FDA Issues Drug Statement, Merck's Hypoglycemic Drug Sitagliptin Detected Potential Carcinogen

Recently, the US Food and Drug Administration (FDA) official website issued a drug statement: The FDA recently found the nitrosamine impurity Nitroso-STG-19 (NTTP) in some samples of the type 2 diabetes drug sitagliptin. To avoid drug shortages and help ensure patients have an adequate supply of the drug, the FDA is not banning sitagliptin, but requires that patients' daily doses be controlled.

The FDA said in the statement that NTTP belongs to the class of nitrosamine compounds, some of which are classified as potentially carcinogenic based on laboratory tests. While there are no data to directly assess the carcinogenic potential of NTTP, the FDA used available information on closely related nitrosamine compounds to calculate lifetime exposure limits for NTTP. FDA experts assessed the risk of exposure to NTTP at interim acceptable intake levels as high as 246.7 nanograms per day and determined that it poses minimal additional cancer risk compared to lifetime exposure levels of 37 nanograms per day. This actually gave instructions on the dosage of sitagliptin.

Public information shows that nitrosamines are strong carcinogens and one of the most important chemical carcinogens. Among the animals tested, none of them can tolerate nitrosamines without causing cancer. Not only long-term small doses can cause cancer in animals or humans, but also a "shock" of a higher dose can cause cancer. At the same time, a large number of animal experiments have also shown that nitrosamines can cause cancer in the offspring of experimental animals through the placenta and milk.

In 2018, the domestic API giant Huahai Pharmaceutical was banned from export by the FDA due to the detection of N-dimethylnitrosamine (NDMA) impurities in the valsartan API, and its export in the European Union, Japan and other places was also restricted. Huahai Pharmaceutical stated in the announcement issued in July of that year that it acknowledged the presence of NDMA in valsartan raw materials, and the content was extremely small; at the same time, the company stated that the relevant raw materials were strictly in accordance with the pharmaceutical production quality management standards and standards of the countries where they are supplied. Registration regulations require compliance with production, and the two indicators of single unknown impurity content and total unknown impurity content of the API have always met international registration standards. After re-evaluation, Huahai Pharmaceutical's exports gradually recovered. However, affected by this incident, Huahai Pharmaceutical's profits dropped sharply that year, and Huahai Pharmaceutical still has many lawsuits in progress in the United States.

In addition to valsartan, the US FDA has subsequently found nitrosamine impurities in a number of drugs, including ranitidine, nizatidine, and metformin from different companies.

Sitagliptin (Jienovel), which involves the detection of nitrosamine compounds, is a dipeptidyl peptidase-4 (DPP-4) inhibitor and is a drug under Merck for the treatment of type 2 diabetes. Approved in the United States in October 2006, sales in 2007 reached 668 million US dollars. Based on this, in 2007, Merck launched "Jenoda", a combination product of sitagliptin and metformin hydrochloride, and then developed related sustained-release dosage forms. According to Merck's annual report, from 2019 to 2021, the global sales of sitagliptin series products exceeded 3 billion US dollars, of which Genovy's global sales were 3.482 billion US dollars, 3.306 billion US dollars and 3.324 billion US dollars respectively.

In China, sitagliptin was approved in 2009, and was listed in the National Medical Insurance Catalog as Category B in 2017. After that, the volume increased rapidly. In 2018, the sales of national hospitals increased by 112% year-on-year. In 2021, the annual domestic sales exceeded 1.5 billion yuan.

At present, many domestic pharmaceutical companies have deployed sitagliptin generic drugs. Among them, Chia Tai Tianqing took the lead in obtaining the first copy approval in February 2020. Other distribution companies include Dongguang Pharmaceutical, Zhejiang Pharmaceutical, Yangzijiang Pharmaceutical, Tonghua East Bao, Chenxin Pharmaceutical, Kelun Pharmaceutical, Qilu Pharmaceutical, Huahai Pharmaceutical, Lepu Pharmaceutical, Jiangsu Wanbang, Nord Pharmaceutical, Yuanyan Pharmaceutical, Meishu Pharmaceutical, etc.

However, sitagliptin is still in the patent protection period. According to Merck's disclosure in its 2022 semi-annual report, the market exclusive rights of the two sitagliptin drugs in the United States will end in January 2023; in China, the compound patent is in Expires in July 2022 and all patents expire in 2024.

Regarding the detection of nitrosamines in sitagliptin, according to a report by the People’s Daily Health Client, an endocrinologist from a tertiary hospital said that, according to the FDA’s statement, it was found in “certain samples” of sitagliptin. Nitrosamines were detected, and normal doses of sitagliptin were used as prescribed by the doctor, which is still a safe drug. There may be risks if you stop taking the drug abruptly. Patients do not need to panic too much because of this. More importantly, the State Food and Drug Administration of my country has paid attention to whether there are nitrosamines in sitagliptin circulating in the domestic market, and it needs to be sampled and evaluated. If there is a health hazard, the State Drug Administration will notify the recall. At present, the patient can take the medicine normally according to the doctor's order. In addition, a senior pharmaceutical expert said that the patent protection period based on sitagliptin is about to expire, and a large number of domestic generic drugs may be listed in the next few years. How pharmaceutical companies can avoid the production of nitrosamines in the production process will also is a test.