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acetaminophen (Tylenol, Paracematol, Panadol, Tempra, Datril, APAP, non-Aspirin)

Tradenames: Tylenol, Paracematol, Panadol, Tempra, Datril. Indications: 1) analgesia, treatment of pain & fever 2) minimal anti-inflammatory effects Contraindications: - hepatic failure Caution: in patients with G6PD deficiency Benefit/risk: - no benefit or harm in critically ill patients with fever [21] - may be of no benefit in patients with influenza [22] Dosage: - 650 mg PO/PR every 4 hours - 500 mg PO/PR every 4 hours - max = 4000 mg/day (adults) [29]; 3000 mg/day [13] - max = 3000 mg/day elderly, use > 1 week [29] - max = 2000 mg/day advanced liver disease, chronic alcohol users [13,29] - do not prescribe drug combinations containing > 325 mg of actetaminophen [19] Pediatrics: 15 mg/kg/dose (max 80 mg/kg/day) * intravenous acetaminophen 1000 mg with comparable analgesic efficacy as 0.5 mg of hydromorphone in elderly (>= 65 years) [30] . Tabs: 160, 325, 500 mg. Tabs: 500 mg tablets may be withdrawn from US market [12] Tabs: (chewable): 80 mg. Suppositories: 120, 325, 650 mg. Elixir: 160 mg/5 mL. Drops: 80 mg/0.8 mL dropperful. Pharmacokinetics: 1) well absorbed orally 2) metabolized in liver 3) small amount metabolized to electrophilic aromatic intermediate 4) metabolic capacity is saturatable 5) 1/2 life (1-4 hours) shorter with pregnancy & hyperthyroidism, longer with liver disease 6) onset of action is 15-30 minutes 7) duration of action is 3-4 hours 8) therapeutic-range: 10-30 ug/mL 9) toxic-range: > 200 ug/mL 4 hours post ingestion 10) does cross the placenta; considered safe in pregnancy [26] Dosage adjustment in renal failure: eGFR* dosage 10-50 (mL/min) every 6 hours < 10 (mL/min) every 8 hours (metabolites may accumulate) * estimated glomerular filtration rate (eGFER) Adverse effects: 1) rash 2) nausea/vomiting 3) blood dyscrasias 4) nephrotoxicity with chronic use [5] (less than NSAIDs) 5) hepatotoxicity - acute liver injury with therapeutic doses of acetaminophen occurs only in patients with excess drinking (alcohol abuse) &/or fasting [28] 6) hypertension, RR=1.34 with frequent use [6,8] 7) no increase in risk of asthma in children & adolescents [11] - association with use for respiratory tract infections [11] - does not increase asthma exacerbations relative to ibuprofen [24] 8) serious skin reactions [16] a) Stevens-Johnson syndrome b) toxic epidermal necrolysis c) acute generalized exanthematous pustulosis 9) in utero exposure may be linked to ADHD [18] - prenatal exposure to acetaminophen in the 2nd & 3rd trimester of pregnancy increases risk for childhood behavioral problems [23] 10) doses 3000-4000 mg/day associated with - increased risk of cardiovascular events, MI, stroke - increased risk of GI bleed - increased risk of renal insufficiency & renal failure - increased risk of death [20] 11) increased risk of hearing loss in women (RR=1.1) [25] Overdose: (also see acetaminophen poisoning) 1) antidote: N-acetylcysteine 2) loading dose: 140 mg/kg PO 3) 70 mg/kg PO every 4 hours for a total of 17 doses 4) if 4 hour serum acetaminophen level is in the toxic range, all 17 doses of N-acetylcysteine must be given Drug interactions: 1) agents that increase acetaminophen hepatotoxicity - carbamazepine, hydantoin, barbiturates, chronic alcohol use, rifampin 2) GLP-1 agonists (incretin mimetics) delay gastric emptying time which can decrease level & affect of acetaminophen [29] 3) serious interactions with acetaminophen may occur with lonafarnib, pexidartinib, or pretomanid [29] 4) acetaminophen can elevate INR in patients takin warfarin Laboratory: 1) specimen: serum, plasma (EDTA, heparin) 2) methods -> GLC, HPLC, GC-MS, EIA, FPIA 3) acetaminophen in specimen - acetaminophen in tissue - acetaminophen in body fluid - acetaminophen in blood - acetaminophen in bile fluid - acetaminophen in gastric fluid - acetaminophen in serum/plasma - acetaminophen in urine Mechanism of action: 1) direct action on hypothalamic temperature regulation centers 2) inhibition of CNS prostaglandin synthetase 3) minimal inhibition of cyclo-oxygenase 4) postulated anxiolytic effects mediated by endocannabinoids [15] Note: - FDA working group makes new recommendations for acetaminophen to reduce hepatic toxicity, May 2009 [9]. These include: - using stronger warnings on the drug's label; - limiting the single adult dose to a maximum of 650 mg; - lowering the maximum daily dose for adults from 4000 mg to no greater than 3250 mg (less than that for chronic alcohol users); - limiting immediate-release tablet formulations for adults to 325 mg; - restricting pediatric liquid formulations to a single mid-strength concentration; - eliminating acetaminophen from combination products

