Drugs

FDA updates on valsartan recalls

Investigation ongoing – statement to be updated as more information is available

FDA releases additional NDMA/NDEA detection method

Update [10/16/2018] FDA is posting a gas chromatography-tandem mass spectrometry (GC-MS/MS) method utilizing liquid injection for detecting the presence of impurities N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) in valsartan drug products.

This method provides an additional option for regulators and industry to detect NDMA and NDEA impurities. This method can be used alone or in combination with the combined gas chromatography-mass spectrometry (GC/MS) headspace method the agency recently posted. Like the previously posted methods, 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.

FDA releases method for detection and quantification of both NDMA and NDEA

Update [10/11/2018] ] FDA is posting a redeveloped combined gas chromatography-mass spectrometry (GC/MS) headspace method for detecting the presence of impurities N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) in valsartan drug products.

FDA previously posted a GC/MS method for detection of NDMA in valsartan products. Upon detection of NDEA in valsartan products manufactured by Zhejiang Huahai Pharmaceuticals, FDA redeveloped the testing method so that it can be used to detect and quantify levels of both NDMA and NDEA. 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.

FDA is also working on a GC/MS direct injection method for detection of NDMA and NDEA. We will post the method when it is available. This will provide an additional option for regulators and industry to use to detect both impurities.

FDA posts laboratory analysis of NDMA levels in recalled valsartan products

Update [10/5/2018] FDA posted laboratory test results showing NDMA levels in recalled valsartan products. FDA will also post test results and an assessment of the cancer risk from NDEA when they are available.

FDA places Zhejiang Huahai Pharmaceuticals on import alert

Update [9/28/2018] FDA placed Zhejiang Huahai Pharmaceuticals on import alert on September 28, 2018, to protect U.S. patients while the active pharmaceutical ingredient (API) manufacturer fully determines how impurities were introduced into its API and remediates its quality systems. 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.

FDA reminds manufacturers that it 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.

FDA updates recall lists and releases method for the detection and quantification of NDMA in valsartan

Update [9/24/2018] FDA has updated the list of valsartan products not under recall with five Teva products that were not previously on either list.

Update [8/24/2018] Torrent Pharmaceuticals Limited is expanding its voluntary recall. FDA has updated the list of valsartan products under recall.

Update [8/22/2018] Torrent Pharmaceuticals Limited is expanding its voluntary recall to all lots of unexpired valsartan-containing drug products due to the detection of NDMA in the active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceuticals.

RemedyRepack, a repackager of Torrent’s valsartan/amlodipine/hydrochlorothiazide (HCTZ) tablets, has also recalled.

FDA has updated the list of valsartan products under recall and the list of valsartan products not under recall.

Additionally, FDA is releasing 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.

FDA updates recalled valsartan-containing product information and presents NDMA levels in some foods

Update [8/20/2018] FDA is alerting health care professionals and patients that Torrent Pharmaceuticals Limited is voluntarily recalling 14 lots of valsartan/amlodipine/hydrochlorothiazide (HCTZ) tablets. Not all Torrent valsartan products distributed in the U.S. are being recalled.

FDA recently learned Torrent used affected valsartan active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceuticals. FDA testing confirmed NDMA in some Torrent products.

To date, Torrent has not received any reports of adverse events related to this recall.

FDA has updated the list of valsartan products under recall and the list of valsartan products not under recall to incorporate additional repackagers of Camber’s valsartan products and Torrent’s recall.

NDMA is a known environmental contaminant. For context, it is found in water and foods including meats, dairy products and vegetables.

Estimated Range of Daily NDMA Consumption for certain foods (Recommended daily food consumption rates based on Dietary Guidelines for Americans 2015-2020)

  • Cured meat - 0.004-0.23 micrograms1

  • Smoked meat - 0.004-1.02 micrograms1

  • Grilled meat - 0.006-0.13 micrograms1

  • Bacon - 0.07-0.09 micrograms2

    • In more ordinary terms, for example, one pound of bacon may contain 0.304-0.354 micrograms of NDMA

FDA reminds patients taking valsartan from a recalled lot that they should continue taking their current medicine until their doctor or pharmacist provides a replacement or a different treatment option. Not all valsartan products contain NDMA, so pharmacists may be able to provide a refill of valsartan medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.

