What Are Nitrosamines and Do They Cause Medication Shortages?

Nitro-say-what? You may have noticed nitrosamines making headlines lately, and not for positive reasons. The impurity is responsible for over 1,400 medication lot (batch) recalls.  A drug recall happens when the quality of a medication is compromised. Usually, the FDA recommends the recall, but it’s up to the medication manufacturer to take it off the shelves.

But what are nitrosamines, and how are they getting into medications? What are the risks? And with the U.S. facing more drug shortages than ever before, are nitrosamines to blame? In this article, we’ll get to the bottom of these questions and more. 

What are nitrosamines?

You might be surprised to learn that we encounter nitrosamines every day. Nitrosamines are chemicals that naturally exist at low levels in our food and water. Nitrosamines are considered safe at low levels. Since most of us aren’t chemists, let’s use an analogy to better understand nitrosamines.

Remember those building blocks you played with as a kid? Think of organic compounds as the building blocks that make up all drugs. The blocks can join together, break apart, or rearrange during the drug-making process.

A nitrosamine contains one oxygen block (“O”) and two nitrogen blocks (“N”). These attach to two other blocks (“R”) that are unique to each type of nitrosamine. The five blocks together make up a nitrosamine. 

How do nitrosamines end up in medications?

Nitrosamines are not intentionally added to medications. But, they can find their way into the finished product through different processes. A few ways nitrosamines can end up in medications include: 

• The manufacturing process. When a medication is made, chemical reactions can occur that promote the creation of nitrosamines.

• The way medications are stored. As medications are stored, chemical processes may lead to the formation of nitrosamines.

• The raw ingredients used. The ingredients used to make a medication can be contaminated right from the start.

• In the body. When you take a medication, nitrosamines can form through chemical reactions in the body.

As of February 2021, five types of nitrosamines had been found in medications. They are:

• N-nitrosodimethylamine (NDMA)

• N-nitrosodiethylamine (NDEA)

• N-nitroso-N-methyl-4-aminobutanoic acid (NMBA)

• N-nitrosoisopropylethyl amine (NIPEA)

• N-nitrosomethylphenylamine (NMPA)

In June 2021, the FDA recalled Chantix (varenicline) — a medication that helps people quit smoking — due to unacceptable levels of a new nitrosamine, N-nitroso-varenicline. This nitrosamine is unique to Chantix.

Not all medications that contain nitrosamines are dangerous. It all depends on the amount of nitrosamines that are present. 

How much nitrosamine is allowed in my medications?

The FDA and other international agencies decide the level of nitrosamines allowed in medications. This is called the acceptable intake limit. Anything below it is safe, while anything above it is considered unsafe. The acceptable intake limit is measured in nanograms (ng) per day, and is different for each type of nitrosamine.

To put things in perspective, one gram weighs about the same as a small paper clip. A nanogram is one-billionth of that weight. So, it’s an extremely small amount of nitrosamines that the FDA will allow in medications. The acceptable intake limits for the six nitrosamines in medications are below.

Are nitrosamines a new problem?

No, nitrosamines aren't a new problem. We’re hearing more about them now because newer, more effective technology allows us to detect nitrosamines at lower amounts than before. Better testing methods allow the FDA to detect even trace amounts of impurities in medications. And because we understand more about the medication-making process, we can identify processes that create nitrosamines before they occur. 

Do nitrosamines lead to drug recalls?

High levels of nitrosamines in medications can lead to drug recalls. As we discussed above, the FDA has set limits on what amount of nitrosamines are safe to take daily. If a medication contains nitrosamines above the acceptable intake limit, the FDA will recommend a recall. The FDA usually can’t force a pharmaceutical company to recall a medication from the market. But even though companies don’t have to follow the FDA’s recommendation to recall a medication, they usually do. This helps protect consumers and avoid negative publicity.

What if my medication gets recalled?

If your medication was recalled, don’t stop it without talking to your healthcare provider. Sometimes a recall only affects a certain manufacturer of a medication. It may also only apply to a specific lot (batch) of a medication.

Your pharmacist or healthcare provider can help you decide if it's safe to keep taking your medication. If it’s unsafe, your healthcare provider may recommend another medication to treat your health condition.

Where can I find the latest FDA news on drugs with nitrosamine?

To learn about recalls, visit the FDA website. Here, you can find information on recalls, market withdrawals, and medication safety information. If you’re wondering whether your medication is safe, you can search the medication by name to see if it's been recalled.

You can also learn about drug recalls and safety information through another FDA website, MedWatch. That’s where you can find the most recent information on medication recalls and even sign up to receive alerts for medication and food products.

Do nitrosamines cause drug shortages? 

Impurities found in medications, like nitrosamines, can contribute to shortages. But, they’re not solely to blame. Manufacturing problems, trouble finding raw ingredients, and general business decisions can also cause shortages.

If a medication is recalled, the FDA takes quick action to prevent the recall from causing a shortage. They work directly with the manufacturer to fix the problem. They may also step in to help other manufacturers ramp up production. If no U.S. manufacturer is able to fix a drug shortage, the FDA may look for a foreign pharmaceutical company to bring the medication to the U.S.

For example, when Chantix (varenicline) was recalled in 2021 due to unacceptable levels of N-nitroso-varenicline, the FDA allowed a Canadian manufacturer (Apotex) to bring their version of Chantix (Apo-varenicline) to the U.S. to avoid a shortage.

Do nitrosamines cause cancer? 

Nitrosamines may raise your risk of cancer if you take them at high levels for a long time. Although the cancer risk in humans is unclear, studies have shown that nitrosamines cause cancer in some animals. Because of this, many experts, like the International Agency for Research on Cancer (IARC), think nitrosamines could cause cancer in humans too.

Keep in mind that low levels of nitrosamines are not a concern. The FDA states that even if you took medications containing a level of nitrosamines below the acceptable intake limit for 70 years, your risk of cancer would not be raised. 

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Written by:

Tegan Smedley, PharmD, APh

Tegan Smedley, PharmD, APh, has 10 years of experience as a pharmacist. She has worked in a variety of settings, including retail, hospital, and ambulatory care.

Edited by:

Amy B. Gragnolati, PharmD, BCPS

Amy Gragnolati, PharmD, BCPS, is a pharmacy editor for GoodRx. Amy currently holds her pharmacist license in Georgia and California.

Reviewed by:

Christina Aungst, PharmD

Christina Aungst, PharmD, is a pharmacy editor for GoodRx. She began writing for GoodRx Health in 2019, transitioning from freelance writer to editor in 2021.

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