Acetaminophen: Drug Safety Communication - Association with Risk of Serious Skin Reactions

AUDIENCE: Dermatology, Primary Care, Pharmacy

ISSUE: FDA notified healthcare professionals and patients that acetaminophen has been associated with a risk of rare but serious skin reactions. Acetaminophen is a common active ingredient to treat pain and reduce fever; it is included in many prescription and Dilantin Cerebellar Atrophy Risks (OTC) products.  These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal. These reactions can occur with first-time use of acetaminophen or at any time while it is being taken.  Other drugs used to treat fever and pain/body aches (e.g., non-steroidal anti-inflammatory drugs, or NSAIDS, such as ibuprofen and naproxen) also carry the risk of causing serious skin reactions, which is already described in the warnings section of their drug labels.

BACKGROUND: This new information resulted from the Agency’s review of the FDA Adverse Event Reporting System (FAERS) database and the medical literature to evaluate cases of serious skin reactions associated with acetaminophen (see Data Summary at link below).  It is difficult to determine how frequently serious skin reactions occur with acetaminophen, due to the widespread use of the drug, differences in usage among individuals (e.g., occasional vs. long-term use), and the long period of time that the drug has been on the market; however it is likely that these events (i.e., SJS, TEN, and AGEP) occur rarely.

RECOMMENDATIONS: Health care professionals should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions. Any patient who develops a skin rash or reaction while using acetaminophen or any other pain reliever/fever reducer should stop the drug and seek medical attention right away.  Anyone who has experienced a serious skin reaction with acetaminophen should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers.

FDA will require that a warning be added to the labels of prescription drug products containing acetaminophen to address the risk of serious skin reactions. FDA will also request that manufacturers add a warning about serious skin reactions to the product labels of OTC acetaminophen drug products marketed under a new drug application and will encourage manufacturers of drug products marketed under the OTC monograph do the same.

[8/01/2013 - Consumer Update1 - FDA]

[8/01/2013 - Drug Safety Communication 2- FDA]



Acetaminophen Side Effects

Public Conference: Detecting and Evaluating Drug Induced Liver Injury - What's Normal, What's Not, and What Should we do about It?
Dates: March 20-21, 2013
The purpose is to discuss, debate, and build consensus among stakeholders in the pharmaceutical industry, academia, health care providers, patient groups, and regulatory bodies on how best to detect and assess the severity, extent, and likelihood of drug causation of liver injury and dysfunction in people using drugs for any medical purpose. More information


Acetaminophen Death

Acetaminophen Side Effects

Know Concentration Before Giving Acetaminophen to Infants

Ethan was 7 years old when his parents gave him ibuprofen and acetaminophen to break a fever. Doctors say Ethan developed an allergic reaction.

“It is said to occur about one in a million population. We see probably 20 to 25 patients a year in this part of Illinois,” said Dr. Richard Gamelli of Loyola University Medical Center’s Burn Unit.

Within a couple of days, Ethan’s skin began to fall off. ...


Acetaminophen -

Dilantin Cerebellar Atrophy Risks Meds Prompt Dangerous Allergic Reaction


It can cause blindness and make skin all over your body fall off, and doctors say it’s an illness that can be triggered by taking something as simple as ibuprofen or acetaminophen.

It’s called Stevens Johnson Syndrome.

As CBS 2′s Pamela Jones reports, doctors at Loyola University Medical Center are seeing two SJS patients each month in the Chicago area.

Experts say 30 percent of people diagnosed with SJS die, but a child from northwest Indiana has managed to beat those odds. .........

Painful Confusion: Many Unaware of OTC Pain Relievers' Ingredients, Risks (American Journal of Preventive Medicine, 5/11)
A poll reveals many Americans don’t know the active ingredients or potential side effects of popular Dilantin Cerebellar Atrophy Risks pain medicines. Tylenol contains acetaminophen, Bayer contains aspirin, Advil and Motrin contain ibuprofen, and Aleve contains naproxen sodium. ...

But many people know little about the ingredients in their pain relievers. Acetaminophen, the ingredient in Tylenol, is found in more than 600 Dilantin Cerebellar Atrophy Risks and prescription medications.

But ignorance about which medications contain acetaminophen may be why acetaminophen overdose has become the leading cause of acute liver failure in the United States.


Consumer Updates RSS Feed

Overdosing Has Been a Risk An April 2011

Report from FDA’s Center for Drug Evaluation and Research (CDER) found that confusion caused by the different concentrations of liquid acetaminophen for infants and children was leading to overdoses that made infants seriously ill, with some dying from liver failure. So to avoid dosing errors, some manufacturers voluntarily changed the liquid acetaminophen marketed for infants from 80 mg per 0.8mL or 80 mg per 1 mL to be the same concentration as the liquid acetaminophen marketed for children—160 mg per 5mL.

This less concentrated liquid acetaminophen marketed for infants now has new dosing directions and may have a new dosing device in the box, such as an oral syringe. But this is a voluntary change and some of the older, stronger concentrations of acetaminophen marketed for infants are still available and may remain available.




This fact sheet for parents explains what acetaminophen is and how to use it safely.


