Introduction
Recently, batches of losartan and irbesartan have also tested positive for carcinogenic impurities. Losartan, irbesartan, and valsartan are in the same class of blood pressure medications (ARBs). The full extent of the valsartan contamination and how many other ARBs contain carcinogenic impurities is still unknown. The numerous regulatory investigations continue to uncover more carcinogenic impurities as legal actions mount. Several lawsuits alleging cancer development due to valsartan impurities have now been filed across the United States, along with numerous class action claims. On October 22, 2018, a motion was filed to consolidate all federal valsartan impurity lawsuits into the District of New Jersey in front of Judge Freda L. Wolfson. The Judicial Panel on Multidistrict Litigation (JPML) heard arguments to consolidate all claims on January 31, 2018, in Miami, Florida. On February 14, 2019, the JPML decided to consolidate all valsartan cases in the District of New Jersey in front of Judge Robert B. Kugler. The valsartan litigation is now known as MDL 2875 – In Re: Valsartan N-Nitrosodimethylamine (NDMA) Contamination Products Liability Litigation. Make sure to bookmark this page to stay up to date as the valsartan investigation continues and the litigation takes form to hold those accountable for this catastrophe responsible.
History of the Case
Valsartan is an angiotensin II receptor blocker (ARB) which is utilized to help control blood pressure. Since 2005, valsartan has been sold by Novartis Pharmaceuticals Corporation under the brand name Diovan. At this time, it is not believed that the brand name version of valsartan (Diovan) has ever been contaminated with NDMA. Before a generic version of valsartan entered the market, Diovan was pulling in over $2 billion in sales for Novartis every year (peaking at $6 billion)! Then in 2012, the patent Novartis had on Diovan/valsartan expired, allowing generic manufactures to enter the highly lucrative valsartan market. Unfortunately, in order to further maximize their profits even further, the generic manufacturers cut corners and cost in the production of generic valsartan.
The pharmaceutical company Mylan released the first generic drug to contain valsartan. The initial generic valsartan sold by Mylan was in a combination pill and was intended to compete against Novartis’ Diovan HCT (valsartan + hydrochlorothiazide). Mylan was granted a 180 day window to be the sole marketer of the generic valsartan combination pill. Shortly thereafter, a division of Novartis known as Sandoz also launched a generic valsartan + hydrochlorothiazide combination to compete against Mylan’s generic Valsartan. Sandoz then further expanded it’s generic Valsartan market in 2014 when they released a non-combination generic valsartan. Then in 2015, the generic drug manufacturing giant Teva Pharmaceuticals Industries Ltd launched its own non-combination generic valsartan. An ever increasing number of generic formulations of valsartan have been discovered to be contaminated with the cancer causing agent NDMA. Because of how generic valsartan became contaminated with NDMA, it is likely that additional cancer causing impurities are also present.
Injuries Related to Product
Have you recently received a valsartan recall letter? If so, you aren’t alone. On July 13, 2018, the United States Food and Drug Administration (FDA) issued a recall due to the generic blood pressure medication valsartan being contaminated with the impurity N-Nitrosodimethylamine (NDMA). A well known side effect of NDMA is cancer formation. 1 in 3 Americans suffer from hypertension, with valsartan being one of the primary drugs utilized to treat hypertension. As a result, approximately 2 million Americans have received recall letters from Humana regarding the FDA’s urgent recall of contaminated valsartan. Time will tell how many experience the unfortunate side effects of contaminated valsartan.
Recently, batches of losartan and irbesartan have also tested positive for carcinogenic impurities. Losartan, irbesartan, and valsartan are in the same class of blood pressure medications (ARBs). The full extent of the valsartan contamination and how many other ARBs contain carcinogenic impurities is still unknown. The numerous regulatory investigations continue to uncover more carcinogenic impurities as legal actions mount. Several lawsuits alleging cancer development due to valsartan impurities have now been filed across the United States, along with numerous class action claims. On October 22, 2018, a motion was filed to consolidate all federal valsartan impurity lawsuits into the District of New Jersey in front of Judge Freda L. Wolfson. The Judicial Panel on Multidistrict Litigation (JPML) heard arguments to consolidate all claims on January 31, 2018, in Miami, Florida. On February 14, 2019, the JPML decided to consolidate all valsartan cases in the District of New Jersey in front of Judge Robert B. Kugler. The valsartan litigation is now known as MDL 2875 – In Re: Valsartan N-Nitrosodimethylamine (NDMA) Contamination Products Liability Litigation. Make sure to bookmark this page to stay up to date as the valsartan investigation continues and the litigation takes form to hold those accountable for this catastrophe responsible.
