Classic stomach medicine is deeply involved in carcinogenic turmoil, drug safety deserves continued attention

2020Year4Month1On the same day, the U.S. Food and Drug Administration (FDA) issued a message requiring manufacturers to immediately withdraw all prescription and non-prescription (OTC) Ranitidine (Ranitidine, also translated as Raniddine) drug. This isFDAFor ranitidine drugs (usually under the brand nameZantac(good stomach) known to people) inN-Nitrosodimethylamine(NDMA) The latest steps in the study of pollutants.FDAIt has been determined that certain ranitidine products inNDMAwill increase over time and storage above room temperature and may result in consumer exposure to unacceptable amountsNDMA.

Ranitidine is aH2(Withdrawal)21) Blocker. Over-the-counter ranitidine is approved for the prevention and relief of heartburn due to ingestion and stomach acid; prescription ranitidine is approved for a variety of indications, including the treatment and prevention of gastric and intestinal ulcers and the treatment of gastroesophageal reflux disease. Ranitidine was developedAllen & HanburysLtd., first developed in1981Year10It is listed in the UK in January. Historical data show that ranitidine is the first global sales of more10The $100 million blockbuster is also the first cumulative sales in pharmaceutical history.500The US $100 million drug has repeatedly ranked first in global drug sales. Ranitidine listed near40Years had unlimited scenery, is the world's widely used classic stomach medicine.

In terms of patents,Allen & HanburysIn1976Year8Month4The application was titled"Aminoalkyl furan derivatives(Aminoalkyl furan derivatives) "patent.GB1565966A, and in1980Year4Month23day authorized. The patent should be the original research patent of ranitidine compound. It has more than 100 patents of the same family in more than 30 countries and regions around the world. Of course, these patents have already expired. In the following decades, many pharmaceutical companies from different countries competed to study different salt forms, crystal forms, dosage forms and preparation processes of ranitidine, and to apply for patents and layout.

This incident can be traced back2019Year9Month13day,FDAA statement said that based on laboratory tests, a small amount was found in the sample of ranitidine.NDMA. At that timeFDAsaid, althoughNDMACould do a lot of damage,FDAPreliminary tests found ranitidine levels barely exceeded those that might be found in ordinary foods.

ForFDAThe first response to this safety warning was Sandoz (Sandoz Inc.），9Month24On the same day, Sandoz voluntarily recalled its production.14Batch of ranitidine prescription capsules. thereafter2020Year2Month27On the 15th, a number of multinational pharmaceutical companies voluntarily recalled a variety of ranitidine tablets, capsules, syrups, etc. Other pharmaceutical companies affected by the recall include Sanofi (Sanofi), GlaxoSmithKline (GSK), Dr. Reddy Pharmaceutical Company of India (RDY), CanadaApotexPharmaceutical companies, IndiaStridesPharmacy and so on.

In the meantime, in2019Year10Month2day,FDAIt is recommended to useLC-HRMStest protocol to test ranitidine samples and start testing otherH2samples of blockers and proton pump inhibitors.10Month23day,FDARelease of the second liquid chromatography-Mass spectrometry (LC-MS) method for the detection and quantification of ranitidine inNDMA.11Month1day,FDAPublished the Center for Drug Evaluation and Research (CDER) About RanitidineNDMANew test results for impurities.12Month4day,FDAannounced that manufacturers of ranitidine and nizatidine products have been asked to expand theirNDMAThe test to include all batches of the drug, if the test showsNDMAexceed the acceptable daily intake limit (daily96 NG means thator0.32 ppm), the manufacturer must notifyFDAIt must not be put on the market.2020Year1Month, Independent LaboratoryEmery PharmaTesting confirms that ranitidine is a suspected carcinogen if stored in a high temperature environment, even if the drug is packaged intact.NDMAwill also increase.2020Year4Month1day,NDMAImpurity risk escalation,FDAFinally requires all prescription and non-prescription (OTC) Ranitidine drug withdrawal.

At the same time, in other countries and regions outside the United States, major drug regulatory agencies are also actively taking a stand.2019Year9Month13Day, inFDAOn the same day that the warning was issued, because tests showed that some drugs containedNDMAimpurities, the European Medicines Agency (EMA) said it would be based on the European Commission (EC) to begin an audit of the ranitidine drug product. The Singaporean authorities seem to be more cautious about the safety of their people,9Month17Singapore's Health Sciences Board said in a statement that Singapore would immediately suspend8The sale and supply of related drugs. In Taiwan, according to the United Daily News, due to carcinogenic ingredients, the Taiwan Food and Drug Administration9Month20The pharmaceutical companies were notified on the 2nd to request that the products sold in Taiwan contain ranitidine.(Ranitidine)of38Stomach medicine, all in23Day at midnight.12Time to complete the preventive off-shelf; It also indicates that the shelves can only be resumed after passing the inspection and providing confirmation from the Food and Drug Administration.9Month25At the request of Health Canada, companies selling ranitidine products in Canada have ceased any further distribution until evidence is provided that they containNDMAThe content does not exceed the acceptable level.9Month26Japan, South Korea food and drug safety department (MFDS) has been discovered7In the raw material of ranitidineNDMAThe content exceeded the standard, and the pharmaceutical companies were notified to suspend the use of ranitidine and prohibit the production, import and sale of related drugs. In addition, the Italian Drug Administration announced the withdrawal of multiple batchesSaraca Laboratories LimitedA drug manufactured by a pharmaceutical company that contains ranitidine.12Month9On the 15th, the Chinese Pharmacopoeia Commission issued the "Announcement on the Revised Draft of National Drug Standards for Ranitidine Hydrochloride and Its Preparations" and the "Announcement on the Revised Draft of National Drug Standards for Ranitidine Bismuth Citrate, Ranitidine Citrate Tablets and Ranitidine Citrate Capsules", which revised the drug standards related to ranitidine and proposed to increase the ranitidine standard.NDMAImpurity control.

N-Nitrosodimethylamine(NDMA) is an organic chemical that has been used to make rocket fuel and is also an unintended by-product of certain chemical reactions. In the World Health Organization (WHO) Subsidiary International Agency for Research on Cancer (IARC) in the published list of carcinogens,NDMAbe classified2Aclass of carcinogens.NDMAMay make people suffering from cancer, through the digestive tract, respiratory tract absorption quickly, slow absorption through the skin, mainly cause liver damage. According to incomplete statistics, drugs have been found in recent years.NDMAThere have been three cases of impurities:2018Year6Yuehuahai Pharmaceutical detected in the antihypertensive drug valsartan bulk drugNDMA;2019Year9MonthFDAdetected in samples of the stomach drug ranitidineNDMA;2019Year12Published in Singapore3The hypoglycemic drug "metformin (metformin) "Trace amount detectedNDMA.

Although the market share of tidine drugs has been gradually eroded by proton pump inhibitors in recent years, ranitidine is still widely used as a classic stomach drug. However, since2019Year9Since January, the ranitidine carcinogenic storm continues to spread, this time.FDAThe full withdrawal of ranitidine marks a further escalation of the carcinogenic storm. For ranitidine, it is dangerous and may be difficult to turn over. It is also a reminder to us that trace amountsNDMAIt has caused a major incident, showing that the impact of impurities on drug quality cannot be ignored, and drug safety deserves the continuous attention of pharmaceutical companies, regulatory agencies and even medical staff and patients!