CNS Drugs 2012; 26 (8): 691-705

REVIEW ARTICLE 1172-7047/12/0008-0691/$49.95/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

Lisdexamfetamine Dimesylate
A New Therapeutic Option for Attention-Deficit
Hyperactivity Disorder
Christopher Steer,1 Jan Froelich,2 César A. Soutullo,3 Mats Johnson4 and Monica Shaw5
1 Paediatric Department, Victoria Hospital, Kirkcaldy, Fife, UK
2 Central Institute of Central Health, Department of Child and Adolescent Psychiatry, University
of Heidelberg, Heidelberg, Germany
3 Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University
of Navarra Clinic, Pamplona, Spain
4 Child Neuropsychiatry Unit, Queen Silvia Children’s Hospital, Göteborg, Sweden
5 Shire Pharmaceuticals, London, UK

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
2. Pharmacology of Lisdexamfetamine Dimesylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
3. Therapeutic Efficacy of Lisdexamfetamine Dimesylate in Attention-Deficit Hyperactivity
Disorder (ADHD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
3.1 Studies in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
3.1.1 Phase III Randomized Placebo-Controlled Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
3.1.2 Classroom Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
3.1.3 Long-Term Efficacy Over 1 Year . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
3.2 Study in Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
3.3 Studies in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
3.3.1 Phase III Randomized Placebo-Controlled Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
3.3.2 Laboratory Adult Workplace Environment Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
3.3.3 Long-Term Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
3.4 Indirect Comparison of Amfetamine with Methylphenidate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
3.5 Efficacy of Lisdexamfetamine Dimesylate in Patients with an Inadequate Response to
Methylphenidate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
4. Tolerability/Safety Profile of Lisdexamfetamine Dimesylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
4.1 Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
4.2 Abuse Liability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
6. Role of Lisdexamfetamine Dimesylate in the Treatment of ADHD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702

Abstract Attention-deficit hyperactivity disorder (ADHD) is associated with sub-

stantial functional, clinical and economic burdens. It is among the most
common psychiatric disorders in children and adolescents, and often persists
692 Steer et al.

into adulthood. Both medication and psychosocial interventions are recom-

mended for the treatment of ADHD. However, ADHD treatment practices
vary considerably, depending on medication availability, reimbursement and
the evolution of clinical practice in each country. In Europe, stimulants and
atomoxetine are widely available medications for the treatment of ADHD,
whereas in the US approved treatment options also include extended-release
formulations of clonidine and guanfacine. Lisdexamfetamine dimesylate
(lisdexamfetamine) is a long-acting, prodrug formulation of dexamfetamine.
It is currently licensed in the US, Canada and Brazil, and is undergoing phase
III studies in Europe. We performed a PubMed/MEDLINE search looking
for recent (2005–2012) scientific papers regarding the pharmacokinetics,
pharmacodynamics, efficacy and safety of lisdexamfetamine. The lisdex-
amfetamine molecule is therapeutically inactive and is enzymatically hydro-
lysed, primarily in the blood, to the active dexamfetamine. This conversion is
unaffected by gastrointestinal pH and variations in normal transit times.
Lisdexamfetamine was developed with the goal of providing an extended
duration of effect that is consistent throughout the day. Clinical trials have
demonstrated robust clinical efficacy of lisdexamfetamine in the treatment of
children, adolescents and adults with ADHD with dose-dependent im-
provements in the core symptoms of ADHD. Studies have further shown that
the duration of action of lisdexamfetamine continues for 13 hours post-dosing
in children and for 14 hours in adults. The tolerability profile of lisdex-
amfetamine is consistent with those of other stimulant medications, with
decreased appetite, insomnia, abdominal pain and irritability among the
more frequent treatment-emergent adverse events, most of which are mild to
moderate in intensity and transient in nature. There are currently no parallel-
group, head-to-head trial data comparing the efficacy and safety of lisdex-
amfetamine with other medications for ADHD. However, the available data,
including a large effect size and consistent plasma concentrations throughout
the day, suggest that lisdexamfetamine is a useful treatment option for
patients with ADHD.

1. Introduction of children continue to meet diagnostic criteria for

Attention-deficit hyperactivity disorder (ADHD)
is one of the most common childhood psychiatric
conditions and is characterized by developmen-
tally inappropriate and impairing degrees of in-
attentiveness, impulsivity and hyperactivity.[1] A
systematic review and meta-regression analysis
found that the pooled prevalence in school-aged
children was 5.29% worldwide, with no significant
difference in prevalence between Europe and North
America.[2] Notably, ADHD symptoms often per-
sists into adolescence and adulthood.[1] It is esti-
mated that 60–85% of children with ADHD will
continue to meet diagnostic criteria during their
teenage years,[1] and that approximately two-thirds
ADHD in adulthood.[3]
ADHD is associated with a wide range of
functional impairments throughout the lifespan,
including deficits in psychological, social, family-
related, academic and occupational functions.[4,5]
Results from the ADORE (ADHD Observational
Research in Europe) study demonstrate that ADHD
in Europe is associated with significant impair-
ments in functioning and quality of life.[6] A study
from Spain revealed that the quality of life of in-
dividuals with ADHD was significantly impaired
compared with that of healthy controls and similar
to or worse than that seen in children with asthma.[7]
Not only are everyday activities (e.g. schoolwork,
family routines, interaction with other children)

