Consumer medicine information

Neupro

Rotigotine

BRAND INFORMATION

Brand name

Neupro

Active ingredient

Rotigotine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Neupro.

What is in this leaflet

This leaflet answers some common questions about Neupro.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Neupro against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Neupro is used for

Neupro is used in the treatment of Parkinson’s disease and Restless Legs Syndrome (RLS).

Parkinson’s disease

This is a disease of the nervous system that mainly affects body movement. The main symptoms are shaking (tremor), muscle stiffness and slow unsteady movement. If untreated, Parkinson’s disease can cause difficulty in performing daily activities.

Parkinson’s disease is caused by the brain not making enough of a chemical called dopamine. Dopamine helps the brain to control muscle movement. When too little dopamine is produced slowness of movement results.

Restless Legs Syndrome (RLS)

RLS is a condition characterised by unpleasant sensations in the legs and the irresistible urge to move in an effort to relieve these feelings. There is a sense of uneasiness, restlessness, and itching often accompanied by twitching and pain in the legs when sitting or lying down, especially in bed at night. Occasionally the arms may also be affected. RLS is thought to be due to insufficient dopamine levels in the brain.

Neupro belongs to a group of medicines called non-ergot dopamine agonists which stimulate dopamine receptors in the brain to increase the effects of dopamine.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

This medicine is available only with a doctor's prescription.

Before you use Neupro

When you must not take it

Do not use Neupro if you have an allergy to:

  • rotigotine
  • sodium metabisulfite
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not use Neupro if you need to have magnetic resonance imaging (MRI) (method to visualise internal organs and tissues of the body) or cardioversion (treatment of an abnormal heart rhythm). You must take your Neupro patch off before the procedure. You can put a new patch on after the procedure.

Do not give this medicine to a child or adolescent. The safety and effectiveness in children and adolescents has not been established.

Do not use this medicine if the packaging is torn or shows signs of tampering.

Do not use this medicine after the expiry date (Exp) printed on the pack. If you take this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start taking Neupro, contact your doctor.

Before you start to use it

Tell your doctor or pharmacist if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have or have had any other health problems or medical conditions, including:

  • liver problems
  • low blood pressure
  • heart problems
  • mental illness
  • compulsive disorders such as gambling or a high sex drive
  • problems with your sight.

Tell your doctor if you are pregnant or intend to become pregnant. The effects of Neupro on pregnancy and the unborn child is not known. Neupro should not be used during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed. Neupro is not recommended if you are breastfeeding, as it is likely to reduce the amount of milk you produce. Neupro may also pass into your breast milk and affect your baby. If your doctor says you need to use Neupro, you should stop breastfeeding.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using Neupro.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may interfere with Neupro. These include:

  • some other medicines used to treat Parkinson’s disease or Restless Legs Syndrome
  • medicines used to treat depression or mental illness
  • medicines used to calm you or help you sleep
  • metoclopramide, a medicine used to treat nausea and vomiting.

These medicines may be affected by Neupro or may affect how well it works. You may need different amounts of your medicine or you may need to take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Neupro.

How to use Neupro

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

The dose varies from patient to patient. Your doctor may start you on a low dose of Neupro first and slowly increase the amount of medicine until you are taking enough to control your condition.

Parkinson's Disease

The usual starting dose is one 2 mg/24 hour patch or one 4mg/24 hour patch daily. This dose will be increased gradually in steps of 2 mg/24 hours until the right (maintenance) dose for your needs is reached.

Restless Legs Syndrome

The usual starting dose is one 1 mg/24 hour patch. If necessary, this dose will be increased gradually in steps of 1 mg/24 hours until the right (maintenance) dose for your needs is reached. The maximum dose is 3 mg/24 hour.

If you do not understand the instructions, ask your doctor or pharmacist for help.

Where to apply the patch

Put the sticky side of the patch onto clean, dry, healthy skin on one of the following areas at a time:

  • shoulder
  • upper arm
  • belly
  • thigh
  • hip
  • flank (your side, between your ribs and your hip).

To help avoid skin irritation, stick the patch onto a different area of skin each day (for example, on the right side of your body one day, then on the left side the next day and on your upper body one day, then on your lower body). You should not stick Neupro on the same area of skin twice within 14 days.

