英文药名：Xadago（safinamide filmcoated tablets）

中文药名：沙非酰胺（甲沙非酰胺薄膜包衣片）

生产厂家：赞邦制药
药品介绍
2016年5月27日，意大利赞邦集团（Zambon）和Newron制药公司开发的帕金森新特药物Xadago (safinamide)在英国上市。
Xadago是一种新型单胺氧化酶B(MAO-B)选择性抑制剂，通过阻断神经元上电压依赖式钠离子通道，进而调控谷氨酸释放。推荐与左旋多巴或者其他帕金森药物合用，用于特发性帕金森病中晚期治疗。
多项临床试验表明，Xadago可在短期内有效控制帕金森患者运动障碍和运动失调症状，疗效可维持2年。一项为期6个月的双盲对照试验结果显示，Xadago可显著性减少帕金森患者运动症状波动(on-off 时间)，并降低相关运动障碍发生风险。
目前，Xadago已相继获得8个欧洲国家的上市授权，分别为：德国、瑞士、西班牙、意大利、比利时、丹麦、瑞典和英国，为欧洲众多帕金森患者带来了更多的临床治疗选择。
包装规格[注：以下包装产品在英国、德国]
50mg×30st
50mg×100st
100mg×30st
100mg ×100st

Xadago 50mg and 100mg film-coated tablets
1. Name of the medicinal product
Xadago 50 mg film-coated tablets
Xadago 100 mg film-coated tablets
2. Qualitative and quantitative composition
Each film-coated tablet contains safinamide methansulfonate equivalent to 100 mg safinamide.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet)
Orange to copper, round, biconcave, film-coated tablet of 9 mm diameter with metallic gloss, embossed with the strength “100” on one side of the tablet.
4. Clinical particulars
4.1 Therapeutic indications
Xadago is indicated for the treatment of adult patients with idiopathic Parkinson's disease (PD) as add-on therapy to a stable dose of Levodopa (L-dopa) alone or in combination with other PD medicinal products in mid-to late-stage fluctuating patients.
4.2 Posology and method of administration
Posology
Treatment with Xadago should be started at 50 mg per day. This daily dose may be increased to 100 mg/day on the basis of individual clinical need.
If a dose is missed the next dose should be taken at the usual time the next day.
Elderly
No change in dose is required for elderly patients.
Experience of use of safinamide in patients over 75 years of age is limited.
Hepatic impairment
Xadago use in patients with severe hepatic impairment is contraindicated (see section 4.3). No dose adjustment is required in patients with mild hepatic impairment. The lower dose of 50 mg/day is recommended for patients with moderate hepatic impairment. If patients progress from moderate to severe hepatic impairment Xadago should be stopped (see section 4.4).
Renal impairment
No change in dose is required for patients with renal impairment.
Paediatric population
The safety and efficacy of safinamide in children and adolescents under 18 years of age have not been established. No data are available.
Method of administration
For oral use.
Xadago should be taken with water.
Xadago may be taken with or without food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Concomitant treatment with other monoamine oxidase (MAO) inhibitors (see sections 4.4 and 4.5).
Concomitant treatment with pethidine (see sections 4.4 and 4.5).
Use in patients with severe hepatic impairment (see section 4.2).
Use in patients with albinism, retinal degeneration, uveitis, inherited retinopathy or severe progressive diabetic retinopathy (see sections 4.4 and 5.3).
4.4 Special warnings and precautions for use
General warning
In general, Xadago may be used with selective serotonin re-uptake inhibitors (SSRIs) at the lowest effective dose, with caution for serotoninergic symptoms. In particular, the concomitant use of Xadago and fluoxetine or fluvoxamine should be avoided, or if concomitant treatment is necessary these medicinal products should be used at low doses (see section 4.5). A washout period corresponding to 5 half-lives of the SSRI used previously should be considered prior to initiating treatment with Xadago.
At least 7 days must elapse between discontinuation of Xadago and initiation of treatment with MAO inhibitors or pethidine (see section 4.3 and 4.5).
Hepatic impairment
Caution should be exercised when initiating treatment with Xadago in patients with moderate hepatic impairment. In case patients progress from moderate to severe hepatic impairment, treatment with Xadago should be stopped (see section 4.2, 4.3 and 5.2).
Potential for retinal degeneration in patients with presence/prior history of retinal disease
Xadago should not be administered to patients with ophthalmological history that would put them at increased risk for potential retinal effects (e.g., albino patients, family history of hereditary retinal disease, retinitis pigmentosa, any active retinopathy, or uveitis) see section 4.3 and 5.3.
