Since July 2018, USFDA has issued as many as 53 drug recall notices, 16 of them this year alone as a result of the detection of this potential carcinogenic contamination in commonly used medicines
A potentially carcinogenic impurity namely NDMA (N-nitrosodimethylamine) has been found in a few medicines that are being widely used worldwide for the treatment of common ailments like hypertension, diabetes and acid-peptic disease. First time this contamination was detected by the US Food and Drug Administration (USFDA) as well as European Medicines Agency (EMA) in July, 2018 in an anti-hypertensive drug called valsartan. Subsequently it was also found in other anti-hypertensive medicines like amlodipine, losartan, irbesartan, hydrochlorthiazide, gastric ulcer prevention drugs like ranitidine, nizatidine and very recently even in anti-diabetic drug metformin. This has caused considerable anxiety and bewilderment among patients taking these medicines owing to the serious consequences of the dreaded disease cancer that this impurity is likely to cause. Since July 2018, USFDA has issued as many as 53 drug recall notices, 16 of them this year alone as a result of the detection of this possibly carcinogenic impurity and drug companies have recalled thousands of batches of such drugs after testing revealed presence of small amounts of cancer-causing chemicals in them.
Probability of causing cancer
The International Agency for Research on Cancer has classified NDMA as a “probable carcinogen”, with animal studies revealing tumor formation predominantly in the gastrointestinal tract and liver but also in lungs and kidneys. It has also been shown to cause liver damage and fibrosis in animal models. This has considerably shaken the faith and confidence of patients consuming these drugs and made them apprehensive about their safety. However it is believed that the trace amounts of carcinogens found in these drugs can increase the risk of cancer if people are exposed to them at above acceptable levels over long periods of time whereas short-term exposure at levels above the acceptable intake limit has not been established as yet to lead to an increase in the risk of cancer in humans. The EMA update on 2 August, 2018 revealed that the average level of NDMA detected was 60 parts per million which could result in one extra case of cancer for every 5000 patients taking the affected medicines at their highest dose every day for 7 years (Farrukh MJ et al, 2019).
Drugs involved
A recall is a voluntary action taken by a pharmaceutical company on its own or on the advice of the regulatory agency at any time to remove a defective drug product from the market. A drug recall is the most effective way to protect the public from a defective or potentially harmful product (USFDA). Valsartan was the first drug to be recalled from the shelves in July 2018, followed by its analogues irbesartan in October and losartan in November, 2018. Till September 23rd, 2019, a total of 1159 batches of valsartan, losartan and irbesartan had been recalled from US markets (White CM, 2019). In September 2019, USFDA alerted the world about the presence of NDMA in some batches of ranitidine, available as Zantac and manufacturers pulled it out from the shelves during the next few months. The USFDA alert came on a day when a US-based online pharmacy, Valisure petitioned the USFDA requesting a recall of all products containing ranitidine, saying its own laboratory tests had revealed high levels of NDMA, above USFDA’s daily limit. Subsequently USFDA recommended that manufacturers of ranitidine must recall all lots and types of these medications. Another heartburn medication, Nizatidine was recalled by its manufacturer Mylan Labs in January 2020.
Companies involved
Many manufacturers including Apotex Corporation, Sandoz, Sanofi, Aurobindo and Dr Reddy Labs had to recall products containing ranitidine because of the high levels of the contaminant. This year NDMA has also been found in Metformin, a diabetes drug taken by over 15.8 million people worldwide. In July this year several leading Indian drug manufacturing companies including Lupin, Marksans Pharma, Aurobindo Pharma and Alembic Pharmaceuticals recalled their pharmaceutical products from the US markets. As per the latest USFDA report, Lupin and Granules India recalled around 9.71 lakh bottles of diabetes drug from the US market whereas Marksans Pharma recalled 11,279 bottles of Metformin tablets. On May 22, 2020 GlaxoSmithKline Pharmaceuticals announced that the company made a decision to discontinue the manufacture and supply of ranitidine tablets manufactured in India after it was contacted by regulatory authorities regarding the detection of NDMA in its products. Dr Reddy’s Laboratories Ltd also initiated a voluntary nationwide recall in October, 2019 of all its ranitidine medications sold in US due to confirmed contamination with NDMA above levels established by the USFDA (Expresspharma, July 5, 2020). All these voluntary recalls have been classified as class II recalls. As per the USFDA, a class II recall is initiated in a situation in which use of, or exposure to, a medicinal product may cause temporary or medically reversible adverse health consequences.
