NEUPRO 2mg / 24h transdermic patch medication leaflet

Neupro 2 mg/24 h transdermal patch

Each patch releases 2 mg of rotigotine per 24 hours. Each patch of 10 cm2 contains 4.5 mg ofrotigotine.

For the full list of excipients, see section 6.1.

Transdermal patch.

Thin, matrix-type, square-shaped with rounded edges, consisting of three layers. The outside of thebacking layer is tan-coloured and imprinted with ‘Neupro 2 mg/24 h’.

Restless Legs Syndrome

Neupro is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs

Syndrome (RLS) in adults.

Parkinson’s disease

Neupro is indicated for the treatment of the signs and symptoms of early-stage idiopathic Parkinson’sdisease as monotherapy (i.e. without levodopa) or in combination with levodopa, i.e. over the courseof the disease, through to late stages when the effect of levodopa wears off or becomes inconsistentand fluctuations of the therapeutic effect occur (end of dose or ‘on-off’ fluctuations).

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, thedose may be increased in weekly increments of 1 mg/24 h to a maximum dose of 3 mg/24 h. The needfor 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 of2 mg/24 h to an effective dose up to a maximum dose of 8 mg/24 h.4 mg/24 h may be an effective dose in some patients. For most patients an effective dose is reachedwithin 3 or 4 weeks at doses of 6 mg/24 h or 8 mg/24 h, respectively.

The maximum 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 of2 mg/24 h to an effective dose up to a maximum 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 isreached 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.

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 ofapplication.

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.

Restless Legs Syndrome

Neupro should be discontinued gradually. The daily dose should be reduced in steps of 1 mg/24 h witha 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 afterdiscontinuation of treatment) has not been observed.

Parkinson’s disease

Neupro should be discontinued gradually. The daily dose should be reduced in steps of 2 mg/24 h witha dose reduction preferably every other day, until complete withdrawal of Neupro (see section 4.4).

Adjustment of the dose is not necessary in patients with mild to moderate hepatic impairment. Cautionis advised when treating patients with severe hepatic impairment, which may result in lower rotigotineclearance. Rotigotine has not been investigated in this patient group. A dose reduction might beneeded in case of worsening of the hepatic impairment.

Adjustment of the dose is not necessary in patients with mild to severe renal impairment, includingthose requiring dialysis. Unexpected accumulation of rotigotine levels may also occur at acuteworsening of renal function (see section 5.2).

The safety and efficacy of rotigotine in children and adolescents have not yet been established.

Currently available data are described in section 5.2 but no recommendation on a posology in childrenwith RLS can be made.

There is no relevant use of Neupro in the paediatric population in Parkinson’s disease.

Neupro is for transdermal use.

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. Neuproshould 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. Onehalf of the release liner should be removed and the sticky side should be applied and pressed firmly tothe skin. Then, the patch is fold back and the second part of the release liner is removed. The stickyside of the patch should not be touched. The patch should be pressed down firmly with the palm of thehand for about 30 seconds, so that it sticks well.

The patch should not be cut into pieces.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Magnetic resonance imaging or cardioversion (see section 4.4).

If a Parkinson’s disease patient is insufficiently controlled while on treatment with rotigotineswitching to another dopamine agonist might provide additional benefit (see section 5.1)

Both indications:

Magnetic resonance imaging and cardioversion

The backing layer of Neupro contains aluminium. To avoid skin burns, Neupro should be removed ifthe patient has to undergo magnetic resonance imaging (MRI) or cardioversion.

Dopamine agonists are known to impair the systemic regulation of the blood pressure resulting inpostural/orthostatic hypotension. These events have also been observed during treatment withrotigotine, but the incidence was similar to that observed in placebo-treated patients.

It is recommended to monitor blood pressure, especially at the beginning of treatment, due to thegeneral risk of orthostatic hypotension associated with dopaminergic therapy.

