What You Need To Know About NDMA In Prescription Drugs (Valsartan & Zantac)

ndma-examined-scientist-lab-microscopeIn late 2019, the U.S. Food and Drug Administration announced recalls of multiple drugs believed to be contaminated with a carcinogenic substance called NDMA. Those recalls affected both prescription and over-the-counter versions of the heartburn and ulcer medication ranitidine, known by the name brand Zantac but also sold as a prescription and over-the-counter generic. The FDA had earlier recalled several types of blood pressure medications—losartan, valsartan, and irbesartan—because of contamination with NDMA. It believes there has been NDMA contamination in those drugs for up to four years.

What Is NDMA?

NDMA is short for N-Nitrosodimethylamine, an organic chemical. It’s present in low levels in certain foods, particularly smoked or cured foods, but most often found as a manufacturing and water treatment by-product. It’s also used in biological science as a way to create cancer in laboratory rats, and according to the World Health Organization, the International Agency for Research on Cancer believes it probably causes cancer in humans. The U.S. Environmental Protection Agency says NDMA comes from a family of known and powerful carcinogens.

In addition, as the Centers for Disease Control and Prevention note, NDMA is known to cause liver damage. As a result, the amount of NDMA that humans can legally be exposed to is strictly controlled and very, very small. The EPA sets the permissible level of NDMA in drinking water at 7 nanograms (seven billionths of a gram) for every liter of water. To put that in standard American measurements, that’s seven billionths of one twenty-eighth of an ounce to about four and one-quarter cups. The FDA, in a recent letter to drug makers, said it is unacceptable to have any detectable amount of NDMA in drugs.

The EPA says NDMA breaks down quickly in sunlight, which means releasing it into the air outside is less concerning than releases into the water or soil. If it gets into soil, it can get into the groundwater, where it won’t readily biodegrade and is not exposed to light. From there, it can get into the foods that humans and animals eat. Studies suggest that it won’t accumulate in the body, but exposure to a lot at once, or chronic exposure, can cause serious illness.

Where Does NDMA Come From?

NDMA occurs naturally in very small amounts in beer, tobacco smoke, and certain foods, generally smoked or cured foods like bacon and fish. The amount found in those substances is not considered dangerous.

Health authorities are more concerned about NDMA in drinking water. The EPA focuses its efforts on NDMA that is created as a byproduct of water treatment processes (like chlorination, chloramination, and ozonation, generally in wastewater treatment). As this 2018 review of past studies shows, scientists are still actively studying how to control the formation of NDMA.

NDMA can also get into drinking water through contamination from manufacturing. NDMA was once used to manufacture an ingredient in rocket fuel called unsymmetrical dimethylhydrazine. That’s not a common usage anymore, but the EPA says NDMA has been found in the groundwater at or near places where rocket fuel was used. It can also be found outside factories that use certain chemical reactions, including plants that make rubber products, pesticides, dyes, and more.

Does NDMA Exposure Cause Death or Serious Illness?

It’s well accepted in the scientific community that NDMA is a dangerous toxin. Cancer researchers use it to create cancer in laboratory animals, so they can study potential cures.

There aren’t many studies of whether NDMA causes cancer in humans, but it’s believed to be carcinogenic after chronic (long-term) exposure to even small amounts, and the federal government classifies it as an extremely hazardous substance under the Emergency Planning and Consumer Right-to-Know Act. The Minnesota Department of Health says it’s also clear that NDMA can be passed from a pregnant woman’s body into the body of a developing child.

It’s better documented that exposure to large amounts is hazardous. Laboratory animals exposed to NDMA in sufficient quantities have died or developed liver disease, liver cancer, and lung cancer. Pregnant rats gave birth to dead offspring or offspring that died quickly after birth.

In humans, NDMA is known to cause liver damage, internal bleeding, and death with large amounts of exposure. Some of this knowledge comes from exposure through food and water, but there have also been cases of intentional poisoning with NDMA. Two of those came in 1978. One was in Germany, where a man put it in some jam that he gave to his wife. The wife died after his trial; the perpetrator died of liver poisoning in prison a few years later.

In another case in 1978, Steven Roy Harper of Omaha slipped NDMA into the food at the home of his former girlfriend. He had already tried to kill her with a gun, and served time for it, before breaking into her home and adulterating food in the refrigerator with NDMA stolen from a former job. The poisoning killed the woman’s husband as well as her 11-month-old nephew, who’d stopped by for a visit and had some lemonade. Harper was sentenced to death, but killed himself in prison in 1990, according to the TV show Forensic Files.

In 2013, a medical student in Shanghai who had written several papers on NDMA poisoned his roommate with the chemical and was executed. More recently, a graduate student in Canada attempted to poison another student with NDMA, piping it into the victim’s food while he was out of the room. The Kingston, Ontario Whig says the victim took two bites of a poisoned apple pie but threw it away because of a bitter taste; four hours later, the victim developed diarrhea and vomiting. (He eventually caught the poisoner with a hidden camera; a police laboratory found NDMA in food samples he’d saved.)

How Do I Know If I’ve Been Exposed to NDMA?

According to the National Institutes of Health, exposure to large amounts of NDMA would create symptoms a lot like the Canadian student’s: Nausea and vomiting, diarrhea, cramps, headache, and fever. Doctors who examine the victim might find signs of reduced liver function including jaundice (a yellowing of the skin in light-skinned people), an enlarged liver, and reduced functioning of the liver as well as kidneys and lungs. Exposure to vapor or liquid may irritate the eyes, skin, and throat.

