FDA advisers vote to take Vicodin, Percocet off market

[Justin]

FDA advisers vote to take Vicodin, Percocet off market Link

Story Highlights

• NEW: Panel votes to kill prescription drugs that combine acetaminophen, narcotics
• Panel advises lower maximum doses of nonprescription acetaminophen drugs
• Those drugs include Tylenol, NyQuil, Pamprin and Allerest
• CDC estimates acetaminophen was the likely cause of most acute liver failures

(CNN) -- A government advisory panel voted Tuesday to recommend eliminating prescription drugs that combine acetaminophen with narcotics -- such as Vicodin and Percocet -- because of their risk for overdose and for severe liver injury.

The panel, assembled by the Food and Drug Administration, voted 20 to 17 to advise the FDA to remove such prescription combination drugs from the market.

The group recommended that the FDA "send a clear message that there's a high likelihood of overdose from prescription narcotics and acetaminophen products," Dr. Sandra L. Kweder of the FDA's Office of New Drugs said at a news conference after Tuesday's meeting.

The panel was meeting for the second day to vote on recommendations to reduce the risk of serious liver injury associated with acetaminophen, which is found not only in prescription drugs, but also in over-the-counter medications such as Tylenol and NyQuil.

It also advised the FDA to lower the maximum daily dose of acetaminophen in over-the-counter and prescription medications, and to address the formulations and dosing recommendations for children.

Kweder said the FDA is already "well on the road" to addressing the pediatric concerns.

The FDA is not required to follow the recommendations of its advisory committees, although the agency typically does.

If the agency does not choose to eliminate prescription combination drugs, the panel said the FDA should lower the amount of acetaminophen in the drugs and also take some action to ensure that subscribers and patients are aware of potential liver damage posed by taking these products, Kweder said.

In another vote, the panel had voted to advise the FDA to put a boxed warning on the prescription combination drugs.

Although acetaminophen is one of the most commonly used drugs in the United States for treating pain and fever, overdoses of acetaminophen have been linked to 56,000 emergency room visits, 26,000 hospitalizations and 458 deaths during the 1990s, according to the FDA, citing one study.

The agency cited another study, a 2007 Centers for Disease Control and Prevention population-based report, that estimated acetaminophen was the likely cause of most of the estimated 1,600 acute liver failures each year.

The advisory panel could have voted to recommend pulling over-the-counter drugs that use acetaminophen in combination with other ingredients -- such as NyQuil, Pamprin and Allerest -- but it chose not to.

Some panelists cited data that suggests that combination over-the-counter drugs account for less than 10 percent of acetaminophen overdoses.

Kweder said families should carefully read medicine labels to know what is in the medicine and how much should be taken.

Abbott Laboratories, which makes the brand-name Vicodin, which has also been available as a generic since the mid-1980s, said in a statement that "today's discussion is an important continuation of the dialog around balancing patient safety with the need for treatment options for patients in pain."

It said, "Pain affects 75 million Americans, more than diabetes, cancer and heart disease combined" and added that it would follow the FDA's final determination.

Endo Pharmaceuticals, which makes the brand-name Percocet, did not immediately return a phone call seeking comment. Percocet is also available as a generic.

CNN's Saundra Young and Taylor Gandossy contributed to this report.

[Justin]

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 Meeting Announcement

Center CDER
June 29-30, 2009
80 a.m. - 50 p.m.
Marriott Conference Centers
UMUC Inn and Conference Center by Marriott
3501 University Blvd. East
Adelphi, Maryland

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 over-the-counter (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: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htm

Background

Acetaminophen is one of the most commonly used drugs in the United States,1 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 over-the-counter (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).

The mechanism of liver injury is not related to acetaminophen itself, but to the production of a toxic metabolite. The toxic metabolite binds with liver proteins, which cause cellular injury. The ability of the liver to remove this metabolite before it binds to liver protein influences the extent of liver injury. In a study that combined data from 22 specialty medical centers in the United States, acetaminophen-related liver injury was the leading cause of acute liver failure for the years 1998 through 2003.2 Patients in this study were found to have taken too much acetaminophen from OTC, Rx products, or both. Almost half of these cases involved overdose in which the patient had not intended to take too much acetaminophen (unintentional overdoses), although many cases of liver injury with acetaminophen result from self-harm, i.e., intentional self-poisoning. The high percentage of cases of liver failure related to unintentional acetaminophen overdose was also observed in a study published in 2007.3 The extent of liver failure cases reported in the medical literature provides an important signal of concern. However, the types of databases available to identify cases make it difficult to determine the full extent of the problem or whether interventions have been successful.

