Active ingredients: Rotigotine
Neupro 2 mg / 24 h Transdermal patch
Neupro 4 mg / 24 h Transdermal patch
Neupro 6 mg / 24 h Transdermal patch
Neupro 8 mg / 24 h Transdermal patch
Why is Neupro used? What is it for?
Neupro contains the active substance rotigotine. It belongs to the class of medicines called dopamine agonists, which stimulate a certain type of cell and which bind to dopamine receptors in the brain.
Neupro is indicated in adults to treat the signs and symptoms of Parkinson's disease alone or in combination with a medicine called levodopa.
Contraindications When Neupro should not be used
Do not take Neupro
- if you are allergic to rotigotine or any of the other ingredients of this medicine (listed in section 6).
- if you are to undergo magnetic resonance imaging (a diagnostic method used to visualize the internal organs and tissues of the body) or cardioversion (treatment of abnormal heart rhythms). You must remove the Neupro patch before undergoing these procedures. at the end of the procedure you can apply a new patch.
Precautions for use What you need to know before taking Neupro
Talk to your doctor, pharmacist or nurse before taking Neupro.
- This medicine can alter your blood pressure: therefore, it is advisable to measure your blood pressure regularly, especially at the beginning of treatment.
- Loss of consciousness may occur. This can especially happen when you start using Neupro or when the dose is increased. Tell your doctor if you lose consciousness or feel dizzy.
- Eye examination at regular intervals is recommended while using Neupro. However, if you notice any vision problems between examinations, you should contact your doctor immediately.
- If you have severe liver problems, your doctor may change your dose. If your liver problems get worse during treatment, you should contact your doctor as soon as possible.
- If you feel very drowsy or if you suddenly fall asleep, contact your doctor (see also below in this section, "Driving and using machines").
- Tell your doctor if you or your family / caregivers notice that you are developing urges or desires that lead you to behaviors that are unusual for you and that you cannot resist the urge or temptation to perform certain activities that could harm you or others. These are called impulse control disorders and can include behaviors such as gambling addiction, excessive eating or spending, an abnormal, exaggerated sexual desire, or apprehension of increased thoughts or feelings about sexual background. Your doctor may find it necessary to change your dose or stop treatment.
- Neupro can cause abnormal thinking and behavior. This abnormal thinking and behavior can consist of one or more variety of manifestations including abnormal thoughts about reality, delirium, hallucinations (seeing or hearing things that are not real), confusion, disorientation, aggressive behavior, agitation and delirium. If you notice these effects, contact your doctor.
- Neupro can cause skin reactions, such as redness and itching. These are usually mild to moderate and affect only the area covered by the patch. The reactions usually go away a few hours after removing the patch. If you experience a skin reaction that lasts more than a few days, a severe skin reaction, or spreads outside the area of skin covered by the patch, contact your doctor. Avoid exposing areas of your skin that exhibit any reactions caused by Neupro to sunlight and tanning beds. To avoid skin reactions, you should apply the patch each day to a different place and only use the same site after 14 days.
Children and adolescents
Neupro should not be used in children because its safety and efficacy have not been established in children.
Interactions Which drugs or foods can change the effect of Neupro
Other medicines and Neupro
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
You should not take the following medicines while using Neupro, as they may decrease their effect: antipsychotics (used to treat certain mental conditions) or metoclopramide (used to treat nausea and vomiting)
If you are treated with Neupro and levodopa at the same time, some side effects may get worse, such as hearing or seeing things that are not real (hallucinations), involuntary movements related to Parkinson's disease (dyskinesia) and swelling in the legs and feet.
Ask your doctor if you can:
- taking medicines that lower blood pressure. Neupro can reduce your blood pressure when standing up; this effect may be aggravated by medicines used to lower blood pressure.
- taking sedatives (for example benzodiazepines, medicines used to treat mental conditions or depression) while using Neupro.
Neupro with food, drink and alcohol
Since rotigotine passes into the blood through the skin, food and drink have no effect on how the drug works. You should consult your doctor if you can drink alcohol while using Neupro.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
You should not use Neupro if you are pregnant, as the effects of rotigotine on pregnancy and the unborn child are not known. Breastfeeding is not recommended during treatment with Neupro. Rotigotine may pass into breast milk and affect the baby and possibly also reduce the amount of milk produced.
Driving and using machines
Neupro can make you feel very drowsy and can make you fall asleep suddenly. If this happens to you, you should not drive or engage in activities (eg using machines) in which lack of attention could expose you or others to the risk of a serious accident. In isolated cases, patients have fallen asleep while they were driving vehicles and thus caused accidents.
Neupro contains sodium metabisulfite (E223)
Sodium metabisulfite (E223) can rarely cause severe hypersensitivity reactions and bronchospasm.
Dose, Method and Time of Administration How to use Neupro: Posology
Always use this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The Neupro initiation pack contains 4 separate packs (one for each amount of active ingredient) with 7 patches each. These packs are usually used in the first four weeks of treatment but, depending on your response to Neupro, you may not need to use all of the packs attached or you may need to use other higher doses after week 4, not included in this pack.
