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FDA works to mitigate shortages of rifampin and rifapentine after manufacturers find nitrosamine impurities

FDA not objecting to rifapentine with CPNP at or below 20 ppm remaining on the market 

[Update 10/29/2020] To continue to mitigate or avoid a shortage and to help ensure patients have access to rifapentine, FDA will not object to certain manufacturers temporarily distributing the medicine containing 1-cyclopentyl-4-nitrosopiperazine (CPNP) above the acceptable intake limit of 0.1 parts per million (ppm) and at or below 20 ppm until they can reduce or eliminate the impurity. 

Manufacturers should contact the Center for Drug Evaluation and Research’s Drug Shortages Staff when their testing of rifapentine shows levels of CPNP that exceed 0.1 ppm. FDA will determine on a case-by-case basis whether those drugs should be released for distribution.   

Tuberculosis is a potentially deadly disease that affects the lungs and sometimes other parts of the body, and the risk of not taking the medicine outweighs any potential risk from CPNP. 

FDA continues its ongoing review, surveillance, compliance and pharmaceutical quality efforts across every product area and will continue to work with drug manufacturers to ensure safe, effective and high-quality drugs for the American public.
 


[8/26/2020] FDA recently became aware of nitrosamine impurities in certain samples of rifampin and rifapentine. These are antibacterial drugs used to treat tuberculosis; rifampin is also used to treat other serious infections. Patients taking rifampin or rifapentine should continue taking their current medicine and consult with their health care professional about any concerns.

To mitigate or avoid shortages and to help ensure patients have access to these necessary medicines, FDA will not object to certain manufacturers temporarily distributing rifampin containing 1-methyl-4-nitrosopiperazine (MNP) or rifapentine containing 1-cyclopentyl-4-nitrosopiperazine (CPNP) above the acceptable intake limits until they can reduce or eliminate the impurities.

The acceptable intake limits are 0.16 parts per million (ppm) for MNP in rifampin and 0.1 ppm for CPNP in rifapentine. The agency will not object to certain manufacturers temporarily distributing rifampin containing MNP below 5 parts per million (ppm). The agency also will not object to certain manufacturers temporarily distributing rifapentine containing CPNP below 14 ppm. FDA will not object to these higher exposures to maintain patient access to these life-saving medications.

Manufacturers should contact the Center for Drug Evaluation and Research’s Drug Shortages Staff when their testing of rifampin or rifapentine shows levels of nitrosamines that exceed the acceptable intake limits of 0.16 ppm for MNP and 0.1 ppm for CPNP. FDA will determine on a case-by-case basis whether those drugs should be released for distribution.

FDA and manufacturers are investigating the origin of these impurities in rifampin and rifapentine, and the agency is developing testing methods for regulators and industry to detect MNP and CPNP in these medicines. FDA continues its ongoing review, surveillance, compliance and pharmaceutical quality efforts across every product area and will continue to work with drug manufacturers to ensure safe, effective and high-quality drugs for the American public.

MNP and CPNP belong to the nitrosamine class of compounds, some of which are classified as probable or possible human carcinogens (substances that could cause cancer), based on laboratory tests such as rodent carcinogenicity studies. Although there are no data available to directly evaluate the carcinogenic potential of MNP and CPNP, information available on closely related nitrosamine compounds was used to calculate lifetime exposure limits for MNP and CPNP.

Tuberculosis is a potentially deadly disease that affects the lungs and sometimes other parts of the body, and the risk of not taking the medicine outweighs any potential risk from MNP or CPNP. Patients taking rifampin for other conditions should discuss with their health care professional whether they can use an alternative medicine.

FDA encourages health care professionals and patients to report adverse reactions or quality problems with any human drugs to the agency’s MedWatch Adverse Event Reporting program:

  • Complete and submit the report online; or
  • Download and complete the form, then submit it via fax at 1-800-FDA-0178
FDA-published testing method to provide an option for regulators and industry to detect nitrosamine impurities
The link below is to an FDA-published testing method to provide an option for regulators and industry to detect nitrosamine impurities in rifampin and rifapentine drug substances 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.
  • LC-ESI-HRMS method: an LC-MS method for the detection of MNP in rifampin and CPNP in rifapentine drug substance and drug products
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