Valsartan Side Effects
The full extent of the potential side effects and injuries due to impurities within valsartan are currently being investigated. The NDMA and other carcinogens within valsartan are rapidly absorbed in the upper part of the small intestine and carried to the liver in the portal blood supply. The liver can effectively metabolize and clear small amounts of NDMA, leaving very little to interact with other organs. Therefore, the liver is most susceptible organ to experience side effects from contaminated valsartan. The side effects of long-term exposure to valsartan is not currently well understood. Our valsartan attorneys are currently filing lawsuits for those who have experienced the follow side effects or injuries:
- Stomach cancer
- Liver cancer
- Colorectal cancer
- Pancreatic cancer
- Esophageal Cancer
- Bowel cancer
- Liver failure
Our valsartan attorneys at Hollis Law Firm continue to investigate other cancer formations that could be side effects related to the impurities within valsartan. Call 1-800-701-3672 to report a cancer formation, liver injury, or other side effect that you think might be related to the impurities within valsartan.
Additional Literature
How did Valsartan Become Contaminated with Cancer Causing Impurities?
If valsartan is manufactured in an environment that is too acidic, NDMA is produced as a byproduct of the chemical reaction that creates the drug valsartan. N-nitrosodiethylamine (NDEA) is another carcinogen that can be produced as a byproduct during the same chemical reaction if the pH is too low. Recently, NDEA impurities have also been confirmed in contaminated valsartan and other ARBs. Once valsartan went generic, pharmaceutical companies began outsourcing the Active Pharmaceutical Ingredient (API) manufacturing process to China and India to further reduce the cost of manufacturing. Because the NDMA contaminate is a byproduct of the API manufacturing process, it is unlikely that this is a small or isolated contamination. In fact, it is becoming increasingly clear that a majority of the valsartan sold across the world has had significant amounts of carcinogenic impurities in them for years. Additionally, our valsartan attorneys allege that companies such as Teva were fully aware that the valsartan they were selling to millions of consumers was contaminated with cancer causing impurities. The contaminations might have happened overseas, but US companies turned a blind eye.
The Following API Manufacturers Have Produced Contaminated Valsartan:
- Zhejiang Hauhai Pharmaceutical Co., Ltd. (Linhai, Zhejiang, China). It is believed that the contaminated Valsartan from Hauhai Pharmaceutical reached the United States and European countries by passing through the following companies: Teva Pharmaceuticals USA, Inc. (North Wales, PA, USA), Teva Pharmaceutical Industries, Ltd. (Petah Tikva, Isreal), Torrent Pharmaceuticals (Ahmedabad, India), Prinston Pharmaceutical, Inc. (Cranbury, NJ, USA), Solco Healthcare U.S., LLC (Cranbury, NJ, USA), Actavis, LLC (Parsippany, NJ, USA), Major Pharmaceuticals (Livonia, MI, USA), A-S Medication Solutions LLC (Libertyville, IL, USA), NuCare Pharmaceuticals, Inc. (Orange, CA, USA), Bryant Ranch Prepack, Inc. (Burbank, CA, USA), Northwind Pharmaceuticals, AvKARE, Inc., and RemedyRepack, Inc.
- Zhejiang Tianyu Pharmaceutical Co. (Zhejiang, China).
- Hetero Labs, Ltd. (Telangana, India).
- Mylan Laboratories Limited (Hyderabad, Telangana, India).
Are Other Generic ARBs Contaminated with Cancer Causing Impurities like Valsartan?
Trace amounts of NDMA have been found in other generic ARBs, including generic losartan. Thus far, the amounts of NDMA detected in other generic ARBs have been lower and less consistently observed than in generic valsartan. However, because a similar chemical reaction is necessary to make any ARB, if the manufacturing environment is too acidic, they too would be contaminated with NDMA. The attorneys at the Hollis Law Firm are continuing to investigate the possible contamination of ARBs other than valsartan. The following drugs undergo a chemical reaction during their manufacturing process that is similar to the chemical reaction necessary to create valsartan:
Valsartan Timeline: Global Investigation
July 5, 2018: The European Medicines Agency (EMA) issued a notice that some valsartan medicines were being recalled across the European Union (EU) after the European Commission requested review pursuant to Article 31 of Directive 2001/83/EC. The EMA stated in their notice that “NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. The presence of NDMA was unexpected and is thought to be related to changes in the way the active substance was manufactured. While review is underway, national authorities across the EU are recalling medicines containing valsartan supplied by Zhejiang Huahai. The EMA vowed that their investigation “will investigate the levels of NDMA in these valsartan medicines, its possible impact on patients who have been taking them and what measures can be taken to reduce or eliminate the impurity form future batches produced by the company. As a precaution, the review will also consider whether other valsartan medicines may be affected.”
July 6, 2018: The Hong Kong Department of Health issued a press release instructing “two licensed medicine wholesalers, namely Actavis Hong Kong Limited and Hong Kong Medical Supplies Ltd (HK Medical), to recall five products containing valsartan from the market as a precautionary measure do to an impurity detected in the raw material.” The Department of Health admitted that contaminated valsartan products had been supplied to hospitals.