Things to remember

  • You should put the patch where it will not be rubbed by tight clothing which could make it fall off.
  • If you need to stick the patch to a hairy area of skin, you must shave the area at least three days before sticking the patch there.
  • Do not stick the patch on broken skin or on skin that is red, irritated or damaged.
  • Do not use creams, oils, lotions, powders or other skin products on the area of skin you will be sticking the patch on or near a patch you are already wearing. The patch may become loose.
  • Bathing, showering and exercising should not affect how Neupro works. There is no need to remove the patch when bathing, showering, swimming or exercising. Nevertheless, check that the patch has not fallen off after such activities.
  • You should avoid external heat (for example excessive sunlight, saunas, hot baths, heating pads or hot-water bottles) on the area of the patch.
  • If the patch has irritated your skin, you should keep that area of skin covered from the sun, as it may cause changes in the colour of the skin.

How to apply the patch

Each patch is packed in a sachet containing the medicine. You should stick Neupro onto your skin as soon as you have opened the sachet and removed the protective liner.

You should stick a Neupro patch onto the skin once a day. You should leave the patch on your skin for 24 hours and then replace it with a new one. Make sure that you take the old patch off before sticking on the new one. You should replace the patch at around the same time every day.

  1. To open the sachet, hold the two sides of the sachet. Peel apart the foil and open the sachet.

  1. Take the patch out of the sachet.

  1. The sticky side of the patch is covered by a transparent protective liner. Hold the patch in both hands with the protective liner facing you.

  1. Bend the patch in half so that the S-shaped break in the liner opens.

  1. Peel off one side of the protective liner. Don’t touch the sticky side of the patch with your fingers.

  1. Hold the other half of the rigid protective liner and put the sticky surface of the patch onto your skin. Press the sticky side of the patch firmly into place.

  1. Fold back the other half of the patch and remove the other side of the protective liner.

  1. Press the patch down firmly with the palm of your hand for about 20 - 30 seconds to make sure the patch is touching the skin and that the edges stick well.

It is important to ensure you press the patch firmly for 20 - 30 seconds.

Wash your hands with soap and water immediately after handling the patch.

How to change the patch

Before you put on a new patch, slowly and carefully peel off the used patch.

Gently washing the area with warm water and mild soap should remove any adhesive that stays on your skin after you remove the patch.

You can also use a small amount of baby oil to remove any adhesive that won’t wash off.

Do not use alcohol or other dissolving liquids such as nail polish remover or other solvents as these may irritate your skin.

If the patch falls off, a new patch should be applied for the rest of the day, then replace the patch at the same time as usual.

How long to use Neupro

Continue taking Neupro for as long as your doctor tells you. This medicine helps to control your condition but does not cure it. It is important to keep using your medicine even if you feel well.

If you forget to use it

If you have forgotten to change the patch at the usual time of day, remove the old patch and use a new patch as soon as you remember.

If you have forgotten to stick on a new patch after removing the old one, use a new patch as soon as you remember. On the following day you should use a new patch at the usual time.

Do not use a double dose to make up for a forgotten dose.

If you use too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) if you think you or anyone else may have taken too much Neupro. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Using higher dosages of Neupro than your doctor has prescribed may cause nausea, vomiting, low blood pressure, fast heart beats, hallucinations, confusion or extreme sleepiness.

If you have used more patches than your doctor told you to, contact your doctor or the Poisons Information Centre immediately, and follow their advice on removal of patches.

While you are using Neupro

Things you must do

If you are about to be started on any new medicines, tell your doctor or pharmacist that you are using Neupro.

Do not take any other medicines, whether they require a prescription or not, without first telling your doctor.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking Neupro. Your doctor may ask you to stop taking Neupro before elective surgery or before some medical tests such as MRIs.

Tell your doctor immediately if you become pregnant while using this medicine.

Keep all of your doctor’s appointments so that your progress can be checked. Your doctor may do some tests, such as blood pressure monitoring or eye examinations from time to time to make sure the medicine is working, and to prevent unwanted side effects.

Some people taking Neupro to treat Restless Legs Syndrome, find their symptoms worsen. For example their symptoms may start earlier in the day than usual or be more intense.

Tell you doctor as soon as possible if your symptoms get worse while taking Neupro.

If you notice any problems with your vision, please contact your doctor.

Like with every patch or bandage, Neupro can cause skin reactions. These are normally mild and usually affect only the area of skin the patch has been on. We recommend that you put the patch in a different place every day. You should not use the same area of skin within 14 days.

If you have a skin reaction which lasts for more than a few days, if a skin reaction becomes serious, or if the skin reaction spreads outside the area covered by the patch, please contact your doctor.

Avoid sunlight and solarium exposure on areas of skin showing any kind of skin reaction caused by Neupro.

Things you must not do

Do not use Neupro to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.

Do not stop using Neupro, or lower the dose, without first checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays. If you stop taking it suddenly your condition may worsen or you may have unwanted side effects.

