Recently, Pfizer, the global pharmaceutical giant, announced on its official website that it would voluntarily recall a popular antihypertensive drug product in the United States because the content of nitrosamine in these drugs is higher than the acceptable level of human body, which may lead to cancer.
this antihypertensive drug is called accuritic and two generic drugs
Accuretic’s Chinese name is quinapril hydrochloride / hydrochlorothiazide tablets. Pfizer believes that this drug component contains nitrosamines, which may increase the risk of human cancer if ingested for a long time
On March 25, the 21st Century Business Herald reporter learned from Pfizer China that quinapril hydrochloride / hydrochlorothiazide tablets are not sold in China and have no impact on the Chinese market. It is understood that the above drugs belong to drugs with expired patent period, and there are many imitation drugs on the market.
it is worth noting that in recent years, drug recalls exceeding the standard due to the presence of nitrosamine carcinogens have occurred from time to time
For example, in July 2021, Pfizer took the initiative to recall 12 batches of anti smoking drug Chantix (vannickland) tablets due to the content of n-nitroso-vannickland; In October 2021, FDA announced that Indian Multinational Pharmaceutical Company lupin pharmaceuticals voluntarily recalled several batches of irbesartan tablets USP, irbesartan and hydrochlorothiazide tablets USP because the analysis found that the impurity content of these batches of products was higher than the specification limit.
Therapeutic drugs may cause cancer, which inevitably makes patients panic.
So, what are nitrosamines?
What is the impact of excessive nitrosamines in drugs on human body?
nitrosamine content exceeds the standard
On March 22, Pfizer announced on its official website that it would voluntarily recall a large number of accuretic (quinapril hydrochloride / hydrochlorothiazide) and two authorized generic drugs sold by its wholly-owned subsidiary greenstone, quinapril HCI / hydrochlorothiazide tablets.
Pfizer said the recall was due to the fact that the content of carcinogenic impurity nitrosamine in the drug was higher than the acceptable daily intake
21st Century Business Herald reporter checked Pfizer’s official website and found that the recall involved six batches of accuretic tablets, one batch of quinazepril and hydrochlorothiazide tablets and four batches of quinazepril hydrochloride and hydrochlorothiazide tablets, which were distributed to wholesalers and distributors in the United States and Puerto Rico from November 2019 to March 2022.
These products can reduce the risk of cardiovascular disease, such as myocardial infarction p align = “center” figure / product figure of recalled batch source: Pfizer official website p align = “center” NDC, batch number, expiration date and configuration details of recalled products p align = “center” source: Pfizer official website
A study conducted by the World Health Organization and Imperial College London shows that the number of patients with hypertension over the age of 30 has doubled in the past 30 years, and more than half of them have not received treatment. Therefore, people’s demand for antihypertensive drugs is also rising.
According to iqvia, accuretic’s generic drugs are composed of quinapril and hydrochlorothiazide, with more than 192000 users and sales of US $4.7 million in 2020.
this recall is due to the presence of N-nitroso Quinapril, a compound called nitrosamine although according to the US Food and drug administration, nitrosamines are common in water and food, such as pickles, barbecues, dairy products and vegetables, and everyone is exposed to certain levels of nitrosamines.
however, if people are exposed to nitrosamine impurities above acceptable levels for a long time, these impurities may increase the risk of cancer
Pfizer stressed that so far, there have been no reports of adverse events related to the recalled drugs, and this recall is voluntary. According to the current data, the benefits of antihypertensive drugs still outweigh the risks caused by nitrosamines.
“The safety of these products has been established through 20 years of marketing and strong clinical programs. Although long-term use of n-nitroso-quinazepril may be associated with an increased potential cancer risk in humans, patients taking this drug have no direct risk. Patients currently taking this product should consult their doctors for information on alternative treatment options,” Pfizer said in a statement
Pfizer said that the company attaches great importance to patient safety and product quality at every step of the production and supply chain.
at this stage of recall, Pfizer has put forward relevant solutions on the official website and informed the consignee by letter to arrange the return of any recalled products. On the official website, the contact number and address have also been attached at the same time, the wholesalers and distributors corresponding to the recalled batch of products shall also immediately stop using and distributing and isolate the products
Pfizer also said the recall had been reported to the U.S. Food and Drug Administration (FDA)P align = “center” figure / return contact information on Pfizer’s official website
several drugs have carcinogens and are recalled
it is worth noting that Pfizer’s hypertension drugs have been involved in “carcinogenic” storm and “recall door” for many times
At the beginning of this month, Pfizer’s Canadian branch recalled accuritic due to the high level of nitrosamine, a potential carcinogenic impurity.