July 9, 2018: Health Canada issued an advisory communication regarding several drugs containing valsartan being recalled due to contamination with a potential carcinogen. Health Canada reported that the contaminated valsartan that made its way into Canada was from Zhejiang Huahai Pharmaceuticals and that five Canadian companies valsaratan was impacted.
July 13, 2018: The FDA announced a voluntary recall of several medicines containing valsartan following detection of an impurity. The FDA alerted “health care professionals and patients of a voluntary recall of several drug products containing the active ingredient valsartan, used to treat high blood pressure and heart failure. This recall is due to an impurity, N-nitrosodimethylamine (NDMA), which was found in the recalled products. However, not all products containing valsartan are being recalled. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. The presence of NDMA was unexpected and is thought to be related to changes in the way the active substance was manufactured.” Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research went on record noting “We have carefully assessed the valsartan-containing medications sold in the United States, and we’ve found that the valsartan sold by these specific companies does not meet our safety standards. This is why we’ve asked these companies to take immediate action to protect patients.”
July 18, 2018: The World Health Organization (WHO) released a Medical Product Alert due to the “Detection of Impurity in the Active Pharmaceutical Ingredient valsartan manufactured by Zhejiang Huahai Pharmaceuticals, Linhai, China.” The WHO cautioned that “The impurity discovered is N-nitrosodimethylamine (NDMA). NDMA is classified as a probable human carcinogen (a substance that could cause cancer). The presence of NDMA is suspected to be related to changes in the way the active pharmaceutical ingredient was manufactured. All batches of valsartan manufactured by Zhejiang Huahai Pharmaceuticals since July 2012 are expected to be affected.” The WHO also foresaw the potential of anti-hypertensive medication shortages due to the valsartan contaminations.
July 18, 2018: The FDA updates health care professionals and patients on recent valsartan recalls. The FDA announced that “there are currently three voluntary recalls related to the NDMA impurity detected in the valsartan API:
- Teva Pharmaceuticals USA labeled as Major Pharmaceuticals – recall is at the retail level because these products are only used in facilities were they are directly administered to patients by health care professionals: Valsartan 80 mg and 160 mg products;
- Prinston Pharmaceuticals Inc. labeled as Solco Healthcare LLC – recall is at the consumer/user level: Valsartan 40 mg, 80 mg, 160 mg, and 320 mg; and valsartan/HCTZ 80 mg/12.5 mg, 160 mg/12.5mg, 160 mg/ 25 mg, 320 mg/ 12.5 mg, and 320 mg/ 25 mg products; and
- Teva Pharmaceuticals labeled as Actavis LLC – recall is at the consumer/user level: Valsartan 40 mg, 80 mg, 160 mg, and 320 mg; and valsartan/HCTZ 80 mg/12.5 mg, 160 mg/ 25 mg, 320 mg/12.5 mg, and 320 mg/25 mg products.”
July 24, 2018: The FDA published a list of valsartan-containing products not part of the recall. The FDA also urged “consumers and health care professionals should continue to report any adverse reactions with valsartan-containing products, to the FDA’s MedWatch program to help the agency better understand the scope of the problem.
- Complete and submit the report online at www.fda.gov/medwatch/report.htm
- Download and complete the appropriate form, then submit it via fax at 1-800-FDA-0178″
July 25, 2018: The Hong Kong Department of Health Drug Office released an update on the recall of valsartan-containing products. The officials noted that 84 pharmaceutical products registered in Hong Kong contain valsartan. The Department of Health stated that its “surveillance system noted that the raw material valsartan produced by a manufacturer in the Mainland and used in certain pharmaceutical products as active ingredient, was found to contain an impurity N-nitrosodimethylamine (NDMA). NDMA is classified as a probable human carcinogen based on results from laboratory test.” Finally the Department of Health confirmed that “the presence of NDMA is unexpected and believed to be related to change of production method of the valsartan raw material since July 2012.”
July 27, 2018: The FDA releases its analysis of N-nitrosodimethylamine (NDMA) levels in recalled valsartan in the U.S. The FDA surprisingly admitted that it was basing its analysis “on records from the manufacturer of the recalled valsartan, some levels of the impurity may have been in the valsartan-containing products for as long as four years.” The FDA also conceded that “NDMA has been found to increase the occurrence of cancer in animal studies.”
July 27, 2018: The FDA adds additional repackagers to the valsartan recall. The FDA announced that “The following additional repackagers are recalling or are expected to recall valsartan-containing products. FDA is working to gather product recall information from these companies and has removed them from the list of products that are not impacted by this recall:
- Bryant Ranch Prepack Inc.
- H.J. Harkins Company Inc. (this company was not originally included on either list)
- Lake Erie Medical, doing business as Quality Care Products LLC
- NuCare Pharmaceuticals Inc.
