Generic drugs are a big deal in the United States. According to the U.S. Food and Drug Administration (FDA), 90% of prescription medications are filled with a generic drug. One of the reasons so many people take generic medications is the cost savings. From 2007 to 2016, generic medications saved $1.67 trillion. A generic version of Zantac has been sold since 1997.

But how is a generic drug different from a brand-name drug? Does this difference matter in the Zantac litigation? If so, where does innovator liability come in? I’ll address these questions in the following blog post. But first, a brief update into the Zantac litigation.

Current Status of Zantac Litigation

In February 2020, the Zantac multi-district litigation (No. 2924) was created in the U.S. District Court for the Southern District of Florida. If a plaintiff sues the maker of Zantac and claims it gave her cancer, there’s a good chance that case will end up in this multi-district litigation, or MDL.

On June 22, 2020, the plaintiffs in the MDL filed their Master Personal Injury Complaint. To learn more about this lengthy legal document, check out my series of blog posts discussing it: Part 1, Part 2 and Part 3.

Right now, the MDL is currently in the pleadings stage and over the next few months, each side will present their arguments concerning the pending motions to dismiss.

What Is a Generic Drug?

A generic drug is a drug that is effectively the same as a name-brand drug, but is made by a company other than the name-brand drug maker.

Name-brand drugs are important in the pharmaceutical world because they give the brand-name holder exclusive rights to sell a medication in a given market. Depending on how popular the medication is, this can mean massive profits for the pharmaceutical company that created the name-brand drug.

How long this protection lasts is complicated, but it can last up to 20 years. After the protection is gone, other drug manufacturers can make a generic version of the drug.

The FDA approves generic medications to ensure that they:

• Contain the same active ingredient,
• Have the same strength,
• Are taken in the same way (injection, oral, etc.), and
• Have the same form (tablet, liquid, etc.).

A Brief History of Zantac

Zantac received patent protection in 1977 and got FDA approval in 1983. By 1988 Zantac became the world’s bestselling drug. In 1997, the patent protection expired and generic drug makers started making and selling ranitidine, the generic version of Zantac.

Why does this history matter? Because when consumers started taking ranitidine can make a difference in a potential lawsuit against a drug maker. That’s where the concept of innovator liability comes in.

What Is Innovator Liability and Why Does it Matter in the Zantac MDL?

Depending on the legal claims alleged, a plaintiff cannot sue the name-brand maker of a drug if he only took the generic version of the drug. So the plaintiff can go after the generic drug maker then, right? Well, that’s not always possible either, due to some oddities in how federal and state laws interact with one another.

This means that if a plaintiff only took ranitidine (and never took a Zantac branded product) and claims personal injuries, the court could potentially dismiss the plaintiff’s case. Given how Zantac became subject to generic competition in 1997, a lot of plaintiffs could be affected. But there’s a possible exception to this legal limitation in a few states: innovator liability.

Innovator liability is the legal theory that will hold the name-brand drug maker liable for injuries caused by the generic version of the drug. In other words, a plaintiff who took ranitidine could still sue the makers of Zantac (several companies have made name-brand Zantac over the years) despite never having taken that name-brand drug.

Because of innovator liability, a ranitidine consumer can still sue in the Zantac MDL, right? Probably not. Innovator liability is not a widely accepted legal theory, and so far is recognized only by the following four states:

• California
• Illinois
• Massachusetts
• Vermont

So to reiterate: if you took ranitidine, the generic version of Zantac, and never took name-brand Zantac, and later developed a qualifying cancer, you will not be able to invoke innovator liability to bring claims against the original makers of Zantac unless you live and developed cancer in the four states listed above.

However, and for further clarification, just because you took generic ranitidine doesn’t mean you can’t sue the name-brand pharmaceutical company. As long as you have taken Zantac, whether exclusively or in combination with ranitidine, you can still bring suit against the makers of Zantac without invoking innovator liability. And don’t forget that Zantac products continued to be widely available, even after generic versions became widespread. Don’t assume you don’t have a legal claim because you mainly took generic ranitidine.

Now What?

Right now we wait for the court to decide the motions to dismiss. There’s also a key study that should come out soon that may play a role in how the litigation proceeds depending on the study’s findings. When there’s a major update in the Zantac case, I’ll let you know. In the meantime, you can reach me at (919) 830-5602 if you have any questions about Zantac and cancer.

