ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Neupro 1 mg/24 h transdermal patch
2.
Each patch releases 1 mg of rotigotine per 24 hours. Each patch of 5 cm
2
contains 2.25 mg of
rotigotine.
For a full list of excipients, see section 6.1.
3.
Transdermal patch.
Thin, matrix-type, square-shaped with rounded edges, consisting of three layers. The outside of the
backing layer is tan-coloured and imprinted with ‘Neupro 1 mg/24 h’.
4.
Neupro is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs
Syndrome in adults.
Posology
Neupro is applied once a day. The patch should be applied at approximately the same time every day.
The patch remains on the skin for 24 hours and will then be replaced by a new one at a different site of
application.
If the patient forgets to apply the patch at the usual time of the day or if the patch becomes detached,
another patch should be applied for the remainder of the day.
Dose
The dose recommendations made are in nominal dose.
A single daily dose should be initiated at 1 mg/24 h. Depending on the individual patient response, the
dose may be increased in weekly increments of 1 mg/24 h to a maximal dose of 3 mg/24 h. The need
for treatment continuation should be reconsidered every 6 months.
Treatment discontinuation
Neupro should be discontinued gradually. The daily dose should be reduced in steps of 1 mg/24 h with
a dose reduction preferably every other day, until complete withdrawal of Neupro (see section 4.4).
Following this procedure, rebound (worsening of symptoms beyond initial intensity after
discontinuation of treatment) was not observed.
Special populations
Hepatic and renal impairment:
Adjustment of the dose is not necessary in patients with mild to
moderate hepatic impairment or in patients with mild to severe renal impairment, including those
requiring dialysis. Caution is advised when treating patients with severe hepatic impairment, which
may result in lower rotigotine clearance. Rotigotine has not been investigated in this patient group. A
dose reduction might be needed in case of worsening of the hepatic impairment. Unexpected
accumulation of rotigotine levels may also occur at acute worsening of renal function (see section 5.2).
2
Paediatric population
The safety and efficacy of rotigotine in the paediatric population have not yet been established. No
data are available.
Method of administration
The patch should be applied to clean, dry, intact healthy skin on the abdomen, thigh, hip, flank,
shoulder, or upper arm. Reapplication to the same site within 14 days should be avoided. Neupro
should not be placed on skin that is red, irritated or damaged. (see section 4.4)
Use and handling:
Each patch is packed in a sachet and should be applied directly after the sachet has been opened. One
half of the protective liner should be removed and the sticky side should be applied and pressed firmly
to the skin. Then, the patch is fold back and the second part of the release liner is removed. The sticky
side of the patch should not be touched. The patch should be pressed down firmly with the palm of the
hand for about 20 to 30 seconds, so that it sticks well.
In the event that a patch should fall off, a new patch should be applied for the remainder of the 24 hour
dosing interval.
The patch should not be cut into pieces.
Hypersensitivity to the active substance or to any of the excipients.
Magnetic resonance imaging or cardioversion (see section 4.4).
Magnetic resonance imaging and cardioversion
The backing layer of Neupro contains aluminium. To avoid skin burns, Neupro should be removed if
the patient has to undergo magnetic resonance imaging (MRI) or cardioversion.
Orthostatic hypotension
Dopamine agonists are known to impair the systemic regulation of the blood pressure resulting in
postural/orthostatic hypotension. These events were also observed during treatment with rotigotine,
however the incidence was similar to that in placebo-treated patients.
Syncope was observed in association with rotigotine, but also at a similar rate in patients treated with
placebo.
It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the
general risk of orthostatic hypotension associated with dopaminergic therapy.
Sudden onset of sleep and somnolence
Rotigotine has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of
sleep during daily activities, in some cases without awareness of any warning signs, has been reported.
Prescribers should continually reassess patients for drowsiness or sleepiness, as patients may not
acknowledge drowsiness or sleepiness until directly questioned. A reduction of dosage or termination
of therapy should be carefully considered.
Impulse control disorders
Pathologic gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists, including rotigotine.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy. Therefore it is recommended to taper treatment (see section 4.2).
3
Hallucinations
Hallucinations have been reported and patients should be informed that hallucinations can occur.
Fibrotic complications
Fibrotic complications: Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion,
pleural thickening, pericarditis and cardiac valvulopathy have been reported in some patients treated
with ergot-derived dopaminergic agents. While these complications may resolve when treatment is
discontinued, complete resolution does not always occur.
Although these adverse reactions are believed to be related to the ergoline structure of these
compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
Neuroleptics
Neuroleptics given as antiemetic should not be given to patients taking dopamine agonists (see also
section 4.5).
Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Augmentation
Augmentation may occur. Augmentation refers to the earlier onset of symptoms in the evening (or
even the afternoon), increase in severity of symptoms, and spread of symptoms to involve other body
parts. Based on two open-label follow-up studies with one year duration, symptoms reflecting
clinically relevant and not relevant augmentation may be as high as 9.4%. However, based on two 6-
month, double-blind, placebo-controlled studies, clinically relevant augmentation was observed in
1.5% of rotigotine-treated patients versus 0.5% of placebo treated patients. In two open-label, follow-
up studies over a subsequent 12 months, the rate of clinically relevant augmentation was 2.9%. None
of these patients discontinued therapy because of augmentation.
Heat application
External heat (excessive sunlight, heating pads and other sources of heat such as sauna, hot bath)
should not be applied to the area of the patch.
Applications site reactions
Application site skin reactions may occur and are usually mild or moderate in intensity. It is
recommended that the application site should be rotated on a daily basis (e.g. from the right side to the
left side and from the upper body to the lower body). The same site should not be used within 14 days.
If application site reactions occur which last for more than a few days or are persistent, if there is an
increase in severity, or if the skin reaction spreads outside the application site, an assessment of the
risk/benefit balance for the individual patient should be conducted.
If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be
avoided until the skin heals. Exposure could lead to changes in the skin color.
If a generalised skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or
pruritus) associated with the use of Neupro is observed, Neupro should be discontinued.
Sulphite sensitivity
Neupro contains sodium metabisulphite, a sulphite that may cause allergic-type reactions including
anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible
people.
Because rotigotine is a dopamine agonist, it is assumed that dopamine antagonists, such as
neuroleptics (e.g. phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish
the effectiveness of Neupro, and co-administration should be avoided. Because of possible additive
effects, caution should be advised when patients are taking sedating medicinal products or other CNS
4
(central nervous system) depressants (e.g. benzodiazepines, antipsychotics, antidepressants) or alcohol
in combination with rotigotine.
Co-administration of L-dopa and carbidopa with rotigotine had no effect on the pharmacokinetics of
rotigotine, and rotigotine had no effect on the pharmacokinetics of L-dopa and carbidopa.
Co-administration of domperidone with rotigotine had no effect on the pharmacokinetics of rotigotine.
Co-administration of omeprazole (inhibitor of CYP2C19), in doses of 40 mg/day, had no effect on the
pharmacokinetics and metabolism of rotigotine in healthy volunteers.
Co-administration of rotigotine (3 mg/24 h) did not affect the pharmacodynamics and
pharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol, 0.15 mg levonorgestrel).
Interactions with other forms of hormonal contraception have not been investigated.
4.6 Fertility,pregnancy and lactation
Pregnancy
There are no adequate data from the use of rotigotine in pregnant women. Animal studies do not
indicate any teratogenic effects in rats and rabbits, but embryo-toxicity was observed in rats and mice
at materno-toxic doses (see section 5.3). The potential risk for humans is unknown. Rotigotine should
not be used during pregnancy.
Breast-feeding
Because rotigotine decreases prolactin secretion in humans, inhibition of lactation is expected. Studies
in rats have shown that rotigotine and/or its metabolite(s) is excreted in breast milk. In the absence of
human data, breast-feeding should be discontinued.
Fertility
For information on fertility studies, please see section 5.3.
Rotigotine may have major influence on the ability to drive and use machines.
Patients being treated with rotigotine and presenting with somnolence and/or sudden sleep episodes
must be informed not to drive or engage in activities (e.g. operating machines) where impaired
alertness may put themselves or others at risk of serious injury or death until such recurrent episodes
and somnolence have resolved (see also sections 4.4 and 4.5).
Based on the analysis of pooled placebo-controlled clinical trials comprising a total of 748 Neupro-
and 214 placebo-treated patients, 65.2% of the patients on Neupro and 33.2% of patients on placebo
reported at least one adverse reaction.
At the beginning of therapy dopaminergic adverse reactions such as nausea and vomiting may occur.
These are usually mild or moderate in intensity and transient even if treatment is continued.
Adverse drug reactions (ADRs) reported in more than 10% of patients treated with Neupro are nausea,
application site reactions, asthenic conditions and headache.
In trials where the application sites were rotated as reflected in the instructions provided in the SmPC
and package leaflet, 34.2% of 748 patients using Neupro, experienced application site reactions. The
majority of these reactions were mild or moderate in intensity, limited to the application areas and
resulted in discontinuation of Neupro in 7.2% of subjects.
