Encouraging the Safe Use of Acetaminophen

Transcription

1 Encouraging the Safe Use of Acetaminophen Edward P. Krenzelok, PharmD, FAACT, DABAT Professor of Pharmacy and Pediatrics Gordon J. Vanscoy Chair in Pharmacy University of Pittsburgh Director, Pittsburgh Poison Center Karen Reed, RPh, FAPhA Staff Pharmacist, Kmart Beckley, West Virginia Activity Development This activity was developed by the American Pharmacists Association, supported by independent educational grants from McNeil Consumer Healthcare and Endo Pharmaceuticals and co-sponsored by the Pharmacy Technician Certification Board. Disclosures Edward P. Krenzelok, PharmD, FAACT, DABAT, has worked as a consultant for Cadence Pharmaceuticals, the producer of Ofirmev, an intravenous acetaminophen product. Karen Reed, RPh, FAPhA, declares no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. APhA's editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. For complete APhA staff disclosures, please see the Education and Accreditation Information section at 1

2 Accreditation Information The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (CPE). This webinar, Encouraging the Safe Use of Acetaminophen, ACPE # L01-P; L01-T, is approved for 1.5 hours of CPE credit (0.15 CEUs). To obtain CPE credit for this activity, participants must actively participate in the entire webinar and complete an online evaluation and CPE recording form located at by July 31, A voucher code and further instructions will be provided during the webinar. In order to complete the online activity evaluation form, participants will need to have a valid pharmacist.com user name and password. A Statement of Credit will be automatically generated upon achieving these requirements. Target Audience: Pharmacists and Pharmacy Technicians ACPE Activity Type: Application-based Learning Level: 2 Initial Release Date: July 10, 2012 Self-Assessment Questions Learning Objectives Describe factors and situations that can contribute to acetaminophen overdoses and strategies that pharmacy personnel can use to help prevent these overdoses Discuss regulatory actions regarding acetaminophen between 2009 and June 2012 and those that are currently under FDA consideration Describe the impact of FDA activities on patient care recommendations and patient education strategies Describe the goals and activities of the NCPDP Acetaminophen Task Group as they relate to acetaminophen prescription labels Discuss opportunities for pharmacy personnel to engage with patients around acetaminophen safe use 2

3 Acetaminophen Pathophysiology of Hepatotoxicity Paracelsian Wisdom Everything is a poison what differentiates a poison from a remedy is the dose KEP1 Acetaminophen Mechanism of Toxicity Dose-dependent hepatotoxin Oxidized to a reactive metabolite (N-acetyl-pbenzoquinoneimine, NAPQI); CYP2E1 path is primarily important clinically NAPQI is detoxified when conjugated with glutathione In overdoses, there is increased formation of NAPQI and glutathione reserve is depleted 3

4 Acetaminophen Toxicity A Consequence of Metabolism NAPQI = N-acetyl-p-benzoquinoneimine KEP5 Mitchell JR et al. Clin Pharmacol Ther. 1974;16: Acetaminophen Toxicity A Consequence of Metabolism Excessive Acetaminophen NAPQI Formation Glutathione Depletion Hepatic Necrosis Survival Death Acetaminophen What Is a Toxic Dose? Therapeutic Pediatric:10-15 mg/kg/dose x 4-5 doses Adult: 4 g/day in divided doses Toxic > Therapeutic? Dilemmas Acute vs chronic 4

5 Acetaminophen What Is a Toxic Dose? >150 mg/kg? >200 mg/kg? >4 g? >7.5 g? >10 g? >15 g? Acetaminophen Toxicity Typical Scenarios 12-month-old child is teething/irritable Mother administers acetaminophen liquid Father administers acetaminophen liquid Babysitter administers acetaminophen liquid 18-year-old depressed patient Ingestion of 100 acetaminophen 325 mg caplets 42-year-old patient suffering from post-op pain Prescription for hydrocodone/acetaminophen 7.5 mg/750 mg 1-2 q4h for pain OTC acetaminophen 9 g/day x 3 days Acetaminophen Treatment of Overdose Do no harm Supportive care Naloxone? GI decontamination? Gastric lavage? Activated charcoal? Extracorporeal? Acetylcysteine Rumack-Matthew nomogram PO vs IV 5

