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Friday, March 24, 2023

The FDA Asks Companies to Stop Selling Ranitidine

With its promise of taming the ravages of stomach acid, ranitidine—best known under the brand name Zantac—was counted among the agents of pharmaceutical salvation, the enduring and reliable drugs that treat intractable diseases and make daily life more tolerable. In 1987, Zantac became the most-prescribed drug in the world.

But last week ranitidine was essentially erased from the US market. The US Food and Drug Administration asked manufacturers to withdraw ranitidine products, both in prescription and over-the-counter forms, because of an “impurity” in the pharmaceutical compound. Over time or in the presence of heat, ranitidine can form unacceptable levels of a probable carcinogen known as N-nitrosodimethylamine, or NDMA, the agency determined.

“We didn’t observe unacceptable levels of NDMA in many of the samples that we tested. However, since we don’t know how or for how long the product might have been stored, we decided that it should not be available to consumers and patients unless its quality can be assured,” Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, wrote in the April 1 statement.

Pharmacy shelves already had been stripped of the product. Sanofi, maker of Zantac, had recalled its products last fall due to earlier FDA findings, as had generic manufacturers. National chains such as Walmart, Walgreen’s, and CVS removed over-the-counter ranitidine. “We take this issue seriously and continue to work closely with the FDA to evaluate any potential safety risks associated with Zantac,” Sanofi spokesperson Nicolas Kressmann told WIRED in an email. “At Sanofi, we stand by the long-standing science that supports the safety of Zantac OTC (over-the-counter) products, which have been used by consumers for over two decades.”

"It is too early to say if and when we will be able to come back to the market as evaluations are ongoing," Kressmann writes. But for the foreseeable future, the FDA’s withdrawal request ends decades of ranitidine use. More broadly, it highlights NDMA contamination in medicines—and troubling questions about drug quality in a global industry dominated by manufacturing in China and India. NDMA has been detected in other commonly prescribed drugs: the blood pressure medicines valsartan, losartan, and irbesartan and—in lower amounts—in metformin, a common diabetes drug.

NDMA is an organic chemical that was once used in the manufacture of rocket fuel and lubricants. It also is a byproduct of other chemical processes; for example, it’s found in rubber, dye, and pesticide production, tanneries, and foundries. It is even a byproduct of the chlorination of drinking water, where it can be detected in very small amounts. There is no federal standard for NDMA in drinking water, although some states have set their own limits.

Foods that contain nitrites or nitrates—including bacon, grilled or smoked meats, and even some fruits and vegetables—can fuel a chemical reaction in the stomach that creates NDMA. Based on studies that showed NDMA can cause liver, kidney, and lung cancer in animals, the US Environmental Protection Agency labels it a probable human carcinogen.

The problem of NDMA turning up in medicine first came to light in 2018, when Prinston Pharmaceuticals Inc. (which operates as Solco Healthcare), a New Jersey-based manufacturer of the high-blood-pressure drug valsartan, notified the FDA about impurities in an active pharmaceutical ingredient the company had received from its parent company in China. Since 2011, the Chinese supplier of that ingredient had been using a new manufacturing process that yielded more of it at a lower cost—but the FDA found that the residue of a reused solvent, combined with another chemical agent, led to the formation of NDMA. The FDA inspected the Chinese plant, cited quality problems, issued a warning letter, and halted US imports from the company. The FDA case is still pending and an import alert remains in place, an FDA spokesperson said.

But the NDMA issue wasn’t confined to that company. The agency began recalling other valsartan products, as well as some batches of losartan and irbesartan when tests showed similar NDMA contamination, or contamination with a similar probable carcinogen, N-Nitrosodiethylamine (NDEA).

The FDA reassured consumers that the actual risk of cancer from taking the tainted blood pressure pills is low. If 8,000 people took the highest dose of a recalled batch of valsartan every day for four years, one additional cancer would occur, Woodcock wrote in a statement issued by the agency in 2018. But then-FDA commissioner Scott Gottlieb and Woodcock acknowledged in a statement that it was troubling that contamination could slip by for years without detection. They promised more intensive testing of the blood pressure medicines, called angiotensin II receptor blockers, or ARBs.

“No one thought to look for NDMA originally, because it shouldn’t have been in prescription products,” says Charles White, a pharmacist at the University of Connecticut who specializes in drug safety and efficacy. “No one tested for it because no one knew it existed. You only test for the things you know. So you’re always going to be a couple of steps behind.”

The FDA tests only a small sampling of drugs each year and primarily relies on manufacturers to monitor quality. In the 2017 fiscal year, for example, the FDA tested losartan from three generic manufacturers—including the maker of the active pharmaceutical ingredient in valsartan that later was found to contain NDMA. They all passed. (At the time, an FDA inspection had found quality problems at a manufacturing plant, but wasn’t yet aware of the NDMA contamination, so the agency’s investigation and testing didn’t focus on NDMA.)