5
The following table covers adverse drug reactions from all studies in patients with Restless Legs
Syndrome. Within the system organ classes, adverse reactions are listed under headings of frequency
(number of patients expected to experience the reaction), using the following categories: very common
(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000);
very rare (<1/10,000); not known (cannot be estimated from the available data). Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System/organ classes
acc. to MedDRA
Very common
Common
Uncommon
Immune system
disorders
Hypersensitivity
Psychiatric disorders
Sleep attacks/sudden
onset of sleep, sexual
desire disorders
a
(incl.
hypersexuality, libido
increased), insomnia,
sleep disorder, abnormal
dreams
Impulse control disorder
a
(incl. pathological
gambling, punding),
obsessive compulsive
disorder
Nervous system
disorders
Headache
Somnolence
Vascular disorders
Hypertension
Orthostatic hypotension
Gastrointestinal
disorders
Nausea
Vomiting, dyspepsia
Skin and subcutaneous
tissue disorders
Pruritus
General disorders and
administration site
conditions
Application and
instillation site reactions
a
(incl. erythema, pruritus,
irritation, rash, dermatitis,
vesicles, pain, eczema,
inflammation, swelling,
discolouration, papules,
excoriation, urticaria,
hypersensitivity),
asthenic conditions
a
(incl.
fatigue, asthenia,
malaise)
Irritability
a
High Level Term
Description of selected adverse reactions
Sudden onset of sleep and somnolence
Rotigotine has been associated with somnolence including excessive daytime somnolence and sudden
sleep onset episodes. In isolated cases “sudden onset of sleep” occurred while driving and resulted in
motor vehicle accidents. See also section 4.4 and 4.7.
Impulse control disorders
Patients treated with dopamine agonists including rotigotine, have been reported as exhibiting signs of
pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the
dose or treatment discontinuation.
Discontinuation rate
The discontinuation rate was studied in 3 clinical trials ranging up to 3 years in duration. The
percentage of subjects discontinuing was 25-38% over the first year, 10% in the second year, and 11%
in the third year. Periodic assessment of efficacy should be performed, along with evaluation of safety,
including augmentation
.
6
The most likely adverse reactions would be those related to the pharmacodynamic profile of a
dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations,
confusion, convulsions and other signs of central dopaminergic stimulation.
There is no known antidote for overdose of dopamine agonists. In case of suspected overdose, the
patch(es) should immediately be removed from the patient. Levels of rotigotine decrease after patch
removal. Before stopping use of rotigotine completely see section 4.2.
The patient should be monitored closely, including heart rate, heart rhythm and blood pressure.
Because rotigotine is over 90% protein bound, dialysis would not be expected to be beneficial.
Treatment of overdose may require general supportive measures to maintain the vital signs.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-parkinsons drugs, dopamine agonists; ATC code: N04BC09
Rotigotine is a non-ergolinic D
3
/D
2
/D
1
dopamine agonist for the treatment of Parkinson’s disease. It is
believed to elicit its beneficial effect by activation of the D
3
, D
2
and D
1
receptors of the caudate-
putamen in the brain.
Rotigotine alleviates signs and symptoms of idiopathic Parkinson’s disease.
Clinical studies:
The efficacy of rotigotine was evaluated in 5 placebo-controlled trials with more than 1,400 patients
with idiopathic Restless Legs Syndrome (RLS). Efficacy was demonstrated in controlled trials in
patients treated for up to 29 weeks. The effect was maintained over a 6 months period.
The changes from baseline in the International RLS Rating Scale (IRLS) and CGI-item 1 (severity of
illness) were primary efficacy parameters. For both primary endpoints statistically significant
differences have been observed for the doses 1 mg/24 h, 2 mg/24 h and 3 mg/24 h in comparison to
placebo. After 6 months of maintenance treatment in patients with moderate to severe RLS, the
baseline IRLS score improved from 30.7 to 20.7 for placebo and from 30.2 to 13.8 for rotigotine. The
adjusted mean difference was -6.5 points (CI
95%
-8.7; -4.4, p <0.0001). CGI-I responder rates (much
improved, very much improved) were 43.0% and 67.5% for placebo and rotigotine respectively
(difference 24.5% CI
95%
: 14.2%; 34.8%, p<0.0001).
In a placebo-controlled, 7-week trial polysomnographic parameters were investigated. Rotigotine
significantly reduced the periodic limb movement index (PLMI) from 50.9 to 7.7
versus
37.4 to 32.7
for placebo (p<0.0001).
5.2 Pharmacokinetic properties
Absorption
Following application, rotigotine is continuously released from the transdermal patch and absorbed
through the skin. Steady-state concentrations are reached after one to two days of patch application
and are maintained at a stable level by once daily application in which the patch is worn for 24 hours.
Rotigotine plasma concentrations increase dose-proportionally over a dose range of 1 mg/24 h to
24 mg/24 h.
Approximately 45% of the active substance within the patch is released to the skin in 24 hours. The
absolute bioavailability after transdermal application is approximately 37%.
7
Rotating the site of patch application may result in day-to-day differences in plasma levels.
Differences in bioavailability of rotigotine ranged from 2% (upper arm
versus
flank) to 46% (shoulder
versus
thigh). However, there is no indication of a relevant impact on the clinical outcome.
Distribution
The
in vitro
binding of rotigotine to plasma proteins is approximately 92%.
The apparent volume of distribution in humans is approximately 84 l/kg.
Metabolism
Rotigotine is metabolised to a great extent. Rotigotine is metabolised by N-dealkylation as well as
direct and secondary conjugation.
In vitro
results indicate that different CYP isoforms are able to
catalyse the N-dealkylation of rotigotine. Main metabolites are sulfates and glucuronide conjugates of
the parent compound as well as N-desalkyl-metabolites, which are biologically inactive.
The infomation on metabolites is incomplete.
Elimination
Approximately 71% of the rotigotine dose is excreted in urine and a smaller part of about 23% is
excreted in faeces.
The clearance of rotigotine after transdermal administration is approximately 10 l/min and its
elimination half-life is 5 to 7 hours.
Because the patch is administered transdermally, no effect of food and gastrointestinal conditions is
expected.
Special patient groups
Because therapy with Neupro is initiated at a low dose and gradually titrated according to clinical
tolerability to obtain the optimum therapeutic effect, adjustment of the dose based on gender, weight,
or age is not necessary.
In subjects with moderate hepatic impairment or mild to severe renal impairment, no relevant increases
of rotigotine plasma levels were observed. Neupro was not investigated in patients with severe hepatic
impairment.
Plasma levels of conjugates of rotigotine and its desalkyl metabolites increase with impaired renal
function. However, a contribution of these metabolites to clinical effects is unlikely.
5.3 Preclinical safety data
In repeated dose and long-term toxicity studies, the major effects were associated with the dopamine
agonist related pharmacodynamic effects and the consequent decrease of prolactin secretion.
After a single dose of rotigotine, binding to melanin-containing tissues (i.e., eyes) in the pigmented rat
and monkey was evident, but was slowly cleared over the 14-day observation period.
Retinal degeneration was observed by transmission microscopy at a dose equivalent to 2.8 times the
maximum recommended human dose on a mg/m² basis in a 3-month study in albino rats. The effects
were more pronounced in female rats. Additional studies to further evaluate the specific pathology
have not been performed. Retinal degeneration was not observed during the routine histopathological
evaluation of the eyes in any of the toxicology studies in any species used. The relevance of these
findings to humans is not known.
In a carcinogenicity study, male rats developed Leydig cell tumours and hyperplasia. Malignant
tumours were noted predominantly in the uterus of mid- and high-dose females. These changes are
well-known effects of dopamine agonists in rats after life-long therapy and assessed as not relevant to
man.
The effects of rotigotine on reproduction have been investigated in rats, rabbits and mice. Rotigotine
was not teratogenic in all three species, but was embryotoxic in rats and mice at materno-toxic doses.
Rotigotine did not influence male fertility in rats, but clearly reduced female fertility in rats and mice,
because of the effects on prolactin levels which are particularly significant in rodents.
Rotigotine did not induce gene mutations in the Ames test, but did show effects in the
in vitro
Mouse
Lymphoma Assay with metabolic activation and weaker effects without metabolic activation. This
8
mutagenic effect could be attributed to a clastogenic effect of rotigotine. This effect was not confirmed
in vivo
in the Mouse Micronucleus Test in the rat Unscheduled DNA Synthesis (UDS) test. Since it
ran more or less parallel with a decreased relative total growth of the cells, it may be related to a
cytotoxic effect of the compound. Therefore, the relevance of the one positive
in vitro
mutagenicity
test is not known.
6.
6.1 List of excipients
Backing layer:
Polyester film, siliconized, aluminized,
colour coated with a pigment (titanium dioxide (E171), pigment yellow 95, pigment red 166) layer and
imprinted (pigment red 144, pigment yellow 95, pigment black 7).
Self adhesive matrix layer:
Poly(dimethylsiloxane, trimethylsilyl silicate)-copolymerisate,
Povidone K90,
sodium metabisulphite (E223),
ascorbyl palmitate (E304) and
DL-α-tocopherol (E307).
Protective liner:
Transparent fluoropolymer coated polyester film.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
6.5 Nature and contents of container
Peel off sachet in a cardboard carton: One side is composed of an ethylene copolymer (innermost
layer), an aluminium foil, low density polyethylene film and paper; the other side is composed of
polyethylene (innermost layer), aluminium, ethylene copolymer and paper.
The carton contains 7, 20, 28, 30, 56, 60, 84 (2x42), 90 or 100 (2x50) transdermal patches,
individually sealed in sachets.
Not all pack sizes may be marketed.