Interactions

drug interactions

Related

acetaminophen in serum/plasma acetaminophen poisoning

General

4-aminophenol analgesic (antalgic) anilide antipyretic agent

Properties

MISC-INFO: elimination route LIVER KIDNEY 1/2life 1-4 HOURS therapeutic-range 10-30 UG/ML toxic-range >200 UG/ML <4 hr post ingestion> protein-binding 20-50% elimination by hemodialysis + peritoneal dialysis - pregnancy-category A safety in lactation +

Database Correlations

PUBCHEM cid=1983

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1160-63
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Prescriber's Letter 8(4):23 2001
  5. Journal Watch 24(17):134, 2004 Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ. Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med. 2004 Jul 26;164(14):1519-24. PMID: 15277282
  6. Prescriber's Letter 12(9): 2005 Non-narcotic Analgesics and the Risk of Hypertension in Women Detail-Document#: 210915 (subscription needed) http://www.prescribersletter.com
  7. Prescriber's Letter 13(7): 2006 Safe Use of Acetaminophen (Tylenol) Detail-Document#: 220714 (subscription needed) http://www.prescribersletter.com
  8. Forman JP et al, Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007, 167:394 PMID: 17325302
  9. Memorandum from Department of Health and Human Services, Food and Drugs Administration, Center For Drug Evaluation and Research dated May 22, 2009 regarding Report dated February 26, 2008 for meeting on June 29-30, 2009 Report is by: The Acetaminophen Hepatotoxicity Working Group Center for Drug Evaluation and Research Food and Drug Administration Department of Health and Human Services Recommendations for FDA Interventions to Decrease the Occurrence of Acetaminophen Hepatotoxicity http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4429b1-01-FDA.pdf
  10. Prescriber's Letter 16(7): 2009 New Warnings and Proposed Changes to Acetaminophen Products Detail-Document#: 250701 (subscription needed) http://www.prescribersletter.com
  11. Beasley RW et al Acetaminophen Use and Risk of Asthma, Rhinoconjunctivitis and Eczema in Adolescents: ISAAC Phase Three. Am J Respir Crit Care Med. 2010 Aug 13. PMID: 20709817 - McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics 2011 Dec; 128:1181 PMID: 22065272 - Cheelo M et al Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis. Arch Dis Child. 26 November 2014 PMID: 25429049 http://adc.bmj.com/content/early/2014/11/07/archdischild-2012-303043
  12. FDA MedWatch, 01/13/11 Acetaminophen Prescription Products Limited to 325 mg Per Dosage Unit: Drug Safety Communication http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm239955.htm
  13. Johnson & Johnson McNeil Consumer Healthcare Announces Plans For New Dosing Instructions For Tylenol Products http://www.jnj.com/connect/news/all/mcneil-consumer-healthcare-announces-plans-for-new-dosing-instructions-for-tylenol-products
  14. Prescriber's Letter 18(9): 2011 COMMENTARY: Changes to Acetaminophen Labeling PATIENT HANDOUT: Safe Use of Acetaminophen (Tylenol) Detail-Document#: 270910 (subscription needed) http://www.prescribersletter.com
  15. Randles D et al. The common pain of surrealism and death: Acetaminophen reduces compensatory affirmation following meaning threats. Psychol Sci 2013 Apr 11 PMID: 23579320 http://pss.sagepub.com/content/early/2013/04/23/0956797612464786
  16. FDA MedWatch. August 1, 2013. Acetaminophen: Drug Safety Communication - Association with Risk of Serious Skin Reactions. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm363519.htm