In clinical studies with rotigotine, syncope has been observed at a rate that was similar to that observedin patients treated with placebo. Because patients with clinically relevant cardiovascular disease wereexcluded in these studies, patients with severe cardiovascular disease should be asked about symptomsof syncope and pre-syncope.

Sudden onset of sleep and somnolence

Rotigotine has been associated with somnolence and episodes of sudden sleep onset. Sudden onset ofsleep 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 notacknowledge drowsiness or sleepiness until directly questioned. A reduction of dosage or terminationof therapy should be carefully considered.

Impulse control and other related disorders

Patients should be regularly monitored for the development of impulse control disorders and relateddisorders including dopamine dysregulation syndrome. Patients and carers should be made aware thatbehavioural symptoms of impulse control disorders including pathologic gambling, increased libido,hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur inpatients treated with dopamine agonists, including rotigotine. In some patients, dopaminedysregulation syndrome was observed under the treatment with rotigotine. Dose reduction/tapereddiscontinuation should be considered if such symptoms develop.

Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawalof dopaminergic therapy. Therefore, it is recommended to taper treatment (see section 4.2).

Dopamine agonist withdrawal syndrome

Symptoms suggestive of dopamine agonist withdrawal syndrome (for example, pain, fatigue,depression, sweating, and anxiety) have been reported with abrupt withdrawal of dopaminergictherapy, therefore, it is recommended to taper treatment (see section 4.2).

Abnormal thinking and behaviour

Abnormal thinking and behaviour have been reported and can consist of a variety of manifestationsincluding paranoid ideation, delusions, hallucinations, confusion, psychotic-like behaviour,disorientation, aggressive behaviour, agitation, and delirium.

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-deriveddopaminergic 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 thesecompounds, 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 alsosection 4.5).

Ophthalmologic monitoring

Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.

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 isrecommended that the application site should be rotated on a daily basis (e.g. from the right side to theleft 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 anincrease in severity, or if the skin reaction spreads outside the application site, an assessment of therisk/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 beavoided until the skin heals, as exposure could lead to changes in the skin color.

If a generalised skin reaction (e.g. allergic rash, including erythematous, macular, papular rash orpruritus) associated with the use of Neupro is observed, Neupro should be discontinued.

Peripheral oedema

In clinical studies in Parkinson’s patients, the 6 month-specific rates of peripheral oedema remained atabout 4% through the entire observation period up to 36 months. Peripheral oedema has also beenobserved in clinical trials conducted in patients with RLS.

Sulphite sensitivity

Neupro contains sodium metabisulphite, a sulphite that may cause allergic-type reactions includinganaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptiblepeople.

Observed in patients with Parkinson’s disease

Dopaminergic adverse reactions

The incidence of some dopaminergic adverse reactions, such as hallucinations, dyskinesia, andperipheral oedema generally is higher when given in combination with L-dopa in Parkinson’s patients.

This should be considered when prescribing rotigotine.

Dystonic reactions

Dystonic reactions including dystonia, abnormal posture, torticollis and pleurothotonus (Pisa

Syndrome) have occasionally been reported in patients with Parkinson’s disease following initiation orincremental dose increase of rotigotine. Although dystonic reactions may be a symptom of Parkinson’sdisease, the symptoms in some of these patients have improved after reduction or withdrawal ofrotigotine. If a dystonic reaction occurs, the dopaminergic medication regimen should be reviewed andan adjustment in the dose of rotigotine considered.

Observed in patients with Restless Legs Syndrome

Augmentation

Augmentation may occur in Restless Legs Syndrome patients. Augmentation refers to the earlier onsetof symptoms in the evening (or even the afternoon), increase in severity of symptoms, and spread ofsymptoms to involve other body parts. In long-term clinical studies with rotigotine, the majority ofaugmentation episodes were seen in the first and second years of treatment. Doses higher than theapproved dose range for RLS should be avoided as this may lead to higher rates of augmentation (seesection 5.1).

