(Health Times reporter Tan Qixin Xu Shiyu)
Ranitidine is a well-known drug for many elderly patients with stomach diseases. However, since 2019, ranitidine has been internationally stopped, recalled, removed from shelves and issued relevant warnings by the United States, the European Union, Canada, South Korea, Singapore and other countries/regions due to the cancer-causing storm.
Domestic pharmacies and primary medical institutions are widely sold, and are rarely used in tertiary hospitals
Health Times reporter Wang Aibing photographed
On April 13, a health times reporter visited a number of pharmacies in Beijing and found that in most offline pharmacies, ranitidine was sold normally. A pharmacy staff told reporters, "Ranitidine is a veteran over-the-counter stomach drug, often have old customers come to buy drugs, annual sales have been relatively stable, we are still eating." ”
The reporter inquired about the Beijing Medical Insurance Public Service Network and found that since March, a total of 26 hospitals in Beijing have purchased ranitidine (capsules), of which 21 are grass-roots community hospitals/township health centers. "A lot of nearby residents come to drive ranitidine, and Medicare reimburses 90%, which is very cheap." The staff of the pharmacy of baoshan town health center in Huairou District, Beijing informed the reporter.
The original drug Ranitidine, zantac, was developed by GlaxoSmithKline and first marketed in the United States in 1983, and is widely used to treat diseases such as peptic ulcers, gastroesophageal reflux and gastrinoma. Once one of the world's "blockbuster drugs" with annual sales of $1 billion, According to Evaluate Pharma, among the top 10 drugs with cumulative sales revenue as of 2018, ranitidine ranked 7th with cumulative sales of $94.72 billion.
According to the latest statistics of Yaohai Data, the sales of ranitidine in public medical institutions in mainland China have increased significantly since 2019, and the annual sales of 2021 will reach 307 million yuan. However, the Health Times reporter consulted a number of gastroenterologists in the top three hospitals and learned that at present, many top three hospitals in Beijing, Shanghai, Guangzhou and other top three hospitals have almost no use of ranitidine preparations.
"Ranitidine is an old drug, which was indeed used more widely before, but at present, most of the top three hospitals are no longer used, and our hospital has long excluded ranitidine from the discharge drug list, and now it is mainly patients who buy and use more in their own pharmacies outside the hospital." Personally, ranitidine has not been prescribed to patients for more than twenty years. In addition to finding that it may have a certain carcinogenic risk, we also found that ranitidine may cause severe liver damage in patients during long-term clinical use. Fang Jingyuan, director of the Department of Gastroenterology at Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine and director of the Shanghai Institute of Digestive Diseases, told the Health Times reporter.
"As far as I know, at present, ranitidine has rarely been used in the clinic, and I have not been prescribed for ranitidine for more than five years, and ranitidine has been replaced by drugs such as omeprazole in the clinic." A clinical expert from the digestive center of Beijing Tsinghua Changgeng Hospital told reporters that however, ranitidine saves money and time, and has a certain curative effect, which is still sold in primary medical institutions and pharmacies.
Deeply involved in the "carcinogenic storm", many countries prohibit production and sales
In 2019, a citizen petition from Valisure (an online pharmacy and an independent drug quality certification agency in the United States) plunged the drug into a "carcinogenic storm". According to the standards of the International Coordinating Committee for Technology for the Registration of Medicinal Products for Human Use (ICH) M7 guidelines, the daily acceptable intake limit for humans is 96 ng (or 0.32 ppm) of N-nitrosamine (NDMA). However, the Test by Valisure, an online pharmacy and an independent drug quality certification agency in the United States, found that at an experimental temperature of 130 °C, the NDMA content detected in each ranitidine sample (original drug and generic drug) was about 2.5 to 3 million ng.
Health Times reporter Wang Aibing photographed
"If I knew about the cancer-causing risks associated with ranitidine, I would definitely consider using alternative drugs that offered patients safety, efficacy and cost advantages." Dr. Jon Ernstoff, a gastroenterologist at MidState Medical Center in the United States, said in the petition.
Shortly after the petition was submitted, on September 13, 2019, the U.S. FDA issued its first warning about the POSSIBLE carcinogenic impurity NDMA contained in some ranitidine drugs, and at the same time initiated a review of the safety of ranitidine.