On the first day of treatment, start with Neupro 2 mg (pack marked "Week 1") and take one Neupro 2 mg transdermal patch each day. Use Neupro 2 mg for 7 days (for example, if you start on Sunday, move on to the next dose on the following Sunday).
At the beginning of the second week, take Neupro 4 mg (pack marked "Week 2").
At the beginning of the third week, take Neupro 6 mg (pack marked "Week 3").
At the beginning of the fourth week, take Neupro 8 mg (pack marked "Week 4").
The most suitable dose for you depends on your needs.
4 mg of Neupro per day may be an effective dose for some patients. In most patients with early-stage Parkinson's disease, the effective dose is achieved within 3 or 4 weeks, with doses of 6 mg / 24 h or 8 mg / 24 h, respectively. The maximum dose is 8 mg per day. For most patients with advanced Parkinson's disease, the effective dose is achieved within 3 to 7 weeks, with doses of 8 mg per day, up to the maximum dose of 16 mg per day. If you need to stop treatment, see section 3, "If you stop taking Neupro".
To use Neupro follow these instructions:
Neupro is a patch for transdermal use to be applied to the skin. You should apply a new Neupro patch to the skin once a day. Leave the patch on your skin for 24 hours, then remove it and put on a new one. Make sure you have removed the old patch before applying a new one, put the new patch on a different area of the skin. You should always change the patch at about the same time every day. Do not cut the Neupro patches into pieces.
Where to apply the patch
Apply the sticky side of the patch to clean, dry and healthy skin in the following regions as indicated in the gray areas of the figure:
- shoulder
- upper arm
- belly
- thigh
- hip
- flank (between the ribs and the hip)
In order to avoid skin irritation:
- apply the patch to a different area of the skin each day, for example one day to the right of the body, then the next day to the left; one day in the upper part of the body, then in the lower part.
- Do not reapply Neupro on the same area of skin for 14 days.
- Do not apply the patch to broken or red skin, or to red or irritated skin.
If you have skin problems due to the patch, see section 4 'Possible side effects' for information on what to do.
To prevent loss or peeling of the patch
- Do not apply the patch to an area that can be rubbed by tight clothing.
- Do not use creams, oils, lotions, powders or other skin products on the area where you will be applying the patch or near another patch you have already put on.
- If you are going to apply the patch to a hair-covered area, you must shave the affected area at least three days before applying the patch.
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.
NOTE
- The action of Neupro is not normally affected by bathing, showering or physical activity. However, make sure the patch hasn't come off.
- Avoid exposing the skin area on which the patch has been applied to external heat (eg excessive sunlight, sauna, very hot baths, thermal pillows or hot water bottles).
- If the patch has caused skin irritation, do not expose the affected area to sunlight, as otherwise the skin may change color.
How to use the patch
Each patch is packed in a separate sachet. Apply Neupro to the skin immediately after opening the sachet and removing the protective film.
- To open the sachet, hold the two sides of the sachet in your hand. Separate the two layers of the foil and open the sachet.
- Take the patch out of the sachet.
- The sticky part of the patch is covered with a transparent protective layer. Hold the patch with both hands, with the protective layer facing you.
- Fold the patch in half so that the S-shaped opening line opens.
- Peel off one side of the protective liner. Do not touch the sticky side of the patch with your fingers.
- Hold the other side of the protective liner in your hand and apply the sticky side of the patch to the skin. Press firmly on the sticky side of the patch.
- Fold the other half of the patch back and peel off the other side of the protective layer.
- With the palm of your hand, press firmly on the patch for 20-30 seconds to make sure that the patch is in contact with the skin and that the corners are snug.
Wash your hands with soap and water immediately after handling the patch.
How to remove a used patch
Remove the used patch slowly and carefully.
To remove any adhesive residue left by the patch, gently wash the affected area with warm water and mild soap. For adhesive residue that does not come off with water, use a small amount of baby oil. Do not use alcohol or other solvents, such as nail polish remover, as they can cause irritation. Choose a new area of skin to apply the patch, then follow the instructions above.
Overdose What to do if you have taken too much Neupro
If you use more Neupro than you should
Using doses of Neupro higher than those prescribed by your doctor can cause side effects such as nausea (feeling nauseous), vomiting, low blood pressure, hallucinations (seeing or hearing things that are not real), confusion, extreme sleepiness, involuntary movements and convulsions. If you have applied more patches than prescribed by your doctor, contact your doctor or hospital for immediate advice and follow their advice on removing the patches.
If you have applied a patch other than that prescribed by your doctor (eg Neupro 4 mg / 24 h instead of Neupro 2 mg / 24 h), contact your doctor or hospital for immediate advice and follow their advice on changing the patches. If any unpleasant reactions occur, please consult your doctor.