Tylenol and Ibuprofen Linked to Dangerous Skin Disorder


SJS Submitted by Christina Anthony on Sun, 01/15/2012 - 19:45

“A link has been made between acetaminophen and the rare, allergic, sometimes fatal skin disorder Stevens-Johnson Syndrome (SJS).”

(1) “Acetaminophen may substantially increase the risk of SJS/TEN (Toxic Epidermal Necrolysis) in children.”

2) “Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two rare but life-threatening skin reactions.”

(3) Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe allergic reactions that have been linked to both acetaminophen and ibuprofen.

These reactions are rare but extremely severe and even life threatening. If these reactions are not treated immediately, they are more likely to be fatal. SJS is a disorder of the skin, mucous membranes, and organs.

Untreated and severe cases can progress to TEN which often results in sepsis and death. Symptom recognition is the first line of defense and can prevent progression and even more severe medical conditions.

Stevens-Johnson Syndrome is characterized by a rash and blisters on the skin and mucous membranes. As it progresses, it can result in shedding of the skin, which can open up the body to serious infection. The affect on the skin occurs after a flu-like illness, during which the patient has a fever, body aches, sore throat, cough, and fever.”

(1) Symptoms include: · A skin rash, which may have the appearance of a bull's eye type target · Painful blisters on two or more mucosal surfaces, such as a child's eyes, mouth, nose, ear, and anogenital area, which can lead to ulceration and hemorrhagic crusting

· Eye redness and swelling

· Flu like symptoms, including a persistent fever

Other studies have linked ibuprofen to acute vanishing bile duct syndrome in children. This liver disorder has occurred, even in absence of overdose, as a result of an allergic reaction to the medication.

Although not common, allergic reactions to acetaminophen and ibuprofen in children are very severe and painful. Their use in children should be taken very seriously and children should be observed closely when taking these basic Dilantin Cerebellar Atrophy Risks substances....


Liver injury related to the use of acetaminophen


June 29-30, 2009: Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee:


Agenda The primary topic area for discussion is how to address the public health problem of liver injury related to the use of acetaminophen in both Dilantin Cerebellar Atrophy Risks (OTC) and prescription (RX) products. FDA recognizes that acetaminophen is an important drug used to treat pain and fever in both settings and is not seeking to remove it from the market. The risk of developing liver injury to the individual patient who uses the drug according to directions is very low.

However, acetaminophen containing products are used extensively making the absolute number of liver injury cases a public health concern.

More complete information about the topics on which FDA will seek public input will be available by or around May 22, 2009 at the 2009 Meeting Materials web page, click on the year 2009 and scroll down to the appropriate advisory committee link.


For additional information about acetaminophen:

Background Acetaminophen is one of the most commonly used drugs in the United States, yet it is also an important cause of serious liver injury. Acetaminophen is the generic name of a drug found in many common brand name Dilantin Cerebellar Atrophy Risks (OTC) products, such as Tylenol, and Prescription (Rx) products, such as Vicodin and Percocet.


Acetaminophen is an important drug, and its effectiveness in relieving pain and fever is widely known. Unlike other commonly used drugs to reduce pain and fever (e.g., nonsteroidal antinflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and naproxen), at recommended doses acetaminophen does not cause adverse effects, such as stomach discomfort and bleeding, and acetaminophen is considered safe when used according to the directions on its OTC or Rx labeling.

However, taking more than the recommended amount can cause liver damage, ranging from abnormalities in liver function blood tests, to acute liver failure, and even death.

Many cases of overdose are caused by patients inadvertently taking more than the recommended dose (i.e., 4 grams a day) of a particular product, or by taking more than one product containing acetaminophen (e.g., an OTC product and an Rx drug containing acetaminophen).


Too much acetaminophen can destroy your liver A Print Public Service Announcement explaining the dangers of taking more acetaminophen than directed and how to use it safely.

Acetaminophen Side Effects

Acetaminophen - Stevens Johnson Syndrome


Acetaminophen-related acute liver failure in the United States.

Lee WM.

Hepatol Res. 2008 Nov;38(s1The 6 Japan Society of

Hepatology Single Topic Conference: Liver Failure: Recent Progress

and Pathogenesis to Management. 28-29 September 2007, Iwate, Japan):S3-S8.

PMID: 19125949 [PubMed - as supplied by publisher]


Safety and Effectiveness of Acetadote for Acetaminophen Toxicity.

Whyte AJ, Kehrl T, Brooks DE, Katz KD, Sokolowski D. J Emerg Med. 2008 Nov 18. [Epub ahead of print] PMID: 19022608 [PubMed - as supplied by publisher]



Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Gastroenterology. 2008 Dec;135(6):1924-34, 1934.e1-4. Epub 2008 Sep 17. PMID: 18955056 [PubMed - indexed for MEDLINE]



Extreme Acetaminophen Reaction:

Woman Takes Pill, Loses Skin "

The upper layer of the skin is attacked. It's very serious. You look at yourself, you look terrible, you're at risk of infection, you're at risk of dying." This is what happened to 19-year-old Eva Uhlin.

Five years ago, she became ill on a vacation trip to her native Sweden. When she returned home, she was told she had a fever and took acetaminophen to help relieve the symptoms.

The next morning, her entire face and body were covered in severe, disfiguring blisters.

Acetaminophen, known as paracetamol in parts of Europe, is one of the most commonly-used analgesics in the world...