6 Extent of the Problem Acetaminophen Use Is Widespread Over 600 products contain acetaminophen (Rx and OTC) IMS DATA 2008 (~50% of sales) 24.6 billion doses sold 80% OTC 200 million Rx acetaminophen-opioid combos Nonprescription analgesic use 16% 20% of adults Assessing the Extent of the Problem Liver Injury Deaths from hepatotoxicity Liver transplants Hospitalizations Emergency visits Subacute effects Budnitz D. Centers for Disease Control and Prevention. Advisory Committee Meeting presentation, June

7 Assessing the Incidence of Overdose Calls to poison control centers Emergency department (ED) visits Liver failure registries Reports to American Poison Centers Involving Acetaminophen Exposure Trends: American Association of Poison Control Centers Database American Association of Poison Control Centers National Poison Data System Overdosages by Age Poison Control Centers Database % Age (Years) American Association of Poison Control Centers National Poison Data System 7

8 Fatalities by Product Type Poison Control Centers Database N = 1217 % of All Fatalities American Association of Poison Control Centers National Poison Data System ED Visits for Acetaminophen Overdose National Electronic Injury Surveillance System from January 1, 2006, to December 31, 2007 Estimated 78,414 ED visits annually for acetaminophen overdoses not related to abuse 69.8% from self-directed violence 16.7% from therapeutic misadventures Majority (56%) involved overuse for medicinal effects rather than use of multiple acetaminophen-containing products or dose confusion 13.4% from unsupervised ingestions by children <6 years of age Budnitz DS et al. Am J Prev Med. 2011;40: Risk of Hepatotoxicity With Acetaminophen Acute Liver Failure (ALF) ALF Study Group Registry from 23 tertiary care centers over 10 years 606 cases in 2009 Approx 50% of all ALF cases in the U.S. are due to acetaminophen Over 450 deaths per year based on national estimates from ALF Study Group and other data 50% are due to unintentional overdose (not intentional overdose or accidental ingestion) Among the unintentional cases 55% took only OTC acetaminophen products 29% took opioid combination only 16% took both OTC and Rx 8

9 FDA Advisory Committee and Regulatory Activity FDA Efforts to Mitigate Hepatotoxicity Risk 1993 Advisory Committee Meeting-Alcohol 1997 Proposed Rule (Alcohol Warning) 1998 Final Rule (Alcohol Warning) 2002 Advisory Committee Meeting-Unintentional Liver Injury from OTC Acetaminophen 2004 Public Education Campaign (FDA & Partners)- ID Acetaminophen on Rx Labels 2006 Proposed Regulations on OTC Labeling-Full Name and Safety Information 2007 CDER Working Group Formed 2009 Advisory Committee Meeting-Adults 2011 Advisory Committee Meeting-Pediatrics 2009 FDA Advisory Committee Meeting Joint meeting Drug Safety and Risk Management Advisory Committee Anesthetic and Life Support Drugs Advisory Committee Nonprescription Drugs Advisory Committee Meeting materials available online htm 9

10 FDA Proposals to Mitigate Risk Limit Maximum Daily Dose 3,250 mg Limit Tablet Strength of Immediate Release 325 mg = Nonprescription 325 mg if with Rx Opioid 500 mg = Prescription Alcohol Warning >3 Drinks One Liquid Preparation Eliminate Acetaminophen Combo Products Packaging Limit Package Sizes Unit-of-Use Rx Packages Awareness Labeling Warnings Black Box Warning Changing 500 mg Tablet to Rx Issues for Consideration Goal: reduce unintentional overdose No evidence to support status change Circumvented easily 3 x 325 mg Legacy of decades Drive toward > risk meds Reducing Daily Dosage Issues for Consideration FDA basis for dose reduction Adult Acute Liver Failure Study Group 10 Years 1,321 Cases 46% Acetaminophen Basis for to 3,250 mg daily dose Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM pdf 10

11 FDA Evidence Base Stroke Study stroke patients 6,000 mg daily x 3 days Osteoarthritis Study 2 Multicenter, randomized, double-blind 4,000 mg daily x 6-12 months Dart and Bailey 3 Systematic literature review Prospective 30,865 subjects 0.4% LFTs Retrospective 9,337 patients 1 liver transplant 6 fatalities Patient care implications? 1. den Hertog HM et al. Lancet Neurol. 2009;8: Temple AR et al. Clin Ther. 2006;28: Dart RC et al. Pharmacotherapy. 2007;27: Pack Size Limits Issues for Consideration United Kingdom Nonpharmacy mg tablets Pharmacy mg tablets Decreased morbidity/mortality 1 Modest reduction London PC 2 Scotland no impact 3 Patient inconvenience Cost 1. Hawton K et al. BMJ. 2001;322: Hawkins LC et al. Drug Safe. 2007;30: Bateman DN. Clin Toxicol. 2009;47: Decoupling Prescription Products Issues for Consideration 200 Million Acetaminophen-Opioid Rx/Yr FDA AERS 59% of fatalities Errors Vicodin ES Hydrocodone 7.5 mg Acetaminophen 750 mg 1-2 q4-6h for pain Diversion/abuse Patient/prescriber inconvenience Risk:benefit impact on patient care 50 million chronic pain 25 million acute pain Acetaminophen + Opioid 11