Because rotigotine is a dopamine agonist, it is assumed that dopamine antagonists, such asneuroleptics (e.g. phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminishthe effectiveness of Neupro, and co-administration should be avoided. Because of possible additiveeffects, caution should be advised when patients are taking sedating medicinal products or other CNS(central nervous system) depressants (e.g. benzodiazepines, antipsychotics, antidepressants) or alcoholin combination with rotigotine.

Co-administration of L-dopa and carbidopa with rotigotine had no effect on the pharmacokinetics ofrotigotine, 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 thepharmacokinetics and metabolism of rotigotine in healthy volunteers.

Neupro may potentiate the dopaminergic adverse reaction of L-dopa and may cause and/or exacerbatepre-existing dyskinesia, as described with other dopamine agonists.

Co-administration of rotigotine (3 mg/24 h) did not affect the pharmacodynamics andpharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol, 0.15 mg levonorgestrel).

Interactions with other forms of hormonal contraception have not been investigated.

Women of childbearing potential, contraception in females

Women of childbearing potential should use effective contraception to prevent pregnancy duringtreatment with rotigotine.

There are no adequate data from the use of rotigotine in pregnant women. Animal studies do notindicate any teratogenic effects in rats and rabbits, but embryo-toxicity was observed in rats and miceat materno-toxic doses (see section 5.3). The potential risk for humans is unknown. Rotigotine shouldnot be used during pregnancy.

Because rotigotine decreases prolactin secretion in humans, inhibition of lactation is expected. Studiesin rats have shown that rotigotine and/or its metabolite(s) are excreted in breast milk. In the absence ofhuman data, breast-feeding should be discontinued.

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 episodesmust be informed not to drive or engage in activities (e.g. operating machines) where impairedalertness may put themselves or others at risk of serious injury or death until such recurrent episodesand 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, 65.5% of the patients on Neupro and 33.2% of patients on placeboreported 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 SmPCand package leaflet, 34.2% of 748 patients using Neupro, experienced application site reactions. Themajority of application site reactions were mild or moderate in intensity, limited to the applicationareas and resulted in discontinuation of Neupro in 7.2% of subjects.

Discontinuation rate

The discontinuation rate was studied in 3 clinical trials ranging up to 3 years in duration. Thepercentage 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.

The following table covers adverse drug reactions from the pooled studies mentioned above in patientswith Restless Legs Syndrome and from post-marketing experience. Within the system organ classes,adverse reactions are listed under headings of frequency (number of patients expected to experiencethe 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 arepresented in order of decreasing seriousness.

System/organ Very common Common Uncommon Rare Not knownclasses acc. to

MedDRA

Immune system Hypersensitivity,disorders which mayincludeangioedema,tongue oedemaand lip oedema

Psychiatric Sleep Obsessive- Aggressive Dopaminedisorders attacks/sudden compulsive behaviour/ dysregulationonset of sleep, disorder, aggressionb, syndromec,sexual desire agitationd disorientationd perceptiondisordersa (incl. disturbancesehypersexuality, (incl.libido hallucination,increased), hallucinationinsomnia, sleep visual,disorder, hallucinationabnormal auditory,dreams, illusion),impulse-control nightmaree,disordersa,d (incl. paranoiae,pathological confusionalgambling, statee, psychoticstereotypy/ disordere,punding, binge delusione,eating/eating deliriumedisorderb,compulsiveshoppingc)

Nervous system Headache Somnolence Dizzinesse,disorders disturbances inconsciousness

NECe (incl.syncope,syncopevasovagal, lossofconsciousness),dyskinesiae,dizzinessposturale,lethargye,convulsione

Eye disorders Vision blurrede,visualimpairmente,photopsiae

Ear and Vertigoelabyrinthdisorders

Cardiac Palpitationse,disorders atrialfibrillatione,supraventriculartachycardiae

Vascular Hypertension Orthostatic Hypotensionedisorders hypotension

Respiratory, Hiccupsethoracic andmediastinaldisorders

Gastrointestinal Nausea Vomiting, Constipatione,disorders dyspepsia dry mouthe,abdominal paine,diarrhoeac