Do not cut Neupro patches into pieces.

Things to be careful of

Neupro may make you feel very drowsy and may cause some people to fall asleep suddenly without any apparent warning of sleepiness.

Make sure you know how Neupro affects you before you drive or operate machinery.

If you feel very drowsy, or experience episodes of falling asleep suddenly without feeling sleepy, do not drive or operate machinery or perform any other dangerous activities, and contact your doctor.

Be careful while drinking alcohol while taking Neupro. Combining Neupro and alcohol can make you more drowsy. Your doctor may suggest you avoid alcohol while you are being treated with Neupro.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Neupro. This medicine helps most people with Parkinson’s disease or restless legs syndrome, but it may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • nausea, vomiting
  • dizziness or lightheadness when standing up quickly
  • vertigo (sensation of spinning)
  • feeling sleepy, falling asleep suddenly, being unable to sleep, nightmares, unusual dreams
  • feeling weak or tired
  • constipation
  • skin irritations under the patch such as redness and itching
  • swelling of legs and feet
  • weight loss or weight increase
  • dry mouth
  • headache
  • heartburn, stomach discomfort and pain
  • increased sweating
  • anxiety
  • agitation
  • hiccups
  • abnormal movements including muscle twitching or spasms (which may occur in Parkinson's disease patients and may or may not resemble Parkinson’s symptoms)

These are mild side effects of the medicine, and usually short-lived.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • seeing or hearing things that are not real (hallucinations)
  • compulsive behaviour such as an unusual urge to carry out a certain activity including excessive gambling, repetitive meaningless actions, increased sex drive, compulsive spending, buying or eating
  • confusion, disorientation
  • falling, fainting
  • rash, generalised itching
  • visual disturbances such as seeing colours or lights or blurred vision

These may be serious side effects. You may need urgent medical attention.

If any of the following happen, tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • psychotic disorders including abnormal thinking about reality and behaviour (paranoid psychosis)
  • irregular heart beat, increased heart rate (palpitations)
  • involuntary muscle spasms (seizure, convulsion)
  • loss of consciousness
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

Ask your doctor or pharmacist if you don’t understand anything in this list.

After using Neupro

Storage

Keep your patches in their package until it is time to use them.

Store below 30°C. Do not store it, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Neupro out of reach of children.

Disposal

Used patches still contain active ingredient, which may be harmful to others. Fold the used patch with the sticky side inwards. Put the patch in the original sachet and then throw it away safely, out of the reach of children.

Do not flush them down the toilet, nor place them in liquid waste disposal systems.

If your doctor tells you to stop using Neupro, or the patches have passed their expiry date, ask your pharmacist what to do with any patches left over.

Product description

What it looks like

Neupro is a transdermal patch that is available in four different strengths, 2 mg/24 h, 4 mg/24 h, 6 mg/24 h and 8 mg/24 h.

1 mg/24 h and 3 mg/24 h transdermal patches are not available in Australia.

The patches are thin and have three layers. They are square-shaped with rounded edges. The outside is tan-coloured and is imprinted with either Neupro 2 mg/24 h, Neupro 4 mg/24 h, Neupro 6 mg/24 h or Neupro 8 mg/24 h.

Neupro is available in cartons containing 28 patches, which are individually sealed in sachets.

Ingredients

The active ingredient is rotigotine.

  • Neupro 2 mg/24 h releases 2 mg of rotigotine per 24 hours.
  • Neupro 4 mg/24 h releases 4 mg of rotigotine per 24 hours.
  • Neupro 6 mg/24 h releases 6 mg of rotigotine per 24 hours.
  • Neupro 8 mg/24 h releases 8 mg of rotigotine per 24 hours.

The other ingredients are:

  • povidone
  • sodium metabisulfite
  • DL-α-tocopherol
  • ascorbyl palmitate
  • silicone adhesives (BIO-PSA Q7-4301 and BIO-PSA Q7-4201)

Backing layer:

  • polyester film
  • silicone
  • aluminium
  • colour coated with a pigment layer (titanium dioxide, pigment yellow 95, pigment red 166) and imprinted (pigment red 144, pigment yellow 95, pigment black 7).

Protective liner:

  • polyester film
  • fluoropolymer.

Supplier

Neupro is supplied in Australia by:

UCB Pharma
A division of UCB Australia Pty Ltd
Level 1, 1155 Malvern Road
Malvern VIC 3144, Australia

Australian Registration Numbers:
Neupro 2 mg/24 h AUST R 131370
Neupro 4 mg/24 h AUST R 131381
Neupro 6 mg/24 h AUST R 131382
Neupro 8 mg/24 h AUST R 131383

This leaflet was prepared in January 2020.

