CNS Drugs DOI 10.1007/s40263-015-0246-y

ORIGINAL RESEARCH ARTICLE

Safety and Tolerability of Lisdexamfetamine: A Retrospective Cohort Study Melissa Voigt Hansen1

•

Lise Darling2 • Helle Holst1

Ó Springer International Publishing Switzerland 2015

Abstract Background Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder in children. Pharmacotherapy plays a main role in multimodal treatment, albeit adverse effects are a concern. Lisdexamfetamine is a newer pharmacological option and postmarketing studies on adverse events are limited. Objective The aim of this study was to investigate the treatment-emergent adverse events (TEAEs) in patients receiving lisdexamfetamine in a clinical setting. Methods We performed a retrospective cohort study at the Department of Child and Adolescent Psychiatry of Glostrup Hospital in Copenhagen, Denmark. We included all consecutive patients [6 years old, with an ICD-10 diagnosis of ADHD who were initiated on lisdexamfetamine between May 2013 and July 2014. TEAEs were assessed by a clinician and chart audit. Results Forty-three patients (91 % male) with a median age of 11 (range 8–15) years were included and received lisdexamfetamine for a median of 188 days (range 3–433). In total, 23.3 % of the patients discontinued treatment due

& Melissa Voigt Hansen [email protected] 1

Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, KBH. NV., 2400 Copenhagen, Denmark

2

Department of Child and Adolescent Psychiatry, The OutpatientClinic, Glostrup Hospital, Vibeholmsvej 17, 2605 Brøndby, Denmark

to a TEAE. 88 % of the patients experienced at least one TEAE and the time to first TEAE B4 weeks in 83.8 % of the patients. A new TEAE was experienced by 39.5 % of the patients compared with the TEAEs that patients had experienced when taking previous ADHD medication. The most common TEAEs (C5 %) were decreased appetite, difficulty falling asleep, tics, stomach ache and weight loss. A subjectively assessed good or good but time-limited (during the day only) effect was observed in 62.7 %. Conclusion Lisdexamfetamine treatment in this small group of patients who had received previous stimulant medication for ADHD was well tolerated and the TEAEs were consistent with findings in previous trials, although more than one third of the patients experienced TEAEs not observed with previously taken ADHD medication. Both the number of patients experiencing TEAEs and the rates of discontinuation due to TEAEs were higher than previously reported

Key Points Lisdexamfetamine treatment was well tolerated and the treatment-emergent adverse events (TEAEs) were consistent with findings in previous trials, although more than one third of the patients experienced TEAEs not observed with previously taken attention-deficit hyperactivity disorder medication. The number of patients experiencing TEAEs and the rates of discontinuation due to TEAEs were higher than previously reported in clinical trials with shorter observation periods and different populations.

M. V. Hansen et al.

1 Introduction Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder worldwide with a mean prevalence of approximately 5 % in children [1]. Moreover, these children often have comorbidities such as autism spectrum disorders, learning disorders and sleep disorders and the use of concomitant medication is widespread [2, 3]. Pharmacological treatment is recommended as part of a multimodal treatment plan which also includes behavioural, psychoeducational and psychological interventions [4]. Various amphetamine- and methylphenidate-based psychostimulants are still the ‘gold standard’ in ADHD treatment and the first were approved more than 50 years ago [5]. Atomoxetine is a non-stimulant, first authorized in the UK in 2004 for the treatment of ADHD in children over the age of 6 years and has been approved by the US FDA since 2002 [6]. Lisdexamfetamine dimesylate is the first long-acting prodrug stimulant for the treatment of ADHD and can be administered once daily [7]. Lisdexamfetamine was initially approved in the US in 2007, in Canada in 2009, and in Brazil in 2010; all labelled with different trade names [8]. In Denmark and in six other European countries it was marketed under the trade name Elvanse in February 2013. Methylphenidate is recommended as first-line treatment in Denmark, followed by either lisdexamfetamine or atomoxetine [4]. Lisdexamfetamine can therefore only be prescribed in Denmark when methylphenidate has been tried and the response is clinically inadequate or the adverse effects too prominent and unacceptable [4]. Adverse reactions to drugs used to treat ADHD are common with reporting rates higher than 50 % for specific reactions such as irritability, sleeping problems, decreased appetite and emotional disturbances, making this a concern for ADHD medications in the paediatric population [9, 10]. As with all other stimulants, safety and tolerability are an issue of consideration for lisdexamfetamine [11, 12]. It has been a concern for almost a decade that long-term surveillance of adverse drug events in children is generally lacking [13, 14]. Thus, postmarketing surveillance of safety needs to be highly prioritized. It is known that the randomized, controlled, clinical trials conducted in order to obtain marketing authorization include a limited number of selected patients and cannot solely be used to assess drug safety [15–17]. Therefore, clinical trials have a restricted ability to detect rare, serious and unexpected adverse drug events [16]. This is especially a problem in children as they are a vulnerable population and are frequently underrepresented in clinical trials [18, 19]. In general, post-marketing studies on treatment-emergent adverse events (TEAEs) of lisdexamfetamine are quite limited [11]. The current clinical trials have several disadvantages and potential sources of bias with regard to the