12 Eliminate OTC Combinations Issues for Consideration Multi-symptom cough/cold relief products FDA drug monograph regulatory process Efficacy studies unnecessary 6% 11% of fatalities Enhanced acetaminophen labeling What Is Wrong With This Rx? 42-year-old female Post-bunionectomy Post-operative pain Rx Vicodin ES 1-2 q4-6h for pain Krenzelok EP. Ther Pharmacol Clin Toxicol. 2011;15: What Is Wrong With This Rx? Hydrocodone 7.5 mg/tablet Acetaminophen 750 mg/tablet Total acetaminophen = 9 g/day 27 g over 3 days Death Rx Vicodin ES 1-2 q4-6h for pain Krenzelok EP. Ther Pharmacol Clin Toxicol. 2011;15:

13 2009 FDA Advisory Committee Options and Vote Outcome: OTC Dose Option Yes No 1. Lower the maximum total daily dose of acetaminophen in nonprescription singleingredient and combination products? Lower maximum OTC single adult dose to 650 mg? If the current doses of OTC products are lowered, should the 1,000 mg (e.g., 2 x 500 mg) dose of acetaminophen be switched to Rx status? Options and Vote Outcome: Other OTC Considerations Option Yes No 4. Do you recommend that pack size limits be implemented for nonprescription acetaminophen products? Eliminate OTC acetaminophen combination products? Only one concentration of nonprescription acetaminophen liquid should be available Options and Vote Outcome: Rx Considerations Option Yes No 7. Eliminate Rx acetaminophen combination products? Require unit of use packages for Rx acetaminophen combination products Require a boxed warning for Rx combination products

14 Options Ranking Each Advisory Committee member identified his or her #1 priority Reduce Max OTC dose Eliminate Rx combos Rx box warning Single liquid formulation Unit-of-use package From the Advisory Committee Mixed vote outcome may reflect: Variety of practice perspectives Limited dose ranging data for acetaminophen efficacy Lack of data on potential impact of proposed interventions Need increased safety margin for acetaminophen Patient education is major factor Address pediatric formulations and dose May 2011: Joint Meeting of the Nonprescription Drugs and the Pediatric Advisory Committees Should new dosing information for oral OTC products containing acetaminophen be added to the label for children <2 years? Add weight-based dosing regimen to the existing age-based dosing regimen for children 2 to 12 years of age? How can administration by caregivers be improved so that medication errors can be minimized? 14

15 Recent Changes Pediatric Liquid Formulations Reduced Acetaminophen in Opioid Combinations 2014 Voluntary Action by McNeil Change in Liquid Concentrations for Infants and Children Historical formulations 80 mg/0.8 ml 160 mg/5 ml 500 mg/15 ml Current formulation 160 mg/5 ml Reduction in Maximum Prescription Dosage January 13, 2011 All acetaminophen-opioid combinations Acetaminophen 325 mg/dosage unit maximum Why? 50% of acetaminophen-related fatalities Phase-in over 3 years Dosing recommendations the same Boxed warnings Patient care implications? 15

16 Voluntary Action by Brand Manufacturer July 28, 2011 label modification 500 mg tablets only 1,000 mg q6h Maximum of 3,000 mg/day (reduced from 4,000 mg/day) 2012 label modification 325 mg tablets 10/day 650 mg q6h Maximum of 3,250 mg/day Krenzelok EP, Royal MA. Drugs R D. 2012; epub ahead of print Confusion! Acetaminophen Dosing Dilemma What is the correct dose? Why does the total daily dose differ by product? Does the IV dose change? Does the toxic dose change? Generic manufacturers generally did not make the same changes How do you explain this to your patients? Krenzelok EP, Royal MA. Drugs R D. 2012; epub ahead of print What Is the Correct Nonprescription Dose? FDA Drug Monograph Process Analgesic, Antipyretic, and Antirheumatic Drug Products for OTC Human Use Monograph dictates dose, indications, etc. Pre-market approval unnecessary mg q4h not >3,900 mg/day for 10 d 500 mg up to 1,000 mg not >4,000 mg/24 hr 650 mg dose not part of monograph process Krenzelok EP, Royal MA. Drugs R D. 2012; epub ahead of print 16