6.6 Special precaution for disposal
After use the patch still contains active substance. After removal, the used patch should be folded in
half, adhesive side inwards so that the matrix layer is not exposed, placed in the original sachet and
then discarded out of the reach of children. Any used or unused patches should be disposed of in
accordance with local requirements or returned to the pharmacy.
9
7.
SCHWARZ PHARMA Ltd.
Shannon, Industrial Estate,
Co.Clare, Ireland
8.
EU/1/05/331/038 - 046
9.
Date of first authorisation: 15 February 2006
Date of latest renewal:
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
10
1.
Neupro 2 mg/24 h transdermal patch
2.
Each patch releases 2 mg of rotigotine per 24 hours. Each patch of 10 cm
2
contains 4.5 mg of
rotigotine.
For a full list of excipients, see section 6.1.
3.
Transdermal patch.
Thin, matrix-type, square-shaped with rounded edges, consisting of three layers. The outside of the
backing layer is tan-coloured and imprinted with ‘Neupro 2 mg/24 h’.
4.
Restless Legs Syndrome
Neupro is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs
Syndrome in adults.
Parkinson’s disease
Neupro is indicated for the treatment of the signs and symptoms of early-stage idiopathic Parkinson’s
disease as monotherapy (i.e. without levodopa) or in combination with levodopa, i.e. over the course
of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent
and fluctuations of the therapeutic effect occur (end of dose or ‘on-off’ fluctuations).
Posology
Neupro is applied once a day. The patch should be applied at approximately the same time every day.
The patch remains on the skin for 24 hours and will then be replaced by a new one at a different site of
application.
If the patient forgets to apply the patch at the usual time of the day or if the patch becomes detached,
another patch should be applied for the remainder of the day.
Dose
The dose recommendations made are in nominal dose.
Restless Legs Syndrome
A single daily dose should be initiated at 1 mg/24 h. Depending on the individual patient response, the
dose may be increased in weekly increments of 1 mg/24 h to a maximal dose of 3 mg/24 h. The need
for treatment continuation should be reconsidered every 6 months.
Parkinson’s disease
Dosing in patients with early-stage Parkinson’s disease:
A single daily dose should be initiated at 2 mg/24 h and then increased in weekly increments of
2 mg/24 h to an effective dose up to a maximal dose of 8 mg/24 h.
11
4 mg/24 h may be an effective dose in some patients. For most patients an effective dose is reached
within 3 or 4 weeks at doses of 6 mg/24 h or 8 mg/24 h, respectively.
The maximal dose is 8 mg/24 h.
Dosing in patients with advanced stage Parkinson’s disease with fluctuations:
A single daily dose should be initiated at 4 mg/24 h and then increased in weekly increments of
2 mg/24 h to an effective dose up to a maximal dose of 16 mg/24 h.
4 mg/24 h or 6 mg/24 h may be effective doses in some patients. For most patients an effective dose is
reached within 3 to 7 weeks at doses of 8 mg/24 h up to a maximum dose of 16 mg/24 h.
For doses higher than 8 mg/24 h multiple patches may be used to achieve the final dose e.g.
10 mg/24 h may be reached by combination of a 6 mg/24 h and a 4 mg/24 h patch.
Treatment discontinuation
Restless Legs Syndrome
Neupro should be discontinued gradually. The daily dose should be reduced in steps of 1 mg/24 h with
a dose reduction preferably every other day, until complete withdrawal of Neupro (see section 4.4).
Following this procedure, rebound (worsening of symptoms beyond initial intensity after
discontinuation of treatment) was not observed.
Parkinson’s disease
Neupro should be discontinued gradually. The daily dose should be reduced in steps of 2 mg/24 h with
a dose reduction preferably every other day, until complete withdrawal of Neupro (see section 4.4).
Special populations
Hepatic and renal impairment:
Adjustment of the dose is not necessary in patients with mild to
moderate hepatic impairment or in patients with mild to severe renal impairment, including those
requiring dialysis. Caution is advised when treating patients with severe hepatic impairment, which
may result in lower rotigotine clearance. Rotigotine has not been investigated in this patient group. A
dose reduction might be needed in case of worsening of the hepatic impairment. Unexpected
accumulation of rotigotine levels may also occur at acute worsening of renal function (see section 5.2).
Paediatric population
The safety and efficacy of rotigotine in the paediatric population have not yet been established. No
data are available.
Method of administration
The patch should be applied to clean, dry, intact healthy skin on the abdomen, thigh, hip, flank,
shoulder, or upper arm. Reapplication to the same site within 14 days should be avoided. Neupro
should not be placed on skin that is red, irritated or damaged. (see section 4.4)
Use and handling:
Each patch is packed in a sachet and should be applied directly after the sachet has been opened. One
half of the protective liner should be removed and the sticky side should be applied and pressed firmly
to the skin. Then, the patch is fold back and the second part of the release liner is removed. The sticky
side of the patch should not be touched. The patch should be pressed down firmly with the palm of the
hand for about 20 to 30 seconds, so that it sticks well.
In the event that a patch should fall off, a new patch should be applied for the remainder of the 24 hour
dosing interval.
The patch should not be cut into pieces.
Hypersensitivity to the active substance or to any of the excipients.
Magnetic resonance imaging or cardioversion (see section 4.4).
12
If a Parkinson’s disease patient is insufficiently controlled while on treatment with rotigotine
switching to another dopamine agonist might provide additional benefit (see section 5.1)
Magnetic resonance imaging and cardioversion
The backing layer of Neupro contains aluminium. To avoid skin burns, Neupro should be removed if
the patient has to undergo magnetic resonance imaging (MRI) or cardioversion.
Orthostatic hypotension
Dopamine agonists are known to impair the systemic regulation of the blood pressure resulting in
postural/orthostatic hypotension. These events were also observed during treatment with rotigotine,
however the incidence was similar to that in placebo-treated patients.
Syncope was observed in association with rotigotine, but also at a similar rate in patients treated with
placebo.
It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the
general risk of orthostatic hypotension associated with dopaminergic therapy.
Sudden onset of sleep and somnolence
Rotigotine has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of
sleep during daily activities, in some cases without awareness of any warning signs, has been reported.
Prescribers should continually reassess patients for drowsiness or sleepiness, as patients may not
acknowledge drowsiness or sleepiness until directly questioned. A reduction of dosage or termination
of therapy should be carefully considered.
Impulse control disorders
Pathologic gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists, including rotigotine.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy. Therefore it is recommended to taper treatment (see section 4.2).
Hallucinations
Hallucinations have been reported and patients should be informed that hallucinations can occur.
Fibrotic complications
Fibrotic complications: Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion,
pleural thickening, pericarditis and cardiac valvulopathy have been reported in some patients treated
with ergot-derived dopaminergic agents. While these complications may resolve when treatment is
discontinued, complete resolution does not always occur.
Although these adverse reactions are believed to be related to the ergoline structure of these
compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
Neuroleptics
Neuroleptics given as antiemetic should not be given to patients taking dopamine agonists (see also
section 4.5).
Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Augmentation
Augmentation may occur in Restless Legs Syndrome patients. Augmentation refers to the earlier onset
of symptoms in the evening (or even the afternoon), increase in severity of symptoms, and spread of
symptoms to involve other body parts.
Based on two open-label follow-up studies with one year
duration, symptoms reflecting clinically relevant and not relevant augmentation may be as high as
13
9.4%. However, based on two 6-month, double-blind, placebo-controlled studies, clinically relevant
augmentation was observed in 1.5% of rotigotine-treated patients versus 0.5% of placebo treated
patients. In two open-label, follow-up studies over a subsequent 12 months, the rate of clinically
relevant augmentation was 2.9%. None of these patients discontinued therapy because of
augmentation.
Heat application
External heat (excessive sunlight, heating pads and other sources of heat such as sauna, hot bath)
should not be applied to the area of the patch.
Application site reactions
Application site skin reactions may occur and are usually mild or moderate in intensity. It is
recommended that the application site should be rotated on a daily basis (e.g. from the right side to the
left side and from the upper body to the lower body). The same site should not be used within 14 days.
If application site reactions occur which last for more than a few days or are persistent, if there is an
increase in severity, or if the skin reaction spreads outside the application site, an assessment of the
risk/benefit balance for the individual patient should be conducted.
If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be
avoided until the skin heals. Exposure could lead to changes in the skin color.
If a generalised skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or
pruritus) associated with the use of Neupro is observed, Neupro should be discontinued.
Dopaminergic adverse events
The incidence of some dopaminergic adverse events, such as hallucinations, dyskinesia, and peripheral
oedema generally is higher when given in combination with L-dopa in Parkinson’s patients. This
should be considered when prescribing rotigotine.
Peripheral edema
In clinical studies in Parkinson’s patients, the 6 month-specific rates of peripheral edema remained at
about 4% through the entire observation period up to 36 months.
Sulphite sensitivity
Neupro contains sodium metabisulphite, a sulphite that may cause allergic-type reactions including
anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible
people.
Because rotigotine is a dopamine agonist, it is assumed that dopamine antagonists, such as
neuroleptics (e.g. phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish
the effectiveness of Neupro, and co-administration should be avoided. Because of possible additive
effects, caution should be advised when patients are taking sedating medicinal products or other CNS
(central nervous system) depressants (e.g. benzodiazepines, antipsychotics, antidepressants) or alcohol
in combination with rotigotine.
Co-administration of L-dopa and carbidopa with rotigotine had no effect on the pharmacokinetics of
rotigotine, and rotigotine had no effect on the pharmacokinetics of L-dopa and carbidopa.
