Clinical Toxicology (2015), 53, 477–485 Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2015.1027903

POISON CENTRE

Comparison of lisdexamfetamine and dextroamphetamine exposures reported to U.S. poison centers* Mingzohn Ellen Kaland# and Wendy Klein-Schwartz

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Department of Pharmacy Practice and Science, Maryland Poison Center, University of Maryland School of Pharmacy, Baltimore, MD, USA­

Context. Lisdexamfetamine is a pro-drug stimulant that requires the enzymatic hydrolysis of lysine from dexamphetamine for pharmacologic effects. There is limited information comparing non-therapeutic lisdexamfetamine and dextroamphetamine exposures. Objective. The objective was to compare lisdexamfetamine exposures with dextroamphetamine/amphetamine extended release and dextroamphetamine/ amphetamine immediate release. Methods. A retrospective observational case series of single-substance exposures to lisdexamfetamine, dextroamphetamine/amphetamine extended release, or dextroamphetamine/amphetamine immediate release reported to the National Poison Data System from 2007 to 2012 was performed. Data were analyzed for demographics, reason, clinical effects, management site, and outcomes. Results. There were 23,553 exposures: lisdexamfetamine (7,113), dextroamphetamine/amphetamine extended release (6,245), and dextroamphetamine/amphetamine immediate release (10,195). The most frequent clinical effects observed for lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release were agitation (19.8%, 21.7%, and 25.1%, respectively) and tachycardia (19.2%, 22.8%, and 23.9%, respectively). The reason was most often exploratory (93.4%) in children  6 years and therapeutic error (65.6%) in children aged 6–12 years. In adolescents and adults most common reasons were suicide attempts (28.4%) followed by abuse (19.5%) and therapeutic errors (18.8%). Overall, 61.6% of cases were managed in a health care facility, with the majority treated in the emergency department only. The majority of cases (76.0%) experienced no or minor effects. More serious outcomes (moderate/major/death) occurred in 21.2% of lisdexamfetamine, 24.7% of dextroamphetamine/amphetamine extended release, and 25.5% of dextroamphetamine/amphetamine immediate release. There were 4 deaths (1 dextroamphetamine/amphetamine extended release and 3 dextroamphetamine/amphetamine immediate release). In patients aged 6 years and more, abuse/misuse was more frequently reported for dextroamphetamine/amphetamine immediate release (32.5%) and dextroamphetamine/amphetamine extended release (23.0%) than that for lisdexamfetamine (13.5%). The odds of abuse/misuse was 2.3 (95% confidence interval [CI]: 2.0–2.4) times higher for dextroamphetamine/amphetamine immediate release than that for lisdexamfetamine and dextroamphetamine/amphetamine extended release combined; the odds of dextroamphetamine/amphetamine extended release abuse/misuse was 1.9 (95% CI: 1.7–2.2) times higher than lisdexamfetamine. In 2011, the number of lisdexamfetamine abuse/misuse cases exceeded dextroamphetamine/amphetamine extended release by approximately 26% and plateaued in 2012, but was significantly lower (∼75%) than dextroamphetamine/amphetamine immediate release. Conclusions. Toxic effects were similar for all three drugs. Although the majority of cases were treated at health care facilities, the majority of patients experienced no effects or minor toxicity. Serious outcomes occurred in approximately 21% of lisdexamfetamine and 25% of dextroamphetamine/amphetamine extended release and dextroamphetamine/amphetamine immediate release. Lisdexamfetamine may have less abuse potential, especially compared with the immediate-release dextroamphetamine/amphetamine formulation. Keywords  ADHD; Overdose; Toxicity; Abuse

Introduction

since 2007, lisdexamfetamine is the first prodrug stimulant marketed in the United States. The inert parent compound requires enzymatic hydrolysis of the lysine from dexamphetamine before exhibiting pharmacologic effects.1 This allows for the active metabolite, dextroamphetamine, to inhibit the reuptake of dopamine (DA) and norepinephrine (NE) and to facilitate their release.2 Utilizing a prodrug formulation, the peak plasma concentration of lisdexamfetamine-derived dextroamphetamine after a therapeutic dose has been observed to be lower and delayed 3–6 h post ingestion, with clinical effects lasting up to 13–14 h.1 This effect on pharmacokinetics allows for convenient once-a-day dosing of this medication as well as possibly a decreased potential for abuse.3

(Vyvanse®)

Lisdexamfetamine dimesylate is a once-aday treatment for attention deficit hyperactivity disorder (ADHD) in patients aged 6 years or more. Approved for use Received 24 November 2014; accepted 5 March 2015. *Poster presentation at North American Congress of Clinical Toxicology, New Orleans, LA, October 2014. #Research completed during Clinical Toxicology Fellowship at Maryland Poison Center (2012–2014). Address correspondence to Wendy Klein-Schwartz, Maryland Poison Center, University of Maryland School of Pharmacy, 220 Arch Street, Office level 1, Baltimore, MD 21201, USA. Tel: (410) 563-5581. E-mail: [email protected]

477

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478  M. E. Kaland & W. Klein-Schwartz Currently, there is limited published literature comparing the safety of both lisdexamfetamine and dextroamphetamine in exploratory/unintentional exposures in pediatric patients and intentional exposures by adults. Although unintentional pediatric ingestions of dextroamphetamine in 118 patients aged 8 months to 7 years led to favorable outcomes, 84% of the patients who were naïve to the medication developed clinical symptoms and were treated in a health care facility (HCF).4 Therapeutic use of lisdexamfetamine in children aged 6–12 and adolescents aged 13–17 years led to mild or moderate adverse effects that commonly include insomnia, irritability, weight loss, and affect lability.5,6 The primary objective of this study was to compare medical outcomes, clinical effects, and level of care of lisdexamfetamine versus dextroamphetamine/amphetamine extended release and immediate release exposures. The secondary objectives of this study were to compare the severity of exposure based on age, and the frequency of abuse and intentional misuse of lisdexamfetamine versus dextroamphetamine/ amphetamine extended release and dextroamphetamine/ amphetamine immediate release.