- Northwind Pharmaceuticals
- Proficient Rx”
August 2, 2018: The EMA issued a preliminary assessment of the possible risk of recalled valsartan to patients. The EMA stated “Following a preliminary evaluation, EMA estimates that there could be one extra case of cancer for every 5,000 patients taking the affected medicines at the highest valsartan dose (320 mg) every day for 7 years. This is based on average levels of this impurity detected in the active substance from Zhejiang Hauhai Pharmaceuticals (60 parts per million). The possible cancer risk has been extrapolated from animal studies…” The EMA continued assuring the public that “Companies that had used the active substance from Zhejiang Hauhai in their valsartan medicines are required to test samples they hold to determine the actual NDMA levels in the final products. Additional checks are being carried out by EU official control laboratories. Once data from all these tests are available, EMA will be able to provide more information on the risk that the impurity may have posed for patients in the EU.” Oddly, the EMA concluded that “it is important to note that there is no immediate risk to patients.”
August 2, 2018: The FDA updated recalled valsartan-containing product information and reminds API manufacturers to evaluate processes for unsafe impurities. The FDA noted that it “is working with drug manufacturers to ensure future valsartan active pharmaceutical ingredients (APIs) are not at risk of NDMA formation. The agency reminds manufacturers to thoroughly evaluate their API manufacturing processes and changes to those processes, to detect any unsafe impurities.”
August 9, 2018: The FDA added more companies to the valsartan recall, announcing “Camber Pharmaceuticals is recalls certain valsartan tablets because they contain the impurity N-nitrosodimethylamine (NDMA) in the active pharmaceutical ingredient (API). Hetero Labs manufactures the API for Camber products using a process similar to Zhejiang Huahai Pharmaceuticals. Test results from Hetero Labs show the amount of NDMA found in its valsartan API exceeds acceptable levels; although it is generally lower than the amount discovered in the API manufactured by Zhejiang. The FDA then explained that “The agency has also contacted other manufacturers of valsartan API to determine if their manufacturing processes are at risk for the formation of NDMA, and is working with them to ensure NDMA is not present in future valsartan API. Valsartan is an angiotensin II receptor blocker (ARB), and FDA is investigating whether other types of ARBs are at risk for the presence of NDMA.”
August 10, 2018: The EMA issued an update on their review of valsartan medicines due to the detection of NDMA, announcing that valsartan manufactured by another Chinese company had tested positive for NDMA contamination. The EMA noted that “the NDMA levels detected in batches of valsartan from Zhejiang Tianyu are much lower than levels seen in the active substance from Zhejiang Huahi, which triggered a recall of several valsartan medicines in July 2018.” The EMA also made known that they were “working closely with international partners to review the impact of the NDMA detected in valsartan from Zhejiang Tianyu and will communicate as soon as additional information is available.”
August 18, 2018: Health Canada issued an Important Safety Information Notice recalling products containing the valsartan ingredient from Zhejiang Huahai Pharmaceuticals. Health Canada noted they were “reviewing long-term potential health impacts of the NDMA impurity on patients. NDMA is classified as a probable human carcinogen based primarily on animal studies, which means that exposure above acceptable levels over the long term could increase the risk of cancer. The review, which will be completed in the coming weeks, will include an assessment of how much NDMA patients may have been exposed to and for how long. Although Health Canada believes that the NDMA was introduced as a result of a change in manufacturing processes at Zhejiang Huahai Pharmaceuticals in 2012, some Canadian companies may have been using the affected valsartan active ingredient for less time.”
August 20, 2018: The FDA updated its recall list on contaminated valsartan-containing products, adding Torrent Pharmaceuticals Limited after they recalled 14 lots of valsartan/amlodipine/hydrochlorothiazide (HCTZ) tablets on August 17, 2018. The FDA noted that they “recently learned Torrent used affected valsartan active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceuticals. FDA testing confirmed NDMA in some Torrent products.”
August 22, 2018: The FDA announced that Torrent Pharmaceuticals Limited was expanding its voluntary recall to all lots of unexpired valsartan-containing drug products.” The FDA also noted that RemedyRepack, a repackager of Torrent’s valsartan/amlodipine/hydrochlorothiazide (HCTZ) tablets, has also recalled.” Additionally, the FDA released “a gas chromatography-mass spectrometry (GC/MS) headspace method for manufacturers and regulators to detect and quantify NDMA in valsartan API and finished drug products. The agency is using this method to test potential NDMA-containing APIs and drug products. This method should be validated by the user if the resulting data are used to support a required quality assessment of the API or drug product, or if the results are used in a regulatory submission.”
August 24, 2018: The FDA noted that Torrent Pharmaceuticals Limited expanded its valsartan recall even further. Swissmedic announced it had withdrawn the contaminated batches of valsartan from the market and would be conducting analysis on additional valsartan-containing products.