If you have forgotten to change the patch at the usual time
If you forgot to change the patch at the usual time, take off the old patch and put on a new one as soon as you remember. If you forgot to put on a new patch after taking off the old one, put on a new one as soon as you remember. In both cases the next day, change the patch at the usual time. Do not apply a double dose to make up for a forgotten dose. If you stop using Neupro Do not suddenly stop using Neupro without informing your doctor. A sudden stop may cause you to develop a medical condition called neuroleptic malignant syndrome which could pose a major health risk. Symptoms include: akinesia (loss of muscle movement), stiff muscles, fever, unstable blood pressure, tachycardia (rapid heart rate), confusion, decreased consciousness (e.g. coma).
The daily dose of Neupro should be gradually reduced
- 2 mg every other day - if you are using Neupro for Parkinson's disease
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Neupro
Like all medicines, this medicine can cause side effects, although not everybody gets them.
You may feel nauseous and vomit at the start of therapy. These effects are usually mild or moderate and only last for a short time. You should contact your doctor if they last for a long time or worry you.
Skin problems caused by the patch
The patch can cause skin reactions such as redness, itching. They are usually mild or moderate and affect only the area of the skin where the patch was applied. The reactions usually go away a few hours after the patch is removed. If you have a skin reaction that lasts more than a few days, and that is severe or spreads outside the patch-covered skin area, you should contact your doctor.
The following side effects may occur:
Inability to resist the urge, will or temptation to take actions that could be harmful to you or others, which may include:
- strong urge to gamble excessively, despite serious personal or family consequences
- altered or increased sexual interest and behavior that is of significant concern to you or others, for example an increase in sexual desire
- uncontrollable and excessive shopping
- binge eating (eating large amounts of food in a short period of time) or compulsive eating (eating more food than normal and more than necessary to satisfy one's appetite)
Tell your doctor if any of these behaviors occur so they can decide what to do to manage or reduce symptoms.
Swelling of the face, tongue and / or lips may occur. Contact your doctor if these symptoms develop.
If you are using Neupro for Parkinson's disease the following side effects may be observed:
Very common side effects: may affect more than 1 in 10 patients
- drowsiness, dizziness, headache
- nausea, vomiting
- skin irritations under the patch, such as redness and itching
Common side effects: may affect up to 1 in 10 patients
- feeling of seeing or hearing things that are not real (hallucinations)
- difficulty falling asleep, sleep disturbance, difficulty sleeping, nightmares, unusual dreams
- loss of consciousness, involuntary movements related to Parkinson's disease (dyskinesia), feeling dizzy when getting up from a sitting or lying position due to a drop in blood pressure
- vertigo (sensation of spinning motion)
- sensation of heartbeat (palpitations)
- decrease in blood pressure when getting up from a sitting or lying position, increase in blood pressure
- hiccup
- constipation, dry mouth, heartburn
- redness, increased sweating, itching
- swollen legs and feet
- feeling of weakness, feeling tired
- fall
- weight loss
- inability to resist the urge to perform an action that could cause harm, including excessive gambling, meaningless repetitive actions, binge eating and compulsive shopping, and compulsive shopping
Uncommon side effects: may affect up to 1 in 100 patients
- allergic reaction
- suddenly falling asleep with no warning signs
- paranoia
- disorientation
- agitation
- increased sexual activities
- confusion
- blurred vision
- visual disturbances such as the vision of colors or lights
- irregular heartbeat
- decrease in blood pressure
- stomach aches and pains
- generalized itching, skin irritation
- inability to achieve or maintain an erection
- increased or abnormal results in liver function tests
- weight gain
- acceleration of the heartbeat
- increased levels of creatine phosphokinase (CPK) in the blood in Japanese patients (CPK is an enzyme found mainly in skeletal muscles). No information is available in other populations.
Rare side effects: may affect up to 1 in 1000 patients
- psychotic disorders
- aggressive behavior / aggression
- involuntary muscle spasms (convulsions)
- generalized rash
- irritability delirium
- raving
Not known: frequency cannot be estimated from the available data
- excessive use of Neupro (craving for high doses of dopaminergic medicines exceeding what is needed to control motor symptoms, known as dopaminergic dysregulation syndrome)
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and carton.
Do not store above 25 ° C.
Disposal of used or unused patches
Used patches still contain the active ingredient, which can be harmful to other people. Fold the used patch with the sticky side in. Return the patch to the original sachet and dispose of it safely, out of the reach of children.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Neupro contains
- The active ingredient is rotigotine.
Neupro 2 mg / 24 h
Each patch releases 2 mg of rotigotine per 24 hours.
Each 10 cm2 patch contains 4.5 mg of rotigotine.
Neupro 4 mg / 24 h
Each patch releases 4 mg of rotigotine per 24 hours.
Each 20 cm2 patch contains 9.0 mg of rotigotine.
Neupro 6 mg / 24 h
Each patch releases 6 mg of rotigotine per 24 hours.
Each 30 cm2 patch contains 13.5 mg of rotigotine.
Neupro 8 mg / 24 h
Each patch releases 8 mg of rotigotine per 24 hours.
Each patch of 40 cm2 contains 18.0 mg of rotigotine.
- The other ingredients are: poly (dimethylsiloxane, trimethylsilyl silicate) copolymerized, povidone K90, sodium metabisulfite (E223), ascorbyl palmitate (E304) and DL-α-tocopherol (E307).
