FDA Articles on Acetaminophen

Article I: FDA Warns of Rare Acetaminophen Risk

Acetaminophen, a fever and pain reliever that is one of the most widely used medicines in the U.S., can cause rare but
serious skin reactions, warns the Food and Drug Administration (FDA).

Although rare, possible reactions to acetaminophen include three serious skin diseases whose symptoms can include
rash, blisters and, in the worst case, widespread damage to the surface of skin. If you are taking acetaminophen and
develop a rash or other skin reaction, stop taking the product immediately and seek medical attention right away.

Used for decades by millions of people, acetaminophen is the generic name of a common active ingredient included in
numerous prescription and non-prescription medicines. Tylenol is one brand name of the pain reliever sold over the
counter, but acetaminophen is also available as a generic under various names. It is also used in combination with other
medicines, including opioids for pain and medicines to treat colds, coughs, allergy, headaches and trouble sleeping.

"This new information is not intended to worry consumers or health care professionals, nor is it meant to encourage them
to choose other medications," says Sharon Hertz, M.D., deputy director of FDA's Division of Anesthesia, Analgesia and
Addiction. "However, it is extremely important that people recognize and react quickly to the initial symptoms of these rare
but serious, side effects, which are potentially fatal."

Other drugs used to treat fever and pain, such as nonsteroidal anti-inflammatory drugs including ibuprofen and
naproxen, already carry warnings about the risk of serious skin reactions. Advil and Motrin are among the common brand
names that include ibuprofen as an active ingredient. Aleve and Midol Extended Relief are among the best-known brand
names that include naproxen as an active ingredient.

FDA is requiring that a warning about these skin reactions be added to the labels of all prescription medicines containing
acetaminophen. FDA will work with manufacturers to get the warnings added to the labels of over-the-counter (OTC)
medicines containing acetaminophen.

On OTC medicines, the word "acetaminophen" appears on the front of the package and on the Drug Facts label's "active
ingredients" section. On prescription medications, the label may spell out the ingredient or use a shortened version such
as "APAP," "acet," "acetamin" or "acetaminoph."

Ingredient Linked to Several Conditions

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are the two most serious skin reactions linked in
rare cases to acetaminophen. They usually require hospitalization and can cause death.

Problems usually begin with flu-like symptoms followed by rash, blistering and extensive damage to the surfaces of the
skin. Recovery can take weeks or months, and possible complications include scarring, changes in skin pigmentation,
blindness and damage to internal organs.

A third skin reaction, acute generalized exanthematous pustulosis (AGEP), usually resolves within two weeks of stopping
the medication that caused the problem.

A serious skin reaction can occur at any time, even if you've taken acetaminophen previously without a problem. There is
currently no way of predicting who might be at higher risk.

If you've ever had a skin reaction when taking acetaminophen, don't take the drug again and discuss alternate pain
relievers/fever reducers with your health care professional.

Evidence of Link

Prior to deciding to add a warning about skin reactions to products containing acetaminophen, FDA reviewed medical
literature and its own database, the FDA Adverse Event Reporting System (FAERS).

A search of FAERS uncovered 107 cases from 1969 to 2012, resulting in 67 hospitalizations and 12 deaths. Most cases
involved single-ingredient acetaminophen products; the cases were categorized as either probable or possible cases
associated with acetaminophen.

A small number of cases, just over two dozen, are documented in medical literature, with cases involving people of
various ages.

FDA has examined—and continues to examine—acetaminophen for safety issues, just as it does with all approved drugs.
The warning comes two years after FDA took new steps to reduce the risk of liver injury from acetaminophen. In that
case, FDA asked all makers of prescription products to limit acetaminophen to 325 milligrams per tablet or capsule. FDA
also required all prescription acetaminophen products to include a Boxed Warning—FDA's strongest warning, used for
calling attention to serious risks.

The agency continues to consider the benefits of this medication to outweigh the risks.

"FDA's actions should be viewed within the context of the millions who, over generations, have benefited from
acetaminophen," says Hertz. "Nonetheless, given the severity of the risk, it is important for patients and health care
providers to be aware of it."

This article appears on
FDA's Consumer Updates page, which features the latest on all FDA-regulated products.

August 1, 2013

Article II Know Concentration Before Giving Acetaminophen to Infants

The Food and Drug Administration (FDA) is urging consumers to carefully read the labels of liquid acetaminophen
marketed for infants to avoid giving the wrong dose to their children.

A less concentrated form of the popular medication is arriving on store shelves, and giving the wrong dose of
acetaminophen can cause the medication to be ineffective if too little is given or cause serious side effects and, possibly,
death if too much is given.

In an attempt to reduce the confusion over different strengths that have been blamed for past overdoses, some
manufacturers are voluntarily offering only the less concentrated version for all children.

Until now, liquid acetaminophen marketed for infants has only been available in a stronger concentration that doesn’t
require giving the infants as much liquid with each dose.

But right now both concentrations of liquid acetaminophen are in circulation. Before giving the medication, parents and
caregivers need to know whether they have the less concentrated version or the older, more concentrated medication.
FDA is concerned that infants could be given too much or too little of the medicine if the different concentrations of
acetaminophen are confused.

“Be very careful when you’re giving your infant acetaminophen” says Carol Holquist, director of FDA’s Division of Medical
Error Prevention and Analysis.