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (8)
Lisdexamfetamine Dimesylate for ADHD
impaired, but relationships (e.g. child-parent, parent-
parent, child-sibling) are negatively affected com-
pared with healthy controls.[8] In addition, ADHD
is associated with a number of co-morbidities, in-
cluding depression, anxiety, oppositional defiant
disorder and substance use disorder.[1]
The treatment of ADHD often involves a
combination of approaches in a multimodal treat-
ment plan[1,5] that includes the use of medica-
tion. Although stimulant medications are one of
the cornerstones of ADHD pharmacotherapy,
unmet efficacy and safety needs remain for many
individuals with the disorder.[1,5,9,10] Lisdex-
amfetamine dimesylate (lisdexamfetamine) is the
first prodrug stimulant and offers an alternative
treatment option with a long duration of action,
potentially a low liability for abuse, and a toler-
ability profile consistent with other stimulant
medications. It has been approved for the treat-
ment of ADHD in children aged 6–12 years
(USA, Canada, Brazil), adolescents aged 13–17
years (USA, Canada) and adults (USA, Canada).
The European phase III pivotal study of lisdex-
amfetamine in children and adolescents has been
completed and further studies are ongoing.[11]
This article reviews the clinical pharmacology,
therapeutic efficacy and safety of lisdexamfetamine
for the treatment of ADHD.
A PubMed/MEDLINE search was conducted
for English-language articles published up to
2012 using the search term ‘lisdexamfetamine’. Of
the 97 publications that were identified, this re-
view focuses primarily on the 31 articles selected
by the limit ‘clinical trials’.
2. Pharmacology of Lisdexamfetamine
Dimesylate
2.1 Mechanism of Action
The effects of stimulants on attention and behav-
iour are mediated by dopamine and noradrenaline
(norepinephrine) pathways.[12] Methylphenidate and
dexamfetamine both act by inhibiting the reup-
take of dopamine and norepinephrine.[12,13] How-
ever, dexamfetamine, but not methylphenidate, also
has a direct-acting effect on dopamine release.[13,14]
This effect by dexamfetamine on both reuptake
Adis ª 2012 Springer International Publishing AG. All rights reserved.
693
and release of monoamines may be important
where inattentive symptoms predominate[13] and
may explain why amfetamine salts seem to be more
effective than methylphenidate,[15] as evidenced by
a significantly greater effect size (see section 3.4).
Lisdexamfetamine is a prodrug of dexamfetamine
bound to lysine. Following oral administration
and absorption into the circulation, the covalent
amide linkage between dexamfetamine and l-lysine
is enzymatically hydrolysed in the blood, releas-
ing the active agent.[16] Since the parent drug does
not bind to sites responsible for noradrenaline
and dopamine reuptake, the drug requires enzymatic
hydrolysis before it becomes pharmacologically
active.[17]
2.2 Pharmacokinetics
Lisdexamfetamine has a unique pharmacokinetic
profile characterized by low peak but sustained
plasma dexamfetamine concentrations (figure 1).
Median peak plasma concentrations (Cmax) of
lisdexamfetamine-derived dexamfetamine are
achieved in approximately 3–6 hours and the
pharmacokinetic parameters (the Cmax and area
under the plasma concentration-time curve [AUC])
are proportional to the dose in children with
ADHD[18,19] and adult volunteers.[20-23] The pharma-
cokinetic parameters of lisdexamfetamine-derived
dexamfetamine in children with ADHD are sum-
marized in table I. These data indicate that plasma
exposure to dexamfetamine is prolonged, smooth
and consistent, and that the intrasubject and in-
tersubject variability in pharmacokinetic param-
eters is low, suggesting long-lasting, predictable
and reliable delivery of active medication.[23]
Furthermore, based on trough plasma concentra-
tions, dexamfetamine steady state is achieved after
approximately five daily doses of lisdexamfetamine,
and there is no unexpected accumulation of the
parent compound or dexamfetamine.[20]
From a clinical perspective, the pharmacokinetic
profile of dexamfetamine following administra-
tion of lisdexamfetamine is consistent with an
extended duration of activity, with ongoing clin-
ical efficacy seen at 13 hours in children[24,25] and
14 hours in adults.[26] Compared with immediate-
release formulations, the benefits to the patient of
CNS Drugs 2012; 26 (8)
694 Steer et al.

Dexamfetamine from LDX 30 mg

Dexamfetamine from LDX 50 mg
Dexamfetamine from LDX 70 mg
Intact LDX from LDX 30 mg
Intact LDX from LDX 50 mg
Intact LDX from LDX 70 mg
140
Plasma concentration (ng/mL)

120

100

80

60

40

20

0
0 6 12 18 24 30 36 42 48
Time (h)

Fig. 1. Plasma concentration-time profile of lisdexamfetamine and lisdexamfetamine-derived dexamfetamine (reproduced from Boellner
et al.,[18] with permission from Elsevier, ª 2010). LDX = lisdexamfetamine dimesylate.