September 10, 2018: Health Canada released an update on the estimates of health risks for recalled valsartan drugs containing NDMA. The agency estimated that contaminated valsartan entered the market in 2012 and that the “longest time affected products were on the Canadian market was approximately three years.” Why Health Canada estimated that contaminated valsartan products were only on the Canadian market for 3 years and not 6 years is currently unknown. Health Canada estimated that the valsartan contaminated ingredient contained 60 parts per million (ppm) NDMA, which is higher than levels considered safe. The agency added that higher doses of valsartan contain proportionally larger amounts of NDMA contaminate.
September 13, 2018: The EMA released an update on their review of valsartan medicines, alerting the public that the EMA had broadened its valsartan investigation to include looking for the presence of N-nitrosodiethylamine (NDEA). The EMA continued to downplay the seriousness of the contamination and attempted to support its position by stating “the low risk estimate is to some extent supported by a Danish study which tracked patients who had taken medicines containing valsartan from Zhejiang Huahai over the past 6 years. However, the authors note that patients were followed up for a relatively short period (4.6 years on average).” Then the EMA admitted that “in addition to NDMA, EMA is assessing the impact of a related substance, N-nitrosodiethylamine (NDEA), which has been detected in valsartan made by Zhejiang Huahai using its previous manufacturing process before changes were introduced in 2012. Both NDEA and NDMA belong to the class of nitrosamines and are classified as probable human carcinogens (substances that could cause cancer). Data on levels of NDEA are currently very limited, and EMA will provide further information on whether its presence impacts the risk assessment once more information becomes available.” The EMA also noted that “EU authorities have now carried out inspections of the manufacturing sites of both companies in China and will consider the findings. Medicines containing valsartan from Zhejiang Huahai and Zhejiang Tianyu are no longer being distributed in the EU or have been recalled. Both companies are not currently authorized to produce valsartan for medicines in the EU. EMA continues to work closely with national authorities, international partners and EDQM to gather the necessary information which would allow the Agency to have a better understanding of why impurities were present in the active substance in the first place. Based on the final outcome of the review, authorities in the EU will take necessary measures to ensure that similar problems not occur in future.”
September 13, 2018: The FDA provided an update on its ongoing investigation into valsartan products; and reports on the finding of an additional impurity identified in one firm’s already recalled products. The FDA announced that “based on FDA testing to date, the agency discovered NDEA in some of ZHP’s valsartan API. This impurity was also found in Torrent’s valsartan 160mg (lot BV47D001) and 320mg (lots BV48D001 and BV48D002) tablets, which were made using API from ZHP and were part of the earlier recall.” FDA Commissioner Scott Gottlieb, M.D. stated that “As we continue to investigate the root cause of the impurities found in products that contain valsartan, our scientists are testing these products to better understand these impurities and to ensure they’re not present in other products.” The Commissioner added “As we expand our investigational efforts, we’ll continue to make sure the public has the most up-to-date information. We’ll also continue to work with global regulatory agencies to learn as much as we can about how these impurities came about and how they may affect patients’ health around the globe.” The FDA also elaborated that “Like N-Nitrosodimethylamine (NDMA), which was found in the recalled valsartan products, NDEA is also formed from a specific sequence of manufacturing steps and chemical reactions. In addition to the FDA’s testing, the agency will post a preliminary method for detecting NDEA. Manufacturers and global regulators can use this method to screen other products for the potential presence of this impurity.” Finally, the FDA candidly warned that “Any patient taking valsartan from a recalled lot who has not yet spoken to their pharmacist or doctor should do so promptly. At this time, the FDA’s testing supports the conclusion that not all valsartan products contain NDMA or NDEA, so pharmacists may be able to provide a valsartan medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.”
September 21, 2018: The EMA expanded its review of impurities in valsartan to include four other sartans, namely losartan, olmesartan, irbesartan, and candesartan. The EMA decided to expand its valsartan investigation due to German authorities discovering NDEA in losartan. Then EMA then notes that these additional sartans could be contaminated due to how the drugs are synthesized. The EMA goes on to state that “further test are required to determine the extent of the contamination and whether impurities are present in sartan medicines above levels that can be considered acceptable.” The valsartan lawyers at the Hollis Law Firm don’t think ingesting a medication every day that has ANY amount of cancer causing impurities present is a good idea, especially when safer alternative blood pressure medications exist.
September 28, 2018: The FDA placed Zhejiang Huahai Pharmaceuticals on import alert. The FDA explained that “The import alert stops all API made by ZHP and finished drug products made using ZHP’s API from legally entering the United States. FDA’s action follows a recent inspection at ZHP’s facility.” The FDA then reminded manufacturers “that is is their responsibility to develop and use suitable methods to detect impurities, including when they make changes to their manufacturing processes. If a manufacturer detects new or higher levels of impurities, they should fully evaluate the impurities and take action to ensure the product is safe for patients.”
September 28, 2018: EU inspection finds Zhejiang Huahai site non-compliant for manufacture of valsartan: EMA and national authorities considering impact on other active substances produced at the site. EU officials declare that Zhejian Huahai did not comply with good manufacturing practice (GMP) in the manufacture of valsartan at the Chuannan site in Linhai, China.