A. Why Acetaminophen Overdoses Occur

There are few data available describing consumer behavior with acetaminophen products or consumer understanding of acetaminophen toxicity. However, based on the prevalence of liver injury, it appears that there are distinct factors associated with acetaminophen and acetaminophen products that contribute to this public health problem. These factors are listed below.

• Taking just a small amount of acetaminophen over the recommended total daily dose (4 grams per day) may lead to liver injury.4 Currently recommended doses and tablet strengths of acetaminophen leave little room for error and the onset of liver injury can be hard to recognize. There is scientific agreement that taking a large amount of acetaminophen over a short period of time causes liver injury, but there is limited agreement as to the specific threshold dose for toxicity. In addition, the onset of symptoms associated with acetaminophen liver injury can take several days, even in severe cases. The symptoms of liver injury may not be readily identified by an individual because they may be non-specific and mimic flu symptoms. The antidote for acetaminophen poisoning, N-acetylcysteine, is less effective when liver injury has progressed too far.
  
• Some individuals may be especially sensitive to liver injury from acetaminophen. The maximum safe dose may not be the same for all persons. Individuals with increased sensitivity may experience toxic effects at lower acetaminophen doses. Available information suggests that some individuals, such as those who use alcohol or have liver disease, may have a greater sensitivity to the effects of the toxic metabolite because they produce more or are unable to clear it from the body as easily. More research is needed to understand whether ethnicity, genetics, nutrition, or other factors might have a role in making some individuals more sensitive.
  
• There is a wide array of OTC and Rx acetaminophen products used in a range of doses for various indications. For some people, it may be difficult to identify the appropriate product to use. Acetaminophen is in many widely used OTC single ingredient products, such as those to treat headaches, and multiple ingredient (combination) products, such as those to treat symptoms of the common cold, like aches and fever. Acetaminophen is also a component of a number of Rx drug products in combination with narcotic pain medicines. So, consumers may reasonably attempt to treat different conditions or symptoms with multiple choices among products containing acetaminophen, but may not realize that acetaminophen is an ingredient common to each.
  
• It can be difficult to identify acetaminophen as an ingredient. Rx products that contain acetaminophen (usually with codeine or oxycodone) are often labeled as containing ‘‘APAP’’ on pharmacy dispensed containers.5 Without clear labeling, patients may take more than one product containing acetaminophen (e.g., a Rx product and an OTC product) without realizing it, and in some cases take a harmful overdose.
  Multiple products exist for children containing different strengths. Liquid acetaminophen formulations intended for use in infants are typically more concentrated (i.e., stronger) to enable proper dosing using less liquid. However, failure to distinguish between the two strengths of liquid can result in an accidental overdose where the parent gives a higher dose of the concentrated drops to a younger child.
  
• The association between acetaminophen and liver injury is not common knowledge.6 Consumers are not sufficiently aware that acetaminophen can cause serious liver injury, and their perceptions may be influenced by the marketing of the products. Finding ways to educate consumers about the risk of liver injury from acetaminophen has been difficult. Current labeling on OTC products may be overlooked, as can the patient information provided with dispensed prescriptions. Programs to educate the public about safe use of acetaminophen have been small and encountered a number of obstacles. Advertisements of OTC drugs often emphasize the effectiveness of products, but are not subject to the same requirements to offset such messages by providing warning information as prescription products. Also, acetaminophen is available in retail outlets in large quantities (e.g., 500 tablets per bottle) which may contribute to the perception that the ingredient is unlikely to be harmful.

B. FDA’s Previous Actions
In the late 1990s, research began to show 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. Responding to these concerns, FDA took a number of steps to reduce the incidence of liver injury related to acetaminophen.

In 1998, FDA finalized a regulation that required all OTC acetaminophen products to include an alcohol warning in labeling. The warning stated: Acetaminophen. ‘‘Alcohol Warning’’: ‘‘If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen may cause liver damage.’’

