There is a fresh twist in the ranitidine saga as a new study from South Korea, published in the Nature journal, has delinked it from cancer in line with some other scientific evidence generated so far.
The latest study is based on an analysis of over 25,000 patients. Half of them had taken ranitidine for up to six years and the rest had taken a ranitidine-like medicine.
The study suggested that the use of ranitidine was not associated with the overall cancer risk and major individual cancers. “The higher cumulative exposure to ranitidine did not increase cancer risk,” it said.
In 2019, ranitidine, a popular drug to treat peptic ulcer & gastroesophageal, reflux disease and heartburn & indigestion, was found to have unacceptably high levels of a carcinogen compound — NDMA (N-Nitrosodimethylamine) — and was banned in several countries.
However, various brands of this molecule are allowed to be sold in the country even though it was dropped from the recently-released National List of Essential Medicines (NLEM). The list contains drugs that are comparatively cost-effective and are aligned with current treatment guidelines.
There is a caveat, though. Given the insufficient follow-up period, these findings should be interpreted carefully, the report added.
Ranitidine, manufactured by several major and small drug makers in India, has been in use for nearly 45 years.
Global concern
NDMA is a volatile chemical belonging to the nitrosamine class of compounds and is a by-product of manufacturing processes involving alkylamines, which reaches air, water and soil.
Human exposure to NDMA may occur through tobacco smoke, food items, especially nitrite-preserved foods such as cured meats and various household goods. It can also form in the stomach endogenously during the digestion of alkylamine-containing foods at very low levels.
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It has been well established that NDMA is a carcinogen compound in animals and the International Agency for Research on Cancer (IARC) classifies it as a possible carcinogen for humans.
Senior pharmacologist Dr Santanu Tripathi pointed out that NDMA is formed in ranitidine Active Pharmaceutical Ingredient (API) because of an intermolecular degradation reaction between ranitidine molecules that occurs primarily in a solid state even though the exact reaction mechanism is unknown.
In 2019, after an alert by the US Food and Drug Administration (USFDA), drug regulators in some countries concluded that the ranitidine molecule itself was capable of generating NDMA while some others linked it to impurities in the API.
The USFDA, after finding that the NDMA levels in some ranitidine products increase with time and temperature and pose a risk to consumers, ordered the withdrawal of all ranitidine products from the US market.
Ranitidine in India
The molecule continues to be sold in India under the brand names Aciloc, Zinetac and Rantac even though it was removed from the NLEM in September 2022.
Senior gastroenterologist and medical researcher from Kerala, Dr Rajeev Jayadevan, pointed out that ranitidine is a cheap and effective remedy for acid-related digestive problems of the stomach.
The cost per day is less than one-fifth of equivalent doses of proton pump inhibitors of which various types are popular in the current worldwide market, he said.
For a patient in India, it costs less than Rs 2 per day, according to Jayadevan, and the cost advantage of this medication should not be overlooked.
“Doctors across India and elsewhere, working in general practice as well as in speciality gastroenterology practice, anecdotally, had only good experience with this drug, which, by the way, lacks the glamour and promotion of its more expensive alternatives,” he stressed.
Jayadevan also underlined that there has been no clinical observation to back up the concern, which was first flagged by the USFDA.
“The cancer risk with this drug remains largely a theoretical concern, which has not been proven by any scientific studies,” he said.
Cancer in humans has not been reported conclusively so far during the past 45 years of use of ranitidine and the recent Korean study is further proof of its safety, said Jayadevan, adding that the concerns about ranitidine appear exaggerated at this time and lack any clinical or research evidence to substantiate the claims against it.
There is a worry, though
Tripathi, however, said that while the presence of NDMA and many of its related compounds — together called nitrosamines — has been a worry, its presence in some medicinal products and substances is a relatively recent phenomenon.
It all started with a sartan-valsartan ( a drug used for hypertension), and then a host of others fall in line — ranitidine, metformin and rifampicin among others.
Worryingly, in India, he said, the Central Drugs Standard Control Organisation is not known to have responded enough to this crisis and has not even set a critical safe limit on medicinal products.
“As far as I know, the statutory drug testing labs in India do not have high-end analytical equipment for detection of nitrosamines impurities in drug samples,” Tripathi said.
Rajeev Singh Raghuvanshi, who has just assumed charge as the new Drugs Controller General of India (DCGI), has come from the Indian Pharmacopoeia Commission that sets standards for manufacturing and quality control of medicinal products.
“We can only hope the nitrosamines-related medicinal risks shall be addressed appropriately sooner,” Tripathi said.
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