Irbesartan FDA Alerts

Lupin Issues Voluntarily Nationwide Recall of All Irbesartan Tablets and Irbesartan and Hydrochlorothiazide Tablets Due to Potential Presence of N-nitrosoirbesartan Impurity

Oct 14, 2021 | Audience: Consumer, Health Professional, Pharmacy

Baltimore, Maryland, October 14, 2021: Lupin Pharmaceuticals Inc. is voluntarily recalling the below-mentioned batches of Irbesartan Tablets and Irbesartan and Hydrochlorothiazide Tablets to the consumer level. As part of Lupin’s ongoing assessment, analysis revealed that certain tested API batches (but not finished product batches) were above the specification limit for the impurity, N-nitrosoirbesartan. Although Lupin has received no reports of illness that appear to relate to this issue, the company, out of an abundance of caution, is recalling all batches of Irbesartan Tablets USP 75mg, 150mg and 300mg and Irbesartan and Hydrochlorothiazide Tablets USP, 150mg/12.5mg and 300mg/12.5mg in the US.

Lupin discontinued the marketing of Irbesartan and Irbesartan and HCTZ tabs in Jan 2021.

Risk Statement: N-nitrosoirbesartan impurity is a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests.

From October 8, 2018 (the earliest date of shipment from the manufacturing site of any of the affected batches), to September 30, 2021, Lupin received 4 reports of illness from Irbesartan and 0 reports from Irbesartan and Hydrochlorothiazide.

Irbesartan tablet USP is an angiotensin II receptor blocker indicated for treatment of hypertension, to lower blood pressure, diabetic nephropathy in hypertensive patients with type 2 diabetes, an elevated serum creatinine, and proteinuria. Irbesartan Tablets USP 75mg, 150mg and 300mg is packaged in 30 and 90 count bottles and was distributed nationwide in the US to wholesalers, drug chains, mail order pharmacies and supermarkets. Lupin discontinued the marketing of Irbesartan Tablets on Jan 7, 2021. The recalled lots are included in the table below:

Irbesartan and hydrochlorothiazide tablet USP is a combination of irbesartan, an angiotensin II receptor antagonist, and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension in patients not adequately controlled with monotherapy or as an initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. Irbesartan and hydrochlorothiazide tablet USP, 150mg/12.5mg and 300mg/12.5mg is packaged in 30 and 90 count bottles and was distributed nationwide in the US to wholesalers, drug chains, mail order pharmacies and supermarkets. Lupin discontinued the marketing of Irbesartan and HCTZ Tablets on Jan 7, 2021. The recalled lots are included in the table below:

Lupin Pharmaceuticals Inc. is notifying its wholesalers, distributors, drug chains, mail order pharmacies and supermarkets by phone and through recall notification and is arranging for the return of all the recalled product lots.

Patients taking, Irbesartan Tablets USP, 75mg, 150mg and 300mg and Irbesartan and Hydrochlorothiazide Tablets USP, 150mg/12.5mg and 300mg/12.5mg are advised to continue taking their medication and contact their pharmacist, physician, or medical provider for advice regarding an alternative treatment.

Wholesalers, distributors and retailers that have Irbesartan Tablets USP, 75mg, 150mg and 300mg and Irbesartan and Hydrochlorothiazide Tablets USP, 150mg/12.5mg and 300mg/12.5mg that are being recalled should discontinue distribution of the recalled product lots immediately and return it to Inmar Rx Solutions, Inc., 635 Vine St, Winston Salem, NC 27101. Tel: (855) 769-3988 / (855) 769-3989.

Consumers, wholesalers, distributors, and retailers with questions regarding this recall should contact Inmar Rx Solutions, Inc. at (855) 769-3988 / (855) 769-3989 Monday – Friday 09:00 am to 05:00 pm EST. For reimbursement, please have the recalled lots returned to Inmar Rx Solutions, Inc.; the lot number can be found on the side of the bottle label.

Adverse reactions or quality problems experienced with the use of this product may be reported to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax.

• Complete and submit the report Online
• Regular Mail or Fax: Download form or call 1- 800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

This recall is being conducted with the knowledge of the U.S. Food and Drug Administration.

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FDA Updates on Angiotensin II Receptor Blocker (ARB) Recalls

Nov 13, 2019 | Audience: Consumer, Health Professional, Pharmacy

IMPORTANT: Medications containing only amlodipine or hydrochlorothiazide (HCTZ) are not being recalled. Manufacturers are recalling medications containing amlodipine in combination with valsartan or losartan, and medications containing hydrochlorothiazide HCTZ in combination with valsartan or losartan.

• Search ARB Recalls List

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UPDATE - FDA warns Mylan for CGMP deviations

Update [11/13/2019] Today, the U.S. Food and Drug Administration posted a warning letter to Mylan Pharmaceuticals, Inc. in Chodavaram Village, Vizianagaram, Andhra Pradesh, India. Mylan manufactures valsartan active pharmaceutical ingredient (API) and has been one subject of an ongoing global investigation into nitrosamine impurities in angiotensin II receptor blockers (ARBs) such as valsartan, losartan and irbesartan.

The warning letter outlines several current good manufacturing practice (CGMP) deviations at this Mylan facility, including failure to have adequate written procedures for the receipt, identification and handling of raw materials and failure to adequately clean equipment and utensils. Failure to correct these deviations may result in further action by the agency. The warning letter is another result of the agency’s ongoing investigation.

FDA reminds patients taking recalled ARBs to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition.

UPDATE - FDA warns Torrent for CGMP violations

Update [10/15/2019] Today, the U.S. Food and Drug Administration posted a warning letter to Torrent Pharmaceuticals in Ahmedabad, Gujarat, India. Torrent manufactures losartan potassium tablets and has been one subject of an ongoing global investigation into nitrosamine impurities in angiotensin II receptor blockers (ARBs) such as valsartan, losartan and irbesartan.

