Acetaminophen Overdose Continues to Cause Severe Liver Injury Litigation

Despite an FDA campaign to raise awareness of the connection between products containing acetaminophen and severe liver injury, the FDA continues to receive reports of acetaminophen related injuries and deaths. In 2009, the American Association of Poison Control Centers reported that it had received 258,016 calls regarding acetaminophen related poisoning.[1]  According to the FDA, there are 56,000 emergency-room visits and 100 deaths caused by acetaminophen poisoning every year.[2]  While acetaminophen litigation has been sparse, it is poised to increase in light of recent FDA action intended to address the increasing number of cases of acetaminophen poisoning around the country. 

Acetaminophen Facts

Acetaminophen is a pain reliever and fever reducer used in both prescription and over-the-counter products. Other names for acetaminophen include paracetamol and N -acetyl-p-aminophenol (APAP). The most common and original brand of acetaminophen is Tylenol, a product of Johnson and Johnson’s McNeil Pharmaceuticals division.  however acetaminophen is used in over two hundred different medications. Tylenol,  is the most popular painkiller in the United States.[3] Americans take over 8 billion pills (tablets or capsules) of Tylenol each year.[4]  In addition to Tylenol, acetaminophen is used in 200 different medications.

Acetaminophen belongs to the category of drugs known as analgesics.  Other analgesics include Aspirin Free Anacin, Datril, Genapap, Genebs, Panadol, Tempra and Valorin. What distinguishes analgesics from other painkillers such as ibuprophen (common brand name Motrin) or naproxen (common brand name Aleve) is that analgesics reduce pain and fever but do not reduce inflammation. 

Pure acetaminophen (not contained in any other formulation or combination) is approved for  sale in the United States in 325-mg and 500-mg immediate-release tablets, and in a 650 mg extended-release product marketed as an anti-arthritic.  Other common over the counter drugs that contain acetaminophen include NyQuil, Sudafed, Theraflu, and many other cold, sinus and flu remedies, including numerous varieties approved and marketed for children.

Acetaminophen is also a component of many prescription combinations.  These drugs are most commonly high powered pain killers that combine acetaminophen and various opiates, for example, Tylenol 3 (combination of acetaminphen and codeine), Percocet (combination of acetaminophen and oxycodone) and Vicoden (combination of acetaminophen and hydrocodone). The label on these drugs may not spell out the whole word or may use abbreviations, such as APAP, AC, Acetaminophn, Acetaminoph, Acetaminop, Acetamin, or Acetam to refer to acetaminophen. When used in a formulation or in combination with opiates, acetaminophen is often supplied in higher concentrations.  For example, prescription Vicodin is approved in versions containing either 500, 650, or 750 mg of acetaminophen.  The highest approved dosage for over the counter acetaminophen tablets or capsules is 500mg.

During the late 1990’s, it became apparent to the FDA that acetaminophen was a major cause of acute liver failure in the United States, with up to half of the cases due to accidental overdose. Acetaminophen overdose is the leading cause of acute liver failure in the United States and the United Kingdom.[5]  According to the FDA, overdoses from prescription products containing acetaminophen account for nearly half of all cases of acetaminophen-related liver failure in the U.S.  Acetaminophen related liver failure often results in liver transplant or death. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute liver failure.  Some studies also suggest that people who use acetaminophen on a regular basis have a significantly increased risk of kidney cancer. [6]

The Injury Mechanism

The liver is the primary site in the body where acetaminophen is metabolized.  In the liver, acetaminophen binds to a sulphate molecule and to a glucuronide molecule before being eliminated in the urine.  When the liver has such a high amount of acetaminophen that the sulphate and glucuronide pathways are completely saturated, acetaminophen starts being processed through another pathway called the cytochrome P-450 system. The P-450 system causes the acetaminophen to form a toxic metabolite called NAPQI. Under normal circumstances the NAPQI metabolite is detoxified by another system called the glutathione system.  When that system becomes saturated, the NAPQI metabolite accumulates in the liver and begins to cause cell damage. [7]

Causes of Acetaminophen Poisoning

Many cases of acetaminophen poisoning result from people accidentally taking a one time overdose, often due to the fact that they do not realize acetaminophen is an ingredient in a combination of drugs they are using.  In a study cited by the FDA from 22 medical facilities in the United States, acetaminophen-related liver injury was the leading cause of acute liver failure for the years 1998 through 2003.[8] Patients in this study were found to have taken too much acetaminophen from both over the counter and prescription drugs or a combination of both. Almost half of these cases involved overdose in which the patient had not intended to take too much acetaminophen.[9]  The majority of cases, however, occur because of chronic use of smaller doses. In the case of chronic use, 4000 mg per day can lead to liver toxicity.[10] Acetaminophen poisoning affects the liver similarly to any other toxin, including alcohol.

In addition to more commonly known risk factors for acetaminophen poisoning such as alcohol use and underlying liver disease, additional conditions may result in higher sensitivity, and therefore lower thresholds for toxicity.  For example, malnourishment, diminished nutritional status, fasting, viral illness with dehydration, and interaction with other drugs known to induce CYP oxidative enzyme activity can lower a person’s toxicity threshold. 

