NEW HAVEN, CT – JANUARY 29, 2021 – Today the Journal of the American Medical Association (JAMA) Network Open published a study, “Analysis of ranitidine-associated N-Nitrosodimethylamine (NDMA) production under simulated physiologic conditions,” conducted by scientists at Valisure in collaboration with leading hospital researchers that illustrates how ranitidine may be a significant source of NDMA under a range of physiologically-relevant conditions. Specifically, under simulated gastric conditions, NDMA yield from a standard tablet of ranitidine was seen to increase with both rising nitrite and decreasing pH, to levels up to three orders of magnitude beyond established limits of exposure.

Initially scheduled for publication on January 10, 2020, the original, peer-reviewed manuscript also contained epidemiological data on the association between ranitidine and cancer. On January 9, 2020, the study was held prior to publication in light of requests that newly published chemical methods be employed and epidemiological data be further analyzed. In the following months, chemical analyses were rerun using the latest, FDA-recommended LC-MS methodology revealing the same ranitidine instability and this data is included in today’s JAMA Network Open study. In the intervening months, initial epidemiologic analyses were also updated but will appear in a separate study.

The authors of today’s JAMA Network Open study believe that both the chemistry and epidemiology regarding the potential carcinogenic nature of ranitidine are of high importance for public health and should be a part of the scientific and medical domain. Therefore, further chemical analysis was conducted by Valisure and added to the reanalyzed epidemiological data for a new study that is also being submitted to the pre-print server, MedRxiv, with the original title from January 2020 of “Ranitidine use, N-Nitrosodimethylamine (NDMA) production and variations in cancer diagnoses.”

The MedRxiv study, which evaluated 10,347 cancer patients, found that there is a significant association between the use of ranitidine and elevated diagnosis rates of breast, thyroid, bladder, and prostate cancers. The chemical data in this study built upon the findings in the JAMA Network Open paper, which found that at higher pHs the formation of NDMA was significantly elevated. The MedRxiv paper’s chemical analysis concluded that this rapid formation of NDMA appears to continue for extended periods of time if the ranitidine remains in gastric conditions, which is of particular concern for ranitidine because its use has been correlated with longer gastric emptying times.

“The data published today strongly supports decades of research that ranitidine is fundamentally unstable, can form NDMA in a variety of conditions including in the human body, and could be carcinogenic and toxic to humans,” said David Light, Founder & CEO of Valisure and an author on the papers. “These findings underscore the vital importance of additional quality assurance testing of on-market drug products.”

Valisure previously detailed its concerns regarding the carcinogenic nature of ranitidine in its September 2019 FDA Citizen Petition and reported its initial findings to the FDA in June of 2019. In April 2020, FDA requested manufacturers withdraw all prescription and over-the-counter ranitidine drugs from the market.

There is a growing body of epidemiologic evidence regarding ranitidine having the potential to cause cancer in humans. A 2008 study conducted at the Fred Hutchinson Cancer Research Center evaluated the three major histamine 2 receptor blockers, cimetidine, famotidine, and ranitidine, with regard to breast cancer risk. After evaluating over 3,000 individuals in a case-control study, the authors concluded that famotidine and cimetidine showed no association; however, ranitidine was significantly associated with a common form of breast cancer. In December of 2020, researchers from The University of Alabama at Birmingham released findings from a study on the positive association between ranitidine use and gastrointestinal cancers.

“Valisure detected NDMA in every brand and every dosage form of ranitidine that we tested whether over the counter or prescription and regardless of manufacturer,” said Dr. Kaury Kucera, Chief Scientific Officer of Valisure. “Valisure routinely tests for the presence of various carcinogens, including NDMA, in all our medications and it was through this routine analysis that Valisure identified ranitidine’s inherent instability and propensity to form high amounts of the probable human carcinogen NDMA. This appears to be a fundamentally different problem than NDMA contamination found in drugs like valsartan and metformin because it occurs in every brand of ranitidine and is inherent to the molecule itself.”

Global concern over NDMA escalated in 2018 when it was detected in the blood pressure drug valsartan; certain lots made by several manufacturers were contaminated and recalled. A similar situation occurred in 2020 for the diabetes drug metformin after Valisure identified NDMA contamination in some medication batches.

Epidemiological studies have also investigated valsartan use since the contamination event and so far, have produced no associations with any cancers in humans. The studies published today strongly underscore that the NDMA problem with ranitidine likely goes beyond contamination and is rooted in the fundamental instability of the drug which affects all products that contain it. Both a nitrite, “N”, and a dimethylamine group, “DMA”, are present on the ranitidine molecule and multiple studies have shown that the drug can directly form NDMA in a variety of conditions.

“Beyond Valisure’s tests, the presence of NDMA in ranitidine is supported by decades of scientific studies at institutions around the world starting as early as 1982. The data published today adds to a growing body of research that raises serious concern regarding ranitidine and its potential to form the potent carcinogen NDMA,” stated David Light. “We applaud the actions of FDA and numerous other authorities around the globe to recall ranitidine from the market. We look forward to continued collaboration with academia, industry, and government to help ensure the safety and quality of all medications.”

A website built and maintained by Valisure and hospital researchers from today’s studies was launched today and contains a broad collection of information and studies on ranitidine. Please visit www.ranitidineinfo.com.

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Media coverage:

The People’s Pharmacy: Is Zantac – Ranitidine and Cancer the Tip of the Iceberg?

HBW Pharma Intelligence: After Finding Nitrosamine In Ranitidine, US Firm Suggests Link To Higher Cancer Diagnosis Rates

Fierce Pharma: Valisure links ‘unstable’ Zantac and its ilk to carcinogen buildup, cancer risk

‍

NEW HAVEN, CT – JANUARY 29, 2021 – Today the Journal of the American Medical Association (JAMA) Network Open published a study, “Analysis of ranitidine-associated N-Nitrosodimethylamine (NDMA) production under simulated physiologic conditions,” conducted by scientists at Valisure in collaboration with leading hospital researchers that illustrates how ranitidine may be a significant source of NDMA under a range of physiologically-relevant conditions. Specifically, under simulated gastric conditions, NDMA yield from a standard tablet of ranitidine was seen to increase with both rising nitrite and decreasing pH, to levels up to three orders of magnitude beyond established limits of exposure.

Initially scheduled for publication on January 10, 2020, the original, peer-reviewed manuscript also contained epidemiological data on the association between ranitidine and cancer. On January 9, 2020, the study was held prior to publication in light of requests that newly published chemical methods be employed and epidemiological data be further analyzed. In the following months, chemical analyses were rerun using the latest, FDA-recommended LC-MS methodology revealing the same ranitidine instability and this data is included in today’s JAMA Network Open study. In the intervening months, initial epidemiologic analyses were also updated but will appear in a separate study.

The authors of today’s JAMA Network Open study believe that both the chemistry and epidemiology regarding the potential carcinogenic nature of ranitidine are of high importance for public health and should be a part of the scientific and medical domain. Therefore, further chemical analysis was conducted by Valisure and added to the reanalyzed epidemiological data for a new study that is also being submitted to the pre-print server, MedRxiv, with the original title from January 2020 of “Ranitidine use, N-Nitrosodimethylamine (NDMA) production and variations in cancer diagnoses.”

The MedRxiv study, which evaluated 10,347 cancer patients, found that there is a significant association between the use of ranitidine and elevated diagnosis rates of breast, thyroid, bladder, and prostate cancers. The chemical data in this study built upon the findings in the JAMA Network Open paper, which found that at higher pHs the formation of NDMA was significantly elevated. The MedRxiv paper’s chemical analysis concluded that this rapid formation of NDMA appears to continue for extended periods of time if the ranitidine remains in gastric conditions, which is of particular concern for ranitidine because its use has been correlated with longer gastric emptying times.

“The data published today strongly supports decades of research that ranitidine is fundamentally unstable, can form NDMA in a variety of conditions including in the human body, and could be carcinogenic and toxic to humans,” said David Light, Founder & CEO of Valisure and an author on the papers. “These findings underscore the vital importance of additional quality assurance testing of on-market drug products.”

Valisure previously detailed its concerns regarding the carcinogenic nature of ranitidine in its September 2019 FDA Citizen Petition and reported its initial findings to the FDA in June of 2019. In April 2020, FDA requested manufacturers withdraw all prescription and over-the-counter ranitidine drugs from the market.

There is a growing body of epidemiologic evidence regarding ranitidine having the potential to cause cancer in humans. A 2008 study conducted at the Fred Hutchinson Cancer Research Center evaluated the three major histamine 2 receptor blockers, cimetidine, famotidine, and ranitidine, with regard to breast cancer risk. After evaluating over 3,000 individuals in a case-control study, the authors concluded that famotidine and cimetidine showed no association; however, ranitidine was significantly associated with a common form of breast cancer. In December of 2020, researchers from The University of Alabama at Birmingham released findings from a study on the positive association between ranitidine use and gastrointestinal cancers.

“Valisure detected NDMA in every brand and every dosage form of ranitidine that we tested whether over the counter or prescription and regardless of manufacturer,” said Dr. Kaury Kucera, Chief Scientific Officer of Valisure. “Valisure routinely tests for the presence of various carcinogens, including NDMA, in all our medications and it was through this routine analysis that Valisure identified ranitidine’s inherent instability and propensity to form high amounts of the probable human carcinogen NDMA. This appears to be a fundamentally different problem than NDMA contamination found in drugs like valsartan and metformin because it occurs in every brand of ranitidine and is inherent to the molecule itself.”

Global concern over NDMA escalated in 2018 when it was detected in the blood pressure drug valsartan; certain lots made by several manufacturers were contaminated and recalled. A similar situation occurred in 2020 for the diabetes drug metformin after Valisure identified NDMA contamination in some medication batches.

Epidemiological studies have also investigated valsartan use since the contamination event and so far, have produced no associations with any cancers in humans. The studies published today strongly underscore that the NDMA problem with ranitidine likely goes beyond contamination and is rooted in the fundamental instability of the drug which affects all products that contain it. Both a nitrite, “N”, and a dimethylamine group, “DMA”, are present on the ranitidine molecule and multiple studies have shown that the drug can directly form NDMA in a variety of conditions.

“Beyond Valisure’s tests, the presence of NDMA in ranitidine is supported by decades of scientific studies at institutions around the world starting as early as 1982. The data published today adds to a growing body of research that raises serious concern regarding ranitidine and its potential to form the potent carcinogen NDMA,” stated David Light. “We applaud the actions of FDA and numerous other authorities around the globe to recall ranitidine from the market. We look forward to continued collaboration with academia, industry, and government to help ensure the safety and quality of all medications.”

A website built and maintained by Valisure and hospital researchers from today’s studies was launched today and contains a broad collection of information and studies on ranitidine. Please visit www.ranitidineinfo.com.

‍

Media coverage:

The People’s Pharmacy: Is Zantac – Ranitidine and Cancer the Tip of the Iceberg?

HBW Pharma Intelligence: After Finding Nitrosamine In Ranitidine, US Firm Suggests Link To Higher Cancer Diagnosis Rates

Fierce Pharma: Valisure links ‘unstable’ Zantac and its ilk to carcinogen buildup, cancer risk

‍