Skin and Pruritus Erythemae,subcutaneous hyperhidrosise,tissue disorders pruritusgeneralisede, skinirritatione,dermatitiscontacte, rashgeneralisede

Reproductive Erectilesystem and dysfunctionebreast disorder

General Application and Irritability,disorders and instillation site oedemaadministration reactionsa (incl. peripheralsite conditions erythema,pruritus,irritation, rash,dermatitis,vesicles, pain,eczema,inflammation,swelling,discolouration,papules,exfoliation,urticaria,hypersensitivity),asthenicconditionsa (incl.fatigue, asthenia,malaise)

Investigations Weightdecreasede,hepatic enzymeincreasede (incl.

AST, ALT,

GGT), weightincreasede, heartrate increasede,

CPK increasedd,e

Injury, Fallepoisoning andproceduralcomplications

Musculoskeletal Rhabdomyolysiscand connectivetissue disordersa High Level Termb Observed in open-label studiesc Observed during post-marketingd Observed in 2011 data pool of double-blind placebo-controlled studiese Observed in studies performed in patients with Parkinson’s disease

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, 72.5% of the patients on Neupro and 58.0% of patients on placeboreported 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 Neuprotransdermal patch are nausea, vomiting, application site reactions, somnolence, dizziness andheadache.

In trials where the application sites were rotated as reflected in the instructions provided in SmPC andpackage leaflet, 35.7% of 830 patients using the Neupro transdermal patch, experienced applicationsite reactions. The majority of application site reactions were mild or moderate in intensity, limited tothe application areas and resulted in discontinuation of treatment with Neupro in only 4.3% of allsubjects receiving Neupro.

The following table covers adverse drug reactions from the pooled studies mentioned above in patientswith Parkinson’s disease and from post-marketing experience. Within the system organ classes,adverse reactions are listed under headings of frequency (number of patients expected to experiencethe 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 arepresented in order of decreasing seriousness.

System/organ Very common Common Uncommon Rare Not knownclasses acc. to

MedDRA

Immune system Hypersensitivity,disorders which mayincludeangioedema,tongue oedemaand lip oedema

Psychiatric Perception Sleep Psychotic Dopaminedisorders disturbancesa attacks/sudden disorder, dysregulation(incl. onset of sleep, obsessive- syndromechallucination, paranoia, sexual compulsivehallucination desire disordersa disorder,visual, (incl. aggressivehallucination hypersexuality, behaviour/auditory, libido aggressionb,illusion), increased), delusiond,insomnia, sleep confusional deliriumddisorder, state,nightmare, disorientationd,abnormal agitationddreams,impulse-controldisordersa,d(incl.pathologicalgambling,stereotypy/punding, bingeeating/eatingdisorderb,compulsiveshoppingc)

Nervous system Somnolence, Disturbances in Convulsion Dropped headdisorders dizziness, consciousness syndromec,eheadache NECa (incl.syncope,syncopevasovagal, lossofconsciousness),dyskinesia,dizzinesspostural,lethargy

Eye disorders Vision blurred,visualimpairment,photopsia

Ear and Vertigolabyrinthdisorders

Cardiac Palpitations Atrial fibrillation Supraventriculardisorders tachycardia

Vascular Orthostatic Hypotensiondisorders hypotension,hypertension

Respiratory, Hiccupsthoracic andmediastinaldisorders

Gastrointestinal Nausea, Constipation, Abdominal pain Diarrhoeacdisorders vomiting dry mouth,dyspepsia

Skin and Erythema, Pruritus Rashsubcutaneous hyperhidrosis, generalised, skin generalisedtissue disorders pruritus irritation,dermatitiscontact

Reproductive Erectilesystem and dysfunctionbreast disorder

General Application and Oedema Irritabilitydisorders and instillation site peripheral,administration reactionsa (incl. asthenicsite conditions erythema, conditionsapruritus, (incl. fatigue,irritation, rash, asthenia,dermatitis, malaise)vesicles, pain,eczema,inflammation,swelling,discolouration,papules,exfoliation,urticaria,hypersensitivity)

Investigations Weight Hepatic enzymedecreased increased (incl.

