An Update on Pharmacological, Pharmacokinetic Properties and Drug–Drug Interactions of Rotigotine Transdermal System in Parkinson’s Disease and Restless Legs Syndrome
An Update on Pharmacological, Pharmacokinetic Properties and Drug-Drug Interactions of Rotigotine Transdermal System in Parkinson's Disease and Restless Legs Syndrome
Jan-Peer Elshoff 0 1
Willi Cawello 0 1
Jens-Otto Andreas 0 1
Francois-Xavier Mathy 0 1
Marina Braun 0 1
0 UCB Pharma , Braine l'Alleud , Belgium
1 UCB Pharma , Alfred-Nobel-Strasse 10, 40789 Monheim am Rhein , Germany
This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D3/D2/D1 dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution ([2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steadystate plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of rotigotine as a continuous non-ergot D3/D2/D1 dopamine receptor agonist in the treatment of PD and RLS.
Parkinsons disease (PD) and restless legs syndrome (RLS)
are two common yet distinct neurological disorders for
which dopaminergic therapy has proven valuable. PD is a
progressive neurodegenerative disorder that afflicts
approximately 1.6 % of adults over 65 years of age, with a
higher rate in men [1, 2]. The underlying pathophysiology
of PD is the selective loss of dopaminergic neurons in the
substantia nigra . New discoveries over the past decade
have led to increased therapeutic options [3, 4]. Patients
with PD have a characteristic set of signs and symptoms,
primarily movement-related motor symptoms (e.g., tremor
at rest, muscle rigidity, bradykinesia, and postural
instability) and non-motor symptoms (e.g., sleep disturbance,
cognitive dysfunction or dementia, mood, and
gastrointestinal/bladder disturbances) . Motor symptoms are
initially asymmetric, but often become bilateral with
advanced disease . Up to 90 % of patients with PD
develop speech impairments during the course of their
disease . Depression, anxiety, dementia, psychosis, and
sleep disturbances often accompany PD . In some
patients, neuropsychiatric problems and sleep disturbance
may have a greater impact on quality of life than the motor
symptoms of PD .
Whilst levodopa is the standard of care in advanced PD,
its benefits are short-lived, requiring frequent dose
escalation and chronic administration that eventually leads to
an increased rate and severity of dyskinesia and off
periods . Another approach to the management of PD is
the use of orally administered dopamine receptor agonists,
such as pramipexole and ropinirole, as monotherapy early
in the disease course, and concomitantly with levodopa in
advanced stages [6, 13]. Initial therapy with a dopamine
agonist rather than levodopa may reduce the risk of motor
complications . However, intermittent oral treatment
with levodopa or dopamine agonists results in pulsatile
stimulation of striatal dopamine receptors which does not
reflect the continuous stimulation observed under
physiological conditions [13, 14]. The problems associated with
fluctuating striatal dopaminergic activity due to peroral
treatment led to the concept of continuous dopaminergic
stimulation in the brain as an alternative treatment
RLS is a motor disorder characterized by the urge to
move the legs during periods of evening rest or inactivity
and is accompanied by unpleasant sensations (paresthesia,
itching, pain) . It affects up to 11 % of the general
population, with a two-fold preponderance among women
. The syndrome has a hereditary component as there is
a 6.7-fold increased risk in patients whose first-degree
relatives have early-onset disease (i.e., occurrence before
45 years of age) . Abnormalities in the central,
subcortical dopamine pathways and impaired iron homeostasis
may also cause RLS . Initially, symptoms occur
predominantly during the evening and night. Over time,
patients with advanced disease often develop debilitating
symptoms during the day. Dopaminergic agents in low
doses are the recommended first-line pharmacological
therapy for moderate to severe RLS . A main
complication of dopaminergic RLS therapy can be the
development of augmentation, characterized by an overall
worsening of symptoms beyond pre-treatment levels .
Augmentation has been reported in 36 of 60 patients
receiving levodopa in a 6-month, open-label, multicenter
study , but appears to occur less frequently with
longeracting dopamine agonists .
(6S)-6-(propyl[2-(2-thienyl)ethyl]amino)5,6,7,8-tetrahydro-1-naphthalenol, is a dopamine receptor
agonist approved for the daily treatment of early- and
advanced-stage idiopathic PD and moderate to severe RLS in
Europe, the USA, and other countries. Table 1 gives the
available dose strengths and their related drug content and
patch size. Continuous transdermal delivery of rotigotine
maintains stable plasma concentrations of unconjugated
active parent drug over 24 h with a single daily application .
Transdermal application has several key advantages over
conventional oral systemic therapy, including elimination of
variables influencing gut absorption (e.g., impaired
gastrointestinal motility, food effects); direct entry into the systemic
circulation, avoiding first pass effects of the liver; and utility
in perioperative and intensive care settings.
The purpose of this narrative review is to provide a
comprehensive account of available data describing the
single-dose and steady-state pharmacokinetics of rotigotine
following administration via a transdermal patch in healthy
subjects and in patients with PD and RLS. Managing the
use of the rotigotine transdermal system in special patient
populations and those receiving concomitant drugs is also
2 Mechanism of Action
The parent drug rotigotine, in its unconjugated state, is the
pharmacologically active compound at the dopamine
receptor. Whilst the exact mechanism of action of rotigotine as
a treatment for PD is not completely understood, rotigotine
has in vitro activity that spans the dopamine D1 through D5
receptors, as well as select adrenergic and serotonergic sites
. Based on the distribution of the different dopamine
receptors in the brain and their contribution to motor
coordination, rotigotine is best described as a D3/D2/D1 receptor
agonist. Recent studies using recombinant dopamine D1, D2,
Table 1 Rotigotine
Patch surface area (cm2)
Total drug content in patch (mg)
Nominal dose delivered in 24 h (mg)
Doses [8 mg/24 h may be achieved by application of a combination of several patches
a Approved for treatment of restless legs syndrome
b Approved for treatment of Parkinsons disease
and D3 receptors and [3H]rotigotine instead of
[3H]antagonists as radioligands in binding and functional
assessments confirmed the high affinity binding of rotigotine on D3
and D2 receptors, but also showed a similarly high affinity
towards the D1 receptor . Thus, in contrast to other
dopamine receptor agonists, which predominantly act as D2
and D3 receptor agonists, rotigotine also acts on D1 dopamine
receptors, suggesting that rotigotine more closely resembles
dopamine or apomorphine than other dopamine agonists
. However, rotigotine is also an antagonist at a2B
adrenergic receptors and an agonist at 5-HT1A receptors, and
interaction could contribute to its beneficial efficacy in vivo
. Rotigotine was shown not to interact with 5-HT2B
receptors . Overall, the capacity of rotigotine to stimulate
dopamine D1D3 receptors within the caudate putamen
regions of the brain is likely the basis for its efficacy in patients
with PD .
Several animal models have characterized the pre- and
post-synaptic activity of rotigotine. The pre-synaptic
activity of rotigotine is exemplified by hypomotility
following low doses of the agonist , as well as reduction in
cbutyrolactonestimulated dopamine synthesis  and
extracellular dopamine concentrations . Post-synaptic
activity of rotigotine was demonstrated in rats via two
models: reserpine reversal and stereotypy induction . In
addition, observations of contraversive turning and
enhanced locomotor activity in 6-hydroxydopaminetreated
rat and MPTP-treated monkey models further prove its
post-synaptic activity on dopamine receptors [29, 30].
3 Pharmacokinetic Properties
3.1 Bioavailability and Metabolism
The physicochemical properties of rotigotine are
compatible with drug permeation through the skin, which not
only avoids the extensive first pass effect after oral
administration but also facilitates continuous drug
administration and systemic exposure over 24 h. In a pilot
study, a 24-h patch-on period of one transdermal rotigotine
patch (4 mg; 20 cm2) resulted in a steady rise in plasma
drug concentrations after a 2- to 4-h lag phase (data on
file, UCB Pharma). The mean maximum plasma drug
concentration (Cmax; 0.56 ng/mL) was evident 19 h
postapplication [time to reach Cmax (tmax)] before plasma drug
concentrations declined to 0.02 ng/mL 24 h after patch
removal. The mean area under the plasma concentration
time curve (AUC) from zero up to the last quantifiable
plasma concentration (AUC0t) was 11.1 ng h/mL, and the
mean terminal elimination half-life (t ) was 5.3 h (data on
file, UCB Pharma). Systemic exposure to rotigotine
approximately doubled when two patches were applied
simultaneously, without any material change in the lag
phase, tmax, and t (data on file, UCB Pharma). Analysis
of plasma samples after transdermal application of 8 mg/
24 h rotigotine detected presence of a despropyl
metabolite in some samples close to the lower limit of
The absolute bioavailability and metabolism of the
patch was determined in a randomized, two-sequence,
twoperiod, crossover study in six male subjects who were
administered the transdermal rotigotine patch (2 mg
unlabelled/24 h) and an intravenous continuous 12-h rotigotine
infusion (1.2 mg of rotigotine including 0.6 mg of
[14Crotigotine]) . Profiles of unconjugated rotigotine
concentrations versus time in plasma were similar following
administration of both formulations (Fig. 1). Furthermore,
similar levels of rotigotine Cmax and a similar decreasing
profile of these concentrations after patch removal was
observed. Median absolute bioavailability of transdermal
rotigotine was 37 % of the applied dose after the 24-h
application time period ([60 % of the drug delivered to the
skin) . Systemically absorbed rotigotine is rapidly
metabolized following intravenous administration (Fig. 2).
