Clinical Toxicology (2013), 51, 941–948 Copyright © 2013 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2013.848282
POISON CENTRE
Fatalities involving acetaminophen combination products reported to United States poison centers SUZANNE DOYON,1,2 WENDY KLEIN-SCHWARTZ,1 SAMANTHA LEE,1 and MICHAEL C. BEUHLER3 1University
of Maryland School of Pharmacy, Maryland Poison Center, Baltimore, MD, USA Hopkins University School of Medicine, Department of Emergency Medicine, Baltimore, MD, USA 3University of North Carolina at Chapel Hill School of Medicine, Department of Emergency Medicine, Chapel Hill, NC USA Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
2Johns
Context. Deaths from overdose of acetaminophen (APAP) combination medications are reported, yet the individual ingredients are not well examined as individual putative causes of death. Objective. To examine the individual contribution of APAP or other ingredient(s) to fatalities resulting from ingestion of APAP combination products reported to poison centers. Materials and methods. A search in the United States (US) National Poison Data System between 1 January 2000 and 31 December 2009 (10 years) was conducted. Only fatal cases determined by American Association of Poison Control Centers Fatality Review team to be caused by ingestion of one or more APAP combination products were included. The fatality abstract narrative for each case was obtained. Each narrative abstract was rated independently by four reviewers and putative cause of death was determined to be APAP, ‘other ingredient’ or ‘unable to determine’. Fleiss’ Kappa test was utilized to assess interrater agreement. Results. Three hundred and thirty-seven deaths met inclusion criteria: 204 were due to suicides, 96 were the result of nonmedical use, 3 were from a therapeutic error, 1 resulted from an unsupervised pediatric ingestion, and 33 were due to unknown reason for exposure. The overall putative cause of death was APAP in 60.8%, other ingredients in 29.7%, and unable to determine in 9.5% of fatalities. APAP was responsible for the fatality in 79.2% of deaths resulting from nonmedical use of APAP combination products. Fleiss Kappa was 0.74, indicating substantial interrater agreement. Discussion and conclusion. The most common putative cause of death in fatal overdoses involving APAP combination products reported to US poison centers is the APAP component. Keywords
acetaminophen, combination, fatalities
Introduction
combination products in 2011, 25498 of which were treated in a health care facility.5 A primary area of concern is whether these popular APAP combination products are associated with increased harm. The Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) concluded that APAP combination medications were the most commonly implicated products in 282 cases of hepatotoxicity between 1998 and 2001. Females represented 60% of these cases; many reported use of higher than recommended doses of APAP for reasons that were unknown but potentially related to the lack of awareness of the toxicity of APAP; the APAP combination product remained unspecified in many of the cases.6 Other authors reported that up to 63% of patients with liver injury unintentionally overdosed on APAP combination products.7 These studies suggest that there is increased risk of hepatotoxicity following the use of APAP combination medications. In its annual report, the AAPCC National Poison Data System (NPDS) reported that APAP combination products were involved in 48% of APAP-associated fatalities.5 Occurrences of death following ingestion of APAP combination products warrant further investigation. The primary objective of the study is to determine whether deaths resulting
Many medications consumed in the United States (US) are combined with others into one single dose unit, tablet, or capsule. Acetaminophen (APAP) has been combined with antihistamines, decongestants, dextromethorphan, caffeine, and/or aspirin in over-the-counter (OTC) preparations. It has been combined with an opioid or with butalbital/caffeine in prescription preparations (Table 1). More than half of the OTC market for APAP is comprised of APAP combination products, and APAP/hydrocodone is the most commonly prescribed medication in the US.1 Retail sales of both OTC and prescription APAP products are increasing, and a total of 136 million prescriptions of APAP/hydrocodone were dispensed in 2011.1–4 The American Association of Poison Control Centers (AAPCC) reported over 49000 single exposures to APAP Received 13 June 2013; accepted 19 September 2013. Address correspondence to Suzanne Doyon, MD, Medical Director, Maryland Poison Center, 220 Arch Street-Office level 1 Baltimore, MD 21201, USA. Tel: ⫹ 410-563-5582. Fax: ⫹ 410-706-7184. E-mail: [email protected]
941
942
S. Doyon et al.
Table 1. List of acetaminophen combination products involved in fatalities reported to the American Association of Poison Control Centers. Generic ingredients Prescription acetaminophen products APAP/codeine APAP/hydrocodone
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
APAP/oxycodone APAP/propoxyphene APAP/tramadol APAP/butalbital/caffeine/⫹ codeine APAP/other opioid Over-the-counter acetaminophen products APAP/diphenhydramine APAP/caffeine APAP/pseudoephedrine APAP/ASA/caffeine APAP/caffeine/pyrilamine APAP/doxylamine/dextromethorphan APAP/phenylephrine/dextromethorphan APAP/doxylamine/phenylephrine/dextromethorphan
Common brand names
Strengths per unit dose (mg)
Tylenol #2, #3, #4 Vicodin, Lortab Norco Percocet, Roxicet Endocet, Tylox Darvocet Ultracet Fioricet, Fioricet-C N/A
APAP, 325; codeine, 15 or 30 or 60 APAP, 325 or 500; hydrocodone, 5 or 7.5 or 10
Tylenol PM Excedrin AF Tylenol Sinus Excedrin Midol Nyquil Nighttime Nyquil liquicaps Dayquil Nyquil liquid
APAP, 500; diphenhydramine, 25 APAP, 500; caffeine, 65 APAP, 500; pseudoephedrine, 30 APAP, 250; ASA, 250; caffeine, 65 APAP, 500; caffeine, 60; pyrilamine, 15 APAP, 325; doxylamine, 6.25; DXM, 10*
APAP, 325 or 500; oxycodone, 5 or 7.5 or 10 APAP, 325 or 650; propoxyphene, 50 or 100 APAP, 325; tramadol, 37.5 APAP, 325; butalbital, 50; caffeine, 40; codeine, 30 N/A
APAP, 325; phenylephrine, 5; DXM, 10* APAP, 325; doxylamine, 6.25; phenylephrine, 10/; DXM, 15
APAP, acetaminophen; DXM, detromethorphan; N/A, not applicable. *Variable formulations and strengths. Examples only.
from ingestion of APAP combination products were due to APAP toxicity or due to the toxicity of the other ingredient(s) in the product.
Methods A retrospective analysis of deaths associated with exposures to APAP combination products reported to the AAPCC NPDS from 1/1/2000 to 12/31/2009 (10 years) was conducted. Calls to poison centers range from simple requests for information to life-threatening poisonings. Every call is recorded in an electronic database that is uploaded into NPDS regularly. A reported exposure is considered a case. Each case will have one coded medical outcome at its conclusion; there are a total of 10 possible medical outcomes. All cases with the medical outcome ‘death’ have additional information entered into the NPDS Fatality module by the poison center medical director. In this module, a separate series of coded fields and a narrative abstract – similar to hospital discharge summaries – are completed. The most important components of the coded fields are the relative contribution to fatality (RCF) and the hierarchy of substances. The possible RCFs are the following: undoubtedly responsible, probably responsible, contributory, probably not responsible, clearly not responsible, unknown, and coding error.5 The RCF is applied to the first substance in the hierarchy of substances in the AAPCC Fatality Table. All deaths are reviewed by two independent reviewers from the AAPCC Fatality Review Team for accuracy and completeness, with special attention paid to the RCF and hierarchy of substances. This review process is illustrated in Fig. 1.
Narrative abstracts were requested for APAP combination product-only cases identified by manual search of fatality tables from all the AAPCC annual reports for the study period. Original poison center records or medical records were not requested. In addition, investigators accessed the coded fields that accompany all narrative abstracts: age, gender, coded substance and hierarchy, chronicity, route of administration, reason for exposure (therapeutic error, suicide, etc.), RCF, and pre-hospital arrest. Inclusion criteria were as follows: death involving any APAP combination product found in the fatality table of the AAPCC Annual Report. Deaths involving more than one APAP combination product were included. Exclusion criteria were as follows: presence of life-threatening co-morbid conditions felt to contribute to the fatality; co-ingestion of additional medications other than APAP combination products discovered upon review of abstract; fatality deemed by raters as not related to APAP combination product (i.e., raters disagreed with AAPCC NPDS Fatality Review team); routes other than oral; and missing information (e.g., absent history, only pills found on the deceased, absent postmortem toxicological analyses for persons found dead on scene). Three examples of fatality abstracts are provided in Supplementary material Appendix 1 to be found online at http://informa healthcare.com/doi/abs/10.3109/15563650.2013.848282. The host university IRB deemed the study not human subject research. Each narrative abstract was analyzed in detail by two of the authors for the following: reason for exposure, exposure chronicity, APAP-product identification, past medical history, past history of ethanol or drug abuse; clinical effects; laboratory results; therapeutic interventions; and Clinical Toxicology vol. 51 no. 10 2013
Deaths from APAP Combination products 943 Exposure with medical outcome ‘death’ uploaded automatically to NPDS Fatality module
Mandatory coding of relative contribution to fatality and narrative write up by poison center medical director.
