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Assessment of Acetaminophen Safety and Efficacy

Assessment of Acetaminophen Safety and Efficacy. FDA Advisory Committees September 19, 2002. Introduction. Debra L. Bowen, MD Vice President, R&D McNeil Consumer & Specialty Pharmaceuticals. Objectives. Provide context for committee consideration of acetaminophen safety.

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Assessment of Acetaminophen Safety and Efficacy

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  1. Assessment of AcetaminophenSafety and Efficacy FDA Advisory Committees September 19, 2002

  2. Introduction Debra L. Bowen, MD Vice President, R&D McNeil Consumer & Specialty Pharmaceuticals

  3. Objectives • Provide context for committee consideration of acetaminophen safety. • Provide the science supporting McNeil’s view that acetaminophen is safe at recommended doses for the general population and special populations. • Provide data and databases that underscore acetaminophen safety. • Review steps we are taking to minimize very rare unintentional product misuse.

  4. Context for Consideration • Available OTC for over 40 years. • >100 million users per year in US. • Harm is rare.

  5. Issue Statement • Hepatotoxicity may result from very high doses when not treated early with the antidote, NAC. • In very rare cases, consumers inadvertently overuse acetaminophen products.

  6. Analgesic Science • Pharmacology and toxicology • Clinical and epidemiological data • Spontaneous reports and cases • Consumer Use Practices • Underlying attitudes • Reported product use

  7. McNeil Actions: Overdose 1979 to present 1982 1985 1986 1994 1978 1999 Initiated NAC IND Tamper-evident packaging Replaced capsules with tamper-resistant caplet formulation Voluntarily added concomitant use statement and proposed alcohol warning Introduced SAFE-TY-LOCK Funded support for Poison Center and developed OD treatment information Funded support for development of NAC

  8. McNeil Actions: “Unintentional Misuse” • Labeling Changes • Prescription and OTC products • Pediatric products • Consumer Education • “Know Your Medicine” • “Be MedWise” Grant • Healthcare Professional Education • American Academy of Family Physicians • American Pharmaceutical Association

  9. Today’s Scientific Experts • John Slattery, PhD Metabolism and • Professor of Pharmaceutics Pharmacokinetics • Richard Dart, MD, PhD Acetaminophen Safety • Professor, Surgery, Medicine, and Pharmacy • Director, Rocky Mountain Poison & Drug Center • Raymond Koff, MD Use in Liver Disease • Professor, Medicine and Director, Clinical Hepatology Research • Daniel Carr, MD Analgesic Benefit • Professor, Pain Research • Anthony Temple, MD Questions & Answers • Vice President, Medical and Regulatory SciencesMcNeil Consumer and Specialty Pharmaceuticals

  10. Conclusions • Data from many sources support the safety of acetaminophen. • Science completely supports the current recommended dose. • True for both general and special populations. • Current recommended dose is needed for safety and efficacy. • Risk management interventions must focus on misuse, and consider health outcomes of changes in utilization.

  11. Acetaminophen Metabolism and Pharmacokinetics John Slattery, PhD Professor, Department of Pharmaceutics University of Washington

  12. Acetaminophen Metabolism and Hepatotoxicity Acetaminophen O || HN-C-CH3 O || HN-C-CH3 O || HN-C-CH3 47% - 62% 25% - 36% OH Glucuronide Sulfate Cytochrome P450 2E1 Active Repletion Process Glutathione Reactive Metabolite (NAPQI) O || HN-C-CH3 Glutathione OH Cysteine & Mercapturic Acid Conjugates 4.8% - 8.0%

  13. Acetaminophen Metabolism • Threshold phenomenon • Need 70-80% depletion of hepatic glutathione before any toxicity • Not toxic at recommended doses

  14. Acetaminophen Oxidation to NAPQI CH3 | || O C | NH OH CH3 | O C || | N CYP2E1 GSH GSH Conjugates (APAP-3-SR) CYP3A4 CYP1A2 O APAP NAPQI glucuronide, sulfate, catechol metabolites