Conjugation of the parent compound results in two primary
metabolites: rotigotine sulfate and rotigotine glucuronide.
In addition, the drug undergoes oxidative
Fig. 1 Mean rotigotine plasma concentrations after application of
rotigotine transdermal patch (2 mg/24 h) or intravenous infusion of
1.2 mg over 12 h. Adapted with permission from Cawello et al. 
biotransformation and is converted to two N-desalkylated
metabolites (N-desthienylethyl- and
N-despropyl-rotigotine), each of which have short-lived activity as they are
rapidly conjugated to inactive moieties. Elimination of
N-despropyl-ro go ne
rotigotine metabolites was primarily via urine (71 %) and
to a minor extent into feces (23 %). Renal elimination of
the unchanged parent compound was negligible (\1 %)
3.2 Mass Balance
The single-dose disposition of transdermally applied
rotigotine in male subjects was characterized in a phase I
study of six Caucasian men who received a single
transdermal patch containing radiolabeled rotigotine (2 mg/
24 h) applied to the forearm for 24 h . Measurement of
unconjugated rotigotine in plasma, urine, and fecal samples
was determined by liquid chromatography with tandem
mass spectrometry. Approximately 95 % of administered
rotigotine was recovered within 96 h of transdermal
application, including drug left in the patch. Within 24 h,
51 % of the total radioactivity was delivered to the body
(46 % of the total radioactivity was absorbed into the
systemic circulation and 5 % remained in the skin) to give
an apparent total dose (i.e., the dose delivered to the skin of
Fig. 2 Metabolic pathway of rotigotine. Adapted with permission from Cawello et al. 
the patient) of 2.3 mg/24 h and an absorbed dose of
2.1 mg/24 h. No radiolabel could be detected in plasma
since all samples were below the limit of quantitation.
Rather, most of the absorbed dose was eliminated in urine
(66 %) and to a lesser extent in feces (22 %) within 96 h of
patch application . Mean peak plasma unconjugated
rotigotine concentrations of 0.28 ng/mL were achieved at
24 h post-application.
3.3 Dose Proportionality
Based on pooled data from 17 phase I studies in largely
healthy subjects, transdermally administered rotigotine
exhibited a dose-proportional pharmacokinetic profile
across the entire therapeutic dose range for RLS and the
lower half of the therapeutic dose range for PD (data on
file, UCB Pharma; Fig. 3). This pooled analysis included
data from a total of 522 subjects (338 healthy subjects, 23
patients with idiopathic RLS, 63 patients with early-stage
PD, 66 patients with advanced PD, eight subjects with
moderate hepatic impairment, and 24 subjects with renal
impairment) who received administration of rotigotine
124 mg/24 h.
Three studies provide evidence that transdermal
administration of rotigotine provides dose-proportional
pharmacokinetics in patients with early- and
advancedstage idiopathic PD [23, 33, 34]. Two of these (SP630 and
SP864) were included in the aforementioned pooled
analysis. In SP630, 63 patients with early PD received an
initial daily rotigotine dose of 2 mg/24 h, which was
increased during a 24-day titration phase in 6-day increments
of 2 mg/24 h to a maintenance dose of 8 mg/24 h .
Patients received the final dose for an additional 6 days to
Fig. 3 Dose proportionality of rotigotine pharmacokinetics based on
mean (SD) area under the plasma drug concentrationtime curve
(AUC) from 1 mg/24 h to supratherapeutic dose rates of 24 mg/24 h.
Data derived from 17 phase I studies comprising healthy subjects and
patients with restless legs syndrome and early- and advanced-stage
ensure steady-state conditions. A dose-proportional
increase in steady-state trough plasma concentrations of
unconjugated rotigotine was observed over the therapeutic
dose range of 2 mg/24 h to 8 mg/24 h rotigotine. Mean
Ctrough,ss values increased from 0.17 ng/mL to 0.90 ng/mL
unconjugated rotigotine . The SP864 study
demonstrated dose-proportional pharmacokinetics of rotigotine at
steady state in patients with advanced PD (n = 66) from
8 mg/24 h rotigotine to the maximum therapeutic dose of
16 mg/24 h, and supratherapeutic doses of 20 and 24 mg/
24 h . Patients in this study received titrated daily
doses of 4, 8, 12, 16, 20, and 24 mg/24 h during study
weeks 1, 2, 3, 4, 5, and 6, respectively. Mean Cmax at
steady state (Cmax,ss) values increased from 1.38 ng/mL
with 8 mg/24 h rotigotine to 4.34 ng/mL with 24 mg/24 h
rotigotine . Finally, SP591 was a dose-escalation study
in 34 patients (mean age 69 years) with advanced PD.
Patients were initiated with a starting dose of rotigotine
transdermal system of 4 mg/24 h and titrated over
4277 days to a target dose of 24 mg/24 h . Plasma
rotigotine concentrations were measured in a subset of
patients immediately prior to patch removal and 212 h
following application. Mean unconjugated rotigotine
plasma concentrations were found to increase proportionally
with dose: 0.5 ng/mL for 4 mg/24 h (n = 3), 1.2 ng/mL
for 8 mg/24 h (n = 3), 2.4 ng/mL for 12 mg/24 h (n = 3),
3.4 ng/mL for 16 mg/24 h (n = 3), 3.8 ng/mL for 20 mg/
24 h (n = 6), and 6.0 ng/mL for 24 mg/24 h (n = 3).
Variability between subjects was high .
3.4 Steady-State Pharmacokinetics
In the 14-day SP503 study, in which multiple daily doses of
rotigotine transdermal patch (4.5 mg; 10 cm2) were
administered to 30 healthy men, steady-state plasma
concentrations were achieved within 12 days of dosing (data
on file, UCB Pharma). Changes in plasma drug
concentrations suggestive of accumulation were not observed.
Instead, mean plasma profiles showed relatively stable
rotigotine concentrations after multiple dosages (Fig. 4),
and mean trough plasma concentration remained stable
over the treatment period.
The stability of mean 24-h plasma rotigotine
concentrations at steady-state was quantified in 40 evaluable,
healthy Caucasian male subjects (mean age of 24 years)
who applied doses (3 mg/24 h) of the transdermal system
either as a single large patch or two smaller patches applied
to six different body sites . A randomized, crossover
design was used for this purpose, wherein subjects received
an initial dosage of 2 mg/24 h rotigotine for 3 days
followed by 3 mg/24 h rotigotine, either in a 15-cm2 patch or
in a patch combination of 1 9 5 cm2 (1 mg/24 h) plus
1 9 10 cm2 (2 mg/24 h), until day 13, when they switched
Fig. 4 Plasma rotigotine concentrations (arithmetic mean SD) in
30 healthy men during a 14-day multiple dosage regimen of rotigotine
transdermal patch (2 mg/24 h; 10 cm2)
to the alternative regimen for day 13 and day 14 dosing.
Subjects were also randomized to a daily patch rotation
schedule for six application sites (i.e., abdomen, thigh, hip,
flank, shoulder, or upper arm), except for days 1214, when
each participant used one specific body site for patch
Stable steady-state 24-h plasma concentrations for
unconjugated rotigotine were observed across all six
application sites . Mean rotigotine plasma concentrations
decreased slightly after application of a new patch owing to
a lag phase of approximately 2 h followed by an increase to
plateau concentrations. Cmax,ss was reached after a median
of 16 h (range 020 h) after patch application. Immediately
prior to patch removal, mean rotigotine plasma
concentrations were equal to the corresponding concentrations at time
of patch removal on the previous days. Delivery via a single
large patch compared with a combination of smaller patches
did not influence the bioavailability of rotigotine, as
evidenced by point estimates for the ratios of geometric means
between the treatments for Cmax,ss [0.52 vs. 0.54 ng/mL;
ratio 0.97, 90 % confidence interval (CI) 0.921.03] and
AUC024 h,ss (9.12 vs. 9.56 ng h/mL; ratio 0.95, 90 % CI
0.911.01). Steady-state conditions in healthy subjects were
similar to patients with early-stage PD (see below).
