Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: UCB Pharma S.A., Allée de la Recherche 60, B-1070, Bruxelles, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Magnetic resonance imaging or cardioversion (see section 4.4).
If a Parkinson’s disease patient is insufficiently controlled while on treatment with rotigotine switching to another dopamine agonist might provide additional benefit (see section 5.1)
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 have also been observed during treatment with rotigotine, but the incidence was similar to that observed 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.
In clinical studies with rotigotine, syncope has been observed at a rate that was similar to that observed in patients treated with placebo. Because patients with clinically relevant cardiovascular disease were excluded in these studies, patients with severe cardiovascular disease should be asked about symptoms of syncope and pre-syncope.
Rotigotine has been associated with somnolence and episodes of sudden sleep onset. 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.
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathologic gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists, including rotigotine. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
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).
Abnormal thinking and behaviour have been reported and can consist of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behaviour, disorientation, aggressive behaviour, agitation, and delirium.
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when treatment is discontinued, complete resolution does not always occur.
Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
Neuroleptics given as antiemetic should not be given to patients taking dopamine agonists (see also section 4.5).
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, as 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.
In clinical studies in Parkinson’s patients, the 6 month-specific rates of peripheral oedema remained at about 4% through the entire observation period up to 36 months. Peripheral oedema has also been observed in clinical trials conducted in patients with RLS.
Neupro contains sodium metabisulphite, a sulphite that may cause allergic-type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people.
The incidence of some dopaminergic adverse reactions, such as hallucinations, dyskinesia, and peripheral oedema generally is higher when given in combination with L-dopa in Parkinson’s patients.
This should be considered when prescribing rotigotine.
Augmentation may occur in Restless Legs Syndrome patients. 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. In long-term clinical studies with rotigotine, the majority of augmentation episodes were seen in the first and second years of treatment. Doses higher than the approved dose range for RLS should be avoided as this may lead to higher rates of augmentation (see section 5.1).
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 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 (inhibitor of CYP2C19), in doses of 40 mg/day, had no effect on the pharmacokinetics and metabolism of rotigotine in healthy volunteers.
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.
Co-administration 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.
Women of childbearing potential should use effective contraception to prevent pregnancy during treatment with rotigotine.
There are no adequate data from the use of rotigotine 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 (see section 5.3). 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) are excreted in breast milk. In the absence of human data, breast-feeding should be discontinued.
For information on fertility studies, please see section 5.3.
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 (see also sections 4.4 and 4.5).
Based on the analysis of pooled placebo-controlled clinical trials comprising a total of 748 Neupro- and 214 placebo-treated patients, 65.5% of the patients on Neupro and 33.2% of patients on placebo reported at least one adverse reaction.
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 are nausea, application site reactions, asthenic conditions and headache.
In trials where the application sites were rotated as reflected in the instructions provided in the SmPC and package leaflet, 34.2% of 748 patients using Neupro, experienced application site reactions. The majority of application site reactions were mild or moderate in intensity, limited to the application areas and resulted in discontinuation of Neupro in 7.2% of subjects.
The discontinuation rate was studied in 3 clinical trials ranging up to 3 years in duration. The percentage of subjects discontinuing was 25-38% over the first year, 10% in the second year, and 11% in the third year. Periodic assessment of efficacy should be performed, along with evaluation of safety, including augmentation.
The following table covers adverse drug reactions from the pooled studies mentioned above in patients with Restless Legs Syndrome and from post-marketing experience. Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Common: Hypersensitivity, which may include angioedema, tongue oedema and lip oedema
Common: Sleep attacks/sudden onset of sleep, sexual desire disordersa (incl. hypersexuality, libido increased), insomnia, sleep disorder, abnormal dreams, impulse-control disordersa,d (incl. pathological gambling, stereotypy/punding, binge eating/eating disorderb, compulsive shoppingc)
Uncommon: Obsessive-compulsive disorder, agitationd
Rare: Aggressive behaviour/aggressionb, disorientationd
Not known: Dopamine dysregulation syndromec, perception disturbancese (incl. hallucination, hallucination visual, hallucination auditory, illusion), nightmaree, paranoiae, confusional statee, psychotic disordere, delusione, deliriume
Very common: Headache
Common: Somnolence
Not known: Dizzinesse, disturbances in consciousness NECe (incl. syncope, syncope vasovagal, loss of consciousness), dyskinesiae, dizziness posturale, lethargye, convulsione
Not known: Vision blurrede, visual impairmente, photopsiae
Not known: Vertigoe
Not known: Palpitationse, atrial fibrillatione, supraventricular tachycardiae
Common: Hypertension
Uncommon: Orthostatic hypotension
Not known: Hypotensione
Not known: Hiccupse
Very common: Nausea
Common: Vomiting, dyspepsia
Not known: Constipatione, dry mouthe, abdominal paine, diarrhoeac
Common: Pruritus
Not known: Erythemae, hyperhidrosise, pruritus generalisede, skin irritatione, dermatitis contacte, rash generalisede
Not known: Erectile dysfunctione
Very common: Application and instillation site reactionsa (incl. erythema, pruritus, irritation, rash, dermatitis, vesicles, pain, eczema, inflammation, swelling, discolouration, papules, exfoliation, urticaria, hypersensitivity), asthenic conditionsa (incl. fatigue, asthenia, malaise)
Common: Irritability, oedema peripheral
Not known: Weight decreasede, hepatic enzyme increasede (incl. AST, ALT, GGT), weight increasede, heart rate increasede, CPK increasedd,e (see Special populations)
Not known: Falle
a High Level Term
b Observed in open-label studies
c Observed during post-marketing
d Observed in 2011 data pool of double-blind placebo-controlled studies
e Observed in studies performed in patients with Parkinson’s disease Parkinson’s disease
Based on the analysis of pooled placebo-controlled clinical trials comprising a total of 1,307 Neuproand 607 placebo-treated patients, 72.5% of the patients on Neupro and 58.0% of patients on placebo reported at least one adverse reaction.
