Nitrosamines Problems Are More Widespread in Drugs Than FDA Anticipated: Report

The EU and Canada have set daily acceptable limits for all nitrosamines, but the FDA has not. During a meeting this week the U.S. regulators met to discuss how to bets address the problem with nitrosames in drugs.

Federal regulators met with generic drug manufacturers on Monday, to discuss the growing problem with nitrosamines, which are cancer-causing chemicals that can be a byproduct of the drug manufacturing process.

The U.S. Food and Drug Administration (FDA) first raised concerns about nitrosamines, specifically nitrosodimethylamine (NDMA), when valsartan recalls were first announced in 2018, after generic versions of the hypertension drug were found to contain unsafe levels of the human carcinogen.

However, as regulators and drug manufacturers became more aware of nitrosames in drug products and the potential cancer risks, they have been found in a number of other drugs, including Chantix, Metformin and Zantac. This has led to numerous recalls and litigation, including more than 100,000 Zantac cancer lawsuits currently begin filed against manufacturers of the heartburn drug.

In response to the growing problem, the FDA issued new guidance in 2020 on how to detect and prevent nitrosamine impurities, which set daily acceptable limits for six different nitrosamines, including NDMA. The guidance was passed on the belief that the problem would be small, but the FDA underestimated the scope of the problem.

According to a report published in Regulatory Focus on Monday, hundreds of drugs turned out to have nitrosamines, many of them not on the list impacted by the FDA guidance. Regulators are now discovering that any drug with an active ingredient that includes a vulnerable amine, a type of nitrogen molecule usually derived from ammonia, could have nitrosamine contamination caused during the manufacturing process.

That includes drugs such as angiotensin-converting enzyme (ACE) inhibitors used in hypertension drugs;  beta blockers in many heart drugs, and selective serotonin reuptake inhibitors (SSRIs), which are commonly used antidepressants.

Under the weight of the recalls, the 2020 guidance quickly became outdated, and now the FDA is trying to decide about all the other nitrosamines they keep discovering in commonly used drugs.

In the European Union and Canada, regulators have set daily acceptable limits for novel nitrosamines, which have not been fully researched as a precaution. The FDA has not.

On Monday, agency officials met with the Association for Accessible Medicines (AAM), a lobbying group for generic drug manufacturers to discuss how to move forward and whether the U.S. should have similar wide-sweeping, daily acceptable limits for all nitrosamines; even if they do not know whether they present a health risk to patients.

FDA officials have also held science workshops, and are reportedly talking to other stakeholders about how to address the nitrosamine problem. It is expected that the agency will update the guidance and some point, but it is unclear whether the FDA will set daily limits for all nitrosamines as a safety precaution.

November 2022 Zantac Lawsuit Update

Most of the litigation resulting from the nitrosamine recalls has been focused on Zantac (ranitidine), which was used by millions of Americans for treatment of heartburn and acid reflux, before it was removed from the market in late 2019 due to the presence of NDMA.

GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Sanofi and various other manufacturers, distributors and retailers involved in the sale of brand name or generic ranitidine pills now face more than 100,000 Zantac lawsuits brought by former users who indicate they have been diagnosed with bladder cancer, esophageal cancer, liver cancer, pancreatic cancer, stomach cancer or other injuries, as NDMA moved through their body.

Given common questions of fact and law raised in litigation brought throughout the federal court system, centralized pretrial proceedings have been established in a federal MDL before U.S. District Judge Robin L. Rosenberg in the Southern District of Florida, who has been presiding over coordinated discovery and a “bellwether” process where a small group of cases are being prepared for early trial dates.

There are also cases filed in state courts as well. In California state court, a series of four Zantac lawsuits have been scheduled for trial next year, with cases scheduled to go before different juries on February 13, 2023, May 1, 2023, August 7, 2023 and October 23, 2023.

These trials will be closely watched by parties involved in the litigation, and may provide a “bellwether” to help gauge how juries will respond to certain evidence and testimony that will be repeated throughout the litigation. If plaintiffs are successful, it is likely to drive up the cost of any Zantac settlements the drug makers will offer to avoid tens of thousands of individual cases going to trial nationwide in the coming years.