英文药名: Neupro(Rotigotine Patch)

中文药名: 罗替戈汀透皮贴片

生产厂家: UCB Pharma Inc
药品介绍
Neupro贴剂用于治疗帕金森病和不宁腿综合征获FDA批准
2012年4月3日，UCB宣布美国食品药品管理局(FDA)已批准Neupro(罗替戈汀)用于治疗进展期特发性帕金森病(PD)的症状和体征，以及治疗中至重度原发性不宁腿综合征(RLS)。Neupro是一种多巴胺激动剂的透皮贴剂，据称可持续释放药物。
作为一种PD治疗药物，Neupro的作用机制与其对尾壳核内多巴胺受体的刺激作用有关，大脑尾壳核区域具有调节运动的功能。与此相似，对于RLS，Neupro可能也通过刺激多巴胺受体而发挥作用。但该药对PD和RLS的确切治疗机制尚不明确。
Neupro对PD症状和体征的疗效在5项平行分组、随机双盲、安慰剂对照试验中得到了确认。依据试验设计，患者服用Neupro的剂量每24 h增加 2 mg，在1周内滴定至随机剂量或最佳剂量。
在其中3项试验中，使用Neupro的早期PD患者与使用安慰剂者相比，统一帕金森病评级量表(UPDRS)的联合评分得到显著改善。UPDRS是一份用于评估心理、日常活动、运动能力和治疗并发症的多项评级量表。这3项试验仅评估了UPDRS的日常活动和运动能力部分。
2项在进展性PD患者中开展的试验评估了从基线到“关机时间”(药物疗效消退、PD症状复现之时)期间的改变。结果显示，使用Neupro的进展性PD患者在“关机时间”时的改变与使用安慰剂者相比有统计学差异。
Neupro对RLS的疗效，主要在2项固定剂量、随机双盲、安慰剂对照的6个月维持期试验中得到了检验。患者所使用的Neupro剂量为0.5~3 mg/24 h不等，每日给药1次。
使用Neupro的RLS患者与使用安慰剂者相比，国际RLS评级量表(IRLS Scale)总分和临床总体印象改善(CGI-I)评估结果有显著改善。IRLS Scale包含10项指标，用于评估感觉与运动症状、睡眠紊乱、日间困嗜睡及RLS对日常活动与情绪的影响的严重程度。CGI-I是一份7分制量表，用于临床评估RLS症状的进展情况。
在临床试验中，使用最大推荐剂量Neupro的PD患者报告的最常见不良反应为恶心、呕吐、嗜睡、给药部位反应、头晕、厌食、多汗和失眠。使用最大推荐剂量Neupro的RLS患者报告的最常见不良反应为给药部位反应、恶心、失眠和头痛。
Neupro含有焦亚硫酸钠，后者是一种亚硫酸盐，在某些易感患者中可能引起过敏反应，包括过敏性症状和危及生命或较不严重的哮喘发作。
在接受Neupro治疗的患者中已有失眠和日常活动中入睡的报告，其中部分并无极度疲倦之类的预兆。应建议患者在接受Neupro治疗期间谨慎地驾驶、操作重型机械或高空作业，并进行相应练习。在这些患者中还有出现幻觉的报告。接受Neupro治疗的进展期帕金森病患者的幻觉风险增加。
使用Neupro可能导致体位性低血压和晕厥(尤其是在剂量增加过程中)、心率加快、血压上升、体重增加和液体潴留。有心血管疾病的患者应慎用Neupro。
报告提示，在使用增加中枢多巴胺能神经紧张性的药物(包括Neupro)期间，患者可出现强烈的赌博、消费、暴饮暴食等冲动，性冲动增加，并且无法控制这些冲动。这些药物常被用于治疗PD。对于使用Neupro的患者应监控新发冲动或冲动加强，如果出现这类冲动，应考虑降低剂量或停用Neupro。
使用Neupro可能加强左旋多巴的多巴胺能副作用，并可能导致和(或)加重运动障碍。在评估Neupro最大推荐剂量的临床试验中，使用Neupro和安慰剂的进展期PD患者的运动障碍发生率相差7%，并且随着剂量增加，这一差异进一步加大。
Neupro 2mg/24h , 4mg/24h , 6mg/24h , 8mg/24h Transdermal patch-Parkinsons disease
1. Name of the medicinal product
Neupro 2 mg/24 h, 4 mg/24 h, 6 mg/24 h , 8 mg/24 h transdermal patch
2. Qualitative and quantitative composition
Neupro 2 mg/24 h transdermal patch
Each patch releases 2 mg of rotigotine per 24 hours. Each patch of 10 cm2 contains 4.5 mg of rotigotine.
