Ranitidine is a histamine-2 blocker, which decreases the amount of acid created by the stomach. Prescription ranitidine is approved for multiple indications, including treatment and prevention of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease. The FDA and EMA investigation also led to the detection of N-nitrosodimethylamine (NDMA) levels in some Ranitidne products. Recent investigation: NDMA is a probable human carcinogen (a substance that could cause cancer). In 2019, FDA became aware of laboratory testing that found NDMA in ranitidine. Low levels of NDMA are commonly ingested in the diet, for example NDMA is present in foods and in water. These low levels would not be expected to lead to an increase in the risk of cancer. However, sustained higher levels of exposure may increase the risk of cancer in humans. The conducted laboratory tests found NDMA in ranitidine at low levels.

1. Nitrosamine impurities traces in Ranitidine
Introduction:
Ranitidine is a histamine-2 blocker, which decreases the amount of acid created by the stomach.
Prescription ranitidine is approved for multiple indications, including treatment and prevention
of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease. The
FDA and EMA investigation also led to the detection of N-nitrosodimethylamine (NDMA)
levels in some Ranitidne products.
Recent investigation:
NDMA is a probable human carcinogen (a substance that could cause cancer). In 2019, FDA
became aware of laboratory testing that found NDMA in ranitidine. Low levels of NDMA are
commonly ingested in the diet, for example NDMA is present in foods and in water. These low
levels would not be expected to lead to an increase in the risk of cancer. However, sustained
higher levels of exposure may increase the risk of cancer in humans. The conducted laboratory
tests found NDMA in ranitidine at low levels. At the time, the agency did not have enough
scientific evidence to recommend whether individuals should continue or stop taking ranitidine
medicines, and continued its investigation and warned the public in September 2019 of the
potential risks. The new FDA testing and evaluation prompted by information from third-party
laboratories confirmed that NDMA levels increase in ranitidine even under normal storage
conditions, and NDMA has been found to increase significantly in samples stored at higher
temperatures, including temperatures the product may be exposed to during distribution and
handling by consumers. The testing also showed that the older a ranitidine product is, or the
longer the length of time since it was manufactured, the greater the level of NDMA. These
conditions may raise the level of NDMA in the ranitidine product above the acceptable daily
intake limit. The agency is taking this action because FDA laboratory testing results show that

2. levels of NDMA in ranitidine may increase to unacceptable levels over time. The tests also
show NDMA levels increase in some ranitidine products when the drug is exposed to higher
than room temperatures. Based on these findings, FDA has determined that many currently
marketed ranitidine products could expose consumers to unacceptable health risks. All
ranitidine products, including the oral liquid/syrup, will be withdrawn by their manufacturers
and will not be available on the U.S. market. As a result of this immediate market withdrawal
request, ranitidine products will not be available for new or existing prescriptions or OTC use in
the U.S.
EMA’s human medicines committee (CHMP) has recommended the suspension of all ranitidine
medicines in the EU due to the presence of low levels of an impurity called N-
nitrosodimethylamine (NDMA). NDMA is classified as a probable human carcinogen based on
animal studies. It is present in some foods and water supplies and is not expected to cause harm
when ingested at very low levels. However, NDMA has been found in several ranitidine
medicines above levels considered acceptable, and there are unresolved questions about the
source of the impurities. There is some evidence that NDMA may form from the degradation of
ranitidine itself with increasing levels seen over its shelf life. It is not clear whether NDMA can
also be formed from ranitidine inside the body. Some studies suggest that it can while others do
not. Given the uncertainties, the CHMP has recommended a precautionary suspension of these
medicines in the EU. This is because national authorities have recalled them as a precaution
while the EMA review was ongoing. EMA has also recommended conditions for lifting the
suspension of ranitidine medicines, including requirements for companies to provide more data.
Since 2018 NDMA and similar compounds known as nitrosamines have been detected in a
number of medicines, with EU regulators taking action to identify possible sources of the
impurities and set strict new requirements for manufacturers..
Conclusion:
FDA has determined that many currently marketed ranitidine products could expose
consumers to unacceptable health risks. EMA will be continuously working with national
authorities, EDQM, the European Commission and international partners to make sure that
effective measures are taken to prevent the presence of these impurities in medicines.
References:
1. FDA update on ranitidine products in market, available at: https://www.fda.gov/news-
events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market
2. FDA Q&A NDMA impurities in ranitidine, available :https://www.fda.gov/drugs/drug-
safety-and-availability/questions-and-answers-ndma-impurities-ranitidine-commonly-
known-zantac
3. FDA updates on ranitidine , available at:https://www.fda.gov/drugs/drug-safety-and-
availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine
4. Ranitidine containing low level of NDMA, available at:
https://www.ema.europa.eu/en/medicines/human/referrals/ranitidine-containing-
medicinal-products