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
AAPCC Fatality Review team reviews all coding of relative contribution to fatality and all narrative abstracts.
Discussion between poison center medical director and AAPCC Fatality Review Team until agreement is reached on relative contribution to fatality and narrative.
Undoubtedly responsible OR Probably responsible OR Contributory
Probably not responsible OR Clearly not responsible OR Unknown
Published in Table 21 of AAPCC annual report
Not published in Table 21
Manual query Table 21 from annual reports from 2000–2009 Identification of fatalities related to acetaminophen combination product exposures
Independent review by 4 raters to determine if APAP or other ingredients was the putative cause of death Acetaminophen Other Ingredient(s) Unable to determine Not due to acetaminophen combo
Fig. 1. Flowchart of NPDS fatality review process and study procedure.
hospitalizations and hospital transfers. Four investigators (two poison center medical directors board-certified in medical toxicology, one poison center pharmacist–toxicologist, and one pharmacist toxicology fellow) independently read each narrative abstract and categorized the causes of death as most likely due to: APAP; other ingredient(s); or unable to determine. Investigators utilized a rubric with defined criteria to attribute death to APAP, opioids (non-propoxyphene), propoxyphene, butalbital, dextromethorphan, antihistamines, aspirin, caffeine, and/or decongestants. Given the brief nature of abstracts, it was impossible to require that all pre-defined criteria for a given drug be met. Therefore, a majority of criteria in one box Copyright © Informa Healthcare USA, Inc. 2013
were deemed sufficient to establish causality (see Supplementary material Appendix 2 to be found online at http:// informahealthcare.com/doi/abs/10.3109/15563650.2013. 848282). Training with ten fatality abstracts was conducted, and performance was assessed and rubrics were refined prior to the start of the study. Agreement between at least three of the four raters was considered sufficient to assign causality. The research team met to resolve disputes and maintain consistency in the assessment of putative cause of death. Suicide was defined as intentional ingestion of the product to take one’s life. Nonmedical use was defined as intentionally taking more than the prescribed dose of an APAP
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
944
S. Doyon et al.
prescription product or more than the recommended dose of an OTC APAP combination product; taking a product prescribed for another individual; documented misuse or abuse of a prescription or OTC product; use that resulted in an ED visit or a call to a poison center for overmedication (i.e., patient taking too much). Nonmedical use did not include suicides, therapeutic errors and malicious intent. This broad definition of nonmedical use was adapted from the Drug Abuse Warning Network (DAWN) Substance Abuse and Mental Health Services Administration (SAMHSA) glossary.9 Therapeutic error was defined as unintentional deviation from the therapeutic regimen that resulted in the wrong dose, administration to the wrong person, administration of the wrong product, or drug–drug interaction.10 Acute was defined as single, repeated, or continuous exposure occurring over a period of 8 h or less; acute-on-chronic as single exposure preceded by a continuous, repeated, or intermittent exposure occurring over a period exceeding 8 h; and chronic as continuous, repeated or intermittent exposure to the same substance lasting longer than 8 h.10 Quantitative data were summarized by medians and categorical data by frequencies. Chi-square test was used to compare past medical history, products involved, and chronicity of exposure. To compare chronicity of exposure, unknown time was combined with chronic because of the small numbers. A figure illustrating the type of APAP combination product involved in fatality by year was generated by performing a count of prescription and OTC products in the included cases. Cases in which both a prescription and OTC APAP combination product were ingested appear in both curves in the figure. Fleiss’ Kappa test was utilized to assess interrater agreement. For interpreting kappa values, an accepted set of magnitude guidelines was used. Values ⬍ 0 indicated no agreement; 0–0.2, a slight agreement; 0.21–0.4, a fair agreement; 0.41–0.6, a moderate agreement; 0.61–0.8, a substantial agreement; and 0.81–1.0, as almost perfect agreement between observers.11
Results Manual search of the fatality tables from AAPCC annual reports 2000–2009 yielded 413 deaths related to exposure to APAP combination products, of which 337 cases met inclusion criteria (Fig. 1). Excluded cases were the following: co-morbid conditions (52) (e.g., hepatitis C, cirrhosis, and pulmonary embolus), co-ingestions (16) (e.g., cyclic antidepressants, salicylates, and phenytoin), missing information (7), and intravenous (1). Of the 337 cases, 17 (5.0%) died in the pre-hospital setting or upon presentation to the emergency department, and 320 (95.0%) died in-hospital. The median age was 42 years (range, 2–89 years) and 68.3% were women. The majority, 204 (60.5%), of deaths were suicides. One death resulted from an unsupervised ingestion in a child. Two pregnant women (each in second trimester) died following nonmedical use of combination products. The fetuses did not survive and were not included in the analysis. A past medical history of cancer or pain was
encountered in 20 persons who committed suicide and in 54 persons who died following nonmedical use. Examples of pain were as follows: back pain, migraine, nontraumatic dental conditions, pancreatitis, endometriosis, fibromyalgia, inflammatory bowel disease, post-surgical pain, combat wounds, bone fractures, rheumatoid arthritis, and temporomandibular joint pain. A history of chronic use was present in 0.5% of suicides and 69% of deaths from nonmedical use, this result was statistically significant. Table 2 summarizes the findings for the 337 deaths. Figure 2 illustrates the number of deaths associated with ingestions of the prescription versus OTC combination products over time. The ingestions of prescription combination products increased by 80% in 2008–2009 compared to that in 2001–2003. The Fleiss Kappa agreement on putative cause of death was 0.74, indicating substantial agreement between raters. Analysis of all 337 deaths revealed that the putative cause of death was APAP in 60.8%, ‘other ingredient(s)’ in 29.7%, and ‘unable to determine’ in 9.5% of cases. Table 3 looks at the 317 deaths from ingestion of one single combination product. One unsupervised ingestion in a child was not included in the table. Of these 317 deaths, APAP/opioid was the most commonly ingested product. APAP/opioid was ingested in 109 (55.1%) cases of suicides and 66 (79.5%) cases of deaths from nonmedical use. The most common putative cause of death was APAP in 109 (55.1%) of suicides and 67 (80.7%) of deaths from nonmedical use. The two previously-described pregnant women used APAP/hydrocodone nonmedically (one misuse for back pain; the other, abuse) and died of APAP-induced liver failure. APAP/ propoxyphene was involved in a total of 41 deaths, 31 suicides, 6 deaths from nonmedical use, and 4 deaths with unknown reason for exposure. The putative cause of death was propoxyphene in 25/31 (80.6%) suicides, 3/6 (50.0%) deaths from nonmedical use, and ¾ (75%) deaths with unknown reason for exposure. Of these 41 deaths, seizures and electrocardiographic abnormalities (QRS or QTc prolongation) were reported in 9 (22.0%) and 9 (22.0%) cases, respectively. Table 3 illustrates these findings. The deaths resulting from ingestions of two or more APAP combination products are found in Table 4. Of the 6 cases of suicides involving more than one APAP combination product, the putative cause of death was other ingredient(s) in 4(66.6%) of the cases. Of the 13 deaths from nonmedical use of more than one APAP combination product, APAP was the cause of death in 9 (69.2%) cases. Among the 320 patients who died in the hospital, 289 (90.3%) received N-acetylcysteine, 205 (64.1%) were intubated and mechanically ventilated, 153 (48.1%) received vasopressors, and 306 (95.6%) were admitted to the intensive care unit (ICU). Of the 237 hospitalized cases where the putative cause of death was APAP or ‘unable to determine’, 225 (94.9%) were treated with N-acetylcysteine and 107 (45.2%) were admitted/transferred to a liver transplantation unit. In most of the cases where N-acetylcysteine was administered, the time to administration was not documented (see Supplementary material Appendix 1 to be found online at Clinical Toxicology vol. 51 no. 10 2013
Deaths from APAP Combination products 945 Table 2. Comparison of fatal ingestions of acetaminophen combination products reported to poison centers.