  17. FDA MedWatch. Jan 14, 2014 FDA MedWatch - Acetaminophen Prescription Combination Drug Products with more than 325 mg: FDA Statement - Recommendation to Discontinue Prescribing and Dispensing. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm381650.htm
  18. Liew Z, Ritz B, Rebordosa C et al Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders. JAMA Pediatr. February 24, 2014 PMID: 24566677 http://archpedi.jamanetwork.com/article.aspx?articleid=1833486 - Cooper M, Langley K, Thapar A Antenatal Acetaminophen Use and Attention-Deficit/Hyperactivity Disorder. An Interesting Observed Association But Too Early to Infer Causality. JAMA Pediatr. February 24, 2014 PMID: 24566519 http://archpedi.jamanetwork.com/article.aspx?articleid=1833483
  19. FDA Drug Safety. April 2014. FDA reminds health care professionals to stop dispensing prescription combination drug products with more than 325 mg of acetaminophen. http://www.fda.gov/Drugs/DrugSafety/ucm394916.htm
  20. Roberts E et al. Paracetamol: Not as safe as we thought? A systematic review of observational studies. Ann Rheum Dis 2015 Mar 2; PMID: 25732175 http://ard.bmj.com/content/early/2015/02/09/annrheumdis-2014-206914
  21. Young P et al. Acetaminophen for fever in critically ill patients with suspected infection. N Engl J Med 2015 Oct 5 PMID: 26436473
  22. Jefferies S et al Randomized controlled trial of the effect of regular paracetamol on influenza infection. Respirology. Dec 6, 2015 PMID: 26638130 http://onlinelibrary.wiley.com/doi/10.1111/resp.12685/full
  23. Stergiakouli E, Thapar A, Smith GD Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood. Evidence Against Confounding. JAMA Pediatr. Published online August 15, 2016 PMID: 27533796 http://archpedi.jamanetwork.com/article.aspx?articleid=2543281
  24. Sheehan WJ et al Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma. N Engl J Med 2016; 375:619-630. August 18, 2016 PMID: 27532828 http://www.nejm.org/doi/full/10.1056/NEJMoa1515990?query=pfw&jwd=000000793830&jspc=FPG - Litonjua AA. Acetaminophen and asthma - a small sigh of relief? N Engl J Med 2016 Aug 18; 375:684. PMID: 27532835
  25. Lin B, Curhan SG, Wang M et al Duration of Analgesic Use and Risk of Hearing Loss in Women. Am J Epidemiol (2016) 1-8. Published 14 December 2016 PMID: 27974293 https://academic.oup.com/aje/article/doi/10.1093/aje/kww154/2661733/Duration-of-Analgesic-Use-and-Risk-of-Hearing-Loss
  26. Medical Knowledge Self Assessment Program (MKSAP) 18, American College of Physicians, Philadelphia 2018
  27. Fenves AZ, Kirkpatrick HM 3rd, Patel VV, Sweetman L, Emmett M. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin J Am Soc Nephrol. 2006 May;1(3):441-7. Review. PMID: 17699243 Free Article
  28. Louvet A, Ntandja Wandji LC, Lemaitre E et al. Acute liver injury with therapeutic doses of acetaminophen: A prospective study. Hepatology 2021 May; 73:1945 PMID: 33306215 https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.31678
  29. Windle ML Fast Five Quiz: Acetaminophen Medscape. July 22, 2021 https://reference.medscape.com/viewarticle/954960_2
  30. Kolli S et al. A randomized study of intravenous hydromorphone versus intravenous acetaminophen for older adult patients with acute severe pain. Ann Emerg Med 2022 Nov; 80:432. PMID: 35965162 PMCID: PMC9588558 (available on 2023-11-01) https://www.annemergmed.com/article/S0196-0644(22)00443-7/fulltext

