FDA relaxes impurity limit on Merck's Januvia after testing flags possible carcinogen. Are recalls next?

A popular diabetes drug has fallen prey to nitrosamine impurities—again. And for once, it isn’t metformin.

The potential cancer agent Nitroso-STG-19, also known as NTTP, has surfaced in certain samples of Merck & Co.’s Type 2 diabetes blockbuster Januvia, the FDA said Tuesday. Januvia, also known as sitagliptin, generated $5.3 billion in 2021 and ranked as Merck’s third best-selling drug behind Keytruda and Gardasil.

It’s unclear how the impurity turned up in Januvia, and the FDA didn’t specify whether Merck or a third-party manufacturer produced the suspect samples.

To sidestep Januvia shortages and keep the drug on tap for patients, the FDA will temporarily OK distribution of Merck’s drug with NTTP above the FDA’s acceptable daily intake level of 37 nanograms (ng). If tests find that the levels of NTTP in Januvia surpass 37 ng per day, Merck and its manufacturers should alert FDA staff, the agency said in its release. The FDA won't allow drugs to go out with samples of more than 246.7 ng per day.

A Merck spokesperson said the "safety, quality and efficacy of our products and the health of the people that use them are our highest priority."

"We have engaged with major health authorities around the world and have implemented additional quality controls to ensure our portfolio of sitagliptin-containing products meet health authorities’ interim acceptable NTTP limits for continuing distribution of product to the market," the spokesperson added. The company doesn't expect supply disruptions from this development.

Lab tests have determined nitrosamines can cause cancer, the FDA points out. The compounds are unavoidable in life, cropping up in water and food like grilled and cured meats, as well as dairy products and vegetables. Everyone crosses paths with nitrosamines in some capacity, with the risk of cancer only following high-level exposure over a long stretch of time.

As for NTTP itself, there aren’t any data on hand to directly evaluate the impurity’s cancer-causing potential. Instead, the FDA used information on “closely related nitrosamine compounds to calculate lifetime exposure limits for NTTP,” the regulator said.

Since about 2019, nitrosamine findings have haunted scores of drugs, from off-patent generics like the popular diabetes med metformin to big brands like Sanofi’s Zantac and Pfizer’s smoking cessation drug Chantix. The contamination saga has triggered recalls, shortages and full-blown marketing culls. More recently, the problem touched Pfizer’s blood pressure meds Accuretic and Inderal in Canada—with recalls eventually creeping into the U.S. on another Pfizer hypertension med called Accupril.

Januvia helps Type 2 diabetes patients manage high blood sugar. It can be dangerous for a patient to stop taking Januvia without doctor input, so the FDA is recommending prescribers continue to use Merck’s drug “when clinically appropriate to prevent a gap in treatment.”

No Januvia shortages are currently listed on the FDA’s virtual database.

This isn’t the first time the FDA has relaxed its rules on daily nitrosamine intake limits, either. During Pfizer’s Chantix contamination snafu last year, a shortage of the smoking cessation drug, also called varenicline, prompted the FDA to allow manufacturers to temporarily distribute varenicline tablets with the impurity N-nitroso-varenicline above the agency’s acceptable intake limit of 37 ng per day but below an interim limit of 185 ng a day. The FDA last July said it would tweak the rule “until the impurity can be eliminated or reduced to acceptable levels."

In a further bid to thwart Chantix gaps, the FDA also summoned Apotex to export its generic Chantix product from Canada to the United States.

While nitrosamines have proven a major headache for the pharma industry, some trade groups have balked at recent rules for monitoring the compounds, arguing that tight tracking procedures may spark shortages of crucial drugs.

What the FDA should do—according to trade groups Pharmaceutical Research and Manufacturers of America (PhRMA), the Association for Accessible Medicines (AAM) and the Consumer Healthcare Products Association (CHPA)—is work with other global regulators to set similar rules, adopt better testing strategies and limit testing to drugs at the highest risk of contamination.

Further, current nitrosamine testing is pricey and often yields false positives, while the timelines for companies to assess risk and complete testing are “too short,” the trade group trio said last summer.

Back to Januvia, this appears to be the first spot of nitrosamine trouble for the drug. However, as Zantac, metformin and Chantix have shown, initial impurity flags are often an omen of recalls to come. For now, diabetes patients—and Merck—will simply have to wait and see.