Males (%) Median age and range, years Past medical history Cancer Pain Cancer or pain Ethanol abuse Substance abuse Prescription products APAP/Opioid APAP/Butalbital/Caffeine ⫾ Codeine Over-the-counter products APAP/DPH APAP ⫾ ASA ⫾ caffeine APAP ⫾ Antihistamine ⫾ Decongestant ⫾ Caffeine ⫾ DXM Chronicity¶ Acute (%) Acute-on-chronic (%) Chronic (%) Unknown (%)
Suicide n ⫽ 204 (%)
Nonmedical use n ⫽ 96 (%)
Therapeutic error n⫽3
Unknown reason n ⫽ 33 (%)
31.4 39 (14–89)
33.3 41 (17–71)
33.3 47 (31–78)
30.3 49 (31–74)
1 19 (9.3) 20 (9.8) 15 (7.4) 17 (8.3)
5 (5.2) 53 (55.2) 54 (56.3) 25 (26.0) 26 (27.1)
1 1 1 1 0
1 8 (24.2) 8 (24.2) 5 (15) 2
116 (56.9) 5 (2.5)
77 (80.2) 4
1 0
22 (66.7) 1
85 (41.6) 3 1
20 (20.8) 5 (5.2) 1 (1.0)
0 0 2
9 (27.2) 0 1
187 (91.6) 16 (7.8) 1 0
12 (12.5) 13 (13.5) 69 (71.9) 2
0 0 3 0
18 (54.5) 5 (15.1) 10 (30.3) 0
One pediatric unsupervised ingestion involving APAP/opioid not included in table. NOTE: Some cases have more than one APAP combination product so total products are ⬎ 337 cases. p ⬍ 0.0001 using chi-square test comparing suicides to nonmedical use. APAP, acetaminophen; DPH, diphenhydramine; ASA, acetylsalicylic acid; DXM, dextromethorphan. Nonmedical use: intentionally taking more than the prescribed or recommended dose of a product; taking a product prescribed to another individual; or documented misuse or abuse of a product.
http://informahealthcare.com/doi/abs/10.3109/15563650. 2013.848282).
Discussion Previous epidemiologic assessments of deaths due to APAPcombination products suffered from limitations such as broad diagnostic criteria, inclusion of unconfirmed cases, failure to account for concomitant use of APAP, other drugs or ethanol, failure to account for contributory medical conditions, and failure to estimate risk.1,6,7 The NPDS annual report Fatality Table provides data on exposure fatalities (Fig. 1). The rationale for extending the 45 40 Number of Fatalities
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Reason for exposure
35
OTC Rx
30 25 20 15 10 5 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Time (year)
Fig. 2. Distribution over time of the fatalities involving acetaminophen combination products included in this study (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx). Copyright © Informa Healthcare USA, Inc. 2013
analysis beyond the NPDS Fatality Table was that patients who die of opioid-induced anoxic brain injury and patients who die from APAP-induced hepatic failure, each following ingestion of APAP/opioid products, are coded identically in the table, and it is only by analyzing the narrative, reviewing the clinical effects, laboratory data and treatments, that the putative cause of death can be determined. The fatality abstracts used in this analysis were written for, and independently reviewed by, the AAPCC Fatality Review team, yielding workable case summaries. The methodology used in this study addressed some of the previously mentioned shortcomings by including cases where the combination product(s) were listed as the only substance(s) in the hierarchy of substances, excluding cases in which co-ingestants and co-morbid conditions might have contributed to the death, maximizing accuracy in product identification and route of administration, and requiring laboratory confirmation, modified King’s College criteria, or postmortem examination for the diagnosis of APAP toxicity.8,12 As a result, 337 fatality abstracts were analyzed, including 204 suicides, 96 deaths from nonmedical use, 33 deaths where the reason for exposure was unknown, 3 deaths resulting from therapeutic errors, and 1 unsupervised ingestion in a child. Figure 2 illustrates how deaths associated with prescription APAP combination products outpaced deaths from OTC products in the study cases, in clear contrast to manufacturers’ reported retail sales data. Between 2004 and 2008, OTC APAP combination products sales grew 36% and prescription APAP combination products grew 25%.2
946
S. Doyon et al. Table 3. Putative causes of death from suicide, nonmedical use, therapeutic error, or unknown reason involving a single acetaminophen combination product. Putative cause of death Other ingredients
Unable to determine
2 29 (50.0) 2 (13.3) 5 (16.1) 0 1 68 (82.9) 0
1 15 (25.8) 11 (73.3) 25 (80.6) 1 2 9 (10.9) 1
0 14 (24.1) 2 1 1 0 5 (6.1) 0
2 109 (55.1)
1 66 (33.3)
0 23 (11.6)
4 37 (88.1) 9 (64.3) 3 12 (85.7) 2 67 (80.7)
0 4 4 3 1 0 12 (14.5)
0 1 1 0 1 1 4
1 1 2
0 0 0
0 1 1
1 8 2 3 0 6 0 1
0 3 2 1 1 2 1 0
0 1 0 0 0 1 0 0
21 (63.6) 199 (62.8)
10 (30.3) 88 (27.8)
2 30 (9.5)
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
APAP Reason for exposure: Suicide n 198 APAP/codeine n ⫽ 3 APAP/hydrocodone n ⫽ 58 (%) APAP/oxycodone n ⫽ 15 (%) APAP/propoxyphene n ⫽ 31 (%) APAP/other opioid n ⫽ 2 APAP/butalbital/caffeine ⫾ codeine n ⫽ 3 APAP/DPH** n ⫽ 82 (%) APAP/antihistamine/decongestant/caffeine/ dextromethorphan** n ⫽ 1 APAP ⫾ ASA ⫾ caffeine** n ⫽ 3 Total n 198 Reason for exposure: Nonmedical use n 83 APAP/codeine n ⫽ 4 APAP/hydrocodone n ⫽ 42 (%) APAP/oxycodone n ⫽ 14 (%) APAP/propoxyphene n ⫽ 6 (%) APAP/DPH** n ⫽ 14 (%) APAP ⫾ ASA ⫾ caffeine † n ⫽ 3 Total n 83 Reason for exposure: Therapeutic Error n 3 APAP/hydrocodone n ⫽ 1 APAP/antihistamine/decongestant/caffeine/DXM** n ⫽ 2 Total n 3 Reason for exposure: Unknown reason n 33 APAP/codeine n ⫽ 1 APAP/hydrocodone n ⫽ 12 APAP/oxycodone n ⫽ 4 APAP/propoxyphene n ⫽ 4 APAP/other opioid n ⫽ 1 APAP/DPH** n ⫽ 9 APAP/butalbital/caffeine n ⫽ 1 APAP/antihistamine/decongestant/dextromethorphan** n⫽1 Total n 33 GRAND TOTAL n 317
**: over-the-counter product. One case of unsupervised pediatric ingestion of acetaminophen/hydrocodone that died from the hydrocodone effects was not included in table. APAP: acetaminophen; DPH: diphenhydramine; ASA: acetylsalicylic acid; DXM: dextromethorphan Nonmedical use: intentionally taking more than the prescribed or recommended dose of a product; taking a product prescribed to another individual; or documented misuse or abuse of a product.
This is a study of critically ill patients who died despite receiving care. Of those who received care in the hospital, 306 (95.6%) were admitted to the ICU and 107 (33.4%) were transferred to liver transplantation centers. Approximately 90% received N-acetylcysteine suggesting that most had suspected or confirmed APAP toxicity, and most (68%) were women. These data correlate well with other assessments of hospitalizations for APAP-induced liver injury.6 For reasons that are unclear, women predominate among patients with drug-induced liver injury and, in one prospective study from 17 tertiary care centers, accounted for 79% of APAP-induced liver failure patients.13 The high frequency of pain and drug abuse in the nonmedical use group was expected, as was the
finding of chronic ingestions. In all, these data suggest that the population studied was largely representative of previously described populations.13–16 The most common combination products involved in all manners of deaths were APAP/opioid. The most common single product was APAP/diphenhydramine in suicides and APAP/hydrocodone in deaths from nonmedical use. These findings are not surprising. APAP/diphenhydramine products are available OTC in both brand-name and generic forms, are heavily marketed to the consumer, and are readily available in US households. APAP/hydrocodone products are frequently used for the treatment of pain because they are easier to prescribe due to their less restrictive Controlled Clinical Toxicology vol. 51 no. 10 2013
Deaths from APAP Combination products 947
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Table 4. Putative causes of deaths from suicide or nonmedical use involving more than one acetaminophen combination product.
Reason for exposure: Suicide n 6 APAP/codeine ⫹ APAP/hydrocodone APAP/propoxyphene ⫹ APAP/oxycodone APAP/codeine ⫹ APAP/ASA/butalbital APAP/DPH ⫹ APAP/propoxyphene APAP/DPH ⫹ APAP/hydrocodone APAP/DPH ⫹ APAP/propoxyphene ⫹ APAP/ hydrocodone Total n 6 Reason for exposure: Nonmedical use n 13 APAP/hydrocodone ⫹ APAP/codeine APAP/hydrocodone ⫹ APAP/propoxyphene APAP/hydrocodone ⫹ APAP/butalbital/caffeine APAP/hydrocodone ⫹ APAP/DPH APAP/hydrocodone ⫹ APAP/ASA/caffeine APAP/hydrocodone ⫹ APAP/caffeine APAP/propoxyphene ⫹ APAP/DPH APAP/DPH ⫹ APAP/pyrilamine/caffeine APAP/DPH ⫹ APAP/pseudoephedrine APAP/DPH ⫹ APAP/dextromethorphan/ /pseudoephedrine Total n 13
APAP
Other active ingredient
0 0 0 0 1 1
1 1 1 1 0 0
2
4
1 0 1 2 1 1 1 1 1 0
0 1 0 1 0 0 0 0 0 1
9
3
APAP, acetaminophen; DPH, diphenhydramine; ASA, acetylsalicylic acid. One death from nonmedical use APAP/hydrocodone ⫹ APAP/propoxyphene not included in table. It was in the ‘unable to determine’ category. Nonmedical use: intentionally taking more than the prescribed or recommended dose of a product; taking a product prescribed to another individual; or documented misuse or abuse of a product.