Neupro is a registered trademark of UCB Pharma GmbH

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Neupro

Active ingredient

Rotigotine

Schedule

S4

 

1 Name of Medicine

Rotigotine.

2 Qualitative and Quantitative Composition

Neupro 1 mg: 5 cm2 patch containing 2.25 mg rotigotine with a nominal release rate of 1 mg rotigotine per 24 hours.
Neupro 2 mg: 10 cm2 patch containing 4.5 mg rotigotine with a nominal release rate of 2 mg rotigotine per 24 hours.
Neupro 3 mg: 15 cm2 patch containing 6.75 mg rotigotine with a nominal release rate of 3 mg rotigotine per 24 hours.
Neupro 4 mg: 20 cm2 patch containing 9.0 mg rotigotine with a nominal release rate of 4 mg rotigotine per 24 hours.
Neupro 6 mg: 30 cm2 patch containing 13.5 mg rotigotine with a nominal release rate of 6 mg rotigotine per 24 hours.
Neupro 8 mg: 40 cm2 patch containing 18.0 mg rotigotine with a nominal release rate of 8 mg rotigotine per 24 hours.
The active ingredient rotigotine is a white to light brownish powder. It is very slightly soluble to freely soluble in organic solvents, sparingly soluble in acidic aqueous solutions and practically insoluble in alkaline aqueous solutions.
The formulation contains sodium metabisulfite.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Neupro is a thin, matrix-type transdermal patch composed of 3 layers:
1. A flexible, tan-colored backfilm that provides structural support and protection of the drug loaded adhesive layer.
2. A self-adhesive drug matrix layer.
3. A clear protective liner which is removed prior to use.
Thin, matrix type transdermal patch that is square shaped with rounded edges. The backing layer comprises a polyester film, siliconized, aluminized, colour coated with a tan coloured pigment (titanium dioxide (E171), pigment yellow 95, pigment red 166) layer and imprinted (pigment red 144, pigment yellow 95, pigment black 7). The protective liner comprises a transparent fluoropolymer coated polyester film. The outside of the tan coloured backing layer is imprinted with Neupro 1 mg/24 h, Neupro 2 mg/24 h, Neupro 3 mg/24 h, Neupro 4 mg/24 h, Neupro 6 mg/24 h or Neupro 8 mg/24 h respectively.

4 Clinical Particulars

4.1 Therapeutic Indications

Parkinson's disease.

Neupro is indicated as monotherapy, or in combination with levodopa, for the treatment of idiopathic Parkinson's disease from early stage to advanced disease.

Restless legs syndrome.

Neupro is indicated for the symptomatic treatment of moderate to severe idiopathic restless legs syndrome in adults.

4.2 Dose and Method of Administration

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.
Neupro can be applied irrespective of the timing of meals.

Dosage.

The dose recommendations made below are in nominal dose.

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.
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.

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 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.

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 for risk/ benefit analysis.

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 (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). Rotigotine has not been investigated in patients with severe hepatic impairment.

Children and adolescents.

Rotigotine is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

Treatment discontinuation.

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 Warnings and Precautions for Use).

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 Special Warnings and Precautions for Use). Following this procedure, rebound (worsening of symptoms beyond initial intensity after discontinuation of treatment) was not observed.

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 Special Warnings and Precautions for Use).

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 folded back and the second part of the protective 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 20-30 seconds, so that it sticks well.
Neupro does not need to be removed for bathing or swimming.
In the event that a patch becomes detached, a new patch should be applied for the remainder of the 24 hour dosing interval.
The patch should not be cut into pieces.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Magnetic resonance imaging or cardioversion (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

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 Neupro, however, the incidence was similar to that in placebo treated patients. 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.

Elevation of blood pressure and heart rate.

Some patients treated with Neupro exhibited increases in systolic blood pressure (greater than 180 mmHg) and/or diastolic blood pressure (greater than 105 mmHg) while supine or standing. Some patients treated with Neupro exhibited increased pulse (greater than 100 beats per minute) while supine and/or standing. These findings of blood pressure and heart rate elevations should be considered when treating patients with cardiovascular disease.

Syncope.

Syncope was observed in association with rotigotine, but also at a similar rate in patients treated with placebo. Patients with severe cardiovascular disease should be asked about symptoms of syncope and pre-syncope.

Somnolence and sudden onset of sleep.