Methods A retrospective observational case series of single-product human exposure cases to lisdexamfetamine, dextroamphetamine/amphetamine extended release, or dextroamphetamine/amphetamine immediate release reported to the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS) between January 2007 and December 2012 and followed to known outcome was performed. NPDS comprises data that are collected from U.S. poison centers. During a consultation with a poison specialist by either the general public or a health care professional, data are collected, coded, and then uploaded electronically to NPDS in real time. Coded data include age, gender, reason for exposure, product, clinical effects, management site (e.g., non-HCF, emergency department [ED], and critical care unit), and medical outcomes. Poison center coding of known medical outcomes include no effect, minor effect, moderate effect, major effect, and death.7 Patients with minor outcomes have some minimally bothersome signs or symptoms as a result of the exposure. Moderate outcomes include signs or symptoms that were more pronounced, more prolonged, or more systemic than minor symptoms and usually some form of treatment is indicated. Major outcomes exhibit signs or symptoms that were life threatening or resulted in significant residual disability or disfigurement. The medical outcome is determined at the end of the case and is dependent on severity of clinical effects. The data entry system has validation checks to confirm the outcome matches the clinical effect severity; if a validation problem is identified the specialist is alerted when attempting to close the case. Fatality abstracts were obtained and reviewed for clinical details regarding the deaths. Poison centers are required to submit fatality abstracts which are judged by the AAPCC Fatality Review Team for relative contribution to fatality (RCF). An exposure-related fatality is an exposure

judged as being at least contributory to the death. The RCF classifications for which the exposure is considered wholly or partially responsible for the death are undoubtedly responsible, probably responsible and contributory. NPDS was searched for Poisindex (Micromedex Healthcare Series) product codes of commercially available lisdexamfetamine, dextroamphetamine/amphetamine extended-release, or dextroamphetamine/amphetamine immediate-release products on the U.S. market. Thirteen lisdexamfetamine codes (brand and generic) and 156 dextroamphetamine/amphetamine codes (brand and generic for extended release and immediate release) were identified and used to search for lisdexamfetamine, dextroamphetamine/ amphetamine extended release, or dextroamphetamine/ amphetamine immediate release exposures. The majority of dextroamphetamine/amphetamine extended-release and dextroamphetamine/amphetamine immediate-release products contained a mixture of dextroamphetamine and amphetamines; a few were dextroamphetamine only. Confirmed non-exposure cases and exposures not followed to a known medical outcome were excluded from the data extraction. Chronic exposures or exposures of unknown chronicity to either product were excluded from the analysis. The data were evaluated for demographics, reason, clinical effects, management site, and medical outcomes. Unintentional reasons include unintentional general (e.g., exploratory) and dosing/therapeutic error. Intentional reasons include suicide attempt, abuse, and misuse. Additional reasons include adverse reaction and unknown reason. When an exposure was the result of a dosing/therapeutic error, scenarios (i.e., reason for the error) were evaluated. Only coded data were available; therefore, the free text was not reviewed. This study was granted exempt status by the university Institutional Review Board. Categorical data were summarized as frequencies and proportions and analyzed by Pearson chi-square with Bonferroni adjustment for multiple comparisons. For data on management site, outcome and reason in Tables 3 and 4, stratified analysis was performed with the Mantel–Haenszel (MH) strategy to control for age. A log-linear model through the procedure PROC CATMOD in SAS was fit to the data. The null hypothesis of a general association was rejected at 5% level; the MH statistic QGMH was reported. For some statistical analyses, HCF management sites (treated in ED, admitted critical care unit, admitted non-critical care unit, and admitted psychiatry) were combined and compared with non-HCF. Unspecified sites were excluded from analysis. Analysis for an association between abuse/misuse and drug (lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release) was performed on patients aged 6 years or more. A Multinomial Discrete Choice (MDC) model was used to determine if there was a statistical significant difference between lisdexamfetamine, dextroamphetamine/ amphetamine extended release, and dextroamphetamine/ amphetamine immediate release, with management sites and outcomes as dependent variables and age as a confounder. Additionally, to evaluate abuse/misuse patterns, a log-linear Clinical Toxicology vol. 53 no. 5 2015

Lisdexamfetamine and dextroamphetamine exposures  479 model was fit to describe the pattern of association among drug (lisdexamfetamine, dextroamphetamine/amphetamine extended release, dextroamphetamine/amphetamine immediate release), age, and reason (abuse/misuse vs. other reasons). Analysis of variance method examined if there was a significant interaction between drug and reason. The effects were tested using the PROC MDC procedure of SAS. All statistical analyses were performed using SAS software (version 9.2, SAS Institute, Cary, NC). Comparisons of the odds of abuse/misuse were performed using observed data. Odds ratios were reported with 95% confidence intervals (CIs).