external generalizability of the findings to the average patient in the clinic. Observational data where co-morbidities and concomitant medication are present have been suggested to provide a better measure of harms experienced by the actual patients in comparison to data collected in clinical trials [20]. The objective for this retrospective cohort study was to investigate the TEAEs of lisdexamfetamine in a clinical setting. We wished to assess the number of TEAEs, classify the different types, explore the consequences with regard to treatment continuation and classify the probability of the adverse events being related to the drug therapy.

2 Methods 2.1 Design and Setting This retrospective cohort study was conducted at the Department of Child and Adolescent Psychiatry of Glostrup Hospital in Copenhagen, Denmark. The study was approved by the Danish Data Protection Agency (BBH2014-048, I-Suite 03066). 2.2 Study Participants The cohort included all consecutive patients above 6 years of age, who satisfied the ICD-10 criteria for a primary diagnosis of ADHD, had previously been treated with other medications for ADHD and were now initiated on lisdexamfetamine (Elvanse) between May 2013 and July 2014. There were no exclusion criteria. The department has a standard for monitoring for TEAEs; patients were contacted by phone within the first week after treatment initiation, were seen in the clinic after 3 months and then every 6 months depending on the specific patient and his/her needs. At these visits in the clinic, TEAEs were assessed by observation and open-ended inquiry by the clinician and also by a structured side-effect assessment form filled out by the parents. 2.3 Variables TEAEs were initially identified using the above-mentioned standard for monitoring TEAEs in the department by the paediatrician/child psychiatrist (LD) who the patients attended for consultation and who treated all the patients. The structured side-effect assessment form has been designed by the department for internal use only and consists of 15 symptoms, including stomach ache, sleep disturbances, nausea and tics. A TEAE was registered if the patient experienced any symptom at all, regardless of how often. Subsequently, a chart audit was performed by the first author (MVH) in order to clarify the details on TEAEs. TEAEs

Safety and Tolerability of Lisdexamfetamine

referred to new or worsening events with onset after the first date of treatment and no later than after termination of treatment. All TEAEs were retrospectively graded by the first author (MVH) according to severity: mild, moderate or severe. Severe TEAEs were defined as clinical occurrences that resulted in death, were life-threatening, required prolonged hospitalization or resulted in persistent or significant disability or incapacity [21]. Moderate TEAEs were defined as TEAEs which led to discontinuation of treatment, and mild TEAEs were defined as those adverse events that did not lead to discontinuation of treatment. Specific TEAEs that patients experienced while on previous ADHD medication were identified by the chart audit and registered. Demographic data on patients were obtained, including age, gender, weight, height, years with ADHD diagnosis and comorbidities. Data on height and weight were also collected at the last on-treatment visit if available in the charts. Furthermore, data on concomitant medication, previous ADHD medication, lisdexamfetamine medication dose and duration of treatment and reasons for discontinuation of treatment were registered. Clinical data on the vital parameters including blood pressure and pulse were registered at the beginning of treatment and at the last ontreatment visit, if the information was noted in the charts. A score from the validated Danish version of the ADHD Rating Scale (ADHD-RS) [22] (a rating system for the severity of ADHD symptoms) before initiating treatment, at check-ups and at the last on-treatment visit was obtained if available in the charts. Subjectively assessed effectiveness (by the clinician, LD) was noted and categorized as none, little, good, good but time limited, or missing. TEAEs are coded using the current version of the Medical Dictionary for Regulatory Activities, Version 12.1 (MedDRA MSSO, McLean, Virginia, USA) and are summarized by System Organ Class (SOC) and Preferred Term (PT). The Naranjo adverse drug reaction probability scale [23] was used to rate each adverse event by the first author (MVH). This scale classifies the probability that an adverse event is related to drug therapy based on a list of weighted questions which examine factors such as the temporal association of drug administration and event occurrence, alternative causes for the event, drug levels, dose-response relationships and previous patient experience with the medication. The adverse drug reaction is then assigned to a probability category from the total score as follows: definite if the overall score is 9 or greater, probable if the score is 5–8, possible for 1–4 and doubtful if the score is 0. 2.4 Statistical Analysis Data on the number of TEAEs per patient and time to first TEAE were calculated. A comparison with previously experienced adverse events was made by assessing whether

