FDA limits acetaminophen in prescription products; requires liver toxicity warnings

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23536

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http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm

FDA NEWS RELEASE

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.
 
why are they afraid of eliminating APAP?

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.
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a stat made even more ostentatious by the fact that most of the people who take acetominophen do so in non-opiate formulations. It should be removed from opiates altogether.

Why not just add APAP to beer, cigarettes and coffee too? If it's such a great abuse deterrent, why not put APAP in everything?
 
Wow, this took them way too long to realize. I got blacklisted when I told my doctor 'no acetaminophen'. My mom works in the hospital here and saw my medical records afterward and it said I was 'a knowledgeable pill seeker.' Ridiculous.
 
235360287471352662 said:
or drank alcohol while taking acetaminophen products.
Click to expand...
This is such bullshit... :\
Alcohol is actually degraded by the enzyme that produces the toxic by-product of acetaminophen metabolism.
So if you drank some alcohol, there will be competition for the enzyme and LESS toxic metabolites will be formed.
In some cases, alcohol can even save your life i.e. in case of acetaminophen overdose.

The only exception to this would be alcoholics, whose liver function is altered by excessive drinking.
But then again, alcoholics benefit most from the competition of alcohol for the same enzyme.
So it's a bullshit statement either way... :\
 
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Why not just add APAP to beer, cigarettes and coffee too? If it's such a great abuse deterrent, why not put APAP in everything?
Click to expand...

^^That made my day.

I am happy that they're capping it at 325, however. It's certainly a step in the right direction.
 
so how will this work? Will hydrocodone/APAP come as 5/325 mg and 7.5/325 mg?

This is such bullshit...
Alcohol is actually degraded by the enzyme that produces the toxic by-product of acetaminophen metabolism.
So if you drank some alcohol, there will be competition for the enzyme and LESS toxic metabolites will be formed.
In some cases, alcohol can even save your life i.e. in case of acetaminophen overdose.
Click to expand...

An interesting point, but is it as simple as that? I don't know the numbers off the top of my head, but both NAPQI and the radicals formed by acute levels of acetaldehyde are scavenged by glutathione. Surely the beneficial competition for CYP2E1 is overshadowed by the competition for glutathione? I mean how many units of acetaldehyde does the body have to clear per 100 mL of ethanol? It's quite a load.

Plus, the pathway from APAP to NAPQI can go through CYP3A4, an enzyme not significantly involved in ethanol biotransformation.

Correct me on this if my reasoning is off: I'm on a lot of Xanax right now.
 
235360287471352662 said:
An interesting point, but is it as simple as that? I don't know the numbers off the top of my head, but both NAPQI and the radicals formed by acute levels of acetaldehyde are scavenged by glutathione. Surely the beneficial competition for CYP2E1 is overshadowed by the competition for glutathione?
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Well, it is definitely not as simple as I primarily put it. ;)
But in the normal situation, you have roughly 90% of acetaminophen metabolized through glucuronidation.
The remaining 10% will be metabolized to NAPQI, which is immediately inactivated by glutathione.
Glucuronidation is the rate-limiting enzyme in this pathway, if you take to much acetaminophen it will overwhelm the glucuronidation enzyme and more NAPQI will be formed.

Alcohol is metabolized to acetaldehyde, which is also toxic, be it less toxic than NAPQI.
However, acetaldehyde is - in healthy, well-fed people - usually incapacitated by vitamin C or other anti-oxidants (B-vitamins, or in some cases glutathione).
As far as I know, there is no 1-on-1 (or 2-on-1) relationship between glutathion conjugation and acetaldehyde metabolism, while this relationship does exist for acetaminophen.

So in a case of acetaminophen overdose, around 50% of acetaminophen will be metabolized to NAPQI.
Add 50 mL of ethanol, and assume 5 grams of acetaminophen as an overdose.
I do not have the affinities for CYP2E1 for both molecules, but in a 50:5 ratio, there should be significant competition for CYP2E1.
So every molecule of ethanol that is metabolized instead of acetaminophen, is a win for your liver.

The above does not hold true in all cases, definitely not in cases of chronic alcohol intake.
But I think it is enough to illustrate why the FDA statement is partly bullshit, just to influence uneducated people in forming an opinion the FDA wants them to form.
 