Patients treated with Neupro have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on Neupro, some perceived no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment.
Somnolence is a common occurrence in patients receiving Neupro. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with Neupro. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with Neupro.
Before initiating treatment with Neupro, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Neupro such as concomitant sedating medications and the presence of sleep disorders. If a patient develops meaningful daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g. conversations, eating, etc.), Neupro should ordinarily be discontinued (see Section 4.2 Dose and Method of Administration, Treatment discontinuation for guidance on discontinuing Neupro). If a decision is made to continue Neupro, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Sedating medicinal products or other CNS (central nervous system) depressants.

Because of possible additive effects, patients should be advised to exercise caution when taking sedating medicinal products or other CNS (central nervous system) depressants (e.g. benzodiazepines, antipsychotics, antidepressants) or alcohol in combination with Neupro (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Ophthalmologic monitoring.

Placebo controlled trials have shown a higher incidence of visual disturbance and eye conditions (see Section 4.8 Adverse Effects (Undesirable Effects)) in the rotigotine groups in comparison with controls. Similar events have been observed in open label trials. It is important to carry out ophthalmological monitoring at regular intervals for early detection of visual abnormalities.

Impulse control and related disorders.

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money or buying, binge eating, compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more medications, including Neupro, that increase central dopaminergic tone and are generally used for the treatment of Parkinson's disease. In some patients, dopamine dysregulation syndrome was observed under the treatment with rotigotine. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognise these behaviours as abnormal, it is important for prescribers to specifically ask their patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Neupro. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Neupro.

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 Dose and Method of Administration).

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 dopaminergic therapy, therefore, it is recommended to taper treatment (see Section 4.2 Dose and Method of Administration).

Hallucinations/ psychotic-like behaviour.

Abnormal thinking and behaviour have been reported with Neupro. This abnormal thinking and behaviour can consist of one or more of a variety of manifestations including paranoid ideation, hallucinations, confusion, psychotic-like behaviour, disorientation, aggressive behaviour, agitation, delusions and delirium. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behaviour.
Patients with a major psychotic disorder should ordinarily not be treated with Neupro because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Neupro (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients should be informed that hallucinations, abnormal thinking and behaviours can occur.

Neuroleptics.

Neuroleptics given as antiemetic should not be given to patients taking dopamine agonists (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Augmentation.

Reports in the literature indicate that treatment of restless legs syndrome with dopaminergic medicinal products can result in augmentation. 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.

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.

Sulfite sensitivity.

Neupro transdermal patches contain sodium metabisulfite, a sulfite that may cause allergic type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people.

Peripheral oedema.

As with other dopamine agonists, rotigotine has been associated with the development of peripheral oedema in some patients with Parkinson's disease. Peripheral oedema has also been observed in clinical studies conducted in patients with RLS.

Weight gain and fluid retention.

Patients taking Neupro for early stage and advanced stage Parkinson's disease had a higher incidence of substantial weight gain (more than 10% of baseline weight) than patients taking placebo. The weight gain was frequently associated with the development of peripheral oedema in patients with Parkinson's disease, suggesting that Neupro may cause fluid retention in some Parkinson's patients. Monitor for weight gain and fluid retention when treating patients with concomitant illnesses such as congestive heart failure or renal insufficiency.

Fibrotic complications.

Neupro is a nonergot derived dopaminergic agent.
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 the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
Cardiac valve abnormalities have been observed in open label trials of rotigotine, however, in placebo controlled clinical trials, the incidence of these adverse events was similar between treatment groups. Regular cardiac review as part of physical examination should be performed. Echocardiograph monitoring may be advisable in accordance with clinical judgment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Ocular toxicity.

After a single dose of rotigotine, binding to melanin containing tissues (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 following subcutaneous administration of rotigotine to albino rats for 3 months. The effects were more pronounced in females. 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.

Use in hepatic impairment.

Caution is advised when treating patients with severe hepatic impairment, which may result in lower rotigotine clearance. Neupro 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 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No dosage adjustment is necessary in the elderly because therapy with Neupro is initiated at a low dose and gradually titrated according to clinical tolerability to obtain the optimum therapeutic effect (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Neupro is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

Effects on laboratory tests.