individual patients experienced at least one of the same TEAEs (PT) as on previous ADHD medication. Changes from baseline were calculated for systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse (beats per minute [bpm]), weight (kg) and height (cm). In addition, categorical levels of outliers were defined as participants having a SBP C 120 mmHg, DBP C 80 mmHg or bpm C 100 at the latest check-up. Weight loss was categorized as yes, no or missing. Due to the non-normal distribution of most of the data, non-parametric statistics were used. Continuous variables are presented as number of observations or median (range or interquartile range [IQR]), while categorical (nominal or ordinal) variables are presented using number of observations or frequencies as percentages. As missing data were assumed to be missing at random, only available data were analyzed. Fishers Exact Test was used to analyse categorical data with two or more groups and correlations were analyzed by Spearman’s rho. For statistical analyses, IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA) was used. A p value of B0.05 was considered statistically significant.

3 Results A total of 43 patients were included in the cohort, which consisted of 39 (90.7 %) males and 4 (9.3 %) females. The median age was 11 (8–15) years with 30 (69.8 %) in the age group 6–12 years and 13 (30.2 %) in the age group 13–17 years. According to ICD-10 criteria, 32 (74.4 %) had other diagnoses (Table 1) in addition to Hyperkinetic Disorder (F90.0), Hyperkinetic Conduct Disorder (F90.1) and Attention Disorder without Hyperkinesia (F98.8). The most common comorbidities were F80-89: Disorders of psychological development (n = 19), Z55-65: Potential health hazards related to socioeconomic or psychosocial circumstances (n = 12) and R41.8: Other and unspecified symptoms and signs involving cognitive functions and awareness (n = 11). A total of 55.8 % of the patients received some type of comedication: melatonin (extemporaneous drug formulation) (n = 16), combination of both melatonin and CircadinÒ (extended-release formulation of melatonin) (n = 5), other ADHD medication (dexamfetamine or methylphenidate) (n = 3) or risperidone, quetiapine, growth hormone, terbutaline/budesonide (n = 4). Demographic characteristics are summarized in Table 1. Data from ADHD-RS could not be reported, as 35 % (15/43) baseline and 74 % (32/43) check-up scores were not registered in the charts. All patients had previously tried methylphenidate, 58 % (25/43) had also tried atomoxetine, whereas 14 % (6/43) had also tried dexamfetamine. Regardless of their prior treatment, all patients were initiated on lisdexamfetamine

M. V. Hansen et al. Table 1 Demographic characteristics at beginning of treatment Characteristics

N = 43

Age, years

11 (8–15)

Age distribution, years: (6–12)/(13–17)

30/13 (69.8 %/ 30.2 %)

Gender (male/female)

39/4 (90.7 %/9.3 %)

Weight, kg

37.3 (22.8–84.7)

Height, cm

143.2 (125.5–178.4)

Years with ADHD diagnosis

5 (1–9)

Children with other diagnoses than ADHD or ADD (F90.0, F90.1, F98.8) F70–79: Mental retardation

32/43 (74.4 %) 5a

F80–89: Disorders of psychological development

19a

F90–98: Behavioural and emotional disorders with onset usually occurring in childhood and adolescence (not including F90.0, F90.1, F98.8)

9a

Z55–65: Potential health hazards related to socioeconomic or psychosocial circumstances

12a

Z80–99: Potential health hazards related to family and personal history and certain conditions influencing health status

5a

Q90.9: Down syndrome

1a

R41.8: Other and unspecified symptoms and signs involving cognitive functions and awareness

11a

E66.0: Obesity due to excess calories

1a

SBP (mmHg) baseline

113 (86–143)