- Support layer: polyester film coated with silicone and aluminum, colored with a layer of pigment (titanium dioxide (E171), yellow pigment 95, pigment red 166) and bearing an inscription (pigment red 144, pigment yellow 95, pigment black 7 ). Protective layer: polyester film coated with transparent fluoropolymer
What Neupro looks like and contents of the pack
Neupro is a transdermal patch. It is thin and consists of three layers. It is a square patch with rounded corners. The outside of the backing layer is beige and imprinted with Neupro 2 mg / 24 h, 4 mg / 24 h, 6 mg / 24 h or 8 mg / 24 h.
Neupro is available in the following pack sizes: The treatment initiation pack contains 28 transdermal patches in 4 cartons containing 7 patches of 2 mg, 4 mg, 6 mg and 8 mg each, sealed in a single sachet.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
NEUPRO
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Neupro 2 mg / 24 h transdermal patch
Each patch releases 2 mg of rotigotine per 24 hours. Each 10 cm2 patch contains 4.5 mg of rotigotine.
Neupro 4 mg / 24 h transdermal patch
Each patch releases 4 mg of rotigotine per 24 hours. Each 20 cm2 patch contains 9.0 mg of rotigotine.
Neupro 6 mg / 24 h transdermal patch
Each patch releases 6 mg of rotigotine per 24 hours. Each 30 cm2 patch contains 13.5 mg of rotigotine.
Neupro 8 mg / 24 h transdermal patch
Each patch releases 8 mg of rotigotine per 24 hours. Each patch of 40 cm2 contains 18.0 mg of rotigotine.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Transdermal patch.
Thin, matrix, square patch with rounded corners, consisting of three layers. The outside of the backing layer is beige in color and imprinted with "Neupro 2 mg / 24 h, 4 mg / 24 h, 6 mg / 24 h or 8 mg / 24 h".
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
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; or in the course of the disease, including the late phases, when the efficacy of levodopa is reduced or discontinued and fluctuations in the therapeutic effect appear (end-of-dose effect or "on / off" phenomena).
04.2 Posology and method of administration
Dosage:
Neupro is applied once a day. The patch should be applied at approximately the same time each day. The patch remains in contact with the skin for 24 hours and is subsequently replaced by a new patch placed in a different application site.
If the patient forgets to apply the patch at the usual time or if the patch falls off, another patch should be applied for the rest of the day.
Dosage:
Dosage recommendations refer to the nominal dose.
Posology in patients with early Parkinson's disease:
A single dose of 2 mg / 24 h should be started and increased weekly by 2 mg / 24 h until the effective dose is reached, up to a maximum of 8 mg / 24 h. In some patients, the administration of 4 mg / 24 h may correspond to the effective dose. In most patients, the effective dose is achieved within 3 or 4 weeks, with doses of 6 mg / 24 h or 8 mg / 24 h, respectively.
The maximum dose is 8 mg / 24 h.
Posology in patients with advanced Parkinson's disease with fluctuations:
A single dose of 4 mg / 24 h should be started and increased weekly by 2 mg / 24 h until the effective dose is reached, up to a maximum of 16 mg / 24 h. In some patients the administration of 4 mg / 24 h or 6 mg / 24 h may correspond to the effective dose. In most patients, the effective dose is achieved within 3 to 7 weeks with doses of 8 mg / 24 h, up to a maximum of 16 mg / 24 h.
The Neupro treatment initiation pack contains 4 different packs (one for each amount of active ingredient) with 7 patches each, to be used in the first four weeks of therapy. Depending on the patient's response, it may not be necessary to perform all the steps for dosing described below or further higher doses may be required after week 4, which are not included in this pack.
On the first day, the patient starts treatment with Neupro 2 mg / 24 h. During the second week, the patient applies Neupro 4 mg / 24 h patches. During the third week, the patient switches to Neupro 6 mg / 24 h and then, in the fourth week, to Neupro 8 mg / 24 h. The packs are labeled "Week 1 (2, 3 or 4)".
Discontinuation of treatment:
Neupro must be discontinued gradually. The daily dose should be reduced in steps of 2 mg / 24 h at a time, possibly every other day, until complete discontinuation of Neupro (see section 4.4).
Special populations:
Changes in liver and kidney function: there is no need to adjust the dose in patients with mild to moderate changes in liver function or with mild to severe changes in renal function, including those undergoing dialysis.Caution is advised when treating patients with severe hepatic impairment as this may result in lower rotigotine clearance. Rotigotine has not been evaluated in this patient group. A dose reduction may be necessary in case of worsening of liver function. Unexpected accumulation of rotigotine levels may be observed in case of acute worsening of renal function (see section 5.2).
Pediatric population
The safety and efficacy of rotigotine in the pediatric population has not yet been established. No data are available.
Method of administration:
The patch should be applied to clean, dry, intact and healthy skin on the abdomen, thighs, hips, hips, shoulders or arms. Reapplication at the same administration site should be avoided for 14 days. Neupro should not be placed on red, irritated or damaged skin (see section 4.4).