In 2002, FDA convened an Advisory Committee meeting to discuss unintentional liver toxicity related to the use of OTC acetaminophen.7 The Advisory Committee recommended a specific liver toxicity warning and distinctive labeling on OTC packages so that products containing acetaminophen could be more easily identified. FDA and manufacturers were also advised to educate consumers and health professionals about the risk of liver injury from acetaminophen.

In early 2004, FDA launched a public education campaign to help consumers use acetaminophen more safely. By most standards, the campaign would be considered small, due to budgetary constraints. It was also limited by reluctance on the part of some commercial outlets to provide a venue for FDA’s message about acetaminophen toxicity as the product was sold or promoted in those outlets. Nonetheless, FDA has continued to expand efforts to improve public education about acetaminophen overdosing and liver injury and has recently updated the acetaminophen information on FDA’s Web site.
In 2004, FDA sent letters to every state board of pharmacy asking them to consider requiring labeling on the immediate container of Rx products containing acetaminophen that: (1) uses the term acetaminophen, not APAP, (2) instructs patients to avoid concurrent use of other acetaminophen containing drugs, (3) instructs patients not to exceed the maximum daily recommended acetaminophen dose, and (4) instructs patients to avoid drinking alcohol during prescription use.8 FDA was informed by the National Association of Boards of Pharmacy that, as of February 2008, no states had implemented regulations related to the request.

In December 2006, FDA issued proposed regulations for OTC labeling for acetaminophen containing products to require inclusion of new safety information and that the container and outer carton identify acetaminophen when it is an ingredient.9 The final version of the regulation is currently under review.
In 2007, the Director of FDA’s Center for Drug Evaluation and Research (CDER) convened a multidisciplinary working group in CDER to continue to evaluate the issues associated with acetaminophen-related liver injury and consider additional steps FDA could take to decrease the number of cases of acetaminophen-related liver injury. The working group considered detailed reviews of the issues from the Office of Nonprescription Products, the Office of Surveillance and Epidemiology and the Division of Anesthesia and Analgesic and Rheumatology Drug Products as part of its deliberations. The working group considered the full range of options proposed and made recommendations to the Center Director regarding which should be considered for implementation. Given the complex nature of the underlying problem of acetaminophen liver toxicity, the Center Director and the Working Group agreed that the options should be presented for public discussion prior to taking further action. The report of the Working Group 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.

1. Kaufman, D.W., J.P. Kelly, L. Rosenberg, et al., ‘‘Recent Patterns of Medication Use in the Ambulatory Adult Population of the United States: The Slone Survey,’’ The Journal of the American Medical Association 2002, Jan 16;287(3) 337–44.
2. Larson, A.M., J. Polson, R.J. Fontana, et al., Acute Liver Failure Study Group (ALFSG), ‘‘Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study,’’ Hepatology 2005, Dec;42(6):1364–72.
3. Bower, W.A., M. Johns, H.S. Margolis, et al., ‘‘Population-Based Surveillance for Acute Liver Failure,’’ The American Journal of Gastroenterology 2007;102:2459–63.
4. Data from both FDA’s Adverse Event Reporting System (AERS) and the ALFSG show that the median daily dose of acetaminophen related to liver injury was 5 to 7.5 grams/day, very near the current maximum daily dose of 4 grams/day.
5. ‘‘APAP’’ is an acronym based on the chemical name of acetaminophen, N-acetyl-paraaminophenol.
6. Stumpf J.L., A.J. Skyles, C. Alaniz, et al., ‘‘Knowledge of Appropriate Acetaminophen Doses and Potential Toxicities in an Adult Clinic Population, Journal of the American Pharmacists Association (2003), 2007 Jan-Feb; 47(1): 35–41.
7. See http://www.fda.gov/OHRMS/DOCKETS/98fr/082002c.htm.
8. Letter from Steven Galson to State Boards of Pharmacy, Acetaminophen Hepatotoxicity and Nonsteroidal Anti-Inflammatory Drug (NSAID)-Related Gastrointestinal and Renal Toxicity (January 22, 2004), available on FDA’s Web site at http://www.fda.gov/downloads/Drugs/D.../UCM171903.pdf.
9. Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the Counter Human Use: Proposed Amendment of the Tentative Final Monograph: Required Warnings and Other Labeling, 71 FR 77314–52 (December 26, 2006) (Docket No.1977N–0094L) (amending 21 CFR 201.66, 201.322, 201.325, 343.50).