AST, ALT,

GGT), weightincreased, heartrate increased,

CPK increasedd

Injury, Fallpoisoning andproceduralcomplications

Musculoskeletal Rhabdomyolysiscand connectivetissue disordersa High Level Termb Observed in open-label studiesc Observed during post-marketingd Observed in 2011 data pool of double-blind placebo-controlled studiese Only observed in Parkinson’s disease patients

Both indications

Sudden onset of sleep and somnolence

Rotigotine has been associated with somnolence including excessive daytime somnolence and suddensleep onset episodes. In isolated cases “sudden onset of sleep” occurred while driving and resulted inmotor vehicle accidents (see also sections 4.4 and 4.7).

Impulse control disorders

Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eatingand compulsive eating can occur in patients treated with dopamine agonists, including rotigotine (seesection 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The most likely adverse reactions would be those related to the pharmacodynamic profile of adopamine 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, removalof the patch(es) should be considered because after removal of the patch(es) the active substance inputis stopped and the plasma concentration of rotigotine decreases rapidly. The patient should bemonitored closely, including heart rate, heart rhythm and blood pressure.

Treatment of overdose may require general supportive measures to maintain the vital signs. Dialysiswould not be expected to be beneficial as rotigotine is not eliminated by dialysis.

If it is necessary to discontinue rotigotine, this should be done gradually to prevent neurolepticmalignant syndrome.

Pharmacotherapeutic group: Anti-parkinson drugs, dopamine agonists; ATC code: N04BC09

Rotigotine is a non-ergolinic dopamine agonist for the treatment of signs and symptoms of Parkinson’sdisease and Restless Legs Syndrome.

Rotigotine is believed to elicit its beneficial effect on Parkinson’s disease by activation of the D3, D2and D1 receptors of the caudate-putamen in the brain.

The precise mechanism of action of rotigotine as a treatment of RLS is unknown. It is thought thatrotigotine may exert its activity mainly via dopamine receptors.

Regarding the functional activity at the various receptor subtypes and their distribution in the brain,rotigotine is a D2 and D3 receptor agonist acting also on D1, D4 and D5 receptors. With non-dopaminergic receptors, rotigotine showed antagonism at alpha2B and agonism at 5HT1A receptors,but no activity on the 5HT2B receptor.

Clinical studies in Restless Legs Syndrome

The efficacy of rotigotine was evaluated in 5 placebo-controlled trials with more than 1,400 patientswith idiopathic Restless Legs Syndrome (RLS). Efficacy was demonstrated in controlled trials inpatients 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 ofillness) were primary efficacy parameters. For both primary endpoints statistically significantdifferences have been observed for the doses 1 mg/24 h, 2 mg/24 h and 3 mg/24 h in comparison toplacebo. After 6 months of maintenance treatment in patients with moderate to severe RLS, thebaseline IRLS score improved from 30.7 to 20.7 for placebo and from 30.2 to 13.8 for rotigotine. Theadjusted mean difference was -6.5 points (CI95% -8.7; -4.4, p <0.0001). CGI-I responder rates (muchimproved, 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. Rotigotinesignificantly reduced the periodic limb movement index (PLMI) from 50.9 to 7.7 versus 37.4 to 32.7for placebo (p<0.0001).

Augmentation

In two 6-month, double-blind, placebo-controlled studies, clinically relevant augmentation wasobserved 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 was2.9%. None of these patients discontinued therapy because of augmentation. In a 5-year open-labeltreatment study, augmentation occurred in 11.9% of patients treated with the approved dosages for

RLS (1-3 mg/24 h), and 5.1% were considered clinically significant. In this study, the majority ofaugmentation episodes occurred in the first and second years of treatment. Furthermore, in this study ahigher dose of 4 mg/24 h that is unapproved in RLS was also used and led to higher rates ofaugmentation.