Substance Act C-III status compared to other APAP/opioids, and they, too, are readily available in many US households. Among suicides, APAP was the putative cause of death in 83% of cases if APAP/diphenhydramine was involved, but in only 35% of cases if APAP/opioid was involved (Table 3). These data could suggest a pharmacokinetic or dynamic interaction between APAP and diphenhydramine but more likely are explained by the severity of opioid toxicity in the APAP/opioid group, where death from respiratory arrest and anoxic brain injury occurred before hepatotoxicity from APAP. Of the deaths from nonmedical use, the vast majority died from APAP-induced hepatic failure regardless of the APAP product involved, although APAP/opioids were involved most frequently (80%). These data suggest that tolerance to the opioid may have protected the patients from respiratory arrest and anoxic brain injury but that self-escalation of doses as well as dependence may have contributed to hepatic failure and death. Tolerance is defined as the reduction in response following repeated administrations. Thus, when tolerance develops, a higher dose of a drug is required to produce the same effect.17 Dependence is a state that develops as a result of the adaptation produced by resetting of homeostatic mechanisms.17 The person with opioid dependence requires continued administration of the opioid to maintain normal function; if administration is abruptly Copyright © Informa Healthcare USA, Inc. 2013
stopped, the person experiences withdrawal. It is recognized that the dose (amount and duration) of APAP is a more important determinant of hepatotoxicity than the host’s metabolic constitution.16 In this study, APAP was the putative cause of death in 80.7% of deaths from nonmedical use likely related to chronic escalation in doses resulting in opioid tolerance and dependence. In 2011, a national audit of total prescriptions dispensed revealed that APAP/hydrocodone was the most frequently prescribed medication in the United States, with 136 million prescriptions dispensed per year. The second most commonly dispensed opioid medication was tramadol-only (32.9 million) followed by APAP/oxycodone (32.8 million).4 The popularity of APAP/hydrocodone over APAP/oxycodone is reflected in the number of suicides (58 vs 15) and deaths from nonmedical use (42 vs 14). Early in the decade, APAP/propoxyphene was very popular. In 2003, APAP/propoxyphene was the second most commonly prescribed opioid, behind APAP/hydrocodone.1 There were 31 suicides from APAP/propoxyphene and 6 deaths from nonmedical use during the study period. The putative cause of death was propoxyphene in the greater majority of these cases, largely related to the neuro- and cardiotoxicity of propoxyphene. These data support the 2010 FDA decision to recommend the withdrawal of propoxyphene from the US market.18 Thirteen deaths were related to nonmedical use of more than one combination product. In many instances, patients mixed two OTC cough and cold products or mixed one migraine product with one APAP/opioid. In both scenarios, the putative cause of death was most likely APAP (69.2%), although this result is limited by the low numbers of multiple product ingestions in our data set. Misunderstanding of the active ingredients and lack of awareness regarding co-administration of APAP is common, particularly among heavy users and those with limited literacy, and could have contributed to these findings.19 Government and industry have recently drawn attention to the problem of combination medications that contain APAP.20,21 In 2009, a 37-member FDA Advisory Committee voted to eliminate prescription APAP combination products and seven members of this committee felt that this alone could be the single most important intervention that would result in a decrease in APAP-related toxicity.22 The data presented in this study support this recommendation. Study limitations include the retrospective design and use of fatality abstracts. Exposure deaths are underreported to poison centers.23 Poison centers may be preferentially contacted regarding APAP-related toxicity and contacted to a lesser degree regarding opioid-related toxicity. The use of very strict inclusion/exclusion criteria resulted in reduced number of cases. Patients who died in the pre-hospital setting were less likely to be reported to a poison center; patients with rapid death after acute ingestion would be due to the other active ingredient.23 Identification of the APAP product was not independently confirmed. Lastly, liver injury resulting from intractable hypotension is at times impossible to distinguish from APAP-induced liver injury.
948
S. Doyon et al.
Conclusions
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Fatal overdoses involving APAP combination products reported to US poison centers are on the rise. This examination of 337 deaths resulting from ingestion of APAP combination products reported to US poison centers reveals that most common presumed cause of death was APAP. APAP is a particularly important putative cause of death in patients who use combination products nonmedically.
5.
6.
Disclaimer
7.
The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) maintains the national database of information logged by the country’s 57 Poison Centers (PCs). Case records in this database are from self-reported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g., an ingestion, inhalation, or topical exposure, etc.), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCs, and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).
8.
Acknowledgement The authors would like to acknowledge Yoland Tra, PhD for her help with statistical analysis.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
9.
10. 11. 12.
13.
14.
15.
16. 17.
18.
References 1. Wysowski DK, Governale LA, Swann J. Trends in out-patient prescription drug use and related costs in the US 1998-2003. Pharmacoeconomics 2006; 24:233–236. 2. Dal Pan GJ. Office of Surveillance and Epidemiology Center for Drug Evaluation and Research June 29, 2009. Available from: http://www.fda. gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ UCM175767.pdf. Accessed October 27, 2012. 3. Michna E, Sheng M, Korves C, Dahl JL. Removal of opioid/ acetaminophen combination prescription medications: assessing the evidence for hepatotoxicity and consequences of removal of these medications. Pain Medicine 2010; 11:3269–378. 4. IMS HEALTH. IMS National Prescription AuditTM. Available from: http://www.imshealth.com/deployedfiles/ims/Global/Content/
19.
20. 21. 22. 23.
Corporate/Press%20Room/Top-Line%20Market%20Data%20&%20 Trends/2011%20Top-line%20Market%20Data/Top_Products_by_ RX.pdf. Accessed June 2013 Bronstein AL, Spyker DA, Cantilena LR, Green JL, Rumack BH, Dart RC. 2010 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clin Toxicol 2011; 49:910–941. Karwoski CB. Briefing document: Acetaminophen containing products and hepatotoxicity. Division of Drug Risk Evaluation. August 2 2002. Available from: http://www.fda.gov/ohrms/dockets/ ac/02/briefing/3882b1_02_C-Acetaminophen%20Hepatotoxicity.pdf. Accessed October 2012 Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis 2007; 11: 525–548. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–443. Drug Abuse Warning Network, Substance Abuse and Mental Services. http://www.samhsa.gov/data/2k12/DAWN2k10/DAWN2k10Glossary.htm. Accessed June 2013 NPDS Reference manual 2009. Available from: http://www.aapcc. org/data-system/. Accessed May 2013. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33:159–174. Reynolds KM, Green RC, Dart RC, Bucher-Bartelson B, Khatri V. Overall quality of poison center data for acetaminophen-containing products is high, but coding of product-specific fields needs improvement. Clin Toxicol 2012; 50:620. (abstract) Ostapowich G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, et al. Results of a retrospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947–954. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study group. Drug-induced acute liver failure: results of a US multicenter, prospective study. Hepatology 2010; 52:2065–2076. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al.; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364–1372. Lee WM. Drug-induced hepatotoxicity. NEJM 2003; 349:474–485. O’Brien CP. Drug addiction. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011:652–654. Woodcock J. FDA Center for Drug Evaluation and Research. November 2010 Memorandum. Available from: http://www.fda.gov/ downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/UCM234349.pdf. Accessed May 2013. Wolf MS, King J, Jacobson K, Di Francesco L, Bailey SC, Mullen R, et al. Risk of unintentional overdose with nonprescription acetaminophen products. J Gen Intern Med 2012; 27: 1587–1593. Woodcock J, Griffin JP, Behrman RE. Development of novel combination therapies. New Engl J Med 2011; 364:985–987. Podolsky SH, Greene JA. Combination drugs- hype, harm and hope. New Engl J Med 2011; 365:488–491. FDA. Available from: http://www.regulations.gov/#!documentDetail; D ⫽ FDA-2011-N-0021-0001. Accessed December 2012 Doyon S, Fowler D. Comparison of exposure fatalities from the medical examiner’s office and the poison center. Clin Toxicol 2012; 50:645 (abstract)
Supplementary material available online Supplementary Appendix 1 & 2.