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.
In trials where the application sites were rotated as reflected in the instructions provided in SmPC and package leaflet, 35.7% of 830 patients using the Neupro transdermal patch, experienced application site reactions. The majority of application site 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.
The following table covers adverse drug reactions from the pooled studies mentioned above in patients with Parkinson’s disease and from post-marketing experience. Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Uncommon: Hypersensitivity, which may include angioedema, tongue oedema and lip oedema
Common: Perception disturbancesa (incl. hallucination, hallucination visual, hallucination auditory, illusion), insomnia, sleep disorder, nightmare, abnormal dreams, impulsecontrol disordersa,d (incl. pathological gambling, stereotypy/punding, binge eating/eating disorderb, compulsive shoppingc)
Uncommon: Sleep attacks/sudden onset of sleep, paranoia, sexual desire disordersa (incl. hypersexuality, libido increased), confusional state, disorientationd, agitationd
Rare: Psychotic disorder, obsessivecompulsive disorder, aggressive behaviour/aggressionb, delusiond, deliriumd
Not known: Dopamine dysregulation syndromec
Very common: Somnolence, dizziness, headache
Common: Disturbances in consciousness NECa (incl. syncope, syncope vasovagal, loss of consciousness), dyskinesia, dizziness postural, lethargy
Rare: Convulsion
Not known: Dropped head syndromec,e
Uncommon: Vision blurred, visual impairment, photopsia
Common: Vertigo
Common: Palpitations
Uncommon: Atrial fibrillation
Rare: Supraventricular tachycardia
Common: Orthostatic hypotension, hypertension
Uncommon: Hypotension
Common: Hiccups
Very common: Nausea, vomiting
Common: Constipation, dry mouth, dyspepsia
Uncommon: Abdominal pain
Not known: Diarrhoeac
Common: Erythema, hyperhidrosis, pruritus
Uncommon: Pruritus generalised, skin irritation, dermatitis contact
Rare: Rash generalised
Uncommon: Erectile dysfunction
Very common: Application and instillation site reactionsa (incl. erythema, pruritus, irritation, rash, dermatitis, vesicles, pain, eczema, inflammation, swelling, discolouration, papules, exfoliation, urticaria, hypersensitivity)
Common: Oedema peripheral, asthenic conditionsa (incl. fatigue, asthenia, malaise)
Rare: Irritability
Common: Weight decreased
Uncommon: Hepatic enzyme increased (incl. AST, ALT, GGT), weight increased, heart rate increased, CPK increasedd (see Special populations)
Common: Fall
a High Level Term
b Observed in open-label studies
c Observed during post-marketing
d^ ^Observed in 2011 data pool of double-blind placebo-controlled studies
e Only observed in Parkinson’s disease patients
Rotigotine has been associated with somnolence including excessive daytime somnolence and sudden sleep onset episodes. In isolated cases “sudden onset of sleep” occurred while driving and resulted in motor vehicle accidents (see also sections 4.4 and 4.7).
Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists, including rotigotine (see section 4.4).
Adverse reactions of increased creatine phosphokinase (CPK) were observed with rotigotine in clinical studies conducted in Japan. These occurred in 3.4% of Japanese subjects on rotigotine compared to 1.9% on placebo in double-blind Parkinson’s disease and RLS studies. The majority of the adverse reactions of increased CPK observed in all double-blind and open-label studies resolved and were considered mild in severity. CPK levels have not been routinely measured in other populations.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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