Clinical studies in Parkinson’s disease

The effectiveness of rotigotine in the treatment of the signs and symptoms of idiopathic Parkinson'sdisease was evaluated in a multinational drug development program consisting of four pivotal,parallel, randomized, double-blind placebo controlled studies and three studies investigating specificaspects of Parkinson’s disease.

Two pivotal trials (SP512 Part I and SP513 Part I) investigating the effectiveness of rotigotine inthe treatment of the signs and symptoms of idiopathic Parkinson’s disease were conducted in patientswho were not receiving concomitant dopamine agonist therapy and were either L-dopa naïve orprevious 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 thesubject’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 the double blind study SP512 Part I, 177 patients received rotigotine and 96 patients receivedplacebo. The patients were titrated to their optimal dose of rotigotine or placebo in weekly incrementsof 2 mg/24 h starting at 2 mg/24 h to a maximum dose of 6 mg/24 h. Patients in each treatment groupwere 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 dosewas the maximal dose allowed i.e. 6 mg/24 h. An improvement of 20% was seen in 48% of thesubjects receiving rotigotine and in 19% of the subjects receiving placebo (Difference 29%, CI95%18%; 39%, p<0.0001). With rotigotine, the mean improvement in the UPDRS score (Parts II + III) was

- 3.98 points (baseline 29.9 points) whereas in the placebo-treated arm a worsening of 1.31 points wasobserved (baseline 30.0 points). The difference was 5.28 points and statistically significant(p<0.0001).

In the double-blind study SP513 Part I, 213 patients received rotigotine, 227 received ropinirole and117 patients received placebo. The patients were titrated to their optimal dose of rotigotine in weeklyincrements of 2 mg/24 h starting at 2 mg/24 h to a maximum dose of 8 mg/24 h over 4 weeks. In theropinirole group, patients were titrated to their optimal dose up to a maximum of 24 mg/day over 13weeks. Patients in each treatment group were maintained for 6 months.

At the end of the maintenance treatment in 92% of the subjects in the rotigotine arm, the optimal dosewas the maximal dose allowed i.e. 8 mg/24 h. An improvement of 20% was seen in 52% of thesubjects receiving rotigotine, 68% of the subjects receiving ropinirole and 30% of the subjectsreceiving placebo (Difference rotigotine versus placebo 21.7%, CI95% 11.1%; 32.4%, differenceropinirole versus placebo 38.4%, CI95% 28.1%; 48.6%, difference ropinirole versus rotigotine 16.6%,

CI95% 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 points in the ropinirole arm (baseline 32.2 points)and 2.33 points in the placebo arm (baseline 31.3 points). All differences between the activetreatments and placebo were statistically significant. This study failed to demonstrate non-inferiorityof rotigotine to ropinirole.

In a subsequent open-label study (SP824), a multicenter, multinational study, the tolerability ofovernight switching from ropinirole, pramipexole or cabergoline to rotigotine transdermal patch andits effect on symptoms in subjects with idiopathic Parkinson’s disease have been studied. 116 patientswere switched from previous oral therapy to receive up to 8 mg/24 h of rotigotine, among these were47 who had been treated with ropinirole up to 9 mg/day, 47 who had been treated with pramipexole upto 2 mg/day and 22 who had been treated with cabergoline up to 3 mg/day. Switching to rotigotinewas feasible, with minor dose adjustment (median 2 mg/24 h) being necessary in only 2 patientsswitching from ropinirole, 5 patients from pramipexole and 4 patients from cabergoline.

Improvements were seen in UPDRS Parts I - IV scores. The safety profile was unchanged from thatobserved in previous studies.

In a randomized, open-label study (SP825) in patients with early-stage Parkinson’s disease, 25patients were randomized to rotigotine treatment and 26 to ropinirole. In both arms treatment wastitrated to optimal or maximum dose of 8 mg/24 h or 9 mg/day, respectively. Both treatments showedimprovements in early morning motor function and sleep. Motor symptoms (UPDRS Part III)improved by 6.3 ± 1.3 points in rotigotine-treated patients, and by 5.9 ± 1.3 points in the ropinirole-group after 4 weeks of maintenance. Sleep (PDSS) improved by 4.1 ± 13.8 points for rotigotine-treated patients, and by 2.5 ± 13.5 points for ropinirole-treated patients. The safety profile wascomparable, with the exception of application site reactions.

