Oops! So sorry about that, Zantac…

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An influential study linking a popular heartburn drug to cancer has been retracted after the authors concluded that their finding was a testing error, writes MedicalBrief. Marketed here as Zantac, Ultak, Ranihexal, and Ranitidine, the medicine was withdrawn as a precautionary move by US and European regulators, while in South Africa four manufacturers withdrew the product and the SA Health Products Regulatory Agency (SAHPRA) advised pharmacies to immediately stop dispensing it.

RetractionWatch reports that the 2016 article, in Carcinogenesis, was the key citation in a 2019 petition to the US Food and Drug Administration urging that ranitidine be recalled. It also played a role in an ongoing class action lawsuit against the makers, claiming that ranitidine caused cancer in more than 100,000 plaintiffs.

The FDA has been investigating contamination of ranitidine and a related drug with NDMA, a known human carcinogen at high doses. On 1 April, 2020, the agency announced that, although its tests did not find concerning levels of NDMA in “many” of the samples it tested, it was recalling all products that contain ranitidine,

The paper in Carcinogenesis, Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine, was written by a pair of researchers at Syracuse and Stanford universities. It received a massive amount of coverage in the global media.

Retraction notice

But as the retraction notice states, the FDA has found that the connection between ranitidine and NDMA that the authors reported might have resulted from issues with the instruments they used to test their samples:

“This article is being retracted at the request of the authors. Recent research (1) has identified the potential for an analytical artefact associated with the use of gas chromatography that could have contributed to the levels of N-nitrosodimethylamine (NDMA) measured in urine samples containing ranitidine in this study. Given this artefact, the authors have informed the journal that their NDMA measurements are not reliable.”

The authors, Teng Zeng and William Mitch, also have corrected a similar article in Environmental Science and Technology from 2015, titled Contribution of N-Nitrosamines and Their Precursors to Domestic Sewage by Greywaters and Blackwaters. According to that notice:

“Our study involved the measurement of N-nitrosamines, and their chloramine- and ozone-reactive precursors in different greywaters (e.g., laundry waters and sink waters) and blackwaters (e.g., urine and feces) contributing to sewage. On the basis of previous research suggesting that the pharmaceutical, ranitidine, serves as a chloramine-reactive precursor for N-nitrosodimethylamine (NDMA), our study included the collection of one urine and one fecal sample from each of two volunteers after the consumption of one 150 mg tablet of ranitidine. Our results indicated the occurrence of NDMA in the two urine samples collected after consumption of ranitidine, but not in the five samples collected without ranitidine consumption. We did not detect NDMA in the fecal samples. We had employed gas chromatography mass spectrometry (GC/MS) to measure NDMA. GC/MS has been a standard technique for the analysis of NDMA in water and wastewater samples by EPA Method 521(1) and by the U.S. Food and Drug Administration (FDA) for the analysis of NDMA in pharmaceuticals as recently as January 25, 2019.

“However, research has since identified the potential for an analytical artifact that could have contributed to the levels of NDMA measured in urine samples containing ranitidine in our study. Specifically, research has demonstrated that ranitidine is thermally unstable, and can convert to NDMA under high temperature conditions, such as might be encountered within GC injection ports.(3) For our GC/MS method, the injection port temperature started at 37 °C but was ramped to 230 °C over the first 20 s after injection. Unfortunately, given the potential for this analytical artifact, our NDMA measurements within urine samples collected after consumption of ranitidine are not reliable, since NDMA could have been formed during the sample analysis from any ranitidine present in the urine. Although the detection of NDMA in these specific urine samples was not reliable, this does not affect the conclusions of the study, since we did not conclude that ranitidine consumption was associated with an important contribution of NDMA or its chloramine- or ozone-reactive precursors to sewage.”

South African situation

SAHPRA announced in October last year that Cipla Medpro, GlaxoSmithKline, Sandoz and Pharma-Q had all recalled their ranitidine products in South Africa, while Biotech Laboratories and Gulf Drug Company had placed batches under quarantine. JSE-listed Aspen Pharmacare announced that it had been forced to restate its financial results for the year to June and write down the value of its heartburn medicine Zantac by R719m.

SAHPRA said at the time that 20 companies were affected in South Africa. Spokesperson Mlungisi Wondo, said, “We told them not to release any products they are having and then also quarantined with companies that were affected. Sandoz decided to recall on their own immediately. We don't want to release the products until we know the root cause.”

 

Full RetractionWatch report (Open access)

 

See also from the MedicalBrief archives:

 

More countries and companies recall heartburn drug Zantac


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