Component-of

acetaminophen/aspirin acetaminophen/aspirin/caffeine (Excedrin Extra, Excedrin migraine) acetaminophen/aspirin/caffeine/codeine/salicylamide acetaminophen/aspirin/caffeine/salicylamide acetaminophen/aspirin/codeine acetaminophen/aspirin/diphenhydramine acetaminophen/aspirin/pseudoephedrine acetaminophen/benzhydrocodone (Apadaz) acetaminophen/brompheniramine acetaminophen/brompheniramine/dextromethorphan/pseudoephedrine acetaminophen/butalbital (Phrenilin) acetaminophen/butalbital/caffeine (Fioricet, Esgic) acetaminophen/butalbital/caffeine/codeine (Fioricet with Codeine) acetaminophen/caffeine acetaminophen/caffeine/chlorpheniramine acetaminophen/caffeine/chlorpheniramine/guaifenesin acetaminophen/caffeine/chlorpheniramine/guaifenesin/n methylephedrine acetaminophen/caffeine/chlorpheniramine/hydrocodone/phenylephrine acetaminophen/caffeine/chlorpheniramine/phenylephrine acetaminophen/caffeine/citrate acetaminophen/caffeine/citrate/phenyltoloxamine/salicylamide acetaminophen/caffeine/citrate/salicylamide acetaminophen/caffeine/dihydrocodeine acetaminophen/caffeine/guaifenesin/phenylephrine acetaminophen/caffeine/isometheptene acetaminophen/caffeine/magnesium salicylate acetaminophen/caffeine/magnesium salicylate/phenyltoloxamine acetaminophen/caffeine/phenyltoloxamine acetaminophen/caffeine/phenyltoloxamine/salicylamide acetaminophen/caffeine/pyrilamine acetaminophen/caffeine/salicylate acetaminophen/chlophedianol/pyrilamine acetaminophen/chlorpheniramine acetaminophen/chlorpheniramine/codeine acetaminophen/chlorpheniramine/codeine/phenylephrine acetaminophen/chlorpheniramine/dextromethorphan acetaminophen/chlorpheniramine/dextromethorphan/doxylamine acetaminophen/chlorpheniramine/dextromethorphan/doxylamine/succinate acetaminophen/chlorpheniramine/dextromethorphan/guaifenesin acetaminophen/chlorpheniramine/dextromethorphan/guaifenesin/phenylephrine acetaminophen/chlorpheniramine/dextromethorphan/phenylephrine acetaminophen/chlorpheniramine/dextromethorphan/pseudoephedrine acetaminophen/chlorpheniramine/diphenhydramine/phenylephrine acetaminophen/chlorpheniramine/diphenhydramine/pseudoephedrine acetaminophen/chlorpheniramine/ephedrine/guaifenesin acetaminophen/chlorpheniramine/guaifenesin acetaminophen/chlorpheniramine/guaifenesin/phenylephrine acetaminophen/chlorpheniramine/phenylephrine acetaminophen/chlorpheniramine/phenylephrine/phenyltoloxamine acetaminophen/chlorpheniramine/phenylephrine/salicylamide acetaminophen/chlorpheniramine/pseudoephedrine acetaminophen/chlorzoxazone acetaminophen/citrate acetaminophen/citrate/diphenhydramine acetaminophen/citrate/phenyltoloxamine acetaminophen/citrate/phenyltoloxamine/salicylamide acetaminophen/citrate/salicylamide acetaminophen/clemastine/fumarate/pseudoephedrine acetaminophen/clemastine/pseudoephedrine acetaminophen/codeine (Tylenol with Codeine) acetaminophen/codeine/guaifenesin/phenylephrine acetaminophen/codeine/guaifenesin/pseudoephedrine acetaminophen/codeine/magnesium salicylate/phenyltoloxamine