In a June, 2009 advisory committee meeting, the FDA spelled out several possible causes for the high incidence of acetaminophen related liver failure.[11]  Based on the widespread prevalence of liver injury, according to the FDA, distinct factors associated with acetaminophen products were contributing to this public health problem including:

1. Current recommended doses were so close to the amount that can be toxic, there is little room for consumer error.

2. The onset of symptoms associated with acetaminophen liver injury can take several days, even in severe cases and mimic flu symptoms, making it difficult for individuals to readily identify the problem. 

3.  The delay in identifying the cause of symptoms leads to a delay in administration of the antidote for acetaminophen poisoning, often rendering this remedy less effective.

4. Some individuals experience toxic effects at lower dosages.  In addition to individuals with known sensitivities, such as people who have liver disease or use alcohol, more research is needed to understand whether ethnicity, genetics, nutrition, or other factors might have a role in acetaminophen sensitivity.

5.  The wide array of acetaminophen products in a range of doses for multiple indications may make consumers reasonably attempt to treat different conditions or symptoms with multiple products containing acetaminophen without realizing that acetaminophen is an ingredient common to each.

6.  Common use of different names to identify acetaminophen, such as the use of the letters APAP typically used on prescription labels, can make it difficult to identify acetaminophen as an ingredient, thereby causing people to inadvertently overdose.

7.  Multiple children’s products contain different concentrations of acetaminophen.  Paradoxically, formulations intended for infants are typically more concentrated to enable proper dosing using less liquid. If a parent does not recognize that an infant formula is stronger than the children’s formula, they may give a higher dose of the infant formula to an older child resulting in an accidental overdose.

8. Consumers are not sufficiently aware that acetaminophen can cause serious liver injury.

9.  Consumers’ perceptions of the safety or dangerousness of acetaminophen products may be influenced by the marketing of the products. For example, advertisements of over the counter drugs often emphasize the effectiveness of products, without being subject to the requirements of prescription products to balance such messages with warning information.

10.  The availability of acetaminophen in large quantities such as 500 tablets per bottle may contribute to the perception that the drug is unlikely to be harmful.

11.  Current labeling on acetaminophen products may be overlooked.[12]

Acetaminophen, Alcohol and Liver Failure

Ingesting acetaminophen and alcohol at the same time increases the risk of liver failure.  The issue of whether this connection is made clear to users and the warnings regarding alcohol and acetaminophen use are sufficient may be the subject of  future litigation. 

In Bell v. Lollar, 791 N.E.2d 849 (Ind. App. 2003), an alcoholic who experienced liver injury after mixing alcohol and acetaminophen filed a failure to warn claim against the manufacturer of a generic version of Tylenol 3 (acetaminophen combined with codeine). The manufacturer argued that the complaint was pre-empted by FDA regulations.  The court in that case held that because the FDA regulations governing the labeling of drugs were minimum standards, they did not preempt state law failure to warn claims because the manufacturer was free to strengthen its label by adding an alcohol warning. The subsequent Supreme Court decision in Wyeth v. Levine, clarified the pre-emption issue.[13]

In 1998, the FDA finalized a regulation requiring alcohol warnings be added to OTC labeling. The warning advised consumers who ingest 3 or more alcoholic drinks every day to ask their doctor whether they should take acetaminophen or other pain relievers/fever reducers.  In 2009, the FDA required a stronger acetaminophen label that, among other things, required that the alcohol warning be part of the liver injury warning, rather than in a separate alcohol warning as previously required.[14] The sufficiency of this strengthened warning has not been tested in litigation.

FDA Action to Decrease the Risk of Acetaminophen Poisoning

One step taken by the FDA to address these causes of liver toxicity, was to announce a new limit on the amount of acetaminophen in each over the counter tablet capsule to 325 mg.[15]  The FDA also announced that it will begin requiring manufacturers to update labels on all prescription combination acetaminophen products to warn of the potential risk for severe liver injury.[16]  In addition, the FDA required a warning on labels of all prescription products that contain acetaminophen that highlights the potential for allergic reactions.[17]  Common allergic reactions include swelling in the face, mouth, and throat; difficulty breathing; itching; and rash.[18]  The FDA’s action called for a three-year phase in of the lower-dose prescription combination acetaminophen in order to prevent a shortage of pain relievers.[19]

The Stages of Liver Failure Caused by Acetaminophen Poisoning        

There are four stages in the clinical presentation of liver failure.[20]  The first phase occurs within the first twenty-four hours.  It is common during this period for the patient to experience general discomfort, nausea and vomiting, and lack of appetite followed by a “latency” period with no symptoms.  It is this asymptomatic period that often leads patients to conclude that they had experienced a minor stomach ailment that has resolved itself, thus delaying diagnosis and treatment.[21]

The second phase occurs between eighteen and seventy-two hours after acetaminophen overdose.  During this phase, the patient often experiences more nausea, vomiting and anexoria, often accompanied by right upper torso pain. This is the first stage in which liver enzyme tests will begin to return abnormal results.[22]

