Ranitidine (Zantac) and risks from carcinogenic N-nitrosodimethylamine (NDMA)

[Mr. Bill]

Not sure yet if this is a significant risk or a microscopic one.  Anyway, here's the FDA's press release:

9/13/19: Statement alerting patients and health care professionals of NDMA found in samples of ranitidine

The U.S. Food and Drug Administration has learned that some ranitidine medicines, including some products commonly known as the brand-name drug Zantac, contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. ...

The FDA is evaluating whether the low levels of NDMA in ranitidine pose a risk to patients. FDA will post that information when it is available. ...

Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.

Ranitidine is an over-the-counter (OTC) and prescription drug. Ranitidine is an H2 (histamine-2) blocker, which decreases the amount of acid created by the stomach. ...

The agency is working with international regulators and industry partners to determine the source of this impurity in ranitidine. The agency is examining levels of NDMA in ranitidine and evaluating any possible risk to patients. The FDA will take appropriate measures based on the results of the ongoing investigation. The agency will provide more information as it becomes available.

The FDA is not calling for individuals to stop taking ranitidine at this time; however, patients taking prescription ranitidine who wish to discontinue use should talk to their health care professional about other treatment options. People taking OTC ranitidine could consider using other OTC medicines approved for their condition. There are multiple drugs on the market that are approved for the same or similar uses as ranitidine. ...

There is, of course, already a class-action lawsuit.  They claim insanely-large amounts of NDMA found in some pills (contary to the FDA's statement).

The lawsuit says that ranitidine can react with itself to produce NDMA, but without referencing any research to prove it.  There was one small study (10 people) in 2016 that showed a lot of NDMA in the urine after using ranitidine, but they didn't check the pills for NDMA, so it's not clear whether the source was NDMA in the pills, NDMA produced in the body, or something else entirely.

My wife is currently going nuts with Google Scholar, collecting more info.  I'll let you know if anthing interesting shows up.

At the moment I'm taking a "don't panic but stay informed" approach.

[Mr. Bill]

Fairly good overview here, courtesy of Bloomberg (via LA Times):

9/13/19: Carcinogen in Zantac and generic heartburn drugs triggers investigations

[Mr. Bill]

Two ranitidine manufacturers have issued voluntary recalls of some varieties and lots:

Sandoz Inc. Issues Voluntary Recall of Ranitidine Hydrochloride Capsules 150mg and 300mg Due to An Elevated Amount of Unexpected Impurity, N-Nitrosodimethylamine (NDMA), in the Product

Apotex Corp. Issues Voluntary Nationwide Recall of Ranitidine Tablets 75mg and 150mg (All pack sizes and Formats) due to the potential for Detection of an Amount of Unexpected Impurity, N-nitrosodimethylamine (NDMA) Impurity in the product

The Apotex recall includes some OTC ranitidine tablets sold at Rite Aid, Walmart, and Walgreens.

You can check for any additional recalls by going to this page and entering "ranitidine" in the Search box:
https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts

[Mr. Bill]

It's a confusing situation. Ranitidine can decompose and create NDMA, but there are two separate issues.

One, are some ranitidine pills contaminated with too much NDMA? This may be limited to specific brands and lots, and it should be fixable by improving the manufacturing method.

Two, does ranitidine spontaneously decompose IN THE BODY to release NDMA? This is iffy, with only one tiny study suggesting it might be the case, and needs more research.

Related: How much NDMA do we get in our diets anyway, and is the amount from ranitidine significant? Again, we've got conflicting data at the moment.

Also, the recalls are currently voluntary, not FDA-mandated or FDA-approved. So the fact that a particular manufacturer has not done a recall may be meaningless.

Famotidine (Pepcid) looks like the closest probably-safe substitute. It's a histamine H2 receptor antagonist like ranitidine, it has fewer drug interactions, and the chemical structure is different enough that there's no NDMA issue.

[Mr. Bill]

How much NDMA do we get in our diets anyway, and is the amount from ranitidine significant?

Some random info:

CDC Agency for Toxic Substances & Disease Registry: Public Health Statement for n-Nitrosodimethylamine

The primary sources of human exposure to NDMA are tobacco smoke, chewing tobacco, diet (cured meats [particularly bacon], beer, fish, cheese, and other food items), toiletry and cosmetic products (for example, shampoos and cleansers), interior air of cars, and various other household goods, such as detergents and pesticides. In addition, NDMA can form in the stomach during digestion of alkylamine-containing foods. Alkylamines are naturally occurring compounds which are found in some drugs and in a variety of foods.

How much NDMA do we typically consume?  Seems to vary a lot.  30 years ago in eastern France it was about 0.2 micrograms per day; 40 years ago in Finland it was 0.05 micrograms.  (There must be newer data but I haven't stumbled across it yet.)  A 2007 paper estimates a "Tolerable Daily Intake" of 4.0 to 9.3 nanograms per kg weight per day (call it about 0.5 micrograms per day for an adult).  That's on the order of what you'd get from a serving of bacon, I think.  The FDA is more conservative, setting their limit at 0.096 micrograms/day.

The class-action lawsuit claims that one 150 mg Zantac pill contains over 2500 micrograms of NDMA, which would be utterly insane if true.  The FDA says nothing about finding NDMA at those levels, but I don't know what levels they did find.

[Mr. Bill]

Followup from the FDA:

4/1/20: FDA Requests Removal of All Ranitidine Products (Zantac) from the Market

The U.S. Food and Drug Administration today announced it is requesting manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately. This is the latest step in an ongoing investigation of a contaminant known as N-Nitrosodimethylamine (NDMA) in ranitidine medications (commonly known by the brand name Zantac). The agency has determined that the impurity in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity. ...

New FDA testing and evaluation prompted by information from third-party laboratories confirmed that NDMA levels increase in ranitidine even under normal storage conditions, and NDMA has been found to increase significantly in samples stored at higher temperatures, including temperatures the product may be exposed to during distribution and handling by consumers. The testing also showed that the older a ranitidine product is, or the longer the length of time since it was manufactured, the greater the level of NDMA. These conditions may raise the level of NDMA in the ranitidine product above the acceptable daily intake limit.

With today’s announcement, the FDA is sending letters to all manufacturers of ranitidine requesting they withdraw their products from the market. The FDA is also advising consumers taking OTC ranitidine to stop taking any tablets or liquid they currently have, dispose of them properly and not buy more...