acetaminophen/codeine/salicylate acetaminophen/dexbrompheniramine acetaminophen/dexbrompheniramine/phenylephrine acetaminophen/dexbrompheniramine/pseudoephedrine acetaminophen/dexchlorpheniramine/pseudoephedrine acetaminophen/dextromethorphan acetaminophen/dextromethorphan/diethylcarbamazine/doxylamine/phenylephrine acetaminophen/dextromethorphan/diphenhydramine acetaminophen/dextromethorphan/diphenhydramine/guaifenesin acetaminophen/dextromethorphan/diphenhydramine/guaifenesin/phenylephrine acetaminophen/dextromethorphan/diphenhydramine/phenylephrine acetaminophen/dextromethorphan/diphenhydramine/pseudoephedrine acetaminophen/dextromethorphan/doxylamine acetaminophen/dextromethorphan/doxylamine/guaifenesin acetaminophen/dextromethorphan/doxylamine/guaifenesin/phenylephrine acetaminophen/dextromethorphan/doxylamine/guaifenesin/pseudoephedrine acetaminophen/dextromethorphan/doxylamine/phenylephrine acetaminophen/dextromethorphan/doxylamine/pseudoephedrine acetaminophen/dextromethorphan/doxylamine/zinc acetate/zinc gluconate acetaminophen/dextromethorphan/doxylamine/zinc sulfate acetaminophen/dextromethorphan/guaifenesin acetaminophen/dextromethorphan/guaifenesin/phenylephrine acetaminophen/dextromethorphan/guaifenesin/pseudoephedrine acetaminophen/dextromethorphan/guaifenesin/zinc acetate/zinc gluconate acetaminophen/dextromethorphan/guaifenesin/zinc sulfate acetaminophen/dextromethorphan/phenylephrine acetaminophen/dextromethorphan/pseudoephedrine acetaminophen/dextromethorphan/pseudoephedrine/pyrilamine acetaminophen/dichloralphenazone acetaminophen/dichloralphenazone/isometheptene (Midrin, Isocom, Amidrine) acetaminophen/diethylcarbamazine acetaminophen/diphenhydramine acetaminophen/diphenhydramine/doxylamine acetaminophen/diphenhydramine/guaifenesin/phenylephrine acetaminophen/diphenhydramine/phenylephrine acetaminophen/diphenhydramine/phenylephrine/pseudoephedrine acetaminophen/diphenhydramine/pseudoephedrine acetaminophen/doxylamine/phenylephrine acetaminophen/doxylamine/pseudoephedrine acetaminophen/doxylamine/salicylamide acetaminophen/ephedrine/guaifenesin acetaminophen/guaifenesin acetaminophen/guaifenesin/phenylephrine acetaminophen/guaifenesin/pseudoephedrine acetaminophen/hydrocodone (Anexsia, Lorcet, Lortab, Vicodin, Norco) acetaminophen/magnesium salicylate acetaminophen/magnesium salicylate/pamabrom acetaminophen/orphenadrine acetaminophen/oxycodone (Percocet, Endocet, Tylox, Roxicet) acetaminophen/pamabrom (Women's Tylenol Menstrual Relief Caplets) acetaminophen/pamabrom/pyridoxine acetaminophen/pamabrom/pyrilamine acetaminophen/pentazocine (Talacen) acetaminophen/pheniramine/phenylephrine acetaminophen/phenylephrine acetaminophen/phenylephrine/pyrilamine acetaminophen/phenyltoloxamine acetaminophen/phenyltoloxamine/salicylamide acetaminophen/propoxyphene (Darvocet, Wygesic) acetaminophen/pseudoephedrine acetaminophen/pseudoephedrine/triprolidine acetaminophen/pyrilamine acetaminophen/salicylamide acetaminophen/tramadol (Ultracet)