FDA Finds Ranitidine Poses Little Risk, But Concerns Linger

Ranitidine no more carcinogenic than grilled meat, says FDA drug center director Janet Woodcock. Agency finds NDMA levels in ranitidine drugs well below those claimed by Valisure, online pharmacy asking FDA to order drug off US market.

Based on its test results through 1 November, the US Food and Drug Administration again refrained from calling for consumers and patients to stop taking ranitidine-containing drugs due to concerns about nitrosamine impurities that could cause cancer.

Agency tests found n-nitrosodimethylamine (NDMA), a nitrosamine impurity, in a range of oral solid and oral liquid dosage forms from 12 manufacturers, but generally at levels below the FDA's s threshold of concern, 96 nanograms per day or 0.32 ppm.

“Through our testing so far,” said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, “we have found levels of NDMA in ranitidine that are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats.”

CDER Director Janet Woodcock: "We’ve tested a huge number of samples, 1,500 samples, trying to figure out what is going on here.”

Woodcock in a same-day statement added that many of the nitrosamine levels the agency found in various ranitidine products, most commonly known in the OTC market by the brand Zantac, “are much lower than the levels some third-party scientists first claimed.”

Valisure, a New Haven, CT, pharmacy startup that tests the drugs it sells, first raised concerns about nitrosamines in Zantac in a 9 September citizen petition to the FDA. Valisure said it found 2 mg to 3 mg of NDMA in ranitidine tablets, orders of magnitude above the FDA threshold. (Also see "Online Pharmacy Stirs Ranitidine Controversy With Petition To Halt Sales" - HBW Insight, 15 Sep, 2019.)

Results From ‘Huge Number’ Of Samples

At a House Energy and Commerce Health Subcommittee hearing on 30 October, Woodcock said, “We’ve tested a huge number of samples, 1,500 samples, trying to figure out what is going on here.”

She explained that the agency’s chemists believe the NDMA is formed during active pharmaceutical ingredient synthesis, finished dosage form manufacturing, or during storage.

"There has also been an allegation that in the body it is transformed into … NDMA," Woodcock said in a reference to Valisure’s petition. “We have not been able to verify that yet. We're still doing tests,” she added.

When FDA Expects Ranitidine Recalls

In the FDA statement, Woodcack also said the agency's testing found some cases of NDMA exceeding agency thresholds, which were set based on methods described in the International Council on Harmonization’s M7(R1) guidance on control of mutagenic impurities after NDMA and other nitrosamines were found last year in valsartan and certain other angiotensin II receptor blockers, a type of blood pressure medication. (Also see "Testing Ranitidine With Too Much Heat Could Generate NDMA, FDA Says" - HBW Insight, 2 Oct, 2019.)

If the FDA or manufacturers find NDMA exceeding those thresholds, “we’re now asking companies to voluntarily recall ranitidine,” she said.

Woodcock added that the agency also expects manufacturers to recall lots of a chemically similar medication, nizatidine, commonly known as Axid, if it is found to contain NDMA at levels exceeding the risk-based thresholds.

Additionally, the agency conducted tests “that simulate what happens to ranitidine after it has been exposed to acid in the stomach with a normal diet,” and results were negative for NDMA formation. Tests in a simulated small intestine environment also were negative, she said. “However, we still must test the drugs in the human body to fully understand if ranitidine forms NDMA."

FDA Wants Testing To Continue

Woodcock stressed that manufacturers should continue to test ranitidine and nizatidine for NDMA, and to send the FDA samples for its scientists to test.

“We are still working with manufacturers to investigate the true source of NDMA and to understand the root cause of the low levels of NDMA present in the drugs,” she said.

While the FDA has not called for people to stop using ranitidine or nizatidine, Woodcock noted that this remains an option for consumers or patients and their health care providers to consider, and that the agency has not found any NDMA in alternative products such as famotidine, cimetidine, esomeprazole, lansoprazole and omeprazole.

She added that NDMA exceeded thresholds in some FDA-tested lots of ranitidine syrup, typically used for newborns and young children, and that recalls are underway.

The agency also is testing ranitidine for injection products.

The FDA reported test results for various OTC and Rx formulations of ranitidine and nizatidine from Sanofi US, Cardinal Health Inc., Watson Pharma Inc., Strides Shasun Ltd., Novitium, Dr. Reddy's Laboratories Ltd., Sandoz Inc., Aurobindo Pharma Ltd., Ajanta Pharma USA Inc., Silarx Pharma, Pharma Associates and Amneal Pharmaceuticals LLC.

Sanofi previously issued a voluntary recall of its OTC Zantac products in the US and Canada "as a precautionary measure due to inconsistencies in preliminary test results of the active ingredient used in the US and Canadian products." (Also see "Zantac Recall And EU Regulatory Issues Hurt Sanofi In Q3" - HBW Insight, 1 Nov, 2019.)

Valisure Emphasizes Dietary Nitrite Risks

Asked about Woodcock’s statement, Valisure replied with its own statement, saying it also found no NDMA in tests with simulated gastric and intestinal fluids. But the pharmacy dismissed such conditions as overly simplistic, saying they failed to show what happens when nitrite comes into the picture.

“Valisure’s stomach-relevant testing conditions were employed with the knowledge that ingesting nitrite-containing foods like hot dogs can significantly increase stomach levels of nitrite,” said the pharmacy, which noted that “these foods are often eaten by individuals either before or after taking antacid products.”

Valisure restated its thesis that “the root cause of NDMA formation is the fundamental instability of the ranitidine molecule.”

The firm applauded the FDA’s findings about nizatidine and urged the agency and industry to recall all products that contain either heartburn medication.

(This article originally was published in The Pink Sheet.)