DBP (mmHg) baseline

73 (51–86)

Pulse (bpm) baseline Patients receiving concomitant medication with LDX

78.5 (53–102) 24/43 (55.8 %) 16a

Melatonin (extemporaneous drug formulation) Ò

Circadin and melatonin (extended release and extemporaneous drug formulation)

5a

Other ADHD medication (methylphenidate, dexamfetamine)

3a

Other medication (risperidone, quetiapine, growth hormone, terbutaline/budesonide)

4a

Data are presented as median (range) or frequencies in percent or numbers ADHD attention-deficit hyperactivity disorder, ADD attention-deficit disorder, bpm beats per minute, DBP diastolic blood pressure, LDX lisdexamfetamine, SBP systolic blood pressure a

Some of the patients are represented in more than one group

30 mg. In the case of inadequate response, the dose was increased to 50 or 70 mg. A total of 24 patients received a highest dose of 50 mg and six patients received a maximum of 70 mg. There was no correlation between age and dose of lisdexamfetamine (p = 0.21). The median length of time on lisdexamfetamine was 188 days (range 3–433 and IQR 70.25–295.75). Forty-nine percent (21/43) of patients received concomitant treatment with melatonin. As of July 2014, 65.1 % (28/43) were still treated with lisdexamfetamine and 34.9 % (15/43) had discontinued treatment. In total, 23.3 % (10/43) of the patients had discontinued treatment due to a TEAE and 4.7 % (2/43) due to inadequate effect. Of the remaining three patients who discontinued treatment, two (4.7 %) had been prescribed a drug holiday and one (2.3 %) had missing data. In total, 62.7 % (27/43) of the patients displayed a subjectively assessed good or good but time-limited (during the day) effectiveness of treatment. Descriptive data are summarized in Table 2.

A total of 88 TEAEs were reported among 38 (88.3 %) of the patients. Most (83.8 %) of the patients experienced their first TEAE within the first month after treatment initiation (Table 3). No TEAEs were experienced by 11.6 % of the patients, 60.4 % experienced either one or two and 27.9 % experienced more than two. The same type of TEAE as experienced on previous ADHD medication was recorded by 41.9 % of the patients and 39.5 % of the patients experienced a new type of TEAE (Fig. 1). No severe TEAEs were found, 27.3 % were classified as moderate (leading to discontinuation of treatment) and 72.7 % as mild. According to the MedDRA SOC classification, metabolic (30) and psychiatric (43) disorders were the most prominent, followed by gastrointestinal (9), cardiac (3), nervous system (2) and respiratory (1). The most common TEAEs (C5 %) included decreased appetite (28.4 %), difficulty falling asleep (13.6 %), tics (6.8 %), stomach ache (6.8 %) and weight loss (5.7 %). The PT classification can be seen in Table 3. No associations were

Safety and Tolerability of Lisdexamfetamine Table 2 Descriptive data

Table 3 Treatment-emergent adverse events

Dosage of LDX tried (30/50/70 mg)

43/24/6

Total number of TEAEs

88

Time on LDX (days) at 30 July 2014

188 (3–433)a

Number of TEAEs per patient

2 (0–6)a

Patients continuing treatment as of 30 July 2014

28

Reason for stopping LDX (n = 15)

11.6 %

1 TEAE

30.2 %

No effect

2 (4.7 %)

2 TEAEs

30.2 %

Adverse events

10 (23.3 %)

3 TEAEs

9.3 %

Drug holiday

2 (4.7 %)

4 TEAEs

9.3 %

Missing data

1 (2.3 %)

5 TEAEs

7.0 %

Subjectively assessed effect of LDX

6 TEAEs

2.3 %

None

7 (16.3 %)

Association between number of TEAEs and gender

Little

6 (14.0 %)

Type of TEAE (MedDRA SOC classification) in numbers

Good

23 (53.5 %)

Gastrointestinal disorders

9

Good but time-limited

4 (9.3 %)

Metabolic disorders

30

Missing data

3 (7.0 %)

