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FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan)

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UPDATES & PRESS ANNOUNCEMENTS

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)

Drug Maximum Daily Dose (mg/day) Acceptable Intake NDMA (ng/day)*    Acceptable Intake NDMA (ppm)** Acceptable Intake NDEA (ng/day)*     Acceptable Intake NDEA (ppm)** Acceptable Intake NMBA (ng/day)*     Acceptable Intake NMBA (ppm)**
Valsartan 320 96 0.3 26.5 0.083 96 0.3
Losartan 100 96 0.96 26.5 0.27 96 0.96***
Irbesartan 300 96 0.32 26.5 0.088 96 0.32
Azilsartan 80 96 1.2 26.5 0.33 96 1.2
Olmesartan 40 96 2.4 26.5 0.66 96 2.4
Eprosartan 800 96 0.12 26.5 0.033 96 0.12
Candesartan 32 96 3.0 26.5 0.83 96 3.0
Telmisartan 80 96 1.2 26.5 0.33 96 1.2

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

      FDA-published testing methods to provide options for regulators and industry to detect NDMA and NDEA impurities

      The links below are to FDA-published testing methods to provide options for regulators and industry to detect nitrosamine impurities in ARB drug substances and drug products. 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.

      • Combined headspace method: a GC/MS method that allows determination of both N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) simultaneously
      • Combined direct injection method: a GC-MS/MS method that allows for determination of both NDMA and NDEA simultaneously
      • Direct injection GC-MS method: a method that can detect NDMA, NDEA, N-Nitrosodiisopropylamine (NDIPA), N-Nitrosoethylisopropylamine (NEIPA), and N-nitrosodibutylamine (NDBA)
      • Headspace GC-MS method: a method that can detect NDMA, NDEA, NDIPA, and NEIPA
      • LC-HRMS method: a method that can detect NDMA, NDEA, NEIPA, NDIPA, NDBA, and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA)
      • RapidFire-MS/MS method: a method that can detect NEIPA, NDIPA, NDBA, and NMBA. We do not recommend using this method to detect NDMA or NDEA because it is less sensitive to those impurities.

      The LC-HRMS and RapidFire-MS/MS methods are the first methods FDA has posted for detecting NMBA. The European Directorate for the Quality of Medicines (EDQM) has also published methods to detect NDMA and NDEA. FDA has not validated EDQM's methods.



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