Clinical Toxicology vol. 51 no. 10 2013
POISON CENTRE
Fatalities involving acetaminophen combination products reported to United States poison centers SUZANNE DOYON,1,2 WENDY KLEIN-SCHWARTZ,1 SAMANTHA LEE,1 and MICHAEL C. BEUHLER3 1University
of Maryland School of Pharmacy, Maryland Poison Center, Baltimore, MD, USA Hopkins University School of Medicine, Department of Emergency Medicine, Baltimore, MD, USA 3University of North Carolina at Chapel Hill School of Medicine, Department of Emergency Medicine, Chapel Hill, NC USA Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
2Johns
Context. Deaths from overdose of acetaminophen (APAP) combination medications are reported, yet the individual ingredients are not well examined as individual putative causes of death. Objective. To examine the individual contribution of APAP or other ingredient(s) to fatalities resulting from ingestion of APAP combination products reported to poison centers. Materials and methods. A search in the United States (US) National Poison Data System between 1 January 2000 and 31 December 2009 (10 years) was conducted. Only fatal cases determined by American Association of Poison Control Centers Fatality Review team to be caused by ingestion of one or more APAP combination products were included. The fatality abstract narrative for each case was obtained. Each narrative abstract was rated independently by four reviewers and putative cause of death was determined to be APAP, ‘other ingredient’ or ‘unable to determine’. Fleiss’ Kappa test was utilized to assess interrater agreement. Results. Three hundred and thirty-seven deaths met inclusion criteria: 204 were due to suicides, 96 were the result of nonmedical use, 3 were from a therapeutic error, 1 resulted from an unsupervised pediatric ingestion, and 33 were due to unknown reason for exposure. The overall putative cause of death was APAP in 60.8%, other ingredients in 29.7%, and unable to determine in 9.5% of fatalities. APAP was responsible for the fatality in 79.2% of deaths resulting from nonmedical use of APAP combination products. Fleiss Kappa was 0.74, indicating substantial interrater agreement. Discussion and conclusion. The most common putative cause of death in fatal overdoses involving APAP combination products reported to US poison centers is the APAP component. Keywords
acetaminophen, combination, fatalities
Introduction
combination products in 2011, 25498 of which were treated in a health care facility.5 A primary area of concern is whether these popular APAP combination products are associated with increased harm. The Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) concluded that APAP combination medications were the most commonly implicated products in 282 cases of hepatotoxicity between 1998 and 2001. Females represented 60% of these cases; many reported use of higher than recommended doses of APAP for reasons that were unknown but potentially related to the lack of awareness of the toxicity of APAP; the APAP combination product remained unspecified in many of the cases.6 Other authors reported that up to 63% of patients with liver injury unintentionally overdosed on APAP combination products.7 These studies suggest that there is increased risk of hepatotoxicity following the use of APAP combination medications. In its annual report, the AAPCC National Poison Data System (NPDS) reported that APAP combination products were involved in 48% of APAP-associated fatalities.5 Occurrences of death following ingestion of APAP combination products warrant further investigation. The primary objective of the study is to determine whether deaths resulting
Many medications consumed in the United States (US) are combined with others into one single dose unit, tablet, or capsule. Acetaminophen (APAP) has been combined with antihistamines, decongestants, dextromethorphan, caffeine, and/or aspirin in over-the-counter (OTC) preparations. It has been combined with an opioid or with butalbital/caffeine in prescription preparations (Table 1). More than half of the OTC market for APAP is comprised of APAP combination products, and APAP/hydrocodone is the most commonly prescribed medication in the US.1 Retail sales of both OTC and prescription APAP products are increasing, and a total of 136 million prescriptions of APAP/hydrocodone were dispensed in 2011.1–4 The American Association of Poison Control Centers (AAPCC) reported over 49000 single exposures to APAP Received 13 June 2013; accepted 19 September 2013. Address correspondence to Suzanne Doyon, MD, Medical Director, Maryland Poison Center, 220 Arch Street-Office level 1 Baltimore, MD 21201, USA. Tel: ⫹ 410-563-5582. Fax: ⫹ 410-706-7184. E-mail: [email protected]
941
942
S. Doyon et al.
Table 1. List of acetaminophen combination products involved in fatalities reported to the American Association of Poison Control Centers. Generic ingredients Prescription acetaminophen products APAP/codeine APAP/hydrocodone
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
APAP/oxycodone APAP/propoxyphene APAP/tramadol APAP/butalbital/caffeine/⫹ codeine APAP/other opioid Over-the-counter acetaminophen products APAP/diphenhydramine APAP/caffeine APAP/pseudoephedrine APAP/ASA/caffeine APAP/caffeine/pyrilamine APAP/doxylamine/dextromethorphan APAP/phenylephrine/dextromethorphan APAP/doxylamine/phenylephrine/dextromethorphan
Common brand names
Strengths per unit dose (mg)
Tylenol #2, #3, #4 Vicodin, Lortab Norco Percocet, Roxicet Endocet, Tylox Darvocet Ultracet Fioricet, Fioricet-C N/A
APAP, 325; codeine, 15 or 30 or 60 APAP, 325 or 500; hydrocodone, 5 or 7.5 or 10
Tylenol PM Excedrin AF Tylenol Sinus Excedrin Midol Nyquil Nighttime Nyquil liquicaps Dayquil Nyquil liquid
APAP, 500; diphenhydramine, 25 APAP, 500; caffeine, 65 APAP, 500; pseudoephedrine, 30 APAP, 250; ASA, 250; caffeine, 65 APAP, 500; caffeine, 60; pyrilamine, 15 APAP, 325; doxylamine, 6.25; DXM, 10*
APAP, 325 or 500; oxycodone, 5 or 7.5 or 10 APAP, 325 or 650; propoxyphene, 50 or 100 APAP, 325; tramadol, 37.5 APAP, 325; butalbital, 50; caffeine, 40; codeine, 30 N/A
APAP, 325; phenylephrine, 5; DXM, 10* APAP, 325; doxylamine, 6.25; phenylephrine, 10/; DXM, 15
APAP, acetaminophen; DXM, detromethorphan; N/A, not applicable. *Variable formulations and strengths. Examples only.
from ingestion of APAP combination products were due to APAP toxicity or due to the toxicity of the other ingredient(s) in the product.
Methods A retrospective analysis of deaths associated with exposures to APAP combination products reported to the AAPCC NPDS from 1/1/2000 to 12/31/2009 (10 years) was conducted. Calls to poison centers range from simple requests for information to life-threatening poisonings. Every call is recorded in an electronic database that is uploaded into NPDS regularly. A reported exposure is considered a case. Each case will have one coded medical outcome at its conclusion; there are a total of 10 possible medical outcomes. All cases with the medical outcome ‘death’ have additional information entered into the NPDS Fatality module by the poison center medical director. In this module, a separate series of coded fields and a narrative abstract – similar to hospital discharge summaries – are completed. The most important components of the coded fields are the relative contribution to fatality (RCF) and the hierarchy of substances. The possible RCFs are the following: undoubtedly responsible, probably responsible, contributory, probably not responsible, clearly not responsible, unknown, and coding error.5 The RCF is applied to the first substance in the hierarchy of substances in the AAPCC Fatality Table. All deaths are reviewed by two independent reviewers from the AAPCC Fatality Review Team for accuracy and completeness, with special attention paid to the RCF and hierarchy of substances. This review process is illustrated in Fig. 1.
Narrative abstracts were requested for APAP combination product-only cases identified by manual search of fatality tables from all the AAPCC annual reports for the study period. Original poison center records or medical records were not requested. In addition, investigators accessed the coded fields that accompany all narrative abstracts: age, gender, coded substance and hierarchy, chronicity, route of administration, reason for exposure (therapeutic error, suicide, etc.), RCF, and pre-hospital arrest. Inclusion criteria were as follows: death involving any APAP combination product found in the fatality table of the AAPCC Annual Report. Deaths involving more than one APAP combination product were included. Exclusion criteria were as follows: presence of life-threatening co-morbid conditions felt to contribute to the fatality; co-ingestion of additional medications other than APAP combination products discovered upon review of abstract; fatality deemed by raters as not related to APAP combination product (i.e., raters disagreed with AAPCC NPDS Fatality Review team); routes other than oral; and missing information (e.g., absent history, only pills found on the deceased, absent postmortem toxicological analyses for persons found dead on scene). Three examples of fatality abstracts are provided in Supplementary material Appendix 1 to be found online at http://informa healthcare.com/doi/abs/10.3109/15563650.2013.848282. The host university IRB deemed the study not human subject research. Each narrative abstract was analyzed in detail by two of the authors for the following: reason for exposure, exposure chronicity, APAP-product identification, past medical history, past history of ethanol or drug abuse; clinical effects; laboratory results; therapeutic interventions; and Clinical Toxicology vol. 51 no. 10 2013
Deaths from APAP Combination products 943 Exposure with medical outcome ‘death’ uploaded automatically to NPDS Fatality module
Mandatory coding of relative contribution to fatality and narrative write up by poison center medical director.