Origin of NDMA
Apart from NDMA, two other nitrosamines namely N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) and N-nitrosodiethylamine (NDEA) have also been detected in at least six more drugs that are consumed by tens of millions of people each year. NDMA and NDEA are “probable human carcinogens” whereas NMBA is a “possible human carcinogen,” according to the USFDA. Origin of NDMA contaminated bulk drugs has been traced back to a Chinese drug manufacturing firm Zhejian Huahai Pharmaceuticals by the European Medicines Agency (EMA) and began recalling medicines containing valsartan manufactured by this company. According to European regulators, the problem likely dates back to 2012 when changes in manufacturing processes were made at this unit, further suggesting that many patients could potentially have been exposed to the cancer risk (Pharmabiz May 30, 2020). Subsequently Drugs Controller General of India (DCGI) ordered its drug inspectors at port offices to closely monitor the import of valsartan bulk drug manufactured by this Chinese firm and draw the samples from every batch of imported consignment of the drug for laboratory testing including test for NDMA impurity. However it is not clear from DCGI’s official website as to how many drugs have been recalled or withdrawn from the Indian markets on account of this contamination over the past two years.
Source of contamination
Interestingly NDMA is also believed to be present in many processed foods and alcoholic beverages including smoked fish, broiled meat, bacon, cereals, dairy products, some fruits and vegetables. Levels of NDMA in these foods are typically much higher than levels of NDMA found in treated drinking water. This NDMA contamination could arise from the water the plants and animals utilize, soil contamination of the food or the food that animals eat, or during processing before sale. Pertinently a study from Kashmir, published in 1988 had found 1,010 nanograms (ng) of NDMA in every kilogram of smoked fish sold in the local markets. There are two main sources of NDMA contamination in medicines. The first source is the use of material like solvents or catalysts contaminated with NDMA in the manufacturing process. The second source of contamination occurs when NDMA is created from an intermediate or from the active ingredient itself. The FDA has set an interim acceptable level of NDMA in a medication tablet or capsule at 96 nanograms/day. Although this is below the 190 ng dose of NDMA that the WHO would find acceptable, it is estimated that senior citizens (above 65 years of age) who take a median number of 4 medications daily, so there could be a multiple risk of NDMA exposure over time in these patients (White CM, 2019).
Advice for patients
Worldwide in 2017, about 10 million people took losartan, over 2.3 million took irbesartan and around 1.8 million people took valsartan, according to the Agency for Healthcare Research and Quality. Many medical professionals have warned against unnecessary panic regarding these medicines. They have urged that the patients should not abruptly stop taking their blood pressure medications because that can lead to a rebound increase in blood pressure, which could put such patients at risk of experiencing a cardiovascular event. USFDA has also advised that the patients taking recalled metformin should continue taking it until a doctor prescribes them a replacement or a different treatment option since it could be dangerous for patients with Type-2 diabetes to abruptly stop taking their metformin without first talking to their health care professionals (Boerner LK, 2020). Then there are many other medications in the market that can be used alternatively by blood pressure and diabetes patients on their doctor’s advice. It is pertinent to mention that other metformin products have not been recalled from the markets.
Measures to be taken
Vigorous testing of all the bulk drugs as well as finished drug formulations for these impurities is the need of the hour since their implications could be devastating to a patient taking these medicines on long-term basis. It is quite possible that these contaminants may have been present in our drugs for several years, but nobody was so far aware of it. Before it is too late Govt. of India must issue necessary guidelines on testing of all such medicines for NDMA contamination, both for drugs presently circulating in the markets as well as those yet to be released. Active pharmaceutical ingredients (APIs) as well as any inactive ingredients prone to NDMA formation should be tested under different environmental conditions to determine how product storage, especially heating, light exposure and time since manufacture, can affect NDMA incorporation. Data regarding drug recalls within Indian markets on this account should also be made public because there is every possibility that drugs withdrawn from American and European markets by the Indian companies could have been resold and circulated in the domestic markets by certain unscrupulous elements as a result of lax quality assurance and drug regulatory system that could lead to a surge in cancer cases in future. Government needs to wake up to this alarming situation well in time and take adequate measures not to allow it to spiral out of control. Further the sources of these impurities need to be plugged and suitable changes need to be made in the manufacturing processes of these drugs.
(Author is a pharmacologist teaching at the Department of Pharmaceutical Sciences, University of Kashmir)