In Part 2 of this series we looked at the development of ranitidine (brand name Zantac), its rise as a hugely profitable heartburn drug, and the discovery that the carcinogen NDMA was found in rantidine, eventually leading to its recall and removal from the market. In this Part 3 I discuss how ranitidine can evolve into the cancer-causing chemical NDMA.

Nanitidine Can Form NDMA in the Stomach

When ranitidine enters the stomach, it can interact with “nitrites.” Nitrites are chemicals often found in spicy or salty foods. Food producers add nitrites to certain foods to prolong shelf life. All the way back in 1981, Dr. Silvio de Flora published a study showing that when ranitidine is introduced to nitrites it can lead to “toxic effects.” Dr. de Flora cautioned that if people take ranitidine, they should eat foods low in nitrites and avoid ranitidine near meal times.

Glaxo Smith Kline responded to this study, quickly and predictably. GSK stated that the levels of nitrite needed to cause such a reaction in the human body were unlikely in the real world. Instead, it continued selling Zantac and continuing not to warn consumers of the possible health risks. According to the Master Complaint, GSK “was involved in covering up the scientific data, offering illegal kickbacks to prescribing physicians, intimidating witnesses, and defrauding Medicare to profit from these medicines.” Pg. 63.

As GSK worked to get FDA approval for ranitidine (Zantac) it conducted several studies parsing out the findings that ranitidine can combine with nitrites in the stomach, thus mutating to NDMA, a known carcinogen. GSK repeatedly represented that the risk was low or unknown, and that patients would not be expected to take ranitidine for extended periods and so should not be exposed to risk of NDMA. In 1983, Dr. de Flora and other researchers confirmed in follow-up studies that mixing rantidine with nitrites can form NDMA. Subsequent studies have shown huge increases in NDMA in the human body after small amounts of rantidine are taken.

Valisure is an independent lab that conducted accredited studies on ranitidine in 2019. Valisure found that one ranitidine tablet produced 2,692,291 ng of NDMA. That’s a lot. According to these recent studies, a person who eats foods with nitrites would need to smoke 500 cigarettes to achieve similar levels of NDMA after taking one dose of 150mg ranitidine. It has become clear that ranitidine should never have been taken for extended periods while consuming foods high in nitrites. Nevertheless, the makers of Zantac advertised that it should be used when eating foods high in nitrites, such as tacos and pizza.

NDMA Can Form in Other Parts of the Body

NDMA can also form inside the human body but outside the stomach. Valisure lab found that an enzyme “DDAH” interacts with ranitidine to produce toxic levels of NDMA. This is complicated chemistry, but essentially the ranitidine binds to the DDAH enzyme, and together produces NDMA. So, where DDAH is most present in the body, more NDMA can be formed. DDAH is most commonly found in the kidneys, but also in the brain, colon, liver, intestine, stomach, bladder, and prostate. And, as we talked about in Part 2, NDMA can cross the blood-brain and placental barriers in a matter of hours, which means it reach most parts of the body.

NDMA Can Form When Ranitidine Exposed to Heat or Time

NDMA can also form when ranitidine or Zantac is exposed to heat or the passage of time. GSK confirmed this in its own studies in the 1980s. Valisure confirmed this finding decades later. These higher temperatures occur in normal conditions when the drug is stored in warehouses or shipped on trucks. Thus, ranitidine breaks down into NDMA in the days and weeks after manufacture under normal conditions when it sits in shipping trucks, or lingers in storage rooms. Even at room temperature, ranitidine can transform into NDMA within weeks.

NDMA Forms in the Ranitidine Manufacturing Process

This discovery was made in the context of other drugs found to contain NDMA, such as Valsartan. Eighty percent of the ingredients used to make drugs sold in the United States come from other countries, mainly China and India. NDMA was discovered in these ingredients, caused when these countries used less expensive solvents in the manufacturing process. As a result, NDMA has even been produced when manufacturing ranitidine or Zantac. Even without introducing nitrites, or enzymes, or heat, or time, the ranitidine tablets studied were found to contain high levels of NDMA.

Zantac has now been removed from the market, but the question is haunting: with all this scientific study about its connections to the cancer-causing NDMA, why did it take over thirty years?

Note: The statements in this blog post are allegations made by plaintiffs in the Zantac litigation. They have not yet been proven in court.