As seen in other dopamine agonists, clinical trials revealed a decrease of prolactin plasma concentrations after exposure to rotigotine.
Patients with early stage Parkinson's disease receiving Neupro had an increased risk for low haemoglobin and low haematocrit below the normal reference range.
There was an increased risk for low serum glucose below the normal reference range in patients with early stage and advanced stage Parkinson's disease receiving Neupro.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 coadministration 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 Neupro.
Coadministration of enzyme inducing active substances (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin, St. John's wort/ Hypericum perforatum) has not been investigated.
Coadministration of levodopa and carbidopa with rotigotine had no effect on the pharmacokinetics of rotigotine, and rotigotine had no effect on the pharmacokinetics of levodopa and carbidopa.
Neupro may potentiate the dopaminergic adverse reaction of levodopa and may cause and/or exacerbate pre-existing dyskinesia, as described with other dopamine agonists.
The incidence of some dopaminergic adverse effects, such as hallucinations, dyskinesia and peripheral oedema generally is higher when given in combination with levodopa.
Coadministration of domperidone with rotigotine had no effect on the pharmacokinetics of rotigotine.
Rotigotine is metabolised by CYP2C19, and also weakly inhibits CYP2C19 at high concentrations. Coadministration of omeprazole (inhibitor of CYP2C19), in doses of 40 mg/day, had no effect on the pharmacokinetics and metabolism of rotigotine in healthy volunteers.
Coadministration 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

Effects on fertility.

Subcutaneous administration of rotigotine to male rats prior to and through mating did not affect fertility, although epididymal sperm motility was reduced at a plasma rotigotine concentration 11-fold the clinical plasma Cmax at the maximal recommended dose; the no effect dose was 4-fold the clinical Cmax. In female mice and rats, rotigotine disrupted implantation and prevented pregnancy, probably due to hypoprolactinaemia. These effects are considered not clinically relevant because, in humans, chorionic gonadotropin rather than prolactin is essential for implantation.
(Category B3)
There are no adequate data on the use of Neupro in pregnant women. Studies in rats have shown that rotigotine and/or its metabolites cross the placenta. There was no evidence of teratogenicity following subcutaneous administration of rotigotine to mice, rats and rabbits during the period of organogenesis; the exposure (plasma AUC) in rabbits was more than 100-fold the maximal clinical exposure. Maternotoxic doses were associated with embryofetal toxicity. Administration to rats from early gestation to weaning was associated with effects in offspring (impaired auditory startle reflex during lactation, delays in some developmental indices). The potential risk for humans is unknown.
Rotigotine should not be used during pregnancy.
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. Subcutaneous administration to rats from early gestation to weaning was associated with adverse effects in offspring (see Use in pregnancy). In the absence of human data, breastfeeding should be discontinued.

4.7 Effects on Ability to Drive and Use Machines

Neupro may have a major influence on the ability to drive and use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).
Neupro has been associated with somnolence including excessive daytime somnolence and sudden sleep onset episodes. Patients being treated with Neupro 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 Section 4.4 Special Warnings and Precautions for Use).

4.8 Adverse Effects (Undesirable Effects)

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.

Parkinson's disease.

Based on the analysis of pooled placebo controlled clinical trials comprising a total of 1307 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.
In trials where the application sites were rotated as reflected in the instructions provided in the Consumer Medicine Information, 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.
Table 1 covers adverse drug reactions from all rotigotine studies in patients with Parkinson's disease. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
In addition, the following potentially important adverse drug reactions have been identified as being reported in clinical trials:
Fluid retention (see Section 4.4 Special Warnings and Precautions for Use).
Adverse events that might be indicative of fibrosis reported in the advanced stage PD clinical trial program are summarised in Table 2.

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.
In trials where the application sites were rotated as reflected in the instructions provided in the SPC 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.
Table 3 covers adverse drug reactions from all studies in patients with restless legs syndrome. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Postmarketing experience (both indications).

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported in postmarketing experience.
Frequency not known: dopamine dysregulation syndrome, diarrhoea, dropped head syndrome*, rhabdomyolysis.
* Only observed in Parkinson's disease patients.
Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

The most likely adverse reactions of overdose of Neupro 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. 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 since rotigotine is not eliminated by dialysis.
If it is necessary to discontinue rotigotine, this should be done gradually to prevent neuroleptic malignant syndrome.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Rotigotine is a non-ergolinic dopamine receptor agonist for the treatment of idiopathic Parkinson's disease and restless legs syndrome (RLS). In vitro binding studies and functional assays indicate a high affinity for the dopaminergic system (D1, D2, D3, D4, D5 receptors), particularly D3 receptors. Rotigotine is thought to elicit its beneficial effect by activation of the D3, D2 and D1 receptors of the caudate-putamen region. Rotigotine improved motor deficits in animal models of Parkinson's disease.
Rotigotine also shows affinities and activities at some nondopaminergic receptors, notably antagonism at alpha2B and agonism at 5HT1A receptor subtypes. The significance of these nondopaminergic interactions to its efficacy profile in vivo has not been clinically demonstrated.
There is no affinity of rotigotine for the 5HT2B receptor, which has been implicated in valvular heart disease.
The mechanism of action of rotigotine for RLS is unknown, but could involve a dopaminergic mechanism, as central dopaminergic dysfunction has been implicated in RLS.
A contribution of rotigotine metabolites to the pharmacological effect of rotigotine in vivo is unlikely.