The warning letter outlines several manufacturing violations at Torrent’s Taluka-Kadi, Indrad, Gujarat facility, including failure to follow written procedures for production and process control and failure to adequately investigate batch discrepancies. Failure to correct these violations may result in further action by the agency. The warning letter is another result of the agency’s ongoing investigation.

FDA reminds patients taking recalled ARBs to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition.

UPDATE - Torrent expands its voluntary recall of losartan

Update [9/20/2019] Torrent Pharmaceuticals is expanding its voluntary recall to include five additional lots of losartan potassium tablets (three lots of losartan potassium tablets and two lots of losartan potassium/hydrochlorothiazide (HCTZ) combination tablets). This recall is due to unacceptable amounts of N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) in the losartan active pharmaceutical ingredient manufactured by Hetero Labs Limited. Torrent is recalling lots of losartan-containing medication that tested positive for NMBA above 9.82 parts per million.

The agency updated the list of recalled angiotensin II receptor blockers (ARBs) accordingly.

FDA reminds patients taking recalled ARBs to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition.

UPDATE - Statement on the agency’s ongoing efforts to resolve safety issue with ARB medications

Update [8/28/19]  Protecting patients is the FDA’s highest priority, and Americans can be confident in the quality of the products the agency approves. The recent Angiotensin II Receptor Blocker (ARB) recalls have deeply concerned patients, the medical community, the agency and international regulatory bodies. The FDA is aware many patients rely on ARB medicines, and we are concerned about the presence of nitrosamine impurities in these drugs. Millions of people benefit from the high-quality products that the FDA regulates, and the U.S. has the most robust drug supply in the world, with strict standards for safety, effectiveness and quality.

Clarifying the risk and scope of exposure

As part of our efforts to be transparent regarding impurities in ARBs, we want to make sure patients have a full understanding of how these impurities may affect them. Notably, we would like to stress that the actual risk to patients is likely much lower than our estimates, which reflect a scientific assessment of the highest possible exposure. Weinitially estimated that if 8,000 people took the highest valsartan dose (320 mg) containing N-Nitrosodimethylamine (NDMA) from the recalled batches daily for four years, there may be one additional case of cancer over the lifetimes of those 8,000 people. In reality, the vast majority of patients exposed to NDMA through ARBs received much smaller amounts of the impurity than this worst-case scenario, and, since not all ARBs are affected, it’s very likely that a patient taking an ARB for four years would not have always received one of the affected products.

One question we have received from many patients and other stakeholders is how big the impact has been – how many patients have been affected? While we know the number of patients taking ARB medicines, we do not know the exact number of patients impacted by these ARB recalls. The reasons for this are nuanced. For example, we understand that health care professionals, out of an abundance of caution, may have replaced their patients’ ARB prescriptions that were not part of the announced recalls. Because patients’ prescription bottles do not always identify lot numbers, it was difficult for patients and pharmacists to determine whether a medicine was part of the recalls. Patients may have returned medication unnecessarily if their supply was not part of a recall, but they were unsure. Therefore, we estimate there were likely more drugs replaced due to recalls than necessary, which means more patients were impacted but not necessarily exposed to an impurity.

Manufacturers only estimate the number of products still in the distribution chain that are subject to recall, but not the number of impacted patients. However, through our ongoing track and trace efforts for prescription drugs in the supply chain, we’re working on ways to improve industry’s ability to track, detect and remove potentially dangerous drugs from the supply chain more rapidly and efficiently. ARB medications that contain impurities above the published interim acceptable limits continue to be recalled, with certain exceptions. However, it’s also important to underscore that there are ARB medicines that remain on the market and have been determined not to contain any nitrosamine impurities. We continue to encourage patients talk to a health care professional if they have questions about their medicine, as the risks of stopping taking an ARB product for treating high blood pressure and heart failure greatly outweighs the potential risk of exposure to trace amounts of nitrosamines.

Enhancing oversight of manufacturing data

As we continue our analysis of this situation to better understand the root causes, we’re learning more about how nitrosamine impurities may have formed and been present in ARBs. Through each step of our investigation, we’ve uncovered new information and taken a number of actions, including regulatory and advisory actions, where appropriate, to prevent the presence of unacceptable levels of these impurities. For example, earlier this month, we issued a warning letter to Lantech Pharmaceuticals Limited in Telangana, India, for current good manufacturing practice violations. Lantech acts as a contract solvent recovery facility for valsartan active pharmaceutical ingredient (API) manufacturing operations. When we inspected Lantech in March 2019, we determined that solvent recovered by the company contained N-Nitrosodiethylamine (NDEA) and that Lantech had insufficiently assessed the risks associated with their processes and did not adequately investigate the impurities. Specifically, the warning letter cites Lantech’s failure to control and monitor procedures to recover solvents to ensure that they meet appropriate standards before reuse. After we gathered and evaluated all the facts, we placed Lantech on import alert in June 2019, preventing API made using its recovered solvent from legally entering the U.S.

We continue to work closely with our global regulatory partners, including the European Medicines Agency (EMA), Health Canada, and many others, to understand the full scope of this issue. We share inspectional findings, laboratory testing methods and results, and our assessments of root cause and impact. We are working to incorporate what we have learned about the process risks that caused these impurities into our oversight of drug manufacturing, which includes how we assess applications and changes to applications, as well as enhancing our inspection coverage to evaluate the controls in place to prevent unacceptable levels of nitrosamine. For example, we plan to adjust inspections of API sites to include enhanced evaluation of impurity controls, particularly when the manufacturing process may lead to the formation of a nitrosamine or when recycled raw materials can create unacceptable contamination. In the past year, the agency has conducted multiple unannounced, for-cause inspections to evaluate the practices at various API manufacturers and to verify appropriate corrective actions to address the risk of nitrosamine contamination. We are also working to improve how companies submit manufacturing changes to the agency with the goal of further improving our review of the more than 5,000 quality-related application change requests (supplements) each year.

