Unraveling the timeline that led to over 7 pharma companies recalling their products off the market.
How did it start?
Valisure sent a petition to the FDA informing them of their discovery of extremely high levels of N-Nitrosodimethylamine NDMA, a probable human carcinogen, in every lot tested, across multiple manufacturers and dosage forms of Ranitidine.
The FDA released a statement communicating to industry that they have been informed that some Ranitidine medicines, including product commonly known as Zantac, contain impurity NDMA at low levels. The levels the FDA is finding in Ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.
The FDA announces the first voluntary recall of prescription Ranitidine capsules due to NDMA impurity found in the recalled medicine.
The FDA announce another voluntary recall of OTC Ranitidine tablets manufactured by Apotex Corp and labelled by Walgreens, Walmart and Rite-Aid. Low levels of the impurity NDMA were found. The FDA has informed health care professionals to not provide recalled products to patients. In addition, the FDA reiterates the progress of their investigation, and shares a test method for which regulators and industry should use to examine the levels of NDMA in Ranitidine. Note - This method does not require high temperatures.
The FDA state that the method used by the third-party lab is not suitable for testing Ranitidine because heating the sample generates NDMA. An alternative LC-HRMS test was suggested and used by the FDA who conducted their own analysis on a selection of products. The FDA share this method here.
The MHRA released a drug alert for GSK who recalled unexpired stock of Zantac prescription only medicines from pharmacies in the UK.
The FDA posted a second method for which manufacturers and regulators can use to detect and quantify NDMA in Ranitidine. This LC-MS/MS method uses more widely available technology than the LC-HRMS method posted originally. Link to the method is available here.
In addition, an Indian Generics company voluntarily recalls all prescription and OTC Ranitidine tablets and capsules manufactured by themselves. Their OTC medicines may also be labelled by retailers such as Walgreens, Walmart, CVS, Target and Kroger. Sanofi also voluntarily recalls OTC Ranitidine.
The MHRA released a drug alert for a UK Pharma Manufacturer who recalled unexpired stock from pharmacies due to possible contamination with an impurity.
An additional 3 pharma companies voluntarily recalled Ranitidine of which the FDA have issued an alert to health care professionals and patients.
FDA conducts laboratory analysis of Ranitidine and nizatidine products. Conclusion: FDA has determined that the levels of NDMA in Ranitidine and nizatidine are similar to the levels you would expect to be exposed to if you at common foods like grilled or smoked meats.
The FDA alerts patients and health care professionals of another voluntary recall by Aurobindo Pharma USA. This includes OTC, prescription and Ranitidine syrup because these products were found to have contained unacceptable levels of NDMA.
The FDA has advised companies to recall Ranitidine products if testing shows levels of NDMA above the acceptable daily intake of 96 nanograms per day or 0.32 ppm.
The FDA also reiterates that the NDMA levels found by themselves are similar to the levels a consumer would expect to be exposed to when eating common foods like grilled and smoked meats.
Two additional voluntary recalls of Ranitidine were announced by the FDA.
The MHRA released a drug alert for another two UK Pharma Companies who recalled all unexpired stock of Ranitidine Oral Solution and Ranitidine Tablets.
The MHRA released a drug alert for another four UK Pharma Companies who have recalled stock from pharmacies and retail stores due to possible contamination with an impurity.
Two repackagers voluntary recalls of Ranitidine were announced by the FDA because they main contain unacceptable levels of NDMA.
So, How Did Ranitidine Get Contaminated?
- Not all Ranitidine medicines marketed are being recalled.
- Some companies may have conducted additional testing to quantify the levels of NDMA, and where the levels are above acceptable daily intake, they issue a recall; however, some companies may choose to issue a recall without conducting testing and based only on the potential for NDMA to be present in the drug.
- The FDA has tested numerous Ranitidine products on the market and have found levels of NDMA that are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats.
- The FDA have also conducted tests that simulate what happens to Ranitidine after it has been exposed to acid in the stomach with a normal diet. The results of these tests indicate that NDMA is not formed through this process.
- Ranitidine and Nizatidine were both found to contain NDMA. The FDA has tested alternative drugs to Ranitidine and Nizatidine and have found the following alternatives to contain no NDMA. In addition, the manufacturing processes of these medicines indicate that they should not contain NDMA:
- Pepcid (Famotidine)
- Tagamet (Cimetidine)
- Nexium (Esomeprazole)
- Prevacid (Lansoprazole)
- Prilosec (Omeprazole)
- Consumers and patients can consider using the above alternative OTC products approved for their condition.
What Happens Now?
- The Impact of Other Older Drugs - The FDA have been asked if testing methods have changed since these products were first approved, and considering this situation, should the safety of other older drugs be investigated. The FDA have an ongoing assessment and surveillance to ensure similar impurities can be kept out of the drug supply.
- Postmarket Surveillance – The FDA maintain a robust practice of postmarket surveillance and risk evaluation programs to identify adverse events that did not appear during the product development process. Evaluations occur on more than 2 million adverse event reports submitted every year, and the FDA use this information to recommend actions to improve product safety and protect the public.
- Request for Information – The FDA are working with manufacturers and global regulators to provide clear and actionable information.