Psychiatric disorders

43

Cardiac disorders Nervous system disorders

3 2

Respiratory disorders

1

LDX lisdexamfetamine a

0 TEAEs

Data presented as median (range)

found between number of TEAEs and gender (p = 0.43) or maximal dose of lisdexamfetamine (p = 0.99). All TEAEs were classified as either possible (44 %) or probable (56 %) according to the Naranjo ADR probability scale. Blood pressure, pulse, height and weight were calculated as median change from baseline (Table 4). SBP changed by -2 mmHg (IQR -10 to 7.5), DBP by -4 mmHg (IQR -9 to 3), pulse by 5 (IQR -4 to 18), weight by -0.5 kg (IQR -2.4 to 1.1) and height by 2.0 cm (IQR 1.1–3.7). The wide range of the weight change (10.4–12.9 kg) is due to two outliers. One patient experienced a massive appetite reduction and a weight loss of 10.4 kg over a period of about 6 months and another started lisdexamfetamine due to weight loss on other ADHD medication but after lisdexamfetamine gained 12.9 kg in about 8 months but also grew 11 cm in height in this period. A total of 16 (37 %) experienced a weight loss during treatment, 11 (26 %) gained weight and 16 (37 %) were missing data. No patients were referred for further investigations of blood pressure changes. Two patients (one experiencing palpitations and one an increased pulse) were decreased in dose due to these symptoms and the symptoms disappeared after the dose reduction.

4 Discussion In this cohort of 43 patients taking lisdexamfetamine for a median of 188 days, we found a total of 88 TEAEs. The most common TEAEs (C5 %) included decreased appetite, difficulty falling asleep, tics, stomach ache and weight loss. All of these were in accordance with the adverse events outlined in the Summary of Product Characteristics (SmPC) [24]. Almost 40 % of the patients experienced a

p = 0.433

Type of TEAE (MedDRA PT classification) in numbers Nausea

3

Decreased appetiteb

25

Aggressive behaviourb

4

Ticb

6

Personality change

2

Emotional labilityb

2

Affect alteredb

1

Angerb

4

Dizzinessb

1

Palpitations Difficulty falling asleep

1 b

12

Sleep disturbances

4

Dyspnea Irritableb

1 1

Weight lossb

5

Stomach acheb

6

Restless legs

1

Affect labilityb

1

Restlessnessb

2

Heart rate increased

1

Chest pain

1

Emotional instabilityb

1

Somatization disorderb

1

Anxietyb

1

Anxious mood

1

Grade of TEAE in numbers (%) Severe

0

Moderate Mild

24 (27.3 %) 64 (72.7 %)

Maximal dose LDX (p = 0.99) 30 mg

2 (0–6)a

50 mg

2 (0–5)a

M. V. Hansen et al. Table 3 continued 70 mg Median time in months to first TEAE (range)

1.5 (0–4)a 0 (0–4)a

Time to first TEAE 0 months

74.4 %

0.5 months

4.7 %

1.0 months

4.7 %

3.5 months

2.3 %

4.0 months

2.3 %

Naranjo ADR probability scale (n = 88) Doubtful = 0 Possible = 1–4

0 39 (44 %)

Probable = 5–8

49 (56 %)

Definite C9

0

ADR adverse drug reaction, LDX lisdexamfetamine, MedDRA Medical Dictionary for Regulatory Activities, PT preferred term, SOC system organ class, TEAEs treatment-emergent adverse events a

Data presented as median (range)

b

TEAEs which led to discontinuation of LDX

Fig. 1 TEAEs in patients on lisdexamfetamine compared with previous ADHD medication (n = 43). The column ‘Same AE’ represents patients with C1 of the same TEAEs (Preferred Term) as experienced on previous ADHD medication. ADHD attention-deficit hyperactivity disorder, AE adverse event, LDX lisdexamfetamine, TEAEs treatment-emergent adverse events

new TEAE compared with the specific TEAEs experienced on previous ADHD medication. Blood pressure did not increase; however, pulse increased slightly and weight loss was experienced by 37 % of the patients, although no statistical z-score calculations were performed. TEAEs led to treatment discontinuation in 23.3 % of the patients, 27.3 % of the total TEAEs were classified as moderate and 72.7 % as mild. According to the Naranjo ADR probability scale, all TEAEs were classified as either possible (44 %) or probable (56 %). A subjectively assessed good or good