Co-administration of domperidone with rotigotine had no effect on the pharmacokinetics of rotigotine.
Co-administration of omeprazole (inhibitor of CYP2C19), in doses of 40 mg/day, had no effect on the
pharmacokinetics and metabolism of rotigotine in healthy volunteers.
Neupro may potentiate the dopaminergic adverse reaction of L-dopa and may cause and/or exacerbate
pre-existing dyskinesia, as described with other dopamine agonists.
14
Co-administration of rotigotine (3 mg/24 h) did not affect the pharmacodynamics and
pharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol, 0.15 mg levonorgestrel).
Interactions with other forms of hormonal contraception have not been investigated.
Pregnancy
There are no adequate data from the use of rotigotine in pregnant women. Animal studies do not
indicate any teratogenic effects in rats and rabbits, but embryo-toxicity was observed in rats and mice
at materno-toxic doses (see section 5.3). The potential risk for humans is unknown. Rotigotine should
not be used during pregnancy.
Breast-feeding
Because rotigotine decreases prolactin secretion in humans, inhibition of lactation is expected. Studies
in rats have shown that rotigotine and/or its metabolite(s) is excreted in breast milk. In the absence of
human data, breast-feeding should be discontinued.
Fertility
For information on fertility studies, please see section 5.3.
Rotigotine may have major influence on the ability to drive and use machines.
Patients being treated with rotigotine and presenting with somnolence and/or sudden sleep episodes
must be informed not to drive or engage in activities (e.g. operating machines) where impaired
alertness may put themselves or others at risk of serious injury or death until such recurrent episodes
and somnolence have resolved (see also sections 4.4 and 4.5).
Restless Legs Syndrome
Based on the analysis of pooled placebo-controlled clinical trials comprising a total of 748 Neupro-
and 214 placebo-treated patients, 65.2% of the patients on Neupro and 33.2% of patients on placebo
reported at least one adverse reaction.
At the beginning of therapy dopaminergic adverse reactions such as nausea and vomiting may occur.
These are usually mild or moderate in intensity and transient even if treatment is continued.
Adverse drug reactions (ADRs) reported in more than 10% of patients treated with Neupro are nausea,
application site reactions, asthenic conditions and headache.
In trials where the application sites were rotated as reflected in the instructions provided in the SmPC
and package leaflet, 34.2% of 748 patients using Neupro, experienced application site reactions. The
majority of these reactions were mild or moderate in intensity, limited to the application areas and
resulted in discontinuation of Neupro in 7.2% of subjects.
The following table covers adverse drug reactions from all studies in patients with Restless Legs
Syndrome. Within the system organ classes, adverse reactions are listed under headings of frequency
(number of patients expected to experience the reaction), using the following categories: very common
(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000);
very rare (<1/10,000); not known (cannot be estimated from the available data). Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System/organ classes
acc. to MedDRA
Very common
Common
Uncommon
15
Immune system
disorders
Hypersensitivity
Psychiatric disorders
Sleep attacks/sudden
onset of sleep, sexual
desire disorders
a
(incl.
hypersexuality, libido
increased), insomnia,
sleep disorder, abnormal
dreams
Impulse control disorder
a
(incl. pathological
gambling, punding),
obsessive compulsive
disorder
Nervous system
disorders
Headache
Somnolence
Vascular disorders
Hypertension
Orthostatic hypotension
Gastrointestinal
disorders
Nausea
Vomiting, dyspepsia
Skin and subcutaneous
tissue disorders
Pruritus
General disorders and
administration site
conditions
Application and
instillation site reactions
a
(incl. erythema, pruritus,
irritation, rash, dermatitis,
vesicles, pain, eczema,
inflammation, swelling,
discolouration, papules,
excoriation, urticaria,
hypersensitivity),
asthenic conditions
a
(incl.
fatigue, asthenia,
malaise)
Irritability
a
High Level Term
Discontinuation rate
The discontinuation rate was studied in 3 clinical trials ranging up to 3 years in duration. The
percentage of subjects discontinuing was 25-38% over the first year, 10% in the second year, and 11%
in the third year. Periodic assessment of efficacy should be performed, along with evaluation of safety,
including augmentation
.
Parkinson’s disease
Based on the analysis of pooled placebo-controlled clinical trials comprising a total of 1,307 Neupro-
and 607 placebo-treated patients, 72.3% of the patients on Neupro and 57.8% of patients on placebo
reported at least one adverse reaction.
At the beginning of therapy dopaminergic adverse reactions such as nausea and vomiting may occur.
These are usually mild or moderate in intensity and transient even if treatment is continued.
Adverse drug reactions (ADRs) reported in more than 10% of patients treated with Neupro
transdermal patch are nausea, vomiting, application site reactions, somnolence, dizziness and
headache.
In trials where the application sites were rotated as reflected in the instructions provided in SmPC and
package leaflet, 35.7% of 830 patients using the Neupro transdermal patch, experienced application
site reactions. The majority of these reactions were mild or moderate in intensity, limited to the
application areas and resulted in discontinuation of treatment with Neupro in only 4.3% of all subjects
receiving Neupro.
16
The following table covers adverse drug reactions from all studies in patients with Parkinson’s disease.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of
patients expected to experience the reaction), using the following categories: very common (≥1/10);
common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare
(<1/10,000); not known (cannot be estimated from the available data). Within each frequency
grouping, undesirable effects are presented in order of decreasing seriousness.
System/organ
classes acc. to
MedDRA
Very common
Common
Uncommon
Rare
Immune system
disorders
Hypersensitivity
Psychiatric
disorders
Perception
disturbances
a
(incl. hallucination,
hallucination
visual,
hallucination
auditory, illusion),
insomnia, sleep
disorder,
nightmare,
abnormal dreams
Sleep
attacks/sudden
onset of sleep,
paranoia, sexual
desire disorders
a
(incl.
hypersexuality,
libido increased),
impulse control
disorder
a
(incl.
pathological
gambling,
punding),
confusional state
Psychotic disorder,
obsessive-
compulsive
disorder
Nervous system
disorders
Somnolence,
dizziness, headache
Disturbances in
consciousness
NEC
a
(incl.
syncope, syncope
vasovagal, loss of
consciousness),
dyskinesia,
dizziness postural,
lethargy
Convulsion
Eye disorders
Vision blurred,
visual disturbance,
photopsia
Ear and labyrinth
disorders
Vertigo
Cardiac disorders
Palpitations
Atrial fibrillation
Supraventricular
tachycardia
Vascular disorders
Orthostatic
hypotension,
hypertension
Hypotension
Respiratory,
thoracic and
mediastinal
disorders
Hiccups
Gastrointestinal
disorders
Nausea, vomiting
Constipation, dry
mouth, dyspepsia
Abdominal pain
Skin and
subcutaneous tissue
disorders
Erythema,
hyperhidrosis,
pruritus
Pruritus
generalised, skin
irritation, dermatitis
contact
Rash generalised
17
Reproductive
system and breast
disorder
Erectile
dysfunction
General disorders
and administration
site conditions
Application and
instillation site
reactions
a
(incl.
erythema, pruritus,
irritation, rash,
dermatitis, vesicles,
pain, eczema,
inflammation,
swelling,
discolouration,
papules,
excoriation,
urticaria,
hypersensitivity)
Oedema peripheral,
asthenic conditions
a
(incl. fatigue,
asthenia, malaise)
Irritability
Investigations
Weight decreased, Hepatic enzyme
increased (incl.
AST, ALT, GGT),
weight increased,
heart rate increased
Injury, poisoning
and procedural
complications
Fall
a
High Level Term
Both indications
Description of selected adverse reactions
Sudden onset of sleep and somnolence
Rotigotine has been associated with somnolence including excessive daytime somnolence and sudden
sleep onset episodes. In isolated cases “sudden onset of sleep” occurred while driving and resulted in
motor vehicle accidents. See also section 4.4 and 4.7
Impulse control disorders
Patients treated with dopamine agonists including rotigotine, have been reported as exhibiting signs of
pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the
dose or treatment discontinuation.
The most likely adverse reactions would be those related to the pharmacodynamic profile of a
dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations,
confusion, convulsions and other signs of central dopaminergic stimulation.
There is no known antidote for overdose of dopamine agonists. In case of suspected overdose, the
patch(es) should immediately be removed from the patient. Levels of rotigotine decrease after patch
removal. Before stopping use of rotigotine completely see section 4.2.
The patient should be monitored closely, including heart rate, heart rhythm and blood pressure.
Because rotigotine is over 90% protein bound, dialysis would not be expected to be beneficial.
Treatment of overdose may require general supportive measures to maintain the vital signs.
5.
5.1 Pharmacodynamic properties
18
Pharmacotherapeutic group: Anti-parkinson drugs, dopamine agonists; ATC code: N04BC09
Rotigotine is a non-ergolinic D
3
/D
2
/D
1
dopamine agonist for the treatment of Parkinson’s disease. It is
believed to elicit its beneficial effect by activation of the D
3
, D
2
and D
1
receptors of the caudate-
putamen in the brain.
Rotigotine alleviates signs and symptoms of idiopathic Parkinson’s disease.
Clinical studies:
Clinical studies in Restless Legs Syndrome
The efficacy of rotigotine was evaluated in 5 placebo-controlled trials with more than 1,400 patients
with idiopathic Restless Legs Syndrome (RLS). Efficacy was demonstrated in controlled trials in
patients treated for up to 29 weeks. The effect was maintained over a 6 months period.