Application and use:
Each patch is packaged in a sachet and must be applied immediately after opening the sachet. Peel off one half of the protective layer and apply the adhesive part to the skin, pressing it firmly onto the skin. Then, fold the patch back and peel off the skin. "other half of the protective layer. Avoid touching the sticky side of the patch. Press the patch firmly onto the skin with the palm of your hand for at least 20-30 seconds so that it adheres well.
Should a patch fall off, a new patch should be applied for the remaining time of the 24 hour dosing interval.
The patch should not be cut into pieces.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Magnetic resonance imaging or cardioversion tests (see section 4.4).
04.4 Special warnings and appropriate precautions for use
If a patient with Parkinson's disease does not respond adequately to rotigotine treatment, switching to another dopamine agonist could provide additional benefit (see section 5.1).
Magnetic resonance imaging and cardioversion:
The backing layer of Neupro contains aluminum. To avoid skin burns, Neupro should be removed if the patient is to undergo magnetic resonance imaging (MRI) or cardioversion.
Orthostatic hypotension:
Dopamine agonists are known to alter the systemic regulation of blood pressure, resulting in postural / orthostatic hypotension. These effects were also seen during treatment with rotigotine, however the incidence was similar to that seen in patients treated with placebo.
Syncope associated with the use of rotigotine has been reported, but with a similar frequency to patients treated with placebo.
It is recommended that blood pressure be monitored, especially at the start of treatment, due to the risk of orthostatic hypotension generally associated with dopaminergic therapy.
Sudden onset of sleep and drowsiness:
Rotigotine has been associated with somnolence and sudden sleep onset episodes. There have been reports of sudden onset of sleep during daily activities, in some cases without any warning signs. Doctors should constantly ask the patient about the presence of drowsiness and sleepiness, as the patient may not recognize these symptoms without a specific question about them. In this case, the possibility of a reduction in dosage or discontinuation of therapy should be carefully considered.
Impulse control disorders:
Cases of pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists, including rotigotine.
Neuroleptic malignant syndrome
Symptoms attributable to a neuroleptic malignant syndrome have been reported in cases of sudden discontinuation of dopaminergic therapy. It is therefore recommended to gradually discontinue treatment (see section 4.2).
Hallucinations:
Hallucinations have been reported and patients should be advised of this eventuality.
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. These complications may regress upon discontinuation of therapy, but not. a complete resolution always occurs.
Although these adverse reactions are considered to be related to the ergoline structure of these compounds, it is not known whether other dopamine agonists, not derived from ergot, could induce their occurrence.
Neuroleptics:
Do not administer neuroleptics as antiemetics to patients treated with dopamine agonists (see also section 4.5).
Ophthalmological monitoring:
Regular ophthalmological monitoring is recommended, or in the presence of visual disturbances.
Heat application:
Avoid exposing the skin area on which the patch has been applied to heat sources such as excessive sunlight, heat pads, and other heat sources, such as a sauna or a very hot bath.
Application site reactions:
Skin reactions, usually mild or moderate in intensity, may occur at the application site. It is recommended that the patch application site be varied daily (e.g. right to left and upper body to lower body). Avoid reapplying the patch to the same site for 14 days. If application site reactions persist for several days or are persistent, worsening, or if the skin reaction extends beyond the application site, the benefit / risk ratio for that patient should be reassessed. In the event of a skin rash or irritation caused by the transdermal patch, avoid exposure to direct sunlight until the skin lesion heals. Exposure to sunlight may lead to discolouration of the skin.
In the event of a generalized skin reaction (eg allergic rash, including erythematous, macular, papular or pruritus rash) associated with the use of Neupro, treatment with Neupro should be discontinued.
Dopaminergic adverse reactions:
The incidence of some dopaminergic-type adverse reactions such as hallucinations, dyskinesia and peripheral edema is generally higher when co-administered with L-DOPA in patients with Parkinson's disease. This should be taken into account when prescribing rotigotine. .
Peripheral edema:
In clinical studies in patients with Parkinson's disease, the specific frequency of peripheral edema after 6 months was approximately 4% and remained so during the entire 36-month observation period.
Sensitivity to sulphites:
Neupro contains sodium metabisulfite, a sulphite which, in some sensitive people, can cause allergic-type reactions, including anaphylactic symptoms and life-threatening asthma episodes or less severe asthma episodes.
04.5 Interactions with other medicinal products and other forms of interaction
Since rotigotine is a dopamine agonist, it is assumed that dopamine antagonists, such as neuroleptics (eg phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of Neupro and therefore their concomitant administration Due to possible additive effects, caution should be used in patients taking sedatives, other CNS (central nervous system) depressants (eg benzodiazepines, antipsychotics, antidepressants) or alcohol in combination with rotigotine.
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.
Co-administration of domperidone with rotigotine had no effect on the pharmacokinetics of rotigotine.