a long-acting stimulant prodrug include reduc- healthy adults found that concomitant omeprazole
tions in the need to store and administer sched- had no effect on total exposure to dexamfetamine,
uled drugs within a school environment, together as assessed by Cmax and AUC values.[36] There are
with stigma associated with receiving psycho- no data regarding the pharmacokinetics of lis-
pharmacotherapy during the day, in the potential dexamfetamine when combined with short-acting
for drug diversion, and finally in the potential stimulants or other psychotropic drugs (e.g. se-
negative impact on treatment adherence.[18,27-29] lective serotonin reuptake inhibitors, antipsy-
Although the elimination time of lisdexamfetamine chotics, atomoxetine) that are sometimes used in
appears to be longer than with other stimulants, combination with long-acting stimulants.[37]
studies have suggested that lisdexamfetamine does
not contribute to sleep disturbances in children[30]
or adults with ADHD.[31,32]
Administration of lisdexamfetamine with food Table I. Pharmacokinetic parameters (– standard deviation) of
lisdexamfetamine-derived dexamfetamine in children with attention-
has no significant effect on the extent of absorp- deficit hyperactivity disorder[18,19]
tion of dexamfetamine (i.e. AUC), although the


Dose No. of tmax Cmax AUC
rate of absorption (i.e. increased time to Cmax and patients (h) (ng/mL) (h ng/mL)
decreased Cmax) is slightly delayed.[33] The US Biederman et al.[19] (2007)
prescribing information states that lisdexamfetamine LDX 70 mg 8 4.5 155 (31.4) 1326 (285.8)
may be taken with or without food.[34] There are MAS XR 30 mg 9 6 119 (52.5) 1019 (436.2)
also few reported drug-drug interactions with Boellner et al.[18] (2010)
lisdexamfetamine. An in vitro analysis of the po- LDX 30 mg 16 3.4 (1.1) 53.2 (9.6) 745.3 (129.3)
tential for cytochrome P450 (CYP) interactions LDX 50 mg 17 3.6 (1.2) 93.3 (18.2) 1448.0 (246.7)
found that lisdexamfetamine did not demonstrate LDX 70 mg 17 3.5 (1.3) 134 (26.1) 2088.0 (394.0)
concentration-dependent inhibition of any of the AUC = area under the plasma concentration-time curve; Cmax =
seven CYP isoforms tested, suggesting that lis- maximum plasma concentration; LDX = lisdexamfetamine dimesy-
dexamfetamine has a low potential for drug-drug late; MAS XR = mixed amfetamine salts extended release; tmax =
time to Cmax.
interactions.[35] Furthermore, a crossover study in 24

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (8)
Lisdexamfetamine Dimesylate for ADHD
3. Therapeutic Efficacy of
Lisdexamfetamine Dimesylate in
Attention-Deficit Hyperactivity
Disorder (ADHD)
The efficacy of lisdexamfetamine in the treat-
ment of ADHD in children, adolescents and adults
has been established across multiple studies.
There were three randomized, placebo-controlled
trials in children (one in a clinical setting and two
in an analogue classroom setting) and one long-
term follow-up. For adolescents there was one
randomized, placebo-controlled trial, and for adults
there were two randomized, placebo-controlled
trials (one in a clinical setting and one in an ana-
logue workplace environment) and one long-term
follow-up. All were conducted in patients diag-
nosed with predominantly combined or hyper-
active-impulsive subtypes of ADHD according to
the DSM-IV-TR. Patients with other serious co-
morbid psychiatric disorders such as psychosis or
bipolar disorder were excluded.
3.1 Studies in Children
3.1.1 Phase III Randomized Placebo-Controlled Trial
A phase III, randomized, forced-dose, parallel-
group study evaluated the efficacy and safety of
lisdexamfetamine 30, 50 or 70 mg versus placebo
50
40
Mean ADHD-RS-IV total score
30 †††
20
10
−10
−20
−30 ***
−40 LDX 30 mg
(n = 69)
Fig. 2. Change from baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale Version IV (ADHD-RS-IV) total scores. Error bars
represent the standard error of the mean (reproduced from Biederman et al.,[38] with permission from Elsevier, ª 2007). LDX =
lisdexamfetamine dimesylate; LS = least squares; *** p < 0.001 vs placebo; --- p < 0.001 vs baseline.
Adis ª 2012 Springer International Publishing AG. All rights reserved.
695
in 290 children aged 6–12 years with ADHD.[38]
Patients were randomized to one of four treatments
during the 4-week active study phase: lisdex-
amfetamine 30 mg, lisdexamfetamine 50 mg (lis-
dexamfetamine 30 mg/day for 1 week, then forced
escalation), lisdexamfetamine 70 mg (30 mg/day
for 1 week, then forced escalation) or placebo.
All doses of lisdexamfetamine were associat-
ed with a significantly greater decrease in the
ADHD Rating Scale Version IV (ADHD-RS-IV)
from baseline versus placebo (figure 2). The effect
of lisdexamfetamine was dose dependent with the
70 mg group achieving significantly greater re-
ductions from baseline in the ADHD-RS-IV than
the 30 mg group (least squares mean difference
-4.91; p < 0.05). Significant improvements versus
placebo were evident for both the ADHD-RS-IV
inattention and hyperactivity subscales in all lis-
dexamfetamine dose groups (figure 3). Similarly,
Clinical Global Impression – Improvement (CGI-I)
scale scores were significantly better for all doses
of lisdexamfetamine versus placebo.[38] At study end-
point, the effect sizes based on the ADHD-RS-IV
were 1.21, 1.34 and 1.60, respectively, in the 30,
50 and 70 mg dose groups. Although care should
be taken not to extrapolate directly from effect
size to clinical meaningfulness, effect sizes are con-
sidered to provide a better estimate of treatment
Baseline
Endpoint
Change (LS mean)
†††
††† †††
***
***
LDX 50 mg LDX 70 mg Placebo
(n = 71) (n = 73) (n = 72)
CNS Drugs 2012; 26 (8)
696 Steer et al.

