Ranitidine and cancer risk: a scary though for many patients. Global market for ranitidine has been in turmoil last month, when firstly The U.S. Food and Drug Administration (FDA) recalled number of products containing ranitidine (including branded Zantac) and shortly afterward, in UK, The Medicines and Healthcare products Regulatory Agency (MHRA) recalled number of 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.
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. Higher-strength of ranitidine tablets (150mg and 300mg) are prescription only medication (POM).
Ranitidine cancer risk: the UK recalls
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 for about 4 weeks.
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 ppm (EMA, 2019).
At the end of November, the Department of Health and Social Care (DHSC) issues 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 alternative drug
- Investigation by the Medicines and Healthcare products Regulatory Agency (MHRA) into ranitidine is being conducted and is progressing
- Affected stock of ranitidine products is quarantined and not released to pharmacies
- Some stock of ranitidine products which is not affected by 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 and cancer: 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).
Ranitidine – NDMA – cancer link
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 NDMA is contained in fried bacon? (Park et al, 2015):
- fried bacon: 0.0067 ppm
- fat component of fried bacon: 0.0149 ppm
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] for ranitidine). 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 of NDMA level ppm.
Ranitidine – cancer risk: What is the advice for patients?
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.
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.
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
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