In Part 1 I discussed the concept of the Master Complaint in product liability multi-district litigation, and we also set the table with the plaintiffs and the many defendant-companies involved in the Zantac litigation. Now let’s keep grinding through the Zantac Master Complaint. The story of Zantac, the presence of the carcinogen NDMA, and the links to cancer can be found in the Factual Allegations, beginning on page 39 of the Master Complaint. (Note that I use the brand-name Zantac and its actual name ranitidine mostly interchangeably in this post.)

These are the key elements of the story:

Inventing and Selling Ranitidine

• Ranitidine is a medication relieves heartburn and acid indigestion.
• According to the Master Complaint, it was developed by GlaxoSmithKline (GSK) predecessors to compete with other “histamine H2-receptor antagonists” on the market, particularly Tagamet (cimetidine).
• A scientist working for a Glaxo subsidiary discovered ranitidine in 1976.
• In 1983, the FDA granted approval for Glaxo to sell Zantac.
• The prescription drug was a smash hit for Glaxo, the first drug to make $1 billion in sales.
• GSK turned Zantac into a blockbuster in part by driving sales. It added 800 salespersons to Zantac’s U.S. sales force.
• In 1993, GSK introduced an OTC version of Zantac, which it began selling a few years later.
• Over the next twenty-five years, other Defendants acquired the rights to sell OTC Zantac, including Pfizer, Boehringer Ingelheim, and Sanofi.
• GSK retained control of prescription Zantac in the U.S., which it sold until 2017.
• On October 18, 2019, Defendant Sanofi recalled all brand-name OTC Zantac in the U.S.
• In 1997, the original Zantac patent expired, allowing other companies to sell generic ranitidine products. Seventy-five companies eventually sold generic versions of ranitidine over the next two decades.
• The Brand-Name Manufacturer Defendants continued to sell prescription and OTC ranitidine.
• OTC Zantac antacid tablets had sales totaling $128.9 million in 2018.

Dangers of NDMA

• N-Nitrosodimethylamine (“NDMA”) is a toxic chemical and a danger to human health.
• NDMA is a carcinogen. As the Master Complaint puts it ominously, “its only use today is to cause cancer in laboratory animals.”
• Since 1980, companies have pulled all kinds of products from stores that were found to contain high levels of NDMA.
• In 2018, there have been recalls of several generic drugs to treat high blood pressure, including Valsartan and Losartan, (which I wrote about here).
• Scientists believe any amount of NDMA can increase risk for cancer or other health problems.
• In studies, laboratory animals taking NDMA orally developed liver, lung, bladder, kidney, pancreas, and stomach cancers.
• NDMA is a small particle, which means it can pass easily through the body, including into the brain and into placenta.
• But, studies also show that small amounts of NDMA can be fully metabolized in the liver, while larger amounts move throughout the body.
• In 1995, several studies showed an increased risk in cancer for humans after ingesting small amounts of NDMA.
• Studies in 1999, 2000, 2011, and 2014 reconfirmed the findings that NDMA can cause several cancers in humans.

NDMA Found in Ranitidine Products

• 

  In September 2019, an independent lab found significant levels of NDMA in ranitidine products. Four days later the FDA issued a warning that ranitidine (Zantac) may contain NDMA.
• In the next days and weeks, companies began voluntarily recalling their Zantac and generic-ranitidine products.
• On November 1, 2019, the FDA announced unacceptable levels of NDMA in ranitidine products based on recent testing, and requested that drug makers recall the medication.
• On December 4, 2019, the FDA issued a statement warning consumers who still take ranitidine to limit intake of nitrite-containing foods, like processed meats.
• The Complaint then throws a haymaker, noting that this was the same advice as the advice given by an Italian scientist . . . in 1981. Had GSK listened to the Italian scientists decades earlier, the Complaint argues, then millions of people may not have been exposed to dangerous levels of NDMA over thirty-eight years.
• In 2020 studies showed that ranitidine products can develop NDMA when exposed to temperature changes over time. The conclusion was that ranitidine is time and temperature sensitive, meaning the longer it sits or the more often it is exposed to temperature fluctuations, the more NDMA it is likely to develop.
• On April 1, 2020, the FDA recommended the removal of all ranitidine products.

In Part 3, we will look at the science behind the way ranitidine becomes NDMA.

Remember: These allegations come from the Master Complaint in the Zantac MDL and have not yet been proven in court.