During the third phase, which occurs between three and four days after the acetaminophen overdose, necrosis of the liver begins.  The patient continues to have abdominal pain, nausea and vomiting, often accompanied by jaundice.  However, much more serious conditions can develop during this stage including kidney failure, bleeding disorders and coma.  Once the disease has reached this phase, death is virtually certain unless the patient receives a liver transplant.[23]

If a patient receives proper and timely treatment, they will enter a fourth phase.  This phase generally lasts from three days to one month.  During this phase, organ failure begins to reverse and eventually the patient is expected to experience complete recovery.[24]

Treatment of Acetaminophen Poisoning

If acetaminophen poisoning is suspected, doctors typically “pump” the patient's stomach to remove any pill fragments.  Doctors also typically administer the antidote for acetaminophen poisoning called N -acetylcysteine (“NAC”).[25]  NAC is an anti-inflammatory and antioxidant that increases oxygen flow of to peripheral tissues in the liver. NAC is most effective when administered within twelve and sixteen hours of an acetaminophen overdose. However, NAC has been shown to decrease mortality rates even after significantly longer periods.[26]

Acetaminophen Poisoning Litigation

The recent FDA activity has reinvigorated interest in acetaminophen litigation, despite the fact that lawsuits related to Tylenol induced liver damage have met with mixed results.[27]  Besides the issues of whether a consumer was sufficiently warned, exceeded the recommended dosage, knowingly mixed acetaminophen and alcohol or had pre-existing liver damage, other issues include federal preemption and “learned intermediary” claims.[28]

In Eck v. Park Davis,[29] a 2001 case from the Eastern District of Oklahoma, the plaintiff experienced acute liver injury after ingesting the acetaminophen containing drug Isocet[30] and the anti-seizure medication Dilantin.  The manufacturer was found not to be liable for failure to warn after the plaintiff’s physician testified that she was aware of the risk of taking these drugs simultaneously and would have prescribed them anyway, because she believed the risk of injury from seizures exceeded the risk created by mixing these drugs.

The “learned intermediary” issue will continue to be a challenge to plaintiffs in future litigation, however, the recent FDA action suggests additional bases for liability, including the fact that the consumer overdosed inadvertently as a result of poor warnings, poor or confusing identification of product ingredients and confusing dosages in children’s products due to differing concentrations.  In fact, this third argument was the basis of a successful lawsuit against Ortho McNeil, the maker of Infants’ Tylenol in September 2006.   Dunson v. Mcneil, is a 2009 case decided by the Supreme Court of Pennsylvania involving a one-year old boy who died after taking Infant’s Tylenol for three days to treat cold symptoms.[31]  The boy’s parents administered two drops of Infants’ Tylenol every four hours. The child became very ill and died within two days. According to the suit, the baby’s parents, like most parents, were not aware that Infants’ Tylenol was three times more potent than regular Children’s Tylenol.  The jury found that Ortho McNeil had failed to adequately warn consumers of the increased potency of Infants’ Tylenol, which the jury believed, directly resulted in the death of the child.  The jury in that case awarded $5 million to the parents in their wrongful death suit.

A 1994 failure to warn case in Virginia was also successful.[32]  The plaintiff in that case, Antonia Benedi, was a former special assistant to former president George Bush. Mr. Benedi claimed that he took the recommended dose of Tylenol in combination with his regular dinner consumption of wine. He said he was in good health until he used Tylenol Extra Strength for several days to treat the flu and slipped into a coma. He received a liver transplant several days later. Benedi was awarded $7.855 million in compensatory damages and an additional $1 million in punitive damages by a federal jury.

Most recently, in January 2010, a New York Superior Court judge dismissed a lawsuit on summary judgment in which it had been claimed that Tylenol had caused a woman to develop cirrhosis of the liver.[33]   Like Benedi, the plaintiff in this case claimed that she had used only the recommended dosage of Tylenol, however, following a Frye hearing, the judge ruled that the plaintiff had “wholly failed to introduce any studies, peer articles, professional literature, judicial opinions or recognized text books that state plaintiff’s simple yet novel premise, namely that normal ingestion of acetaminophen causes cirrhosis  of the liver.”  That case should have little impact on likely future litigation in which the plaintiff suffered from liver failure, as the connection between acetaminophen and liver failure, particularly acute liver failure as opposed to cirrhosis of the liver, is rather well documented.

Conclusion

Given the enormous volume of acetaminophen sales in the U.S., the increasing number of cases of acetaminophen related liver failure in the U.S. every year, and the precedents set by the Dunson and Benedi cases, it is likely that litigation in this area will increase.  Additionally, increased public awareness of the acetaminophen/liver poisoning connection created by the FDA public awareness campaign will hopefully result in fewer cases of liver failure, but will likely also bring more plaintiffs forward.  Likewise, current FDA activity, particularly its studies and reports on the “human factors” causes of accidental acetaminophen overdose, should generate greater public awareness, additional research and additional litigation.