On September 25, 2019, Canada also made a positive statement, requiring companies selling ranitidine products in Canada to immediately stop the distribution of ranitidine; on September 26, the South Korean Department of Food and Drug Safety requested a suspension of the use of ranitidine and banned the production, import and sale of ranitidine drugs.
On October 2, 2019, the US FDA issued another statement that the content of NDMA impurities in some ranitidine samples was found to be "unacceptable" in experimental tests. Less than a week after the announcement, GlaxoSmithKline announced a moratorium on supplying ranitidine to all markets, including India, and initiated a voluntary recall.
On April 1, 2020, the US FDA required the withdrawal of all ranitidine products on the market. The investigation report revealed that at higher experimental temperatures, the content of NDMA will increase significantly, not only that, even under normal storage conditions, the NDMA content in ranitidine will continue to accumulate, which may eventually lead to the NDMA level of ranitidine products exceeding the acceptable safety level of the human body.
Just after the United States issued a "delisting" directive against ranitidine, the European Union announced that it would "suspend the use of all ranitidine drugs". The European Medicines Agency has found that NDMA may be formed by the degradation of ranitidine itself, and the content of NDMA will continue to increase during its shelf life.
This storm has not stopped, in the United States, since 2019, a number of patients with cancer after taking ranitidine have filed lawsuits against relevant pharmaceutical companies and chain pharmacies, as of now, the number of cases submitted has exceeded 700, and it is still increasing.
In the mainland, a Health Times reporter inquired about the domestic ranitidine related drug instructions and found that in the adverse reaction column, it was marked with "long-term use can because it can continuously reduce the acidity of gastric juice, and it is conducive to the multiplication of bacteria in the stomach, so that the nitrate in the food is reduced to nitrite and the formation of N-nitroso compounds."
N-Nitrosodimethylamine, or NDMA, is a very strong hepatotoxic substance that can cause cancer in the human body and can damage the body's liver through rapid absorption by the respiratory and digestive tracts. In the list of carcinogens published by the World Health Organization's International Agency for Research on Cancer, NDMA is a class 2A carcinogen.
However, the Health Times reporter consulted dozens of patients who have been taking ranitidine capsules for a long time and said, "I don't understand what N-nitroso compounds are." ”
The State Food and Drug Administration issued a document: the risk of nitrosamine impurities should be actively assessed
Why have many countries withdrawn from the market, but the domestic market has not yet been removed? Is there a potential risk of ranitidine currently on the market? The Health Times reporter consulted the State Food and Drug Administration, and as of press time, the State Food and Drug Administration has not given a reply.
On December 9, 2019, the State Pharmacopoeia Commission issued the "Announcement on the Draft Revision of the National Drug Standards for Ranitidine Hydrochloride and Its Preparations" and the "Announcement on the Draft Revision of the National Drug Standards for Bismuth Ranitidine Citrate, Ranitidine Citrate Tablets, and Ranitidine Citrate Capsules", revising the standards for ranitidine-related drugs.
A researcher of the National Pharmacopoeia Commission revealed to the Health Times reporter that "the draft revision of drug standards related to ranitidine has begun to be formally implemented, according to the standards, the current pharmaceutical companies on the market need to evaluate their own drug production processes, if the product is found to have the risk of carcinogenic impurities, it is necessary to carry out relevant testing, meet the requirements before it can be marketed." However, we cannot be sure how it will be implemented. ”
The Health Times reporter found that since 2019, the national drug regulatory authorities have not released recall requirements and information on relevant drugs in China. However, according to the "Technical Guidelines for the Study of Nitrosamine Impurities in Chemical Drugs (Draft for Comment)" issued by the State Food and Drug Administration in January 2020, manufacturers should establish analytical testing methods for nitrosamine impurities in drugs. For listed drugs, drug approval number holders/manufacturers should also take the initiative to assess the risk of nitrosamine impurities.
The ranitidine generic drug produced by Shanghai Sixth Pharmaceutical Factory was first marketed in mainland China in 1985 as a classic drug for the treatment of digestive diseases, and is widely used in the treatment of gastric and duodenal ulcers, stress ulcers, gastric bleeding, gastroesophageal reflux disease, etc. The Health Times reporter inquired about the official website of the State Food and Drug Administration and found that at present, many pharmaceutical companies such as CSPC Ouyi Pharmaceutical, Foshan Palm Pharmaceutical, Hongsen Pharmaceutical and so on have relevant approvals for ranitidine drugs.
