Ranitidine Use and Incident Cancer in a Multinational Cohort

Seng Chan You, Seung In Seo, Thomas Falconer, Chen Yanover, Talita Duarte-Salles, Sarah Seager, Jose D. Posada, Nigam H. Shah, Phung Anh Nguyen, Yeesuk Kim, Jason C. Hsu, Mui Van Zandt, Min Huei Hsu, Hang Lak Lee, Heejoo Ko, Woon Geon Shin, Nicole Pratt, Rae Woong Park, Christin G. Reich, Marc A. SuchardGeorge Hripcsak, Chan Hyuk Park*, Daniel Prieto-Alhambra

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
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Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020.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. 


To examine the comparative risk of cancer associated with the use of ranitidine vs other H2RAs. 

Design, Setting, and Participants: 

This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H2RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021. 


The main exposure was use of ranitidine vs other H2RAs (famotidine, lafutidine, nizatidine, and roxatidine). 

Main Outcomes and Measures: 

The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality. 


Among 1 183 999 individuals in 11 databases, 909 168 individuals (mean age, 56.1 years; 507 316 [55.8%] women) were identified as new users of ranitidine, and 274 831 individuals (mean age, 58.0 years; 145 935 [53.1%] women) were identified as new users of other H2RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H2RA users. After PS matching, cancer risk was similar in ranitidine compared with other H2RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 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. 

Conclusions and Relevance: 

In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H2RAs. Further research is needed on the long-term association of ranitidine with cancer development.

Original languageEnglish
Article numbere2333495
JournalJAMA network open
Issue number9
Publication statusPublished - 19 Sept 2023

Bibliographical note

This research was supported by a grant from the Korea Health Technology R&D Project
through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of
Korea (grant No. HI19C0143), and the National Research Foundation of Korea grant funded by the Korean
government (grant No. 2021R1C1C1005728). This research was supported by grant No. 22213MFDS486 from the
Ministry of Food and Drug Safety in 2022.


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