Impulse control disorders (ICDs)
Impulse control disorders can occur in patients treated with dopamine agonists and/or dopaminergic treatments. Some reports of ICDs have also been observed with other MAO-inhibitors. Safinamide treatment has not been associated with any increase in the appearance of ICDs.
Patients and carers should be made aware of the behavioural symptoms of ICDs that were observed in patients treated with MAO-inhibitors, including cases of compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behaviour and compulsive spending or buying.
Dopaminergic side effects
Safinamide used as an adjunct to levodopa may potentiate the side effects of levodopa, and pre-existing dyskinesia may be exacerbated, requiring a decrease of levodopa. This effect was not seen when safinamide was used as an adjunct to dopamine agonists in early stage PD patients.
4.5 Interaction with other medicinal products and other forms of interaction
In vivo and in vitro pharmacodynamic drug interactions
MAO inhibitors and pethidine
Xadago must not be administered along with other MAO inhibitors (including moclobemide) as there may be a risk of non-selective MAO inhibition that may lead to a hypertensive crisis (see section 4.3).
Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors. As this may be a class-effect, the concomitant administration of Xadago and pethidine is contraindicated (see section 4.3).
There have been reports of medicinal product interactions with the concomitant use of MAO inhibitors and sympathomimetic medicinal products. In view of the MAO inhibitory activity of safinamide, concomitant administration of Xadago and sympathomimetics, such as those present in nasal and oral decongestants or cold medicinal products containing ephedrine or pseudoephedrine, requires caution (see section 4.4).
Dextromethorphan
There have been reports of medicinal product interactions with the concomitant use of dextromethorphan and non-selective MAO inhibitors. In view of the MAO inhibitory activity of safinamide, the concomitant administration of Xadago and dextromethorphan is not recommended, or if concomitant treatment is necessary, it should be used with caution (see section 4.4).
Antidepressants
The concomitant use of Xadago and fluoxetine or fluvoxamine should be avoided (see section 4.4), this precaution is based on the occurrence of serious adverse reactions (e.g. serotonin syndrome), although rare, that have occurred when SSRIs and dextromethorphan have been used with MAO inhibitors. If necessary, the concomitant use of these medicinal products should be at the lowest effective dose. A washout period corresponding to 5 half-lives of the SSRI used previously should be considered prior to initiating treatment with Xadago.
Serious adverse reactions have been reported with the concomitant use of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic/tetracyclic antidepressants and MAO inhibitors (see section 4.4). In view of the selective and reversible MAO-B inhibitory activity of safinamide, antidepressants may be administered but used at the lowest doses necessary.
Tyramine/safinamide interaction
Results of one intravenous and two short term oral tyramine challenge studies, as well as results of home monitoring of blood pressure after meals during chronic dosing in two therapeutic trials in PD patients, did not detect any clinically important increase in blood pressure. Three therapeutic studies performed in PD patients without any tyramine restriction, also did not detect any evidence of tyramine potentiation. Xadago can, therefore, be used safely without any dietary tyramine restrictions.
In vivo and in vitro pharmacokinetic drug interactions
There was no effect on the clearance of safinamide in patients with PD receiving safinamide as adjunct to chronic L-dopa and/or DA-agonists and safinamide treatment did not change the pharmacokinetic profile of co-administered L-dopa.
In an in vivo drug-drug interaction study performed with ketoconazole, there was no clinically relevant effect on the levels of safinamide. Human studies evaluating the interaction of safinamide with CYP1A2 and CYP3A4 substrates (caffeine and midazolam), did not demonstrate any clinically significant effects on the pharmacokinetic profile of safinamide. This is in line with the results of the in vitro tests in which no meaningful CYP induction or inhibition by safinamide was observed and it was shown that CYP enzymes play a minor role in the biotransformation of safinamide (see section 5.2)
Safinamide may transiently inhibit BCRP in vitro. However, in a drug-drug-interaction study with diclofenac in humans no significant interactions were observed. Therefore, no precautions are necessary when safinamide is taken with medicinal products that are BCRP substrates (e.g., pitavastatin, pravastatin, ciprofloxacin, methotrexate, topotecan, diclofenac or glyburide).
Safinamide is almost exclusively eliminated via metabolism, largely by high capacity amidases that have not yet been characterized. Safinamide is eliminated mainly in the urine. In human liver microsomes (HLM), the N-dealkylation step appears to be catalysed by CYP3A4, as safinamide clearance in HLM was inhibited by ketoconazole by 90%. There are currently no marketed medicinal products known to cause clinically significant drug-drug interactions through inhibition or induction of amidase enzymes.
The metabolite NW-1153 is a substrate for OAT3 at clinically relevant concentrations.