We continue to work with our global regulatory partners and industry as members of the International Conference on Harmonization (ICH) to publish guidance on controlling impurities in drugs and managing changes (e.g., ICHQ3A, Q3C, Q3D, Q7, Q11, and M7). These guidances and others developed through ICH are revised as new impurities and risks are identified and have helped prevent unacceptable impurities in drugs. We work with manufacturers during application review and after marketing begins over the lifecycle of their drugs to evaluate proposed process changes, conduct facility inspections, test samples of marketed drugs, evaluate complaints, and investigate issues that arise, all to protect the safety and quality of medicines.

Expanding our investigation

We have known that certain drug manufacturing processes pose a risk for forming genotoxic impurities, and this is an issue the FDA and other regulators have been working on for a number of years – well before the nitrosamine impurities were discovered in ARBs last summer. In fact, we issued guidance in early 2018 to provide information to manufacturers regarding their responsibilities to assess the risks and implement appropriate controls for their manufacturing process. Now that we know some of the root causes of the nitrosamine impurity problem, we’re using these findings to inform our evaluation of medicines other than ARBs. We are testing samples of other drugs with similar manufacturing processes. If we detect a problem, we will take appropriate action. In the meantime, we continue to work with ARB manufacturers to remove all affected drugs from the market, and we work with API manufactures to fix their processes so they do not distribute affected API to drug product manufacturers.

Our list of affected products and products without impurities remains available to the public, and we will update it when we have new information to share. We will also continue to provide timely updates about any future issues associated with this ongoing incident that may impact public health.

As we work to safeguard the quality of our medicines, the American public can expect that we will act quickly to address any issue as soon as we find out about it to prevent as much harm to patients as possible. We’re also committed to communicating as transparently as possible. When we found out about the impurities in ARB products, we worked with industry and our international regulatory colleagues to understand the situation and take preventative measures. We have also communicated frequently over the past year to share timely safety and manufacturing information. We have consistently and transparently communicated with pharmacists, patients and health care professionals about the ARB recalls as they have evolved.

Ultimately, our goal is to be certain that no ARBs with unacceptable impurity levels reach patients. Based on our current assessments, including lab testing, the agency has identified 43 ARB medications that have been determined not to contain any nitrosamine impurities. As we continue our assessments and as companies continue to manufacture ARBs without nitrosamine impurities to replenish the U.S. supply, we expect this figure to rise. We know that ARBs can be produced without nitrosamine impurities, and we are working with manufacturers to reach that point.

UPDATE - Macleods Pharmaceuticals voluntarily recalls losartan containing NMBA

Update [6/26/2019] FDA is alerting patients and health care professionals to Macleods Pharmaceuticals’ voluntary recall of two lots of losartan potassium tablets (50mg strength) and 30 lots of losartan potassium/hydrochlorothiazide (HCTZ) combination tablets (12 lots of 50mg/12.5mg strength, three lots of 100mg/12.5mg strength, and 15 lots of 100mg/25mg strength). This recall is due to unacceptable amounts of N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) in the losartan active pharmaceutical ingredient (API) manufactured by Hetero Labs Limited.

FDA is working with manufacturers to reduce and remove nitrosamines from angiotensin II receptor blockers (ARBs). The agency also updated the list of recalled angiotensin II receptor blockers (ARBs) .

FDA reminds patients taking recalled ARBs to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition.

UPDATE - Teva expands its voluntary recall of losartan

Update [6/12/2019] Teva Pharmaceuticals is expanding its voluntary recall to include seven additional lots of losartan potassium tablets (three lots of 50 mg strength and four lots of 100 mg strength) labeled by Golden State Medical Supply. This recall is due to unacceptable amounts of N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) in the losartan active pharmaceutical ingredient (API) manufactured by Hetero Labs Limited. Teva is recalling lots of losartan-containing medication that tested positive for NMBA above 9.82 parts per million.

The agency updated the list of recalled angiotensin II receptor blockers (ARBs) accordingly.

FDA reminds patients taking recalled ARBs to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition.

UPDATE - FDA alerts patients and health care professionals to Vivimed’s recall of losartan medication due to NMBA

Update [5/6/2019] FDA is alerting patients and health care professionals to a voluntary recall of 19 lots of losartan potassium tablets made by Vivimed Life Sciences Pvt Ltd in Alathur, Chennai, India and distributed by Heritage Pharmaceuticals Inc, East Brunswick, New Jersey, due to the detection of the impurity N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). Vivimed is recalling lots of losartan-containing medication that tested positive for NMBA above 9.82 parts per million.

Manufacturers should contact FDA’s Drug Shortages Staff when their testing of losartan shows levels of NMBA that exceed the interim acceptable intake limit of 0.96 ppm. FDA will determine, on a case-by-case basis, whether lots containing NMBA greater than 0.96 ppm should be released for distribution.

FDA reminds patients taking recalled angiotensin II receptor blockers (ARBs) to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition.

The agency also updated the list of recalled ARBs.

UPDATE - Laboratory analysis of valsartan products

Update [5/2/2019] FDA posted laboratory test results showing NDEA levels in recalled valsartan products as well as an assessment of the cancer risk from NDEA in valsartan.

FDA alerts patients and health care professionals to Teva’s recall and Legacy’s expanded recall of losartan medication due to NMBA

Update [4/29/2019] FDA is alerting patients and health care professionals to a voluntary recall of 44 lots of losartan potassium tablets manufactured by Teva Pharmaceuticals and labeled as Golden State Medical Supply due to the detection of the impurity N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). The recalled products were made with active pharmaceutical ingredient (API) manufactured by Hetero Labs. Teva is recalling lots of losartan-containing medication that tested positive for NMBA above 9.82 parts per million.

Additionally, Legacy expanded its recall to include one additional lot of losartan tablets made with API manufactured by Hetero Labs.

Manufacturers should contact FDA’s Drug Shortages Staff when their testing of losartan shows levels of NMBA that exceed the interim acceptable intake limit of 0.96 ppm. FDA will determine, on a case-by-case basis, whether lots containing NMBA greater than 0.96 ppm should be released for distribution.

The agency also updated the list of recalled losartan medicines.