  15. Contribution of CYP2E1, 1A2 and 3A4 to the Formation of NAPQI in Human Liver Microsomes Acetaminophen conc (mM) Liver H105 H108 Inhibitor DDCa FFb TAOc DDC FF TAO Target CYP 2E1 1A2 3A4 2E1 1A2 3A4 0.1 35 ± 3 44 ± 3 12 ± 8 37 ± 1 12 ± 1 8 ± 4 2.0 43 ± 4 52 ± 1 7 ± 0.2 53 ± 4 16 ± 9 4 ± 5 (% Inhibition of NAPQI Formation) All incubations contained 0.05% v/v methanol aDDC = 150 µM Diethyldithiocarbamate; bFF = 25 µM Furafylline; cTAO = 100 µM Trolcandomycin

  16. Omeprazole on Caffeine and Acetaminophen • Omeprazole, 40 mg/d for 7 days • 4 rapid, 4 slow mephenytoin metabolizers by phenotype and CYP2C19 • No alcohol for 1 week before to study end Rapid Metabolizers Slow Metabolizers • Caffeine Cl,L/kg/hr Clf, APAPthiols, L/kg/hr - Omep 0.13 ± 0.03 0.019 ± 0.005 + Omep 0.13 ± 0.02 0.019 ± 0.005 - Omep 0.08 ± 0.01 0.014 ± 0.002 + Omep 0.14* ± 0.01 0.015 ± 0.002 *P < 0.001

  17. Rifampin on Acetaminophen • Rifampin 600 mg/d for 7 days • Alcohol for 1 week before and to end of study • n = 8 Clf, APAP thiols, L/kg/hr - Rifampin 0.036 ± 0.011 • + Rifampin 0.040 ± 0.012

  18. Disulfiram on Acetaminophen • 500 mg disulfiram 10 hr before APAP • No alcohol 1 week before to 1 week after study • n = 8 Clf, APAP thiols, L/kg/hr - Disulfiram 0.039 ± 0.023 • + Disulfiram 0.010 ± 0.003 P < 0.01

  19. Concomitant DrugsP450 Isoenzymes • CYP2E1 is primarily responsible for conversion of acetaminophen to NAPQI • CYP3A4 and CYP1A2 play negligible roles in metabolism of acetaminophen

  20. Induction of CYP2E1 Stabilization Through Occupation of Active Site S S S + I I I I

  21. Time-Course: Inhibition & Induction NAPQI Formation by Ethanol Cl(t) Clo 7 & 37 hr 15 & 79 hr 1.6 100 mg/dL EtOH 1.4 1.2 1.0 0.8 CYP2E1 t½ 0.6 0.4 0.2 0 5 10 15 20 25 Time (hr)

  22. Gilbert’s Syndrome: Genetic deficiency of UGT1A1 • UGT1A6 is predominant in acetaminophen glucuronidation • Km = 2.2 mM (Cmax @ ~20g dose), • 1A1 and 1A9 are minor (Court et al, JPET 2001) • If UGT1A1 is gone (@ 0.5 mM, or ~ 5g dose) • NAPQI increases from 6.4% of dose to 7.3% • Overall APAP-G formation variability in 56 HLM was 15 fold

  23. Acetaminophen Multiple-Dose Pharmacokinetics and Metabolism • Healthy adults 4, 6 or 8 grams per day for three days (divided at 6 hr intervals) • n = 12/group active, 6/group placebo

  24. Acetaminophen Time Course 4 g/day 8 g/day 40 40 35 35 30 30 25 25 APAP (g/mL) APAP (g/mL) 20 20 15 15 10 10 5 5 0 0 0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90 Time (h) Time (h)