Co-administration of omeprazole (CYPC19 inhibitor), at doses of 40 mg per day, had no effect on the pharmacokinetics and metabolism of rotigotine in healthy volunteers. Neupro may potentiate dopaminergic adverse reactions of L-DOPA and may cause and / or exacerbate pre-existing dyskinesias, as described for other dopamine agonists.
Co-administration of rotigotine (3 mg / 24 h) did not change 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 studied.
04.6 Pregnancy and lactation
Pregnancy:
There are no adequate data on the use of rotigotine in pregnant women. Animal studies show no teratogenic effects in rats and rabbits, but embryotoxic effects were observed in rats and mice following administration of toxic doses to pregnant females. (see section 5.3). The potential risk to humans is unknown. The use of rotigotine should be avoided during pregnancy.
Feeding time:
Since rotigotine reduces prolactin secretion in humans, an inhibitory effect on lactation is expected. Studies in rats have shown that rotigotine and / or its metabolite (s) are excreted in human milk. In the absence of human data, breastfeeding should be discontinued.
Fertility:
For information on fertility studies, see section 5.3.
04.7 Effects on ability to drive and use machines
Rotigotine may impair the ability to drive or use machines.
Patients treated with rotigotine who present with somnolence and / or episodes of sudden sleep attack should not drive and should not engage in activities (eg operating machinery) in which impaired alertness could expose themselves or others. people at risk of serious injury or death until these recurrent episodes and sleepiness have resolved (see also sections 4.4 and 4.5).
04.8 Undesirable effects
Based on analysis of overall data from placebo-controlled clinical trials, including a total of 1,307 patients treated with Neupro and 607 patients treated with placebo, in 72.3% of patients treated with Neupro and 57.8% of patients treated with placebo, at least one adverse reaction occurred.
Dopaminergic-type adverse reactions such as nausea and vomiting may occur upon initiation of therapy. They are generally mild or moderate in intensity and transient, even if treatment is not stopped. Adverse reactions reported in more than 10% of patients treated with Neupro transdermal patch are nausea, vomiting, application site reactions, somnolence, dizziness and headache.
In studies where the application site was changed as described in the instructions provided in the Summary of Product Characteristics and package leaflet, 35.7% of 830 patients treated with the Neupro transdermal patch experienced application site reactions. Most of these reactions were mild or moderate in intensity and limited to the application site, and discontinuation of Neupro treatment was required in only 4.3% of all patients treated.
Within each frequency class, undesirable effects are reported in descending order of severity.
The table below summarizes the adverse drug reactions reported in all studies conducted with patients with Parkinson's disease. Within the system organ classifications, adverse reactions are listed by frequency (number of patients expected to develop the reaction), using the following categories: very common (≥1 / 10); common (≥1 / 100 to
high-level term
Description of selected adverse reactions:
Sudden onset of sleep and drowsiness:
Rotigotine has been associated with somnolence, including "excessive daytime sleepiness and episodes of sudden sleep onset. In isolated cases," the "sudden onset of sleep" has occurred while the patient was driving a motor vehicle, resulting in accidents. road. See also sections 4.4 and 4.7.
Impulse control disorders:
Patients treated with dopamine agonists, including rotigotine, have exhibited symptoms attributable to pathological gambling, increased libido and hypersexuality, generally reversible after dose reduction or discontinuation of treatment.
04.9 Overdose
The most likely adverse reactions would be those related to the pharmacodynamic profile of a dopamine agonist and include: nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, seizures and other signs of central dopaminergic stimulation. There are no known antidotes to treat dopamine agonist overdose. If overdose is suspected, the patch (s) should be removed from the patient's skin immediately. Rotigotine levels decrease after removing the patch. Before stopping rotigotine completely, see section 4.2.
The patient should be carefully monitored, including assessment of heart rate and rhythm and blood pressure. Since more than 90% of rotigotine is bound to plasma proteins, no clinical benefit is expected from dialysis.
Treatment of overdose may require general therapeutic measures to keep vital signs stable.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiparkinsonians, dopamine agonists; ATC code: N04BC09.
Rotigotine is a non-ergolinic D3 / D2 / D1 dopamine agonist indicated for the treatment of Parkinson's disease. Its positive effects are believed to be due to the activation of the D3, D2 and D1 receptors in the caudate-putamen brain area. Rotigotine relieves the signs and symptoms of idiopathic Parkinson's disease.
Clinical studies:
The efficacy of rotigotine in the treatment of signs and symptoms of idiopathic Parkinson's disease was evaluated in a multinational clinical development program comprising 4 pivotal, double-blind, placebo-controlled, randomized, parallel group studies.
Two studies concerning the efficacy of rotigotine in treating the signs and symptoms of idiopathic Parkinson's disease were conducted in patients not previously receiving concomitant dopamine agonist therapy, who had never received L-DOPA or in whom the administration of L-DOPA was not longer than 6 months The primary efficacy variable was the value of the component Activities of Daily Living (ADL), part II, plus the component Motor Examination, part III, of the "Unified Parkinson's Disease Rating Scale (UPDRS).