There were 23,553 exposures that met inclusion criteria, of which 7,113 were lisdexamfetamine, 6,245 dextroamphetamine/amphetamine extended release, and 10,195 dextroamphetamine/amphetamine immediate release. A total of 222 lisdexamfetamine, 189 dextroamphetamine/amphetamine extended release, and 477 dextroamphetamine/amphetamine immediate release chronic exposure or unknown chronicity exposures cases were excluded from analysis. Figure 1 shows increasing numbers of dextroamphetamine/amphetamine immediate release and lisdexamfetamine cases over the study period with a slight decline in dextroamphetamine/ amphetamine extended release cases. Overall, there were more males than females exposed to lisdexamfetamine (60.6%), dextroamphetamine/amphetamine extended release (55.8%), and dextroamphetamine/ amphetamine immediate release (54.8%). Children less than 6 years of age comprised the largest single-age group (lisdexamfetamine: 35.8%, dextroamphetamine/amphetamine extended release: 41.5%, and dextroamphetamine/amphetamine immediate release: 51.8%). Table 1 displays a break2000 1800 Number of Exposures

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Results

1600 1400 1200 1000

down of age by drug. There was an association between drugs and age (c2  1610.4, p  0.0001) with more children aged 6–12 years taking lisdexamfetamine and more children aged 13–19 years taking dextroamphetamine/amphetamine extended release, and more adults taking dextroamphetamine/amphetamine immediate release. The most common reasons for exposure for all three drugs were unintentional general (exploratory in nature) accounting for 36.2% of lisdexamfetamine, 42.2% of dextroamphetamine/amphetamine extended release, and 52.0% of dextroamphetamine/amphetamine immediate release. The next most common reason was therapeutic error (lisdexamfetamine: 37.6%; dextroamphetamine/amphetamine extended release: 25.3%; and dextroamphetamine/amphetamine immediate release: 14.3%). For lisdexamfetamine, dextroamphetamine/amphetamine extended release and immediate release, respectively, the most frequent scenarios for therapeutic errors were inadvertently took medication twice (53.6%, 49.6%, and 34.1%), inadvertently took/given someone else’s medication (20.6%, 19.6%, and 28.2%), and wrong medication taken/given (15.4%, 14.2%, and 19.6%). There was a significant difference in the distribution of scenarios (c2  212.1, p  0.0001). For dextroamphetamine/ amphetamine immediate release “inadvertently took medication twice” occurred less than expected and “inadvertently took/given someone else’s medication” occurred more than expected. For lisdexamfetamine, more cases than expected ‘inadvertently took the drug twice’. Overall, clinical effects due to lisdexamfetamine, dextroamphetamine/amphetamine extended release, or dextroamphetamine/amphetamine immediate release were similar and included agitation, tachycardia, and hypertension. Severe/ life-threatening clinical effects occurred rarely, but were more commonly observed with dextroamphetamine/ amphetamine immediate release. Table 2 displays common clinical effects and severe clinical effects by drug. There was an association between drug and clinical effects overall (c2  30.1, p  0.0075) but not for common effects versus severe clinical effects (c2   3.9, p  0.1372). Compared with expected, hypertension occurred more often with dextroamphetamine/amphetamine extended release and agitation occurred more often with dextroamphetamine/amphetamine immediate release, while hypotension occurred less with lisdexamfetamine.

800 600

Table 1  Age breakdown by drug*.

400 200 0 2007

2008

2009

2010

2011

2012

Year LD

DXR

DIR

Fig. 1.  Trends in lisdexamfetamine and dextroamphetamine cases reported to U.S. poison Centers. LD, lisdexamfetamine; DXR, dextroamphetamine extended release; DIR, dextroamphetamine immediate release. Note: LD came into the U.S. market in 2007. Copyright © Informa Healthcare USA, Inc. 2015

Age (years)

LD n  7113 (%)

DXR n  6245 (%)

DIR n  10195 (%)

 6 6–12 13–19  20 years Unknown child Unknown age

2544 (35.8) 2167 (30.5) 1522 (21.4) 871 (12.2) 5 (0.07) 4 (0.06)

2593 (41.5) 1097 (17.6) 1394 (22.3) 1154 (18.5) 3 (0.05) 4 (0.06)

5284 (51.8) 981 (9.6) 1628 (16.0) 2284 (22.4) 4 (0.04) 14 (0.1)

­LD, lisdexamfetamine; DXR, dextroamphetamine extended release; DIR, dextroamphetamine immediate release. *Significant difference in age distribution between drugs, p  0.0001.

480  M. E. Kaland & W. Klein-Schwartz #

Table 2.  Clinical effects* by drug .

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LD DXR DIR n  7113 (%) n  6245 (%) n  10195 (%) Common clinical effects Agitation 1408 (19.8) Tachycardia 1363 (19.2) Hypertension 513 (7.2) Severe clinical effects Seizures 31 (0.44) Intracranial bleed 0 Dysrhythmias 15 (0.21) Conduction 17 (0.24) disturbances Bradycardia 2 (0.03) Hypotension 4 (0.06) Asystole/cardiac 0 arrest Respiratory 4 (0.06) depression Respiratory arrest 1 (0.01)

1356 (21.7) 1422 (22.8) 602 (9.6)

2562 (25.1) 2435 (23.9) 932 (9.1)

18 (0.29) 0 18 (0.29) 12 (0.19)

52 (0.51) 2 (0.02) 24 (0.24) 32 (0.31)

6 (0.10) 8 (0.13) 2 (0.04)

11 (0.11) 27 (0.26) 0

4 (0.06)

7 (0.07)

2 (0.03)

2 (0.02)

­LD, lisdexamfetamine; DXR, dextroamphetamine extended release; DIR, dextroamphetamine immediate release. *Clinical effects are from the NPDS coding options available at the time of case documentation by the poison center. #Significant difference in clinical effects distribution between drugs, p  0.0075.