Here’s what the agency wants parents and caregivers to do:

Read the Drug Facts label on the package very carefully to identify the concentration of the liquid acetaminophen, the
correct dosage, and the directions for use.
Do not depend on a banner proclaiming that the product is “new.” Some medicines with the old concentration also have
this headline on their packaging.
Use only the dosing device provided with the purchased product in order to correctly measure the right amount of liquid
Consult your pediatrician before giving this medication and make sure you’re both talking about the same concentration.

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.

“There is still some on store shelves; there is still some in homes; and there is still some in distribution,” says Holquist.

Why does this pose a danger?

If a pediatrician prescribes a 5 mL dose of the less concentrated liquid acetaminophen, but the parents administer a 5 mL
dose of the more concentrated liquid acetaminophen, the child can receive a potentially fatal overdose during the course
of therapy, Holquist explains.

Conversely, if a physician prescribes a dose based on the more concentrated liquid acetaminophen and the less
concentrated medication is used, the child might not receive enough medication to fight a fever, she says.

FDA has issued a Drug Safety Communication with more information for consumers about how to avoid confusion and
potential dosing errors with the different concentrations of liquid acetaminophen.

What Should You Do?

Adding to the confusion is the fact that that the box and the bottle may look much the same for both old and new versions
of the medication, Holquist says.

Read the Drug Facts label to tell the difference between the two liquid acetaminophen products:

Look for the “Active ingredient” section of the Drug Facts label usually printed on the back of an over-the-counter (OTC)
medication package.

If the package says “160 mg per 5 mL” or “160 mg (in each 5 mL)”, then this is the less concentrated liquid
acetaminophen.  This medication should come with an oral syringe to help you measure the dose.

If the package says “80 mg per 0.8 mL” or “80 mg per 1 mL,” then this is the more concentrated liquid acetaminophen.
This product may come with a dropper.

If the dosing instructions provided by your healthcare provider differ from what is on the label, check with a healthcare
professional before administering the medication.  Do not rely on dosing information provided from other sources such as
the Internet, old dosing charts, or family members.

It is important to understand that there is no dosing amount specified for children younger than 2 years of age.  If you
have an infant or child younger than 2 years old, always check with your healthcare provider for dosing instructions.

Acetaminophen is marketed for infants under brand names such as Little Fevers Infant Fever/Pain Reliever, Pedia Care
Fever Reducer Pain Reliever and Triaminic Infants’ Syrup Fever Reducer Pain Reliever. There are also store brands on
the shelves.

This article appears on FDA's Consumer Updates page, which features the latest on all FDA-regulated products.

Dec. 22, 2011

Article III FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings

Agency strategy caps maximum at 325 milligrams to reduce risk of liver toxicity

The U.S. Food and Drug Administration is asking manufacturers of prescription combination products that contain
acetaminophen to limit the amount of acetaminophen to no more than 325 milligrams (mg) in each tablet or capsule.

The FDA also is requiring manufacturers to update labels of all prescription combination acetaminophen products to warn
of the potential risk for severe liver injury.

Acetaminophen, also called APAP, is a drug that relieves pain and fever and can be found in both prescription and over-
the-counter (OTC) products. It is combined in many prescription products with other ingredients, usually opioids such as
codeine (Tylenol with Codeine), oxycodone (Percocet), and hydrocodone (Vicodin). OTC acetaminophen products are
not affected by today's action.

“FDA is taking this action to make prescription combination pain medications containing acetaminophen safer for patients
to use,” said Sandra Kweder, M.D., deputy director of the Office of New Drugs in FDA’s Center for Drug Evaluation and
Research (CDER). “Overdose from prescription combination products containing acetaminophen account for nearly half
of all cases of acetaminophen-related liver failure in the United States; many of which result in liver transplant or death.”

The elimination of higher-dose prescription combination acetaminophen products will be phased in over three years and
should not create a shortage of pain medication. Patients and health care professionals are being notified of the new
limitation on acetaminophen content, and of the labeling change, in a drug safety communication issued by CDER. The
FDA believes that prescription combination products containing no more than 325 mg of acetaminophen per tablet are
effective for treating pain.

“There is no immediate danger to patients who take these combination pain medications and they should continue to take
them as directed by their health care provider,” said Kweder. "The risk of liver injury primarily occurs when patients take
multiple products containing acetaminophen at one time and exceed the current maximum dose of 4,000 milligrams within
a 24-hour period.”

Acetaminophen is also widely used as an over-the-counter pain and fever medication, and is combined with other OTC
ingredients, such as cough and cold ingredients. The actions FDA is taking for prescription acetaminophen products do
not affect OTC acetaminophen products.

Because of continued reports of liver injury, FDA proposes that boxed warnings, the agency’s strongest warning for
prescription drugs, be added to all acetaminophen prescription products. Most of the cases of severe liver injury
occurred in patients who took more than the prescribed dose of an acetaminophen-containing product in a 24-hour
period, took more than one acetaminophen-containing product at the same time, or drank alcohol while taking
acetaminophen products.

An FDA advisory committee discussed the issue at a meeting in June, 2009, and recommended strengthening the
warning about severe liver injury on the drug labels of prescription products containing acetaminophen.

For more information and a list of affected products, please visit:
Toxic Effect, Side Effects, Warning, Toxicity, Liver damage, death, Tylenol August 31, 2013