No tumors have been found in people who’ve been accidentally exposed to lesser amounts of NDMA, but it’s well known that exposure causes tumors in other mammals. Researchers working with human liver cells in a laboratory have also seen signs of cancer. The Federal Occupational Safety and Health Administration suggests medical monitoring of people whose jobs might expose them to NDMA.

Researchers in Denmark studied 5,150 people who’d taken Valsartan, one of the blood pressure medicines recalled in the U.S. for having unacceptable levels of NDMA. Over four and a half years, they found only a slight increase in cancer risk, but cautioned that more studies must be done to assess long-term cancer risk.

In its FAQ about NDMA contamination in ARB drugs, the FDA says that the risk of cancer from ARBs is still relatively low. Its statistical calculations say that in a hypothetical population of 8,000 people who all took the maximum dose of valsartan for four years, there would be one more cancer diagnoses than the average cancer rate for Americans. Most patients take less than the maximum dose, it says, and they are also likely to have gotten drugs from a variety of sources, because not all types of ARBs are contaminated.

Which Drugs Have Been Recalled for NDMA?

As of late 2019, the most recent round of drug recalls for NDMA exposure is recalls of ranitidine, marketed as Zantac or its generic versions. Zantac is a histamine-2 blocker, also called an H2 blocker, used for controlling stomach acid. It’s used over the counter and prescribed for heartburn and acid indigestion, and it may be prescribed to control digestive problems like stomach ulcers and GERD (gastrointestinal reflux disease).

Since Zantac/ranitidine comes in prescription and over-the-counter versions from multiple manufacturers, it’s important to know that not every kind has been recalled, or found to have concerning levels of NDMA. Confirmed NDMA contamination was why Sandoz Pharmaceuticals announced a recall on September 23, 2019 of 14 lots of ranitidine, in both 150-mg and 300-mg capsules. Three days later, as a precaution, Apotex Corp. recalled generic ranitidine sold at Wal-Mart, Walgreens, and Rite Aid in 75-mg and 150-mg doses.

On October 23, 2019 the FDA announced recalls of ranitidine from Dr. Reddy’s Laboratories, which makes generics for both over-the-counter and prescription use, and Sanofi, recalling all name-brand over-the-counter Zantac. Five days later, October 28, 2019 three more companies announced recalls: Perrigo Company recalled all sizes of ranitidine; Novitium Pharma recalled all ranitidine hydrochloride tablets; and Lannett Company recalled all unexpired lots of prescription ranitidine syrup.

The FDA notes that pharmacies may have taken ranitidine/Zantac products that haven’t been recalled off their shelves out of caution. FDA testing of ranitidine continues, and other products may still be recalled.

Prior to the ranitidine recalls, the FDA had spent more than a year identifying and studying NDMA contamination in another class of drugs: ARBs, or angiotensin II receptor blockers, which are prescribed for heart failure and high blood pressure. This class of drugs, also called “-sartan” drugs, includes valsartan, losartan, and irbesartan. In the Summer of 2018, the FDA found unexpected NDMA in ARBs.

As of late September of 2019, this finding resulted in 1,159 recalls, so many that the FDA made the list searchable. Patients who want to check their medications against that list should use a prescription label to find details like dosage and National Drug Code (NDC). The FDA also offers a searchable list of ARBs with notations about whether they have been tested and whether they were found to be free of NDMA.

Why Is NDMA in Prescription Drugs?

The FDA has several theories. In a letter to ARB manufacturers, the agency says NDMA can form during certain drug manufacturing processes and when using certain ingredients. These include ingredients not intended to be in the final product that are not adequately “purged” during manufacturing, the letter says.

Another idea the FDA suggests in its letter is contamination. In addition to contaminated raw materials, it suggests that recycled materials (such as solvents or catalysts) being used in manufacturing may be causing the problems. These materials may not be adequately purified by the recycler, or they may come into contact with inadequately cleaned equipment during the process. There’s evidence suggesting that, the FDA notes: Some makers of ARBs have found chemicals related to NDMA in their drugs even though the process of making the drug cannot create NDMA.

Because the NDMA is unexpected, it’s harder for manufacturers to detect and stop the contamination, the FDA notes. Manufacturers may not believe NDMA contamination is possible from a non-NDMA-forming chemical process, and drug purity testing may not find NDMA. (In fact, the FDA’s material for patients suggests that that’s why neither the FDA nor the manufacturers found the NDMA earlier.) Furthermore, the letter says, contamination by a third-party vendor may vary so much between vendors and between batches from the same vendor that it doesn’t follow a predictable pattern, making it difficult to isolate the problem.

What Should Patients Do About Drugs Contaminated With NDMA?

If you’re taking Zantac/ranitidine, you may want to check the FDA’s drug recall page for information on which specific manufacturers, dosages, and lots have been recalled. For patients taking ARBs, the FDA has set up a special page on blood pressure medication recalls that you can search.

The FDA recommends that people who were taking recalled over-the-counter ranitidine medicines look for alternatives. These include Prilosec (omeprazole), Nexium (esomeprazole), Tagamet (cimetidine), Prevacid (lansoprazole) and Pepcid (famotidine), all of which the agency has tested and knows to be free of NDMA.

Users of prescription ranitidine and prescription ARBs are advised to talk to the doctor who prescribed their drugs about alternatives. Despite the long list of ARBs recalled for NDMA contamination, the FDA says pharmacies are unlikely to run out of ARBs.

In late 2019, a few patients who were injured by taking NDMA-contaminated drugs had filed lawsuits against the drugs’ manufacturers. More of these NDMA contamination lawsuits are likely as time goes on. Our law firm is currently investigating Valsartan cancer lawsuits involving the stomach, liver and colon. We are also working on Zantac cancer lawsuits involving the liver, GI tract, colon and stomach.