When consumers get a prescription drug from the pharmacy, they assume it has been tested and is safe to use. But what if a drug changes in harmful ways while it’s on the shelf or in the body?
A dangerous result was the creation of N-nitrosodimethylamine (NDMA), a probable carcinogen, in some drugs. NDMA is found in chlorinated water, foods and medicines in trace amounts. To minimize exposure, the United States Food and Drug Administration has set an acceptable level of NDMA in each pill at less than 96 nanograms.
But in recent years, the FDA has found excessive amounts of NDMA in several drugs for hypertension, diabetes and heartburn. As a result, the agency has issued recalls to protect the public. These products have been contaminated with NDMA during the manufacturing process. The FDA has recommended best practices for manufacturers to minimize this risk in the future.
Unfortunately for the buying public, new evidence suggests that NDMA can also be created because some pills sit on the store shelf or in the medicine cabinet. Thus, there is no way to test its presence at the factory.
I am a pharmacist who has written extensively about the manufacturing issues and FDA oversight associated with both drugs and food supplementsincluding the question of NDMA contamination. In January 2021, I discussed how NDMA can end up in a patient’s medication even if it was not present during manufacture. Two new FDA studies clarify how this chemistry works and may help to partially alleviate patient concerns.
NDMA levels increase after manufacturing
Ranitidine (Zantac) was a prescription and over-the-counter medication commonly used for heartburn and ulcers for decades before it was recalled by the FDA on April 1, 2020. Now it may be the canary in the coal mine for creation post-manufacturing of NDMA.
In one study, researchers found that ranitidine only contained 18 nanograms of NDMA after it was made. However, when stored at 158 degrees Fahrenheit (70 degrees Celsius) for 12 days – as if the drug had been left in a hot car – NDMA doses exceeded 140 ng. This is only slightly above the 96 ng limit that the FDA deemed safe, but that was after just 12 days.
In another study, storing ranitidine where it was exposed to higher temperatures or high humidity improved NDMA creation over time. This suggests that some drugs may leave the factory with a safe amount of NDMA, but if kept too long at home or on the store shelf, they may exceed known acceptable limits at the time patients use them. .
In a study from January 2021 in Open JAMA Network, investigators simulated the stomach environment and found that when ranitidine was exposed to an acidic environment with a nitrite source, these chemicals could create over 10,000 ng of NDMA. However, FDA researchers more recently discovered that the previous experiment used levels of nitrite far beyond what would ever be found in the body. When they reran the study with normal dietary levels of nitrite, only one a minimum amount of NDMA has been created.
Other reassuring news arrived in May 2021, with the withdrawal from a clinical study for five years earlier. Originally, the researchers took urine samples from 10 adults before and after using ranitidine. After people swallowed ranitidine, their urinary NDMA levels rose from around 100 ng to over 40,000 ng the next day. But now the scientists suggest that the NDMA levels they measured reflect what was created in urine samples awaiting testing, rather than the NDMA actually made inside the body. Also, a new FDA trial that gave patients ranitidine with a nitrite-rich meal and found no concerning increase in urinary NDMA.
Other drugs require further investigation
The body’s ability to create NDMA after taking ranitidine appears to be limited. But the fact that NDMA can be generated while ranitidine is on the shelf or in the medicine cabinet is still of concern, and this same phenomenon could also occur in other drugs.
In another study, researchers added chloramine, a disinfectant commonly added to sterilize drinking water, to water samples containing one of several drugs structurally similar to ranitidine. They found that several commonly used medications, including antihistamines (doxylamine and chlorpheniramine), a migraine medication (sumatriptan), another heartburn medication (nizatidine), and a blood pressure medication (diltiazem) all generated NDMAs.
It is unclear whether the amount of NDMA created by these drugs when stored in hot, humid environments is harmful, as with ranitidine. I believe that further studies should be done immediately to find out. Prevention is always better than cure, especially when dealing with a possible carcinogen.
Editor’s note: This is an updated version of an article originally published on February 4, 2021.
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