Bioavailability showed some variability depending on patch
application site; the respective mean ratio for AUC024 h,ss
normalized for total drug content ranged between 0.87
(90 % CI 0.830.93) for abdomen versus flank, and 1.46
(90 % CI 1.381.54) for shoulder versus thigh .
3.5 Special Populations
3.5.1 Effects of Sex Pharmacokinetics of single-dose rotigotine transdermal system (2 mg/24 h) were assessed in 48 healthy male and female subjects of either Caucasian or Japanese ethnicity
during and after a patch-on period of 24 h . Female
subjects had higher mean Cmax (Caucasians 0.23 vs.
0.17 ng/mL; Japanese 0.29 vs. 0.17 ng/mL) and AUC from
zero up to infinity (AUC0?) (Caucasians 4.74 vs.
3.70 ng h/mL; Japanese 5.8 vs. 3.5 ng h/mL) than male
subjects in both ethnic groups . The relative nominal
differences in plasma concentrations of unconjugated
rotigotine and derived pharmacokinetic parameters
between genders were mitigated when corrected for
differences in body weight and apparent dose .
3.5.2 Effects of Ethnicity
Small differences in the pharmacokinetics of unconjugated
and total rotigotine as well as high inter-individual
variability in drug exposure were observed between healthy
Japanese and Caucasian subjects following single-dose and
multiple daily doses of the transdermal system . In an
open-label, parallel-group study, healthy male and female
subjects of Japanese (n = 24) or Caucasian (n = 24)
ethnic origin were matched by sex, body mass index, and age
before application of a single transdermal patch delivering
2 mg/24 h rotigotine to the ventral/lateral abdomen for
24 h . The mean apparent dose of rotigotine was
comparable in both groups (2.0 0.5 mg for Japanese
subjects and 2.1 0.6 mg for Caucasian subjects) and in
line with the labeled drug delivery rate over 24 h. Plasma
concentrationtime profiles of unconjugated rotigotine
were similar for both ethnic groups, as evidenced by
geometric mean ratios (without normalization) for Cmax of
1.14 (90 % CI 0.881.47) and AUC from time zero to last
quantifiable concentration (AUC0t) of 1.10 (90 % CI
0.841.44). For both parameters, the differences between
groups were minimized by normalization for body weight
and increased by normalization for apparent dose, but
normalization for both factors resulted in a ratio for
Japanese versus Caucasians of 1.08 (90 % CI 0.881.32) for
Cmax and 1.05 (90 % CI 0.851.28) for AUC0t. However,
a difference between ethnic groups was observed for total
rotigotine exposure, with geometric mean ratios for Cmax
1.30 (90 % CI 1.121.52) and AUC0t 1.25 (90 % CI
1.081.45) exceeding unity even after correction for body
weight and apparent dose .
Multiple doses of open-label rotigotine transdermal
system (1, 2, and 4 mg/24 h) in 12 Japanese and 12
Caucasian men and women produced mean plasma
concentrationtime profiles for unconjugated rotigotine that were
similar in both ethnic groups at day 3 for each dosage .
When the data were pooled across dose rates without
normalization, statistical comparison (Japanese vs.
Caucasian) for Cmax,ss (1.06, 90 % CI 0.841.34) and
AUC024 h,ss (1.09, 90 % CI 0.861.37) for unconjugated
rotigotine indicated no relevant differences between the
two ethnic groups. Normalization for weight and apparent
dose reduced variability as indicated by narrower 90 % CIs
for Cmax,ss (1.11, 90 % CI 0.921.33) and AUC024,ss (1.13,
90 % CI 0.941.36). Plasma level of total rotigotine was
about ten times higher than the plasma level of
unconjugated rotigotine. Unlike in the single-dose study ,
Caucasian subjects had a slightly higher concentration of
total rotigotine than Japanese subjects, based on the
weight- and apparent dose-normalized point estimate of
geometric mean ratios for Cmax,ss (0.90, 90 % CI
0.791.03) and AUC024 h,ss (0.89, 90 % CI 0.791.00).
Overall, the findings from these two studies suggest similar
dose requirements for Japanese and Caucasian populations
Pharmacokinetic data collected in 48 healthy Korean
men and women found that approximately 50 % of the
total drug content of the rotigotine patch was delivered to
the skin over 24 h , which is a similar percentage to
that observed in the mass balance study of Caucasian men
. At the 2 mg/24 h and 4 mg/24 h dose rate,
respectively, steady-state geometric means for unconjugated
rotigotine Cmax were 0.35 and 0.84 ng/mL and for
AUC024 h were 5.88 and 13.74 ng h/mL . Thus, the
pharmacokinetic parameters of unconjugated rotigotine in
Korean subjects were similar to that observed in separate
studies of Caucasian and Japanese subjects .
The pharmacokinetics of a single-dose, 24-h abdominal
application of transdermal rotigotine 2 mg/24 h was
assessed in a single-center, open-label study of healthy
black African (n = 21) and Caucasian subjects (n = 24)
(data on file, UCB Pharma). Based on visual inspection,
Fig. 5 shows that there was little difference between the
two ethnic groups regarding the plasma concentration
profile of unconjugated rotigotine. Again, a lag phase of
2 h was observed before the detection of unconjugated
Caucasian healthy subjects
Black healthy subjects
Fig. 5 Plasma rotigotine concentrations (arithmetic mean SD) in
21 black African and 24 Caucasian subjects after single-dose
administration of rotigotine transdermal system 2 mg/24 h
rotigotine in plasma. Despite the Caucasian and black
African subjects being well matched demographically and
both cohorts receiving the same nominal dose, mean
plasma rotigotine concentrations at most time points in the
Caucasian group were slightly higher than in the black
African group. Pharmacokinetic analysis of AUC ratios
revealed that total systemic exposure to rotigotine in black
African subjects may be slightly lower than in Caucasian
subjects (Table 2).
3.5.3 Effects of Liver and Renal Impairment
Steady-state pharmacokinetics following administration of
a single rotigotine transdermal patch with a 24-h patch-on
period (2 mg/24 h over 3 days) were evaluable in eight
patients with moderate hepatic impairment (Child-Pugh
grade B) versus eight healthy adult male subjects .
Mean plasma concentrationtime curves for unconjugated
rotigotine showed no considerable differences between
healthy subjects and subjects with moderate hepatic
impairment. For unconjugated rotigotine, point estimates for
Cmax,ss and AUC024 h,ss between the two groups
(geometric mean ratio of impaired hepatic function to
normal) were 0.94 (90 % CI 0.661.35) and 0.90 (90 % CI
0.591.38), respectively. Compared with healthy subjects,
subjects with moderate hepatic impairment had a slightly
shorter mean unconjugated rotigotine elimination half-life
(6.7 vs. 5.6 h), similar mean renal clearance (0.11 vs.
0.10 L/h), and higher overall total body clearance (both
332 vs. 377 L/h). The generally high value for total body
clearance can be mainly attributed to the rapid and
complete metabolism, as described above . Overall, a
moderate degree of liver insufficiency did not alter the
steady-state pharmacokinetics of unconjugated rotigotine
to a relevant extent. The lack of accumulation of
unconjugated rotigotine in patients with moderate liver
dysfunction provides evidence that dose adjustment is not
required for patients with mild or moderate hepatic
Assessment of the pharmacokinetics of unconjugated
rotigotine following a single transdermal (2 mg/24 h) 24-h
patch-on period was explored in 32 subjects with varying
degrees of renal function . Pharmacokinetic data were
available for eight healthy subjects, one subject with mild
impairment of renal function, seven patients with moderate
impairment of renal function, eight patients with severe
impairment of renal function, and eight patients with
endstage renal disease (ESRD) requiring hemodialysis.
