UCB Pharma Limited

• In section 4.4 (Special warnings and precautions for use) removal of the words Fibrotic complications under the sub heading Fibrotic complications

Also addition of the following text :

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

• In section 4.9 (Overdose) Revision to the following paragraph:

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.

If it is necessary to discontinue rotigotine, this should be done gradually to prevent neuroleptic malignant syndrome

• In section 5.1     Pharmacodynamic properties revision to the following text is a follows:

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.

Adittion of the following paragraph under section 5.1 

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).

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

• In section 7. MARKETING AUTHORISATION HOLDER

Change in the name from Schwarz Pharma Ltd to UCB Manufacturing Ireland Ltd

• In section 10 Date of Revision of the Text

Change in the date from 2/11 to 10/11

4.4     Special warnings and precautions for use

Under the sub-section Augmentation the following text has been added:

"Analysis of a 5-year open label treatment study showed that augmentation occurred in 11.9% of patients treated with the approved dosages for RLS 1-3 mg/24h), and that 5.1% were considered clinically significant.  The majority of augmentation episodes occurred in the first and second years of treatment.  This study also allowed 4 mg/24h dosing, which showed higher rates of augmentation.  The 4 mg/24h dosage is not approved for the treatment of RLS (see section 4.2)

4.2 Posology and method of administration

underlined sub heading Posology

Sub heading Dose replaces previous sub-heading dosage

Rotigotine has replace the word Neupro in the paragraph under special population

Paediatric population -"new change in wording"

The safety and efficacy of rotigotine in the paediatric population have not yet been established. No data are available

4.4 Special warnings and precautions for use

Under this subheading Orthostatic hypotension the word Rotigotine (x2) has replace the word Neupro

Sub heading Sudden onset of sleep and somnolence is now underlined

Under this subheading Sudden onset of sleep and somnolence the word Rotigotine (x1) has replaced the word Neupro

Sub heading Impulse control disorders is now underlined

Sub heading Neuroleptic malignant syndrome is now underlined

Sub heading Hallucinations is now underlined

Sub heading Fibrotic complications is now underlined

Sub heading Neuroleptics is now underlined

Sub heading Ophthalmologic monitoring is now underlined

Sub heading Augmentation is now underlined

Sub heading Heat application is now underlined

4.6 Fertility, pregnancy and lactation - addition of the lactation in the title

sub heading Pregnancy has been added and underlined

under this heading the word Rotigotine (x1) has replaced the word Neupro

sub heading Breast Feeding has been added and underlined

sub heading Fertility has been added and underlined

under this sub-heading the following wording has been added "For information on fertility studies, please see section 5.3."

4.8 Undesirable effects

"under the sub heading - Restless leg syndrome SmPC replace SPC

sub heading Fertility has been added and underlined under this sub-heading the following wording has been added "

Under the same sub heading new text has been added –

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)". A revision to the frequency table(s) has also been made

5.1  Pharmacodynamic properties

Under this sub heading addition of the words Anti-parkinsons drugs and lower case d has been applied to the word dopamine

under this heading the word Rotigotine (x6) has replaced the word Neupro

6. PHARMACEUTICAL PARTICULARS

Under the sub heading 6.1 List of Excipients the following has been italicised:

Backing layer

Self adhesive matrix layer:

Protective liner:

Under the sub heading 6.4 Special precautions for storage deletion of the following:  "store in the orginal package"

Under the sub heading 6.5 Nature and contents of container the following changes have been highlighted in red: The carton

contains 7, 20, 28, 30, 56, 60, 84 (2x42), 90 or 100 (2x50) transdermal patches, individually sealed in sachets.

Under section 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION, the following changes have been made:

Date of first authorisation: 15 February 2006

Date of latest renewal: 11/2010

Under section 10 Date of Revision of the Text: the date has been amended

Section 4.4
Additional paragraph concerning sodium metabisulphite and the potential allergic-type reactions that may occur.
The paragraph concerning neuroleptic malignant syndrome has had “Although not reported with Neupro” removed from the start of the opening sentence.
The first sentence of the paragraph on Augmentation now states that this may occur in RLS patients.  Previously it did not state the patient group that this was applicable to.

Section 4.8
Updated to reflect changes in frequencies of ADRs and numbers of patients in clinical trials

Section 5.1
Sub-heading in the clinical studies section on RLS studies has been clarified to refer to RLS.

Section 10
Updated to reflect approval of the above changes

The following changes have been made:

Section 4.4: Updated to include augmentation rates from clinical studies.

Section 4.8: Additional paragraph included to provide discontinuation rates from clinical trials.

Section 10: Updated to reflect approval of variation to updated above sections.