The changes from baseline in the International RLS Rating Scale (IRLS) and CGI-item 1 (severity of
illness) were primary efficacy parameters. For both primary endpoints statistically significant
differences have been observed for the doses 1 mg/24 h, 2 mg/24 h and 3 mg/24 h in comparison to
placebo. After 6 months of maintenance treatment in patients with moderate to severe RLS, the
baseline IRLS score improved from 30.7 to 20.7 for placebo and from 30.2 to 13.8 for rotigotine. The
adjusted mean difference was -6.5 points (CI
95%
-8.7; -4.4, p <0.0001). CGI-I responder rates (much
improved, very much improved) were 43.0% and 67.5% for placebo and rotigotine respectively
(difference 24.5% CI
95%
: 14.2%; 34.8%, p<0.0001).
In a placebo-controlled, 7-week trial polysomnographic parameters were investigated. Rotigotine
significantly reduced the periodic limb movement index (PLMI) from 50.9 to 7.7
versus
37.4 to 32.7
for placebo (p<0.0001).
Clinical studies in Parkinson’s disease
The effectiveness of rotigotine in the treatment of the signs and symptoms of idiopathic Parkinson's
disease was evaluated in a multinational drug development program consisting of four pivotal,
parallel, randomized, double-blind placebo controlled studies.
Two trials investigating the effectiveness of rotigotine in the treatment of the signs and symptoms of
idiopathic Parkinson’s disease were conducted in patients who were not receiving concomitant
dopamine agonist therapy and were either L-dopa naïve or previous L-dopa treatment was ≤ 6 months.
The primary outcome assessment was the score for the Activities of Daily Living (ADL) component
(Part II) plus the Motor Examination component (Part III) of the Unified Parkinson’s Disease Rating
Scale (UPDRS).
Efficacy was determined by the subject’s response to therapy in terms of responder and absolute
points improvement in the scores of ADL and Motor Examination combined (UPDRS part II+III).
In one double blind study, 177 patients received rotigotine and 96 patients received placebo. The
patients were titrated to their optimal dose of rotigotine or placebo in weekly increments of 2 mg/24 h
starting at 2 mg/24 h to a maximum dose of 6 mg/24 h. Patients in each treatment group were
maintained at their optimal dose for 6 months.
At the end of the maintenance treatment in 91% of the subjects in the rotigotine arm, the optimal dose
was the maximal dose allowed i.e. 6 mg/24 h. An improvement of 20% was seen in 48% of the
subjects receiving rotigotine and in 19% of the subjects receiving placebo (Difference 29% CI
95%
18%;
39%, p<0.0001). With rotigotine, the mean improvement in the UPDRS score (Parts II + III) was -3.98
points (baseline 29.9 point) whereas in the placebo-treated arm a worsening of 1.31 points was
observed (baseline 30.0 points) The difference was 5.28 points and statistically significant (p<0.0001).
In a second double-blind study, 213 patients received rotigotine, 227 received ropinirole and
117 patients received placebo. The patients were titrated to their optimal dose of rotigotine in weekly
increments of 2 mg/24 h starting at 2 mg/24 h to a maximum dose of 8 mg/24 h over 4 weeks. In the
ropinirole group, patients were titrated to their optimal dose up to a maximum of 24 mg/day over 13
weeks. Patients in each treatment group were maintained for 6 months.
19
At the end of the maintenance treatment in 92% of the subjects in the rotigotine arm, the optimal dose
was the maximal dose allowed i.e. 8 mg/24 h. An improvement of 20% was seen in 52% of the
subjects receiving rotigotine, 68% of the subjects receiving ropinirole and 30% of the subjects
receiving placebo (Difference rotigotine
versus
placebo 21.7%; CI
95%
11.1% ; 32.4% , difference
ropinirole
versus
placebo 38.4% CI
95%
28.1% ; 48.6% , difference ropinirole
versus
rotigotine 16.6%;
CI
95%
7.6% ; 25.7%).The mean improvement in the UPDRS score (Parts II + III) was 6.83 points
(baseline 33.2 points) in the rotigotine arm, 10.78 point in the ropinirole arm (baseline 32.2 points)
and 2.33 points in the placebo arm (baseline 31.3 points). All differences between the active
treatments and placebo were statistically significant. The difference in effect between ropinirole and
rotigotine was also statistically significant in favour of ropinirole.
Two additional trials were conducted in patients who were receiving concomitant levodopa therapy.
The primary outcome assessment was the reduction in “off” time (hours). Efficacy was determined by
the subject’s response to therapy in terms of responder and absolute improvement in the time spent
“off”.
In one double blind study, 113 patients received rotigotine up to a maximum dose of 8 mg/24 h, 109
patients received rotigotine up to a maximum dose of 12 mg/24 h and 119 patients received placebo.
The patients were titrated to their optimal doses of rotigotine or placebo in weekly increments of
2 mg/24 h starting at 4 mg/24 h. Patients in each treatment group were maintained at their optimal
dose for 6 months. At the end of the maintenance treatment an improvement of at least 30% was seen
in 57% and 55% of the subjects receiving rotigotine 8 mg/24 h and 12 mg/24 h, respectively and in
34% of the subjects receiving placebo (Differences 22% and 21%, respectively CI
95%
10%; 35% and
8%; 33%, respectively, p<0.001 for both rotigotine groups). With rotigotine, the mean reductions in
“off” time were 2.7 and 2.1 hours, respectively whereas in the placebo-treated arm a reduction of 0.9
hours was observed. The differences were statistically significant (p<0.001 and p=0.003, respectively).
In a second double-blind study, 201 patients received rotigotine, 200 received pramipexole and
100 patients received placebo. The patients were titrated to their optimal dose of rotigotine in weekly
increments of 2 mg/24 h starting at 4 mg/24 h to a maximum dose of 16 mg/24 h. In the pramipexole
group, patients received 0,375 mg in the first week, 0.75 mg in the second week and were titrated
further in weekly increments of 0.75 mg to their optimal dose up to a maximum of 4.5 mg/day.
Patients in each treatment group were maintained for 4 months.
At the end of the maintenance treatment an improvement of at least 30% was seen in 60% of the
subjects receiving rotigotine, 67% of the subjects receiving pramipexole and 35% of the subjects
receiving placebo (Difference rotigotine
versus
placebo 25%; CI
95%
13%; 36% , difference
pramipexole
versus
placebo 32% CI
95%
21% ; 43% , difference pramipexole
versus
rotigotine 7%;
CI
95%
-2% ; 17%).The mean reduction in the “off” time was 2.5 hours in the rotigotine arm, 2.8 hours
in the pramipexole arm and 0.9 hours in the placebo arm. All differences between the active treatments
and placebo were statistically significant.
5.2 Pharmacokinetic properties
Absorption
Following application, rotigotine is continuously released from the transdermal patch and absorbed
through the skin. Steady-state concentrations are reached after one to two days of patch application
and are maintained at a stable level by once daily application in which the patch is worn for 24 hours.
Rotigotine plasma concentrations increase dose-proportionally over a dose range of 1 mg/24 h to
24 mg/24 h.
Approximately 45% of the active substance within the patch is released to the skin in 24 hours. The
absolute bioavailability after transdermal application is approximately 37%.
Rotating the site of patch application may result in day-to-day differences in plasma levels.
Differences in bioavailability of rotigotine ranged from 2% (upper arm
versus
flank) to 46% (shoulder
versus
thigh). However, there is no indication of a relevant impact on the clinical outcome.
Distribution
20
The
in vitro
binding of rotigotine to plasma proteins is approximately 92%.
The apparent volume of distribution in humans is approximately 84 l/kg.
Metabolism
Rotigotine is metabolised to a great extent. Rotigotine is metabolised by N-dealkylation as well as
direct and secondary conjugation.
In vitro
results indicate that different CYP isoforms are able to
catalyse the N-dealkylation of rotigotine. Main metabolites are sulfates and glucuronide conjugates of
the parent compound as well as N-desalkyl-metabolites, which are biologically inactive.
The infomation on metabolites is incomplete.
Elimination
Approximately 71% of the rotigotine dose is excreted in urine and a smaller part of about 23% is
excreted in faeces.
The clearance of rotigotine after transdermal administration is approximately 10 l/min and its
elimination half-life is 5 to 7 hours.
Because the patch is administered transdermally, no effect of food and gastrointestinal conditions is
expected.
Special patient groups
Because therapy with Neupro is initiated at a low dose and gradually titrated according to clinical
tolerability to obtain the optimum therapeutic effect, adjustment of the dose based on gender, weight,
or age is not necessary.
In subjects with moderate hepatic impairment or mild to severe renal impairment, no relevant increases
of rotigotine plasma levels were observed. Neupro was not investigated in patients with severe hepatic
impairment.
Plasma levels of conjugates of rotigotine and its desalkyl metabolites increase with impaired renal
function. However, a contribution of these metabolites to clinical effects is unlikely.
5.3 Preclinical safety data
In repeated dose and long-term toxicity studies, the major effects were associated with the dopamine
agonist related pharmacodynamic effects and the consequent decrease of prolactin secretion.
After a single dose of rotigotine, binding to melanin-containing tissues (i.e., eyes) in the pigmented rat
and monkey was evident, but was slowly cleared over the 14-day observation period.
