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Neupro^® (Rotigotine Transdermal Patch)

What is Neupro^®?

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Neupro^® is a medicine for the treatment of Parkinson’s disease. It belongs to a class of treatments called dopamine agonists.

Neupro^® works by continuously releasing its active substance rotigotine through the patient’s skin into the body.

Neupro^® Availability

Neupro^® is currently available in the following countries:

• 
  Austria
• 
  Finland
• 
  Germany
• 
  Greece
• 
  Ireland
• 
  Netherlands
• 
  Norway
• 
  Spain
• 
  Sweden
• 
  Switzerland
• 
  United Kingdom

Availability - Formulation

Neupro^® is a thin, matrix-type, square-shaped transdermal patch with rounded edges, consisting of three layers. The outside of the backing layer is tan-coloured and imprinted with Neupro 4 mg/24 h, 6 mg/24 h, or 8 mg/24 h, respectively.

Four different dosages are available.

Who is suitable for this treatment?

Neupro^® is suitable for all stages of idiopathic Parkinsons’s disease patients.

Neupro® can offer an alternative to conventional oral therapies. Due to its transdermal administration and specific metabolism and excretion may be of benefit in patients with difficulties swallowing, delayed gastric emptying and resorption of PD medication, undergoing central anaesthesia and dialysis.

Therapeutic indication

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

Contra-indications (When not to use)

• Hypersensitivity to the active substance or to any of the excipients.
• Magnetic resonance imaging or cardioversion (see section “special warning & precautions for use”)

How To take

How to apply the patch

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.

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

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

To help avoid skin irritation, stick Neupro^® 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.

For application instructions, please see downloads section of this page on the EPDA website (www.epda.eu.com/medinfo/neupro).

How to store (updated 04 June 2008)

• Neupro^® must be stored in a refrigerator (at a temperature of between 2ºC and 8ºC).
• The storage conditions are intended to reduce the possible occurrence of crystallisation of the active substance which has been reported in patches of Neupro^® (see EPDA News item: Neupro^® recall (27 March 2008).
• The crystals resemble snowflakes and may cover up to 40% of the patch’s surface. The effect of the crystal formation on the efficacy of Neupro^® is still unclear and is currently under investigation.
• It is important that patients do not stop taking their existing medication, even if they notice snowflake crystal patterns on the surface of the patch, without first speaking to their doctor or pharmacist.

Special warning & precautions for use

• If a patient is insufficiently controlled while on treatment with rotigotine switching to another dopamine agonist might provide additional benefit.
• 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.
• 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.
  Syncope was observed in association with Neupro^®, but also at a similar rate in patients treated with placebo.
  It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of orthostatic hypotension associated with dopaminergic therapy.
• Neupro^® has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness of any warning signs, has been reported. Prescribers should continually reassess patients for drowsiness or sleepiness, as patients may not acknowledge drowsiness or sleepiness until directly questioned. A reduction of dosage or termination of therapy should be carefully considered.
• Pathologic gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson’s disease, including Neupro^®.
• Although not reported with Neupro^®, symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy. Therefore it is recommended to taper treatment.
• Hallucinations have been reported and patients should be informed that hallucinations can occur.
• 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 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.
• Neuroleptics given as antiemetic should not be given to patients taking dopamine agonists.
• Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
• 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 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.
• 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.
• The incidence of some dopaminergic adverse events, such as hallucinations, dyskinesia, and peripheral oedema generally is higher when given in combination with L-dopa. This should be considered when prescribing rotigotine.
• In clinical studies, the 6 month-specific rates of peripheral edema remained at about 4% through the entire observation period up to 36 months.

Interactions with other medicinal products

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

Co-administration of enzyme inducing active substances (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin, St John’s wort/Hypericum perforatum) has not been investigated.

Co-administration of L‑dopa and carbidopa with rotigotine had no effect on the pharmacokinetics of rotigotine, and rotigotine had no effect on the pharmacokinetics of L‑dopa and carbidopa.

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

Pregnancy & lactation

Ask your doctor or pharmacist for advice before taking any medicine.

There are no adequate data from the use of Neupro^® in pregnant women. Animal studies do not indicate any teratogenic effects in rats and rabbits, but embryo-toxicity was observed in rats and mice at materno-toxic doses. 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. In the absence of human data, breast-feeding should be discontinued.

Effects on ability to drive & use machines

Rotigotine may have major influence on the ability to drive and use machines.

Patients being treated with rotigotine and presenting with somnolence and/or sudden sleep episodes must be informed not to drive or engage in activities (e.g. operating machines) where impaired alertness may put themselves or others at risk of serious injury or death until such recurrent episodes and somnolence have resolved.

Possible undesirable effects

Like all medicines, Neupro^® can cause side effects, although not everybody gets them.

