Nitrosamine Impurities Traces in Ranitidine

Nitrosamine impurities -A regulatory perspective
Nitrosamine Impurity: A Regulatory Perspective
July 6, 2020
Elemental Impurities: Risk Assessment and Significances
Elemental Impurities: Risk Assessment and Significances
July 8, 2020
Nitrosamine impurities traces in Ranitidine
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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 Ranitidine 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. They 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 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 are 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 the 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 a low level of NDMA, available at https://www.ema.europa.eu/en/medicines/human/referrals/ranitidine-containing-medicinal-products

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