Median plasma concentrationtime profiles were similar for all
renal function cohorts, with peak concentrations occurring
approximately 16 h following patch application, with the
exception of the ESRD-hemodialysis cohort, who achieved
maximum blood levels 24 h post-application. As expected,
Table 2 Race-based rotigotine pharmacokinetic metrics in 21 black African and 24 Caucasian subjects who received single-dose administration
of rotigotine transdermal system 2 mg/24 h
Parameter (mean SD)
Black African (n = 21)
Caucasian (n = 24)
Geometric mean ratioa
AUC024 h area under the plasma concentration versus time curve from zero up to 24 h, AUC0t area under the plasma concentrationtime curve
from zero up to the last analytically quantifiable concentration, AUC0? area under the plasma concentrationtime curve from zero up to infinity,
CI confidence interval, Cmax maximum plasma concentration, t terminal half-life, tmax time to reach a maximum plasma concentration
a Black African/Caucasian
conjugated rotigotine concentrations increased with
worsening renal function , as the inactive conjugates are
mainly eliminated by renal excretion . Bioavailability
of unconjugated rotigotine was not affected by varying
renal function, as the respective ratios for Cmax and AUC0t
between the groups with moderate to severe renal
impairment and healthy subjects were 0.93 (90 % CI 0.601.47)
and 0.88 (90 % CI 0.581.33) for moderate renal
impairment, 1.18 (90 % CI 0.761.82) and 1.14 (90 % CI
0.761.71) for severe renal impairment, and 1.25 (90 % CI
0.811.93) and 1.05 (90 % CI 0.701.57) for end-stage
renal insufficiency requiring hemodialysis . The
elimination half-life of rotigotine was also comparable
among the cohorts. With point estimates near 1, these data
suggest that no dose adjustments are required for rotigotine
transdermal system in patients with different stages of
chronic renal insufficiency, including patients on
hemodialysis. These observations are particularly valuable as
RLS is often a co-morbid condition in patients with ESRD.
3.6 Target Population: Early- to Advanced-Stage
PD and Moderate to Severe RLS
PD who received 824 mg/24 h rotigotine via the
transdermal system over a 6-week period, stable steady-state
plasma concentrations of unconjugated rotigotine were
demonstrated over the 24-h application time period at each
dose rate . Over the 24-h sample period, mean
steadystate plasma concentrations of unconjugated rotigotine
fluctuated close to 1 ng/mL at the 8 mg/24 h dose rate,
increasing by 0.5 ng/mL for every 4 mg/24 h dose increase
up to a slightly broader range around 3.5 ng/mL for the
24 mg/24 h dose .
Rotigotine elimination after patch removal was
assessed in 20 subjects with RLS at steady-state conditions for
4 mg/24 h, using one- and two-compartment model
analyses . The one-compartment model yielded an
average elimination half-life of 57 h. Use of a
twocompartment model revealed initial rapid systemic
clearance of the drug (e.g., from 0.65 to 0.15 ng/mL within
46 h post-removal) with an elimination half-life (alpha
phase) of 23 h. The subsequent terminal elimination
half-life (beta phase) was approximately 1020 h, with
detection of much lower plasma levels (0.010.03 ng/mL
at 36 h post-removal).
3.6.1 Steady-State Pharmacokinetics
3.6.2 Effects of Age and Sex
Two phase I studies (SP630, SP651) in overall 99 subjects
with early-stage PD assessed rotigotine steady-state
pharmacokinetics following administration of the once-daily
patch at the highest therapeutic dose for treatment of early
PD (8 mg/24 h) . Rotigotine release from the patch,
which is an indicator for the dose absorbed , ranged
from 3148 %. Similar to healthy subjects (see above),
stable steady-state 24-h plasma concentrations of
unconjugated rotigotine were observed in both studies . For
study SP630, a mean Cmax,ss of 1.35 ng/mL was reached at
a median of 16 h and mean AUC024 h,ss was 19.62 ng h/
mL. Corresponding mean values for study SP651 were 1.13
ng/mL and 17.75 ng h/mL. In 66 patients with advanced
A phase I study (SP630) evaluated the effects of age and
sex on steady-state rotigotine pharmacokinetics in 63
patients with early idiopathic PD . Rotigotine was
initiated at a daily dose of 2 mg/24 h that was increased to a
maintenance dose of 8 mg/24 h. No major differences were
observed between age cohorts and sex in unconjugated
rotigotine plasma concentrations or derived
pharmacokinetics. Steady-state geometric mean ratios for AUC024 h,ss
and Cmax (normalized by body weight and apparent dose)
comparing patients \65 years with those C65 years were
1.06 (90 % CI 0.931.20) and 1.09 (90 % CI 0.951.25),
and, for comparison of males to females, were 1.04 (90 %
CI 0.921.18) and 0.99 (90 % CI 0.861.14) .
In a phase III, multinational, randomized controlled
trial (CLEOPATRA-PD) , the pharmacokinetic
profile of rotigotine following removal and reapplication of
transdermal patches was examined in 56 patients with
advanced-stage PD . A total of 986 samples with
measurable unconjugated rotigotine concentrations were
collected immediately before patch removal and 14 h
after administration of a new patch. Dose proportionality
was observed from 2 to 16 mg/24 h during the 7-week
titration phase. At the end of the titration phase and
completion of the daily 16 mg/24 h dose, mean plasma
drug concentration was 1.2 ng/mL. Maintenance
concentrations just prior to patch removal were stable, as
indicated by levels of 1.5, 1.4, and 1.3 ng/mL for days 1,
29, and 85, respectively. As identified in the study
assessing rotigotine steady-state pharmacokinetics in
patients with early idiopathic PD , age (\65 or
C65 years) and sex had no impact on mean trough
plasma concentrations of unconjugated rotigotine
following removal and reapplication of the transdermal
system. Overall, stable plasma levels over the 4-month
maintenance phase were observed, with minimal
fluctuations following patch change.
3.6.3 Long-Term Plasma Concentrations of Rotigotine
In an open-label extension of a phase IIb trial (SP710),
rotigotine plasma levels were monitored during long-term
treatment with rotigotine transdermal system in 284
patients with moderate to severe idiopathic RLS . Each
patient received once-daily transdermal patches of
rotigotine titrated within 4 weeks to their optimal dose (0.5, 1.0,
2.0, 3.0, or 4.0 mg/24 h). Valid rotigotine plasma
concentrations were available for 187 patients after 1 year and
103 patients after 5 years. Dose proportionality was
observed from 0.5 to 4 mg/24 h and confirmed after treatment
over 1 and 5 years (Table 3). Comparing the plasma
concentration data, stable plasma levels were found across
dose rates over the 5-year period, suggesting that long-term
administration did not alter the pharmacokinetics of
4 DrugDrug Interactions
4.1 DrugDrug Interactions with Common
Four studies have evaluated the drugdrug interaction
potential between rotigotine and levodopa/carbidopa,
domperidone, oral contraceptives, cimetidine, and omeprazole
under steady-state conditions . According to the
generally accepted regulatory requirements,
bioequivalence was concluded (i.e., no relevant interaction) if
the 90 % CIs for the ratio of the geometric means for
unconjugated rotigotine alone versus in combination with test
drugs, or vice versa, were within the 80125 % acceptance
range for all primary pharmacokinetic parameters .
In an open-label phase I study, 24 patients with RLS (12
Caucasian men, 12 Caucasian women) received
levodopa/carbidopa (100/25 mg twice daily) and rotigotine
transdermal system (initial dose 2 mg/24 h for 3 days,
followed by 4 mg/24 h) in a randomized sequence .
Treatment sequence A was initiated with rotigotine
followed by the combination treatment, while treatment
sequence B was initiated with levodopa/carbidopa followed
by the combination treatment. Each treatment sequence
lasted 12 days. Mean plasma concentrationtime profiles
of levodopa/carbidopa were similar when given alone or in
combination with rotigotine. Likewise, steady-state
unconjugated rotigotine plasma concentrationtime profiles
were not altered in the presence of levodopa/carbidopa
(Fig. 6a). Importantly, mean apparent rotigotine doses
were similar for both treatment sequences (A: 4.72 mg on
day 7 and 4.18 mg on day 10; B: 4.18 mg on day 9 and
4.36 mg on day 12). Derived pharmacokinetic parameters
indicated absence of an interaction between
levodopa/carbidopa and rotigotine, and vice versa. The geometric means
of levodopa/carbidopa Cmax,ss and AUC012 h,ss with (and
without) rotigotine were 1,612/160 ng/mL (1563/152 ng/
mL) and 2561/789 ng h/mL (2632/764 ng h/mL). For
Table 3 Mean (SD) plasma concentrations of unconjugated
rotigotine after year 1 and year 5 of maintenance therapy in 284 patients
with moderate to severe idiopathic restless legs syndrome .