[Justin]

Final Rule link --> Organ-Specific Warnings; Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Final Monograph


Questions and Answers on Final Rule for Labeling Changes to Over-the-Counter Pain Relievers

1. What is the Food and Drug Administration (FDA) publishing today?

The Food and Drug Administration (FDA) today finalized a regulation which requires that the labeling for over-the-counter (OTC) Internal Analgesic, Antipyretic and Antirheumatic (IAAA) drug products contain important new safety information. These OTC IAAA products include nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. Consumers use these products to treat pain, fever, headaches, and muscle aches.

The regulation requires that the labeling of NSAIDs, such as aspirin, ibuprofen, naproxen and ketoprofen, contain important warnings regarding the potential for stomach bleeding. In addition, new warnings are required for labeling of acetaminophen about potential liver damage and when to consult a doctor.

FDA proposed labeling changes for IAAA drug products on December 26, 2006. In today's final rule, FDA is requiring the labeling changes proposed in the 2006 proposed rule as well as additional labeling suggested by comments received from the public in response to the 2006 proposed rule.

2. What specific labeling changes is FDA requiring for acetaminophen?

FDA is requiring

• that the ingredient acetaminophen is prominently identified on the product’s principal display panel (PDP) of the immediate container, and the outer carton (if applicable). This is intended to help consumers identify the active ingredient and reduce the number of consumers inadvertently exposed to multiple products containing acetaminophen.
• that the product label contain new warnings that highlight the potential for liver toxicity and warn consumers against using more than the recommended dose of acetaminophen; using more than one product (over-the-counter or prescription) containing with acetaminophen, and taking acetaminophen with moderate amounts of alcohol.
• that the product label contain a warning not to use acetaminophen with any other drug containing acetaminophen and to ask a doctor or pharmacist if persons are not sure whether a drug contains acetaminophen, a warning to ask a doctor before use if persons have liver disease, and a warning to ask a doctor or pharmacist before use if persons are taking the blood thinning drug warfarin.
• that the statement "see new warnings information" appears on the product's PDP for one year after the final rule is published.

3. What specific labeling changes is FDA requiring for NSAIDs?

FDA is requiring

• that the term “NSAID” is prominently identified on the product’s principal display panel (PDP) of the immediate container and the outer carton (if applicable). This is intended to help consumers identify that the active ingredient of the product is an NSAID ingredient.
• that the product label contain a new "Stomach bleeding warning" which highlights the potential for stomach bleeding in persons over age 60, in persons who have had prior ulcers or bleeding, in persons who take a blood thinner, when taking more than one product containing an NSAID, when taken with moderate amounts of alcohol, and when taking for longer time than directed.
• that the product label contain warnings to ask a doctor before use if persons are at increased risk for stomach bleeding problems (which are listed on the label to assist consumers in identifying if they are at risk), and to stop use and ask a doctor if specific signs of stomach bleeding occur (which are listed on the label to assist consumers in identifying symptoms of stomach bleeding).
• that the statement "see new warnings information" appears on the product's PDP for one year after the final rule is published.

4. How is this final rule different than the 2006 proposed rule for NSAID and acetaminophen products?

We are requiring much of the labeling included in the 2006 proposed rule, but are also requiring the following labeling that was not included in the 2006 proposed rule:

• Liver warning and stomach bleeding warnings are required on immediate container labels in addition to the carton or outer container
• Revised the first bullet of the liver warning from “more than [insert maximum number of daily dosage units] in 24 hours” to “more than [insert maximum number of daily dosage units] in 24 hours, which is the maximum daily amount”
• Revised warning about using multiple products containing acetaminophen to clarify that consumers should ask a doctor or pharmacist if they are unsure whether a drug contains acetaminophen
• New warning about taking warfarin and acetaminophen at the same time
• Revised directions statement for all OTC IAAA drug products labeling for children under 12 years of age from “This product does not contain directions or warnings for adult use” to “This product does not contain directions or complete warnings for adult use”
• Revised the stomach bleeding warning to indicate that the stomach bleeding can be severe
• Revised NSIAD warning “ask a doctor if you have liver disease” to “ask a doctor if you have liver cirrhosis”
• Revised NSAID warnings to remove redundant information in stomach bleeding warning and other warnings
• “NSAID” needs to be highlighted on the principal display panel, but the name of the active ingredient, such as ibuprofen, does not need to be highlighted.

