[Press Release, May 26, 2020 / unofficial translation] Temporary ban imposed on manufacture and sale of 31 metformin diabetes drugs - 31 out of 288 domestic products found to have NDMA in excess of provisional management standard - Human impact assessment shows very low level of harm; patients should not stop taking medicine without consulting medical doctor or pharmacist ◈ NDMA inspection of metformin Active Pharmaceutical Ingredients(APIs) and finished pharmaceutical in Korea is completed - NDMA levels in APIs are below the provisional management standard and those in some finished products exceed the standard. ◈ Temporary ban imposed on manufacture, sale, and prescription of 31 metformin drugs ◈ Human impact assessment shows negligible possibility of causing additional cancer □ The Ministry of Food and Drug Safety (MFDS; Minister Lee, Eui-kyung) collected and inspected all domestically distributed APIs and finished pharmaceuticals containing “metformin”*, a diabetes treatment drug. It found NDMA** in excess of the provisional management standard in 31 domestically manufactured items, and imposed a temporary suspension on their manufacture and sales and restriction on prescriptions. * Metformin: medication ingredient used to treat diabetics who cannot control blood sugar by diet and exercise ** NDMA (N-Nitrosodimethylamine): WHO IARC-designated probable carcinogen (2A) □ The human impact assessment of the 31 items which contained NDMA in excess of the provisional management standard showed that the possibility of additional cancer development in patients who took the drugs is 0.21 out of 100,000. Therefore, patients are advised not to stop taking them arbitrarily without consultation with doctors and pharmacists. * ICH M7 Guidelines: If the possibility of developing additional cancers is no more than 1 in 100,000 people, it may be ignored. <　Temporary suspension on manufacture and sales of 31 out of 288 items of finished drugs in circulation ＞ □ The Ministry of Food and Drug Safety has been checking medicines in the domestic market one by one for NDMA. ○ Since December 2019, some foreign countries announced the recalls of metformin drugs containing NDMA, and the ministry collected and inspected APIs and domestically manufactured and imported finished drugs. ○ The ministry also worked out a method which drug makers can use in the self-conducted testing for the presence of NDMA in metformin drugs and released it in January. □ Tests have confirmed that NDMA levels in all 973 APIs used in the manufacture of 973 finished drugs (by 12 manufacturers) are below the provisional management standard (0.038 ppm). * NDMA was not detected in 963 of them; the rest 10 had from 0.010 to 0.016 ppm, a limit of quantification level(0.010ppm) ○ In the case of finished drugs, all 34 imported products were below the provisional management standard, while 31 out of 254 domestic products exceeded the provisional management standard, resulting in the temporary suspension of manufacturing, sale and prescriptions, and recalls. ※ How to find medicines subject to suspension of sales and prescription restriction ◈ Search site - The website of the Ministry of Food and Drug Safety (www.mfds.go.kr) or Drug Safety Country (nedrug.mfds.go.kr) or blog (mfdsblog.com) or Facebook (www.facebook.com/mfds) - Korea Institute of Drug Safety and Risk Management homepage (www.drugsafe.or.kr) - Ministry of Health and Welfare homepage (www.mohw.go.kr) - Internet portal site “Naver (www.naver.com)” etc. ◈ Search method: type in “diabetes treatment,” “metformin,” “NDMA” □ The NDMA provisional management standard for metformin, which is based on a lifetime intake of a maximum daily dose (96 nanograms), is: ○ 0.096 ppm for intake of up to 1,000 milligrams a day and 0.038 ppm for intake of up to 2,550 milligrams per day. ○ This standard was set after comprehensively reviewing the guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH M7), domestic and foreign data, and advice from the experts of the Central Pharmacist Deliberation Committee. ＜　Little risk to human body even if taken for a long time　＞　 □ The Ministry of Food and Drug Safety said the level of NDMA found only in some metformin medicines exceeded the provisional management standard, so it won’t affect most patients. ○ Human impact assessment of patients who took medicines containing NDMA in excess of the provisional management standard was performed on the assumption that they had taken the maximum dose from the date of approval of the product and to the end of this year. The result showed that: - The risk of additional cancer in the lifetime was found to be “very