By: Mandy Zheng, PharmD Candidate c/o 2024

              “Where can I find Zantac?”. From April 2020 to May 2021, the answer was, you cannot. On April 1, 2020, the Food and Drug Administration (FDA) ordered for all ranitidine (Zantac®)- containing products to be removed from the U.S. market.¹ Ranitidine was a popular over-the-counter (OTC) and prescription medication treating heartburn, acid reflux, stomach ulcers, gastroesophageal reflux disease (GERD), and other related health conditions in which the stomach produces excessive acid. Zantac® was FDA-approved in 1983, and in 1988, became the world’s best-selling drug and one of the first drugs to reach $1 billion in sales.²

Ranitidine, the active ingredient in Zantac®, belongs to a class of medications called histamine-2 blockers (H2 blockers) or histamine H2-receptor antagonists (H2RA). H2 receptors are found in stomach linings and are activated by histamine – a chemical naturally produced by certain cells of the body. Once histamine is released, it stimulates the parietal cells in the lining of the stomach to release acid, which aids in food digestion and the killing of bacteria.³ H2 blockers are antagonists that compete with histamine for binding to H2 receptors, thus reducing the production of stomach acid. The reduction of gastric acid secretion provides patients with symptomatic relief from heartburn, indigestion, acid regurgitation, sour stomach, or bitter belching.³

Some advantages of H2 blockers, compared to other treatments for stomach acid-related symptoms, are their fairly quick onset of action and lasting effects. Proton pump inhibitors (PPIs), like omeprazole (Prilosec®) and esomeprazole (Nexium®), are only approved for treating frequent heartburn (heartburn that occurs 2 or more days a week) over-the-counter, and may take several days of continued use in order for patients to experience the maximal effects.⁴ PPIs are not intended for immediate relief of symptoms and work best when taken daily, compared to antacids and H2 blockers, which are taken as needed and provide more rapid relief. H2 antagonists begin to work in 30-45 minutes and their effects can last anywhere from four to ten hours, compared to traditional antacids like calcium carbonate (Tums) that tend to wear off within twenty to thirty minutes, requiring more frequent dosing.⁵

The marketability for ranitidine was high due to these positive attributes, but this all changed in the summer of 2019. The FDA began its investigation when they became aware of an independent laboratory that found the presence of a contaminant known as N-Nitrosodimethylamine (NDMA) in ranitidine.¹ NDMA is classified as a B2 (probable human) carcinogen, which is found at low levels in water and many foods, such as cured meats, cheese, and beer, because of their cooking and fermentation processes.^6,7 Low levels of exposure to NDMA are not expected to cause health concerns, but higher levels of exposure can lead to an increased risk of liver toxicity and cancers such as esophageal cancer, bladder cancer, gastric cancer, liver cancer, among others. In September of 2019, the FDA had insufficient scientific evidence to pull ranitidine off the shelves, so they informed the public of their findings, warned people of the potential risks, and recommended patients to consider alternative medications for their symptoms.⁸

Nearly six months afterwards, the FDA released a statement in April 2020 requesting an immediate market withdrawal of ranitidine products. The FDA determined that traces of NDMA in ranitidine medications increase over time when stored at higher than room temperature, which could result in unacceptable levels of human exposure.¹ However, more than a year after the drug recall, Zantac® was “reformulated” and made a comeback into the consumer market as Zantac 360°™ in original strength (10 mg of famotidine) and in maximum strength (20 mg of famotidine). No longer containing the original active ingredient, ranitidine, Zantac 360°™ is now formulated to contain a different H2 antagonist known as famotidine. Famotidine (Pepcid®) was approved by the FDA in 1998, and has been on the market to treat acid-related symptoms, such as GERD, ulcers, and heartburn.⁹ Famotidine has similar uses and effects as ranitidine without the same risks of NDMA exposure.¹ This move was made by Sanofi, the pharmaceutical company that owns the brand name Zantac®. Currently facing a class-action lawsuit encompassing more than 70,000 former patients in the US, Sanofi is being accused of deleting emails that contained information suspecting ranitidine’s link to NDMA in Zantac® products.¹⁰

While ranitidine will not be coming back to the market anytime soon, famotidine (Zantac 360°™), is now available on store shelves and online retailers. Sanofi is now using the well-known Zantac® name to sell their “new” product that contains the same active ingredient as Pepcid®, which can confuse consumers and those unaware of the FDA’s recall of ranitidine (Zantac®) products. Not everyone reads the back of the medication box for the active ingredient list, and this is one of many areas where the pharmacist should be assisting patients at every opportunity available. Pharmacists should stay aware of new drug updates and be more vigilant in verifying the ingredients in OTC products so they can properly counsel patients on treatment options and relief from symptoms.

References:

1. “FDA Requests Removal of All Ranitidine Products (Zantac) from the Market.” U.S. Food and Drug Administration, 2 Apr. 2020, fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market. Accessed November 3, 2021.
2. Zantac OTC – ClassAction.Com. classaction.com/zantac/. Published July 10 2021. Accessed November 3, 2021.
3. Knott, Dr Laurence. H2 Blockers (H2-Receptor Antagonists) | Reducing Stomach Acid. 3 Apr. 2020, patient.info/digestive-health/indigestion-medication/h2-blockers. Accessed November 3, 2021.
4. “Questions and Answers on Prilosec OTC (Omeprazole).” U.S. Food and Drug Administration. fda.gov/about-fda/center-drug-evaluation-and-research-cder/questions-and-answers-prilosec-otc-omeprazole . Published November 3, 2018. Accessed November 3, 2021
5. Whetsel, Tara, and Gretchen Garofoli. “‘Chapter 13: Heartburn and Dyspepsia,’ Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care, 20th Edition.” American Pharmacists Association, https://doi-org.jerome.stjohns.edu/10.21019/9781582123172.ch13. Accessed November 3, 2021.
6. “Technical Fact Sheet – N-Nitroso-Dimethylamine (NDMA).” United States Environmental Protection Agency, epa.gov/sites/default/files/2014-03/documents/ffrrofactsheet_contaminant_ndma_january2014_final.pdf. Accessed November 3, 2021.
7. Boerner, Leigh Krietsch. NDMA, a Contaminant Found in Multiple Drugs, Has Industry Seeking Sources and Solutions. cen.acs.org/pharmaceuticals/pharmaceutical-chemicals/NDMA-contaminant-found-multiple-drugs/98/i15. Accessed November 3, 2021.
8. “Statement on New Testing Results, Including Low Levels of Impurities in Ranitidine Drugs.” U.S. Food and Drug Administration, 24 Mar. 2020, fda.gov/news-events/press-announcements/statement-new-testing-results-including-low-levels-impurities-ranitidine-drugs. Accessed November 3, 2021.
9. Drug approval package. Pecid RPD (Famotidine) NDA# 020752. https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20752s000_PecidTOC.cfm. Accessed November 3, 2021.
10. Feeley, Jef. Sanofi Accused of Destroying Emails Tied to Zantac Recall. bloomberg.com/news/articles/2021-05-11/sanofi-accused-of-destroying-internal-emails-about-zantac-recall. Published May 11, 2021. Accessed November 3, 2021.
11. Zantac 150 tablets. Asti’s South Hills Pharmacy. https://astis-south-hills-pharmacy.myshopify.com/products/zantac-150-tablets. Accessed November 3, 2021.
12. Zantac 360 maximum strength heartburn prevention and relief tablets. https://www.cvs.com/shop/zantac-360-maximum-strength-heartburn-prevention-and-relief-tablets-prodid-320781. Accessed November 3, 2021.

Published by Rho Chi Post