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1 Mavelle, T., B. Bouchikhi, and G. Debry, The occurrence of volatile N-nitrosamines in French foodstuffs. Food Chemistry, 1991. 42(3): p. 321-338.

2 Park, J., et al., Distribution of Seven N-Nitrosamines in Food. Toxicol Res, 2015. 31(3): p. 279-288.


FDA updates recalled valsartan-containing product information

Update [8/9/2018] FDA has updated the list of valsartan products under recall and the list of valsartan products not under recall to incorporate recalls of valsartan-containing products manufactured by Hetero Labs Limited, in India, labeled as Camber Pharmaceuticals Inc. Not all Camber valsartan products distributed in the U.S. are being recalled.

Camber Pharmaceuticals is recalling certain valsartan tablets because they contain the impurity N-nitrosodimethylamine (NDMA) in the active pharmaceutical ingredient (API). Hetero Labs manufactures the API for the 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.

FDA is testing samples of valsartan API and finished products to confirm the extent and amount of NDMA and help inform the ongoing investigation. 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.

Recalled valsartan products labeled as Camber may be repackaged by other companies. FDA will provide updates as more information becomes available.


FDA updates recalled valsartan-containing product information and reminds API manufacturers to evaluate processes for unsafe impurities

Update [8/2/2018] FDA continues to evaluate valsartan-containing products and has updated the list of products included in the recall and the list of products not included in the recall. In addition to updating the lists, FDA revised information related to A-S Medication on the list of products included in the recall. The agency will continue to provide information when it becomes available.

FDA 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. If a manufacturer detects new or higher levels of impurity, they should take action to prevent changes to the product’s safety profile. 


FDA updates recalled valsartan-containing product information

Update [7/27/2018] FDA is updating health care professionals and patients after discovering that several additional companies that repackage drug products are also recalling valsartan-containing products.

FDA has product recall information from three additional repackagers of valsartan-containing products made by Teva Pharmaceuticals and Prinston Pharmaceuticals Inc. – labeled as A-S Medication Solutions LLC, AvKARE and RemedyRepack – and the agency has added them to the recalled products list. Two of these companies, A-S Medication and RemedyRepack, may also distribute valsartan products not affected by the recall. The agency is confirming this information and will provide an update once it is available.

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

It is possible that not all valsartan-containing products repackaged by these companies are impacted by the recall. FDA continues to evaluate valsartan-containing products and will update the list of products included in the recall and the list of products not included in the recall as more information becomes available.

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Analysis of N-nitrosodimethylamine (NDMA) Levels in Recalled Valsartan in the U.S.

Update [7/27/2018] On July 13th, FDA announced a recall of certain batches of valsartan tablets because of an impurity, a chemical known as N-nitrosodimethylamine (NDMA). Valsartan is a medication commonly used to treat high blood pressure and heart failure.

NDMA has been found to increase the occurrence of cancer in animal studies. These animal studies were done using amounts of NDMA much higher than the impurity levels in recalled valsartan batches. Based on these animal studies, the U.S. Environmental Protection Agency considers NDMA a probable human carcinogen—a chemical that can increase the risk of cancer in humans. NDMA is found in some water supplies and in some foods1. Consuming up to 96 nanograms NDMA/day is considered reasonably safe for human ingestion2. It is estimated that over the course of a person’s lifetime, consuming this amount of NDMA would result in less than one additional case of cancer for every 100,000 people. To put this in context, currently one out of every three people in the US will experience cancer in their lifetime.

The amounts of NDMA found in the recalled batches of valsartan exceeded these acceptable levels. The agency wanted to put some context around the actual potential risk posed to patients who used versions of valsartan that may have contained high levels of NDMA. Based 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. FDA scientists estimate that if 8,000 people took the highest valsartan dose (320 mg) from the recalled batches daily for the full four years, there may be one additional case of cancer over the lifetimes of these 8,000 people. This assessment led to FDA’s decision to have these batches recalled.

