4/3/2015 1 ACETAMINOPHEN TOXICITY Anthony Nelson Pharm. D., PGY1 BVAMC Resident Jessica LitkePharm. D., PGY2 BVAMC Resident Objectives 1. Recognize what medications contain acetaminophen and the percentage of acute liver failure cases observed in the United States caused by its misuse 2. Describe the pathogenesis of acetaminophen toxicity and the classic signs and symptoms indicating toxicity and need for treatment 3. Recognize what medications are used to treat acetaminophen toxicity and when they are indicated 4. State the number for Poison Control Center from memory
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4/3/2015
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ACETAMINOPHEN TOXICITYAnthony Nelson Pharm. D., PGY1 BVAMC Resident
Jessica Litke Pharm. D., PGY2 BVAMC Resident
Objectives
1. Recognize what medications contain acetaminophen and the percentage of acute liver failure cases observed in the United States caused by its misuse
2. Describe the pathogenesis of acetaminophen toxicity and the classic signs and symptoms indicating toxicity and need for treatment
3. Recognize what medications are used to treat acetaminophen toxicity and when they are indicated
4. State the number for Poison Control Center from memory
� Your first born son, now 23 months old, has developed a mild fever (100.5◦ F). It’s the middle of the night and he’s crying incessantly. Your spouse (who does not have your medical background) wants to give some acetaminophen. WHAT DOSE DO YOU GIVE?
� May increase risk for hepatotoxicity with multiple ingestions of excessive acetaminophen doses
� Data conflicting regarding a single overdose
� Usually lower total daily doses of APAP are
recommended for those who drink more
than recommended amounts chronically
� ~2,000mg/day
https://www.youtube.com/watch?v=T3ybmcnEJDE
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MALES: >2 DRINKS/DAYWOMEN: >1 DRINK/DAY
HOW MUCH ALCOHOL IS TOO MUCH?HOW MUCH BEER, WINE, OR LIQUOR IS
CONSIDERED “1 DRINK”?
12 OZ BEER5 OZ WINE
1.5 OZ OF 80 PROOF LIQUOR
https://www.youtube.com/watch?v=T3ybmcnEJDE
HISTORY OF FDA’S OPINION ON APAP
� Late 1990’s, research demonstrated APAP as leading cause of acute liver failure, majority resulting from accidental overdoses.
� 1998, FDA issued warning that people that drink >3 alcoholic beverages/day consult a physician before using APAP
� 2002, FDA added a warning for potential of hepatotoxicity to ALL acetaminophen-containing product labeling
Heard 2008, FDA briefing 2013
http://www.fda.gov/
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HISTORY OF FDA’S OPINION ON APAP
� 2009: new labeling developed to helps patient’s
easily identify which products contain
acetaminophen
� Black box warning was placed for potential of severe
liver injury (and anaphylaxis)
� 2013: alerted consumers of rare but serious and
potentially fatal skin reactions
Heard 2008, FDA briefing 2013
http://www.fda.gov/
HISTORY OF FDA’S OPINION ON APAP
� 1/14/2014 recommendation:
“FDA is recommending health care professionals discontinue prescribing and dispensing prescription combination drug products that contain more than 325 milligrams (mg) of acetaminophen per tablet, capsule or other dosage unit.”
� No evidence that taking a higher dose provides additional benefit
MedWatch
http://www.fda.gov/
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HISTORY OF FDA’S OPINION ON APAP
� Maximum recommended dose per FDA is 4000mg/day
� *Some experts recommend no more than 3,250mg/day
HOW MANY REGULAR STRENGTH TABLETS WOULD THAT BE?
10!
FDA Drug Safety
http://www.fda.gov/
Incidence of APAP Toxicity
� Accounts for:
� 56,000 ED visits
� 26,000 hospitalizations
� 450 deaths annually
� Most common cause of:
� Acute liver failure
� Second most common cause of:
� Liver failure requiring transplantation
� Approx. 50% of cases are intentional, approx. 50%
U.S. Food and Drug Administration; National Institutes of Health; Medscape.com; Dr. Paul Watkins, University of North Carolina. (ProPublica/Al Granberg)
1-800-222-1222
Poison Prevention Hotline
www.jumpstartforhealth.org
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Treatment of Toxicity
� Activated charcoal if present within 1 hour
after ingestion
UpToDate 2015ehealer.hubpages.com
Treatment of Toxicity
� Based on blood
levels, not
symptoms
� Rumack-
Matthew
nomogram
� For acute
ingestions
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Treatment of Toxicity
� Most important: N-acetylcysteine (NAC)
� Brand names: Mucomyst (oral) or Acetadote (IV)
� Ideally within 8-10 hours post ingestion
� Oral or IV
NAC
� Oral
� 140mg/kg loading dose, then 70mg/kg x17 doses
q4h (total 72hr course)
� Tastes bad. Can be given chilled on ice, diluted
� Encouraging patients to use 325mg tablets, with a maximum dose of 650mg at one timeHOW MANY PRODUCTS DO YOU THINK CONTAIN APAP?
≥600!
DO YOU STILL REMEMBER THE POISON PREVENTION HOTLINE???
Poison Prevention hotline:
1-800-222-1222
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Case
GF is a 67 year old woman with chronic back pain who
recently ruptured her Achilles tendon trying to
impress her grandkids
� Currently takes Norco
(hydrocodone/acetaminophen) 5/325 2 tablets
every 8 hours for back pain and two Tylenol PM ES
at night to help sleep
� Recommended to increase hydrocodone/acetaminophen
to 2 tablets to every 6 hours for painHow much acetaminophen/day is she currently
taking?Now how much acetaminophen/day will she be taking?
insanemutterings.wordpress.com
Case
� GF has continued her pain medication at 2
tablets every 6 hours and is still having pain
� A friend told her acetaminophen can help
opioid pain medications work better, so she
has started taking 2 extra strength
acetaminophen 3 times/day
� How much acetaminophen now?
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Case
� As if that wasn’t enough, GF has come down
with a cold and has started taking an over the
counter cold medication to help
Potentially up to 9000mg APAP each day!
References
1. Nourjah P, Ahmad SR, Karwoski C, et al. Estimates of acetaminophen (paracetamol)-associated overdoses in the United States. PharmacoepidemiolDrug Saf. 2006;15:398-405.
2. FDA. Acetaminophen Prescription Combination Drug Products with more than 325 mg: FDA Statement - Recommendation to Discontinue Prescribing and Dispensing. Retrieved from: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm381650.htm (accessed 04/02/2015)
3. FDA. Questions and Answers about Oral Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit. Retrieved from: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm239871.htm (accessed 04/02/2015)
5. 39. Hornsby LB, Whitley HP, Hester EK, et al. Survey of patient knowledge related to acetaminophen recognition, dosing, and toxicity. J Am Pharm Assoc. 2010;50:485-489.
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References
6. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359:285-292.
7. 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: FDA briefing material. Updated July 30, 2013. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM164897.pdf. Accessed March 3, 2015.
8. Dimitropoulos E, Ambizas E. Acetaminophen Toxicity: What Pharmacists Need to Know. Retrieved from: http://www.uspharmacist.com/content/d/feature/c/47337/ (accessed 04/02/2015)