Neupro 4 mg/24 h transdermal patch
Each patch releases 4 mg of rotigotine per 24 hours. Each patch of 20 cm2 contains 9.0 mg of rotigotine.
Neupro 6 mg/24 h transdermal patch
Each patch releases 6 mg of rotigotine per 24 hours. Each patch of 30 cm2 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.
3. Pharmaceutical form
Transdermal patch.
Thin, matrix-type, square-shaped with rounded edges, consisting of three layers. The outside of the backing layer is tan-coloured and imprinted with 'Neupro 2 mg/24 h, 4 mg/24 h, 6 mg/24 h or 8 mg/24 h'.
4. Clinical particulars
4.1 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, 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).
4.2 Posology and method of administration
Posology
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.
Dose
The dose recommendations made are in nominal dose.
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 maximum 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 maximum dose is 8 mg/24 h.
Dosing in patients with advanced stage Parkinson's disease with fluctuations:
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 maximum 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 mg/24 h 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.
Treatment discontinuation
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 populations
Patients with hepatic impairment: Adjustment of the dose is not necessary in patients with mild to moderate hepatic impairment. Caution is advised when treating patients with severe hepatic impairment, which may result in lower rotigotine clearance. Rotigotine has not been investigated in this patient group. A dose reduction might be needed in case of worsening of the hepatic impairment.
Patients with renal impairment: Adjustment of the dose is not necessary in patients with mild to severe renal impairment, including those requiring dialysis. Unexpected accumulation of rotigotine levels may also occur at acute worsening of renal function (see section 5.2).
Paediatric population
The safety and efficacy of rotigotine in the paediatric population have not yet been established. No data are available.
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)
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 release liner should be removed and the sticky side should be applied and pressed firmly to the skin. Then, the patch is fold back and the second part of the release 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 to 30 seconds, so that it sticks well.
In the event that a patch should fall off, 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 listed in section 6.1.
Magnetic resonance imaging or cardioversion (see section 4.4).
4.4 Special warnings and precautions for use
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)
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 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.
Syncope
Syncope has been observed in clinical trials with rotigotine, but at a rate that was similar to that observed in patients treated with placebo.
Sudden onset of sleep and somnolence
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.
Impulse control disorders
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.
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).
Abnormal thinking and behaviour
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.
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 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
Neuroleptics given as antiemetic should not be given to patients taking dopamine agonists (see also section 4.5).
Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
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, 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.
Peripheral oedema
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.
Dopaminergic adverse events
The incidence of some dopaminergic adverse events, 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.
Sulphite sensitivity
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.
4.5 Interaction with other medicinal products and other forms of interaction
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.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential, contraception in females
Women of childbearing potential should use effective contraception to prevent pregnancy during treatment with rotigotine.
Pregnancy
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.
Breast-feeding
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.
Fertility
For information on fertility studies, please see section 5.3.
4.7 Effects on ability to drive and 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 (see also sections 4.4 and 4.5).
4.8 Undesirable effects
Summary of the safety profile
Based on the analysis of pooled placebo-controlled clinical trials comprising a total of 1,307 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.
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.
Tabulated list of adverse reactions
The following table covers adverse drug reactions from the pooled studies mentioned above in patients with Parkinson's disease. 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.

