If, on the other hand, your tests show damage to the liver or other organs, or even cancer, you may wonder what your legal rights are. Like Valisure’s CEO, the attorneys at Dobbs & Porter, PLLC, believe that “There’s no acceptable cancer risk for a drug like this.”[36]

[1] U.S. Food & Drug Administration, FDA Requests Removal of All Ranitidine Products (Zantac) from the Market (Apr. 1, 2020), available at https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market (last visited July 7, 2020).

[2] Harris, Richard, Pharmacies Pull Zantac Over Concern that Contaminant Poses Cancer Risk (Oct. 1, 2019), available at https://www.npr.org/2019/10/01/766176704/pharmacies-pull-zantac-over-concern-that-contaminant-poses-cancer-risk (last visited July 7, 2020).

[3] Valisure Detects NDMA in Ranitidine, available at https://www.valisure.com/blog/valisure-news/detection-of-ndma-in-raniditine/ (last visited July 7, 2020).

[4] Harris, Richard, Pharmacies Pull Zantac Over Concern that Contaminant Poses Cancer Risk (Oct. 1, 2019), available at https://www.npr.org/2019/10/01/766176704/pharmacies-pull-zantac-over-concern-that-contaminant-poses-cancer-risk (last visited July 7, 2020).

[5] U.S. Food & Drug Administration, Statement Alerting Patients and Health Care Professionals of NDMA Found in Samples of Ranitidine (Sept. 13, 2019), available at https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine (last visited July 7, 2020).

[6] U.S. Environmental Protection Agency, Technical Fact Sheet – N-Nitroso-dimethylamine (NDMA) (Nov. 2017), available at https://www.epa.gov/sites/production/files/2017-10/documents/ndma_fact_sheet_update_9-15-17_508.pdf (last visited July 7, 2020).

[7] Id.

[8] Id.

[9] Id.

[10] U.S. Food & Drug Administration, Laboratory Tests – Ranitidine (Nov. 1, 2019), available at https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-ranitidine (last visited July 7, 2020).

[11] Id.; World Health Organization, Guidelines for Drinking-Water Quality, 3rd ed. incl. 1st and 2nd addenda (2008), available at https://www.who.int/water_sanitation_health/dwq/chemicals/ndmasummary_2ndadd.pdf (last visited July 7, 2020); Mitacek, Eugene J., Klaus D. Brunnemann, Dietrich Hoffmann, Thiran Limsila, Maitree Suttajit, Nimit Martin, & Lee S. Caplan, Volatile Nitrosamines and Tobacco-Specific Nitrosamines in the Smoke of Thai Cigarettes:  A Risk Factor for Lung Cancer and a Suspected Risk Factor for Liver Cancer in Thailand, 20 Carcinogenesis 133-37 (1999), available at https://academic.oup.com/carcin/article/20/1/133/2529713 (last visited July 8, 2020).

[12] U.S. Environmental Protection Agency, Technical Fact Sheet – N-Nitroso-dimethylamine (NDMA) (Nov. 2017), available at https://www.epa.gov/sites/production/files/2017-10/documents/ndma_fact_sheet_update_9-15-17_508.pdf (last visited July 7, 2020).

[13] U.S. Food & Drug Administration, Laboratory Tests – Ranitidine (Nov. 1, 2019), available at https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-ranitidine (last visited July 7, 2020).

[14] Koenig, Debbie, Heartburn Drugs and Cancer:  What Are the Risks? (Sept. 26, 2019), available at https://www.webmd.com/heartburn-gerd/news/20190926/heartburn-drugs-and-cancer-what-are-the-risks (last visited July 7, 2020).

[15] Id.

[16] Id.

[17] U.S. Environmental Protection Agency, Technical Fact Sheet – N-Nitroso-dimethylamine (NDMA) (Nov. 2017), available at https://www.epa.gov/sites/production/files/2017-10/documents/ndma_fact_sheet_update_9-15-17_508.pdf (last visited July 7, 2020).

[18] Id.

[19] Id.

[20] Agency for Toxic Substances & Disease Registry, Public Health Statement N-Nitrosodimethylamine CAS#: 62-75-9 (Dec. 1989), available at https://www.atsdr.cdc.gov/ToxProfiles/tp141-c1-b.pdf (last visited July 7, 2020).

[21] Id.

[22] Id.

[23] Id.

[24] Straif, Kurt, Stephan K. Weiland, Martina Bungers, Dagmar Holthenrich, Dirk Taeger, Sun Yi, & Ulrich Keil, Exposure to High Concentrations of Nitrosamines and Cancer Mortality Among a Cohort of Rubber Workers, 57 Occup. Environ. Med. 180-187 (2000), available at https://oem.bmj.com/content/oemed/57/3/180.full.pdf (last visited July 7, 2020).

[25] World Health Organization, Guidelines for Drinking-Water Quality, 3rd ed. incl. 1st and 2nd addenda (2008), available at https://www.who.int/water_sanitation_health/dwq/chemicals/ndmasummary_2ndadd.pdf (last visited July 7, 2020).

[26] See Francis v. Boehringer Ingelheim Pharms., Inc., Case 5:19-cv-04824-JDW (E.D. Penn.) (citing additional tests and associated cancer risks).

[27] U.S. Food & Drug Administration, Statement Alerting Patients and Health Care Professionals of NDMA Found in Samples of Ranitidine (Sept. 13, 2019), available at https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine (last visited July 7, 2020).

[28] U.S. Food & Drug Administration, FDA Announces Voluntary Recall of Sandoz Ranitidine Capsules Following Detection of an Impurity (Sept. 24, 2019), available at https://www.fda.gov/news-events/press-announcements/fda-announces-voluntary-recall-sandoz-ranitidine-capsules-following-detection-impurity (last visited July 7, 2020).

[29] Id.

[30] U.S. Food & Drug Administration, UPDATE – FDA Releases Additional NDMA Testing Method and Alerts Health Care Professionals and Patients to Multiple Voluntary Recalls of Ranitidine (Oct. 23, 2019) and U.S. Food & Drug Administration, UPDATE – FDA Alerts Health Care Professionals and Patients to Multiple Voluntary Recalls of Ranitidine (Oct. 28, 2019), both available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine (last visited July 7, 2020).

[31] See, generally FDA press releases available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine (last viewed July 7, 2020).

[32] U.S. Food & Drug Administration, FDA Requests Removal of All Ranitidine Products (Zantac) from the Market (Apr. 1, 2020), available at https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market (last visited July 7, 2020).

[33] Id.

[34] Id.

[35] Id.

[36] Valisure Detects NDMA in Ranitidine, available at https://www.valisure.com/blog/valisure-news/detection-of-ndma-in-raniditine/ (last visited July 7, 2020).

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