17 Correct Nonprescription Dose? Brand manufacturer s dosing change VOLUNTARY NOT FDA mandated No safety implications Does not apply if rec d by HCP Health care implications??? Generics vs Brand = CONFUSION Presenter Perspective The maximum therapeutic dose has not changed = 4,000 mg/day The labeling change = voluntary No safety issues with generics Never mix analgesics 70% of ED visits = self-harm The toxicity signal is low Health care providers can recommend the monograph doses What Does the Future Hold for FDA Action? Reduce maximum daily dose? 500 mg = prescription only? Reduce package size? Eliminate OTC combo products? Eliminate Rx combo products? Unit-of-use Rx products? Boxed warning? 17

18 Safe Use Initiative and NCPDP Recommendations FDA Safe Use Initiative The mission of the Safe Use Initiative is to create and facilitate public and private collaborations within the healthcare community. The goal of the Safe Use Initiative is to reduce preventable harm by identifying specific, preventable medication risks and developing, implementing and evaluating cross-sector interventions with partners who are committed to safe medication use. Addressing Labeling Issues National Council for Prescription Drug Programs (NCPDP) FDA s Safe Use Initiative Broad Group of Stakeholders Formed the Acetaminophen Best Practices Task Group, which produced the white paper: NCPDP Recommendations for Improved Prescription Container Labels for Medicines Containing Acetaminophen (PDF-974KB) 18

19 Issues Addressed by NCPDP Recommendations To prevent unintentional overdose, patients need to be able to: Read labels Recognize when their medicines contain acetaminophen Acetaminophen is clearly listed on OTC labels but may not be clear on Rx labels (i.e., APAP ) Goals of NCPDP Recommendations Help patients to: Identify that their prescription pain reliever contains acetaminophen Compare active ingredients on their prescription and OTC labels Take action to avoid taking two medicines with acetaminophen NCPDP Recommendations Complete spelling of acetaminophen and all active ingredients on pharmacy labels containing acetaminophen Standardized concomitant use and liver pharmacy warning label Formatting and wording on prescription container labels consistent with plain language and health literacy principles Call to action among stakeholders: adopt, implement, adhere, communicate, and educate 19

20 Challenges for Replacing APAP Labeling Software State Board Regulations Space Abbreviating something else? Warning Label Priority in printing Standardization with OTC warning Software State Board Regulations Industry Changes Larger vials, unit-of-use, waste Patient Education General Patient Education Needs What is Acetaminophen? Acetaminophen overdose can cause liver damage Not common knowledge Acetaminophen is sometimes abbreviated as APAP Acetaminophen is an ingredient in over 600 products, including multiple brands as well as generics Stumpf JL et al. J Am Pharm Assoc. 2007;47:

21 Opportunities for Pharmacy Staff to Intervene and Provide Education Provide education to patients using Rx opioid-acetaminophen combos Be alert for opportunities to educate patients who purchase OTC acetaminophen products Educate purchasers of cough/cold products (and others) about risks of therapeutic duplication MTM reviews Other awareness initiatives: Messages on in-store signage, shelf talkers, register receipts, etc. Watch for Problematic Situations Therapeutic duplication with cough/cold, analgesic (OTC and Rx), fever, and/or sleep aid products Many brands of OTC products include acetaminophen due to line extensions Opioid-acetaminophen prescriptions from multiple prescribers Prescriptions labeled with APAP Patients do not realize this means acetaminophen Starting the Conversation This product contains acetaminophen; it is important that you take the right dosage and do not use other products containing acetaminophen Open-ended questions: Is this product for you or someone else? What symptoms are you using this product for? What dosage of this product do you plan to use? For liquid products: Can you show me how to prepare the correct dosage? Draw a mark at the indicator for the correct dosage 21