Side effects that occur frequently are those due to the central neuropharmacological activity of dopamine agonists or due to being a transdermal patch.

Very common side effects (happening in more than 1 in 10 patients)

Very common side effects are nausea, dizziness, feeling sleepy and skin irritations under the patch such as redness and itching.

Common side effects (happening in 1 in 100 to 1 in 10 patients)

Common side effects are seeing or hearing things that are not real (hallucinations), involuntary movements related to Parkinson’s disease (dyskinesia), feeling dizzy when standing up after sitting or lying down because of reduced blood pressure, increased or abnormal liver function test results, falling, rash, swelling of legs and feet, vomiting, diarrhoea, constipation, feeling weak (conditions including fatigue, debility and feeling of discomfort), confusion, having unusual dreams, being unable to sleep, weight loss, increased sweating, headache, heartburn, dry mouth

Uncommon side effects (happening in 1 in 1,000 to 1 in 100 patients)

Uncommon side effects are falling asleep suddenly without warning, psychotic disorders including abnormal thinking about reality and behaviour (paranoid psychosis), unusual urge to carry out a certain activity including excessive gambling, repetitive meaningless actions and increased sex drive, fainting, fainting due to a drop in blood pressure, irregular heart beat, increased heart rate, increased blood pressure, reduced blood pressure, visual disturbances such as seeing colours or lights or blurred vision, feeling of abnormal motion (vertigo),slow movement or extended spasm in group of muscles, poor balance, being unable to walk properly, tremors, shortness of breath, generalised itching, anxiety, sleep disorders, nightmares, increased sleepiness, disorientation, lethargy, reduced concentration, loss of memory, numbness or tingling sensation, food and drink tasting different, decreased appetite (anorexia), weight increase, stomach discomfort and pain, swelling of the joints, impotence in men (being unable to achieve or maintain an erection), feeling of increased heart rate (palpitations), feeling abnormal, cough, hiccups.

Rare side effects (happening in 1 in 10,000 to 1 in 1,000 patients)

Rare side effects are involuntary muscle spasms (seizure, convulsion), and loss of consciousness.

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, the patch(es) should immediately be removed from the patient. Levels of rotigotine decrease after patch removal.

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.

The terminal half-life of rotigotine is 5 to 7 hours.

Pharmacological properties

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.

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, parallel, random
ized, double-blind placebo controlled studies.

Two trials investigating the effectiveness of Neupro^® in the treatment of the signs and symptoms of idiopathic Parkinson’s disease were conducted in patients who were not receiving concomitant dopamine agonist therapy and were either L-dopa naïve or previous L-dopa treatment was ≤ 6 months. The primary outcome assessment was the score for the Activities of Daily Living (ADL) component (Part II) plus the Motor Examination component (Part III) of the Unified Parkinson’s Disease Rating Scale (UPDRS).

Two additional trials were conducted in patients who were receiving concomitant levodopa therapy. The primary outcome assessment was the reduction in “off” time (hours). Efficacy was determined by the subject’s response to therapy in terms of responder and absolute improvement in the time spent “off”.

Special patient groups

Because therapy with Neupro^® is initiated at a low dose and gradually titrated according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the dose based on gender, weight, or age is not necessary.

Downloads

Please click on the links below to download detailed information on the Neupro^® transdermal patch, its handling and use.

Further detailed information on the Neupro^® transdermal patch can be downloaded via the EPDA wesite (www.epda.eu.com/medinfo/neupro).

Patient Information Leaflets available for download
(Adobe Acrobat pdf files)

• Neupro^® 6mg per 24h
• Application Instructions

UK Summary of Product Characteristics (SPC) available for download (Adobe Acrobat pdf file)

Please note that SPCs are designed for healthcare professionals.

• Neupro^® (Rotigotine Transdermal Patch)

Further reading: Clinical trials with rotigotine transdermal patch

1. Parkinson Study Group, A Controlled Trial of Rotigotine Monotherapy in Early Parkinson’s Diseae. Arch Neur, Vol 60, Dec. 2003, pg. 1721 - 1728
2. Rascol O. et al, Transdermal Delivery of Dopaminergic Agents. Neurology 65 (Suupl 1), July 2005, S1 - S14
3. Watts RL. et al., Randomized, blid, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 68, No. 4, January 23, 2007, pg. 271 – 276
4. LeWitt P. et al., Rotigotine Transdermal System in Treatment of Patients with Advanced-Stage Parkinson’s Disease. Eur J of Neur 12, Suppl. 2, 2005, 11-36:SC115

You can obtain copies of these clinical papers through your local library.

Useful Links & References

To learn more about Neupro^® please visit www.neupro.com or contact info@schwarzpharma.com.

Further Information

SCHWARZ PHARMA AG
Alfred-Nobel-Straße 10
Monheim
40789
Germany

e: info@schwarzpharma.com