October 1, 2018: Swissmedic announced “an initial review of finished products with the active substances valsartan, losartan, olmesartan and candesartan available on the Swiss market is now concluded. The measurements showed that none of the medicinal products analysed give any cause for concern in respect to NDMA.” (Of note, it appears the Swiss didn’t utilize valsartan manufactured by the companies later found to have high contamination levels)
October 5, 2018: The FDA posted laboratory test results showing NDMA levels in recalled valsartan products. The FDA noted that “For reference, consuming up to 0.096 micrograms of NDMA per day is considered reasonably safe for human ingestion based on lifetime exposure.” Valsartan from Teva Pharmaceuticals tested over 100 times the reasonably safe level and valsartan from Prinston Pharmaceutical tested over 200 times the safe level of NDMA!
October 11, 2018: The FDA announced that due to also detecting NDEA in valsartan products manufactured by Zhejiang Huahai Pharmaceuticals, the FDA has developed a testing method to detect and quantify levels of both NDMA and NDEA in contaminated valsartan products.
October 15, 2018: EU authorities take further action in ongoing review of sartans: Zheijiang Huahai placed under increased supervision; Aurobindo Pharma stopped from supplying irbesartan to the EU. The investigation was noted to have expanded after NDEA was found in losartan made by Hetero Labs in India. Levels of NDEA had now been detected in a third sartan, irbesartan, made by another Indian company, Aurobindo Pharma. EU authorities are unsure at this time if they should recall medications containing irbesartan produced by Aurobindo Pharma. The EU has now expanded its investigation into contaminated sartans to now include candesartan, irbesartan, losartan, olmesartan, and valsartan.
October 30, 2018: FDA announces Irbesartan recalled due to detection of NDEA. ScieGen Pharmaceuticals, Inc. recalls Irbesartan tablets produced by Aurobindo Pharma Limited which were contaminated with NDEA. ScieGen Pharmaceuticals, Inc. labels their Irbesartan as Westminster Pharmaceuticals and Golden State Medical Supply, Inc.
Check back soon, our valsartan timeline continues to grow as the investigation into the extent of the valsartan contamination continues.
November 5, 2018: Swissmedic announced “Medicines currently available on the Swiss market containing the active substances valsartan, losartan, olmesartan, candesartan and irbesartan satisfy the requirement in respect of NDMA. The investigation for other impurities will be continued.”
November 8, 2018: Sandoz Inc. issues nationwide recall on losartan due to detection of NDMA.
November 19, 2018: EU authorities suspend Mylan Laboratories Limited certificate of compliance with European standards for quality testing due to NDEA impurities being detected in Mylan’s valsartan. National authorities of the EU have stepped in to determine the full extent of Mylan’s contaminated valsartan. The EU has requested that all companies marketing valsartan to test their products for these cancer causing impurities.
November 20, 2018: Mylan Pharmaceuticals initiates nationwide recall of 15 lots of valsartan and valsartan HCT, due to the detection of NDEA. The contaminated valsartan was manufactured by Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited.
November 27, 2018: Teva Pharmaceuticals recalls ALL lots of amlodipine / valsartan in the United States due to the detection of a cancer causing impurity. The lots of valsartan that Teva recalled were manufactured by Mylan India.
November 29, 2018: FDA issues a warning letter to Zhejiang Huahai Pharmaceuticals. The warning letter notes “significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).” Zhejiang had claimed that only one of its valsartan manufacturing processes was impacted by the presence of NDMA. However, the FDA “identified NMDA in multiple batches manufactured with a different process.” The FDA also indicated that to lower cost, Zhejiang Huahai changed the solvent used in manufacturing the valsartan API in 2011 without testing for the formation of mutagenic impurities.
December 4, 2018: Mylan expanded its recall to include all lots of valsartan-containing products within expiry. Mylan claimed the expanded recall was done out of “an abundance of caution.”
December 11, 2018: FDA announces that it is “still looking into the root cause of the impurity.” Additionally, the FDA notes that it “continues to test all ARBs” (not just ARBs containing a tetrazole ring).
December 19, 2018: In an attempt to prevent drug shortages, the FDA publishes interim acceptable intake levels of nitrosamine impurities in ARBs. These interim levels are expected to stay in place for a few years to allow the various manufacturers time to change their manufacturing process.
December 20, 2018: Torrent Pharmaceuticals Limited issues nationwide recall of losartan potassium tablets after detecting NDEA in the API manufactured by Hetero Labs Limited.
January 3, 2019: Torrent Pharmaceuticals expands its recall of losartan.
February 14, 2019: JPML consolidates all valsartan cases in the District of New Jersey, creating MDL 2875 – In Re: Valsartan N-Nitrosodimethylamine (NDMA) Contamination Products Liability Litigation.
February 22, 2019: Macleods Pharmaceuticals Limited recalls one lot of losartan potassium/hydrochlorothiazide combination tablets 100mg/25mg due to detection of NDEA.