Torrent further expands its voluntary recall of losartan; FDA posts new nitrosamine testing methods

Update [4/19/2019] Torrent Pharmaceuticals Limited is further expanding its voluntary recall to include 104 additional lots of losartan potassium and losartan potassium/hydrochlorothiazide combination tablets. This recall is due to unacceptable amounts of N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) in the losartan active pharmaceutical ingredient (API) manufactured by Hetero Labs Limited.

FDA reminds patients taking recalled angiotensin II receptor blockers (ARBs) to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition.

FDA is also posting new testing methods which can help manufacturers and international regulators detect and identify multiple nitrosamine impurities. FDA and international regulators have identified N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA) and NMBA in ARBs.

• A direct injection GC-MS method that is able to detect NDMA, NDEA, N-Nitrosodiisopropylamine (NDIPA), N-Nitrosoethylisopropylamine (NEIPA), and N-nitrosodibutylamine (NDBA)
• A headspace GC-MS method that is able to detect NDMA, NDEA, NDIPA, and NEIPA

These methods 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 and losartan-containing medicine information

Update [3/22/2019] FDA has updated the list of valsartan medicines under recall to incorporate additional repackagers of Aurobindo’s valsartan-containing medicine.

FDA not objecting to losartan with NMBA below 9.82 ppm remaining on the market

Update [3/20/2019] To ensure patient access to losartan, FDA will not object to certain manufacturers temporarily distributing losartan containing N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) above the interim acceptable intake limit of 0.96 parts per million (ppm) and below 9.82 ppm until the impurity can be eliminated. The agency expects many companies will be able to manufacture losartan without nitrosamine impurities and replenish the U.S. supply in approximately six months.

Agency scientists evaluated the risk of exposure to NMBA at levels up to 9.82 ppm and determined that it presents no meaningful difference in cancer risk over a six-month time period when compared to a lifetime of exposure to NMBA at 0.96 ppm. Distributing losartan containing NMBA up to 9.82 ppm, will help maintain adequate losartan supply while companies obtain approval for manufacturing processes that produce nitrosamine-free losartan for patients.

FDA reminds patients taking recalled losartan to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition. 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. Untreated diabetic nephropathy (kidney disease) leads to worsening renal (kidney) disease.

Manufacturers should contact FDA’s Drug Shortages Staff when their testing of losartan shows levels of NMBA that exceed the interim acceptable intake limit of 0.96 ppm. FDA will determine, on a case-by-case basis, whether lots containing NMBA greater than 0.96 ppm should be released for distribution.

FDA continues to work with companies and international regulators to ensure products entering the U.S. market do not contain nitrosamine impurities.

Torrent again expands its voluntary recall of losartan; Hetero also voluntarily recalls losartan

Update [3/1/2019] Torrent Pharmaceuticals Limited is further expanding its voluntary recall to include 114 additional lots of losartan potassium and losartan potassium/hydrochlorothiazide combination tablets. This recall is due to unacceptable amounts of N-Methylnitrosobutyric acid (NMBA) in the losartan active pharmaceutical ingredient manufactured by Hetero Labs Limited.

Today, the agency also issued a press release to provide additional information about its ongoing investigation and another voluntary recall by Hetero/Camber Pharmaceuticals, which was announced on February 28, of 87 lots of losartan potassium tablets (25 mg, 50 mg and 100 mg). The recalled losartan potassium and losartan potassium/hydrochlorothiazide tablets are also manufactured by Hetero, which are distributed by Camber, and contain the impurity NMBA.

Torrent and Hetero/Camber are only recalling lots of losartan-containing medication with NMBA above the interim acceptable intake limits of 0.96 parts per million (ppm).

Aurobindo expands its voluntary recall of valsartan and amlodipine/valsartan

Update [3/1/2019] AurobindoPharma USA is expanding its voluntary recall to include 38 additional lots of valsartan and amlodipine/valsartan combination tablets. The recall is due to unacceptable amounts of N-Nitrosodiethylamine (NDEA) found in the medicine.

Aurobindo is only recalling lots of valsartan-containing medication where NDEA has been detected above the interim acceptable intake limit of 0.083 parts per million. FDA is working with manufacturers to reduce and remove nitrosamines from angiotensin II receptor blockers (ARBs).

The agency also updated the valsartan products under recall.

FDA updates table of interim limits for nitrosamine impurities in ARBs

Update [2/28/2019] FDA is posting the updated table of interim acceptable intake limits for nitrosamine impurities to reflect N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) limits, which are the same as those for NDMA.

The agency will use the interim limits below to recommend manufacturers conduct a voluntary recall if laboratory testing confirms the presence of nitrosamine impurities in finished drug product. FDA is working with industry and international regulators to ensure products entering the market do not contain these impurities, but we are tolerating the impurities below the level established in the table for a short period of time to avoid a possible shortage of ARBs.

Not all ARB products contain NDMA, NDEA or NMBA impurities, so pharmacists may be able to provide an alternative medication not affected by the recalls, or health care professionals may prescribe a different medication that treats the same condition.

Interim Limits for NDMA, NDEA, and NMBA in Angiotensin II Receptor Blockers (ARBs)

* The acceptable intake is a daily exposure to a compound such as NDMA, NDEA, or NMBA that approximates a 1:100,000 cancer risk after 70 years exposure
** These values are based on a drug's maximum daily dose as reflected in the drug label

Losartan distributed by Macleods Pharmaceuticals voluntarily recalled

Update [2/25/2019] FDA is alerting patients and health care professionals to a voluntary recall of one lot of losartan potassium/hydrochlorothiazide (HCTZ) 100mg/25mg combination tablets manufactured by Macleods Pharmaceuticals. The recall is due to unacceptable amounts of N-Nitrosodiethylamine (NDEA) found in the medicine made with active pharmaceutical ingredient manufactured by Hetero Labs Limited.

Macleods is only recalling lots of losartan-containing medication where NDEA has been detected above the interim acceptable intake limit of 0.27 parts per million. FDA is working with manufacturers to reduce and remove nitrosamines from angiotensin II receptor blockers (ARBs).