LDX 30 mg (n = 69) icant improvement in the primary outcome mea-

LDX 50 mg (n = 71)
LDX 70 mg (n = 73)
sure, the Swanson, Kotkin, Agler, M Flynn, and
Placebo (n = 72) Pelham (SKAMP) scale[42] (a widely utilized and
Inattention subscale Hyperactivity subscale validated measure of functional impairments asso-
Mean change in ADHD-RS-IV

0 ciated with ADHD) versus placebo across the

−2 treatment day.[19] Lisdexamfetamine was also asso-
subscale score

−4 ciated with significant improvements versus placebo

−6
−8
−10
−12 * *
*
−14
* illustrated in figure 5. Although the overall effi-
* *
Fig. 3. Change from baseline in Attention-Deficit/Hyperactivity
Disorder Rating Scale Version IV (ADHD-RS-IV) Inattention and
Hyperactivity subscale scores. Error bars represent the standard
error of the mean (reproduced from Biederman et al.,[38] with per-
mission from Elsevier, ª 2007). LDX = lisdexamfetamine dimesylate;
*
p < 0.001 vs placebo.
effects than simple p-values alone, and an effect
size greater than 0.8 is traditionally held to cor-
respond to a large magnitude of effect.[39,40]
Treatment with lisdexamfetamine was also asso-
ciated with significantly greater improvements in
symptoms throughout the day versus placebo as
assessed by the Conners’ Parent Rating Scale
(figure 4), demonstrating a consistent effect through-
out 10am, 2pm and 6pm. A responder analysis
showed that, compared with placebo, all doses
of lisdexamfetamine were associated with signif-
icantly higher response rates (‡30% decrease in
ADHD-RS-IV total score and a CGI scale score of
‘very much improved’ or ‘much improved’).[38] Over-
all, 79.3% of patients receiving lisdexamfetamine
in the Permanent Product Measure of Performance
(PERMP) and CGI-I scales.[19] The time course of
changes in SKAMP and PERMP mean scores are
cacy of lisdexamfetamine and MAS XR were
similar, there is a suggestion that size of the clin-
ical effect (with respect to mean PERMP scores)
decreases with MAS XR at 6–12 hours post-dose.
Similar results were observed in another random-
ized, placebo-controlled, two-way, 4-week, cross-
over trial assessing lisdexamfetamine in a laboratory
setting among 117 children aged 6–12 years with
ADHD.[24] Lisdexamfetamine was initiated at
30 mg/day with weekly adjustments until the dose
was optimized. The optimized dose (one that de-
creased ADHD-RS-IV ‡30%, achieved a CGI
scale score of 1 or 2, and was tolerable) was used
for the double-blind phase. Lisdexamfetamine
was associated with significant improvement on
the SKAMP deportment (SKAMP-D) subscale
(primary endpoint) from the first assessment
LDX 30 mg
LDX 50 mg
LDX 70 mg
Placebo

were classified as responders compared with 29.2% Morning Afternoon Evening

(~10am) (~2pm) (~6pm)
of those in the placebo group.[41] n= 67 68 70 72 67 66 71 72 67 69 69 72
Mean change in CPRS score

0
3.1.2 Classroom Studies −2
−4 † †
Lisdexamfetamine has also demonstrated effi- −6
cacy in a laboratory classroom environment. A −8
phase II, randomized, double-blind, placebo- and −10
active-controlled, dose-ranging crossover study −12 †* †*
†*
in 52 children aged 6–12 years with ADHD com- −14
* †* *
−16 † *
†* †* †
pared lisdexamfetamine 30, 50 and 70 mg with †
mixed amfetamine salts controlled release (MAS
Fig. 4. Change from baseline to endpoint in Conners’ Parent Rating
XR) 10, 20 or 30 mg.[19] The study was conducted Scale (CPRS) in children receiving 4 weeks of treatment with lis-
in an analogue classroom environment with serial dexamfetamine once daily vs placebo. Error bars represent the
standard error of the mean (reproduced from Biederman et al.,[38]
assessments over the 12-hour post-dose period. with permission from Elsevier, ª 2007). LDX = lisdexamfetamine
Lisdexamfetamine was associated with a signif- dimesylate; * p < 0.001 vs placebo; - p < 0.001 vs baseline.