^there's an error in your math but correcting it actually helps your argument:

Add 50 mL of ethanol, and assume 5 grams of acetaminophen as an overdose.
I do not have the affinities for CYP2E1 for both molecules, but in a 50:5 ratio, there should be significant competition for CYP2E1.
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your 50:5 ratio is based on mass, not moles. Ethanol is about a 3rd of the molar mass of APAP so (correcting for density) the ratio is close to 150:5


...but you're not seeing a couple of more important points:

  • APAP is converted to NAPQI by CYP2E1 and CYP3A4. Ethanol is a CYP3A4 inducer and an inducer of CYP2E1*, so the transformation of APAP to NAPQI is maybe not as hindered by ethanol as you claim it to be?

  • Reactive oxygen intermediates contribute to the pathogenesis of various hepatic disorders such as paracetamol intoxication, hemochromatosis, toxic hepatitis, and alcoholic liver injury[1-4]. Increased oxygen radical production leads to lipid peroxidation by induced cytochrome P4502E1[5,6]. Enhanced generation of acetaldehyde was shown to cause lipid peroxidation in isolated perfused livers[7]. Oxidative damage correlates with the amount of ethanol consumed[8]. Antioxidants such as vitamin E have been demonstrated as therapeutic options in acute and chronic liver diseases[9,10]. N-acetylcysteine (NAC) exerts a strong antioxidant activity, and is the choice of treatment in acetaminophen intoxication. NAC provides protection from toxic liver damage by elevating intacellular glutathione concentrations[1,11]. It has also been used in the treatment of CCl4 poisoning[12].

    http://www.wjgnet.com/1007-9327/9/791.htm
    Click to expand...
* I didn't know this until now.

 
3rd I blind you've got a good point:

NSFW:
Aliment Pharmacol Ther. 2002 Apr;16(4):707-15.

Influence of acute and chronic alcohol intake on the clinical course and outcome
in acetaminophen overdose.

Schiødt FV, Lee WM, Bondesen S, Ott P, Christensen E.

Department of Hepatology, Rigshospitalet, Copenhagen, Denmark.
[email protected]

BACKGROUND: Animal studies on acetaminophen toxicity suggest that chronic alcohol
intake affects the outcome adversely, whereas acute alcohol intake seems
protective. Few clinical data are available.
METHODS: We studied 209 consecutive patients with single-dose acetaminophen
overdose. The combined influence of independent variables (gender, age, dose,
delay to antidote treatment, chronic and acute alcohol intake and nomogram risk
group) on dependent variables (death, development of hepatic encephalopathy and
biochemical liver markers) was studied using multiple or logistic regression
analysis.
RESULTS: Fifty-seven (27.3%) patients had chronic alcohol intake and 45 (21.5%)
patients had acute alcohol intake. Forty-four (21.1%) patients developed hepatic
coma and 20 (43.5%) of these patients died. Chronic alcohol intake was
significantly and independently associated with the development of hepatic coma,
with a lower prothrombin index, lower platelet count, higher creatinine and
higher bilirubin. The relative risks for hepatic coma and death were 5.3 (95%
confidence interval, 2.2-12.4) and 1.4 (95% confidence interval, 0.5-3.9),
respectively, in the chronic alcohol intake group compared with the no chronic
alcohol intake group. Acute alcohol intake was not significantly associated with
any of the dependent variables studied.
CONCLUSIONS: Chronic alcohol intake enhances acetaminophen hepatotoxicity,
whereas acute alcohol intake does not affect the clinical course.


PMID: 11929388 [PubMed - indexed for MEDLINE]



(nsfw for size)
 
Crankinit said:
If 5 grams was an OD I'd be dead 50 times over by now.
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I never actually said 5 grams IS an overdose, I just assumed it for easy calculations.
That said, 4 to 6 grams IS considered an overdose, in the sense that hepatic damage will start from that amount.
BTW, overdose does not necessarily imply you will die; it just means you are outside of the therapeutic range of your drug. :)

About the CYP3A4/CYP2E1 induction:
This is definitely true, this is what I meant by 'altered liver function' in my first post.
But this is not a short-term induction.
It's not like you pour down three shots now, and tomorrow you need twice the alcohol because your enzymes are up.
I guess most people have experienced first-hand the rate at which alcohol tolerance builds up? ;)

EDIT: Oh yeah, shameful mistake with the math...luckily for me, my professor is not likely to browse this site, ehh! =D
 
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Lol, I can't tag along in ya'lls scientific research... but i'm glad about this. :)
 
I'm not sure how others feel about this, but I see this as the more tactful, roundabout, indirect way for the FDA to lower their recommended maximum daily dose of acetaminophen, something that many health professionals have contested as being too much. They're saving face, in my opinion, and avoiding lawsuits to boot, I bet.
 
Does anyone know if the FDA's ruling is in effect yet?
In particular I was wondering if the "M357" vicodins have had their acetaminophen content lowered to 325 yet
 
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