Torrent further expands its voluntary recall of losartan

Update [1/23/2019] Torrent Pharmaceuticals is further expanding its voluntary recall to include six additional lots of losartan potassium and hydrochlorothiazide combination tablets, for a total of 16 lots of losartan-containing medicines. This recall is due to unacceptable amounts of N-Nitrosodiethylamine (NDEA) in the losartan active pharmaceutical ingredient manufactured by Hetero Labs Limited.

Torrent is only recalling lots of losartan-containing medication containing NDEA above the interim acceptable intake limits of 0.27 parts per million (ppm).

Irbesartan distributed by Solco Healthcare voluntarily recalled

Update [1/18/2019] FDA is alerting patients and health care professionals to a voluntary recall of one lot of irbesartan and seven lots of irbesartan and hydrochlorothiazide (HCTZ) combination tablets distributed by Solco Healthcare LLC, a Prinston Pharmaceutical Inc. subsidiary. The recall is due to unacceptable amounts of N-Nitrosodiethylamine (NDEA) in the irbesartan active pharmaceutical ingredient manufactured by Zhejiang Huahai Pharmaceuticals (ZHP).

Solco is only recalling lots of irbesartan-containing medication where NDEA has been detected above the interim limit of 0.088 parts per million. FDA is working with manufacturers to reduce and remove nitrosamines from angiotensin receptor II blockers (ARBs).

The agency also updated the list of irbesartan products under recall.

Torrent expands its voluntary recall of losartan

Update [1/3/2019] Torrent Pharmaceuticals is expanding its voluntary recall to include eight additional lots of losartan potassium tablets, for a total of 10 lots. This recall is due to trace amounts of N-Nitrosodiethylamine (NDEA) in the losartan active pharmaceutical ingredient (API) manufactured by Hetero Labs Limited.

Torrent is only recalling lots of losartan medication containing NDEA above the interim acceptable intake level of 0.27 parts per million.

FDA alerts patients and health care professionals to Aurobindo’s recall of valsartan medication due to NDEA

Update [1/2/2019] FDA is alerting patients and health care professionals to Aurobindo Pharma USA’s voluntary recall of two lots of valsartan tablets, 26 lots of amlodipine and valsartan combination tablets, and 52 lots of valsartan and hydrochlorothiazide (HCTZ) combination tablets due to the amount of N-Nitrosodiethylamine (NDEA) in the valsartan active pharmaceutical ingredient. Aurobindo is recalling amlodipine and HCTZ only in combination medications containing valsartan. Neither amlodipine nor HCTZ is currently under recall by itself.

Aurobindo is recalling lots of valsartan-containing medication that tested positive for NDEA above the interim acceptable daily intake level of 0.083 parts per million.

The agency continues to investigate and test all angiotensin II receptor blockers (ARBs) for the presence of NDEA and N-Nitrosodimethylamine (NDMA) and is taking swift action when it identifies these impurities that are above interim acceptable daily intake levels.

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

FDA reminds patients taking any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition. Some ARBs contain no NDMA or NDEA.

FDA alerts patients and health care professionals to Torrent’s recall of losartan medication due to NDEA

Update [12/20/2018] FDA is alerting patients and health care professionals to Torrent Pharmaceuticals’
voluntary recall of two lots of losartan potassium 100 mg tablets due to N-Nitrosodiethylamine (NDEA) in the losartan active pharmaceutical ingredient (API) manufactured by Hetero Labs Limited.

Not all Torrent losartan-containing medications distributed in the U.S. are being recalled. Torrent is recalling only those lots of losartan medication that tested positive for NDEA above the acceptable daily intake of 0.27 ppm.

The agency continues to investigate and test all angiotensin II receptor blockers (ARBs) for the presence of NDEA and N-Nitrosodimethylamine (NDMA) and is taking swift action when it identifies these impurities that are above acceptable daily intake levels.

FDA posted a list of losartan medications under recall. Additionally, FDA reminds patients taking this medication or any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. It also is important to know not all ARBs contain NDMA or NDEA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.

FDA presents interim limits of nitrosamines in currently marketed ARBs

Update [12/19/2018] FDA is publishing interim acceptable intake levels of nitrosamine impurities in angiotensin II receptor blockers (ARBs) for manufacturers to use to ensure their finished drug products are safe for patients.

The agency evaluated safety data for N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) to determine an interim acceptable intake level for these impurities in the ARB class. NDMA and NDEA are probable human carcinogens and should not be present in drug products. We are currently aware of NDMA and NDEA in certain valsartan, irbesartan and losartan-containing products, and those products and some active pharmaceutical ingredients (API) used to manufacture them have been recalled from the U.S. market. See the list of valsartan products under recall and the list of irbesartan products under recall. 

Drug products that contain NDMA or NDEA above the limits in the table below pose an unacceptable risk to patients. The agency will use the interim limits to recommend manufacturers conduct a voluntary recall if laboratory testing confirms the presence of nitrosamine impurities in finished drug product. FDA is working with industry and international regulators to ensure products entering the market do not contain these impurities, but we are tolerating the impurities below the level established in the table for a short period of time to avoid a possible shortage of ARBs.

The agency reminds manufacturers they are responsible for developing and using suitable methods to detect impurities, including when they make changes to their manufacturing processes. If a manufacturer detects a new impurity or higher level of impurities, they should fully evaluate the impurities and take action to ensure the product is safe for patients. To aid industry and regulatory agencies, FDA has developed and published methods to detect NDMA and NDEA impurities – the gas chromatography/mass spectrometry (GC/MS) headspace method, the combined GC/MS headspace method, and the combined GC/MS direct injection method. These methods can be used for drug substances and products, and users should validate them as part of good manufacturing practices and where data are used to support a regulatory submission or required quality assessment of the API or drug product.

Not all ARB products contain NDMA or NDEA impurities, so pharmacists may be able to provide an alternative medication not affected by the recalls, or health care professionals may prescribe a different medication that treats the same condition.