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (8)
Lisdexamfetamine Dimesylate for ADHD 697

LDX
MAS XR
a Placebo
0.8
(change from first measurement)

0.6
LS mean SKAMP score

0.4

0.2

0 Deportment Attention
*
* *
−0.2 *
*
* *
* *
*
−0.4 * * * *
*
* * * *
* * *
−0.6 *
* *
*
*
−0.8
1 2 3 4.5 6 8 10 12 1 2 3 4.5 6 8 10 12
Time (h)
b
60 ** ** **
(change from first measurement)

** ** ** **
** ** ** ** **
40
LS mean PERMP score

** **
** ** ** ** ** **
20 ** **
** ** ** **
** **
Number attempted Number correct
0

−20

−40

−60
1 2 3 4.5 6 8 10 12 1 2 3 4.5 6 8 10 12
Time (h)

Fig. 5. Time-course change in (a) Swanson, Kotkin, Agler, M Flynn, and Pelham (SKAMP) and (b) Permanent Product Measure of Perfor-
mance (PERMP) least squares mean scores from baseline in children aged 6–12 years with attention-deficit hyperactivity disorder (reproduced
from Biederman et al.,[19] with permission from Elsevier, ª 2007). LDX = lisdexamfetamine dimesylate; LS = least squares; MAS XR = mixed
amfetamine salts extended release. * p < 0.05, ** p <0.001 vs placebo.

(1.5 hours) through to the last assessment (13 hours) imum of 70 mg/day. Fifty-four percent of children
[figure 6]. Results for the PERMP attempted completed the trial with the primary reasons for
(PERMP-A), PERMP correct (PERMP-C) and discontinuation including withdrawal of consent
SKAMP attention (SKAMP-A) subscales were (15.1%), loss to follow-up (13.6%), adverse events
consistent with those of the SKAMP-D, with (9.2%) and lack of efficacy (4.0%). At study end-
significant improvements versus placebo at all point, the mean ADHD-RS-IV total score had de-
timepoints.[24] creased more than 60% from baseline (-27.2 – 13.0
points; p < 0.0001) with similar decreases in both
3.1.3 Long-Term Efficacy Over 1 Year
hyperactivity (-13.8 – 7.0; p < 0.001) and inattentive
The efficacy of lisdexamfetamine has been subscores (-13.4 – 7.0; p < 0.001).[43]
shown to be maintained with long-term therapy.
Lisdexamfetamine was evaluated over 11 months 3.2 Study in Adolescents
in 272 children aged 6–12 years with ADHD.[43]
All subjects were initiated on a 30 mg dose with In a randomized, placebo-controlled, forced-dose
increases allowed at 20 mg increments to a max- titration study, the efficacy of lisdexamfetamine

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (8)
698 Steer et al.

versus placebo was evaluated in 314 adolescents associated with significantly greater change from
aged 13–17 years.[44] Patients were randomized to baseline at all weeks and at endpoint in the
one of three lisdexamfetamine dose groups (30, ADHD-RS-IV total score than that observed with
50 or 70 mg) or placebo for a forced-dose titra- placebo. Least squares mean differences (95% con-
tion of 3 weeks followed by a 1-week mainte- fidence interval [CI]) between lisdexamfetamine
nance phase. All doses of lisdexamfetamine were and placebo for ADHD-RS-IV total scores were

SKAMP-D
LDX
Placebo
SKAMP-A
LDX
Placebo
1.8

1.6 **

1.4

1.2 ** **
LS mean score

** **
1.0
** *
0.8 ** **
*
0.6
*
*
0.4 *
* *
0.2

0
1.0

0.8

0.6
LS mean change in score

0.4

0.2 *
*
0
*
*
−0.2 *
* *
−0.4
**
**
−0.6 **
**
−0.8
**
** **
−1.0
−1 0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time (h)

Fig. 6. Time course of Swanson, Kotkin, Agler, M Flynn, and Pelham (SKAMP) deportment (SKAMP-D) and SKAMP attention (SKAMP-A)
least squares mean scores from baseline assessed over laboratory school day (reproduced from Wigal et al.,[24] with permission; ª 2009
BioMed Central Ltd). LDX = lisdexamfetamine dimesylate; LS = least squares; * p < 0.005, ** p £ 0.001 vs placebo.

