Neupro 1mg/24hr and 3 mg/24 hTransdermal Patch

Changing the pharmacode position and size on the Neupro frontside primary packaging; Replacement of NIP by a carton packaging & change of the booklet to a standard P

Changing the pharmacode position and size on the Neupro frontside primary packaging; Replacement of NIP by a carton packaging & change of the booklet to a standard P

Update to section warnings & precautions related to impulse control and other disorders (dopamine dysregulation disorder and dopamine agonist withdrawal syndrome).

Addition of ‘’or nurse’’ in various sections.

Update to section 4.4 related to impulse control and other disorders (dopamine dysregulation disorder and dopamine agonist withdrawal syndrome).

Removal of information for skin adhesion in section 5.1.

To include “Rhabdomyolysis” as undesirable effect with frequency “not known” and widen the scope of an existing undesirable effect “increased CPK” based on new pharmacovigilance data.

To include “Rhabdomyolysis” as undesirable effect with frequency “not known” and widen the scope of an existing undesirable effect “increased CPK” based on new pharmacovigilance data.

Changes concerning the following review: Dropped Head Syndrome and additional changes
Section 4.8 Undesirable effect- Tabulated list of adverse reactions; Section 10 Date of revision of the text

Changes were made to the following sections:

Section 4.2: Changes to duration of pressing during the application of the patch.

 Section 6.5: amendment to reflect the change of design from cardboard to plastic and to change an existing pack-size.

5.1 Pharmacodynamic properties

Reference to a skin adhesion study has been included.

6.3 Shelf life

The shelf life has increased to 30 months (from 2 years).

6.4 Special precautions for storage

The storage conditions have been updated to “Do not store above 30°C” (previously 25°C).

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

The date of last renewal has been added: 22 January 2016

10. DATE OF REVISION OF THE TEXT

The date of revision has been added: 02/2016

Changes were made to the following sections:

Section 1, 2, 3: Changes to reflect the combination of different strengths in one SmPC.

Section 4.1: Editorial changes

Section 4.2: Editorial changes and removal of a sentence about the case a patch fall off.

Section 4.4:Changes to the syncope and augmentation sub-sections.

Section 4.8: addition of  new side effects, and changing in the frequency for already registered side effects. The section 'Description of selected adverse reactions' has also been edited.

Section 5.1: Addition of an 'augmentation sub-section'.

Section 6.1: Editorial changes

Section 6.5: Deletion of registered pack-sizes

Section 6.6: Editorial changes

In section 4.2 (Posology and method of administration): Update on the Paediatric population sub-section

In section 4.8 (undesirable effects), Addition of the Dopamine dysregulation syndrome side effect, Frequency: Not known.

In section 5.2 (Pharmacokinetics properties) Addition of data on the Paediatric population.

Section 4.8: undesirable effects is updated with inclusion of delirium and delusion as rare psychiatric disorders and investigations has been added as the new system organ class with increased CPK as the common undesirable effect.

 
Section 4.2 & 4.4 : No changes - only rewording

Section 4.8      

Restless Legs Syndrome

Immune system disorders

Common: Hypersensitivity, which may include angioedema, tongue oedema and lip oedema

Psychiatric disorders

Common: Sleep attacks/sudden onset of sleep, sexual desire disorders^a (incl. hypersexuality, libido increased), insomnia, sleep disorder, abnormal dreams, impulse-control disorders^a (incl. pathological gambling, stereotypy/punding, compulsive shopping^c)

Uncommon: Obsessive-compulsive disorder, disorientation, agitation

Rare: Aggressive behaviour/
aggression^b, binge eating/eating disorder^b

General disorders and administration site conditions

Very Common: Application and instillation site reactions^a (incl. erythema, pruritus, irritation, rash, dermatitis, vesicles, pain, eczema, inflammation, swelling, discolouration, papules, exfoliation, urticaria, hypersensitivity), asthenic conditions^a (incl. fatigue, asthenia, malaise)

Common: Irritability, oedema peripheral

Parkinson’s disease

Immune system disorders

Common: Hypersensitivity, which may include angioedema, tongue oedema and lip oedema

Psychiatric disorders

Common: Perception disturbances^a
(incl. hallucination, hallucination visual, hallucination auditory, illusion), insomnia, sleep disorder, nightmare, abnormal dreams, impulse-control disorders^a (incl. pathological gambling, stereotypy/
punding, compulsive shopping^c)

Uncommon: Sleep attacks/sudden onset of sleep, paranoia, sexual desire disorders^a (incl. hypersexuality, libido increased), confusional state, disorientation, agitation

Rare: Psychotic disorder, obsessive-compulsive disorder, aggressive behaviour/
aggression^b, binge eating/eating disorder^b

Eye disorders

Uncommon: Vision blurred, visual impairment, photopsia

General disorders and administration site conditions

Very common: Application and instillation site reactions^a  (incl. erythema, pruritus, irritation, rash, dermatitis, vesicles, pain, eczema, inflammation, swelling, discolouration, papules, exfoliation, urticaria, hypersensitivity)

^a High Level Term

^b Observed in open-label studies

^c Observed during post-marketing

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

Ireland Pharmacovigilance Section, Irish Medicines Board…. etc.