Interim Limits for NDMA and NDEA in Angiotensin II Receptor Blockers (ARBs)

* The acceptable intake is a daily exposure to a compound such as NDMA or NDEA that results in a 1:100,000 cancer
risk after 70 years exposure
** These values are based on a drug's maximum daily dose as reflected in the drug label

For comparison with the levels of NDMA found in some common foods, please see our Aug. 20, 2018, update.

FDA updates NDMA and NDEA detection methods, announces posting of ZHP warning letter

Update [12/12/2018] The FDA has updated its testing methods to detect NDMA and NDEA impurities – the (GC/MS) headspace method, the combined headspace method, and the combined direct injection method – by adding the limits of detection (LOD) and clarifying that the methods can be used for both drug substances and drug products. These methods were validated with respect to valsartan drug substances and drug products, but the agency expects them to have comparable LODs and limits of quantitation (LOQ) for other angiotensin II receptor blockers (ARB).

Mylan expands its voluntary recall of valsartan-containing products

Update [12/6/2018] Mylan Pharmaceuticals is expanding its voluntary recall to include all lots of non-expired valsartan-containing products due to trace amounts of N-Nitrosodiethylamine (NDEA) in the valsartan active pharmaceutical ingredient (API) manufactured by Mylan Laboratories Limited. The 104 additional lots include 26 lots of amlodipine and valsartan tablets, 51 lots of valsartan tablets and 27 lots of valsartan and hydrochlorothiazide tablets. These lots were distributed in the U.S. between March 2017 and November 2018. 

The agency also updated the list of valsartan products under recall and the list of valsartan products not under recall.

FDA alerts patients and health care professionals to Teva’s recall of valsartan products due to NDEA

Update [11/27/2018] FDA is alerting patients and health care professionals to Teva Pharmaceuticals’ voluntary recall of valsartan-containing products manufactured using active pharmaceutical ingredient (API) from Mylan Pharmaceuticals. Mylan voluntarily recalled valsartan-containing products on November 20.

Teva is recalling all lots of amlodipine and valsartan combination tablets and amlodipine, valsartan, and hydrochlorothiazide (HCTZ) combination tablets due to the presence of N-Nitrosodiethylamine (NDEA). Teva has recalled other valsartan-containing products in recent months due to the presence of N-Nitrosodimethylamine (NDMA). With this recall, Teva has now recalled all their unexpired valsartan-containing products from the U.S. market.

The agency continues to investigate and test all angiotensin II receptor blocker (ARBs) for the presence of NDMA and NDEA and is taking swift action when it identifies these impurities that are above acceptable levels.

FDA has updated the list of valsartan products under recall and the list of valsartan products not under recall. The agency reminds patients taking this medication or any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. It also is important to know that not all ARBs contain NDMA or NDEA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.

FDA alerts patients and health care professionals to Mylan’s recall of valsartan products due to NDEA

Update [11/21/2018] FDA is alerting patients and health care professionals to Mylan Pharmaceuticals’ voluntary recall of 15 lots of valsartan-containing products due to the presence of N-Nitrosodiethylamine (NDEA).

Not all Mylan valsartan-containing products distributed in the U.S. are being recalled. Mylan is recalling only those lots of valsartan-containing products that tested positive for NDEA above the acceptable level. The agency continues to investigate and test all angiotensin II receptor blockers (ARBs) for the presence of NDEA and N-Nitrosodimethylamine (NDMA) and is taking swift action when it identifies these impurities that are above acceptable levels.

FDA has updated lists of valsartan products under recall and valsartan products not under recall. Additionally, FDA reminds patients taking this medication or any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. It also is important to know not all ARBs contain NDMA or NDEA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.

FDA has also posted questions and answers to assist health care professionals and patients.

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FDA alerts patients and health care professionals to Sandoz’s losartan potassium and hydrochlorothiazide recall of one lot due to NDEA

Update [11/9/2018] FDA is alerting patients and health care professionals to Sandoz’s voluntary recall of one lot – JB8912 – of losartan potassium and hydrochlorothiazide 100mg/25mg tablets, that contain losartan, an angiotensin II receptor blocker (ARB), and hydrochlorothiazide, a diuretic, used in combination for the treatment of hypertension. Sandoz’s product was made using an active pharmaceutical ingredient (API) that has tested positive for NDEA. The API was manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd, which is on import alert.

Sandoz’s losartan drug products make up less than 1 percent of the total losartan drug products in the U.S. market.

FDA continues to investigate the presence of NDEA and NDMA, which are probable human carcinogens, in ARBs and is taking swift action when it identifies unacceptable impurities in API and finished drug products.

FDA reminds patients taking this medication or any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. It also is important to know not all ARBs contain NDEA or NDMA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.

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FDA alerts patients and health care professionals to ScieGen’s irbesartan recall due to NDEA

Certain irbesartan products labeled as Westminster Pharmaceuticals Inc. and GSMS Inc. recalled

Update [10/30/2018] FDA is alerting patients and health care professionals to ScieGen’s voluntary recall of certain lots of irbesartan, an angiotensin II receptor blocker (ARB), because they contain N-Nitrosodiethylamine (NDEA), a known animal and suspected human carcinogen (causes cancer). FDA laboratory testing confirmed NDEA in some lots of ScieGen’s irbesartan. ScieGen’s irbesartan products are labeled as Westminster Pharmaceuticals and Golden State Medical Supply, Inc. (GSMS). See the list of irbesartan products under recall. This is the first non-valsartan drug product the agency has found to contain the NDEA impurity.

ScieGen’s recall affects about 1 percent of the irbesartan drug products in the U.S. market.

Additionally, Aurobindo, which manufactures the active pharmaceutical ingredient (API) for ScieGen’s irbesartan products, is recalling all unexpired lots of its irbesartan API supplied to the U.S. market with NDEA. FDA and Aurobindo laboratory testing confirmed NDEA in certain lots of their irbesartan API.