System/organ classes acc. to MedDRA	Very common	Common	Uncommon	Rare
Immune system disorders			Hypersensitivity, which may include angioedema, tongue oedema and lip oedema
Psychiatric disorders		Perception disturbancesa (incl. hallucination, hallucination visual, hallucination auditory, illusion), insomnia, sleep disorder, nightmare, abnormal dreams, impulse-control disordersa (incl. pathological gambling, stereotypy/ punding, compulsive shoppingc)	Sleep attacks/sudden onset of sleep, paranoia, sexual desire disordersa (incl. hypersexuality, libido increased), confusional state, disorientation, agitation	Psychotic disorder, obsessive-compulsive disorder, aggressive behaviour/ aggressionb, binge eating/eating disorderb
Nervous system disorders	Somnolence, dizziness, headache	Disturbances in consciousness NECa (incl. syncope, syncope vasovagal, loss of consciousness), dyskinesia, dizziness postural, lethargy		Convulsion
Eye disorders			Vision blurred, visual impairment, photopsia
Ear and labyrinth disorders		Vertigo
Cardiac disorders		Palpitations	Atrial fibrillation	Supraventricular tachycardia
Vascular disorders		Orthostatic hypotension, hypertension	Hypotension
Respiratory, thoracic and mediastinal disorders		Hiccups
Gastrointestinal disorders	Nausea, vomiting	Constipation, dry mouth, dyspepsia	Abdominal pain
Skin and subcutaneous tissue disorders		Erythema, hyperhidrosis, pruritus	Pruritus generalised, skin irritation, dermatitis contact	Rash generalised
Reproductive system and breast disorder			Erectile dysfunction
General disorders and administration site conditions	Application and instillation site reactionsa (incl. erythema, pruritus, irritation, rash, dermatitis, vesicles, pain, eczema, inflammation, swelling, discolouration, papules, exfoliation, urticaria, hypersensitivity)	Oedema peripheral, asthenic conditionsa (incl. fatigue, asthenia, malaise)		Irritability
Investigations		Weight decreased,	Hepatic enzyme increased (incl. AST, ALT, GGT), weight increased, heart rate increased
Injury, poisoning and procedural complications		Fall

a High Level Term
b Observed in open-label studies
c Observed during post-marketing
Post-marketing experience: The post-marketing experience to date is consistent with the adverse reactions profile observed in the clinical trials.
Description of selected adverse reactions
Sudden onset of sleep and somnolence
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 section 4.4 and 4.7
Impulse control disorders
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 'Special warnings and precautions for use').
Reporting of suspected adverse reactions
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
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4.9 Overdose
Symptoms
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.
Management
There is no known antidote for overdose of dopamine agonists. In case of suspected overdose, removal of the patch(es) should be considered because after removal of the patch(es) the drug input is stopped and the plasma concentration of rotigotine decreases rapidly. The patient should be monitored closely, including heart rate, heart rhythm and blood pressure.
Treatment of overdose may require general supportive measures to maintain the vital signs. Dialysis would not be expected to be beneficial as rotigotine is not eliminated by dialysis.
If it is necessary to discontinue rotigotine, this should be done gradually to prevent neuroleptic malignant syndrome.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-parkinson drugs, dopamine agonists; ATC code: N04BC09
Rotigotine is a non-ergolinic dopamine agonist for the treatment of signs and symptoms of Parkinson's disease and Restless Legs Syndrome.
Mechanism of action
Rotigotine is believed to elicit its beneficial effect on Parkinson's disease by activation of the D3, D2 and D1 receptors of the caudate-putamen in the brain.
The precise mechanism of action of rotigotine as a treatment of RLS is unknown. It is thought that rotigotine may exert its activity mainly via dopamine receptors.
Pharmacodynamic effects
Regarding the functional activity at the various receptor subtypes and their distribution in the brain, rotigotine is a D2 and D3 receptor agonist acting also on D1, D4 and D5 receptors. With non-dopaminergic receptors, rotigotine showed antagonism at alpha2B and agonism at 5HT1A receptors, but no activity on the 5HT2B receptor.
Clinical efficacy and safety
The effectiveness of rotigotine 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, randomized, double-blind placebo controlled studies and three studies investigating specific aspects of Parkinson's disease.
Two pivotal trials (SP512 Part I and SP513 Part I) investigating the effectiveness of rotigotine 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).
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).
In the double blind study SP512 Part I, 177 patients received rotigotine and 96 patients received 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 6 mg/24 h. Patients in each treatment group were maintained at their optimal dose for 6 months.
At the end of the maintenance treatment in 91% of the subjects in the rotigotine arm, the optimal dose was the maximal dose allowed i.e. 6 mg/24 h. An improvement of 20% was seen in 48% of the subjects receiving rotigotine and in 19% of the subjects receiving placebo (Difference 29%, CI95% 18%; 39%, p<0.0001). With rotigotine, 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 was 5.28 points and statistically significant (p<0.0001).
In the double-blind study SP513 Part I, 213 patients received rotigotine, 227 received ropinirole and 117 patients received placebo. The patients were titrated to their optimal dose of rotigotine 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 rotigotine arm, the optimal dose was the maximal dose allowed i.e. 8 mg/24 h. An improvement of 20% was seen in 52% of the subjects receiving rotigotine, 68% of the subjects receiving ropinirole and 30% of the subjects receiving placebo (Difference rotigotine 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 rotigotine 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. This study failed to demonstrate non-inferiority of rotigotine to ropinirole.