Plasma concentrations at the lower dose rates (0.5 and 1 mg/24 h)
should be interpreted with caution because of the small numbers of
patients in those cohorts
Transdermal rotigotine dosage (mg/24 h)
Plasma drug concentration at year 1 (ng/mL)
Plasma drug concentration at year 5 (ng/mL)
Rotigotine alone (4 mg/24 h)
Rotigotine (4 mg/24 h) + omeprazole (40 mg/day)
Fig. 6 Mean (SD) steady-state rotigotine plasma concentrations with and without co-administration of a levodopa/carbidopa (100/25 mg)
, b domperidone (10 mg/day) , c cimetidine (400 mg bid), and d omeprazole (40 mg/day) . bid twice daily
unconjugated rotigotine, the mean Cmax,ss and AUC024 h,ss
were 0.83 ng/mL and 15.5 ng h/mL with
levodopa/carbidopa, and 0.84 ng/mL and 15.1 ng h/mL without
levodopa/carbidopa. Since the point estimates for the ratio
of geometric means (combined vs. monotherapy) for
Cmax,ss and AUCs for levodopa (1.04, 90 % CI 0.901.19;
and 0.97, 90 % CI 0.921.03), carbidopa (1.06, 90 % CI
0.971.15; and 1.03, 90 % CI 0.961.12), and
unconjugated rotigotine (0.98, 90 % CI 0.871.12; and 1.02, 90 %
CI 0.931.13) were close to 1 and respective 90 % CIs
were within the acceptance range of bioequivalence
(0.81.25), these data support the use of these two agents
without the need for dose adjustments from a
pharmacokinetics perspective .
4.1.2 Domperidone Like all other dopaminergic therapies, rotigotine activates dopamine receptors in the gastrointestinal tract and the chemoreceptor trigger zone, resulting in gastrointestinal
side effects including nausea and vomiting [41, 4951].
The peripheral dopamine receptor antagonist domperidone
stimulates upper gastrointestinal tract motility and has
antiemetic effects, and these properties are used to prevent
dopaminergic side effects of levodopa and dopamine
agonists [49, 52, 53]. It was therefore of importance to
demonstrate that domperidone does not influence rotigotine
pharmacokinetics since these drugs may be
In a two-way crossover study, 16 healthy male subjects
(mean age 30 years) received rotigotine transdermal
system (2 mg/24 h over 4 days) alone and in combination
with domperidone (10 mg three times daily 9 5 days)
. The mean apparent rotigotine dose absorbed was
2.01 mg when given alone, which was similar following
concomitant domperidone administration (2.08 mg). Mean
steady-state plasma concentrationtime profiles of
unconjugated rotigotine were similar with and without
domperidone (Fig. 6b). The median rotigotine tmax value was
17.8 h with and without domperidone. Derived
unconjugated rotigotine pharmacokinetic parameters were
not altered in the presence of domperidone: mean Cmax,ss
and AUC024 h,ss values were 0.26 ng/mL and 5.15 ng h/
mL, respectively, with domperidone, and 0.27 ng/mL and
5.30 ng h/mL, respectively, without domperidone.
Statistical analysis showed no effect of domperidone on these
parameters, as evidenced by the ratio of geometric means
for Cmax,ss (0.96, 90 % CI 0.861.08) and AUC024,ss (0.97,
90 % CI 0.871.08) close to 1, and the respective 90 % CIs
were within the acceptance range of bioequivalence .
Renal clearance of unconjugated rotigotine (mean 0.26 and
0.27 L/h, respectively) and its metabolites were also
similar with and without concomitant domperidone. Hence,
no dose adjustments for rotigotine are needed when taken
concomitantly with domperidone. Accordingly,
domperidone may be used in case of potential gastrointestinal
dopaminergic side effects without need for rotigotine dose
4.1.3 Oral Contraceptives
In a randomized, double-blind, crossover study, 40 healthy
women received oral contraceptives (0.03 mg
ethinylestradiol and 0.15 mg levonorgestrel 9 28 days)
with rotigotine transdermal system (2 mg/24 h on days
13, then 3 mg/24 h maintenance dose thereafter for a total
of 13 days) or placebo . In the luteal phase, mean
progesterone serum concentrations were unaffected by
coadministration of rotigotine, with observed peak levels of
1.16 and 1.21 ng/mL following rotigotine and placebo,
respectively; progesterone levels were consistently \2 ng/
mL for all women at all time points during the luteal phase.
In addition, no clinically relevant differences in estradiol,
luteinizing hormone, and follicle stimulating hormone
values were observed following rotigotine and placebo
treatments. The concentrations of all four endogenous
hormones were adequately suppressed at each time point,
suggesting the absence of ovulation with concomitant
rotigotine. Presence of rotigotine did not alter the
pharmacokinetic metrics of ethinylestradiol and levonorgestrel
since geometric mean ratios for Cmax,ss and AUC024 h,ss,
respectively, were as follows: 1.05 (90 % CI 0.931.19)
and 1.05 (90 % CI 0.91.22) for ethinylestradiol, and 1.01
(90 % CI 0.961.06) and 0.98 (90 % CI 0.951.01) for
levonorgestrel. The oral contraceptive did not change the
pharmacokinetic profile of rotigotine; mean plasma
concentrations of unconjugated rotigotine were stable
throughout day 13 (patch-on period). Derived steady-state
pharmacokinetic parameters of unconjugated rotigotine
(mean Cmax,ss of 0.58 ng/mL and AUC024 h,ss of
10.62 ng h/mL) were similar to data in healthy subjects
(see above). Overall, rotigotine administered via a
transdermal patch (3 mg/24 h) did not impact the
pharmacodynamics (i.e., ovulation suppression) or
pharmacokinetics of the combined oral contraceptive of
ethinylestradiol and levonorgestrel in healthy females,
which infers that the contraceptive efficacy of this hormone
combination will not be impacted by rotigotine .
It was not anticipated that rotigotine has clinically
relevant pharmacokinetic interactions with cytochrome P450
(CYP) isoenzyme inhibitors since the major route of
rotigotine metabolism is via direct phase 2 conjugation
reactions generating the rotigotine O-sulphate and
rotigotine O-glucuronide . Furthermore, the minor
rotigotine metabolic pathway is mediated via several
cytochrome CYP isoenzymes (1A2, 2C9, 2C19, 2D6, and
3A4; Fig. 2), for which rotigotine has high inhibitory
concentrations and inhibitory constants , and so the
risk for shifts in plasma rotigotine levels due to
concomitant use of a CYP450 substrate is less than for a drug
which is metabolized solely by one of these isoenzymes.
Two drugdrug interaction studies were undertaken to
investigate the potential for drugdrug interaction via this
pathway (cimetidine: an inhibitor of CYP1A2, CYP2C19,
CYP2D6, and CYP3A4; and omeprazole: a CYP2C19
inhibitor). In vitro evaluations with rotigotine (using
human microsomes and hepatocytes) suggest a low drug
interaction potential with CYP2D6 .
In an open, repeated-dose, randomized, two-way crossover
study (SP627) of rotigotine (2 mg/24 h for 2 days, then
4 mg/24 h for 4 days), co-administration of cimetidine
(400 mg twice daily for 7 days) did not affect steady-state
plasma pharmacokinetics of unconjugated rotigotine in 12
healthy, non-smoking subjects (Fig. 6c) (data on file, UCB
Pharma). The geometric mean Cmax,ss calculated for
rotigotine with and without cimetidine was 0.5 ng/mL. The
geometric mean AUC024 h,ss calculated for rotigotine with
cimetidine was 8.2 ng h/mL (range 2.014.5 ng h/mL) and
without cimetidine was 8.4 ng h/mL (range 2.815.5 ng h/
mL). The geometric mean ratio of rotigotine plus
cimetidine to rotigotine alone for Cmax,ss (1.01, 90 % CI
0.901.13) and AUC024 h,ss (0.98, 90 % CI 0.891.07)
demonstrated that there was no effect of cimetidine
coadministration on the extent of the bioavailability of
rotigotine. Geometric mean elimination half-lives of rotigotine
were also similar without cimetidine (6.8 h) and with
cimetidine (6.5 h). These data provide evidence that
coadministration of the non-specific CYP inhibitor cimetidine
had no influence on the pharmacokinetics of rotigotine.
An open-label, multiple-dose study, evaluated the effect of
omeprazole 40 mg, a competitive CYP2C19 inhibitor, on the
steady-state pharmacokinetics of rotigotine in 37 evaluable
healthy Caucasian male subjects (mean age 24 years) .
Each subject initially received rotigotine transdermal system
(2 mg/24 h on days 13 and days 1314, followed by 4 mg/
24 h on days 412) followed by concomitant omeprazole
treatment (40 mg once daily on days 712). All subjects
were confirmed to be extensive metabolizers for CYP2C19.