FDA reminds patients taking any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. Not all ARBs contain NDEA or N-Nitrosodimethylamine (NDMA), a probable human carcinogen previously found in certain recalled valsartan products, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.

To date, ScieGen is the only manufacturer of irbesartan drug products found to contain NDEA. FDA continues to test all ARBs for the presence of impurities and has publicly posted two methods for manufacturers and regulatory agencies around the world to test their ARBs for the unexpected NDMA and NDEA impurities. The combined headspace method and the combined direct injection method can detect and quantify NDMA and NDEA simultaneously in ARB API and finished drug products.

FDA continues to work with API and drug manufacturers to ensure their products are not at risk for NDMA or NDEA formation. The agency reminds manufacturers they are responsible for developing and using 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.

For additional information about ARB products, see:

• list of valsartan products under recall
• list of valsartan products not under recall

FDA updates recalled valsartan-containing product information

Update [10/24/2018] FDA continues to evaluate valsartan-containing products and other angiotensin II receptor blockers (ARBs), and has updated the list of products included in the recall to add one additional lot of RemedyRepack.

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.

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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.

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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. 

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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.

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

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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.accessdata.fda.gov/scripts/medwatch/index.cfm
• Download and complete the appropriate form, then submit it via fax at 1-800-FDA-0178

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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.

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 the 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
• Download and complete the appropriate form, then submit it via fax at 1-800-FDA-0178

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Prinston Pharmaceutical Inc. Issues Voluntary Nationwide Recall of Irbesartan and Irbesartan HCTZ Tablets Due to Detection of a Trace Amount of Unexpected Impurity, N-Nitrosodiethylamine (NDEA) in the Products

Jan 18, 2019 | Audience: Consumer, Health Professional, Pharmacy

Prinston Pharmaceutical Inc., dba Solco Healthcare LLC., has initiated a voluntary recall of one (1) lot of Irbesartan and seven (7) lots of Irbesartan HCTZ Tablets to the consumer level due to the detection of trace amount of an unexpected impurity found in an active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceuticals.

Prinston is only recalling lots of Irbesartan-containing products that contain N- nitrosodiethylamine (NDEA) above the acceptable daily intake levels released by the FDA.

N-nitrosodiethylamine (NDEA) is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes and has been classified as a probable human carcinogen as per International Agency for Research on Cancer (IARC) classification.

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

Irbesartan and Irbesartan HCTZ are used to control high blood pressure and for the treatment of heart failure. Irbesartan in combination with amlodipine plus hydrochlorothiazide is used to control high blood pressure.

Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication. Patients who are on Irbesartan should continue taking their medication, until their pharmacist provides a replacement, or their doctor prescribes a different medication that treats the same condition as the risk of harm to a patient’s health may be higher if the treatment is stopped immediately without any alternative treatment.

The product subject to recall are listed below and packaged in bottles. The product can be identified by checking the product name, manufacturer details and batch or lot number on the bottle containing these products.

 

Prinston’s Irbesartan and Irbesartan/HCTZ tablets were distributed nationwide to wholesale, distributor, repackager and retail customers. Prinston Pharmaceutical Inc. dba Solco Healthcare LLC. is notifying its distributors and customers by phone and in writing to immediately discontinue distribution of the specific lots being recalled and to notify their sub-accounts. Prinston Pharmaceutical Inc. dba Solco Healthcare LLC. is arranging for return of all recalled products. Instructions for returning recalled products are given in the recall letter.

Retail pharmacies in possession of any unused products: Irbesartan Tablets, 300 mg/90 ct. and Irbesartan-HCTZ Tablets, 300mg/12.5mg, 150mg/12.5mg, in 30 and 90 ct. within the above expiry dates should immediately return the product by following the instructions below:

• Immediately examine your inventory and quarantine product subject to recall.
• Immediately discontinue use and distribution of the identified lot numbers. A credit memo will be issued covering the quantity of your product returned.

Return products to:

Eversana
Attn: Returns Department C/O Solco Healthcare 4580 S. Mendenhall,
Memphis, TN 38141

Note: A return label will be provided to you, free of charge. For the call tag, contact customer service via email customerservice@solcohealthcare.com; fax 1-866-931-0709. Wholesalers: No call necessary, just send debit memo via email or fax to customerservice@solcohealthcare.com; fax 1-866-931-0709

Solco is notifying its distributors and customers by letter and email and is arranging for return of all recalled products. Pharmacies and wholesalers that received the impacted products will receive a letter as well as a copy of this press release with their recall notification information.

Consumers should contact their physician or healthcare provider if they have experienced any problems that may be related to using this product.

Adverse reactions or quality problems associated with the use of this product may be reported to FDA's MedWatch Adverse Event Reporting program either by phone, on line, by regular mail or by fax.

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Sciegen Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Irbesartan Tablets, USP 75 mg, 150 mg, and 300 mg Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in The Active Pharmaceutical Ingredient (API)

Oct 30, 2018 | Audience: Consumer, Health Professional, Pharmacy

October 30, 2018 -- ScieGen Pharmaceuticals, Inc. is voluntarily recalling listed lots, within expiry, of Irbesartan Tablets, USP 75 mg, 150 mg, and 300 mg dosage forms to the consumer level. These products are being recalled due to the presence of an impurity, N-nitrosodiethylamine (NDEA) contained in the API Irbesartan, USP manufactured by Aurobindo Pharma Limited. This impurity, which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, has been classified as a probable human carcinogen as per International Agency for Research on Cancer (IARC)

To date, Sciegen Pharmaceuticals Inc has not received any reports of adverse events related to this product.

Irbesartan tablets, USP are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

Irbesartan Tablets, USP 75 mg, 150 mg, and 300 mg were manufactured by ScieGen Pharmaceuticals Inc and are labeled as Westminster Pharmaceuticals and Golden State Medical Supply, Inc [GSMS].

The recalls and returns will be managed by the respective distributors separately for the lots distributed by them as outlined below.