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (8)
Lisdexamfetamine Dimesylate for ADHD
-5.5 (-9.7, -1.3), -8.3 (-12.5, -4.1) and -7.9
(-12.1, -3.8), respectively, for the lisdexamfeta-
mine 30, 50 and 70 mg dose groups (p £ 0.0056 vs
placebo for each). ADHD-RS-IV inattention and
hyperactivity/impulsivity subscale scores were
also significantly improved at endpoint in all lis-
dexamfetamine dose groups.
3.3 Studies in Adults
3.3.1 Phase III Randomized Placebo-Controlled Trial
A phase III, randomized, forced-dose, parallel-
group, placebo-controlled, 4-week study evaluated
the efficacy and safety of lisdexamfetamine in
420 adults. Patients were randomized to receive
final doses of lisdexamfetamine 30, 50 or 70 mg,
or placebo, for a forced-dose titration of 3 weeks
followed by a 1-week maintenance phase.[26]
At study endpoint, changes from baseline in
ADHD-RS-IV mean scores were significantly
greater for all doses of lisdexamfetamine than for
placebo. Least squares mean differences (95% CI)
between lisdexamfetamine and placebo for ADHD-
RS-IV total scores were -8.0 (-12.1, -3.9), -9.2
(-13.2, -5.1) and -10.4 (-14.5, -6.3), respectively,
for the lisdexamfetamine 30, 50 and 70 mg dose
groups (p < 0.0001 vs placebo for each). CGI-I
scores were significantly lower at endpoint for all
lisdexamfetamine groups than with placebo, with
57–62% of patients receiving lisdexamfetamine
30–70 mg rated ‘improved’ or ‘very much improved’
at study endpoint, significantly greater than the 29%
of patients receiving placebo (p < 0.01).[26]
3.3.2 Laboratory Adult Workplace Environment Study
An assessment of lisdexamfetamine on executive
function impairment in a 4-week, open-label dose-
optimization phase of a simulated adult work-
place environment study, demonstrated that in
adults with ADHD, executive function was sig-
nificantly improved from baseline on the Brown
Attention-Deficit Disorder Scale (BADDS) with
lisdexamfetamine 30–70 mg (p < 0.001 for total
BADDS scores).[45] In the following 2-week ran-
domized, double-blind, placebo-controlled cross-
over phase of the adult workplace environment
study, patients receiving lisdexamfetamine had
significantly improved total mean scores from
baseline on the PERMP scale versus placebo
Adis ª 2012 Springer International Publishing AG. All rights reserved.
699
(p < 0.001).[46] Furthermore, medium-to-large ef-
fect sizes based on PERMP scales were main-
tained until 14 hours post-dose.[47]
3.3.3 Long-Term Follow-up
The efficacy of lisdexamfetamine in adults
has been confirmed in long-term follow-up. In a
12-month open-label single-arm study of 349 adults
with ADHD, a mean relative improvement in
ADHD-RS-IV total score from baseline of 60.7%
(p < 0.0001) was observed. The study was com-
pleted by 54.7% of patients, with the most common
reasons for discontinuation including withdrawal
of consent (12.0%), loss to follow-up (11.7%),
adverse events (8.0%), protocol violations (7.7%)
and lack of efficacy (3.2%).[48]
3.4 Indirect Comparison of Amfetamine with
Methylphenidate
Methylphenidate has established efficacy in
the treatment of ADHD and is one of the most
widely available agents in Europe.[5,9,10,49] Am-
fetamines are less widely available in Europe than
in the US, and although comparative efficacy has
not been demonstrated in head-to-head studies,
indirect comparisons have been made comparing
efficacy of amfetamines and methylphenidate.
A meta-analysis of 23 studies published between
1987 and 2008 (including one lisdexamfetamine
study) found that the effect size was significantly,
although moderately, greater for amfetamines than
for methylphenidate (1.03 vs 0.77; p = 0.02).[50]
The number needed to treat (NNT) was lower for
amfetamines (2.0; 95% CI 1.7, 2.2) than for
methylphenidate (2.6; 95% CI 2.4, 2.8).[50] NNT
has been described as the effect size estimate that
is most useful in conveying the clinical signif-
icance of treatment effects.[51] For hyperactive/
impulsive symptoms the effect size difference was
also significantly greater for amfetamines than for
methylphenidate (1.20 vs 0.91; p = 0.01). There is
currently insufficient data to allow a statistical
comparison between the effect of amfetamines
and methylphenidate on inattention symptoms.
It is interesting to note, however, that the effect
size for lisdexamfetamine was 1.52 compared
with 0.84 for methylphenidate.
CNS Drugs 2012; 26 (8)
700 Steer et al.

3.5 Efficacy of Lisdexamfetamine Dimesylate
in Patients with an Inadequate Response to
Methylphenidate
A post hoc analysis of the phase III randomized
controlled study in children with ADHD assessed
the efficacy of lisdexamfetamine in the subset of
children (n = 26) who were receiving methylphen-
idate at screening and had an ADHD-RS-IV score
>18.[52] The prior methylphenidate users treated
with lisdexamfetamine experienced a mean re-
duction in ADHD-RS-IV from baseline of -24.0.
Comparable reductions were observed between
patients who received prior treatment with methyl-
phenidate ‡1 mg/kg and <1 mg/kg. Similarly, un-
published analyses from a 7-week open-label
trial[53] and a laboratory classroom study[24] found
that response rates for children with prior methyl-
phenidate use was 86.7% in the open-label study
and 80.6% for those in the classroom study.[54]
Overall, efficacy was similar between those who
had received prior methylphenidate therapy and
those in the overall study population.
4. Tolerability/Safety Profile of
Lisdexamfetamine Dimesylate
4.1 Adverse Events
The adverse events associated with lisdex-
amfetamine are consistent with those expected
with stimulants. In children, the most commonly
reported adverse events were decreased appetite,
insomnia, upper abdominal pain, irritability, mood
changes, headache and dizziness, with most events
being mild to moderate and transient (table II).[19,38]
In adults, the most frequently reported adverse
events were decreased appetite, insomnia, dry
mouth, diarrhoea, nausea, anxiety and anorexia.[26]
The safety profile in children and adults after
long-term treatment is consistent with that re-
ported in the short-term studies.[43,48] Most events
are reported in the first 4 weeks of treatment and
the discontinuation rate due to adverse events over
12 months of treatment is low (9.2%) and similar
to that reported with other stimulants.[43]
Consistent with its pharmacological profile,
lisdexamfetamine is associated with modest dose-
related increases in blood pressure (mean increases
of 0.7–0.9 mmHg and 0.6–1.8 mmHg, respectively,
for systolic and diastolic blood pressure), with
peak effects noted approximately 1–3 hours after
a dose and not considered clinically signif-
icant.[22,43,53,55] In the long-term study, the mean
changes from baseline at endpoint were 1.4 beats
per minute for pulse and 0.7 and 0.6 mmHg, re-
spectively, for systolic and diastolic blood pres-
sure.[43] ECGs revealed no clinically significant
increases in QT or corrected QT intervals.[19] As
reported for other stimulants, lisdexamfetamine
is associated with reductions in expected height,
weight and body mass index, with the effects
greatest in the heaviest and tallest children.[43,56]