Overall, 61.6% of cases were managed in an HCF, with the majority of these patients treated and released from the ED. A relatively small number of patients in each group were admitted to the critical care unit or a general medical floor. The majority of cases for lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release had no or minor effects. However, moderate and major effects occurred more frequently in dextroamphetamine/amphetamine extended release and immediate release exposures. There were 4 deaths (1 dextroamphetamine/amphetamine extended release and 3 dextroamphetamine/amphetamine immediate release). The resulting estimates from the MDC model showed that drug had an effect on management site and outcome but not their interaction while the effect of age on this interaction was significant (p  0.001). The odds of being managed in an HCF versus non-HCF was 1.2 (95% CI: 1.1–1.3) times lower for lisdexamfetamine than that of dextroamphetamine/amphetamine extended release and immediate release combined. There were 23,352 cases with data on age (7,070 lisdexamfetamine; 6,191 dextroamphetamine/amphetamine extended release; and 10,091 dextroamphetamine/amphetamine immediate release). There was a significant association between age and reason (p  0.001); therefore, reason was not used as a confounder. Table 3 provides a breakdown of management site and outcome by age. Adjusting for age group, there were significant differences in distribution of both management sites and medical outcomes (p  0.001). The odds of being managed at an HCF versus non-HCF was 3.2 (95% CI: 2.9–3.5) times higher for  12 years of age compared with  6 years and 6–12 years combined, and 3.8 (95% CI: 3.4–4.1) times higher for patients  6 years compared with 6–12 or   12 years combined. There was a significant interaction between age, drug, and management

site (c2  220.1, p  0.0001) as well as between age, drug, and outcomes (c2  166.7, p  0.0001). After controlling for age group, drug and management site were strongly associated (QGMH  109.9, p  0.0001) as were drug and outcome (QGMH  54.8, p  0.0001). In children  6 years, exposures to lisdexamfetamine, dextroamphetamine/amphetamine extended release, or dextroamphetamine/amphetamine immediate release were overwhelmingly unintentional general, that is, exploratory in nature (93.4%); 4.8% were therapeutic errors. For all three drugs, just over half of the cases were treated and discharged from the ED. The next most common site was non-HCF. Although most children were asymptomatic or experienced minor effects, children who ingested lisdexamfetamine had a higher frequency of moderate or major effects (N  436, 17.2%) than those with dextroamphetamine/amphetamine extended release (N  342, 13.2%) and dextroamphetamine/ amphetamine immediate release (N  740, 14.0%). In children aged 6–12 years, the most common reason for exposure was therapeutic error, occurring most often with lisdexamfetamine (70.6%) followed by dextroamphetamine/ amphetamine extended release (66.5%) and dextroamphetamine/amphetamine immediate release (57.7%). This was followed by exploratory, which occurred more often with dextroamphetamine/amphetamine immediate release (16.2%), than dextroamphetamine/amphetamine extended release (12.9%) and lisdexamfetamine (10.7%). In this age group, non-HCF was the most frequent management site for all three products. Dextroamphetamine/amphetamine immediate release exposures were more often managed in the ED or HCF (44.5%) compared with those of dextroamphetamine/ amphetamine extended release (34.8%) and lisdexamfetamine (35.9%). Overall, outcomes were similar for lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release, with serious outcomes in 14.4% of lisdexamfetamine, 14.5% of dextroamphetamine/amphetamine extended release, and 15.1% of dextroamphetamine/amphetamine immediate release. In adolescents and adults (13 years or more) most exposures were suicide attempts (28.4%) and abuse (19.5%) followed by therapeutic errors (18.8%) and intentional misuse (5.8%). Adolescents and adults were most often managed in an HCF, regardless of the product. In this age group, lisdexamfetamine was more likely to be managed in a non-HCF and less likely to be admitted for medical care than dextroamphetamine/amphetamine extended release and dextroamphetamine/amphetamine immediate release. There were 4 fatalities following exposure to dextroamphetamine/ amphetamine extended release (1) and dextroamphetamine/ amphetamine immediate release (3). Two adults experienced cardiac arrests and could not be resuscitated after ingesting 24 dextroamphetamine/amphetamine pills in one case and an unknown number of extended-release dextroamphetamine/ amphetamine in the second case. Two adults presented with altered mental status (agitation and disorientation), diaphoresis, and hypertension. One had fallen and hit his head after ingesting an unknown number of capsules resulting in a massive intracranial bleed, underwent surgery to remove Clinical Toxicology vol. 53 no. 5 2015

Lisdexamfetamine and dextroamphetamine exposures  481 Table 3.  Management site and medical outcome stratified by age.*  6 years

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LD n  2544 (%) Management siteǂ Non-HCF ED treat/discharge Critical care admit Non-critical care admit Psych admit Other** Outcomeǂ No effect Minor Moderate Major Death

DXR n  2593 (%)

6–12 Years DXR n  1097 (%)

DIR n  981 (%)

LD n  2393 (%)

708 (27.8) 805 (31.1) 1750 (33.1) 1333 (61.5) 672 (61.3) 1405 (55.2) 1347 (52.0) 2725 (51.6) 641 (29.6) 303 (27.6) 145 (5.7) 124 (4.8) 265 (5.0) 40 (1.9) 33 (3.0) 219 (8.6) 252 (9.7) 389 (7.4) 79 (3.7) 40 (3.7)

502 (51.2) 349 (35.6) 28 (2.9) 43 (4.4)

833 (34.8) 883 (36.9) 191 (8.0) 143 (6.0)

663 (26.0) 735 (18.8) 944 (37.0) 1579 (40.4) 322 (12.6) 530 (13.6) 216 (8.5) 357 (9.1)

16 (1.6) 43 (4.4)

237 (9.9) 106 (4.4)

223 (8.8) 180 (7.1)

0 67 (2.6)

0 65 (2.5)

DIR n  5284 (%)

LD n  2167 (%)

 13 years

0 155 (2.9)

15 (0.7) 59 (2.8)

6 (0.6) 43 (3.9)

1419 (55.8) 1622 (62.6) 3073 (58.2) 1274 (58.8) 636 (58.0) 689 (27.1) 629 (24.3) 1471 (27.8) 580 (26.8) 313 (28.5) 416 (16.4) 327 (12.6) 712 (13.5) 300 (13.8) 147 (13.4) 20 (0.8) 15 (0.6) 28 (0.5) 13 (0.6) 1 (0.1) 0 0 0 0 0

552 (56.3) 281 (28.4) 142 (14.5) 6 (0.6) 0

DXR n  2548 (%)

DIR n  3912 (%)

414 (10.6) 297 (7.6)

859 (35.9) 634 (24.9) 847 (21.7) 776 (32.4) 861 (33.8) 1357 (34.7) 737 (30.8) 999 (39.2) 1627 (41.6) 21 (0.9) 53 (2.1) 78 (2.0) 0 1 (0.04) 3 (0.08)

­ED, Emergency Department; ICU, Intensive care unit; Psych, Psychiatry; AMA, Against Medical Advice; LD, lisdexamfetamine; DX, Dextroamphetamine Extended Release; DIR, Dextroamphetamine Immediate Release. *34 cases were excluded, 12 unknown pediatric age, and 22 unknown ages. **Other: includes other site, no show, left AMA; excluded from statistical analysis. ǂAfter controlling for age group, drug and management site were strongly associated (p  0.0001) as were drug and outcome (p  0.0001).

the hematoma, and was declared brain dead the following day. The other patient, who had ingested 104 20-mg dextroamphetamine/amphetamine capsules, complained of severe headache, then developed bradycardia, and had a respiratory arrest. Imaging showed a dissected aneurysm at the base of his skull; neurologic status remained poor and he died several days later. In the latter two cases, dextroamphetamine/ amphetamine exposures were considered contributory. After excluding cases involving children less than 6 years, there were 3,045 (23.3%) abuse and misuse cases. In this subset of patients, there were 616 (13.5%) lisdexamfetamine abuse or misuse cases compared with 840 (23.0%) dextroamphetamine/amphetamine extended release and 1589 (32.5%) dextroamphetamine/amphetamine immediate release. Abuse was less common than misuse for lisdexamfetamine (294 vs. 322), but occurred more frequently for dextroamphetamine/ amphetamine extended release (479 vs. 361) and dextroamphetamine/amphetamine immediate release (993 vs. 596). Table 4 displays abuse and misuse counts compared with

counts for all other reasons. Abuse/misuse occurred in less than 10% of children aged 6–12 years (5.2% lisdexamfetamine, 6.4% dextroamphetamine/amphetamine extended release, and 9.5% dextroamphetamine/amphetamine immediate release). Abuse/misuse occurred most often in the age group of 13–19 years, accounting for 21.9% of lisdexamfetamine, 32.1% of dextroamphetamine/amphetamine extended release, and 43.7% of dextroamphetamine/amphetamine immediate release. There was no significant interaction between age, drug and reason (misuse/abuse vs. other reasons) ((p  0.0624). After controlling for age group, drug and reason (abuse/misuse vs. other reasons) were strongly associated (QGMH  249.2, p  0.0001), with the odds of abuse/misuse found to be 2.3 (95% CI: 2.0–2.4) times higher for dextroamphetamine/amphetamine immediate release than that for lisdexamfetamine and dextroamphetamine/ amphetamine extended release combined, and with the odds of dextroamphetamine/amphetamine extended release abuse/ misuse being 1.9 (95% CI: 1.7–2.2) times higher than that of

Table 4.  Abuse and intentional misuse vs. other reasons stratified by age* and drugǂ. Age (years)

LD n  4560

DXR n  3645

DIR n  4893

Abuse Misuse Other Abuse Misuse Other Abuse Misuse Other n  294 (%)≠ N  322 (%)≠ n  3944 (%)≠ n  479(%)≠ N  361(%)≠ n  2805 (%)≠ n  993 (%)≠ n  596 (%)≠ n  3304 (%)≠ 6–12 13–19  20 % of total by drug

18 (6.1) 183 (62.2) 93 (31.6) 6.4

94 (29.2) 151 (46.9) 77 (23.9) 7.1

2055 (52.1) 4 (0.8) 1188 (30.1) 279 (58.2) 701 (17.8%) 196 (40.9) 86.5 13.1

66 (18.3) 169 (46.8) 126 (34.9) 9.9

1027 (36.6) 946 (33.7) 832 (29.7) 77.0

21 (2.1) 501 (50.4) 471 (47.4) 20.3

­LD, lisdexamfetamine; DXR, Dextroamphetamine Extended Release; DIR, Dextroamphetamine Immediate Release. *34 cases were excluded, 12 unknown pediatric age, and 22 unknown ages. ≠column percent. ǂAfter controlling for age group, drug and reason (abuse/misuse vs. other reasons) were strongly associated (p  0.0001). Copyright © Informa Healthcare USA, Inc. 2015

72 (12.1) 210 (35.2) 314 (52.7) 12.2

888 (26.9) 917 (27.8) 1499 (45.4) 67.5

482  M. E. Kaland & W. Klein-Schwartz 350

Number of Exposures

300 250 200 150 100 50 0

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2007

2008 LD

2009 2010 Year DXR

2011

2012 DIR

Fig. 2.  Trends in lisdexamfetamine and dextroamphetamine abuse/ misuse cases reported to U.S. poison Centers (Age  6 years). LD, lisdexamfetamine; DXR, dextroamphetamine extended release; DIR, dextroamphetamine immediate release. Note: LD came into the U.S. market in 2007.

lisdexamfetamine. Figure 2 displays abuse/misuse patterns in patients aged 6 years or more over the study period. The highest number of abuse/misuse cases annually involved dextroamphetamine/amphetamine immediate release. In 2011, the number of lisdexamfetamine abuse/misuse cases exceeded dextroamphetamine/amphetamine extended release by approximately 26% and plateaued in 2012, but was significantly lower (∼75%) than dextroamphetamine/ amphetamine immediate release.

Discussion The worldwide prevalence of ADHD in adults is 2.5%.8 In the U.S., 10% of children aged 3–17 years have ADHD.9 As the prevalence of ADHD diagnoses rises, so does the use of stimulant medications, which are considered the first-line treatment options. This is associated with the potential for an increase in adverse effects with therapeutic use as well as toxicity associated with non-medical use (abuse/misuse) and overdoses. There was a 39% increase in the number of ADHD stimulant prescriptions dispensed in the U.S. between 2007 and 2011.10 During this time period the number of dispensed prescriptions for ADHD amphetamines (including dextroamphetamine/amphetamine, but not methylphenidate) increased from ∼15 million to 20.3 million, while lisdexamfetamine increased from ∼2.5 million to 8.5 million.10 In this study, cases involving lisdexamfetamine increased dramatically after its introduction to the U.S. market in 2007 with an annual call volume close to that of dextroamphetamine/amphetamine immediate release in 2011 and 2012. Dextroamphetamine/amphetamine immediate-release cases increased between 2007 and 2010 and then plateaued. The initial increase may be related to an overall increase in poison center call volume until 2010, availability of generic

products for immediate release but not extended release until 2009, and increase in calls relating to abuse/misuse of this product from 2007 to 2009 before leveling off in 2010. While generic dextroamphetamine/amphetamine extended release became available in 2009, cases showed a slight decline, which may in part be attributed to a drop in total calls to poison centers during this time period.7 Other factors impacting prescription of dextroamphetamine/amphetamine extended-release products that may be reflected in poison center annual call volumes include competition from other extended-release ADHD drugs introduced into the market (e.g., Intuniv® XR approved in 2009) and availability of less expensive generic ADHD stimulants (e.g., generic Concerta® in 2011; generic Ritalin® LA; and Metadate® CD in 2012). Shire PLC (UK) reported a 35% drop in sales of Adderall® XR (dextroamphetamine/amphetamine extended release) and an 18% increase in Vyvanse® (lisdexamfetamine) in the fourth quarter of 2012.11 As a long-acting once-a-day dosed medication, lisdexamfetamine is a therapeutic alternative to dextroamphetamine/amphetamine extended release. Amphetamine overdose results in mainly neurologic and cardiovascular toxicity. Neurologic effects include agitation, combativeness, confusion, hallucinations, delirium, tremor, hyper-reflexia, and seizures. Cardiovascular effects include tachycardia, hypertension, and arrhythmias. Other effects include hyperthermia and rhabdomyolysis. Less common but serious toxicities include status epilepticus, ischemic stroke, intracerebral hemorrhage, myocardial infarction, late refractory hypotension, and gastrointestinal ischemia.12 In our study, most of the reported clinical effects in Table 2 were typical direct sympathomimetic effects on neurologic and cardiovascular systems. Hypotension and respiratory depression/arrest were rare but possibly late signs of toxicity attributed to indirect effects. Hypotension may be a preterminal effect in serious amphetamine toxicity. Bradycardia may also be a late indirect effect or reflex associated with hypertension. While overdoses of lisdexamfetamine display a spectrum of toxicity similar to those of other stimulant ADHD medications, animal studies find that conjugation of amphetamine with lysine may be protective, with lethal doses of lisdexamfetamine being more than five times higher than that of dextroamphetamine.13 Our study also found less serious toxicity with lisdexamfetamine compared with dextroamphetamine/ amphetamine extended release and dextroamphetamine/ amphetamine immediate release. While the clinical effects profile was similar for all three drugs, patients exposed to lisdexamfetamine were less likely to be admitted to the hospital and had less serious outcomes than those exposed to dextroamphetamine/amphetamine extended release and dextroamphetamine/amphetamine immediate release. Adverse effects with therapeutic use of lisdexamfetamine are similar to those associated with other stimulants and include decreased appetite and insomnia.14 In 28 patients reporting adverse events to five poison centers during the first 10 months after lisdexamfetamine was marketed, the clinical effects included agitation (43%), tachycardia (39%), insomnia (29%), dystonia (29%), vomiting (18%), chest pain (14%), hallucinations (11%), and jitters (11%).15 In 86% of Clinical Toxicology vol. 53 no. 5 2015

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Lisdexamfetamine and dextroamphetamine exposures  483 cases, the adverse event occurred within the first week of treatment. There is limited information on therapeutic errors associated with lisdexamfetamine use. A case series of 27 children aged 3–17 years with double doses, ranging from 40 to 140 mg, of their lisdexamfetamine reported to a poison center found that 77.1% had no effect and 22.2% had minor effects.16 Drowsiness occurred in three children and one child each had dry mouth, hypertension, tachycardia, and shakiness. The study concluded that double doses can be safely observed at home. In our study, therapeutic errors occurred most often in children aged 6–12 years and the majority of children in this age group were managed in a non-HCF. While there are no studies of lisdexamfetamine overdoses, there are several pediatric case reports. A 6-year-old girl developed serotonin-like syndrome including mental status changes (combative, hallucinations, and excessively talkative), clonus, and hyper-reflexia; vomiting; tachycardia; hypertension; diaphoresis; and hyperactive bowel sounds after unintentional ingestion of an unknown quantity of 30-mg lisdexamfetamine capsules.17 Urine toxicology screen was positive for amphetamine. Agitation worsened after midazolam but responded to dexmedetomidine. A 2-year-old who ingested three 50-mg lisdexamfetamine capsules developed sympathomimetic effects including agitation, confusion, hyperactivity, tachycardia, hypertension, and mydriasis.18 Similar to the previous case, agitation was resistant to multiple doses of several benzodiazepines (diazepam, midazolam, and lorazepam) but responded to pentobarbital. A 17-year-old experienced headache, blurred vision, chest pain, vomiting, mydriasis, tremor, and hypertension (180/110 mm Hg) 7 h after intentional overdose of fifty 40-mg lisdexamfetamine capsules.19 Temperature and heart rate remained normal. Urine toxicology screen was positive for amphetamines. Treatment included phentolamine for hypertension. In our study, the most frequently reported clinical effects were agitation, tachycardia, and hypertension for all three drugs. In our study there was a significant association between age and reason; age was an important confounder for measuring severity of exposure (management sites and coded medical outcomes). Over 90% of children aged  6 years were exposed to the three drugs unintentionally. Although most were asymptomatic or experienced minor effects, children aged  6 years who ingested lisdexamfetamine were more likely to be managed in the ED or admitted compared with those exposed to dextroamphetamine/amphetamine extended release and dextroamphetamine/amphetamine immediate release. This finding may be attributed to the fact that lisdexamfetamine is not indicated for use in this age group. As a relatively new drug without the benefit of years of experience with childhood exposures, the more conservative approach would be for these children to be observed directly under medical care. Children aged 6–12 years were most often managed in a non-HCF with most experiencing no effect or minor effects for all three drugs. Only 14–15% experienced moderate or major toxicity. The reason was most often therapeutic errors reflect the fact that children in this age group are treated with these medications for ADHD. Situations considered therapeutic errors include double Copyright © Informa Healthcare USA, Inc. 2015

dosing or incorrect dose, where the dose may be supratherapeutic, but is usually not a large overdose. Adolescents and adults were more often managed in a medical facility, with higher frequencies of hospital admissions following dextroamphetamine/amphetamine extended release or dextroamphetamine/amphetamine immediate release than lisdexamfetamine. In this age group, where exposures were often intentional (abuse, misuse, and suicide attempt), the situations were more likely to involve non-medical use (abuse/misuse) and probably higher doses. Over 40% of these patients experienced more serious medical outcomes with dextroamphetamine/amphetamine immediate release and dextroamphetamine/amphetamine extended release compared with just over 30% for lisdexamfetamine. There were no deaths with lisdexamfetamine, but 4 deaths involving dextroamphetamine/amphetamine extended release (1) and dextroamphetamine/amphetamine immediate release (3). Of note, there were three additional deaths from dextroamphetamine/amphetamine that were excluded from this study since chronicity was coded as unknown. RCF was assessed as undoubtedly and probably responsible in two cases and unknown in the third. For all three drugs, the proportions of moderate outcomes are high compared with those of admission rates. Some clinical effects associated with moderate outcomes may resolve during ED treatment/observation resulting in discharge from that site. ED “admit” for observation is also not considered medical admission. These factors as well as possible limitations with criteria for coding outcomes may contribute to the apparent differences between outcomes and management sites. Amphetamine abuse and misuse is well documented. Amphetamines are abused for their euphoric effects and performance-enhancing effects. Students consider these drugs as study aids and use them without a prescription, often obtaining them by illegal diversion of ADHD medications from friends with prescriptions. Dextroamphetamine and methylphenidate are commonly taken by college students to produce neurocognitive enhancement during periods of high stress including midterms, finals, and the last week of classes.20 Abuse potential is not the same for all ADHD medications. Post-marketing surveys suggest limited abuse potential for lisdexamfetamine. Surveys have found that the rate of non-medical use of lisdexamfetamine is lower than that of other stimulants, both immediate-release and longacting formulations.14,21 Evaluation of data from numerous sources (DAWN Live!, internet, media, supply chain monitoring, post-marketing adverse event reports, and RADARS) found little evidence of non-medical use of lisdexamfetamine during the first 3 years post approval.22 This study found lower frequency of abuse and misuse with lisdexamfetamine than that with dextroamphetamine/ amphetamine immediate release and dextroamphetamine/ amphetamine extended release. Excluding children under 6 years of age, abuse/misuse occurred in close to 14% of lisdexamfetamine exposures compared with almost a quarter of dextroamphetamine/amphetamine extended-release and a third of dextroamphetamine/amphetamine immediate-release cases. Product formulations and the resulting differences in