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
AAPCC Fatality Review team reviews all coding of relative contribution to fatality and all narrative abstracts.
Discussion between poison center medical director and AAPCC Fatality Review Team until agreement is reached on relative contribution to fatality and narrative.
Undoubtedly responsible OR Probably responsible OR Contributory
Probably not responsible OR Clearly not responsible OR Unknown
Published in Table 21 of AAPCC annual report
Not published in Table 21
Manual query Table 21 from annual reports from 2000–2009 Identification of fatalities related to acetaminophen combination product exposures
Independent review by 4 raters to determine if APAP or other ingredients was the putative cause of death Acetaminophen Other Ingredient(s) Unable to determine Not due to acetaminophen combo
Fig. 1. Flowchart of NPDS fatality review process and study procedure.
hospitalizations and hospital transfers. Four investigators (two poison center medical directors board-certified in medical toxicology, one poison center pharmacist–toxicologist, and one pharmacist toxicology fellow) independently read each narrative abstract and categorized the causes of death as most likely due to: APAP; other ingredient(s); or unable to determine. Investigators utilized a rubric with defined criteria to attribute death to APAP, opioids (non-propoxyphene), propoxyphene, butalbital, dextromethorphan, antihistamines, aspirin, caffeine, and/or decongestants. Given the brief nature of abstracts, it was impossible to require that all pre-defined criteria for a given drug be met. Therefore, a majority of criteria in one box Copyright © Informa Healthcare USA, Inc. 2013
were deemed sufficient to establish causality (see Supplementary material Appendix 2 to be found online at http:// informahealthcare.com/doi/abs/10.3109/15563650.2013. 848282). Training with ten fatality abstracts was conducted, and performance was assessed and rubrics were refined prior to the start of the study. Agreement between at least three of the four raters was considered sufficient to assign causality. The research team met to resolve disputes and maintain consistency in the assessment of putative cause of death. Suicide was defined as intentional ingestion of the product to take one’s life. Nonmedical use was defined as intentionally taking more than the prescribed dose of an APAP
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
944
S. Doyon et al.
prescription product or more than the recommended dose of an OTC APAP combination product; taking a product prescribed for another individual; documented misuse or abuse of a prescription or OTC product; use that resulted in an ED visit or a call to a poison center for overmedication (i.e., patient taking too much). Nonmedical use did not include suicides, therapeutic errors and malicious intent. This broad definition of nonmedical use was adapted from the Drug Abuse Warning Network (DAWN) Substance Abuse and Mental Health Services Administration (SAMHSA) glossary.9 Therapeutic error was defined as unintentional deviation from the therapeutic regimen that resulted in the wrong dose, administration to the wrong person, administration of the wrong product, or drug–drug interaction.10 Acute was defined as single, repeated, or continuous exposure occurring over a period of 8 h or less; acute-on-chronic as single exposure preceded by a continuous, repeated, or intermittent exposure occurring over a period exceeding 8 h; and chronic as continuous, repeated or intermittent exposure to the same substance lasting longer than 8 h.10 Quantitative data were summarized by medians and categorical data by frequencies. Chi-square test was used to compare past medical history, products involved, and chronicity of exposure. To compare chronicity of exposure, unknown time was combined with chronic because of the small numbers. A figure illustrating the type of APAP combination product involved in fatality by year was generated by performing a count of prescription and OTC products in the included cases. Cases in which both a prescription and OTC APAP combination product were ingested appear in both curves in the figure. Fleiss’ Kappa test was utilized to assess interrater agreement. For interpreting kappa values, an accepted set of magnitude guidelines was used. Values ⬍ 0 indicated no agreement; 0–0.2, a slight agreement; 0.21–0.4, a fair agreement; 0.41–0.6, a moderate agreement; 0.61–0.8, a substantial agreement; and 0.81–1.0, as almost perfect agreement between observers.11
Results Manual search of the fatality tables from AAPCC annual reports 2000–2009 yielded 413 deaths related to exposure to APAP combination products, of which 337 cases met inclusion criteria (Fig. 1). Excluded cases were the following: co-morbid conditions (52) (e.g., hepatitis C, cirrhosis, and pulmonary embolus), co-ingestions (16) (e.g., cyclic antidepressants, salicylates, and phenytoin), missing information (7), and intravenous (1). Of the 337 cases, 17 (5.0%) died in the pre-hospital setting or upon presentation to the emergency department, and 320 (95.0%) died in-hospital. The median age was 42 years (range, 2–89 years) and 68.3% were women. The majority, 204 (60.5%), of deaths were suicides. One death resulted from an unsupervised ingestion in a child. Two pregnant women (each in second trimester) died following nonmedical use of combination products. The fetuses did not survive and were not included in the analysis. A past medical history of cancer or pain was
encountered in 20 persons who committed suicide and in 54 persons who died following nonmedical use. Examples of pain were as follows: back pain, migraine, nontraumatic dental conditions, pancreatitis, endometriosis, fibromyalgia, inflammatory bowel disease, post-surgical pain, combat wounds, bone fractures, rheumatoid arthritis, and temporomandibular joint pain. A history of chronic use was present in 0.5% of suicides and 69% of deaths from nonmedical use, this result was statistically significant. Table 2 summarizes the findings for the 337 deaths. Figure 2 illustrates the number of deaths associated with ingestions of the prescription versus OTC combination products over time. The ingestions of prescription combination products increased by 80% in 2008–2009 compared to that in 2001–2003. The Fleiss Kappa agreement on putative cause of death was 0.74, indicating substantial agreement between raters. Analysis of all 337 deaths revealed that the putative cause of death was APAP in 60.8%, ‘other ingredient(s)’ in 29.7%, and ‘unable to determine’ in 9.5% of cases. Table 3 looks at the 317 deaths from ingestion of one single combination product. One unsupervised ingestion in a child was not included in the table. Of these 317 deaths, APAP/opioid was the most commonly ingested product. APAP/opioid was ingested in 109 (55.1%) cases of suicides and 66 (79.5%) cases of deaths from nonmedical use. The most common putative cause of death was APAP in 109 (55.1%) of suicides and 67 (80.7%) of deaths from nonmedical use. The two previously-described pregnant women used APAP/hydrocodone nonmedically (one misuse for back pain; the other, abuse) and died of APAP-induced liver failure. APAP/ propoxyphene was involved in a total of 41 deaths, 31 suicides, 6 deaths from nonmedical use, and 4 deaths with unknown reason for exposure. The putative cause of death was propoxyphene in 25/31 (80.6%) suicides, 3/6 (50.0%) deaths from nonmedical use, and ¾ (75%) deaths with unknown reason for exposure. Of these 41 deaths, seizures and electrocardiographic abnormalities (QRS or QTc prolongation) were reported in 9 (22.0%) and 9 (22.0%) cases, respectively. Table 3 illustrates these findings. The deaths resulting from ingestions of two or more APAP combination products are found in Table 4. Of the 6 cases of suicides involving more than one APAP combination product, the putative cause of death was other ingredient(s) in 4(66.6%) of the cases. Of the 13 deaths from nonmedical use of more than one APAP combination product, APAP was the cause of death in 9 (69.2%) cases. Among the 320 patients who died in the hospital, 289 (90.3%) received N-acetylcysteine, 205 (64.1%) were intubated and mechanically ventilated, 153 (48.1%) received vasopressors, and 306 (95.6%) were admitted to the intensive care unit (ICU). Of the 237 hospitalized cases where the putative cause of death was APAP or ‘unable to determine’, 225 (94.9%) were treated with N-acetylcysteine and 107 (45.2%) were admitted/transferred to a liver transplantation unit. In most of the cases where N-acetylcysteine was administered, the time to administration was not documented (see Supplementary material Appendix 1 to be found online at Clinical Toxicology vol. 51 no. 10 2013
Deaths from APAP Combination products 945 Table 2. Comparison of fatal ingestions of acetaminophen combination products reported to poison centers.