In studies SP824 and SP825 conducted since the initial comparative trial, rotigotine and ropinirole atequivalent doses were shown to have comparable efficacy.

Two additional pivotal trials (SP650DB and SP515) were conducted in patients who were receivingconcomitant 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 andabsolute improvement in the time spent “off”.

In the double blind study SP650DB, 113 patients received rotigotine up to a maximum dose of8 mg/24 h, 109 patients received rotigotine up to a maximum dose of 12 mg/24 h and 119 patientsreceived placebo. The patients were titrated to their optimal doses of rotigotine or placebo in weeklyincrements of 2 mg/24 h starting at 4 mg/24 h. Patients in each treatment group were maintained attheir optimal dose for 6 months. At the end of the maintenance treatment an improvement of at least30% 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,

CI95% 10%; 35% and 8%; 33%, respectively, p<0.001 for both rotigotine groups). With rotigotine, themean reductions in “off” time were 2.7 and 2.1 hours, respectively whereas in the placebo-treated arma reduction of 0.9 hours was observed. The differences were statistically significant (p<0.001 andp=0.003, respectively).

In the double-blind study SP515, 201 patients received rotigotine, 200 received pramipexole and100 patients received placebo. The patients were titrated to their optimal dose of rotigotine in weeklyincrements of 2 mg/24 h starting at 4 mg/24 h to a maximum dose of 16 mg/24 h. In the pramipexolegroup, patients received 0,375 mg in the first week, 0.75 mg in the second week and were titratedfurther 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 thesubjects receiving rotigotine, 67% of the subjects receiving pramipexole and 35% of the subjectsreceiving placebo (Difference rotigotine versus placebo 25%, CI95% 13%; 36%, differencepramipexole versus placebo 32%, CI95% 21%; 43%, difference pramipexole versus rotigotine 7%,

CI95% -2%; 17%). The mean reduction in the “off” time was 2.5 hours in the rotigotine arm, 2.8 hoursin the pramipexole arm and 0.9 hours in the placebo arm. All differences between the active treatmentsand placebo were statistically significant.

A further multinational double-blind study (SP889) was conducted in 287 patients with early oradvanced stages of Parkinson’s disease who had unsatisfactory early morning motor symptom control.81.5% of these patients were on concomitant levodopa therapy. 190 patients received rotigotine, and97 placebo. The patients were titrated to their optimal dose of rotigotine or placebo in weeklyincrements of 2 mg/24 h starting at 2 mg/24 h to a maximum dose of 16 mg/24 h over 8 weeks,followed by a maintenance period of 4 weeks. Early morning motor function, assessed by UPDRS part

III, and nocturnal sleep disturbances, measured by the modified Parkinson’s Disease Sleep Scale(PDSS-2), were co-primary outcome measures. At the end of maintenance, the mean UPDRS part IIIscore had improved by 7.0 points in rotigotine-treated patients (baseline 29.6), and by 3.9 points in theplacebo-group (baseline 32.0). Improvements in the mean PDSS-2 total score were 5.9 (rotigotine,baseline 19.3) and 1.9 points (placebo, baseline 20.5). Treatment differences for the coprimaryvariables were statistically significant (p=0.0002 and p<0.0001).

Following application, rotigotine is continuously released from the transdermal patch and absorbedthrough the skin. Steady-state concentrations are reached after one to two days of patch applicationand 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 to24 mg/24 h.

Approximately 45% of the active substance within the patch is released to the skin in 24 hours. Theabsolute 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% (shoulderversus thigh). However, there is no indication of a relevant impact on the clinical outcome.

The in vitro binding of rotigotine to plasma proteins is approximately 92%.

The apparent volume of distribution in humans is approximately 84 l/kg.