Clinical trials.

Parkinson's disease.

The effectiveness of Neupro 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, Phase III, parallel, randomized, double blind placebo controlled studies.
Two trials investigating the effectiveness of Neupro for the treatment of idiopathic Parkinson's disease were conducted in patients with early stage Parkinson's disease who were not receiving concomitant dopamine agonist therapy and were either levodopa naive or previous levodopa 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).
Two additional trials were conducted in patients with advanced idiopathic Parkinson's disease 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'.

Clinical trials of Neupro in early stage disease.

In a double blind study, 177 patients received Neupro and 96 patients received placebo. The patients were titrated to their optimal dose of Neupro 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. Onset of treatment benefits began as early as the second week of treatment. Patients were maintained at their optimal dose for 6 months.
For 91% of the subjects in the Neupro arm, the optimal dose was the maximal dose allowed, i.e. 6 mg/24 h at the end of the maintenance treatment. An improvement of 20% was seen in 48% of the subjects receiving Neupro and in 19% of the subjects receiving placebo (difference 29%, confidence interval CI95% 18%; 39%, p < 0.0001). With Neupro, 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 was observed (baseline 30.0 points). The difference from placebo was 5.28 points and statistically significant (p < 0.0001).
In a second double blind study, 213 patients received Neupro, 227 received ropinirole and 117 patients received placebo. The patients were titrated to their optimal dose of Neupro 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.
At the end of the maintenance treatment in 92% of the subjects in the Neupro arm the optimal dose was the maximal dose allowed, i.e. 8 mg/24 h at the end of the maintenance treatment. An improvement over baseline of 20% was seen in 52% of the subjects receiving Neupro, 68% of the subjects receiving ropinirole and 30% of the subjects receiving placebo (difference Neupro versus placebo 21.7%; CI95% 11.1%; 32.4%, difference ropinirole 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 Neupro 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 active treatments and placebo were statistically significant.

Clinical trials of Neupro in advanced disease.

In a double blind study, 113 patients received Neupro in conjunction with levodopa up to a maximum dose of 8 mg/24 h, 109 patients received Neupro up to a maximum dose of 12 mg/24 h and 119 patients received placebo. The patients were titrated to their optimal doses of Neupro 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 period an improvement of at least 30% was seen in 57% and 55% of the subjects receiving Neupro 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 Neupro groups). With Neupro, 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 Neupro, 200 received pramipexole and 100 patients received placebo. All patients were also receiving levodopa. The patients were titrated to their optimal dose of Neupro 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 Neupro, 67% of the subjects receiving pramipexole and 35% of the subjects receiving placebo (difference Neupro versus placebo 25%; CI95% 13%; 36%, difference pramipexole 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 Neupro 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.

Clinical trial on effect of Neupro in early morning motor function and sleep.

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. Patients in both treatment groups were maintained at their optimal dose for 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 coprimary outcome measures. At the end of maintenance, the mean UPDRS part III score had improved by 7.0 points in rotigotine treated patients (baseline 29.7), and by 3.9 points in the placebo group (baseline 31.8). Improvements in the mean PDSS-2 total score were 5.9 (rotigotine, baseline 19.3) and 1.9 points (placebo, baseline 20.3). Treatment differences for the coprimary variables were statistically significant (p = 0.0002 and p < 0.0001).
In the secondary outcome measures, numerical improvement from baseline to end of maintenance was seen with rotigotine compared to placebo in the Nocturnal Akinesia, Dystonia and Cramps Score (NACDS), and little change in either group was observed for the number of nocturias.

Restless legs syndrome.

