NDMA in Ranitidine Raises Concerns about Drug Safety

The U.S. Food and Drug Administration (FDA) announced on April 1, 2020,to request manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately, because of a contaminant known as N-nitrosodimethylamine (NDMA) in ranitidine medications (commonly known by the brand name Zantac). The FDA has determined that NDMA in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of NDMA.

Ranitidine is an H2 (histamine-2) blocker. OTC ranitidine is approved to prevent and relieve heartburn associated with acid ingestion and sour stomach; while 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 original drug of ranitidine, developed by Allen & Hanburys Ltd., first entered the market in the UK in October 1981. Historical data shows that ranitidine is the first blockbuster in the world to sell more than $ 1 billion, it is also the first drug in the history of pharmaceuticals with cumulative sales of $ 50 billion, and it has repeatedly ranked first in the global pharmaceutical sales. Ranitidine has been in the market for nearly 40 years, and it is a classic stomach medicine widely used in the world.

In terms of patents, patent application GB1565966A entitled "Aminoalkyl furan derivatives" was filed by Allen & Hanburys on August 4, 1976, and was granted on April 23, 1980. The patent should be the original drug patent of the ranitidine compound, and it has more than 100 patents of the same family in more than 30 countries and regions. Of course, these patents have already expired. In the following decades, many pharmaceutical companies from different countries have competed to study the different salt forms, crystal forms, dosage forms and preparation processes of ranitidine, and conducted patent applications and patent layout.

This incident can be traced back to September 13, 2019. The FDA released a statement saying that based on laboratory testing, a small amount of NDMA was found in the ranitidine sample. At the time, the FDA expressed that although NDMA may cause a lot of harm, FDA preliminary tests found that the content of ranitidine hardly exceeded the amount that may be found in ordinary food.

In response to this safety warning issued by the FDA, a number of multinational pharmaceutical companies have voluntarily recalled a variety of ranitidine tablets, capsules, syrups, etc. The pharmaceutical companies involved in the recall include Sandoz, Sanofi, GSK, RDY, Apotex, Strides and so on.Meanwhile, the drug regulatory agencies in countries and regions including Europe, Singapore, Canada, South Korea, and Italy have expressed their positions and taken measures such as withdrawal or sales suspension of ranitidine-related drugs. The Chinese Pharmacopoeia Commission issued a public announcement on December 9, 2019, to revise the standards for ranitidine-related drugs and add NDMA impurity control provisions.

NDMA is an unintended by-product of certain chemical reactions, which is classified as a class 2A carcinogen in the list of carcinogens published by the International Agency for Research on Cancer (IARC), an affiliate of WHO. NDMA may cause people to suffer from cancer. It is rapidly absorbed through the digestive tract and respiratory tract, and slowly absorbed through the skin, mainly causing liver damage. According to incomplete statistics, there have been three incidents of NDMA impurities found in pharmaceuticals in recent years: In June 2018, Huahai Pharmaceuticals detected NDMA in the antihypertensive drug valsartan API; in September 2019, the FDA detected NDMA in the sample of gastric drug ranitidine; and in December 2019, Singapore announced the detection of trace amounts of NDMA in three types of hypoglycemic drugs "metformin".

Since September 2019, Ranitidine's cancer-causing storm has continued to spread. The FDA's full withdrawal of ranitidine marks a further escalation of the storm. This is a huge crisis for ranitidine, the drug may be difficult to stand up again. It is also a reminder to us that trace NDMA has caused major events, and it has aroused concerns about drug safety for pharmaceutical companies, regulatory agencies, and even medical personnel and patients.