Rotigotine is metabolised to a great extent. Rotigotine is metabolised by N-dealkylation as well asdirect and secondary conjugation. In vitro results indicate that different CYP isoforms are able tocatalyse the N-dealkylation of rotigotine. Main metabolites are sulfates and glucuronide conjugates ofthe parent compound as well as N-desalkyl-metabolites, which are biologically inactive.

The information on metabolites is incomplete.

Approximately 71% of the rotigotine dose is excreted in urine and a smaller part of about 23% isexcreted in faeces.

The clearance of rotigotine after transdermal administration is approximately 10 l/min and its overallelimination half-life is 5 to 7 hours. The pharmacokinetic profile shows a biphasic elimination with aninitial half-life of about 2 to 3 hours.

Because the patch is administered transdermally, no effect of food and gastrointestinal conditions isexpected.

Special patient groups

Because therapy with Neupro is initiated at a low dose and gradually titrated according to clinicaltolerability 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 relevantincreases of rotigotine plasma levels were observed. Neupro was not investigated in patients withsevere hepatic impairment.

Plasma levels of conjugates of rotigotine and its desalkyl metabolites increase with impaired renalfunction. However, a contribution of these metabolites to clinical effects is unlikely.

Limited pharmacokinetic data obtained in adolescent patients with RLS (13-17 years, n=24) followingtreatment with multiple doses of 0.5 to 3mg/24h showed that systemic exposure to rotigotine wassimilar to that observed in adults. Efficacy/safety data is insufficient to establish a relation betweenexposure and response (see also paediatric information in section 4.2).

In repeated dose and long-term toxicity studies, the major effects were associated with the dopamineagonist 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 ratand 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 themaximum recommended human dose on a mg/m² basis in a 3-month study in albino rats. The effectswere more pronounced in female rats. Additional studies to further evaluate the specific pathologyhave not been performed. Retinal degeneration was not observed during the routine histopathologicalevaluation of the eyes in any of the toxicology studies in any species used. The relevance of thesefindings to humans is not known.

In a carcinogenicity study, male rats developed Leydig cell tumours and hyperplasia. Malignanttumours were noted predominantly in the uterus of mid- and high-dose females. These changes arewell-known effects of dopamine agonists in rats after life-long therapy and assessed as not relevant toman.

The effects of rotigotine on reproduction have been investigated in rats, rabbits and mice. Rotigotinewas 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. Thismutagenic effect could be attributed to a clastogenic effect of rotigotine. This effect was not confirmedin vivo in the Mouse Micronucleus Test in the rat Unscheduled DNA Synthesis (UDS) test. Since itran more or less parallel with a decreased relative total growth of the cells, it may be related to acytotoxic effect of the compound. Therefore, the relevance of the one positive in vitro mutagenicitytest is not known.

Backing layer

Polyester film, siliconized, aluminized,colour coated with a pigment (titanium dioxide (E171), pigment yellow 13, pigment red 166, pigmentyellow 12) layer and imprinted (pigment red 146, pigment yellow 180, 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).

Release liner

Transparent fluoropolymer coated polyester film.

Not applicable.

30 months.

Do not store above 30°C.

Peel off sachet in a carton: One side is composed of an ethylene copolymer (innermost layer), analuminium 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, 14, 28, 30 or 84 (multipack containing 3 packs of 28) transdermal patches,individually sealed in sachets.

Not all pack sizes may be marketed.

After use the patch still contains active substance. After removal, the used patch should be folded inhalf, adhesive side inwards so that the matrix layer is not exposed, placed in the original sachet andthen discarded. Any used or unused patches should be disposed of in accordance with localrequirements or returned to the pharmacy.

UCB Pharma S.A.

Allée de la Recherche 60

B-1070 Bruxelles

Belgium

EU/1/05/331/001

EU/1/05/331/002

EU/1/05/331/015

EU/1/05/331/018

EU/1/05/331/057

Date of first authorisation: 15 February 2006

Date of latest renewal: 22 January 2016

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Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.