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Regulatory Focus™ > News Articles > 2020 > 8 > FDA addresses nitrosamines in TB drugs

FDA addresses nitrosamines in TB drugs

Posted 26 August 2020 | By Kari Oakes 

FDA addresses nitrosamines in TB drugs

Nitrosamine impurities have now been found in two tuberculosis drugs, prompting the US Food and Drug Administration (FDA) to clarify how it will handle elevated levels of the potential carcinogen in life-saving antibiotics.
 
Both rifampin and rifapentine are antibiotics used to treat tuberculosis, and rifampin is also used to treat other serious bacterial infections. Elevated levels of nitrosamines have been found in samples of both substances: the nitrosamine 1-methyl-4-nitrosopiperazine (MNP) was found above the acceptable intake limit of 0.16 parts per million (PPM) in rifampin. Rifapentin samples had another nitrosamine, 1-cyclopentyl-4-nitrosopiperazine (CPNP), at levels above that substance’s acceptable intake limit of 0.1 ppm.
 
“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 and rifapentine containing nitrosamines above the acceptable intake limits “until they can reduce or eliminate the impurities,” said FDA. However, levels of both MNP must be below 5 ppm in rifampin and rifapentin must contain no more than 14 ppm of CPNP.
 
The decision was based on a risk-benefit analysis of withholding important medication for those with tuberculosis, a potentially fatal disease, said FDA.
 
The agency is directing manufacturers whose samples of the two antibiotics test above the acceptable daily intake for nitrosamines to contact the Center for Drug Evaluation and Research’s Drug Shortage Staff for case-by-case determinations of whether 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,” said the agency.
 
Nitrosamines are naturally occurring substances, but long-term exposure to elevated nitrosamine levels may increase cancer risk. Elevated nitrosamine levels have previously been found in some samples of the diabetes drug metformin, as well as the antacid ranitidine and angiotensin converting enzyme inhibitors and angiotensin receptor blockers, both classes of antihypertensive drugs. (RELATED: More metformin recalled for NDMA; 6 firms now affected, Regulatory Focus 08 July 2020)
 
This week, Bayshore Pharmaceuticals issued a voluntary recall of its metformin extended release formulations because of N-nitrosodimethylamine (NDMA) impurities. The European Medicines Agency provided updated guidance for industry on risk evaluation for nitrosamines earlier this month.  (RELATED: EMA addresses risk evaluation, mitigation for nitrosamines, Regulatory Focus 06 August 2020)
 
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