In a subsequent open-label study (SP824), a multicenter, multinational study, the tolerability of overnight switching from ropinirole, pramipexole or cabergoline to rotigotine transdermal patch and its effect on symptoms in subjects with idiopathic Parkinson's disease have been studied. 116 patients were switched from previous oral therapy to receive up to 8 mg/24 h of rotigotine, among these were 47 who had been treated with ropinirole up to 9 mg/day, 47 who had been treated with pramipexole up to 2 mg/day and 22 who had been treated with cabergoline up to 3 mg/day. Switching to rotigotine was feasible, with minor dose adjustment (median 2 mg/24 h) being necessary in only 2 patients switching from ropinirole, 5 patients from pramipexole and 4 patients from cabergoline. Improvements were seen in UPDRS Parts I - IV scores. The safety profile was unchanged from that observed in previous studies.
In a randomized, open-label study (SP825) in patients with early stage Parkinson's disease, 25 patients were randomized to rotigotine treatment and 26 to ropinirole. In both arms treatment was titrated to optimal or maximum dose of 8 mg/24 h or 9 mg/day, respectively. Both treatments showed improvements in early morning motor function and sleep. Motor symptoms (UPDRS Part III) improved by 6.3 ± 1.3 points in rotigotine-treated patients, and by 5.9 ± 1.3 points in the ropinirole-group after 4 weeks of maintenance. Sleep (PDSS) improved by 4.1 ± 13.8 points for rotigotine-treated patients, and by 2.5 ± 13.5 points for ropinirole-treated patients. The safety profile was comparable, with the exception of application site reactions.
In studies SP824 and SP825 conducted since the initial comparative trial, rotigotine and ropinirole at equivalent doses were shown to have comparable efficacy.
Two additional pivotal trials (SP650DB and SP515) 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”.
In the double blind study SP650DB, 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 patients were titrated to their optimal doses of rotigotine 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 treatment an improvement of at least 30% was seen in 57% and 55% of the subjects receiving rotigotine 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 rotigotine groups). With rotigotine, 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 the double-blind study SP515, 201 patients received rotigotine, 200 received pramipexole and 100 patients received placebo. The patients were titrated to their optimal dose of rotigotine 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 rotigotine, 67% of the subjects receiving pramipexole and 35% of the subjects receiving placebo (Difference rotigotine 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 rotigotine 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.
A further multinational double-blind study (SP889) was conducted in 287 patients with early or advanced stages of Parkinson's disease who had unsatisfactory early morning motor symptom control. 81.5% of these patients were on concomitant levodopa therapy. 190 patients received rotigotine, and 97 placebo. The patients were titrated to their optimal dose of rotigotine or placebo in weekly increments of 2 mg/24 h starting at 2 mg/24 h to a maximum dose of 16 mg/24 h over 8 weeks, followed by a maintenance period of 4 weeks. Early morning motor function, assessed by UPDRS part III, and nocturnal sleep disturbances, measured by the modified Parkinson's Disease Sleep Scale (PDSS-2), were co-primary outcome measures. At the end of maintenance, the mean UPDRS part III score had improved by 7.0 points in rotigotine-treated patients (baseline 29.6), and by 3.9 points in the placebo-group (baseline 32.0). Improvements in the mean PDSS-2 total score were 5.9 (rotigotine, baseline 19.3) and 1.9 points (placebo, baseline 20.5). Treatment differences for the coprimary variables were statistically significant (p=0.0002 and p<0.0001).
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 concentrations increase 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 2% (upper arm versus flank) to 46% (shoulder versus thigh). However, there is no indication of a relevant impact on the clinical outcome.
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.
Biotransformation
Rotigotine is metabolised to a great extent. Rotigotine is 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-dealkylation of rotigotine. Main metabolites are sulfates and glucuronide conjugates of the parent compound as well as N-desalkyl-metabolites, which are biologically inactive.
The infomation on metabolites is incomplete.
Elimination
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 to 3 hours.
Because the patch is administered transdermally, no effect of food and gastrointestinal conditions is expected.
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.
Hepatic and renal impairment
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
In repeated dose and long-term toxicity studies, the major effects were associated with the dopamine agonist related pharmacodynamic effects and the consequent decrease of prolactin secretion.