Table II. Number (%) of adverse events occurring in >2% of children with attention-deficit hyperactivity disorder aged 6–12 years[19]
Adverse event Titration period Double-blind period
MAS XR LDX MAS XR Placebo
(n = 52) (n = 50) (n = 50) (n = 52)
Any event 24 (46) 8 (16) 9 (18) 8 (15)
Abdominal pain 3 (6) 0 0 0
Upper abdominal pain 3 (6) 0 2 (4) 1 (2)
Upper respiratory tract infection 2 (4) 1 (2) 1 (2) 0
Decreased appetite 7 (14) 3 (6) 2 (4) 0
Headache 8 (15) 0 0 0
Affect lability 2 (4) 0 0 0
Insomnia 5 (10) 4 (8) 1 (2) 1 (2)
Vomiting 1 (2) 0 1 (2) 2 (4)
Anorexia 1 (2) 2 (4) 0 0
LDX = lisdexamfetamine dimesylate; MAS XR = mixed amfetamine salts extended release.

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (8)
Lisdexamfetamine Dimesylate for ADHD
However, longer-term follow-up is required to
determine whether ultimate adult height is affected.
4.2 Abuse Liability
Enzymatic hydrolysis of lisdexamfetamine pro-
vides a gradual release of dexamfetamine. Since
free dexamfetamine is not present in the capsules,
mechanical manipulation (such as by crushing or
extraction) will not yield the active ingredient.[55]
Available data suggest that nonmedical use is
more common with immediate-release formula-
tions of both methylphenidate and amfetamine
than with extended-release formulations of either
drug, although the relationship with availability
based on prescriptions has not been studied or
published.[57-60]
In abuse liability studies among individuals with
a history of stimulant abuse, lisdexamfetamine
was associated with attenuated responses on mea-
sures of abuse liability compared with immediate-
release dexamfetamine (e.g. drug liking).[22,55]
Subjects expressed significantly greater liking
scores for dexamfetamine 40 mg than for lisdex-
amfetamine 50 mg.[55] Further, in contrast to
dexamfetamine and diethylproprion, drug liking
scores for licensed doses of lisdexamfetamine did
not significantly differ from placebo.[22,55] The
real-world abuse potential of lisdexamfetamine is
highlighted by recent unpublished data from the
Researched Abuse, Diversion and Addiction-
Related Surveillance (RADARS) system in the
US, which found that, as per data collected from
poison control centres from September 2007 to
February 2010, lisdexamfetamine has a low rate
of intentional exposure (defined as intentional
suspected suicide, intentional misuse, intentional
abuse and intentional unknown) that is similar to
that of other extended-release stimulants.[61]
5. Dosage and Administration
The initial dosage for lisdexamfetamine is 30 mg
once daily, taken in the morning up to a maximum
of 70 mg/day.[62] Lisdexamfetamine is usually ti-
trated slowly, increasing the dose every 4–7 days
(in 20 mg increments) until a therapeutic dose
is reached. The contents of a lisdexamfetamine
Adis ª 2012 Springer International Publishing AG. All rights reserved.
701
capsule can also be dissolved in water to form a
clear solution. In day-to-day clinical practice, this
useful property may be utilized in circumstances
when swallowing tablets or capsule formulations
creates difficulty, such as for younger patients or
those with neurodevelopmental delay.
6. Role of Lisdexamfetamine Dimesylate
in the Treatment of ADHD
ADHD is associated with a wide range of co-
morbidities and functional impairments through-
out the lifespan, including deficits in psychological,
social, family-related, academic and occupational
functions.[1,5] In order to realize an effective and
continuous treatment plan, patients with ADHD
should undergo regular reassessment as part of a
multimodal treatment package, which should in-
clude medical and psychosocial interventions as
dictated by individual circumstances.[5,9,63]
Increasingly, the focus of medical treatment is
not solely on showing a decrease in symptoms,
but rather to try to achieve improvement in func-
tional outcomes and minimize impairment, which
contribute to improved quality of life. Optimiza-
tion of medical treatment by ensuring titration
of dose or switching of treatment, where appro-
priate, may improve these outcomes. In addition,
the development of novel agents and formula-
tions has helped to provide more options for
patients and should drive the individualization
of medication.[64] As a result, medication can be
managed to improve efficacy and according to
patient preference, thus improving adherence.
Treatment guidelines in the US recommend
stimulant medications (methylphenidate or am-
fetamine) as a first-line treatment option alongside
psychoeducation.[1,37,65] In Canada, long-acting
preparations of amfetamine or methylphenidate,
or atomoxetine are recommended as first-line treat-
ments.[66] The establishment of treatment guide-
lines in Europe has been hampered by differing
treatment practices within European countries.[9]
Specifically, there are marked differences in the
availability of medications and prescribing prac-
tices between countries. This variability in drug
use is likely a reflection of country-specific health-
care policies, for instance prescribing restrictions
CNS Drugs 2012; 26 (8)
702 Steer et al.