Selective inhibition of CYP2C19 by omeprazole did not alter
the steady-state plasma pharmacokinetictime profile
(Fig. 6d) or primary pharmacokinetic parameters
(AUC024 h,ss and Cmax,ss) of unconjugated rotigotine. Mean
steady-state concentrations of unconjugated rotigotine
ranged from 0.44 ng/mL 2 h post-dosing to 0.57 ng/mL 4 h
post-dosing on day 6; similar values were observed on day
12. Mean Cmax,ss and AUC024,ss values were 0.73 ng/mL
and 11.46 ng h/mL, respectively, with omeprazole, and
0.69 ng/mL and 11.63 ng h/mL, respectively, without
omeprazole. Point estimates for the geometric mean ratios of
Cmax,ss and AUC024,ss of unconjugated rotigotine for the
comparison rotigotine plus omeprazole versus rotigotine
alone were close to 1 (1.06, 90 % CI 0.971.16; and 0.99,
90 % CI 0.901.08, respectively). Based on the negligible
effect of selective inhibition of CYP2C19 by omeprazole on
levels of active unconjugated rotigotine, no rotigotine dose
adjustment is advised for patients receiving concomitant
The safety of rotigotine transdermal system has been
extensively evaluated in patients with early- and
advancedstage PD, and RLS. Rotigotine is generally well tolerated,
with typical adverse-event (AE) profile characteristics of a
dopamine agonist and transdermal administration system.
Application site reactions were the most common AEs.
Based on data from double-blind, placebo-controlled trials
in patients with early- or advanced-stage PD or RLS,
approximately one-third (range 1546 %) of
rotigotinetreated patients reported at least one application site
reaction compared with 221 % of placebo recipients .
Most events were of mild to moderate intensity, and the
majority of reactions resolved rapidly after removal of the
patch . Other common dopaminergic AEs reported in
C5 % of patients included gastrointestinal disturbances
(e.g., nausea, vomiting), somnolence, dizziness, and
headache. In 6-month clinical trials, premature
discontinuation of rotigotine due to AEs occurred in 1415 % of
patients with early PD [51, 57, 58] and 17 % with
advanced PD . In 6-month RLS trials, premature
discontinuation of rotigotine due to AEs ranged from
1519 % [50, 60]. Application site reactions were the AEs
most commonly leading to early termination.
Dyskinesia has been reported following long-term
rotigotine use in patients with early-stage PD, with an
incidence of 17 %; however, most cases (72 %) developed
after treatment with levodopa and were potentially due to
pulsatile stimulation . Clinically significant
augmentation was reported in 39 patients (13 %) with RLS
following long-term (5 years) rotigotine treatment and led to
discontinuation in 12 of 39 (31 %); however, only 15
patients (5 %) were receiving approved doses (13 mg/24 h),
suggesting that augmentation following extended treatment
is relatively infrequent . As with other dopamine
receptor agonists, rotigotine has been associated with
impulse control problems and disorders. The incidences of
these AEs have yet to be determined [63, 64].
The cardiac safety of rotigotine was evaluated in a phase I,
double-blind, randomized, placebo- and
moxifloxacin-controlled, parallel-group study (SP864) to assess the potential
effects of the rotigotine transdermal system at therapeutic
and supratherapeutic doses (titrated to 24 mg/24 h) on
cardiac repolarization . A total of 130 patients with
advanced-stage PD (mean age 63 years) stabilized on levodopa
were enrolled and randomized to rotigotine (n = 66) or
placebo (n = 64). Each patient underwent two baseline days
with 24-h ECG recording prior to receiving study drugs
followed by serial 24-h 12-lead ECGs performed from study
days 14 to 43. As part of the parallel study, each patient
assigned to the placebo group was also randomized to
receive a 400-mg infusion of moxifloxacin (a known
QTprolonging drug) on either day 32 or day 39 and a placebo
infusion on the alternate day. Rotigotine-treated patients
were given infusions of placebo on both day 32 and day 39. A
total of 126 patients completed the study. Moxifloxacin
induced a prolongation of QTc as expected (maximum mean
effect of 13.5 ms). There was no effect of rotigotine up to
supratherapeutic doses on the QTc interval, indicating no
association of rotigotine and cardiac repolarization.
Rotigotine versus placebo QTc differences in time-matched
changes from baseline showed mean effects close to zero
(upper confidence limits were below ?5 ms and lower
confidence limits were above -5 ms).
6 Role of Rotigotine Transdermal System in PD and RLS
Rotigotine represents the first available transdermally
applied drug with proven efficacy as monotherapy for
earlystage PD and moderate to severe RLS, and as add-on
therapy to levodopa for advanced-stage PD. Five phase III,
randomized, placebo-controlled trials in patients with
early- or advanced-stage PD confirmed that continuously
delivered rotigotine led to significant and sustained
improvement in symptoms [41, 51, 5759, 65]. The
therapeutic effects of rotigotine appeared rapidly (during
the titration period) and were largely maintained over the
6-month treatment period in these studies. In two trials of
patients with early-stage PD, statistically significant
improvement in Unified Parkinsons Disease Rating Scale
(UPDRS) scores and clinically relevant increases in
responder rates were observed with rotigotine at doses of up
to 8 mg/24 h, compared with placebo [51, 57, 58].
Furthermore, rotigotine at doses up to 16 mg/24 h significantly
reduced off time for patients with advanced-stage PD
who were not adequately controlled with levodopa [41, 59,
65]. Significant improvement in early morning motor
function and nocturnal sleep disturbances among 287 PD
patients with inadequate control of morning motor
symptoms has also been demonstrated in a multinational,
double-blind, placebo-controlled trial . The long-term
safety and efficacy of rotigotine treatment in early PD have
been investigated in two open-label extension studies of up
to 6 years, in which rotigotine was well tolerated, with
more than half of patients remaining on treatment for
4 years or longer [61, 67].
Rotigotine also has proven efficacy as monotherapy
for the management of moderate to severe idiopathic
RLS, as demonstrated in two phase III, randomized,
placebo-controlled trials [50, 60]. In one clinical trial of
458 patients (341 rotigotine 13 mg/24 h and 117
placebo), all dosages of rotigotine showed significant
improvement in patients RLS symptoms based on two
primary outcome measures (i.e., absolute change from
baseline to end of the 6-month maintenance phase in the
International Restless Legs Scale sum score and Clinical
Global Impression item-1 score) . In a similarly
designed trial of 505 evaluable RLS patients, those
receiving rotigotine at doses of 2 mg/24 h and 3 mg/24 h
had significantly reduced symptoms compared with
placebo . In a double-blind, randomized,
placebocontrolled, multicenter study, the efficacy of rotigotine
transdermal system in 46 patients with moderate to
severe idiopathic RLS and periodic limb movement
(PLM) in sleep was demonstrated using
polysomnography . Specifically, rotigotine-treated patients who
received a mean 2.1 mg/24 h maintenance dose had
significantly reduced PLM during sleep (i.e., a reduction
from 50.9 PLM/h at baseline to 8.1 PLM/h at end of
maintenance). A long-term, open-label study of extended
rotigotine treatment found that rotigotine at optimal
doses up to 4 mg/24 h provided sustained efficacy and
was generally well tolerated for up to 5 years, with a
low incidence of augmentation at licensed doses .
The extensive investigations of the pharmacokinetics of
rotigotine following administration via a transdermal patch
permit the following general conclusions: plasma
concentrationtime profiles and derived pharmacokinetic
parameters of rotigotine are similar in healthy subjects,
patients with early- or advanced-stage PD, and patients
with RLS; dose-proportional pharmacokinetics are
observed up to supratherapeutic dose rates (24 mg/24 h) in
healthy subjects and target populations; age, sex, and
ethnicity do not influence the pharmacokinetic profile of
rotigotine in a relevant manner; and dose adjustments are
unnecessary in patients with advanced renal insufficiency,
including ESRD requiring hemodialysis, and moderate
hepatic impairment. Importantly, no clinically relevant
drugdrug interactions were observed following
co-administration with levodopa/carbidopa, domperidone, or
oral contraceptives, as well as cimetidine and omeprazole,
thereby demonstrating the absence of an effect by the
inhibition of CYP450 metabolism. Also, pharmacodynamics
and pharmacokinetics of an oral hormonal contraceptive
were not influenced by rotigotine co-administration. These
observations, combined with the long-term efficacy, safety,
and tolerability of rotigotine, support its use as a
continuous non-ergot D3/D2/D1 dopamine receptor agonist in
the treatment of patients with early- and advanced-stage
PD and moderate to severe RLS.