Scientific Studies and Literature on the Carcinogenicity of NDMA and Valsartan
“NDMA is believed to have been introduced into the valsartan products as a result of the manufacturing process of the active pharmaceutical ingredient. The contamination is in all likelihood related to a change in the manufacturing process in Zhejiang Huahai Pharmaceuticals in 2012. Sodium azide and N-dimethylformamide (DMF) were used for the formation of the tetrazole ring in valsartan. Subsequently, excess sodium azide remaining after the formation of the tetrazole ring, was quenched with sodium nitrite under acidic conditions, resulting in the formation of nitrous acid. One potential source of NDMA could be the degradation of DMF under the acidic conditions and reactions with nitrous acid.”
Jan 2019: Irbesartan Induced Cutaneous Melanoma! Second Case in the Medical Literature!
“Possible, but unlikely, in our opinion, is that the intake of angiotensin receptor blockers (in particular irbesartan), and the progression of benign precursor lesions to malignant do not have a direct relationship. The growing number of data in the literature for drug-induced melanoma and massive withdrawal of products with valsartan and irbesartan due to the content of probable carcinogens speaks, however in favour of the opposite, namely that it is more likely to speak about established dependence than of a sporadic associated. Drug-induced melanoma-rather a reality than a myth.”
Jan 2019: Valsartan Recall: Global Regulatory Overview and Future Challenges
“NDMA is an organic chemical that forms in both industrial and natural processes, and has been used to make liquid rocket fuel, softeners, and lubricants. NDMA has been studied in animals and found to increase the occurrence of cancer. The US Environmental Protection Agency found an association between NDMA and liver toxicity, which could lead to liver cancer: NDMA exposure may be associated with bladder, renal, pancreatic, intestinal, colon, and stomach cancers.”
“More and more data are in favour of the claim that commonly used antihypertensive drugs also contain the risk of developing melanoma. The most evidence is that angiotensin receptor blockers may be carcinogenic. Two representatives from this group, valsartan and irbesartan, produced by certain pharmaceutical companies are being withdrawn from the market due to finding content of NDMA and NDEA, which are believed to be potent carcinogens. Another representative of this group, losartan, according to in vitro data, potentiates cell adhesion and invasion of human melanoma cells.” “The prevailing number of data, however, is in the direction of claiming that ARBs are highly associated with melanoma development.”
Nov 2018: Dietary N-nitroso Compounds and Risk of Pancreatic Cancer: Results From a large Case-Control Study
A dietary study conducted by MD Anderson Cancer Center in Houston, Texas noted “significant positive associations of NDEA and NDMA with risk of pancreatic cancer. NDEA and NDMA are the most abundant NOCs identified in foods and are potent pancreatic carcinogens in animal models. NDEA could directly bind to DNA to form DNA alkylation products, and human pancreatic cells can activate NDMA to their ultimate carcinogenic forms. Chronic exposure to NOCs could potentially overwhelm DNA repair capabilities and the unrepaired DNA alkylation damage would lead to gene mutation and cancer development.”
Nov 2018: Valsartan Induced Melanoma?! First Description in Medical Literature!
The authors note that “according to recent data, widely used angiotensin receptor blockers (ARBs) for the treatment of arterial hypertension, also carry a risk of malignancy development. The content of probable carcinogens, such as NDMA or NDEA in the drug valsartan (ARBs), causes the product to be withdrawn from the market. Recent experimental data suggest that another angiotensin receptor blocker-losartan also stimulates cell adhesion and melanoma cell invasion.” The authors conclude by noting “this case reaches important conclusions, indicating that the systemic intake of valsartan may trigger the development of malignant melanoma and the likelihood of its progression being directly proportional to the dose.”
“NDMA is a probable human carcinogen with a calculated lifetime cancer risk of 10-6 at 0.7 ng/L in drinking water.”
“Generic drugs are widely used worldwide to decrease pharmaceutical expenditures for patients and payers. Between a given generic and its corresponding brand-name drug, the strength of the active ingredient, the galenic form, the route of administration, and the indication must be identical. However, inactive ingredients may differ greatly. To ensure pharmacokinetic similarity between generics and the brand-name counterpart, most Generics will undergo comparative bioavailability studies in humans before being licensed. There is an exception to every rule: pseudogenerics. Pseudogenerics are known to be “exact copies” of the brand-name drug; their composition is exactly the same (active and inactive ingredients) and sometimes referred to as “best” generics. Therefore, health authorities do not require in vivo comparative bioavailability tests to license pseudogenerics, as normally demonstrated in respective product monographs.”
3,625 people never exposed to NDMA were compared to 3,450 people who were exposed to NDMA contaminated Valsartan. There was nearly a doubling of cancer formations in those who were exposed to Valsartan contaminated with NDMA. The authors of the study noted that “increases in risk were observed for colorectal cancer and for uterine cancers.”
