The global market for ranitidine has been in turmoil in recent months, due to number of ranitidine recalls (including branded Zantac) by The U.S. Food and Drug Administration (FDA) in the US and shortly afterward, in UK. The Medicines and Healthcare Regulatory Agency (MHRA) recalled number of ranitidine products due to possible contamination with N-nitrosodimethylamine (NDMA), which has genotoxic and carcinogenic potential, a substance that could possibly cause cancer. Ranitidine – cancer scare was born.
Note: Ranitidine (the chemical) does not have carcinogenic potential, but NDMA, a contaminant, which was found in many ranitidine containing products (tablets).
Ranitidine is a commonly prescribed medication used mainly for the treatment of acid reflux and stomach ulcers. At a lower dose of 75mg per tablet, ranitidine can be purchased from a pharmacy or supermarkets (General Sale License – GSL). Higher-strength of ranitidine tablets (150mg and 300mg) are prescription-only medication (POM).
Ranitidine recalls in the UK
MHRA issued class 2 medicines recalls for various Zantac products (branded ranitidine) and some generic versions of ranitidine. Recalls included prescription only medication Zantac 150mg and 300mg, over the counter ranitidine containing products (75mg of ranitidine) including Zantac and many own branded ‘Heartburn & Indigestion’ remedies found in pharmacies and supermarkets. Lastly, ranitidine effervescent tablets 150mg and 300mg (Teva) and ranitidine oral solution (Rosemont Pharmaceutical) were also recalled.
Although not all generic versions of POM ranitidine 150mg and 300mg were affected by the recalls, quickly all ranitidine products became out of stock / pulled out from the market. At the present time (January 2020), ranitidine (POM and GSL) is out of stock.
All UK recalls were taken as a precautionary measure due to possible contamination with an impurity N-nitrosodimethylamine (NDMA).
Similarly, last year MHRA recalled Valsartan containing products (medication used in the treatment of high blood pressure and heart failure) from all UK pharmacies due to possible contamination with NDMA. The highest average NDMA contamination of Valsartan was found to be 75.4 parts per million, ppm (EMA, 2019). In the US, FDA advises to recall products, which contain more than 0.32ppm of NDMA.
Ranitidine: supply problems in the UK
A number of recalls which were issued for ranitidine products have been causing supply problems across the UK. At the end of November, the Department of Health and Social Care (DHSC) issued an update regarding ranitidine supply disruption with the following key messages:
- All ranitidine formulations are expected to be out of stock with no date for resupply
- New patients should not be started on ranitidine
- Current patients who have ranitidine as their repeated medication should be reviewed to choose an alternative drug
- An investigation by the Medicines and Healthcare products Regulatory Agency (MHRA) into ranitidine is being conducted and is progressing
- The affected stock of ranitidine products is quarantined and not released to pharmacies
- Some stock of ranitidine products which is not affected by the UK recalls exist in pharmacies and wholesalers, however, it is advised to reserve it only for patients for whom switching to alternative treatment is not possible
Ranitidine recalls: from the USA to the UK
The UK recalls of ranitidine products followed a similar situation from across the pond, where recalls for ranitidine / Zantac were issued in September 2019. Swiss and German regulatory agencies identified NDMA in samples of ranitidine (DHSC, 2019). FDA produced a statement in which they explained that some ranitidine products, including branded Zantac, were found to contain NDMA, as confirmed by results from laboratory tests. Although many US ranitidine products were recalled due to the potential presence of NDMA, some products recalled, for example, ranitidine hydrochloride tablets (150mg and 300mg) and ranitidine syrup (15mg/mL) were found to contain unacceptable levels of NDMA (FDA, 2019).
FDA removes all ranitidine products from the market
In its latest press release on 01/04/2020, FDA requested the removal of all ranitidine products from the US market. FDA explained that there is av evidence of an increase of NDMA over time in some ranitidine products, which are stored at higher than room temperatures. Increased temperature may result in a patient’s exposure to unacceptable levels of NDMA. Ranitidine will not be available to existing or new patients who need this medication on prescription in the US. Ranitidine will not be available to purchase over the counter in the US.
Why NDMA is a human carcinogen?
NDMA can be found in the water, certain foods, mostly smoked or cured meats and fish, dairy products and vegetables. The biggest source of human exposure to NDMA comes from drinking water (ATSDR, 1989). Exposure to NDMA in laboratory tests of animals confirmed that this compound is a carcinogen. When exposed to high daily doses of NDMA over several weeks, lab animals developed tumours, mainly in the liver and respiratory tract. Short term exposure of animals to air containing 16 parts per million (ppm) NDMA produces liver damage and death (ibid). Other examples of exposure in animals (ATSDR, N.D.):
- exposure to food containing NDMA (50 ppm) caused liver damage in rats (5 months)
- exposure to food containing NDMA (100 ppm) over 62-93 days caused death in rats
- exposure to water containing 5.5 ppm over 30 weeks caused death in rats
- exposure to water containing 20 ppm over 28 days caused liver damage in hamsters
- exposure to air containing NDMA (16 ppm) over 4 hour in three dogs caused death of one of the dog and two moribund (almost dead) (WHO, 2002)
Based on animal studies, NDMA is classified as a probable human carcinogen.