Acknowledgments Author conflicts of interest: Jens-Otto Andreas,
Marina Braun, Willi Cawello, and Jan-Peer Elshoff are all employees
of UCB Pharma, Monheim am Rhein, Germany. Francois-Xavier
Mathy is an employee of UCB Pharma, Braine lAlleud, Belgium.
The authors acknowledge Steve Dobson and Malcolm Darkes
(Evidence Scientific Solutions, Horsham, UK) for writing support, which
was funded by UCB Pharma SA, Brussels, Belgium.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which
permits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and the source are credited.
4.2 Drug-Drug Interactions Involving the Effect of P450 Enzyme Inhibition
1. de Rijk MC , Tzourio C , Breteler MM , Dartigues JF , Amaducci L , Lopez-Pousa S , et al. Prevalence of parkinsonism and Parkinson 's disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson's disease. J Neurol Neurosurg Psychiatry . 1997 ; 62 ( 1 ): 10 - 5 .
2. Van Den Eeden SK , Tanner CM , Bernstein AL , Fross RD , Leimpeter A , Bloch DA , et al. Incidence of Parkinson's disease: variation by age , gender, and race/ethnicity. Am J Epidemiol . 2003 ; 157 ( 11 ): 1015 - 22 .
3. Smith Y , Wichmann T , Factor SA , DeLong MR . Parkinson's disease therapeutics: new developments and challenges since the introduction of levodopa . Neuropsychopharmacology . 2012 ; 37 ( 1 ): 213 - 46 .
4. Rascol O , Lozano A , Stern M , Poewe W. Milestones in Parkinson's disease therapeutics . Mov Disord . 2011 ; 26 ( 6 ): 1072 - 82 .
5. Clarke CE . Parkinson's disease . BMJ . 2007 ; 335 ( 7617 ): 441 - 5 .
6. Rao SS , Hofmann LA , Shakil A. Parkinson's disease: diagnosis and treatment . Am Fam Physician . 2006 ; 74 ( 12 ): 2046 - 54 .
7. Jankovic J. Parkinson 's disease: clinical features and diagnosis . J Neurol Neurosurg Psychiatry . 2008 ; 79 ( 4 ): 368 - 76 .
8. Ramig LO , Fox C , Sapir S. Speech treatment for Parkinson's disease . Expert Rev Neurother . 2008 ; 8 ( 2 ): 297 - 309 .
9. Simpson J , Lekwuwa G , Crawford T. Predictors of quality of life in people with Parkinson's disease: evidence for both domain specific and general relationships . Disabil Rehabil . 2014 ; 36 ( 23 ): 1964 - 70 .
10. Duncan GW , Khoo TK , Yarnall AJ , O'Brien JT , Coleman SY , Brooks DJ , et al. Health-related quality of life in early Parkinson's disease: the impact of nonmotor symptoms . Mov Disord . 2014 ; 29 ( 2 ): 195 - 202 .
11. Schrag A , Jahanshahi M , Quinn N. What contributes to quality of life in patients with Parkinson's disease ? J Neurol Neurosurg Psychiatry . 2000 ; 69 ( 3 ): 308 - 12 .
12. Hametner E , Seppi K , Poewe W. The clinical spectrum of levodopa-induced motor complications . J Neurol . 2010 ; 257 (Suppl 2): S268 - 75 .
13. Pedrosa DJ , Timmermann L. Review: management of Parkinson's disease . Neuropsychiatr Dis Treat . 2013 ; 9 : 321 - 40 .
14. Rodriguez-Oroz MC , Marin C , de Fabregues O. Continuous dopaminergic stimulation: clinical aspects and experimental bases . Neurologist . 2011 ; 17 ( 6 Suppl 1 ): S30 - 7 .
15. Trenkwalder C , Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management . Nat Rev Neurol . 2010 ; 6 ( 6 ): 337 - 46 .
16. Berger K , Luedemann J , Trenkwalder C , John U , Kessler C. Sex and the risk of restless legs syndrome in the general population . Arch Intern Med . 2004 ; 164 ( 2 ): 196 - 202 .
17. Allen RP , La Buda MC , Becker P , Earley CJ . Family history study of the restless legs syndrome . Sleep Med . 2002 ; 3 (Suppl): S3 - 7 .
18. Winkelman JW . Considering the causes of RLS . Eur J Neurol . 2006 ; 13 (Suppl 3): 8 - 14 .
19. Garcia-Borreguero D , Williams AM . An update on restless legs syndrome (Willis Ekbom disease): clinical features, pathogenesis and treatment . Curr Opin Neurol . 2014 ; 27 : 493 - 501 .
20. Garcia-Borreguero D , Allen RP , Kohnen R , Hogl B , Trenkwalder C , Oertel W , et al. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute . Sleep Med . 2007 ; 8 ( 5 ): 520 - 30 .
21. Hogl B , Garcia-Borreguero D , Kohnen R , Ferini-Strambi L , Hadjigeorgiou G , Hornyak M , et al. Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study . J Neurol . 2010 ; 257 ( 2 ): 230 - 7 .
22. Garcia-Borreguero D , Kohnen R , Silber MH , Winkelman JW , Earley CJ , Hogl B , et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group . Sleep Med . 2013 ; 14 ( 7 ): 675 - 84 .
23. Elshoff JP , Braun M , Andreas JO , Middle M , Cawello W. Steadystate plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies . Clin Ther . 2012 ; 34 ( 4 ): 966 - 78 .
24. Scheller D , Ullmer C , Berkels R , Gwarek M , Lubbert H. The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson's disease . Naunyn Schmiedebergs Arch Pharmacol . 2009 ; 379 ( 1 ): 73 - 86 .
25. Millan M , Maiofiss L , Cussac D , Audinot V , Boutin JA , Newman-Tancredi A. Differential action of antiparkinson agents at multiple classes of monoaminergic receptor . I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes . JEPT . 2002 ; 303 : 791 - 804 .
26. Van der Weide J , Tendijck ME , Tepper PG , De Vries JB , Dubocovich ML , Horn AS . The enantiomers of the D-2 dopamine receptor agonist N-0437 discriminate between pre- and postsynaptic dopamine receptors . Eur J Pharmacol . 1988 ; 146 ( 2-3 ): 319 - 26 .
27. Van der Weide J , De Vries JB , Tepper PG , Horn AS . Pharmacological profiles of three new, potent and selective dopamine receptor agonists : N-0434, N-0437 and N-0734. Eur J Pharmacol . 1986 ; 125 ( 2 ): 273 - 82 .
28. Timmerman W , Dubocovich ML , Westerink BH , De Vries JB , Tepper PG , Horn AS . The enantiomers of the dopamine agonist N-0437: in vivo and in vitro effects on the release of striatal dopamine . Eur J Pharmacol . 1989 ; 166 ( 1 ): 1 - 11 .
29. Schmidt WJ , Lebsanft H , Heindl M , Gerlach M , Gruenblatt E , Riederer P , et al. Continuous versus pulsatile administration of rotigotine in 6-OHDA-lesioned rats: contralateral rotations and abnormal involuntary movements . J Neural Transm . 2008 ; 115 ( 10 ): 1385 - 92 .
30. Stockwell KA , Scheller D , Rose S , Jackson MJ , Tayarani-Binazir K , Iravani MM , et al. Continuous administration of rotigotine to MPTP-treated common marmosets enhances anti-parkinsonian activity and reduces dyskinesia induction . Exp Neurol . 2009 ; 219 ( 2 ): 533 - 42 .
31. Cawello W , Braun M , Boekens H. Absorption , disposition, metabolic fate, and elimination of the dopamine agonist rotigotine in man: administration by intravenous infusion or transdermal delivery . Drug Metab Dispos . 2009 ; 37 ( 10 ): 2055 - 60 .
32. Cawello W , Wolff HM , Meuling WJ , Horstmann R , Braun M. Transdermal administration of radiolabelled [14C]rotigotine by a patch formulation: a mass balance trial . Clin Pharmacokinet . 2007 ; 46 ( 10 ): 851 - 7 .
33. Malik M , Andreas JO , Hnatkova K , Hoeckendorff J , Cawello W , Middle M , et al. Thorough QT/ QTc study in patients with advanced Parkinson's disease: cardiac safety of rotigotine . Clin Pharmacol Ther . 2008 ; 84 ( 5 ): 595 - 603 .