After a single dose of rotigotine, binding to melanin-containing tissues (i.e., 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 at a dose equivalent to 2.8 times the maximum recommended human dose on a mg/m2 basis in a 3-month study in albino rats. The effects were more pronounced in female rats. 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.
In a carcinogenicity study, male rats developed Leydig cell tumours and hyperplasia. Malignant tumours were noted predominantly in the uterus of mid- and high-dose females. These changes are well-known effects of dopamine agonists in rats after life-long therapy and assessed as not relevant to man.
The effects of rotigotine on reproduction have been investigated in rats, rabbits and mice. Rotigotine was not teratogenic in all three species, but was embryotoxic in rats and mice at materno-toxic doses. Rotigotine did not influence male fertility in rats, but clearly reduced female fertility in rats and mice, because of the effects on prolactin levels which are particularly significant in rodents.
Rotigotine did not induce gene mutations in the Ames test, but did show effects in the in vitro Mouse Lymphoma Assay with metabolic activation and weaker effects without metabolic activation. This mutagenic effect could be attributed to a clastogenic effect of rotigotine. This effect was not confirmed in vivo in the Mouse Micronucleus Test in the rat Unscheduled DNA Synthesis (UDS) test. Since it ran more or less parallel with a decreased relative total growth of the cells, it may be related to a cytotoxic effect of the compound. Therefore, the relevance of the one positive in vitro mutagenicity test is not known.
6. Pharmaceutical particulars
6.1 List of excipients
Backing layer:
Polyester film, siliconized, aluminized,
colour coated with a pigment (titanium dioxide (E171), pigment yellow 95, pigment red 166) layer and imprinted (pigment red 144, pigment yellow 95, pigment black 7).
Self adhesive matrix layer:
Poly(dimethylsiloxane, trimethylsilyl silicate)-copolymerisate,
Povidone K90,
sodium metabisulphite (E223),
ascorbyl palmitate (E304) and
DL-α-tocopherol (E307).
Release liner:
Transparent fluoropolymer coated polyester film.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Peel off sachet in a cardboard carton: One side is composed of an ethylene copolymer (innermost layer), an aluminium foil, low density polyethylene film and paper; the other side is composed of polyethylene (innermost layer), aluminium, ethylene copolymer and paper.
The carton contains 7, 20, 28, 30, 56, 60, 84 (multipack containing 2 packs of 42), 90 or 100 (multipack containing 2 packs of 50) transdermal patches, individually sealed in sachets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
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.
7. Marketing authorisation holder
UCB Manufacturing Ireland Ltd.
Shannon, Industrial Estate,
Co. Clare, Ireland
8. Marketing authorisation number(s)
EU/1/05/331/001 - 003
EU/1/05/331/014 - 019
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 15 February 2006
Date of latest renewal: 17 February 2011
10. Date of revision of the text
24/02/2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
----------------------------------------------------
产地国家: 美国
原产地英文商品名:
Neupro 3 MG 24HR PATCH 30 Patches
原产地英文药品名:
Rotigotine
中文参考商品译名:
Neupro 24小时贴 3毫克 30贴
中文参考药品译名:
Rotigotine
生产厂家中文参考译名:
UCB INC
生产厂家英文名:

UCB INC
----------------------------------------------------
产地国家: 美国
原产地英文商品名:
Neupro 1MG 24HR PATCH 30 Patches
原产地英文药品名:
Rotigotine
中文参考商品译名:
Neupro 24小时贴 1毫克 30贴
中文参考药品译名:
Rotigotine
生产厂家中文参考译名:
UCB INC
生产厂家英文名:

UCB INC  
----------------------------------------------------------
产地国家: 欧洲共同体国家
原产地英文商品名:
Neupro tts 8mg 24h 28transdermal patches
原产地英文药品名:
Rotigotine
中文参考商品译名:
Neupro贴 8毫克 28贴
中文参考药品译名:
Rotigotine
生产厂家中文参考译名:
SCHWARZ PHARMA LTD
生产厂家英文名:
SCHWARZ PHARMA LTD
----------------------------------------------------------
产地国家: 欧洲共同体国家
原产地英文商品名:
Neupro tts 2mg 24h 7transdermal patches
原产地英文药品名:
Rotigotine
中文参考商品译名:
Neupro贴 2毫克 7贴
中文参考药品译名:
Rotigotine
生产厂家中文参考译名:
SCHWARZ PHARMA LTD
生产厂家英文名:
SCHWARZ PHARMA LTD