The effectiveness of Neupro in the treatment of moderate to severe idiopathic RLS was evaluated in a multinational drug development program consisting of two pivotal, parallel, randomized, double blind, placebo controlled studies and a placebo controlled, optimal dose sleep lab trial.
The primary outcome assessment in the two pivotal trials was the absolute change from baseline at the end of the maintenance period in the International RLS Study Group Rating Scale (IRLS) sum score and the Clinical Global Impression (CGI) Item 1 score (Severity of Illness).
The primary objective of the first double blind trial (SP790) was to demonstrate efficacy of 3 different transdermal doses of Neupro (1, 2 and 3 mg/24 h) versus placebo in subjects with moderate to severe idiopathic RLS over a 6 month maintenance period. A total of 333 patients received rotigotine in the three active treatment arms and 114 patients received placebo. At the end of maintenance both efficacy variables showed clinically relevant efficacy for all 3 rotigotine doses tested. (See Table 4.)
The primary objective of the second double blind trial (SP792) was to demonstrate efficacy of 4 different transdermal doses of Neupro (0.5, 1, 2 and 3 mg/24 h) versus placebo in subjects with moderate to severe idiopathic RLS over a 6 month maintenance period. A total of 395 patients received rotigotine in the 4 active treatment arms and 99 patients received placebo. At the end of maintenance both efficacy variables showed clinically relevant efficacy of rotigotine 2 mg/24 h and 3 mg/24 h. (See Table 4.)
In a third study (SP794) patients were investigated in a sleep lab setting. The objective of the double blind phase 3 sleep lab trial was to demonstrate that rotigotine is effective in subjects with moderate to severe idiopathic RLS based on the Periodic Limb Movement Index (PLMI; PLMs/total time in bed) as measured by polysomnography (PSG). The patients were titrated to their optimal dose of rotigotine or placebo in weekly increments of 1 mg/24 h starting at 1 mg/24 h to a maximum dose of 3 mg/24 h. Patients were maintained at their optimal dose for 4 weeks. Efficacy was assessed by the PLMI at the end of the maintenance period compared to baseline. A total of 46 patients received rotigotine treatment and 20 patients received placebo. The efficacy of Neupro over placebo was demonstrated for the primary efficacy variable. The PLMI decreased from 50.9 at baseline to 7.7 with rotigotine treatment and from 37.4 to 32.7 with placebo (p < 0.001). Rotigotine was 4.25 times more effective than placebo in the reduction of the PLMI at the end of the maintenance period.

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 concentration increases 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 1% (hip versus abdomen) to 46% (shoulder versus thigh). However, there is no indication of a relevant impact on the clinical outcome.
Because the patch is administered transdermally, no effect of food and gastrointestinal conditions is expected.

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 extensively 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-desalkylation of rotigotine. Main metabolites are sulfates and glucuronide conjugates of the parent compound as well as N-desalkyl metabolites.
The information on metabolites is incomplete.

Excretion.

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 overall elimination half-life is 5 to 7 hours. The pharmacokinetic profile shows a biphasic elimination with an initial half-life of about 2.4 to 3 hours.

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, race 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

Genotoxicity.

There was no evidence of genotoxicity in assays for bacterial gene mutation and unscheduled DNA synthesis in rat hepatocytes. A positive result was obtained in the in vitro mouse lymphoma assay, but there was no evidence of clastogenicity in in vivo mouse micronucleus assays, with plasma exposure up to about 50 times the clinical plasma Cmax value. On the weight of evidence, the genotoxic potential of rotigotine is considered to be low.

Carcinogenicity.

Two year subcutaneous carcinogenicity studies with rotigotine were conducted in mice and rats, achieving respective systemic exposures (plasma AUC) up to 5 and 2-fold the clinical plasma AUC at the maximal recommended dose. There was no evidence of carcinogenicity in mice. Rats developed Leydig cell adenomas and uterine tumours (adenocarcinomas, squamous cell carcinomas), but the findings are of questionable significance because the endocrine mechanisms are not considered relevant to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients contained in the self adhesive matrix are povidone, ascorbyl palmitate, dl-alpha-tocopherol and sodium metabisulfite. The adhesive matrix consists of a mixture of two proprietary silicone adhesives (BIO-PSA Q7-4301 and BIO-PSA Q7-4201).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

30 months.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Available in the following presentations:
Neupro 1 mg: Pack sizes: 7s, 28s, 100s.
Neupro 2 mg: Pack sizes: 7s, 28s, 100s.
Neupro 3 mg: Pack sizes: 7s, 28s, 100s.
Neupro 4 mg: Pack sizes: 7s, 28s, 100s.
Neupro 6 mg: Pack sizes: 7s, 28s, 100s.
Neupro 8 mg: Pack sizes: 7s, 28s, 100s.
Please note Neupro 1 mg and 3 mg patches are not supplied. Pack sizes 7s and 100s are not supplied.
Each patch is individually sealed in a sachet.

6.6 Special Precautions 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.

6.7 Physicochemical Properties

Chemical name: (6S)-6-{propyl-[2-(2-thienyl)ethyl]amino}- 5,6,7,8-tetrahydro-1-naphthalenol.
Molecular formula: C19H25NOS.
MW: 315.48.

Chemical structure.


CAS number.

99755-59-6.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes