Research conducted by MD Seng Chan You at Yonsei University College of Medicine, Korea, studied the risk of cancer associated with the use of the drug ranitidine compared to other histamine-2 receptor antagonists (H 2 RA) using a large-scale cohort study method in multiple countries.
The results of research were published in JAMA Network Open.
Ranitidine: what are the real risks?
In the article “Ranitidine Use and Incident Cancer in a Multinational Cohort,” researchers state that despite contamination with a probable human carcinogen N-nitrosodimethylamine (NDMA) found in ranitidine, there was no statistically significant evidence that exposure to drug was associated with an increased risk of cancer.
In a statement on the findings the authors say: “In this cohort study including 1,183,999 individuals from 11 large databases across Europe, North America and Asia, the risk of cancer among ranitidine users did not differ from that of of other H 2 RA . Ranitidine use was not associated with an increased risk of esophageal, gastric, or colorectal cancer or 13 other cancer subtypes.”
The data provided in their study refutes this finding claim in some significant ways. First, the actual group was much smaller.
To compare ranitidine use to available alternatives within cohorts in a 1:1 ratio, the actual data used for the study’s primary analysis included 434,812 individuals from four databases, half of whom were exposed to ranitidine.
One such database, IQVIA US Ambulatory Electronic Medical Research (AmbEMR), has 381,628 individuals, making up the majority of the primary analysis, and has the shortest follow-up period of ranitidine users at 2.61 years.
Columbia University Irving Medical Center (CUIMC) data warehouse databases (average follow-up of 3.6 years), NHIS-NSC, Korea National Health Insurance System-National Sample Cohort (NHIS- NSC) with an average follow-up duration of 4.5 years and the Spanish Information System for Research in Primary Care (SIDIAP) with an average follow-up duration of 5.8 years.
A subgroup meta-analysis was provided with the excluded cohorts and the numbers were reduced to correspond to the lower rates of local use of alternatives to ranitidine. In the case of the UK’s IQVIA Medical Research Data (IMRD), the number of ranitidine users was reduced from 178,298 to just 633 individuals.
While the hazard ratio (HR) in 16 different cancers in the primary study of four cohorts over four different follow-up durations was 1.04 overall, some individual cancer types showed a more significant HR.
The authors stated that ranitidine use was not associated with an increased risk of cancer of the esophagus (HR 1.08) or stomach (HR 1.17), although an 8% increase in events and 17% seems significant.
The authors said that ranitidine was not associated with an increased risk in 13 other cancers such as leukemia (HR 1.12) and gallbladder/biliary tract cancer (HR1.14), although increases of 12% and of 14% appear significant.
It is unclear how the rates of endometrial cancer of the uterine body (HR 1.20) and ovary (HR 1.26) were not considered above the threshold for significant event associations, especially in a study with such a short term.
It would be interesting to know the age ranges of women with these events since NDMA can interfere with DNA replication during cell division, something that is more likely to occur in the tissues of the ovaries and uterine body in reproductive age, but such data were excluded from the study.
Exposures to carcinogens are known to contribute to disease formation in later life even after the source of exposure has been removed, requiring a long-term study, which is why the drug was withdrawn from the market in the first place.
Ranitidine, sold under the brand name Zantac, was once widely used to treat conditions such as heartburn and peptic ulcers, but was pulled from the market in 2020 at the request of the FDA due to contamination with NDMA.
The FDA investigation found that factors such as heat and time since ranitidine was manufactured led to higher levels of NDMA. These conditions may increase the level of NDMA in the ranitidine product above the acceptable daily intake limit.
NDMA is a DNA-damaging agent that creates 3-methyladenine, which can interfere with DNA copying. Damaged DNA causes mutations that cause cancer, which can take many years to develop.
NDMA exposure has been specifically linked to childhood cancer rates in a real-world scenario. The Olin Corporation chemical manufacturing plant, now a chemical superfund site, in Wilmington, MA, has exposed local residents to high levels of NDMA through drinking water for several years. The exposure was discovered only through the unusual group of 22 children in a city with fewer than 22,000 people who developed cancer.
The drinking water was eventually tested, and NDMA was identified in a rare case where the isolation of a single type of prolonged chemical exposure could be linked to health consequences.
MIT researchers continued studies in mice and determined that childhood cancer rates likely began in the womb when cell division was highest. They also found an interesting pivot point for NDMA’s effects that depended on levels of the Alkyladenine DNA glycosylase (AAG) enzymes.
Excessive cell division causes cancer when AAG is low compared to cell death when AAG is high. Humans can vary up to 10-fold in their AAG levels, requiring that any study of NDMA’s effects include signals of degenerative disease, something missing in the current study.
First approved for U.S. markets in 1983, ranitidine (Zantac) was one of the first drugs to reach $1 billion in sales and went on to generate $4 billion in annual sales before being withdrawn from the market.
Several pharmaceutical companies sold prescription, over-the-counter, brand-name, or generic versions of the drug before the FDA advised consumers to discard any ranitidine products. The recall damaged the reputation and stock value of several companies, and they have since battled litigation and liability issues.
The Zantac brand has been reformulated as Zantac 360º OTC and now contains famotidine, one of the FDA-approved non-NDMA-forming RA H 2 and ranitidine was compared in the present study.
It’s unclear why the researchers chose to study ranitidine, a drug that is currently off the market and unlikely to return. In a statement about the limitations of the study the authors state: “The study period was relatively short and may underestimate the cancer risk associated with long-term use of ranitidine,” and yet they are still able to conclude that their results “…do not support proactive cancer screening or surveillance among individuals previously exposed to ranitidine.”
Previously, it was revealed that a substance that could cause cancer has been found in some ranitidine-based heartburn and ulcer medications, including the brand-name drug Zantac, and the source of this contamination is being investigated. study, says the U.S. Food and Drug Administration.
Although preliminary testing has found low levels of the nitrosamine impurity N-nitrosodimethylamine (NDMA) in some ranitidine products, the FDA said that doesn’t mean patients taking the drugs should stop using them now.
NDMA is the same contaminant found in many brands of blood pressure and heart failure medicines over the past year, leading to recalls.
Patients taking prescription ranitidine and wish to stop using it should discuss alternatives with their doctor, the FDA advised. Those taking over-the-counter (OTC) ranitidine may be switched to other OTC medicines.
Several drugs are approved for the same or similar uses, the FDA noted.
NDMA is an environmental contaminant found in water and foods, including meats, dairy products and vegetables. It is classified as a probable human carcinogen.
“Drug impurities remain a major concern nationwide,” said Dr. David Robbins, associate chief of endoscopy at Lenox Hill Hospital in New York City. “While Zantac may prove safe in the long term, this latest statement adds to confusion and concern, so my interim advice to patients is simple: switch to another drug… and, of course, confirm with your doctor the need for an antacid. ”
The FDA said it is evaluating whether the low levels of NDMA in ranitidine pose a risk to patients and will release that information as it becomes available.
Sanofi, maker of Zantac, did not respond to a request for comment.
Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said the FDA is working with international regulators and industry partners to find out where the contamination originated.
“The agency is examining the levels of NDMA in ranitidine and evaluating any possible risks to patients,” it said in a press release. “The FDA will take appropriate action based on the results of the ongoing investigation.”
Large amounts of NDMA may pose a risk, but the levels of NDMA in ranitidine found in preliminary tests barely exceed the amounts found in common foods, according to the FDA.
Ranitidine decreases the amount of acid created by the stomach. Over-the-counter ranitidine is approved to prevent and relieve heartburn, while prescription ranitidine is approved for numerous uses, including the treatment and prevention of stomach and intestinal ulcers and the treatment of gastroesophageal reflux disease.
Similar contamination in heart medicines is also being studied.
“The FDA has been studying NDMA and other nitrosamine impurities in blood pressure and heart failure drugs called angiotensin II receptor blockers (ARBs) since last year,” Woodcock said. “In the case of ARBs, the FDA has recommended numerous recalls because it has discovered unacceptable levels of nitrosamines.”
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