The efficacy was determined on the basis of the patient's response to therapy, in terms of the percentage of responders and of improvement expressed as an absolute value on the ADL and Motor Examination scales (UPDRS part II + III). In a first double study blinded, rotigotine was administered to 177 patients and placebo to 96 patients. The dose of rotigotine or placebo was titrated to the optimal dose and administered to patients in weekly increments of 2 mg / 24 h, starting with 2 mg / 24 h and up to a maximum dose of 6 mg / 24 h.Patients in each group received their optimal maintenance dose for 6 months.
At the end of maintenance therapy, in 91% of patients in the rotigotine group the optimal dose was the maximum allowable dose, i.e. 6 mg / 24 h. An improvement of 20% was seen in 48% of rotigotine-treated patients and 19% of placebo-treated patients (difference 29% CI95% 18%; 39%, p
In a second double-blind study, 213 patients were administered rotigotine, 227 patients were treated with ropinirole and 117 patients received placebo. The dose of rotigotine was titrated to the optimal dose and administered to patients in weekly increments of 2 mg / 24 h, starting with 2 mg / 24 h and up to a maximum dose of 8 mg / 24 h, over a period of 4 weeks In the ropinirole group, the dose was titrated up to the optimal dose, up to a maximum of 24 mg / day, over 13 weeks. Patients in each group received their maintenance dose for 6 months.
At the end of maintenance therapy, in 92% of patients in the rotigotine group, the optimal dose was the maximum allowable dose, i.e. 8 mg / 24 h. An improvement of 20% was seen in 52% of rotigotine-treated subjects, 68% of ropinirole-treated subjects and 30% of placebo-treated patients (difference between rotigotine versus placebo 21.7%; 95% CI 11.1 %; 32.4%, difference in ropinirole versus placebo 38.4% CI95% 28.1%; 48.6%, difference in ropinirole versus rotigotine 16.6%; CI95% 7.6%; 25.7%). The mean improvement in UPDRS score (parts II + III) was 6.83 points (baseline 33.2 points) in the rotigotine group, 10.78 points in the ropinirole group (baseline 32.2 points) and 2, 33 points in the placebo group (baseline 31.3 points). All differences between active treatments and placebo were statistically significant. The difference in efficacy between ropinirole and rotigotine was also statistically significant in favor of ropinirole. Two further studies were conducted in patients receiving concomitant levodopa therapy. The primary efficacy variable was the reduction in "off" time (hours). The efficacy was determined on the basis of the patient's response to therapy, in terms of the percentage of responders and the improvement in the absolute value of the duration of the "off" time.
In the first double-blind study, 113 patients received rotigotine up to a maximum dose of 8 mg / 24 h, 109 patients received rotigotine up to a maximum dose of 12 mg / 24 h and 119 patients received placebo. The dose of rotigotine or placebo was titrated to the optimal dose and administered to patients in weekly increments of 2 mg / 24 h, starting with 4 mg / 24 h. Patients in each group received their optimal maintenance dose for 6 months. At the end of maintenance therapy, an improvement of at least 30% was seen in 57% and 55% of patients administered 8 mg / 24 h and 12 mg / 24 h of rotigotine, respectively, and in 34% patients. treated with placebo (differences respectively 22% and 21%, CI95% respectively 10%; 35% and 8%; 33%, p
In the second double-blind study, 201 patients received rotigotine, 200 patients received pramipexole, and 100 patients received placebo. The dose of rotigotine was titrated to the optimal dose and administered to patients in weekly increments of 2 mg / 24 h, starting with 4 mg / 24 h and up to a maximum dose of 16 mg / 24 h. In the pramipexole group, patients received 0.375 mg the first week, 0.75 mg the second week and the dose was titrated in further weekly increments of 0.75 mg until the optimal dose was reached, up to a maximum of 4.5 mg / day. Patients in each group received their maintenance dose for 4 months.
At the end of maintenance therapy, an improvement of at least 30% was seen in 60% of rotigotine-treated patients, 67% of pramipexole-treated patients and 35% of placebo-treated patients (difference between rotigotine versus placebo 25%; CI95% 13%; 36%, difference between pramipexole versus placebo 32% CI95% 21%; 43%, difference between pramipexole versus rotigotine 7%; CI95% - 2%; 17%). The mean reduction in "off" time was 2.5 hours in the rotigotine group, 2.8 hours in the pramipexole group and 0.9 hours in the placebo group. All differences between active treatments and placebo were statistically significant.
05.2 "Pharmacokinetic properties
Absorption:
After application, the transdermal patch constantly releases rotigotine, which is absorbed by the skin. steady-state are achieved one or two days after patch application and are maintained at a stable level with a single daily patch application for 24 hours. Rotigotine plasma concentrations show a dose-proportional increase in the ranges from 1 mg / 24 h to 24 mg / 24 h.
In 24 hours approximately 45% of the active ingredient contained in the patch is released. The absolute bioavailability after transdermal application is approximately 37%.
Rotation of the patch application site may result in daily differences in plasma levels. The differences in the bioavailability of rotigotine are between 2% (upper limb versus flank) and 46% (shoulder versus thigh). However, there are no indications of a relevant impact of these differences on clinical outcome.