Details of batches sent to Westminster

The Irbesartan tablets subject to recall are packed in 30-count and 90-count bottles. To help identify the recalled product, the NDCs, product description, lot numbers and expiration dates are listed below. These lots were distributed nationwide in the USA to Westminster’s direct accounts.

Westminster is notifying its direct accounts by email and by phone to immediately discontinue distribution of the product being recalled and to notify their wholesale and retail accounts of this product recall and make arrangements for impacted product to be returned to Westminster. Instructions for returning recalled products are provided in the Recall Notice Letter and Recall Response Form. Patients should return the effected medication to their pharmacy. Pharmacies should return their effected stock to their wholesaler.

If you are taking Irbesartan, please examine your tablets and look for the specific markings to determine if you’re product is affected by this recall. Products can be best identified by patients as being white, oval shaped tablets debossed with SG 160; SG 161; or SG 162.

Customers and patients with medical-related questions, information about an adverse event or other questions about the Westminster’s product’s being recalled should contact Westminster’s Regulatory Affairs department by phone at: 888-354-9939

• Live calls are received Monday-Friday, 9:00AM - 5:00PM EST with voicemail available 24 hours/day, 7 days/week or email recalls@wprx.com.

Details of batches sent to Golden State Medical Supply, Inc [GSMS] 

The products subject to recall are packed in 30-count and 90-count bottles. To help identify the recalled product, the NDCs, Product Description, Lot numbers and Expiration dates are listed below. These lots were distributed nationwide in the USA to GSMS’ direct accounts.

Complete the Recall Inventory Response Form and return to Golden State Medical Supply Incorporated email: recalls@gsms.us or by via Fax: (805) 477-9869 Contact Golden State Medical Supply Incorporated for directions on return authorizations by calling (800) 284-8633 ext. 215 between 7:30AM-4:00PM Pacific; or email: recalls@gsms.us.

If you are taking Irbesartan, please examine your tablets and look for the specific markings to determine if you’re product is affected by this recall. Products can be best identified by patients as being white, oval shaped tablets debossed with SG 160; SG 161; or SG 162.

Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication. Patients who are on Irbesartan should continue taking their medication, as the risk of harm to a patient’s health may be higher if the treatment is stopped immediately without any alternative treatment. Patients should contact their physician or healthcare provider if they have experienced any problems that may be related to taking or using Irbesartan.

Adverse reactions or quality problems experienced with the use of this product may be reported to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax.

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Aurobindo Pharma Limited Issues Voluntary Recall of Irbesartan Drug Substance due to the Detection of Trace Amounts of NDEA (NNitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Oct 26, 2018 | Audience: Consumer, Health Professional, Pharmacy

October 26, 2018 -- Aurobindo Pharma Limited is voluntarily recalling 22 Batches of the drug substance Irbesartan due to the presence of an impurity, N-nitrosodiethylamine (NDEA). The impurity, which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, has been classified as a probable human carcinogen as per International Agency for Research on Cancer (IARC).

These 22 batches of Irbesartan drug substance were supplied to ScieGen Pharmaceuticals Inc., U.S. for the manufacturing of finished Irbesartan drug product (see attached annexure).

Aurobindo Pharma Limited has notified ScieGen Pharmaceuticals, Inc. of the recall and is arranging for the return of all available Irbesartan drug substance. Aurobindo Pharma Limited has further advised Sciegen Pharmaceuticals, Inc. to contact its distributors and retailers to return Irbesartan drug product and finished Irbesartan tablets that has been identified by Aurobindo Pharma Limited.

Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication. Patients who are on Irbesartan should continue taking their medication, as the risk of harm to a patient’s health may be higher if the treatment is stopped immediately without any alternative treatment. Patients should contact their physician or healthcare provider if they have experienced any problems that may be related to taking or using Irbesartan.

 Annexure -I
Irbesartan batches Supplied to US Customers

 

 

Remark: For Dispatch batch no. 1701114283 & 1701114284, Mother Batch is common 170111255 8

For Dispatch batch no. 1701117039 & 1701117041, Mother Batch is common 1701115460

Total No. of Mother Batches: 20

Total No. of dispatch Batches: 22.

Source: FDA

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Angiotensin Receptor Blockers (ARBs): Drug Safety Communication - Drug Safety Review Completed

Jun 2, 2011 | Audience: Cardiology, Oncology, Family Practice

[UPDATED 06/02/2011] FDA’s meta-analysis of 31 randomized controlled trials comparing ARBs to other treatment found no evidence of an increased risk of incident (new) cancer, cancer-related death, breast cancer, lung cancer, or prostate cancer in patients receiving ARBs.

 

[Posted 07/15/2010]

ISSUE: A recently published study - a meta-analysis combining cancer-related findings from several clinical trials - suggested use of ARBs may be associated with a small increased risk of cancer.

BACKGROUND: ARBs are used in patients with high blood pressure and other conditions. Brand names include Atacand, Avapro, Benicar, Cozaar, Diovan, Micardis, and Teveten.

The meta-analysis included data from over 60,000 patients in several long-term, randomized, controlled clinical trials evaluating ARBs for which adverse events related to cancer were captured during the study. The mean duration of follow-up ranged from 1.7 to 4.8 years.

The study reported the frequencies of new cancer occurrence to be 7.2% for patients receiving ARBs compared to 6.0% for those not receiving ARBs (risk ratio = 1.08, 95% Confidence Interval: 1.01-1.15). No statistically significant difference in cancer deaths was noted.

RECOMMENDATION: FDA has not concluded that ARBs increase the risk of cancer. The Agency is reviewing information related to this safety concern and will update the public when additional information is available. FDA believes the benefits of ARBs continue to outweigh their potential risks.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Online: www.accessdata.fda.gov/scripts/medwatch/index.cfm
• Phone: 1-800-332-1088
• Mail: return the postage-paid FDA form 3500, which may be downloaded from the MedWatch "Download Forms" page, to address on the pre-addressed form
• Fax: 1-800-FDA-0178

[06/02/2011 - Drug Safety Communication - FDA]
[07/15/2010 - Drug Safety Communication - FDA]

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