Rifampin and Rifapentine are antibiotics used to treat and prevent tuberculosis or meningococcal disease. The FDA became aware and subsequently released guidance on August 26, 2020, about the potential of nitrosamine impurities in certain samples of Rifampin and Rifapentine. The nitrosamines in question are 1-methyl-4-nitrosopiperazine (MNP) for Rifampin and 1-cyclopentyl-4-nitrosopiperazine (CPNP) for Rifapentine. Both MNP and CPNP have the potential for carcinogenicity and toxicity but the benefits may outweigh the detriments.
MNP belongs to the nitrosamine class of compounds, some of which are classified as possible human carcinogens a substance that could cause cancer after use as based on laboratory tests such as rodent carcinogenicity studies. At the moment there is no data available to directly evaluate the carcinogenic potential of MNP, but the information available on closely related nitrosamine compounds was used to calculate lifetime exposure limits for MNP. The same can also be inferred for CPNP.
While the dangers of nitrosamines in these antibiotics are of concern, it puts the FDA in a tough spot. To not limit the access of patients to these life-saving treatments and avoid shortages, the FDA set temporary limits for MNP in Rifampin and CPNP in Rifpentine for certain manufacturers. Per the FDA guidance, “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.”
Additionally, on October 29, 2020, the FDA released another update stating, “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.”
In conclusion, the FDA will continue working with manufacturers to ensure that Rifampin and Rifapentine are safe for consumer use. Additionally, manufacturers should also take any necessary steps that include testing and confirmation of the MNP and CPNP levels in their products.
Adamson Analytical Laboratories is fully equipped to test MNP, CPNP, and many other nitrosamines down to ppb levels such as:
- N- N-Nitroso-N-methyl-4-aminobutyric acid – NMBA
- N-Nitrosodimethylamine – NDMA
- N-Nitroso-N-methylethylamine – NMEA
- N-Nitrosodiethylamine – NDEA
- N-Nitrosopyrrolidine – NPYR
- N-Nitrosomorpholine – NMOR
- N-Nitrosodi-n-propylamine – NDPA
- N-Nitrosopiperidine – NPIP
- N-Nitrosodi-n-butylamine – NDBA
- N-Nitrosodi-iso-propylamine – NDiPA
- N-Nitrosodiethanolamine – NDELA
Contact for more Information about testing MNP and CPNP in your products
Sales: peter.darbey@tentamus.com
Technical: tobias.wiezorek@tentamus.com