Males (%) Median age and range, years Past medical history Cancer Pain Cancer or pain Ethanol abuse Substance abuse Prescription products APAP/Opioid APAP/Butalbital/Caffeine ⫾ Codeine Over-the-counter products APAP/DPH APAP ⫾ ASA ⫾ caffeine APAP ⫾ Antihistamine ⫾ Decongestant ⫾ Caffeine ⫾ DXM Chronicity¶ Acute (%) Acute-on-chronic (%) Chronic (%) Unknown (%)
Suicide n ⫽ 204 (%)
Nonmedical use n ⫽ 96 (%)
Therapeutic error n⫽3
Unknown reason n ⫽ 33 (%)
31.4 39 (14–89)
33.3 41 (17–71)
33.3 47 (31–78)
30.3 49 (31–74)
1 19 (9.3) 20 (9.8) 15 (7.4) 17 (8.3)
5 (5.2) 53 (55.2) 54 (56.3) 25 (26.0) 26 (27.1)
1 1 1 1 0
1 8 (24.2) 8 (24.2) 5 (15) 2
116 (56.9) 5 (2.5)
77 (80.2) 4
1 0
22 (66.7) 1
85 (41.6) 3 1
20 (20.8) 5 (5.2) 1 (1.0)
0 0 2
9 (27.2) 0 1
187 (91.6) 16 (7.8) 1 0
12 (12.5) 13 (13.5) 69 (71.9) 2
0 0 3 0
18 (54.5) 5 (15.1) 10 (30.3) 0
One pediatric unsupervised ingestion involving APAP/opioid not included in table. NOTE: Some cases have more than one APAP combination product so total products are ⬎ 337 cases. p ⬍ 0.0001 using chi-square test comparing suicides to nonmedical use. APAP, acetaminophen; DPH, diphenhydramine; ASA, acetylsalicylic acid; DXM, dextromethorphan. Nonmedical use: intentionally taking more than the prescribed or recommended dose of a product; taking a product prescribed to another individual; or documented misuse or abuse of a product.
http://informahealthcare.com/doi/abs/10.3109/15563650. 2013.848282).
Discussion Previous epidemiologic assessments of deaths due to APAPcombination products suffered from limitations such as broad diagnostic criteria, inclusion of unconfirmed cases, failure to account for concomitant use of APAP, other drugs or ethanol, failure to account for contributory medical conditions, and failure to estimate risk.1,6,7 The NPDS annual report Fatality Table provides data on exposure fatalities (Fig. 1). The rationale for extending the 45 40 Number of Fatalities
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Reason for exposure
35
OTC Rx
30 25 20 15 10 5 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Time (year)
Fig. 2. Distribution over time of the fatalities involving acetaminophen combination products included in this study (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx). Copyright © Informa Healthcare USA, Inc. 2013
analysis beyond the NPDS Fatality Table was that patients who die of opioid-induced anoxic brain injury and patients who die from APAP-induced hepatic failure, each following ingestion of APAP/opioid products, are coded identically in the table, and it is only by analyzing the narrative, reviewing the clinical effects, laboratory data and treatments, that the putative cause of death can be determined. The fatality abstracts used in this analysis were written for, and independently reviewed by, the AAPCC Fatality Review team, yielding workable case summaries. The methodology used in this study addressed some of the previously mentioned shortcomings by including cases where the combination product(s) were listed as the only substance(s) in the hierarchy of substances, excluding cases in which co-ingestants and co-morbid conditions might have contributed to the death, maximizing accuracy in product identification and route of administration, and requiring laboratory confirmation, modified King’s College criteria, or postmortem examination for the diagnosis of APAP toxicity.8,12 As a result, 337 fatality abstracts were analyzed, including 204 suicides, 96 deaths from nonmedical use, 33 deaths where the reason for exposure was unknown, 3 deaths resulting from therapeutic errors, and 1 unsupervised ingestion in a child. Figure 2 illustrates how deaths associated with prescription APAP combination products outpaced deaths from OTC products in the study cases, in clear contrast to manufacturers’ reported retail sales data. Between 2004 and 2008, OTC APAP combination products sales grew 36% and prescription APAP combination products grew 25%.2
946
S. Doyon et al. Table 3. Putative causes of death from suicide, nonmedical use, therapeutic error, or unknown reason involving a single acetaminophen combination product. Putative cause of death Other ingredients
Unable to determine
2 29 (50.0) 2 (13.3) 5 (16.1) 0 1 68 (82.9) 0
1 15 (25.8) 11 (73.3) 25 (80.6) 1 2 9 (10.9) 1
0 14 (24.1) 2 1 1 0 5 (6.1) 0
2 109 (55.1)
1 66 (33.3)
0 23 (11.6)
4 37 (88.1) 9 (64.3) 3 12 (85.7) 2 67 (80.7)
0 4 4 3 1 0 12 (14.5)
0 1 1 0 1 1 4
1 1 2
0 0 0
0 1 1
1 8 2 3 0 6 0 1
0 3 2 1 1 2 1 0
0 1 0 0 0 1 0 0
21 (63.6) 199 (62.8)
10 (30.3) 88 (27.8)
2 30 (9.5)
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
APAP Reason for exposure: Suicide n 198 APAP/codeine n ⫽ 3 APAP/hydrocodone n ⫽ 58 (%) APAP/oxycodone n ⫽ 15 (%) APAP/propoxyphene n ⫽ 31 (%) APAP/other opioid n ⫽ 2 APAP/butalbital/caffeine ⫾ codeine n ⫽ 3 APAP/DPH** n ⫽ 82 (%) APAP/antihistamine/decongestant/caffeine/ dextromethorphan** n ⫽ 1 APAP ⫾ ASA ⫾ caffeine** n ⫽ 3 Total n 198 Reason for exposure: Nonmedical use n 83 APAP/codeine n ⫽ 4 APAP/hydrocodone n ⫽ 42 (%) APAP/oxycodone n ⫽ 14 (%) APAP/propoxyphene n ⫽ 6 (%) APAP/DPH** n ⫽ 14 (%) APAP ⫾ ASA ⫾ caffeine † n ⫽ 3 Total n 83 Reason for exposure: Therapeutic Error n 3 APAP/hydrocodone n ⫽ 1 APAP/antihistamine/decongestant/caffeine/DXM** n ⫽ 2 Total n 3 Reason for exposure: Unknown reason n 33 APAP/codeine n ⫽ 1 APAP/hydrocodone n ⫽ 12 APAP/oxycodone n ⫽ 4 APAP/propoxyphene n ⫽ 4 APAP/other opioid n ⫽ 1 APAP/DPH** n ⫽ 9 APAP/butalbital/caffeine n ⫽ 1 APAP/antihistamine/decongestant/dextromethorphan** n⫽1 Total n 33 GRAND TOTAL n 317
**: over-the-counter product. One case of unsupervised pediatric ingestion of acetaminophen/hydrocodone that died from the hydrocodone effects was not included in table. APAP: acetaminophen; DPH: diphenhydramine; ASA: acetylsalicylic acid; DXM: dextromethorphan Nonmedical use: intentionally taking more than the prescribed or recommended dose of a product; taking a product prescribed to another individual; or documented misuse or abuse of a product.
This is a study of critically ill patients who died despite receiving care. Of those who received care in the hospital, 306 (95.6%) were admitted to the ICU and 107 (33.4%) were transferred to liver transplantation centers. Approximately 90% received N-acetylcysteine suggesting that most had suspected or confirmed APAP toxicity, and most (68%) were women. These data correlate well with other assessments of hospitalizations for APAP-induced liver injury.6 For reasons that are unclear, women predominate among patients with drug-induced liver injury and, in one prospective study from 17 tertiary care centers, accounted for 79% of APAP-induced liver failure patients.13 The high frequency of pain and drug abuse in the nonmedical use group was expected, as was the
finding of chronic ingestions. In all, these data suggest that the population studied was largely representative of previously described populations.13–16 The most common combination products involved in all manners of deaths were APAP/opioid. The most common single product was APAP/diphenhydramine in suicides and APAP/hydrocodone in deaths from nonmedical use. These findings are not surprising. APAP/diphenhydramine products are available OTC in both brand-name and generic forms, are heavily marketed to the consumer, and are readily available in US households. APAP/hydrocodone products are frequently used for the treatment of pain because they are easier to prescribe due to their less restrictive Controlled Clinical Toxicology vol. 51 no. 10 2013
Deaths from APAP Combination products 947
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Table 4. Putative causes of deaths from suicide or nonmedical use involving more than one acetaminophen combination product.
Reason for exposure: Suicide n 6 APAP/codeine ⫹ APAP/hydrocodone APAP/propoxyphene ⫹ APAP/oxycodone APAP/codeine ⫹ APAP/ASA/butalbital APAP/DPH ⫹ APAP/propoxyphene APAP/DPH ⫹ APAP/hydrocodone APAP/DPH ⫹ APAP/propoxyphene ⫹ APAP/ hydrocodone Total n 6 Reason for exposure: Nonmedical use n 13 APAP/hydrocodone ⫹ APAP/codeine APAP/hydrocodone ⫹ APAP/propoxyphene APAP/hydrocodone ⫹ APAP/butalbital/caffeine APAP/hydrocodone ⫹ APAP/DPH APAP/hydrocodone ⫹ APAP/ASA/caffeine APAP/hydrocodone ⫹ APAP/caffeine APAP/propoxyphene ⫹ APAP/DPH APAP/DPH ⫹ APAP/pyrilamine/caffeine APAP/DPH ⫹ APAP/pseudoephedrine APAP/DPH ⫹ APAP/dextromethorphan/ /pseudoephedrine Total n 13
APAP
Other active ingredient
0 0 0 0 1 1
1 1 1 1 0 0
2
4
1 0 1 2 1 1 1 1 1 0
0 1 0 1 0 0 0 0 0 1
9
3
APAP, acetaminophen; DPH, diphenhydramine; ASA, acetylsalicylic acid. One death from nonmedical use APAP/hydrocodone ⫹ APAP/propoxyphene not included in table. It was in the ‘unable to determine’ category. Nonmedical use: intentionally taking more than the prescribed or recommended dose of a product; taking a product prescribed to another individual; or documented misuse or abuse of a product.