UK: The Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

 

4.2     Posology and method of administration

Patients with hepatic impairment: Adjustment of the dose is not necessary in patients with mild to moderate hepatic impairment. 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. Patients with renal impairment: Adjustment of the dose is not necessary in patients with mild to severe renal impairment, including those requiring dialysis. Unexpected accumulation of rotigotine levels may also occur at acute worsening of renal function (see sections 4.2 and 5.2).

4.6     Fertility, Pregnancy and lactation

Women of childbearing potential, contraception in females

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

4.8     Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

6.5     Nature and contents of container

The carton contains 7, 20, 28, 30, 56, 60, 84 (multipack containing 2 packs of 42), 90 or 100 (multipack containing 2 packs of 50) transdermal patches, individually sealed in sachets.

Other minor changes are editorial, including new headings, bold text etc.

4.2     Posology and method of administration

Abnormal thinking and behaviour

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

4.8     Undesirable effects

Immune system disorders

Not known: Angioedema, tongue oedema and lip oedema

Psychiatric disorders

Uncommon: disorientation

4.4     Special warnings and precautions for use

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathologic gambling, increased libido,hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur  in patients treated with dopamine agonists, for Parkisons disease, including rotigotine.  Dose reduction/tapered discontinuation should be considered if such symptoms develop.

4.8     Undesirable effects

Restless Legs Syndrome

Rare

Psychiatric disorders

Aggressive behaviour/ aggression^b, binge eating and compulsive eating^b

Parkinson’s disease

Rare

Psychiatric disorders

Psychotic disorder, obsessive-compulsive disorder, aggressive behaviour/
aggression^b, binge eating and compulsive eating^b

^b Observed in open-label studies

Impulse control disorders

Pathological gambling, increased libido,hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including rotigotine  (see section 4.4 ‘Special warnings and precautions for use’).

5.1     Pharmacodynamic properties

Clinical studies in Parkinson’s disease

In further studies the effects of rotigotine on specific aspects of Parkinson’s disease were evaluated.

This study failed to demonstrate non-inferiority of rotigotine to ropinirole.

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

In a randomized, open-label study in patients with early-stage Parkinson’s disease, 25 patients were randomized to rotigotine treatment and 26 to ropinirole. In both arms treatment was titrated to optimal or maximum dose of 8 mg/24 h or 9 mg/day, respectively. Both treatments showed improvements 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 was comparable, with the exception of application site reactions.

In these studies conducted since the initial comparative trial, rotigotine and ropinirole at equivalent doses were shown to have comparable efficacy.

Two additional pivotal trials were conducted in patients who were receiving concomitant levodopa therapy.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 February 2006

Date of last renewal: 17 February 2011

.4       Special warnings and precautions for use

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.

4.8     Undesirable effects

The following table covers adverse drug reactions from the pooled studies mentioned above 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.

Post-marketing experience: The post-marketing experience to date is consistent with the adverse effects profile observed in the clinical trials.

4.9     Overdose

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, removal of the patch(es) should be considered because after removal of the patch(es) the drug input is stopped and the plasma concentration of rotigotine decreases rapidly. The patient should be monitored closely, including heart rate, heart rhythm and blood pressure.

Treatment of overdose may require general supportive measures to maintain the vital signs. Dialysis would 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 neuroleptic malignant syndromeThere 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.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

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

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

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.

Rotigotine is believed to elicit its beneficial effect on Parkinson’s disease by activation of the D₃, D₂ and 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 that rotigotine may exert its activity mainly via dopamine receptors.

Rotigotine is a non-ergolinic D₃/D₂/D₁ dopamine agonist for the treatment of Parkinson’s disease. It is believed to elicit its beneficial effect by activation of the D₃, D₂ and D₁ receptors of the caudate-putamen in the brain.

Rotigotine alleviates signs and symptoms of idiopathic Parkinson’s disease.

Clinical studies in Parkinson’s disease

A further multinational double-blind study was conducted in 287 patients with early or advanced 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, and 97 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 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 III score had improved by 7.0 points in rotigotine-treated patients (baseline 29.6), and by 3.9 points in the placebo-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 coprimary variables were statistically significant (p=0.0002 and p<0.0001).

5.2     Pharmacokinetic properties

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. The pharmacokinetic profile shows a biphasic elimination with an initial half-life of about 2 to 3 hours.

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

4.6     Fertility, Pregnancy and lactation

Fertility

For information on fertility studies, please see section 5.3.