ACETAMINOPHEN Steven A. Seifert, MD, FACMT, FAACT Professor, Medical Toxicology University of New Mexico School of Medicine Medical Director New Mexico Poison & Drug Information Center sseifert@salud.unm.edu 1

Jess Benson, PharmD, DABAT, Managing Director Sara, PharmD, CSPI Karen, PharmD Rose, PharmD, CSPI Robert, PharmD, CSPI Holly, PharmD, CSPI Stevie, PharmD, CSPI Ina Bawaya, Educator Drug Info. Jess Benson, PharmD, DABAT, Managing Director Steven Seifert, MD Medical Director Lee, PharmD, CSPI Lauri Ivy, Admin Asst. Jennifer, PharmD, CSPI LaDonna PharmD, CSPI Damon, PharmD, CSPI Gordon, PharmD, CSPI

Common Things Are Common Analgesics (2008 NPDS) Exposures 13.3% of all human exposures (#1) 17.2% of adult exp. (#1) 9.7% of pediatric (<6y) exp. (#2) Deaths Analgesics #1 in fatalities APAP in combination #5 APAP alone #8 ASA alone #13

FDA Advisory Committee – June 30, 2009 Lowering the MDD of nonprescription APAP for adults, MDD not specified (21 – 6) Reduce the maximum single adult dose and tablet strength to 650 mg (24 – 13) 1,000-mg dose be prescription-only (26 – 11) Eliminating prescription acetaminophen combination products (20 -17) If APAP-combination prescription drugs stay on the market, they carry a black-box warning (36 – 1) As of 10/25/10, none of the recommendations have been acted upon http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm

APAP Liquid Preparations Elixir: 160mg/5mL Drops: 80mg/0.8mL = 500 mg/5mL

APAP Metabolism 2

4

APAP Metabolism Primary process is sulfation: high affinity, low capacity Secondary is glucuronidation: lower affinity, high capacity P450 pathway (CYP2E1, 1A2, & 3A4) when 1o and 2o saturated. Generates N-acetyl parabenzoquinone imine (NAPQI) and a semiquinone=reactive species Ultimately, APAP-mercapturate formed by neutralization of NAPQI w/ glutathione 3

Risk Factors for Liver Injury Rate of production of NAPQI Amount and production rate of native glutathione Regenerative ability of liver These are all dependent on: Quantity & rate of APAP absorption Metabolic activity of CYP2E1, 1A2, & 3A4, rate of elimination/disposition of APAP metabolites, genetics Nutritional status Only quantifiable factors are total amount taken and peak levels

Triage and Treatment In acute OD We use total dose for triage decisions We use blood level (> 4 h) for treatment In chronic OD or unknown We use history and/or lab and/or empirical tx

Dose-based Risk Referral protocols Poor correlation between history and dose Pediatric, Acute: > 200 mg/kg Adult, Acute: > 150 mg/kg Chronic (<24 hours): More than 10 gms in 24 hrs in adults More than 200 mg/kg in 24 hrs in peds Repeated Supratherapeutic Ingestion (RSI) Definition: More than maximum rec’d dose for more than 24 hours (4 g/d) Referred in for lab evaluation

Level-Based Risk Caveats Only for acute ingestion Not useful < 4 h Less useful > 12 h Cannot be used for chronic ingestion or sub- acute over > 8 h May need multiple levels for delayed-release; large amts or if combined with opioids or anticholinergics

Caution No clear cutoff for toxicity 1.6% to 10% (abstinent alcoholics) risk of hepatotoxicity below 150 mcg/mL @ 4 hr1 Patients tx w/in 8 hrs w/ IV NAC developed hepatotoxicity in 5.2% of cases2 Hepatotoxicity = AST or ALT > 1,000 1Ali FM, Boyer EW, Bird SB. Alcohol. 2008 May;42(3):213-8. Epub 2008 Mar 20 2Doyon S, Klein-Schwartz W. Acad Emerg Med. 2009 Jan;16(1):34-9 17

Glutathione Glutathione is a tripeptide Glutamate-Cysteine-Glycine Need to provide adequate supply of intracellular glutathione in locations of p450 enzymes (liver, kidney) Other beneficial effects may make it useful in late presenters and hepatic failure from other causes But does not cross cell membranes

N-Acetylcysteine (NAC) N-actylecysteine (NAC) crosses cell membrane, is de-acetylated, and thus provides intracellular cysteine Rate-limiting step in the production of intracellular glutathione If NAC started before depletion of glutathione (~8 h), highly unlikely to see significant hepatotoxity

Course of Liver Injury w/o NAC 7

Prevention of Injury Acute Exposure Time to first NAC dose < 8 hours Treat if above 150 mcg/mL line PO / IV protocols w/ equal efficacy Must have no APAP at end of IV NAC Acute & > 8 hrs to first NAC dose IV or PO NAC x 36 hrs from ingestion Can stop IF non-detectable APAP and no increase in AST/ALT @ end of NAC Acute ingestion with hepatotoxicity PO or IV NAC with continuation until clearly improving, transplant or death

Prevention of Injury RSI Often detected serendipitously in ED Management IF no measurable APAP (<10 mcg/mL) AND no increased AST/ALT No treatment IF measurable APAP Admit for 24 hrs NAC, recheck APAP/AST/ALT and discontinue if all negative IF elevated AST/ALT Treat as for acute presentation with hepatotoxicity

Very Late Presenters Increased survival in patients presenting in fulminant hepatic failure tx w/ IV NAC.1, Retrospective (n=100): Mortality was 37% in patients who received NAC compared with 58% in patients not given NAC1 Prospective (n=50): Survival was significantly higher with NAC (48%) than controls (20%)2 NAC treated patients Had a lower incidence of cerebral edema (40% v. 68%) Developed less hypotension requiring inotropic support (48% v. 80%) Liver function was unchanged 1Harrison PM, Keays R, Bray GP, et al. Lancet 1990;335:1572-1573. 2Keays R, Harrison PM, Wendon JA, et al. BMJ 1991;303:1026-1029. 37

Transplant Referral and Outcome Prognostic Factors Possible need for transplant (alert team) Arterial pH < 7.3 after fluid replacement INR > 6.5 Serum Cr > 3.4 Encephalopathy, grade 3 or 4 Grade 3: Somnolence, confusion, gross disorientation Grade 4: Coma During hospital course Poor Development of King’s criteria Persistent elevation of lactate > 12 Good Phosphorus < 3.0 Spontaneously improving INR, ammonia, and mental status

What is the Optimal NAC Route? No class “A” studies and no controlled study has compared IV to PO PO v. IV efficacy appears equivalent in early presenters Adverse events PO: Nausea/vomiting; usually first 1 – 2 doses IV: Allergic rxns Minor rxns ~ 14% Severe ~ 0.1% to 0.3% Current poison center recs: Use PO unless specific indications for IV or CI to PO IV indications: Late presentation, >8 h, acidosis, encephalopathy, renal injury, pregnancy, persistent vomiting PO contraindications: CNS depression, caustics, hydrocarbons, obstruction 19

Proposed UNMH Actions Acetaminophen Task Force approved the following: Pharmacy should stock only combination agents with acetaminophen 325mg Pharmacy should only stock acetaminophen 325mg and maximum single adult dose should be 650mg Combination agents should be avoided in the inpatient, oxycodone and acetaminophen should be administered as separate agents. The newly implemented total daily acetaminophen dose calculator should be programmed to fire at 3,200mg. Over-the-counter combination agents containing acetaminophen should be removed from the formulary Stock only elixir (160 mg/5 mL) concentration Plan to obtain input from providers prior to implementation

Questions?