Purpose

The presence of the impurity N-nitrosodimethylamine (NDMA) has been a reason for recent drug product recalls in 2019–2020.

Methods

This document reviews the timing of ranitidine and valsartan recalls due to NDMA; the numerical values reported in the available literature are compared, while the proposed mechanisms and influencing factors are discussed in detail. The liability of other histamine H₂ receptor antagonists such as famotidine and cimetidine is also investigated according to the information available in the literature.

Results

The presence of nitrate ions, acidity of the environment, and nitrate contamination of the pharmaceutical excipients and temperature are effective factors in the production of this impurity. The effect of excipients is also discussed. Special attention is necessary to select the proper type of analytical method in examining trace amounts of this impurity in drug samples.

Conclusion

The available data builds a case for the evaluation of NDMA formation in all histamine H₂ receptor antagonists especially famotidine as a liable agent at different conditions and in the presence or absence of nitrite ions and some pharmaceutical excipients in vitro and in vivo. Special pharmaceutical formulation and manufacturing designs may be able to prevent the formation of this impurity.

中文翻译：

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雷尼替丁中 N-亚硝基二甲胺 (NDMA) 杂质检测的影响因素和其他组胺 H2 受体拮抗剂的可能反应性

目的

杂质 N-亚硝基二甲胺 (NDMA) 的存在是最近 2019-2020 年药品召回的一个原因。

方法

本文件回顾了因 NDMA 召回雷尼替丁和缬沙坦的时间；比较了现有文献中报道的数值，同时详细讨论了所提出的机制和影响因素。其他组胺 H ₂受体拮抗剂如法莫替丁和西咪替丁的作用也根据文献中的可用信息进行了研究。

结果

硝酸根离子的存在、环境的酸度以及药物赋形剂的硝酸盐污染和温度是产生这种杂质的有效因素。还讨论了赋形剂的作用。在检查药物样品中痕量的这种杂质时，需要特别注意选择适当类型的分析方法。

结论

现有数据为评估所有组胺 H ₂受体拮抗剂中 NDMA 的形成提供了一个案例，特别是法莫替丁在不同条件下以及在存在或不存在亚硝酸根离子和一些药物赋形剂的情况下在体外和体内作为一种有用的药物。特殊的药物配方和制造设计可能能够防止这种杂质的形成。