  25. Fraction of Dose in Urine 0.8 60 40 0.6 20 G S T A G S T A Fraction of Dose in Urine % ChangeRelativeto 4 g/Day 0.4 0 -20 0.2 -40 0.0 -60 G S T A G S T A G S T A 8 g 6 g 4 g 6 g 8 g APAP Dose per Day APAP Dose per Day

  26. Formation Clearances 60 0.24 0.20 0.16 0.12 0.08 0.04 0.00 40 20 G S T A G S T A Clearance(L/h/kg) % ChangeRelativeto 4 g/Day 0 -20 -40 -60 G S T A G S T A G S T A 8 g 6 g 4 g 6 g 8 g APAP Dose per Day APAP Dose per Day

  27. Summary: Acetaminophen Metabolism and Pharmacokinetics • NAPQI formed by CYP2E1 • Modulation of other CYPs is unimportant • Toxicity follows substantial GSH depletion • Mitochondrial pool is critical • Absence of UGT1A1 (Gilbert’s) is not a significant risk factor • Does not accumulate on multiple doses up to 8 g/d

  28. Assessment of Acetaminophen Safety Richard C. Dart, MD, PhD Director, Rocky Mountain Poison and Drug Center Professor, Surgery, Medicine, and Pharmacy University of Colorado

  29. Today’s Topics • Acute Substantial Acetaminophen Overdose • Data Sets of Reported Overdose and Misadministrations • Chronic Alcohol Use • Repeated Supratherapeutic Overdose

  30. Single Large Overdoses: Up to 9.1 Grams Study Christophersen [2002] Green [2001] Hassig [1993] Rose [1991] Douglas [1996] Stork [1996] Vance [1992] GenderM/F 5/7 7/3 12 10/0 7/7 7/3 6/6 Weight(kg) 71.8 77.4 N/A 73 67.8 73 N/A Dose (g)(Range) 3.6(2.8–5.3) 4.0(na) 4.0(na) 5.0(na) 5.6(4.2–7.8) 5.7(3.8–7.2) 6.1(4.1–9.1) T½ (hrs) 2.2 2.3(0.6) N/A 2.6(0.3) 2.6(0.4) 2.6(0.9) N/A

  31. Dose Relative to Risk and Treatment Lines of Acetaminophen Nomogram 200 160 120 APAP (mcg/mL) 80 75 mg/ kg 40 15 mg/ kg 0 0 2 4 6 8 10 12 14 16 Time (h) Risk Line Treatment Line Douglas [1996] BE Study 98-054

  32. FDA-Selected AERS Data Set • FDA identified set of AERS reports • January 1998 through March 2001 • Acetaminophen as suspect therapy • Hepatic adverse events with serious outcome • Events occurred over approximately 25 years • 307 reports identified • 281 adult reports • 25 pediatric reports • 1 report did not involve acetaminophen

  33. Limitations to Case Reports • Causality cannot be ascertained using retrospective data • History of dose is often inaccurate • Inherent clinical bias • to omit intentional overdose • to report unusual cases (e.g. low reported dose) • to truncate evaluation (e.g. work-up bias)

  34. Expert Review Panel • Richard Dart, MD, PhD EM, Toxicology • Gordon Benson, MD Hepatology • Martin Caravati, MD EM, Toxicology • Raymond Koff, MD Hepatology • Victor Navarro, MD Hepatology • Kent Olson, MD EM, Toxicology • Barry Rumack, MD Peds, Toxicology • Donna Seger, MD EM, Toxicology • K.V. Speeg, MD, PhD Hepatology

  35. Expert Review Panel 281 FDA AERs Cases Adults Panel Training Standardized Data Collection Instrument Panel Case Review – Clinical Judgement Panel Consensus Meeting Assigned Probability of Association with APAP: Definite, Probably, Possibly, Unlikely, Definitely Not, Insufficient Information

  36. Consensus Probabilities Expert Review Panel Numberof reports N = 281 adult reports Probability Category

  37. Expert Panel Review FDA AERS Adult Reports • Most definite/probable cases were considered to be associated with substantial overdoses. • More often, definite/probable cases spontaneously reported alcohol and alcohol abuse.