On April 1, a Health Times reporter called a number of relevant pharmaceutical companies as a patient, and all replied that the drugs currently shipped from the factory meet the national pharmacopoeia standards.
Health Times reporter Wang Aibing photographed
The relevant person in charge of Foshan Palm Pharmaceutical told reporters that since March 2020, Foshan Palm Pharmaceutical has tested each batch of ranitidine, improving the problem of storage temperature and processing technology, and all the products in circulation meet the national requirements of the drug NDMA content is less than 0.32ppm (96 ng / 300 mg), and the ranitidine beyond 0.32ppm has been directly destroyed.
"Through our regular testing of different batches of samples, ranitidine produced after March 2020 will not exceed the NDMA impurity standard during the 24-month storage period." The above-mentioned person in charge told the Health Times reporter.
"In fact, from the production to transportation and storage of drugs, there may be certain impurities, but before the US FDA issued a warning, our pharmaceutical industry rarely paid attention to the impurity problem of NDMA in drugs, and did not do the corresponding testing and direct release when it was produced." The US FDA's warning is a wake-up call for us, and many companies have found that the NDMA content exceeded the standard when testing many previous samples of each batch of products between 2019 and 2020, and can only be recalled and destroyed in large quantities. A pharmaceutical company quality leader, who did not want to be named, told the Health Times reporter.
According to the information disclosed by the Yunnan Institute of Food and Drug Supervision and Inspection on February 20, during the sampling of 45 batches of ranitidine hydrochloride capsule samples, the Class 2A carcinogen NDMA (N-nitrosodimethylamine) identified by the World Health Organization was detected, of which 29 batches exceeded the limit.
In February 2022, Zuo Wensong and others of the Yunnan Institute of Food and Drug Supervision and Inspection pointed out in an article in the journal "Stoanalysis and Metrology". "The longer ranitidine drugs are stored after leaving the factory, the higher the content of N-nitroso compounds, resulting in the content of N-nitrosatine compounds in ranitidine drugs may exceed the maximum daily intake limit of the human body, which will pose a huge risk to consumers, so it is necessary to accurately determine the content of N-nitroso compounds in ranitidine hydrochloride capsules."
"Scientific evidence confirms that N-nitrosodimethylamine is indeed a high risk factor for cancer, and although there is still no conclusive thesis on the definitive carcinogenicity of ranitidine, its possible carcinogenic risk cannot be ignored." Fang Jingyuan told the Health Times reporter that in the drug instructions of ranitidine, although the adverse reactions of the drug were mentioned, they did not give sufficient warnings, resulting in many patients who took drugs for many years without attracting attention.
Resources
Valisure Citizen Petition on Ranitidine .
https://www.valisure.com/wp-content/uploads/Valisure-Ranitidine-FDA-Citizen-Petition-v4
N-nitrosodimethylamine (NDMA) in Ranitidine: Emery Pharma’s Perspective, the road to filing the company’sfirst Citizen Petition, CBS News coverage, and the FDA’s response.
https://emerypharma.com/blog/n-nitrosodimethylamine-ndma-in-ranitidine-emery-pharmas-perspective-the-road-to-filing-the-companys-first-citizen-petition-cbs-news-coverage-and-the-fdas-response/
ICH(M7):M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk Guidance for Industry.U.S. Department of Health and Human Services, Food and Drug Administration ,Center for Drug Evaluation and Research (CDER) ,Center for Biologics Evaluation and Research (CBER).2018,03
ZUO Wensong; Liu Jihua (Yunnan Institute of Food and Drug Supervision and Inspection).Determination of N-Nitrosyldimethylamine in Ranitidine Hydrochloride Capsules by High Performance Liquid Chromatography Tandem Mass Spectrometry. [J].Stolytical Andmetrics,2022,02(31):58-61.
EMA：Suspension of ranitidine medicines in the EU.,updated 30/04/2020.
https://www.ema.europa.eu/en/news/suspension-ranitidine-medicines-eu
FDA: FDA Requests Removal of All Ranitidine Products (Zantac) from the Market. , updated 01/04/2020.
https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market
Zantac-Class-Action,UNITED STATES DISTRIC COURT SOUTHERN DISTRICT OF OHIO. updated 20/01/2022.
https://newyork.legalexaminer.com/wp-content/uploads/sites/7/2020/03/2020-1-22-Zantac-class-action