Substance Act C-III status compared to other APAP/opioids, and they, too, are readily available in many US households. Among suicides, APAP was the putative cause of death in 83% of cases if APAP/diphenhydramine was involved, but in only 35% of cases if APAP/opioid was involved (Table 3). These data could suggest a pharmacokinetic or dynamic interaction between APAP and diphenhydramine but more likely are explained by the severity of opioid toxicity in the APAP/opioid group, where death from respiratory arrest and anoxic brain injury occurred before hepatotoxicity from APAP. Of the deaths from nonmedical use, the vast majority died from APAP-induced hepatic failure regardless of the APAP product involved, although APAP/opioids were involved most frequently (80%). These data suggest that tolerance to the opioid may have protected the patients from respiratory arrest and anoxic brain injury but that self-escalation of doses as well as dependence may have contributed to hepatic failure and death. Tolerance is defined as the reduction in response following repeated administrations. Thus, when tolerance develops, a higher dose of a drug is required to produce the same effect.17 Dependence is a state that develops as a result of the adaptation produced by resetting of homeostatic mechanisms.17 The person with opioid dependence requires continued administration of the opioid to maintain normal function; if administration is abruptly Copyright © Informa Healthcare USA, Inc. 2013
stopped, the person experiences withdrawal. It is recognized that the dose (amount and duration) of APAP is a more important determinant of hepatotoxicity than the host’s metabolic constitution.16 In this study, APAP was the putative cause of death in 80.7% of deaths from nonmedical use likely related to chronic escalation in doses resulting in opioid tolerance and dependence. In 2011, a national audit of total prescriptions dispensed revealed that APAP/hydrocodone was the most frequently prescribed medication in the United States, with 136 million prescriptions dispensed per year. The second most commonly dispensed opioid medication was tramadol-only (32.9 million) followed by APAP/oxycodone (32.8 million).4 The popularity of APAP/hydrocodone over APAP/oxycodone is reflected in the number of suicides (58 vs 15) and deaths from nonmedical use (42 vs 14). Early in the decade, APAP/propoxyphene was very popular. In 2003, APAP/propoxyphene was the second most commonly prescribed opioid, behind APAP/hydrocodone.1 There were 31 suicides from APAP/propoxyphene and 6 deaths from nonmedical use during the study period. The putative cause of death was propoxyphene in the greater majority of these cases, largely related to the neuro- and cardiotoxicity of propoxyphene. These data support the 2010 FDA decision to recommend the withdrawal of propoxyphene from the US market.18 Thirteen deaths were related to nonmedical use of more than one combination product. In many instances, patients mixed two OTC cough and cold products or mixed one migraine product with one APAP/opioid. In both scenarios, the putative cause of death was most likely APAP (69.2%), although this result is limited by the low numbers of multiple product ingestions in our data set. Misunderstanding of the active ingredients and lack of awareness regarding co-administration of APAP is common, particularly among heavy users and those with limited literacy, and could have contributed to these findings.19 Government and industry have recently drawn attention to the problem of combination medications that contain APAP.20,21 In 2009, a 37-member FDA Advisory Committee voted to eliminate prescription APAP combination products and seven members of this committee felt that this alone could be the single most important intervention that would result in a decrease in APAP-related toxicity.22 The data presented in this study support this recommendation. Study limitations include the retrospective design and use of fatality abstracts. Exposure deaths are underreported to poison centers.23 Poison centers may be preferentially contacted regarding APAP-related toxicity and contacted to a lesser degree regarding opioid-related toxicity. The use of very strict inclusion/exclusion criteria resulted in reduced number of cases. Patients who died in the pre-hospital setting were less likely to be reported to a poison center; patients with rapid death after acute ingestion would be due to the other active ingredient.23 Identification of the APAP product was not independently confirmed. Lastly, liver injury resulting from intractable hypotension is at times impossible to distinguish from APAP-induced liver injury.
948
S. Doyon et al.
Conclusions
Clinical Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Fatal overdoses involving APAP combination products reported to US poison centers are on the rise. This examination of 337 deaths resulting from ingestion of APAP combination products reported to US poison centers reveals that most common presumed cause of death was APAP. APAP is a particularly important putative cause of death in patients who use combination products nonmedically.
5.
6.
Disclaimer
7.
The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) maintains the national database of information logged by the country’s 57 Poison Centers (PCs). Case records in this database are from self-reported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g., an ingestion, inhalation, or topical exposure, etc.), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCs, and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).
8.
Acknowledgement The authors would like to acknowledge Yoland Tra, PhD for her help with statistical analysis.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
9.
10. 11. 12.
13.
14.
15.
16. 17.
18.
References 1. Wysowski DK, Governale LA, Swann J. Trends in out-patient prescription drug use and related costs in the US 1998-2003. Pharmacoeconomics 2006; 24:233–236. 2. Dal Pan GJ. Office of Surveillance and Epidemiology Center for Drug Evaluation and Research June 29, 2009. Available from: http://www.fda. gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ UCM175767.pdf. Accessed October 27, 2012. 3. Michna E, Sheng M, Korves C, Dahl JL. Removal of opioid/ acetaminophen combination prescription medications: assessing the evidence for hepatotoxicity and consequences of removal of these medications. Pain Medicine 2010; 11:3269–378. 4. IMS HEALTH. IMS National Prescription AuditTM. Available from: http://www.imshealth.com/deployedfiles/ims/Global/Content/
19.
20. 21. 22. 23.
Corporate/Press%20Room/Top-Line%20Market%20Data%20&%20 Trends/2011%20Top-line%20Market%20Data/Top_Products_by_ RX.pdf. Accessed June 2013 Bronstein AL, Spyker DA, Cantilena LR, Green JL, Rumack BH, Dart RC. 2010 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clin Toxicol 2011; 49:910–941. Karwoski CB. Briefing document: Acetaminophen containing products and hepatotoxicity. Division of Drug Risk Evaluation. August 2 2002. Available from: http://www.fda.gov/ohrms/dockets/ ac/02/briefing/3882b1_02_C-Acetaminophen%20Hepatotoxicity.pdf. Accessed October 2012 Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis 2007; 11: 525–548. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–443. Drug Abuse Warning Network, Substance Abuse and Mental Services. http://www.samhsa.gov/data/2k12/DAWN2k10/DAWN2k10Glossary.htm. Accessed June 2013 NPDS Reference manual 2009. Available from: http://www.aapcc. org/data-system/. Accessed May 2013. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33:159–174. Reynolds KM, Green RC, Dart RC, Bucher-Bartelson B, Khatri V. Overall quality of poison center data for acetaminophen-containing products is high, but coding of product-specific fields needs improvement. Clin Toxicol 2012; 50:620. (abstract) Ostapowich G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, et al. Results of a retrospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947–954. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study group. Drug-induced acute liver failure: results of a US multicenter, prospective study. Hepatology 2010; 52:2065–2076. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al.; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364–1372. Lee WM. Drug-induced hepatotoxicity. NEJM 2003; 349:474–485. O’Brien CP. Drug addiction. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011:652–654. Woodcock J. FDA Center for Drug Evaluation and Research. November 2010 Memorandum. Available from: http://www.fda.gov/ downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/UCM234349.pdf. Accessed May 2013. Wolf MS, King J, Jacobson K, Di Francesco L, Bailey SC, Mullen R, et al. Risk of unintentional overdose with nonprescription acetaminophen products. J Gen Intern Med 2012; 27: 1587–1593. Woodcock J, Griffin JP, Behrman RE. Development of novel combination therapies. New Engl J Med 2011; 364:985–987. Podolsky SH, Greene JA. Combination drugs- hype, harm and hope. New Engl J Med 2011; 365:488–491. FDA. Available from: http://www.regulations.gov/#!documentDetail; D ⫽ FDA-2011-N-0021-0001. Accessed December 2012 Doyon S, Fowler D. Comparison of exposure fatalities from the medical examiner’s office and the poison center. Clin Toxicol 2012; 50:645 (abstract)
Supplementary material available online Supplementary Appendix 1 & 2.
Clinical Toxicology vol. 51 no. 10 2013