Table III. Prevalence of the use of attention-deficit hyperactivity undertreated in developed countries around the
disorder medications world.
Country Rate of treatment (% of total population
of children and adolescents)
Canada[68-70] 1.3–1.6 7. Conclusion
Denmark[49] 2.4
Finland[49] 1.23 In summary, clinical trials have demonstrated
France[71] 1.8 that lisdexamfetamine is effective and well toler-
Germany[72] 1.06 ated in children, adolescents and adults with
Iceland[49] 12.46 ADHD. Lisdexamfetamine is a prodrug and is
Israel[73-75] 1.2–2.5 inactive until it is hydrolysed in the blood. This
Netherlands[76] 0.8–4.2 mechanism provides a gradual release of the drug
Norway[49] 4.73 throughout the day and results in efficacy lasting
Spain[77] 0.77–1.28 (6–14 y) 13 hours in children and 14 hours in adults. This
Sweden[49] 2.52 long duration may be particularly important for
Switzerland[78] 1.02 those who require a consistent effect throughout
UK[79,80] 0.53–0.6 the afternoon and into the early evening, either to
USA[81-84] 2.5–4.6 facilitate studying/homework or family interac-
tions. Where indicated, administration of lisdex-
amfetamine dissolved in water may be clinically
useful. Post hoc analyses suggest lisdexamfetamine
and reimbursement rates, rather than differences
is efficacious in patients who have previously shown
in epidemiology.[6,49,67] For example, atomoxetine,
an inadequate response to methylphenidate. Lis-
dexamfetamine and methylphenidate are all
dexamfetamine may therefore be useful in treat-
available in the UK,[5] whereas methylphenidate
ment optimization when greater efficacy, longer
is the primary pharmacological agent in Germany,
duration of action, or greater predictability and
where atomoxetine is also available. Although
reliability is needed. Further studies are required to
amfetamines can be used in Germany, they must
provide head-to-head data with other long-acting
be manufactured on an individual basis in a local
ADHD medications and long-term safety data, as
pharmacy. In Spain, Denmark and Sweden, methyl-
well as to assess the impact of lisdexamfetamine on
phenidate (immediate release and long acting with
quality of life and functional outcomes.
osmotic and bead technology) and atomoxetine are
available. In Italy, only atomoxetine and methyl-
phenidate (long-acting with osmotic technology) are Acknowledgements
available, but only in some reference centres and via
a national registry system, which limits patients’ This review was supported by funding from Shire Devel-
opment Inc. The authors were responsible for the interpreta-
access to medication. tion of the information presented and for the decision to
The approach to therapy varies between coun- submit this manuscript for publication in CNS Drugs. The
tries (i.e. pharmacotherapy vs behavioural therapy). authors thank Bret Fulton of RPh and Sarah Griffiths from
Oxford Pharmagenesis Ltd for suggestions on the text, the
Pharmacotherapy in conjunction with behav- collation of authors’ comments, and the editing the paper for
ioural therapy is most commonly used in the UK, submission. This editorial help was funded by Shire Devel-
Denmark, Germany, Spain, Iceland and the opment Inc.
Netherlands, whilst behavioural therapy or other All authors were involved in the conception and planning
of the focus and content of this review, and in directing ac-
forms of psychotherapy predominate in France, quisition, analysis and interpretation of the published litera-
Austria and Finland.[6,49] However, even in coun- ture included. They were all involved in drafting and critical
tries where pharmacotherapy is common, rates of revision of the manuscript for important intellectual content
European children receiving medication is far and provided approval of the final submitted version of the
manuscript.
below the prevalence of ADHD (table III).[49,77-84] Dr Steer has received consulting fees, honoraria or
These data indicate that the disease is substantially speakers’ fees from Shire, Jannsen and Eli Lilly. Dr Frölich

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (8)
Lisdexamfetamine Dimesylate for ADHD
has received research funding, consultancy fees and speakers’
fees from Shire, Medice, Novartis, Lilly and Janssen Cila.
Dr Soutullo has received research funding, consultancy fees,
speakers’ fees or royalties from Abbott, Alicia Koplowitz
Foundation, Astra Zeneca, Bristol-Myers Squibb, Carlos III
Institute (FIS): Redes Temáticas de Investigación Co-
operativa, Editorial Médica Panamericana, EINAQ (Europ-
ean Interdisciplinary Network ADHD Quality Assurance),
Eli Lilly, GlaxoSmithKline, Gobierno de Navarra, Grupo
Aula Médica, Grupo Correo, Janssen, Medice/Juste, Novartis,
Pfizer, Otsuka, PIUNA (University of Navarra Research Pro-
gram), Stanley Medical Research Institute-NAMI, Shire and
Solvay. Dr Johnson has received study funding, advisory board
fees and speakers’ fees from Shire. Dr Shaw was previously an
employee of Shire PLC and owns stock in the company.
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Correspondence: Dr Christopher Steer, Paediatric Depart-
ment, Victoria Hospital, Hayfield Road, Kirkcaldy, Fife,
Scotland, KY2 5AH, UK.
E-mail: christopher.steer@nhs.net
CNS Drugs 2012; 26 (8)