but time-limited effect of treatment was displayed by 62.7 % of the patients. Psychiatric comorbidity is very common in patients with ADHD and patients typically present with co-occurring or comorbid psychiatric conditions, such as oppositional defiant disorder and conduct disorder, mood and anxiety disorders, autism spectrum disorders, learning disabilities and sleep disorders [2]. In addition, various medical conditions frequently co-occur with ADHD such as enuresis and encopresis [2]. This heterogeneity is indeed reflected in our population, consisting of a typical cross section of patients with ADHD. As far as many of the pivotal studies of both efficacy and safety of lisdexamfetamine are concerned, patients with comorbid psychiatric diagnoses and patients receiving other medications affecting the central nervous system were excluded, leaving a very selected population [7, 25–29]. The patient population in the present study was equally distributed with regard to age and gender compared with the population included in two of the pivotal studies assessed for the marketing authorization procedure in the EU [7, 26]. Thus, the median age was 11 years and the patients were predominantly male. However, the length of treatment in this study was longer with a median time on lisdexamfetamine of 188 days with a range up to 433 days, compared with 7 and 26 weeks of observation period in the pivotal studies, respectively [7, 26]. Additionally, the patients in our population were diagnosed with ADHD 5 years before initiating lisdexamfetamine, compared with 1.5–2.5 years in the pivotal studies [7, 26]. The latter could have led to reporting bias with regard to TEAEs. Mild adverse events might not even be reported by patients or parents as they are willing to except/tolerate more. This could be due to both having had the diagnosis for a longer time and thereby also having tried various other pharmacological treatments. The concept of ‘willingness to pay’ is an important issue dealing with the degree of adverse effects that is acceptable for a given treatment benefit for an individual patient and their family [30]. A previous study in American children aged 6–12 years showed a higher incidence of more severe adverse events of lisdexamfetamine in stimulant-naı¨ve than previous-exposure subjects [31], possibly also owing to the concept of willingness to pay and reporting bias. With regard to TEAEs associated with lisdexamfetamine, several studies, both short- and long-term, openlabel, crossover or RCTs have investigated this [7, 25–29]. In general, the most common TEAEs are decreased appetite, insomnia, decreased weight, abdominal pain, irritability and headache, which are in overall accordance with our findings with the exception of tics, which was not a common finding in these studies. This could be due to our study including children having a pre-existing tic diagnosis

Safety and Tolerability of Lisdexamfetamine Table 4 Summary of vital signs, height and weight

Median SBP C 120 mmHg at latest check-up (yes/no)

5/21

DBP C 80 mmHg at latest check-up (yes/no)

3/23

Pulse C 100 bpm at latest check-up (yes/no)

2/23

Weight loss during treatment (yes/no/missing)

16/11/16

Range

IQR

SBP (mmHg) Baseline (n = 39)

113

86 to 143

105 to 121

Change from baseline (n = 25)

-2

-16 to 20

-10 to 7.5

DBP (mmHg) Baseline (n = 39)

73

51 to 86

65 to 79

Change from baseline (n = 25)

-4

-19 to 14

-9 to 3

Pulse (bpm) Baseline (n = 38)

78.50

53 to 102

68 to 91

Change in bpm from baseline (n = 23)

5

-12 to 25

-4 to 18

Change in weight from baseline (kg) (n = 27)

-0.5

-10.4 to 12.9

-2.4 to 1.1

Change in height from baseline (cm) (n = 26)

2.0

-0.1 to 11.4

1.1 to 3.7

bpm beats per minute, DBP diastolic blood pressure, IQR interquartile range, SBP systolic blood pressure

or having experienced tics on previous ADHD medication and thereby having a predisposition. Our finding of TEAEs being experienced by 88 % of patients receiving lisdexamfetamine is at the high end compared with other studies with rates ranging from 68 to 84 % [7, 25–29]. This is conflicting with the abovementioned theoretical risk of underreporting and might be due to the indication for lisdexamfetamine in our patients being inadequate response or unacceptable adverse events on previous ADHD medication. Moreover, this finding could be due to the high rates of patients with comorbidities and on comedication included in this study. Most TEAEs occurred within the first 4 weeks of treatment which is consistent with the finding of a recent review [11] and underlines the importance of close assessment of adverse events within the first month after treatment initiation. Discontinuation rates due to TEAEs vary from 3 to 16 % in other studies [25, 26, 28, 29]. We believe that our finding of 23.3 % highlights the reality of the consequences of adverse events in a true clinical setting in an unselected population with no influence of trial participation. One study found a dose-dependent increase in the percentage of participants with TEAEs [27]. We could not find this trend, although it is possibly due to a type II error. The findings of many reviews seem to agree largely on the common adverse effects of both short- and long-acting stimulants [10, 32, 33] and much focus has been on specific tolerability and safety concerns such as reduced weight and growth and cardiovascular events [11]. Specifically with regard to weight, our finding of an overall weight loss from baseline of 0.5 kg during the treatment period is in accordance with a recent review [11]. We found an increase in heart rate which is consistent with the findings of two

