Seoul, Korea—In 2020, the FDA asked manufacturers to remove from the market all products containing ranitidine, a histamine-2 receptor antagonist (H2RA) that has been widely used to treat gastroesophageal reflux disease and peptic ulcer disease.

The interim evaluation was of the 2023 Southern Hemisphere influenza vaccine formulation, which is similar to that now being administered in the Northern Hemisphere, was conducted using data from five countries.

The action was especially significant because in the United States, more than 14 million ranitidine prescriptions were issued annually from 2013 to 2018. In 2018, ranitidine was the third most prescribed gastrointestinal medication. The FDA said that some ranitidine medications contained N-nitrosodimethylamine (NDMA), a known human carcinogen, and that those NDMA concentrations increased over time when the products were stored at temperatures above room temperature.

Despite the fear that consumers had been exposed to unacceptable levels of the carcinogen, a new large study has suggested that a history of ranitidine use is not associated with an increased risk of cancer compared with other H2RAs. The researchers from several Korean and U.S. universities, including University of California Los Angeles, Columbia University, and Stanford University, are calling for further research on the long-term effects of ranitidine on cancer development.

The cohort study included nearly 1.2 million people from 11 large databases across Europe, North America, and Asia. Despite past concerns, ranitidine use was not associated with an increased risk of esophageal, stomach, colorectal, or 13 other subtypes of cancer. The results were published in the Journal of the American Medical Association Network Open.

“Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern,” the authors wrote.

In response, the study team sought to examine the comparative risk of cancer associated with the use of ranitidine versus other H2RAs. The new-user active comparator international network cohort study was conducted using three health claims and nine electronic health record databases from the U.S., the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. The participants were aged at least 20 years with no history of cancer and used H2RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April 2021 to September 2021.

The main exposure was the use of ranitidine compared with other H2RAs, including famotidine, lafutidine, nizatidine, and roxatidine. The primary outcome was defined as incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancers except thyroid cancer, 16 cancer subtypes, and all-cause mortality.

Of the study participants, 909,168 individuals were identified as new users of ranitidine, and 274,831 people were identified as new users of other H2RAs. The groups were similar with mean ages in the late 50s, and slightly more than one-half were women.

The results indicated that crude incidence rates of cancer were 14.30 events per 1,000 person-years (PYs) in ranitidine users and 15.03 events per 1,000 PYs among other H2RA users. After propensity score matching, researchers determined that cancer risk was similar in ranitidine compared with other H2RA users (incidence, 15.92 events per 1,000 PYs vs. 15.65 events per 1,000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration.

“Given the worldwide popularity of ranitidine, exposure of several populations to NDMA and the potential risk of cancer development are important epidemiological concerns, and cancer screening may be required in individuals with previous prolonged exposure to ranitidine,” the authors concluded. “However, the risk of cancer among individuals who used NDMA-contaminated ranitidine has not been fully evaluated. Although some studies have attempted to address this issue, the results are probably underpowered and lack generalizability due to using a single data source. Hence, a large-scale, multinational, multicenter cohort study was conducted to determine whether ranitidine use was associated with increased cancer risk.”

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