34. Babic T , Boothmann B , Polivka J , Rektor I , Boroojerdi B , Hack HJ , et al. Rotigotine transdermal patch enables rapid titration to effective doses in advanced-stage idiopathic Parkinson disease: subanalysis of a parallel group, open-label, dose-escalation study . Clin Neuropharmacol . 2006 ; 29 ( 4 ): 238 - 42 .
35. Cawello W , Kim SR , Braun M , Elshoff JP , Ikeda J , Funaki T. Pharmacokinetics , safety and tolerability of rotigotine transdermal patch in healthy Japanese and Caucasian subjects . Clin Drug Investig . 2014 ; 34 ( 2 ): 95 - 105 .
36. Cawello W , Kim SR , Braun M , Elshoff J-P , Masahiro T , Ikeda J , et al. Pharmacokinetics , safety and tolerability of rotigotine transdermal system in healthy Japanese and Caucasian subjects following multiple dose administration . Eur J Drug Metab Pharmacokinet . 2015 (in press).
37. Kim B-H , Yu K-S , Jang I-J , Soo Lim K , Kim J-R , Elshoff J-P , et al. Pharmacokinetic properties and tolerability of rotigotine transdermal patch after repeated-dose application in healthy Korean volunteers . Clin Ther . 2015 (in press).
38. Cawello W , Fichtner A , Boekens H , Braun M. Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist rotigotine . Eur J Drug Metab Pharmacokinet . 2014 ; 39 ( 3 ): 155 - 63 .
39. Cawello W , Ahrweiler S , Sulowicz W , Szymczakiewicz-Multanowska A , Braun M. Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function . Br J Clin Pharmacol . 2012 ; 73 ( 1 ): 46 - 54 .
40. Cawello W , Elshoff JP , Boekens H , Braun M. Characteristics of rotigotine elimination after patch removal . Eur J Neurol . 2006 ; 13 (Suppl 2): 42 .
41. Poewe WH , Rascol O , Quinn N , Tolosa E , Oertel WH , Martignoni E , et al. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson's disease: a double-blind, doubledummy, randomised controlled trial . Lancet Neurol . 2007 ; 6 ( 6 ): 513 - 20 .
42. Whitesides J , Cawello W , Woltering F , Boroojerdi B , Poewe W. Stable plasma levels of rotigotine following transdermal patch removal and new patch application during long-term treatment of patients with advanced Parkinson's disease . Mov Disord . 2011 ; 26 ( 2 ): S288 .
43. Whitesides J , Cawello W , Braun M , Fichtner A , Oertel WH . Stability of rotigotine plasma levels during long-term transdermal application for patients with idiopathic restless legs syndrome . Mov Disord . 2011 ; 26 ( 2 ): S365 .
44. Braun M , Cawello W , Andreas JO , Boekens H , Horstmann R. Lack of pharmacokinetic interactions between transdermal rotigotine and oral levodopa/carbidopa . J Clin Pharmacol . 2009 ; 49 ( 9 ): 1047 - 55 .
45. Braun M , Cawello W , Boekens H , Horstmann R. Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine . Br J Clin Pharmacol . 2009 ; 67 ( 2 ): 209 - 15 .
46. Braun M , Elshoff JP , Andreas JO , Muller LI , Horstmann R. Influence of transdermal rotigotine on ovulation suppression by a combined oral contraceptive . Br J Clin Pharmacol . 2009 ; 68 ( 3 ): 386 - 94 .
47. Elshoff JP , Cawello W , Andreas JO , Braun M. No influence of the CYP2C19-selective inhibitor omeprazole on the pharmacokinetics of the dopamine receptor agonist rotigotine . Clin Pharmacol Drug Devel . 2014 ; 3 ( 3 ): 187 - 93 .
48. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1. 20 January 2010 . Available online at URL: http://www.ema. europa.eu/docs/ en_GB/document_library/Scientific_guideline/ 2010 /01/WC5000 70039.pdf. Accessed 27 Feb 2015 .
49. Barone JA . Domperidone: a peripherally acting dopamine2-receptor antagonist . Ann Pharmacother . 1999 ; 33 ( 4 ): 429 - 40 .
50. Trenkwalder C , Benes H , Poewe W , Oertel WH , Garcia-Borreguero D , de Weerd AW , et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial . Lancet Neurol . 2008 ; 7 ( 7 ): 595 - 604 .
51. Watts RL , Jankovic J , Waters C , Rajput A , Boroojerdi B , Rao J. Randomized , blind, controlled trial of transdermal rotigotine in early Parkinson disease . Neurology . 2007 ; 68 ( 4 ): 272 - 6 .
52. Brogden RN , Carmine AA , Heel RC , Speight TM , Avery GS . Domperidone . A review of its pharmacological activity, pharmacokinetics and therapeutic efficacy in the symptomatic treatment of chronic dyspepsia and as an antiemetic . Drugs . 1982 ; 24 ( 5 ): 360 - 400 .
53. Parkes JD . Domperidone and Parkinson's disease . Clin Neuropharmacol . 1986 ; 9 ( 6 ): 517 - 32 .
54. Hansen K , Braun M , Horstmann R , Cawello W , Schaffenecker U. Low drug drug interaction potential of rotigotine . Neurodegenerative Dis . 2007 ; 4 ( Suppl I ): 1 - 350 .
55. Boroojerdi B , Wolff HM , Braun M , Scheller DK . Rotigotine transdermal patch for the treatment of Parkinson's disease and restless legs syndrome . Drugs Today (Barc) . 2010 ; 46 ( 7 ): 483 - 505 .
56. Sanford M , Scott LJ . Rotigotine transdermal patch. A review of its use in the treatment of Parkinson's disease . CNS Drugs . 2011 ; 25 ( 8 ): 699 - 719 .
57. Jankovic J , Watts RL , Martin W , Boroojerdi B. Transdermal rotigotine: double-blind, placebo-controlled trial in Parkinson disease . Arch Neurol . 2007 ; 64 ( 5 ): 676 - 82 .
58. Giladi N , Boroojerdi B , Korczyn AD , Burn DJ , Clarke CE , Schapira AH . Rotigotine transdermal patch in early Parkinson's disease: a randomized, double-blind, controlled study versus placebo and ropinirole . Mov Disord . 2007 ; 22 ( 16 ): 2398 - 404 .
59. LeWitt PA , Lyons KE , Pahwa R. Advanced Parkinson disease treated with rotigotine transdermal system : PREFER Study. Neurology. 2007 ; 68 ( 16 ): 1262 - 7 .
60. Hening WA , Allen RP , Ondo WG , Walters AS , Winkelman JW , Becker P , et al. Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States . Mov Disord . 2010 ; 25 ( 11 ): 1675 - 83 .
61. Giladi N , Boroojerdi B , Surmann E. The safety and tolerability of rotigotine transdermal system over a 6-year period in patients with early-stage Parkinson's disease . J Neural Transm . 2013 ; 120 ( 9 ): 1321 - 9 .
62. Oertel W , Trenkwalder C , Benes H , Ferini-Strambi L , Hogl B , Poewe W , et al. Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study . Lancet Neurol . 2011 ; 10 ( 8 ): 710 - 20 .
63. Schreglmann SR , Gantenbein AR , Eisele G , Baumann CR . Transdermal rotigotine causes impulse control disorders in patients with restless legs syndrome . Parkinsonism Relat Disord . 2012 ; 18 ( 2 ): 207 - 9 .
64. Hinnell C , Hulse N , Martin A , Samuel M. Hypersexuality and compulsive over-eating associated with transdermal dopamine agonist therapy . Parkinsonism Relat Disord . 2011 ; 17 ( 4 ): 295 - 6 .
65. Nicholas AP , et al. A randomized study of rotigotine dose response on 'off' time in advanced Parkinson's disease . J Parkinsons Dis . 2014 ; 4 : 361 - 73 .
66. Trenkwalder C , Kies B , Rudzinska M , Fine J , Nikl J , Honczarenko K , et al. Rotigotine effects on early morning motor function and sleep in Parkinson's disease: a double-blind, randomized, placebo-controlled study (RECOVER) . Mov Disord . 2011 ; 26 ( 1 ): 90 - 9 .
67. Elmer LW , Surmann E , Boroojerdi B , Jankovic J. Long-term safety and tolerability of rotigotine transdermal system in patients with early-stage idiopathic Parkinson's disease: a prospective, open-label extension study . Parkinsonism Relat Disord . 2012 ; 18 ( 5 ): 488 - 93 .
68. Oertel WH , Benes H , Garcia-Borreguero D , Hogl B , Poewe W , Montagna P , et al. Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: a randomized, placebocontrolled polysomnographic study . Sleep Med . 2010 ; 11 ( 9 ): 848 - 56 .