pivotal trials [7, 26], though the clinical relevance of this modest increase is not known. Conversely, we did not find an increase in SBP or DBP, which could be due to higher baseline values than in the pivotal trials or a type II error. Sleep disturbances are a prominent comorbidity in patients with ADHD and possibly even a pre-comorbidity, being present even before the first ADHD symptoms [2]. There is no sleep problem specific to ADHD; however, the most commonly reported is difficulty falling asleep [34]. Our finding of a high concomitant use of melatonin is even higher than in a Danish registry study which showed that 8–14 % of children aged 6–17 years who were prevalent ADHD drug users also redeemed prescriptions for melatonin [3]. We believe our finding of 49 % concomitant melatonin use is noteworthy and can reflect a variety of intertwined factors; the severity of ADHD, the associated sleep disorders in this specific population or the treatment of common adverse event to ADHD medication. With reference to CYP enzymes, CYP 2D6 metabolizer status has been shown to be a modifying factor in the adverse effects of atomoxetine [35]. However, lisdexamfetamine is not metabolized by CYP enzymes and metabolism is restricted to the formation of d-amfetamine and its metabolites [24, 36]. Furthermore, it has been reviewed that lisdexamfetamine is unlikely to be involved in drug–drug interactions mediated by CYP enzymes or by P-gp [36]. Therefore, we do not expect that CYP polymorphisms or drug–drug interactions can explain differences in numbers or severity of TEAEs in our population. Some obvious limitations of the study are the fairly small number of patients, the retrospective design and the method of chart audit with missing data being inevitable. With the initiation of lisdexamfetamine, no wash-out

M. V. Hansen et al.

period was effectuated and therefore a carry-over effect may be a potential confounder. However, we assess the influence of any possible carry-over effect to be minimal as the half-lives of both methylphenidate and atomoxetine are short. Another limitation is that the findings are limited to patients who have previously failed on other ADHD medication. In addition, it could have been interesting to have specific data on previously experienced TEAEs grouped according to prior pharmacotherapy for ADHD to clarify whether specific types of medications led to the same types of TEAEs in individual patients. Furthermore, a typical problem for studies investigating adverse events is that the symptoms of the illness itself can be difficult to distinguish from the adverse events. The major strength of our study is the nature of the study being post-marketing surveillance, truly reflecting reality in the clinic by following a cohort of patients initiating lisdexamfetamine treatment and not excluding any patients due to comorbidity or co-medication. Our assessment of TEAEs by both a structured assessment form and by observation and open-ended inquiry can be viewed as another strength of our study and provided a thorough screening for adverse events.

5 Conclusion In conclusion, this study of children in a clinical setting showed that treatment with lisdexamfetamine in this small group of patients who had received previous stimulant medication for ADHD was well tolerated and the types of adverse events were consistent with findings in previous clinical trials. However, both the number of patients experiencing TEAEs and the rates of discontinuation due to TEAEs were higher than in previous clinical trials in selected populations. Finally, the types of TEAEs experienced by individual patients differed to those that patients had experienced while on other previous ADHD medications. Acknowledgments

None.

Role of the funding source There were no funding sources and the study received no financial support from the industry. All activities regarding the design and conduct of the study; collection, management analysis, and interpretation of data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication were done solely by the authors. Contributors All three authors had full access to all the data in the study and take responsibility for the integrity of the data, the accuracy of the data analysis and had final responsibility for the decision to submit for publication. All authors have agreed to be accountable for all aspects of the work and have all approved the final version of the manuscript to be published. Additionally, the following contributions were made: MVH: planned the study, designed the study, initiated the

study, collected the data, analysed and interpreted the data, prepared the first draft of the manuscript, revised and coordinated revision of the manuscript. LD: planned the study, designed the study, initiated the study, interpreted the data and revised the manuscript. HH: planned the study, designed the study, initiated the study, interpreted the data and revised the manuscript. Conflict of interest flicts of interest.

The authors (MVH, LD, HH) declare no con-

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