How much of NDMA was found in ranitidine?
Since the recalls, MHRA has not provided any further information. In its statement, the European Medicines Agency (EMA) informed that investigation is conducted and information on whether patients are at any risk from NDMA will be provided as soon as possible.
In the US, the FDA recommended to recall ranitidine products if the testing for NDMA is above the acceptable daily intake of (96 nanograms per day or 0.32 parts per million [ppm]). The results published so far by FDA show many ranitidine products containing NDMA above daily recommended intake with some results showing as high as 2.85 ppm of NDMA. No information has been published so far in the UK or Europe showing how much NDMA is present in ranitdine products.
How does NDMA contaminate ranitidine?
Based on previous recalls of valsartan drug last year due to contamination with NDMA, in the US, FDA suggested a number of causes of NDMA presence in ranitidine products (FDA, 2019):
- NDMA contamination can be formed during the manufacturing process due to processing conditions when certain types of raw materials are used.
- NDMA presence can be caused by the use of contaminated raw materials.
- Use of equipment between the production of drugs that have not been adequately cleaned.
Tests which are usually performed to check for purity of the final product are unlikely to detect NDMA, hence the scale of the contamination.
Ranitidine recalls: the advice for patients who take ranitidine?
Are patients at immediate risk of cancer?
There is no instant risk to patients from ranitidine or NDMA. Long term exposure to high doses of NDMA may cause cancer.
Patients should not stop taking ranitidine suddenly. Patients are advised to speak to their doctors in the first place to seek alternative treatment, should they wish to stop taking ranitidine. A number of drugs exist on the market which can be taken instead of ranitidine.
Ranitidine recalls: alternative options
Proton pump inhibitors (PPIs) such as omeprazole or esomeprazole, antacids (such as Gaviscon) and lifestyle changes can help with the management of heartburn (acid reflux) and can be considered as an alternative to ranitidine. You can learn more about ranitidine alternative drugs, which are available over the counter and on prescription in the post ‘14 best ranitidine alternative drugs‘.
I also discussed the effectiveness of omeprazole vs ranitidine in the following post: Ranitidine vs Omeprazole: which drug is better?
Is there a recall on ranitidine?
In the UK number of ranitidine products were recalled at the end of 2019, due to possible contamination with NDMA (a probable human carcinogen). This was a pharmacy level recall. Not all ranitidine products were recalled, however, at present, there is limited supply of ranitidine in the UK.
Is ranitidine the same as Zantac?
Zantac is a branded version of ranitidine. Both drugs are the same.
Is ranitidine a PPI?
Ranitidine is not PPI. Ranitidine belongs to a group of drugs called an H2-receptor antagonist (commonly called H2-blockers). H2 blockers have a different mechanism as compared to PPIs.
What is an alternative to Zantac?
Common drugs which are alternative to Zantac (ranitidine) include other H2-antagonists such as famotidine and cimetidine (not commonly used in the UK); proton pump inhibitors (PPIs) such as omeprazole and esomeprazole and antacids (least effective alternative).
Agency for Toxic Substances and Disease Registry (ATSDR), (1989). Toxicological Profile for n-Nitrosodimethylamine. Available at: https://www.atsdr.cdc.gov/phs/phs.asp?id=882&tid=173 and www.atsdr.cdc.gov/toxprofiles/tp141.pdf Accessed on 15/11/2019
Agency for Toxic Substances and Disease Registry, ATSDR, (N.D.). Public health statement. Available at: https://www.atsdr.cdc.gov/toxprofiles/tp141-c1.pdf Accessed on 12/12/2019
DHSC (2019). Ranitidine: all oral formulations – Supply Disruption Alert. Available at: https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAttachment.aspx?Attachment_id=103298 Accessed on 15/11/2019
European Medicines Agency, EMA (2019). Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group. Available at: https://www.ema.europa.eu/en/documents/referral/sartans-article-31-referral-chmp-assessment-report_en.pdf Accessed on 12/12/2019
FDA (2019). FDA is alerting patients and health care professionals to two voluntary recalls of ranitidine. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine#5dcd01d9bdd01 Accessed on 14/11/2019
FDA (2019). Questions and Answers: NDMA impurities in ranitidine (commonly known as Zantac). Available at: https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-ranitidine-commonly-known-zantac Accessed on 25/01/2020
Park, Jong-eun, Jung-eun Seo,1 Jee-yeon Lee,2 and Hoonjeong Kwon (2015). Toxicol Res. 2015 Sep; 31(3): 279–288. Available at: https://dx.doi.org/10.5487%2FTR.2015.31.3.279 Accessed on 12/12/2019
WHO (2002). Concise International Chemical Assessment Document 38. Available at: https://www.who.int/ipcs/publications/cicad/en/cicad38.pdf Accessed on 12/12/2019