Sept 2018: Regulatory Response to Contaminated Valsartan.
“Regulators took rapid action, but exposed patients still require long term monitoring.”
The authors of the study note that “Nitrosamines such as nitrosodimethylamine (NDMA) in drinking water have recently attracted great attention because of their high carcinogenicity and high detection rate. Nitrosamines have also been repeatedly detected in drinking water in [China], leading to a lot of concerns about [China’s] drinking water safety.” The authors concluded that “In view of potential health risks of NDMA, it’s necessary to adopt more effective, economical and also environmental water treatment techniques and develop reasonable safety standards to ensure the quality of drinking water and people’s health.”
July 2016: Occurrence of Nitrosamines and their Precursors in Drinking Water Systems Around Mainland China.
“N-Nitrosamines (NAs) in drinking water have attracted considerable attention in recent years due to their high carcinogenicity, frequent occurrence, and their potential regulation.”
Sept 2011: The Effect of N-nitrosodimethylamine (NDMA) on Bax and Mcl-1 Expression in Human Neutrophils.
The study looks into how NDMA impacts leukocyte function, neutrophils, and the human immune system in general.
2008: N-Nitrosodimethylamine (NDMA).
The World Health Organization released guidelines for NDMA in drinking water. The World Health Organization noted that “N-Nitrosodimethylamine, or NDMA, can occur in drinking-water through the degradation of dimethylhydrazine (a component of rocket fuel) as well as from several other industrial processes.” The World Health Organization concluded that “there is conclusive evidence that NDMA is a potent carcinogen in experimental animals by several routes of exposure, including through ingestion of drinking-water. NDMA has been classified by IARC as probably carcinogenic to humans. The mechanism by which NDMA produces cancer is well understood to involve biotransformation by liver microsomal enzymes, generating the methyldiazonium ion. This reactive metabolite forms DNA adducts, with most evidence pointing to O6-methylguanine as the likely proximal carcinogenic agent. As a consequence of the clear evidence of carcinogenicity, there have been few studies of other possible toxic end-points.”
1997: Approaches to Cancer Prevention Based on an Understanding of N-Nitrosamine Carcinogenesis.
Considerable evidence is available that nitrosamines are important causative agents for a number of different human cancer types including cancers of the oral cavity, lung, esophagus, pancreas, liver, nasopharynx, and bladder.
Damage to tissue DNA as a result of NDMA were found in the highest amount in the “gastric mucosa and liver and were only about 50% lower in DNA from white blood cells, esophagus, ovary, pancreas, urinary bladder and uterus. With ethanol [alcohol] co-exposure, amounts of [DNA damage] increased at least 2-fold in all tissues except liver. The largest effect was in esophagus (17-fold increase), followed by ovary, large intestine, urinary bladder, spleen, and cerebellum (9- to 13-fold increases), and uterus cerebrum and brain stem (7-to 8-fold increases). Of particular interest, it was noted that “a high percentage of NDMA clearance in patas monkeys could be extrahepatic, in contrast to rodents, where metabolism occurs almost exclusively in liver, and with obvious implications regarding potential genotoxic damage in extrahepatic organs.”
1990: Interspecies Scaling of the Pharmacokinetics of N-Nitrosodimethylamine.
“Most likely, the assumption that the liver is the only clearing organ is incorrect.”
The study found that “Tumours of the kidney and lung were each found in approximately 30% of rats given NDMA.” Shockingly, the study also found “a significant excess of malignant lymphomas in the mice given NDMA. The lymphoma incidence of (55%) after NDMA was much higher than untreated controls (4%).”
How Dangerous is Valsartan Contaminated with NDMA?
Ingestion of N-Nitrosodimethylamine or NDMA poses a significant risk for cancer formation. In 2002, the World Health Organization (WHO) declared “NDMA has been consistently potently carcinogenic in all experimental species examined.” In fact, NDMA is considered so dangerous and carcinogenic that human trials are not even allowed, and therefore have never been performed! Even acute, single exposure studies in animals have demonstrated that NDMA causes liver (hepatotoxicity), kidney (tumors), and testes (necrosis of the seminiferous epithelium). Additionally, as the amount and/or the time of NDMA exposure increased in animals, so did the rates of tumor and cancer formation.
Valsartan Lawsuit
Call the Hollis Law Firm at 1-800-701-3672 if you or a loved one has taken valsartan since 2013 and developed cancer. All calls and case evaluations are free and carry no obligation. The Hollis Law Firm works on cases on a contingent fee basis, which means we don’t get paid if you don’t get paid. Call 1-800-701-3672 to speak to one of our trained valsartan intake specialist so that your potential valsartan cancer claim can be reviewed by an attorney at the Hollis Law Firm. The injuries and damages caused by contaminated valsartan will not be uniform; therefore, claims will need to proceed on an individual basis and not as part of a class action.
Content Created By:
C. Brett Vaughn RN, BSN, JD
