Notice: Nitrosamine impurity found in Priftin®® (rifapentine) drug substance and drug product
Priftin® (rifapentine) is a prescription medication that is currently not approved or marketed in Canada, but is being imported into Canada from the US under the Urgent Public Health Need (UPHN) regulatory pathway by the Public Health Agency of Canada (PHAC) and Indigenous Services Canada (ISC). Rifapentine is a drug prescribed as part of a 3-month, taken once weekly, regimen with isoniazid (3HP) to treat latent tuberculosis infection (LTBI). Rifapentine is manufactured by Sanofi and supplied in Canada as Priftin®® 150 mg tablets. Priftin® is authorized for sale in the U.S. by the Food and Drug Administration (FDA).
In June 2020, Health Canada was made aware that a new nitrosamine impurity, 1-cyclopentyl-4- nitrosopiperazine, was detected in Priftin® (rifapentine) drug substance and drug product. Sanofi is conducting a root-cause investigation to determine the source of the impurity. The investigation underway is the result of impurity detection and not due to observed adverse events. Similar to other nitrosamine impurities, 1-cyclopentyl-4-nitrosopiperazine is expected to exhibit mutagenic and carcinogenic activity. Low levels of this impurity have been detected in some rifapentine at the production facilities in Italy, which includes some market-ready Priftin®. Sanofi is expected to submit their test results for lots of drug product imported into Canada through UPHN by the end of July 2020.
Sanofi has put a hold on the release of Priftin® from their production sites, which will in turn affect the availability of rifapentine in Canada.
At this time, neither the FDA nor Sanofi have recalled the Priftin® supply that has already been distributed. PHAC and ISC, in consultation with TB experts, conclude that patients presently taking Priftin® as part of a short three-month course of 3HP for LTBI treatment can continue with this regimen until completion. However new LTBI treatment with Priftin®, should not be started until further notice. When new information becomes available, a new notice regarding the use of this medication will be shared at that time. If discontinuation of 3HP is preferred, treatment for LTBI can be restarted with a complete alternative regimen, or it can be completed with a proportionate duration of an alternative regimen. According to the Canadian Tuberculosis Standards 7 th Edition, the standard regimen of first choice for LTBI treatment is 9 months of daily isoniazid (INH), however other short-course regimens for treating LTBI may be considered. The current short course LTBI treatments in Canada are: 6 months of daily INH, 3-4 months of daily isoniazid and rifampin, or 4 months of daily rifampin.
In March 2020 Health Canada released a notice that slightly higher than acceptable levels of the nitrosamine impurity 1-nitroso-4-methylpiperazine were detected in batches of another TB drug Rifampin (used in the treatment of active and latent TB). To mitigate a national shortage of Rifampin, Health Canada concluded that the risks associated with not treating the disease were greater than the potential risk from short-term use of the drug. Rifampin is typically taken for relatively short periods of time (three to four months) and the very low increased lifetime risk of cancer was outweighed by the need for immediate critical treatment. More recently, analytical test results for Rifampin drug product were submitted to Health Canada which demonstrated that the 1-nitroso-4-methylpiperazine impurity was below the acceptable level.
We encourage you to share this notice with fellow clinicians, patients and partners in TB prevention. PHAC and ISC will continue to monitor this and will advise if any of the above information changes.
Health Canada continues to work with international regulatory agencies, including the FDA, to determine the long-term acceptable limits for nitrosamine impurities in drugs. Nitrosamines are classified as probable or possible human carcinogens according to animal studies. Everyone is exposed to low levels of nitrosamines through a variety of foods (such as smoked and cured meats, dairy products and vegetables), water and air pollution. At low levels, nitrosamines are not expected to cause harm.
Please visit the Health Canada, FDA, and CDC websites for more information about nitrosamine impurities in drug products.