Retinal degeneration was observed by transmission microscopy at a dose equivalent to 2.8 times the
maximum recommended human dose on a mg/m² basis in a 3-month study in albino rats. The effects
were more pronounced in female rats. Additional studies to further evaluate the specific pathology
have not been performed. Retinal degeneration was not observed during the routine histopathological
evaluation of the eyes in any of the toxicology studies in any species used. The relevance of these
findings to humans is not known.
In a carcinogenicity study, male rats developed Leydig cell tumours and hyperplasia. Malignant
tumours were noted predominantly in the uterus of mid- and high-dose females. These changes are
well-known effects of dopamine agonists in rats after life-long therapy and assessed as not relevant to
man.
The effects of rotigotine on reproduction have been investigated in rats, rabbits and mice. Rotigotine
was not teratogenic in all three species, but was embryotoxic in rats and mice at materno-toxic doses.
Rotigotine did not influence male fertility in rats, but clearly reduced female fertility in rats and mice,
because of the effects on prolactin levels which are particularly significant in rodents.
Rotigotine did not induce gene mutations in the Ames test, but did show effects in the
in vitro
Mouse
Lymphoma Assay with metabolic activation and weaker effects without metabolic activation. This
mutagenic effect could be attributed to a clastogenic effect of rotigotine. This effect was not confirmed
in vivo
in the Mouse Micronucleus Test in the rat Unscheduled DNA Synthesis (UDS) test. Since it
ran more or less parallel with a decreased relative total growth of the cells, it may be related to a
cytotoxic effect of the compound. Therefore, the relevance of the one positive
in vitro
mutagenicity
test is not known.
21
6.
6.1 List of excipients
Backing layer:
Polyester film, siliconized, aluminized,
colour coated with a pigment (titanium dioxide (E171), pigment yellow 95, pigment red 166) layer and
imprinted (pigment red 144, pigment yellow 95, pigment black 7).
Self adhesive matrix layer:
Poly(dimethylsiloxane, trimethylsilyl silicate)-copolymerisate,
Povidone K90,
sodium metabisulphite (E223),
ascorbyl palmitate (E304) and
DL-α-tocopherol (E307).
Protective liner:
Transparent fluoropolymer coated polyester film.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
6.5 Nature and contents of container
Peel off sachet in a cardboard carton: One side is composed of an ethylene copolymer (innermost
layer), an aluminium foil, low density polyethylene film and paper; the other side is composed of
polyethylene (innermost layer), aluminium, ethylene copolymer and paper.
The carton contains 7, 20, 28, 30, 56, 60, 84 (2x42), 90 or 100 (2x50) transdermal patches,
individually sealed in sachets.
Not all pack sizes may be marketed.
6.6 Special precaution for disposal
After use the patch still contains active substance. After removal, the used patch should be folded in
half, adhesive side inwards so that the matrix layer is not exposed, placed in the original sachet and
then discarded out of the reach of children. Any used or unused patches should be disposed of in
accordance with local requirements or returned to the pharmacy.
7.
SCHWARZ PHARMA Ltd.
Shannon, Industrial Estate,
Co.Clare, Ireland
22
8.
EU/1/05/331/001 - 003
EU/1/05/331/014 - 019
9.
Date of first authorisation: 15 February 2006
Date of latest renewal:
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
23
1.
Neupro 3 mg/24 h transdermal patch
2.
Each patch releases 3 mg of rotigotine per 24 hours. Each patch of 15 cm
2
contains 6.75 mg of
rotigotine.
For a full list of excipients, see section 6.1.
3.
Transdermal patch.
Thin, matrix-type, square-shaped with rounded edges, consisting of three layers. The outside of the
backing layer is tan-coloured and imprinted with ‘Neupro 3 mg/24 h’.
4.
Neupro is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs
Syndrome in adults.
Posology
Neupro is applied once a day. The patch should be applied at approximately the same time every day.
The patch remains on the skin for 24 hours and will then be replaced by a new one at a different site of
application.
If the patient forgets to apply the patch at the usual time of the day or if the patch becomes detached,
another patch should be applied for the remainder of the day.
Dose
The dose recommendations made are in nominal dose.
A single daily dose should be initiated at 1 mg/24 h. Depending on the individual patient response, the
dose may be increased in weekly increments of 1 mg/24 h to a maximal dose of 3 mg/24 h. The need
for treatment continuation should be reconsidered every 6 months.
Treatment discontinuation
Neupro should be discontinued gradually. The daily dose should be reduced in steps of 1 mg/24 h with
a dose reduction preferably every other day, until complete withdrawal of Neupro (see section 4.4).
Following this procedure, rebound (worsening of symptoms beyond initial intensity after
discontinuation of treatment) was not observed.
Special populations
Hepatic and renal impairment:
Adjustment of the dose is not necessary in patients with mild to
moderate hepatic impairment or in patients with mild to severe renal impairment, including those
requiring dialysis. Caution is advised when treating patients with severe hepatic impairment, which
may result in lower rotigotine clearance. Rotigotine has not been investigated in this patient group. A
24
dose reduction might be needed in case of worsening of the hepatic impairment. Unexpected
accumulation of rotigotine levels may also occur at acute worsening of renal function (see section 5.2).
Paediatric population
The safety and efficacy of rotigotine in the paediatric population have not yet been established. No
data are available.
Method of administration
The patch should be applied to clean, dry, intact healthy skin on the abdomen, thigh, hip, flank,
shoulder, or upper arm. Reapplication to the same site within 14 days should be avoided. Neupro
should not be placed on skin that is red, irritated or damaged. (see section 4.4)
Use and handling:
Each patch is packed in a sachet and should be applied directly after the sachet has been opened. One
half of the protective liner should be removed and the sticky side should be applied and pressed firmly
to the skin. Then, the patch is fold back and the second part of the release liner is removed. The sticky
side of the patch should not be touched. The patch should be pressed down firmly with the palm of the
hand for about 20 to 30 seconds, so that it sticks well.
In the event that a patch should fall off, a new patch should be applied for the remainder of the 24 hour
dosing interval.
The patch should not be cut into pieces.
Hypersensitivity to the active substance or to any of the excipients.
Magnetic resonance imaging or cardioversion (see section 4.4).
Magnetic resonance imaging and cardioversion
The backing layer of Neupro contains aluminium. To avoid skin burns, Neupro should be removed if
the patient has to undergo magnetic resonance imaging (MRI) or cardioversion.
Orthostatic hypotension
Dopamine agonists are known to impair the systemic regulation of the blood pressure resulting in
postural/orthostatic hypotension. These events were also observed during treatment with rotigotine,
however the incidence was similar to that in placebo-treated patients.
Syncope was observed in association with rotigotine, but also at a similar rate in patients treated with
placebo.
It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the
general risk of orthostatic hypotension associated with dopaminergic therapy.
Sudden onset of sleep and somnolence
Rotigotine has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of
sleep during daily activities, in some cases without awareness of any warning signs, has been reported.
Prescribers should continually reassess patients for drowsiness or sleepiness, as patients may not
acknowledge drowsiness or sleepiness until directly questioned. A reduction of dosage or termination
of therapy should be carefully considered.
Impulse control disorders
Pathologic gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists, including rotigotine.
Neuroleptic malignant syndrome
25
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy. Therefore it is recommended to taper treatment (see section 4.2).
Hallucinations
Hallucinations have been reported and patients should be informed that hallucinations can occur.
Fibrotic complications
Fibrotic complications: Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion,
pleural thickening, pericarditis and cardiac valvulopathy have been reported in some patients treated
with ergot-derived dopaminergic agents. While these complications may resolve when treatment is
discontinued, complete resolution does not always occur.
Although these adverse reactions are believed to be related to the ergoline structure of these
compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
Neuroleptics
Neuroleptics given as antiemetic should not be given to patients taking dopamine agonists (see also
section 4.5).
Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Augmentation
Augmentation may occur. Augmentation refers to the earlier onset of symptoms in the evening (or
even the afternoon), increase in severity of symptoms, and spread of symptoms to involve other body
parts.
Based on two open-label follow-up studies with one year duration, symptoms reflecting
clinically relevant and not relevant augmentation may be as high as 9.4%. However, based on two 6-
month, double-blind, placebo-controlled studies, clinically relevant augmentation was observed in
1.5% of rotigotine-treated patients versus 0.5% of placebo treated patients. In two open-label, follow-
up studies over a subsequent 12 months, the rate of clinically relevant augmentation was 2.9%. None
of these patients discontinued therapy because of augmentation.
Heat application
External heat (excessive sunlight, heating pads and other sources of heat such as sauna, hot bath)
should not be applied to the area of the patch.
Application site reactions
Application site skin reactions may occur and are usually mild or moderate in intensity. It is
recommended that the application site should be rotated on a daily basis (e.g. from the right side to the
left side and from the upper body to the lower body). The same site should not be used within 14 days.
If application site reactions occur which last for more than a few days or are persistent, if there is an
increase in severity, or if the skin reaction spreads outside the application site, an assessment of the
risk/benefit balance for the individual patient should be conducted.
If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be
avoided until the skin heals. Exposure could lead to changes in the skin color.
If a generalised skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or
pruritus) associated with the use of Neupro is observed, Neupro should be discontinued.
Sulphite sensitivity
Neupro contains sodium metabisulphite, a sulphite that may cause allergic-type reactions including
anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible
people.
