Risk of Nitrosamines in Rizatriptan and Recall

Glenmark recalled several lots of Rizatriptan Benzoate Tablets and Rizatriptan Benzoate Orally Disintegrating Tablets in US due presence of Nitrosamine impurities. The recall is triggered due to the Nitrosamine Drug Substance Related Impurity (NDSRI) N-Nitroso Desmethyl Rizatriptan results that are above the FDA acceptable limit. Rizatriptan benzoate is a serotonin receptor agonist (triptan) indicated for the acute treatment of migraine.

USFDA Enforcement Report: Glenmark Recall of Rizatriptan Benzoate tablets

Nitrosamine drug substance-related impurities (NDSRIs) are a class of nitrosamines sharing structural similarity to the API. NDSRIs can be generated during manufacturing or during the shelf-life storage period of the drug product. APIs that contain secondary amine or dimethyl tertiary amine centers are at risk of forming NDSRIs by nitrosation of the amine center. This can occur under conditions related to the formulation and manufacturing process for the drug product, such as by reaction with residual nitrites in excipients used to formulate the drug product. Rizatriptan has a secondary amine group susceptible to generation of Nitrosamine impurities.

FDA guidance require Drug Manufacturers to implement nitrosamine risk mitigation activities which include risk assessment, testing products for nitrosamines and NDSRIs and taking actions to prevent / reduce risk of NDSRIs.

N-nitroso-desmethyl-rizatriptan is a category 1 NDSRI with a maximum Acceptable Intake (AI) of 26.5ng/day. (Refer USFDA: Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs). USFDA has provided a recommended framework for predicting the mutagenic and carcinogenic potential of NDSRIs with five categories identified along with corresponding recommended AI limits. The Predicted Carcinogenic Potency Categorization (PCPC) approach for arriving at AIs for Nitrosamine impurities is based on the SAR (structure activity relationship) concept. An estimate of the carcinogenic potency of an NDSRI is generated based on structure and reactivity of a surrogate similar to the NDSRI. Surrogates are compounds containing an N-nitroso structural alert in the same chemical environment as an NDSRI and for which robust carcinogenicity data are available. The class specific limit for nitrosamine impurities for Category 1 are based on the most potent, robustly tested nitrosamine in the category. NDSRIs assigned to Category 1 are predicted to have carcinogenic potency no higher than the class-specific limit for nitrosamine impurities.(Refer USFDA Guidance: Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities)

Additional Reading: Risk of Nitrosamines, NDSRIs, Nitrosamine vulnerable actives – How Lhasa’s Nitrile Excipient database can help