As early as February 2019, Pfizer’s Japan branch also recalled four batches of more than 260000 antihypertensive drugs amubaro from Japan because valsartan API contains impurities that may cause cancer.
It is understood that the recall is due to the discovery of excessive NDEA (N-nitrosodimethylamine) and NDMA (N-nitrosodimethylamine) in the products.
Like the n-nitroso-quinapril mentioned above, ndea and NDMA are also nitrosamine carcinogens
NDMA is common in pesticides, pesticides, lubricating oil additives, and even in some cosmetics and shampoo.
However, if exposed for a long time, it may cause liver and kidney damage.
These nitrosamines are produced under specific chemical reaction due to the use of some excipients in the process of drug production, which is difficult to be removed. In China, nitrosamine carcinogens were also detected in hypertension drugs, which triggered a global recall.
in June 2018, Zhe Jiang Hua Hai Pharmaceuticalco.Ltd(600521) during the optimization and evaluation of the production process of valsartan API, it was found and verified that an unknown impurity was NDMA
Affected by this incident, in July of the same year, the European Drug Administration (EMA) issued an announcement to review the Valsartan produced by Zhe Jiang Hua Hai Pharmaceuticalco.Ltd(600521) and recall the drugs within the EU. At the same time, the incident also triggered an EU wide review of all valsartan drugs shortly afterwards, the European Drug Administration found that the Valsartan active substance produced by a company in Zhejiang also contained low levels of NDMA
And the event is not over.
In September of the same year, low levels of NDEA were also found in losartan manufactured by hetero labs, India Thus, the review of EMA was extended to all sartan drugs. A month later, another Indian company, Aurobindo Pharma, also found low levels of NDEA in irbesartan, which became the third sartan drug found to contain NDEA
In November 2018, the European Drug Administration announced again that NDEA was found in some valsartan produced by mylan Laboratories Limited in India, which is the API manufacturer of Pfizer’s recalled drugs in Japan mentioned in the article.
regulatory authorities strengthen the quality control of nitrosamine drugs
NDMA has been detected in valsartan API, and various nitrosamine impurities, such as NDMA, N-nitrosodiethylamine (NDE), have also been detected in other valsartan API. Nitrosamine impurities, such as ranitidine and quinazepril hydrochloride and hydrochlorothiazide mentioned at the beginning of the article, have even been detected in non sartan drugs of individual suppliers.
Therefore, nitrosamine impurities have become an issue of close concern to global regulators.
On October 27, 2017, the World Health Organization and the international agency for research on cancer included NDMA in the list of class 2A carcinogens. The European Drug Administration tentatively set the acceptable limit index of NDMA in valsartan as 0.3ppm, and the FDA also limited the acceptable dosage of NDMA in pharmaceutical preparations to 96ng per day.
China has also strengthened the supervision of nitrosamine impurities. On August 20, 2018, the revised draft of national standard on valsartan issued by the State Pharmacopoeia Commission added the production requirements of valsartan: the production process must be evaluated to determine the possibility of forming NDMA if necessary, the production process shall be verified to show that the content of NDMA in the finished product meets the requirements, and the limit shall not exceed 3 / 10 million
On December 9, 2019, the Chinese Pharmacopoeia Commission issued the publicity of the revised draft of the national drug standard for ranitidine hydrochloride and its preparations and the publicity of the revised draft of the national drug standard for ranitidine bismuth citrate, ranitidine citrate tablets and ranitidine citrate capsules to revise the drug standards related to ranitidine. The NDMA impurity control is proposed to be added to the ranitidine standard.
In addition, China has further implemented and clarified the supervision of the recall of problematic drugs.
In October 2020, the State Food and Drug Administration issued the measures for the administration of drug recall (Draft for comments).
The measures point out that for drugs with quality problems or other potential safety hazards due to R & D, production, sales, storage and transportation, labeling and other reasons, the drug marketing license holder shall take back the listed drugs with defects according to the specified procedures, and take corresponding measures to control and eliminate the defects the State Food and drug administration is responsible for guiding the supervision and administration of national drug recall in this process.
The Measures specify that “the holder of the drug marketing license has the obligation to recall the defective drugs, shall establish and improve the drug recall system, collect relevant information on drug safety, investigate and evaluate the drugs that may have defects, and recall the defective drugs in time.”
It also stipulates that “if the drug recall is only implemented outside China and does not involve domestic drug varieties and batches, the enterprise legal person in China designated by the drug listing license holder shall report the relevant information to the drug regulatory department of the province, autonomous region or municipality directly under the jurisdiction of the locality within 5 working days after the overseas recall is started.”