Distribution:
In vitro, the plasma protein binding of rotigotine is approximately 92%.
The apparent volume of distribution in humans is approximately 84 l / kg.
Metabolism:
Rotigotine is extensively metabolised: metabolism occurs via N-dealkylation and direct and secondary conjugation. The results achieved in vitro indicate that different CYP isoforms are able to catalyze the N-dealkylation of rotigotine. The main metabolites are sulphates and glucuronides conjugated of the main product, as well as biologically inactive N-dealkylated metabolites.
Data on metabolites are incomplete.
Elimination:
About 71% of rotigotine is excreted in the urine and a minor part, corresponding to about 23%, is excreted in the faeces.
The clearance of rotigotine after transdermal administration is approximately 10 L / min and the elimination half-life is between 5 and 7 hours.
Since the drug is administered transdermally, no changes related to the presence of food or gastrointestinal disturbances are expected.
Special categories of patients:
Since Neupro therapy is initiated with a low dose, which is gradually increased according to clinical tolerability in order to achieve an optimal therapeutic result, there is no need to adjust the dose based on gender, weight or age.
No significant increases in rotigotine plasma levels were observed in patients with moderate hepatic impairment or mild to severe changes in renal function.
Neupro has not been studied in patients with severe hepatic impairment.
Plasma levels of conjugates of rotigotine and its dealkylated metabolites increase in the presence of impaired renal function. However, these metabolites are unlikely to contribute to clinical effects.
05.3 Preclinical safety data
In repeated dose and long-term toxicity studies, the main effects were associated with the pharmacodynamics of dopamine agonists and the consequent reduction in prolactin secretion.
Following a single administration of rotigotine, binding to melanin-containing tissues (e.g. eyes) was evident in pigmented rats and monkeys, but regressed slowly over the 14-day observation period.
In a 3-month study in albino rats, retinal degeneration was observed by transmission microscopy following administration of doses equivalent to 2.8 times the maximum recommended human dose, calculated in mg / m2. Effects they were more pronounced in female rats. No further studies were conducted to evaluate the specific pathology. In any of the toxicological studies conducted and in none of the animal species used, retinal degeneration was observed on routine histopathological examination of the eye. The clinical relevance of these data for humans is still unknown.
Tumors and Leydig cell hyperplasia were found in male rats in carcinogenicity studies. The appearance of malignant tumors was found predominantly in the uterus of females treated with medium and high doses. These alterations represent well-known effects of dopamine agonists in the rat following life-long treatment and are considered not relevant to humans. The effects of rotigotine on reproduction were studied in rats, rabbits and mice. Rotigotine was found to be non-teratogenic in all three species, but was embryotoxic in rats and mice following administration of toxic doses to pregnant females. In rats, rotigotine had no effect on male fertility, but it did induce a significant reduction in female fertility in rats and mice due to its effects on prolactin levels, which are particularly significant in rodents.
Rotigotine did not induce gene mutations in the Ames test, but showed effects in the Mouse Lymphoma Assay in mice. in vitro after metabolic activation and less marked effects without metabolic activation. This mutagenic effect has been attributed to a clastogenic effect of rotigotine. This effect has not been confirmed in vivo in the Mouse Micronucleus Test in the mouse and in the Unscheduled DNA Synthesis test (UDS) in the rat. Since it has broadly been shown to parallel a relative reduction in total cell growth, it may be related to a cytotoxic effect of the substance. Therefore, the significance of a single positive result in the mutagenic test in vitro it is not known.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Support layer:
Polyester film coated with silicone and aluminum, colored with a layer of pigment (titanium dioxide (E171), yellow pigment 95, pigment red 166) and bearing an inscription (pigment red 144, pigment yellow 95, pigment black 7).
Self-adhesive matrix:
Poly (dimethylsiloxane, trimethylsilyl silicate) copolymerized, Povidone K90, sodium metabisulfite (E223), ascorbyl palmitate (E304) and DL-α-tocopherol (E307).
Protective layer:
Polyester film coated with transparent fluoropolymer.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
18 months.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
06.5 Nature of the immediate packaging and contents of the package
Tear-off bag in cardboard box: one side consists of an ethylene copolymer (inner layer), an aluminum film, a low density polyethylene film and paper; the other side consists of polyethylene (inner layer), aluminum, ethylene copolymer and paper.
The treatment initiation pack contains 28 transdermal patches in 4 cartons containing 7 patches of 2 mg, 4 mg, 6 mg and 8 mg each, sealed in a single sachet.
06.6 Instructions for use and handling
After use, the patch still contains the active ingredient. After removal fold the patch in half, with the adhesive layer facing inwards, so as not to expose the matrix, then put it back in the original sachet and dispose of it away from the reach of children. children. Any used or unused patches should be disposed of in accordance with local requirements or returned to the pharmacy.
07.0 MARKETING AUTHORIZATION HOLDER
SCHWARZ PHARMA Ltd.
Shannon, Industrial Estate,
Co. Clare, Ireland
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/05/331/013 A.I.C. 037152131
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 15 February 2006