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484  M. E. Kaland & W. Klein-Schwartz pharmacokinetics may help explain differences in abuse potential. To feel high from stimulants, the concentration in the blood needs to rise rapidly. There is a relationship between peak plasma dextroamphetamine concentration and abuserelated liking measures.3 Dextroamphetamine/amphetamine salts are available in immediate-release and extended-release formulations. The extended-release capsule (Adderall XR) contains two types of beads which are designed to deliver the amphetamines in a double pulse. The time to peak plasma concentration for immediate release is 3 h compared with 7 h for extended release. This shorter time to peak may explain why abuse/misuse occurred more frequently with dextroamphetamine/amphetamine immediate release than dextroamphetamine/amphetamine extended release in our study. Lisdexamfetamine is rapidly absorbed and then converted to dextroamphetamine by red blood cell hydrolysis. After ingestion of a therapeutic dose of lisdexamfetamine, maximum plasma lisdexamfetamine concentrations occur at 1 h, while maximum plasma dextroamphetamine concentrations occur at 3 h.23 This conversion may delay onset of toxicity for several hours in overdoses as well as decrease abuse-related drug-liking effect and abuse liability.3 A study comparing intravenous lisdexamfetamine with dextroamphetamine found that lisdexamfetamine produced abuse-related liking scores (a measure of abuse liability) and euphoric effects similar to placebo, while dextroamphetamine produced significant liking and euphoric effects.3 Pharmacokinetic studies with intravenous administration of lisdexamfetamine showed delayed time to peak and lower peak dextroamphetamine concentrations possibly as a result of rate-limited conversion of lisdexamfetamine to dextroamphetamine. An important formulation difference between lisdexamfetamine and extended-release dextroamphetamine that may impact abuse potential is the fact that it is not possible to obtain dextroamphetamine by crushing lisdexamfetamine or opening the capsule and dissolving the contents. In contrast, if dextroamphetamine/amphetamine extended-release capsules are opened and the beads are crushed, the entire dose will be delivered immediately. All of these factors likely play a role in why lisdexamfetamine is less likely to be abused/misused than dextroamphetamine-containing formulations. In patients aged 6 years through adulthood, the lowest frequency of abuse/misuse occurred in children aged 6–12 years and the highest occurred in 13–19-year-olds. A higher proportion of lisdexamfetamine exposures were due to misuse rather than abuse. Overall, our data support post-marketing surveys and other research that suggest that lisdexamfetamine has a lower abuse potential than dextroamphetamine-containing formulations, especially immediate-release products. However, the trend toward more abuse/misuse of lisdexamfetamine compared with that of dextroamphetamine/amphetamine extended release in the last 2 years of the study is of concern. It is conceivable that this trend is in part a reflection of increased prescribing, and therefore availability, of lisdexamfetamine compared with dextroamphetamine/amphetamine extended release. Abuse/ misuse patterns are constantly changing, emphasizing the need for ongoing surveillance of this potential problem.

The findings of this study are subject to several limitations. Data are based on health professional or public reports without laboratory confirmation of the exposure. Only coded data were available so free-text fields were not reviewed. Coded NPDS data do not include laboratory findings so it was not possible to ascertain how often toxicology screens were positive for amphetamines. As such there is no laboratory confirmation of exposures. The information obtained is based on reported exposures. As reporting to poison centers is voluntary, these data do not capture cases that are not reported and there is potential for reporting bias (e.g., possibly more likely reporting of lisdexamfetamine cases shortly after its introduction since there is less experience managing these cases).24 Data coding was performed by professional staff at approximately 57 poison centers, leading to the potential for variability in coding or the potential for incorrect or incomplete coding. Validation checks between clinical effects and outcome prevent coding a less serious outcome when certain related clinical effects are coded but do not preclude coding a higher outcome with less serious clinical effects. Thus, outcome severity may be higher in some cases than warranted by coded effects. Since this is a retrospective study of data collected for a purpose other than this specific study, some data may be incomplete.24 Underreporting of clinical effects and treatments in coded poison center data have been previously described.25 However, it is unlikely that there were differences in completeness or accuracy of coding for one of the studied drugs compared with those of the other drugs.

Conclusions Toxic effects were similar for all three drugs. Although the majority of cases were treated at HCFs, most patients experienced no effects or minor toxicity. There were no lisdexamfetamine deaths. More serious outcomes occurred in approximately 21% of lisdexamfetamine and 25% of dextroamphetamine/amphetamine extended release and dextroamphetamine/amphetamine immediate release. Lisdexamfetamine might have less abuse potential than dextroamphetamine/amphetamine, especially immediate-release formulations.

Disclaimer The AAPCC (http://www.aapcc.org) maintains the national database of information logged by the country’s 57 Poison Centers. Case records in this database are from self-reported calls: they reflect only information provided when the public or health care professionals report an actual or potential exposure to a substance (e.g., an ingestion, inhalation, 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 Clinical Toxicology vol. 53 no. 5 2015

Lisdexamfetamine and dextroamphetamine exposures  485 represent the complete incidence of national exposures to any substance(s).­­­­

Acknowledgements We thank Bruce Anderson, Pharm.D., Managing Director, for his assistance with study design, and Larry Gonzales, B.S., senior IT specialist, and Yolande Tra, PhD, senior statistician at the Maryland Poison Center for their assistance with data analysis.

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Declaration of interest  The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

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