22 Medication Review Questions Develop a tool to include in your medication review that will help you assess OTC use and possible therapeutic duplication Questions could include: What do you take for pain relief? What do you take for sleep? What do you take for cold or cough? What do you take for headaches? Patient Counseling Information for OTC Products Point out acetaminophen in Active Ingredients section of Drug Facts Do not use more than one OTC product containing acetaminophen (products indicated for pain or fever reduction, including migraine, cough/cold/allergy, sleep, overindulgence, menstrual symptoms) Follow dosing directions and warning information carefully Measure liquid formulations accurately and store medication safely 22

23 When Dispensing Prescription Combinations Avoid use of APAP, ACET, or other acronyms or abbreviations If unavoidable, explain to patients what it means Advise patients not to use OTCs containing acetaminophen at the same time Monitor patients with chronic pain for opioid tolerance and increased usage; be mindful of acetaminophen exposure Special Considerations for Acetaminophen Use in Children Up to half of analgesic doses given to children are administered incorrectly Caregivers are frequently confused about ingredients in combination Rx or OTC products 65% of parents reported giving Tylenol to their child, but only 8% reported using acetaminophen Dlugosz CK et al. J Pediatr Health Care. 2006;20: Simon KH et al. Arch Pediatr Adolesc Med. 1997;151: Acetaminophen Safety in Children Hepatotoxicity usually occurs from large single doses, but can occur from multiple supratherapeutic doses Max labeled OTC dose 75 mg/kg/day Increased risk in children with diabetes, concomitant viral infections, family history of hepatotoxic reactions, obesity, or chronically malnourished children Dlugosz CK et al. J Pediatr Health Care. 2006;20:

24 Potential Issues for Pediatric Versions of Acetaminophen Caregivers may still have old products with discontinued concentrations Ask parents/caregivers to check the label before providing advice over the phone Reinforce importance of using the dosing device that comes with the product Use teach back method to ensure caregiver can administer an appropriate dose Sample bottles from prescribers do not have measuring devices Administering ANY Meds in Children Calculate doses based on age/weight ALWAYS use calibrated syringe, dropper, or cup Kitchen teaspoon can vary from 2 ml to 10 ml Remind parents that many products contain the same ingredients Use caution with dosage forms (e.g., infant drops vs children s formulations old products may still be in medicine cabinets) Watch out for brand name recommendations (product line extensions, etc.) Patient Education Resources Acetaminophen Awareness Coalition How to read your label, OTC and Rx, free posters, brochures, video, talking points Consumer Healthcare Products Association (CHPA) OTC medicine safety for parents, seniors, pregnant, and nursing moms, health care professionals Chart for acetaminophen dosing/changes, how to recognize Medication Use Safety Training for Seniors Reading a drug label, caregiver corner, older adults and medicine use National Council on Patient Information and Education (NCPIE) Resource kits and handouts on safe use designed for teens, college students, seniors 24

25 If All Else Fails! Take Home Points Acetaminophen is an ingredient in hundreds of Rx and OTC products Inadvertent overdose can lead to morbidity and mortality Identifying which products contain acetaminophen can be confusing for patients Pharmacists and pharmacy staff can have an important role in educating patients about acetaminophen and recent product changes Self-Assessment Questions 25

26 Based on calls to poison control centers, which product is most likely to be associated with acetaminophen overdosage? A. Acetaminophen alone. B. Acetaminophen in combination with an opioid. C. Acetaminophen combinations with cough/cold products. D. Multiple acetaminophen products. Which one of the following statements about acetaminophen dosages is true? A. The 500 mg brand acetaminophen product label has a higher maximum daily dosage than the 325 mg brand acetaminophen product label. B. All generic manufacturers of acetaminophen have implemented the same dosage reductions that the brand manufacturer implemented. C. FDA is updating the monograph for acetaminophen to reduce the maximum allowed daily dosage. D. The maximum labeled daily dosage for the 500 mg brand acetaminophen product is 3,000 mg/day. Which of the following issues was a primary focus of the National Council for Prescription Drug Programs (NCPDP) recommendations for acetaminophen? A. Patients do not recognize that APAP is an abbreviation for acetaminophen. B. Intentional self-harm is the leading cause of acetaminophen overdosage. C. The availability of different maximum daily dosages for OTC products leads to patient confusion. D. Patients do not always following the directions on OTC product labels. 26

27 How to Obtain CPE Credit Note the voucher code provided during webinar Go to to provide APhA with your required NABP e Profile ID Log in using your Pharmacist.com user name and password Go to Go to Online CPE Quick List and click on Encouraging the Safe Use of Acetaminophen Complete the evaluation to gain immediate access to your Statement of Credit Questions: mostrander@aphanet.org 27