  38. Pediatric Reports FDA AERS Data Set • 25 reports identified by FDA AERS were pediatric reports • 4 involved unintentional single ingestion • 3 involved maternal overdoses • 18 involved misadministration; most reported children < 2 years of age

  39. Putative Risk Subsets • History of Liver Disease • Co-ingestion of Hepatotoxic Medications • Ethanol Use

  40. Chronic Alcohol UseKuffner and Dart 2001 • Randomized, double-blinded, placebo-controlled trial • Alcoholic patients received acetaminophen 1000 mg or placebo 4 times daily for 2 days • All currently drinking by history • 50% drinking >20 yrs • 1/3 with low body mass index • No statistically significant differences in mean AST, ALT or INR at 2 and 4 days for acetaminophen group compared to placebo • Additional study underway

  41. Repeated Supratherapeutic Ingestion (RSI): Prospective Study Call to RMPDC (n=194,927) Acetaminophen calls (n=7298) Acute Single Exposure n=7021 Repeated Supratherapeutic Ingestion n=277 Enrolled 249 Declined n=28 Acetaminophen level > 10 mg/L AST > 50 IU/L Yes Treat with Aceytlcysteine No Discharge Followup Over 72 hours Validation of History O’Malley 2000, Daly submitted

  42. Outcome of RSI Study *ULN = Upper Limits of Normal

  43. RSI Study: Dose and Duration are Related to Peak AST Level Dose (g/24 hr) Duration (24 hr periods) *ULN = Upper Limits of Normal

  44. Distribution of APAP-Associated Deaths by Liver Condition Acetaminophen -associated deaths (FDA Estimate from NMCD files) 458 Acute liver toxicity 58 Chronic liver diseases 21 61 318 Other No liver disease reported

  45. Distribution of APAP-Associated Deaths with Acute Liver Toxicity by Intentionality Intentional Unintentional Accidental overdose and therapeutic misuse 30 28 Total = 58

  46. Relative Risk of Serious GI Hospitalization For OTC Pain Relievers, As Compared to ‘No Drug’ Group 5 4.14 3.92 4 3.50 3.42 3 Relative risk(vs. no drug) 2 0.76 1 0 No Drug APAP ASA** IBU* NAP* Any** NSAID * p =.05 **p = .01 (error bars represent 95% lower C.I.s based on one-tailed test) Singh, unpublished

  47. Conclusions • Prospective studies indicate no toxicity at or near the recommended dose • Serious hepatotoxicity occurs following substantial overdose (single dose ~15 g or multiple days, ~12 g/day) • Chronic alcoholics may safely take current recommended doses of acetaminophen; therefore no need for dose reduction

  48. Acetaminophen: Safe Use in Liver Disease Raymond S. Koff, MD Professor of Medicine University of Massachusetts Medical School Director, Clinical Hepatology Research UMass Memorial Medical Center

  49. Acetaminophen • Current recommended dose (4 g/day) is safe to use in patients with liver disease • Supportive evidence • prospective single dose studies • prospective multiple dose studies • clinical experience • Concerns of increased risk for hepatotoxicity: based on anecdotal case reports

  50. Chronic Liver Disease: No Change in Acetaminophen Metabolism after 1.5 g* Normal subjects Mild liver disease Severe liver disease Sulfate 33±1.2 29±1.9 35±3.1 Glucuronide 54±1.4 29±2.3 50±3.7 Cysteine 3.8±0.1 4.4±0.6 4.2±0.9 Mercapturate 4.8±0.2 4.3±0.7 4.2±0.6 • 24-hour urinary recovery • Single dose • Normal subjects (n=8); mild disease (n=8); severe disease (n=7) *Forrest et al, 1979

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