In addition, we are allowing voluntary highlighting of information under the “Active Ingredient” and “Purpose” headings in Drug Facts for all OTC IAAA drug products.

5. What products does this regulation affect?

The new labeling is required for all OTC drug products that contain an NSAID or acetaminophen even if combined with other active ingredients, such as cold symptom relievers. This regulation is applicable only to OTC drug products and not to prescription products that NSAIDs or acetaminophen. Consumers may also be taking an NSAID or acetaminophen in their prescription medications, so it is important that they know the contents of both their prescription and OTC medications.

6. Are NSAID and acetaminophen products safe to use?

NSAID and acetaminophen drug products have been available for many years without a prescription to treat pain, fever, headaches and muscle aches. These products are safe and effective when properly used by consumers. FDA believes that consumers need to know that these products can cause serious side effects, such as severe liver injury and stomach bleeding, when used improperly. FDA urges consumers to read the labels of all the OTC medicines they take to use the medicines properly.

7. When can consumers expect to see these labeling changes on marketed NSAID and acetaminophen products?

A number of manufacturers already have voluntarily implemented labeling changes to identify these potential safety concerns. All OTC manufacturers of NSAID and acetaminophen products must comply with these labeling requirements by [insert date].

8. Is FDA taking other steps to help ensure that acetaminophen and NSAIDs are used safely?

The Food and Drug Administration (FDA) will convene a public advisory committee meeting to be held on June 29 and June 30, 2009 regarding acetaminophen use in both over-the-counter (OTC) and prescription (Rx) products, the potential for liver injury, and potential interventions to reduce the incidence of liver injury.

[Cindylou]

I can't imagine that the FDA would leave pain patients suffering without Percocet or Vicodin, so is it just going to be a different additive with the opiates? Sorry, I'm a little ADD, so didn't read the whole story.

[KBear]

I think that consumer education is the way to go about this, not removing vicodin and percocet. I, know and have known, not to take other products containing acetamenophine. I also know that many cold products, headache pills, energy pills, etc. contain it. I don't even take ibuprofen or other NSAIDS, out of fear of liver damage. I think they need to address the question of what about all the chronic pain sufferers who need these medications? Can they not require the dr and/or pharmacist prescribing to warn of the dangers? It seems completely unreasonable to suggest removing them from the market, when they are effective and very safe when used correctly.

[New-disc]

Thanks Justin!!!

[DanielleP924]

I've been on vicodin since 2001 and so far, I have no known issues from its usage. I've always heard about the possible side effect if taking more than prescribed as being possible liver damage. It says that in the literature I've rec'd from the pharmacy when I get the meds filled.

I don't think my doctors would continually prescribe this medication if they were worried about my liver. Granted, I do get my liver levels checked on a couple times a year and thus far, I've not had any issues with those levels.

All medications come with their own risks and it's up to the doctors and pharmacists to ensure that we, the patients, are provided with the appropriate warnings lables and literature when the medication is prescribed. My doctors have always been very forthcoming regarding possible side-effects.

If it's between worrying about possible liver damage versus the constant pain....I'm taking my pain meds until such time as someone actually does something to fix my back. (Hopefully, my trip to Mayo in a few weeks will provide me with some hope.)

Justin, thanks for your detailed information. I found it interesting and frustrating all at the same time. You are awesome!

Regards,
DanielleP924

[Justin]

Justin, thanks for your detailed information. I found it interesting and frustrating all at the same time. You are awesome!

Regards,
DanielleP924

No problem, Danielle. This information is important to many Spine Patients.

[JK2234]

Scary...

[Jack-of-all-trades]

It's not the hydrocodone or oxycodone that is the problem it's the Tylenol. Hydrocodone is already available with other NSAIDs as a combination and as a stand alone though it changes to a Schedule II if it is not combined with another medicine like Tylenol. Oxycodone is available, even without Tylenol. Any oxycodone, even in combination, is already a Schedule II.