Just as the first reports emerged in 2018 of NDMA contamination of valsartan, a pharmacy startup called Valisure launched with a mission of testing each batch of drugs before dispensing them to their customers. In June, 2019, Valisure’s lab tested valsartan and detected a solvent, N,N-Dimethylformamide or DMF, which is also a probable carcinogen. In March, 2020, Valisure officials also reported that they had found NDMA in metformin, a drug that helps people with Type 2 diabetes control their blood sugar levels. It is one of the most prescribed drugs in the US.

The FDA tested metformin from about eight generic manufacturers and concluded that any detected levels of NDMA were below the agency’s “acceptable daily limit” of 96 nanograms. (A nanogram is a billionth of a gram.) Someone ingesting NDMA at or below that level every day for 70 years “is not expected to have an increased risk of cancer,” Woodcock wrote in a statement.

But NDMA testing by government labs in Canada and Singapore led to metformin recalls in those countries. Valisure officials filed a citizen petition, a formal way to ask the FDA to take action, requesting a recall of all drug batches that contained NDMA above the FDA’s 96-nanogram limit based on the company’s tests and to conduct further investigation of NDMA in metformin. (The FDA does not have the authority to require drug recalls, but it can request one—and companies usually comply.)

Valisure is now crowdsourcing its testing—asking consumers to send metformin pills they have received from any pharmacy for free analysis. They have already received 100 samples, but won’t have results for a few weeks. “It’s a real snapshot of what’s going on in the metformin that patients are taking from around the United States,” says CEO and co-founder David Light.

The ranitidine story illustrates just how powerful that random quality testing can be. Valisure found NDMA in ranitidine last year when the company tested a prescription syrup that co-founder Adam Clark-Joseph had ordered to treat his infant daughter’s reflux. Unlike the valsartan and metformin incidents, with ranitidine the issue wasn’t ultimately linked to a manufacturing problem. The ranitidine compound itself contains the building blocks of NDMA—nitrite and a dimethylamine (DMA). Ranitidine can react with itself in the right conditions, such as at high heat or in the human digestive system, Valisure officials wrote in their 2019 citizen petition. The company reported levels as high as 3 million nanograms per tablet. “Even if the manufacturing has produced a clean product, that can’t guarantee that it remains free of NDMA,” Light says.

The FDA initially took issue with Valisure’s high-temperature testing method, but on April 1 issued a press release stating that the agency’s testing “confirmed that NDMA levels increase in ranitidine even under normal storage conditions.” The same statement requested the removal of all ranitidine products from the market.

People with heartburn and gastric reflux must now switch to other drugs, including Tagamet (cimetidine), Pepcid (famotidine), Prevacid (lansoprazole), Nexium (esomeprazole), and Prilosec (omeprazole). Cleveland Clinic gastroenterologist Scott Gabbard, a specialist in esophageal and swallowing disorders, advises patients to talk to their doctor about the options. And in the midst of so much health anxiety related to the coronavirus pandemic, he urges people not to overreact to the potential cancer risk of ranitidine. “We don’t know if ranitidine use truly increases a patient’s risk of cancer or not,” he says.

Gabbard points to a Danish study of 5,150 people who had taken valsartan for an average of almost five years. It compared those who took a product with ingredients made by the Chinese company linked to NDMA contamination and those who took products without known NDMA problems. This short-term study did not find an overall increased risk of cancer.

But others say the news about ranitidine is particularly disturbing because of the long history of the drug’s use; it has been around for three decades and was used by about 16 million people in 2017 alone. Joe Graedon, a pharmacologist who writes about medication issues and addresses consumer questions in his newspaper column and public radio show “The People’s Pharmacy,” says he hopes the FDA will look more closely into the cancer concerns with epidemiological studies of people who took ranitidine for many years. He also supports a more robust system of testing for drug impurities.

“Now people are told after the fact, ‘Every day that you swallowed this pill you may have been consuming a dose of a potential or probable carcinogen.’ At the very least this has got to be psychologically upsetting,” he says. “Who wants to be taking a dose of carcinogen with their pill every day?”

In October, Sanofi officials described the voluntary recall of Zantac as “a precautionary measure” due to “inconsistencies in preliminary test results of the active ingredient” used in the US products. “At that time, all retailers and consumers were instructed to return or destroy the product,” Kressmann, the spokesperson, noted in an email.

Meanwhile, the coronavirus pandemic heightens drug quality concerns, as the FDA recently announced that the agency is suspending inspections of overseas operations through April, due to travel advisories and restrictions. The agency will still conduct “mission-critical” inspections on a case-by-case basis, and would use other methods to check quality, such as asking for records from manufacturers and testing samples of imported products. “We stand ready to resume foreign inspections as soon as feasible,” FDA Commissioner Stephen Hahn said in a March 10 statement.

Still, without overseas inspections, regulators will generate less information about quality at a time when the public needs to know more, says Michael Ganio, director of pharmacy practice and quality at the American Society of Health-System Pharmacists. Even when the FDA conducts inspections, the publicly available reports don’t say which drugs are produced at a facility that had manufacturing deficiencies, he says. “There needs to be some sort of public reporting mechanism for quality,” he says.

Finding drugs to fight Covid-19 is clearly a front-burner issue. But if ranitidine has a lasting legacy, perhaps it will be a new imperative to make sure hazardous chemicals don’t seep into our medicine.

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