Ranitidine containing medicinal products

At the request of the European Commission, the European Medicines EMA triggered a review of ranitidine medicines after tests showed that some of these products contained an impurity called Nnitrosodimethylamine (NDMA). NDMA is classified as a probable human carcinogen (a substance that could cause cancer) on the basis of animal studies.

Ranitidine medicines are used widely to reduce the production of stomach acid in patients with conditions such as heartburn and stomach ulcers. They are available over-the-counter and on prescription. Patients who have any questions about their current treatment can speak to their doctor or pharmacist. There are several other medicines used for the same conditions as ranitidine that could be used as an alternative.

Ranitidine belongs to a class of medicines known as H2 (histamine-2) blockers, which work by blocking histamine receptors in the stomach and reducing the production of stomach acid. It is used to treat and prevent conditions caused by excess acid in the stomach such as heartburn and stomach ulcers. Ranitidine-containing medicines are authorised by national authorities and are available as tablets and injectable formulations (EMA, 2019).

In 2018, NDMA and similar compounds known as nitrosamines were found in a number of blood pressure medicines known as ‘sartans’, leading to some recalls and to an EU review, which set strict new manufacturing requirements for these medicines. In 2019, a nitrosamine impurity has been detected in a few batches of pioglitazone from one company and in batches of ranitidine.

The chemical is present in some foods and in water supplies but is not expected to cause harm when ingested in very low levels.

The review of ranitidine medicines was initiated on 12 September 2019 at the request of the European Commission, under Article 31 of Directive 2001/83/EC. The review will be carried out by the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which will adopt an opinion. The CHMP opinion will then be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU Member States. The EMA evaluated the data to assess whether patients using ranitidine are at any risk from NDMA and undertook to provide information about this (at the time of writing, no further information was made available) (EMA, 2019b).

The U.S. FDA has also been investigating NDMA and other nitrosamine impurities in blood pressure and heart failure medicines called Angiotensin II Receptor Blockers (ARBs) since last year. In the case of ARBs, the FDA has recommended numerous recalls as it discovered unacceptable levels of nitrosamines. According to the FDA, some ranitidine medicines, including some products commonly known as the brand-name drug Zantac, contain a nitrosamine impurity. The FDA is evaluating whether the low levels of NDMA in ranitidine pose a risk to patients (FDA, 2019a).

In 2019, the FDA announced that a voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., used to decrease the amount of acid created by the stomach, had taken place in relation to N-nitrosodimethylamine (FDA, 2019b).

EMA (2019a) EMA to provide guidance on avoiding nitrosamines in human medicines, European Medicines Agency, at: https://www.ema.europa.eu/en/documents/press-release/ema-provide-guidance-avoiding-nitrosamines-human-medicines_en.pdf  (accessed 6^th November 2019)

EMA (2019b) EMA to review ranitidine medicines following detection of NDMA. European Medicines Agency, at: https://www.ema.europa.eu/en/documents/referral/ranitidine-article-31-referral-ema-review-ranitidine-medicines-following-detection-ndma_en.pdf (accessed 6th November 2019)

FDA (2019a) Statement alerting patients and health care professionals of NDMA found in samples of ranitidine, US Food and Drug Administration at: https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine (accessed 6th November 2019)

FDA (2019b) FDA announces voluntary recall of Sandoz ranitidine capsules following detection of an impurity, US Food and Drug Administration at: https://www.fda.gov/news-events/press-announcements/fda-announces-voluntary-recall-sandoz-ranitidine-capsules-following-detection-impurity (accessed 6th November 2019)

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)