Patients taking valsartan from a recalled batch should continue taking their current medicine until their doctor or pharmacist provides a replacement or a different treatment option. It is important to know that not all valsartan products contained NDMA, so pharmacists may be able to provide a refill of valsartan medication from batches that that are not affected by the recall, or doctors may prescribe a different medication that treats the same indications.

FDA continues to evaluate the safety of valsartan-containing products and will update the list of products included in the recall and the list of products not included in the recall as more information becomes available. If you are taking a valsartan product, be sure to check to back as the lists may change.

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1 From Toxnet: https://toxnet.nlm.nih.gov/

Average Daily Intake: WATER: (assume 3 to 6 ng N-nitrosodimethylamine/l)(1) 6 to 12 ng; direct intake from drinking water is probably much less than 1 ug/day(2). FOOD: (assume <0.1 to 84 ug/kg)(4) <0.16 to 134 ug.
[(1) Kimoto WI et al; Water Res 15: 1099-1106 (1981) (2) USEPA; Ambient Water Quality Criteria Doc: Nitrosamines p.C-14 (1980) EPA 440/5-80-064 (4) IARC; IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 17: 125-76 (1978)]

2 The calculated acceptable intake for NDMA is based on methods described in the ICH Guidance M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk
(
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM347725.pdf)


FDA publishes a list of valsartan-containing products not part of the recall

Update [7/24/2018] FDA is updating health care professionals and consumers on the agency’s progress in responding to the ongoing recalls of valsartan, which is used to treat high blood pressure and heart failure, due to the presence of NDMA. The agency has posted a list of valsartan-containing products not impacted by this recall. FDA continues to evaluate valsartan-containing products and will update the list of products included in the recall and the list of products not included in the recall as more information becomes available.

Manufacturers of these products often produce multiple dosage strengths, however not all of them are being recalled. FDA recommends health care professionals and patients carefully check these lists. Health care professionals and patients should check this statement frequently for any updates.

FDA reminds consumers to continue taking your current medicine until your doctor or pharmacist gives you a replacement or a different treatment option. Untreated hypertension (high blood pressure) leads to an increase in the risk of heart attacks and stroke. Untreated heart failure increases the risk of hospitalization and death.

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


FDA updates health care professionals and patients on recent valsartan recalls

[7/18/2018] The U.S. Food and Drug Administration is updating health care professionals and consumers following a recent FDA press release about voluntary recalls of several drug products containing the active pharmaceutical ingredient (API) valsartan. Valsartan is used to treat high blood pressure and heart failure. Not all products containing valsartan are being recalled, and this update will clarify which valsartan-containing products are being recalled.

The recalled products contain an impurity, N-nitrosodimethylamine (NDMA), in the API manufactured by Zhejiang Huahai Pharmaceuticals, Linhai, China. The presence of the potentially cancer-causing NDMA was unexpected, and the agency believes the NDMA is related to changes in the way the active substance was manufactured. Some levels of the impurity may have been in the valsartan-containing products for as long as four years.

The investigation into valsartan-containing products is ongoing, and the following list may change. We will update this statement as we have more information.

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 where 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/12.5 mg, 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/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg, and 320 mg/25 mg products.

Detailed list of products included in the recall (PDF - 87 KB)

What should patients know:

  • Continue taking your current medicine until your doctor or pharmacist gives you a replacement or a different treatment option.
  • Not all valsartan-containing medications are affected and being recalled.
  • If you are taking any medication containing valsartan, compare the information on your prescription bottle with the information in this list (company, National Drug Code, lot number) to determine if your current medicine has been recalled. If you are not certain, contact your pharmacist.
  • If you have medicine included in the recall, contact your pharmacist. The pharmacist may be able to provide you with valsartan made by another company. If not, contact your doctor immediately to discuss other treatment options.

What health care professionals should know:

  • FDA has determined the recalled valsartan products pose an unnecessary risk to patients. Therefore, FDA recommends patients use valsartan-containing medicines made by other companies or consider other available treatment options for the patient’s medical condition.
  • If you have medication samples from these companies, quarantine the products and do not provide them to patients.

Consumers and health care professionals should 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

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Page Last Updated: 10/18/2018
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