low” with 0.21 out of 100,000 people. ○ There is virtually no risk to the human body even if patients have taken the medicines containing NDMA in excess of the standard. Therefore, patients should not stop taking medicines arbitrarily without consulting their doctor and pharmacist. <　Ministry suspends prescription and dispensing of 31 metformin medications　＞ □ The Ministry of Health and Welfare (Minister Park Neung-hoo) said that it has suspended medical institutions and pharmacies from prescribing and dispensing medicines whose manufacturing and sale had been temporarily banned. ○ The total number of patients who have been taking the drugs is 262,466 as of midnight, May 25. * There are 10,379 medical institutions and 13,754 pharmacies that handle the drugs. ○ In order to make sure medical institutions and pharmacies do not prescribe and dispense the concerned medications from 00:00 a.m. May 26, the Health Insurance Review and Assessment Service's Drug Utilization Review (DUR) system blocked their prescriptions and dispensing, and also halted the application of health insurance benefits. * Drug Utilization Review (DUR): A service that provides doctors and pharmacists with real-time information on drug safety, such as side effects of medicines when taken together or overlapping medications. ** Related inquiries: DUR Management Office of the Health Insurance Review and Assessment Service (033-739-0874-5, 0897-9). □ Patients should not stop taking their subscription drugs because experts’ examination of the impact on the human body found that there is little risk even though they had taken the metformin drugs in which NDMA was found in excess of the provisional management standard for a long period of time. ○ Patients who wish to get new prescription is advised to consult with the medical professionals about whether to continue to take the medication or get new prescription. ** Related inquiries: Drug Management Office of the Health Insurance Review and Assessment Service (033-739-1308~10,1312) ** Related matters, such as how medical care institutions claim insurance: Health Insurance Review and Assessment Service website > notification > notice or medical care institutions service portal > comprehensive screening standard service > others > notice □ Lastly, the ministry will support the following to facilitate the recall of the medicines currently in circulation. ○ To provide relevant pharmaceutical companies with the distribution information of the medicines that had been temporarily banned as reported to the Health Insurance Review and Assessment Service (Medicine Management General Information Center). ○ To provide information on the supply of medicines to wholesalers, medical institutions, and pharmacies that purchased the medicines so that they can recall and return them quickly. * Related inquiries: The Health Insurance Review and Assessment Service's Medicine Management General Information Center for (033-739-2263-4) < Investigation on the cause of NDMA detection and follow-up measures > □ Unlike the cases of valsartan and ranitidine, the NDMA found in metformin was below the provisional management standard. The discovery of NDMA in finished drugs in excess of the standard indicates that it was caused during manufacturing process. ○ In order to prevent similar cases of impurities contained in medications, the Ministry of Food and Drug Safety plans to form a “panel to investigate the cause of NDMA found in drugs” experts and find out the exact cause together with. □ The government also plans to improve the social safety net through continuous discussions with the private-public consultative body comprised of medical doctors, pharmacists, and the pharmaceutical industry* to minimize inconvenience and cost to patients in the event of safety accidents caused by medications containing impurities such as NDMA. * Composition: Private organizations (Korea Pharmaceutical Bio-Association, Korea Global Pharmaceutical Industry Association, Korea Pharmaceutical Traders Association, Korea Pharmaceutical Distribution Association, Korea Biopharmaceutical Association, Korean Medical Association, Korea Pharmaceutical Association, Korean Hospital Association, Korea Hospital Pharmacy Association), Government (Ministry of Health and Welfare, Ministry of Food and Drug Safety) ○ The government will also oversee tests and examinations of impurities like NDMA, which are currently carried out by pharmaceutical companies, and keep expanding the on-site inspection of overseas manufacturers so that the medication safety management system is strengthened for the safety of medications distributed in the country.