People who took Ranitidine (Zantac) for at least a month were no more likely to develop cancer than people who used other histamine-2 receptor antagonists (H2RAs), according to a retrospective observational study with a multinational cohort.

After propensity score matching among more than 1.18 million individuals across seven countries, the incidence of cancer was 15.92 cases per 1,000 person-years for those who used ranitidine versus 15.65 cases per 1,000 person-years for those who used a different H2RA (HR 1.04, 95% CI 0.97-1.12), reported Chan Hyuk Park, MD, PhD, of Hanyang University College of Medicine in Guri, Korea, and colleagues in JAMA Network Open.

Ranitidine was one of the most common medications used to treat gastroesophageal reflux disease and peptic ulcer disease for several decades until the FDA found N-nitrosodimethylamine (NDMA) in some ranitidine medications in September 2019, the authors explained. NDMA is classified as a human carcinogen, and its consumption was found to be linked to increased Risk of cancer, particularly rectal cancer, in a 2011 prospective cohort study.

The FDA therefore requested withdrawal of all prescription and over-the-counter medications containing ranitidine in April 2020, a move mirrored by the European Medicines Agency.

As the third most prescribed gastrointestinal medication before its removal and more than 14 million ranitidine prescriptions written per year from 2013-2018, millions of people had potentially been exposed to the carcinogen. However, Park and colleagues found no increased risks for esophageal, stomach, colorectal, or 13 subtypes of cancer from ranitidine use, matching the findings of previous studies.

“The observed lack of significant association between ranitidine use and cancer risk may be due to low levels of NDMA in ranitidine products,” they wrote. “Although a large amount of NDMA would be harmful, NDMA levels in ranitidine found in preliminary tests conducted by the FDA barely exceeded the amount found in common foods.”

Reid M. Ness, MD, MPH, a gastroenterologist and associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee, told MedPage Today that he was not surprised by the findings, especially given the low NDMA concentrations found by the FDA in ranitidine samples.

“The study illustrates that the FDA is very watchful and effective in their efforts to eliminate any cancer risk from our available pharmacologic milieu,” he said. “There was great anxiety amongst our patients initially, both about the cancer risk posed by ranitidine and their medical therapy going forward,” but that anxiety has waned over time, he added. “If a patient expresses their concern about their ongoing cancer risk due to ranitidine, I can point to this study to reassure them.”

Ness and his colleagues transitioned patients taking ranitidine to alternative agents as quickly as possible after the NDMA contamination was first reported, but that response was complicated by a shortage in availability of alternative treatments for acid reflux, he said. Today, he typically treats patients who need an H2RA with famotidine (Pepcid AC) or nizatidine (Axid). He avoids cimetidine due to its higher incidence of side effects, and uses omeprazole (Prilosec) or another proton pump inhibitor (PPI) for patients who need more effective chronic therapy.

Lawrence R. Kosinski, MD, MBA, a retired gastroenterologist who is founder and chief medical officer for SonarMD, was similarly unsurprised by the findings, but recalled less concern among his patients in 2019-2020. He said GI physicians already use ranitidine rarely and generally prefer PPIs such as esomeprazole (Nexium). Given these findings, he “would reassure patients that ranitidine has always been a safe drug but there are better alternatives like the PPIs.”

Though Ness found these results reassuring, he expressed greater concern about patients’ risk of “serious allergic reactions, known side effects, and potentially devastating unintended interactions with other medications.” He said he advises providers to be “parsimonious and careful” in prescribing medications and mindful of these risks.

“Pharmacists must provide a robust double-check for potential issues surrounding changes to and maintenance of their clients’ medication profiles,” he added. “In this struggle to provide necessary medical therapy at minimum risk, the benefit of a vigorous electronic health record that can flag potential problems and issues cannot be overstated.”

For this study, Park and colleagues analyzed health claims data from health record databases from the U.S., the U.K., France, Germany, Spain, South Korea, and Taiwan. The population of 1,183,999 people included anyone ages 20 or older who used H2RAs for at least 30 days between January 1986 and December 2020, with at least 1 year without exposure prior to initiating H2RAs. The primary outcome was incidence of any cancer except non-melanoma skin cancer, with secondary outcomes looking at all cancers (except thyroid), 16 cancer subtypes, and all-cause mortality.

Three in four people in the study (n=909,168) had used ranitidine while the other 274,831 people had used a different H2RA — either famotidine, lafutidine, or roxatidine. The authors excluded anyone who used cimetidine or nizatidine since the former has been found to have anticancer effects and the latter also had reported NDMA contamination. They also excluded individuals with a history of cancer. The average age of ranitidine users was similar to that of other H2RA users (56 vs 58 years), with similar breakdowns in sex.

Crude cancer rates differed slightly between ranitidine and other H2RAs (14.30 vs 15.03 per 1,000 person-years), but the difference shrunk after propensity score matching.

No significant associations were found between ranitidine use and any secondary outcomes after calibration.

“The results from South Korean and Spanish administrative data sources or the meta-analysis from Asia demonstrated an increase in cancer risk (