Because rotigotine is a dopamine agonist, it is assumed that dopamine antagonists, such as
neuroleptics (e.g. phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish
the effectiveness of Neupro, and co-administration should be avoided. Because of possible additive
26
effects, caution should be advised when patients are taking sedating medicinal products or other CNS
(central nervous system) depressants (e.g. benzodiazepines, antipsychotics, antidepressants) or alcohol
in combination with rotigotine.
Co-administration of L-dopa and carbidopa with rotigotine had no effect on the pharmacokinetics of
rotigotine, and rotigotine had no effect on the pharmacokinetics of L-dopa and carbidopa.
Co-administration of domperidone with rotigotine had no effect on the pharmacokinetics of rotigotine.
Co-administration of omeprazole (inhibitor of CYP2C19), in doses of 40 mg/day, had no effect on the
pharmacokinetics and metabolism of rotigotine in healthy volunteers.
Co-administration of rotigotine (3 mg/24 h) did not affect the pharmacodynamics and
pharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol, 0.15 mg levonorgestrel).
Interactions with other forms of hormonal contraception have not been investigated.
Pregnancy
There are no adequate data from the use of rotigotine in pregnant women. Animal studies do not
indicate any teratogenic effects in rats and rabbits, but embryo-toxicity was observed in rats and mice
at materno-toxic doses (see section 5.3). The potential risk for humans is unknown. Rotigotine should
not be used during pregnancy.
Breast-feeding
Because rotigotine decreases prolactin secretion in humans, inhibition of lactation is expected. Studies
in rats have shown that rotigotine and/or its metabolite(s) is excreted in breast milk. In the absence of
human data, breast-feeding should be discontinued.
Fertility
For information on fertility studies, please see section 5.3.
Rotigotine may have major influence on the ability to drive and use machines.
Patients being treated with rotigotine and presenting with somnolence and/or sudden sleep episodes
must be informed not to drive or engage in activities (e.g. operating machines) where impaired
alertness may put themselves or others at risk of serious injury or death until such recurrent episodes
and somnolence have resolved (see also sections 4.4 and 4.5).
Based on the analysis of pooled placebo-controlled clinical trials comprising a total of 748 Neupro-
and 214 placebo-treated patients, 65.2% of the patients on Neupro and 33.2% of patients on placebo
reported at least one adverse reaction.
At the beginning of therapy dopaminergic adverse reactions such as nausea and vomiting may occur.
These are usually mild or moderate in intensity and transient even if treatment is continued.
Adverse drug reactions (ADRs) reported in more than 10% of patients treated with Neupro are nausea,
application site reactions, asthenic conditions and headache.
In trials where the application sites were rotated as reflected in the instructions provided in the SmPC
and package leaflet, 34.2% of 748 patients using Neupro, experienced application site reactions. The
majority of these reactions were mild or moderate in intensity, limited to the application areas and
resulted in discontinuation of Neupro in 7.2% of subjects.
27
The following table covers adverse drug reactions from all studies in patients with Restless Legs
Syndrome. Within the system organ classes, adverse reactions are listed under headings of frequency
(number of patients expected to experience the reaction), using the following categories: very common
(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000);
very rare (<1/10,000); not known (cannot be estimated from the available data). Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System/organ classes
acc. to MedDRA
Very common
Common
Uncommon
Immune system
disorders
Hypersensitivity
Psychiatric disorders
Sleep attacks/sudden
onset of sleep, sexual
desire disorders
a
(incl.
hypersexuality, libido
increased), insomnia,
sleep disorder, abnormal
dreams
Impulse control disorder
a
(incl. pathological
gambling, punding),
obsessive compulsive
disorder
Nervous system
disorders
Headache
Somnolence
Vascular disorders
Hypertension
Orthostatic hypotension
Gastrointestinal
disorders
Nausea
Vomiting, dyspepsia
Skin and subcutaneous
tissue disorders
Pruritus
General disorders and
administration site
conditions
Application and
instillation site reactions
a
(incl. erythema, pruritus,
irritation, rash, dermatitis,
vesicles, pain, eczema,
inflammation, swelling,
discolouration, papules,
excoriation, urticaria,
hypersensitivity),
asthenic conditions
a
(incl.
fatigue, asthenia,
malaise)
Irritability
a
High Level Term
Description of selected adverse reactions
Sudden onset of sleep and somnolence
Rotigotine has been associated with somnolence including excessive daytime somnolence and sudden
sleep onset episodes. In isolated cases “sudden onset of sleep” occurred while driving and resulted in
motor vehicle accidents. See also section 4.4 and 4.7.
Impulse control disorders
Patients treated with dopamine agonists including rotigotine, have been reported as exhibiting signs of
pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the
dose or treatment discontinuation.
Discontinuation rate
The discontinuation rate was studied in 3 clinical trials ranging up to 3 years in duration. The
percentage of subjects discontinuing was 25-38% over the first year, 10% in the second year, and 11%
in the third year. Periodic assessment of efficacy should be performed, along with evaluation of safety,
including augmentation
.
28
The most likely adverse reactions would be those related to the pharmacodynamic profile of a
dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations,
confusion, convulsions and other signs of central dopaminergic stimulation.
There is no known antidote for overdose of dopamine agonists. In case of suspected overdose, the
patch(es) should immediately be removed from the patient. Levels of rotigotine decrease after patch
removal. Before stopping use of rotigotine completely see section 4.2.
The patient should be monitored closely, including heart rate, heart rhythm and blood pressure.
Because rotigotine is over 90% protein bound, dialysis would not be expected to be beneficial.
Treatment of overdose may require general supportive measures to maintain the vital signs.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-parkinson drugs, dopamine agonists; ATC code: N04BC09
Rotigotine is a non-ergolinic D
3
/D
2
/D
1
dopamine agonist for the treatment of Parkinson’s disease. It is
believed to elicit its beneficial effect by activation of the D
3
, D
2
and D
1
receptors of the caudate-
putamen in the brain.
Rotigotine alleviates signs and symptoms of idiopathic Parkinson’s disease.
Clinical studies:
The efficacy of rotigotine was evaluated in 5 placebo-controlled trials with more than 1,400 patients
with idiopathic Restless Legs Syndrome (RLS). Efficacy was demonstrated in controlled trials in
patients treated for up to 29 weeks. The effect was maintained over a 6 months period.
The changes from baseline in the International RLS Rating Scale (IRLS) and CGI-item 1 (severity of
illness) were primary efficacy parameters. For both primary endpoints statistically significant
differences have been observed for the doses 1 mg/24 h, 2 mg/24 h and 3 mg/24 h in comparison to
placebo. After 6 months of maintenance treatment in patients with moderate to severe RLS, the
baseline IRLS score improved from 30.7 to 20.7 for placebo and from 30.2 to 13.8 for rotigotine. The
adjusted mean difference was -6.5 points (CI
95%
-8.7; -4.4, p <0.0001). CGI-I responder rates (much
improved, very much improved) were 43.0% and 67.5% for placebo and rotigotine respectively
(difference 24.5% CI
95%
: 14.2%; 34.8%, p<0.0001).
In a placebo-controlled, 7-week trial polysomnographic parameters were investigated. Rotigotine
significantly reduced the periodic limb movement index (PLMI) from 50.9 to 7.7
versus
37.4 to 32.7
for placebo (p<0.0001).
5.2 Pharmacokinetic properties
Absorption
Following application, rotigotine is continuously released from the transdermal patch and absorbed
through the skin. Steady-state concentrations are reached after one to two days of patch application
and are maintained at a stable level by once daily application in which the patch is worn for 24 hours.
Rotigotine plasma concentrations increase dose-proportionally over a dose range of 1 mg/24 h to
24 mg/24 h.
Approximately 45% of the active substance within the patch is released to the skin in 24 hours. The
absolute bioavailability after transdermal application is approximately 37%.
29
Rotating the site of patch application may result in day-to-day differences in plasma levels.
Differences in bioavailability of rotigotine ranged from 2% (upper arm
versus
flank) to 46% (shoulder
versus
thigh). However, there is no indication of a relevant impact on the clinical outcome.
Distribution
The
in vitro
binding of rotigotine to plasma proteins is approximately 92%.
The apparent volume of distribution in humans is approximately 84 l/kg.
Metabolism
Rotigotine is metabolised to a great extent. Rotigotine is metabolised by N-dealkylation as well as
direct and secondary conjugation.
In vitro
results indicate that different CYP isoforms are able to
catalyse the N-dealkylation of rotigotine. Main metabolites are sulfates and glucuronide conjugates of
the parent compound as well as N-desalkyl-metabolites, which are biologically inactive.
The infomation on metabolites is incomplete.
Elimination
Approximately 71% of the rotigotine dose is excreted in urine and a smaller part of about 23% is
excreted in faeces.
The clearance of rotigotine after transdermal administration is approximately 10 l/min and its
elimination half-life is 5 to 7 hours.
Because the patch is administered transdermally, no effect of food and gastrointestinal conditions is
expected.
Special patient groups
Because therapy with Neupro is initiated at a low dose and gradually titrated according to clinical
tolerability to obtain the optimum therapeutic effect, adjustment of the dose based on gender, weight,
or age is not necessary.
In subjects with moderate hepatic impairment or mild to severe renal impairment, no relevant increases
of rotigotine plasma levels were observed. Neupro was not investigated in patients with severe hepatic
impairment.
Plasma levels of conjugates of rotigotine and its desalkyl metabolites increase with impaired renal
function. However, a contribution of these metabolites to clinical effects is unlikely.
