The FDA will still allow continued distribution of sitagliptin containing NTTP with an acceptable intake limit of 37 ng per day and up to 246.7 ng per day.
FDA updated the dosage limits of Sitagliptin. (Courtesy of Katherine Welles/Getty Images)
The U.S. Food and Drug Administration announced Tuesday that certain samples of sitagliptin were contaminated with the nitrosamine Nitroso-STG-19 (NTTP). Sitagliptin is the main compound in Merck’s blockbuster type 2 diabetes drug Januvia.
The regulatory body said it will allow continued distribution of sitagliptin even if the nitrosamine impurities are present at levels above the acceptable intake limits. This is to prevent a drug shortage and ensure that people with diabetes can continue to access their medicines.
The FDA has set a daily acceptable intake limit of 37 ng per day but is expanding this to an interim threshold of 246.7 ng per day. As per agency scientists, this higher limit poses only a minimal additional risk of cancer compared to the stricter cut-off.
Sitagliptin, dispensed only through prescriptions, helps control blood sugar levels in people suffering from type 2 diabetes mellitus. Because this condition can overload the bloodstream with too much glucose, eventually leading to complications in the circulatory and nervous systems, it can prove dangerous to cut off medication in patients. The FDA recommends that physicians continue to prescribe sitagliptin as appropriate.
In a statement to Bloomberg, Merck confirmed that it has “recently detected a nitrosamine identified as NTTP in some batches of our sitagliptin-containing medicines.” Aside from Januvia, the company has also detected impurity in certain batches of Janumet, which combines sitagliptin with metformin, and Steglujan, containing both sitagliptin and ertugliflozin. All three drugs are indicated for type 2 diabetes.
The company is working with health authorities across the globe and is implementing additional quality control mechanisms to meet the FDA’s interim thresholds of NTTP.
“We remain confident in the safety, efficacy and quality of our sitagliptin-containing medicines,” Merck said. “No significant impact on supply of these medicines for patients is anticipated.”
Januvia and Janumet are Merck’s best-selling drugs, behind only its melanoma medicine Keytruda (pembrolizumab) and its HPV vaccine Gardasil. In the second quarter of 2022, Januvia and Janumet delivered combined earnings of more than $1.2 billion, a mild decline of 2% from the same period the year prior.
Merck lost market exclusivity for Januvia and Janumet in China earlier this year and is expected to face the same challenge in the European Union in September. Still, the news of impurities in its top assets dealt a blow to the company. Its shares dropped by 1.9% after the FDA’s announcement.
NTTP falls under a class of compounds called nitrosamine. Some nitrosamines, such as nitrosodimethylamine (NDMA) and N-nitrosodiethylamine, have shown carcinogenic activity in animal studies. No such data is yet available for NTTP, however, and the FDA’s move to flag this impurity as a safety concern in sitagliptin may be a decision to err on the side of caution.
In 2018, the agency detected unacceptable levels of NDMA in valsartan, an angiotensin II receptor blocker used to control high blood pressure and treat heart failure. This set off a years-long investigation process that also found unacceptable levels of NDMA in other commonly used drugs, such as the heartburn medications ranitidine and nizatidine.
In early 2020, the FDA also found certain batches of metformin, another diabetes drug, to be contaminated with NDMA, though at acceptable levels. In February 2021, the agency published a comprehensive guidance document to help drug manufacturers detect, prevent and address unacceptable levels of nitrosamine contaminations in their products.
