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Concerns that trace amounts of nitrosamine compounds in the H2 inhibitor drug ranitidine (Zantac) could cause cancer are unfounded, examination of health records for millions of people suggested.

Among some 65 million individuals with longitudinal records in the -- including about 1.6 million who had taken ranitidine and 3.4 million users of a different H2 inhibitor, famotidine, for which nitrosamine contamination is not known to be an issue -- overall incidence of cancer was lower in the ranitidine users than in those who had taken famotidine (26.4% vs 31.1%), according to Nabeeha Mohy-ud-din, MD, of Allegheny Health Network in Pittsburgh, and colleagues.

Risk of cancer appeared significantly lower with ranitidine versus famotidine for most individual cancers as well, with odds ratios of 0.54 to 0.99 and 95% confidence intervals below 1.0 for cancers of the colon/rectum/pancreas, lung, bladder, uterus, prostate, breast, and liver. Rates of malignant melanoma were essentially equal, the group reported in an abstract accepted for presentation at the cancelled .

When the analysis was restricted to individuals without major cancer risk factors such as smoking, obesity, and family history, there was no difference at all in cancer rates in the ranitidine and famotidine users (OR 1.01).

Unadjusted data showed substantially higher rates of cancer among users of either drug compared with the roughly 60 million non-users in the Explorys database, in whom cancer diagnoses were recorded for 13%. But cancer risk factors were markedly more common for the H2 inhibitor users. For example, 34% of ranitidine users and 38% of those taking famotidine were older than 65, compared with 24% of the "general population." Similarly, about 75% of users of either drug had significant smoking histories versus 28% of non-users. Dramatic differences were also seen for obesity and alcohol use.

The question of ranitidine and cancer first emerged last year as part of broad revelations concerning trace contamination of various drugs with nitrosamine compounds such as N-nitrosodimethylamine (NDMA). Many of these substances are considered probable human carcinogens.

Initially, NDMA was found in certain generic versions of valsartan, an angiotensin receptor blocker (ARB), and then some other members of this drug class. Many (but not all) were subject to FDA-mandated recalls. It was never definitively determined whether the contamination arose from particular manufacturing processes or simply failed quality control. Reports of nitrosamines in some samples of metformin emerged as well, but the FDA .

Last summer, NDMA was found in ranitidine. As with the ARBs, it initially appeared confined to certain generic products, but further study revealed that NDMA could develop in the packaged drug products while on shelves and in medicine cabinets. That discovery prompted the FDA on April 1, 2020, to request that all ranitidine products including branded Zantac be withdrawn from the market.

The FDA has generally maintained that nitrosamine levels in ARBs and metformin are too low to cause significant cancer risk, and a database analysis of valsartan bore this out. At first, the FDA said the same for ranitidine, but the revelation that NDMA levels increased during storage to levels above the agency's specified daily intake limit was decisive.

Limitations to the Explorys database analysis included lack of reported data on the extent of individuals' use of ranitidine or famotidine. Also, records in the database could be inaccurate, and the retrospective design means that unmeasured confounders could have influenced the findings.

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