No Association Between Chronic use of Ranitidine, Compared With Omeprazole or Famotidine, and Gastrointestinal Malignancies

Yeseong D. Kim; Jiasheng Wang; Fahmi Shibli; Kamrine E. Poels; Stephen J. Ganocy; Ronnie Fass

Disclosures

Aliment Pharmacol Ther. 2021;54(5):606-615. 

In This Article

Abstract and Introduction

Abstract

Background: In 2019, the United States Food and Drug Administration detected above-regulation levels of the human carcinogen N-nitrosodimethylamine (NDMA) in ranitidine, resulting in a complete removal of the medication from the market. NDMA is known to cause gastrointestinal malignancies in animal models.

Aim: To determine if patients who were receiving ranitidine have a higher risk of developing cancers of the digestive tract compared to patients taking other anti-reflux medications.

Methods: Using the nationwide database IBM Explorys, patients taking ranitidine were compared to patients on either famotidine or omeprazole. Incidence data of new malignancies of the oesophagus, stomach, liver, pancreas, and colon/rectum were obtained in 1-year intervals for up to 10 years. Two multivariable logistic regression models were used to calculate odds ratios (ORs), one adjusting for common risk factors for each cancer studied, and the other for demographic factors.

Results: Patients on ranitidine who were compared to patients on famotidine had ORs of 0.51(95% CI 0.43–0.60), 0.43(95% CI 0.36–0.51), 0.39(95% CI 0.36–0.41), 0.54(95% CI 0.49–0.62), and 0.46(95% CI 0.43–0.49) of developing oesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers, respectively (P < 0.001). Patients on ranitidine compared to omeprazole had ORs of 0.62(95% CI 0.52–0.72), 0.58(95% CI 0.49–0.68), 0.81 (95% CI 0.76–0.86), 0.68(95% CI 0.60–0.76), and 0.66(95% CI 0.62–0.70) of developing oesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers respectively (P < 0.001).

Conclusions: Use of ranitidine was not associated with an increased odds of developing gastrointestinal malignancies compared to omeprazole or famotidine use.

Introduction

Histamine-2-receptor antagonists (H2RA) are commonly used medications for the treatment of gastrooesophageal reflux disease (GORD), as well as symptoms of dyspepsia and peptic ulcer disease.[1,2] There are four H2RAs available in the United States, including cimetidine (Tagamet®, SmithKline Beecham, among others), ranitidine (Zantac®, GlaxoSmithKline, London, England; among others), famotidine (Pepcid®, Merck & Co. Inc, Kenilworth, New Jersey, USA.among others), and nizatidine (Axid®, Eli Lilly and Company, Indianapolis, Indiana, USA. among others). H2RAs are historically among the highest revenue-generating medications, with Tagamet and Zantac being among the earliest billion dollar drugs during the 1980s. As anti-acid medications, H2RAs lower gastric acid secretion via competitive inhibition of histamine at the H2 receptors on the surface of the parietal cells.[3] Since the secretion of acid by the stomach depends on the binding of either gastrin, acetylcholine, or histamine to their respective receptors, blocking acetylcholine or histamine receptors on parietal cells, or gastrin receptors on enterochromaffin-like (ECL) cells, leads to a reduction in gastric acid output.[4,5] Thus, H2RAs are able to inhibit gastric acid secretion that follows vagal stimulation (via gastrin and acetylcholine), in addition to histamine.[6] The various H2RAs demonstrate similar pharmacokinetic profiles with minor individual variations. In ranitidine, specifically, peak plasma concentration is achieved within 1~2 hours after oral administration, which is not influenced by the presence of food in the stomach.[7] Mean bioavailability is approximately 50%, and hepatic clearance is 73% after oral ingestion. The mean elimination half-life of ranitidine is about ~3 hours but is dependent on glomerular filtration rate (GFR).[8]

In 2019, the United States Food and Drug Administration issued a statement in response to a citizen petition that N-nitrosodimetyhlamine (NDMA) had been detected in ranitidine above the accepted daily intake (ADI) levels of 0.096 μg. Consequently, a complete removal of ranitidine products from the market was ordered.[9] Although human data are scarce, the relationship between ranitidine and cancer has been studied in animal models, in which ranitidine has been shown to cause DNA fragmentation of the liver and gastric mucosa in mice.[10] As a member of the N-Nitrosamines, NDMA is a known animal carcinogen which is well studied in murine models and has been shown to cause tumours of various gastrointestinal organs including the liver, colon, pancreas, and stomach.[11,12] NDMA's mechanism of oncogenesis is primarily via its metabolism to methyldiazonium by cytochrome P-450 in the liver, causing mutations through alkylation of end-organs.[13,14] This mechanism of action has been well established in rat models, and has been shown to also be preserved in primates, including humans as well.[15] Given the wide use of H2RAs, and patients' as well as prescribers' apprehension about post-utilisation of ranitidine, we aimed to investigate whether chronic use of ranitidine confers an increased risk of developing gastrointestinal malignancies as compared with famotidine (another H2RA), and omeprazole (a PPI).

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