5.3 Preclinical safety data
In repeated dose and long-term toxicity studies, the major effects were associated with the dopamine
agonist related pharmacodynamic effects and the consequent decrease of prolactin secretion.
After a single dose of rotigotine, binding to melanin-containing tissues (i.e., eyes) in the pigmented rat
and monkey was evident, but was slowly cleared over the 14-day observation period.
Retinal degeneration was observed by transmission microscopy at a dose equivalent to 2.8 times the
maximum recommended human dose on a mg/m² basis in a 3-month study in albino rats. The effects
were more pronounced in female rats. Additional studies to further evaluate the specific pathology
have not been performed. Retinal degeneration was not observed during the routine histopathological
evaluation of the eyes in any of the toxicology studies in any species used. The relevance of these
findings to humans is not known.
In a carcinogenicity study, male rats developed Leydig cell tumours and hyperplasia. Malignant
tumours were noted predominantly in the uterus of mid- and high-dose females. These changes are
well-known effects of dopamine agonists in rats after life-long therapy and assessed as not relevant to
man.
The effects of rotigotine on reproduction have been investigated in rats, rabbits and mice. Rotigotine
was not teratogenic in all three species, but was embryotoxic in rats and mice at materno-toxic doses.
Rotigotine did not influence male fertility in rats, but clearly reduced female fertility in rats and mice,
because of the effects on prolactin levels which are particularly significant in rodents.
Rotigotine did not induce gene mutations in the Ames test, but did show effects in the
in vitro
Mouse
Lymphoma Assay with metabolic activation and weaker effects without metabolic activation. This
30
mutagenic effect could be attributed to a clastogenic effect of rotigotine. This effect was not confirmed
in vivo
in the Mouse Micronucleus Test in the rat Unscheduled DNA Synthesis (UDS) test. Since it
ran more or less parallel with a decreased relative total growth of the cells, it may be related to a
cytotoxic effect of the compound. Therefore, the relevance of the one positive
in vitro
mutagenicity
test is not known.
6.
6.1 List of excipients
Backing layer:
Polyester film, siliconized, aluminized,
colour coated with a pigment (titanium dioxide (E171), pigment yellow 95, pigment red 166) layer and
imprinted (pigment red 144, pigment yellow 95, pigment black 7).
Self adhesive matrix layer:
Poly(dimethylsiloxane, trimethylsilyl silicate)-copolymerisate,
Povidone K90,
sodium metabisulphite (E223),
ascorbyl palmitate (E304) and
DL-α-tocopherol (E307).
Protective liner:
Transparent fluoropolymer coated polyester film.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
6.5 Nature and contents of container
Peel off sachet in a cardboard carton: One side is composed of an ethylene copolymer (innermost
layer), an aluminium foil, low density polyethylene film and paper; the other side is composed of
polyethylene (innermost layer), aluminium, ethylene copolymer and paper.
The carton contains 7, 20, 28, 30, 56, 60, 84 (2x42), 90 or 100 (2x50) transdermal patches,
individually sealed in sachets.
Not all pack sizes may be marketed.
6.6 Special precaution for disposal
After use the patch still contains active substance. After removal, the used patch should be folded in
half, adhesive side inwards so that the matrix layer is not exposed, placed in the original sachet and
then discarded out of the reach of children. Any used or unused patches should be disposed of in
accordance with local requirements or returned to the pharmacy.
31
7.
SCHWARZ PHARMA Ltd.
Shannon, Industrial Estate,
Co.Clare, Ireland
8.
EU/1/05/331/047 - 055
9.
Date of first authorisation: 15 February 2006
Date of latest renewal:
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
32
1.
FURTHER INFORMATION
What Neupro contains
-
The active substance is rotigotine.
Neupro 2 mg/24 h
Each patch releases 2 mg of rotigotine per 24 hours. Each patch of 10 cm
2
contains 4.5 mg of
rotigotine.
Neupro 4 mg/24 h
Each patch releases 4 mg of rotigotine per 24 hours. Each patch of 20 cm
2
contains 9.0 mg of
rotigotine.
Neupro 6 mg/24 h
Each patch releases 6 mg of rotigotine per 24 hours. Each patch of 30 cm
2
contains 13.5 mg of
rotigotine.
Neupro 8 mg/24 h
Each patch releases 8 mg of rotigotine per 24 hours. Each patch of 40 cm
2
contains 18.0 mg of
rotigotine.
-
The other ingredients are poly(dimethylsiloxane, trimethylsilyl silicate)-copolymerisate,
povidoneK90, sodium metabisulphite (E223), ascorbyl palmitate (E304) and DL-α-tocopherol
(E307).
Backing layer: Polyester film, siliconized, aluminized, colour coated with a pigment (titanium
dioxide (E171), pigment yellow 95, pigment red 166) layer and imprinted (pigment red 144,
pigment yellow 95, pigment black 7).
Protective liner: Transparent fluoropolymer coated polyester film.
What Neupro looks like and contents of pack
Neupro is a transdermal patch. It is thin and has three layers. It is square-shaped with rounded edges.
The outside is tan-coloured and is imprinted with Neupro 2 mg/24 h, 4 mg/24 h, 6 mg/24 h or
8 mg/24 h.
201
Neupro is available in the following pack-sizes:
One treatment initiation pack contains 28 transdermal patches in 4 cartons with 7 patches of 2 mg,
4 mg, 6 mg, and 8 mg each, which are individually sealed in sachets.
Marketing Authorisation Holder and Manufacturer
SCHWARZ PHARMA Ltd.
Shannon, Industrial Estate,
Co.Clare, Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
UCB Pharma SA /NV
Tel/Tél: +32 / (0)2 559 92 00
Luxembourg/Luxemburg
UCB Pharma SA/NV
Tél/Tel: +32 / (0)2 559 92 00
България
Ю СИ БИ България ЕООД
Teл.: + 359 (0) 2 962 99 20
Magyarország
UCB Magyarország Kft.
Tel.: + 36-(1) 391 0060
Česká republika
UCB s.r.o.
Tel: + 420 221 773 411
Malta
Pharmasud Ltd.
Tel: +356 / 21 37 64 36
Danmark
UCB Nordic A/S
Tlf: + 45 / 32 46 24 00
Nederland
UCB Pharma B.V.
Tel.: +31 / (0)76-573 11 40
Deutschland
UCB Pharma GmbH
Tel: + 49 / (0) 2173 48 48 48
Norge
UCB Nordic A/S
Tlf: +45 / 32 46 24 00
Eesti
UCB Pharma Oy Finland
Tel: + 358 10 234 6800 (Soome)
Österreich
UCB Pharma GmbH
Tel: + 43 (1) 291 80 00
Ελλάδα
UCB Α.Ε.
Τηλ: +30 / 2109974000
Polska
UCB Pharma Sp. z o.o.
Tel.: + 48 22 696 99 20
España
UCB Pharma, S.A.
Tel: + 34 / 91 570 34 44
Portugal
UCB Pharma (Produtos Farmacêuticos), Lda
Tel: + 351 / 21 302 5300
France
UCB Pharma S.A.
Tél: + 33 / (0)1 47 29 44 35
România
UCB Pharma România S.R.L.
Tel: + 40 21 300 29 04
Ireland
UCB (Pharma) Ireland Ltd.
Tel: + 353 / (0)1-46 37 395
Slovenija
Medis, d.o.o.
Tel: + 386 1 589 69 00
202
Ísland
Vistor hf.
Tel: +354 535 7000
Slovenská republika
UCB s.r.o., organizačná zložka
Tel: + 421 (0) 2 5920 2020
Italia
UCB Pharma S.p.A.
Tel: + 39 / 02 300 791
Suomi/Finland
UCB Pharma Oy Finland
Puh/Tel: + 358 10 234 6800
Κύπρος
Lifepharma (Z.A.M.) Ltd
Τηλ: + 357 22 34 74 40
Sverige
UCB Nordic A/S
Tel: + 46 / (0) 40 29 49 00
Latvija
UCB Pharma Oy Finland
Tel: + 358 10 234 6800 (Somija)
United Kingdom
UCB Pharma Ltd.
Tel : +44 / (0)1753 534 655
Lietuva
UCB Pharma Oy Finland
Tel: + 358 10 234 6800 (Suomija)
This leaflet was last approved in
{MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency web site:
203
ANNEX IV
GROUNDS FOR ONE ADDITIONAL RENEWAL
204
Grounds for one additional renewal
Based upon the data that have become available since the Marketing Authorisation, the CHMP considers
that the benefit-risk balance of Neupro remains positive, but considers that its safety profile is to be closely
monitored for the following reasons:
The reports of snowflake-like alterations have been a major issue for this product since approval. To
prevent occurrence of these alterations, the product now has to be stored in the refrigerator. This has
however only been accepted as a temporary measure and the MAH has been requested to reformulate the
product to allow storage at room temperature. This reformulation is ongoing and a type II variation is
expected to be submitted in 2011.
Being currently marketed in 15 out of the 27 EU countries, exposure to the product is still considered
limited.
Therefore, based upon the safety profile of Neupro, the ongoing reformulation strategy, and the limited
exposure to the product, the CHMP concluded that the MAH should submit one additional renewal
application in 5 years time.
The MAH will restart the PSUR submission cycle, i.e. four 6-month reports, two 1-year reports, followed
by the next 5-year renewal unless otherwise specified by the CHMP.
205
Source: European Medicines Agency
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