Update on nitrosamine impurity in sitagliptin products

Since the discovery of nitrosamine impurities in medicines in 2018, HSA and international regulators have required manufacturers and companies to conduct assessments of their products for risk of nitrosamine contamination.

Sitagliptin is an oral anti-diabetic medicine that helps control blood sugar levels in patients with type 2 diabetes mellitus. Recently, a new nitrosamine impurity, Nitroso-STG-19 (also known as NTTP), has been detected in trace amounts in sitagliptin products by the manufacturer. These levels were higher than the internationally acceptable limit in only certain samples of the products.

A very conservative approach is used internationally to set limits for nitrosamine impurities in medicines. The acceptable limits are determined based on what is considered reasonably safe if a patient takes the affected medicine every day for a lifetime of 70 years. Therefore, although the trace amounts of NTTP detected were above the international acceptable limit, HSA has assessed that the risk to patients taking the affected sitagliptin medicines is very low.

The company will be making the necessary changes in the manufacturing processes to eliminate or reduce the amount of the impurity to stipulated levels. In the interim period, in consideration of the benefits of the medicines versus the potential risks, HSA is temporarily allowing a higher limit of NTTP in sitagliptin products so that patients can have continued access to these medicines. HSA has assessed that taking the affected sitagliptin medicines containing NTTP at the higher interim limit for an additional short-term exposure during the interim period presents minimal additional risk to patients. While there are other anti-diabetic medicines available, switching patients from sitagliptin to alternative medicines could potentially result in disruption in diabetes control in patients. This could pose greater health risks to patients compared to the low risk of taking the affected products. Patients taking sitagliptin medicines are advised not to stop taking these medicines on their own as sudden stoppage in the use of the medicines can raise blood sugar levels. This approach of HSA’s is consistent with those taken by other regulatory authorities^1,2.

HSA is working closely with international regulatory agencies and the company supplying these medicines to implement measures to eliminate or reduce the amount of the impurity to acceptable levels.

About nitrosamine impurities

Nitrosamines are environmental contaminants, and they are also found in food or the environment in very small amounts. There is no immediate risk associated with the use of medicines containing trace levels of nitrosamine impurities. In animal studies, exposure over a prolonged period to amounts of nitrosamine impurities that are much higher than the usual human exposure has been reported to cause cancer in animals. Based on these animal studies, it is postulated that nitrosamine may cause cancer in humans. Acceptable levels of nitrosamines are set in nanograms (ng), i.e., one billionth of a gram, and is based on what is considered reasonably safe if a person takes the affected medicine every day for 70 years.

References

1. https://www.fda.gov/drugs/drug-safety-and-availability/fda-works-avoid-shortage-sitagliptin-following-detection-nitrosamine-impurity (Accessed September 2022)

2. https://www.tga.gov.au/news/safety-alerts/sitagliptin ↗ (opens in new tab)Accessed September 2022