Medicinal products that are inhibitors of OAT3 given concomitantly with safinamide may reduce clearance of NW-1153, i.e., and thus may increase its systemic exposure. The systemic exposure of NW-1153 is low (1/10 of parent safinamide). This potential increase is most likely of no clinical relevance as NW-1153, the first product in the metabolic pathway, is further transformed to secondary and tertiary metabolites.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Xadago should not be given to women of childbearing potential unless adequate contraception is practiced.
Pregnancy
No clinical data for safinamide on exposed pregnancies is available. Animal studies have shown adverse reactions when exposed to safinamide during pregnancy or lactation (see section 5.3). Women of childbearing potential should be advised not to become pregnant during safinamide therapy. Xadago should not be given during pregnancy.
Breast-feeding
Safinamide is expected to be excreted in milk as adverse reactions have been observed in rat pups exposed via milk (see section 5.3). A risk for the breast-fed child cannot be excluded. Xadago should not be given to breast-feeding women.
Fertility
Animal studies indicate that safinamide treatment is associated with adverse reactions on female rat reproductive performance and sperm quality. Male rat fertility is not affected (see section 5.3).
4.7 Effects on ability to drive and use machines
Xadago has no or negligible influence on the ability to drive and use machines, however, patients should be cautioned about using hazardous machines, including motor vehicles, until they are reasonably certain that Xadago does not affect them adversely.
4.8 Undesirable effects
Summary of the safety profile
The overall safety profile of Xadago is based on the clinical development program performed in over 3000 subjects, of whom over 500 were treated for more than 2 years
Serious adverse reactions are known to occur with the concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors, such as hypertensive crisis (high blood pressure, collapse), neuroleptic malignant syndrome (confusion, sweating, muscle rigidity, hyperthermia, CPK increase), serotonin syndrome (confusion, hypertension, muscle stiffness, hallucinations), and hypotension. With MAO-inhibitors there have been reports of drug interactions with concomitant use of sympathomimetic medicinal products.
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 and/or other dopaminergic treatments.
Tabulated list of adverse reactions
The tabulation below includes all adverse reactions in clinical trials where adverse events were considered related.
Adverse reactions are ranked under headings of frequency using the following conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

System Organ Class	Very common	Common	Uncommon	Rare
Infections and infestations			Urinary tract infection	Bronchopneumonia, furuncle, nasopharyngitis, pyoderma, rhinitis, tooth infection, viral infection
Neoplasms benign, malignant and unspecified (incl cysts and polyps)			Basal cell carcinoma	Acrochordon, melanocytic naevus, seborrhoeic keratosis, skin papilloma
Blood and lymphatic system disorders			Anaemia, leukopenia, red blood cell abnormality	Eosinophilia, lymphopenia
Metabolism and nutrition disorders			Decreased appetite, hypertriglyceridaemia, increased appetite, hypercholesterolaemia, hyperglycaemia,	Cachexia, hyperkalaemia
Psychiatric disorders		Insomnia	Hallucination, depression, abnormal dreams, anxiety, confusional state, affect lability, libido increased, psychotic disorder, restlessness, sleep disorder	Compulsions, delirium, disorientation, illusion, impulsive behaviour, loss of libido, obsessive thoughts, paranoia, premature ejaculation, sleep attacks, social phobia, suicidal ideation
Nervous system disorders		Dyskinesia somnolence, dizziness, headache, Parkinson's disease	Paraesthesia, balance disorder, hypoaesthesia, dystonia, head discomfort, dysarthria, syncope, cognitive disorder	Coordination abnormal, disturbance in attention, dysgeusia, hyporeflexia, radicular pain, Restless Legs Syndrome, sedation
Eye disorders		Cataract	Vision blurred, scotoma, diplopia, photophobia, retinal disorder, conjunctivitis, glaucoma	Amblyopia, chromatopsia, diabetic retinopathy, erythropsia, eye haemorrhage, eye pain, eyelid oedema, hypermetropia, keratitis, lacrimation increased, night blindness, papilloedema, presbyopia, strabismus
Ear and labyrinth disorders			Vertigo
Cardiac disorders			Palpitations, tachycardia, sinus bradycardia, arrhythmia	Myocardial infarction
Vascular disorders		Orthostatic hypotension	Hypertension, hypotension, varicose vein	Arterial spasm, arteriosclerosis, hypertensive crisis
Respiratory, thoracic and mediastinal disorders			Cough, dyspnoea, rhinorrhoea	Bronchospasm, dysphonia, oropharyngeal pain, oropharyngeal spasm
Gastrointestinal disorders		Nausea	Constipation, dyspepsia, vomiting, dry mouth, diarrhoea, abdominal pain, gastritis, flatulence, abdominal distension, salivary hypersecretion, gastrooesophageal reflux disease, aphthous stomatitis	Peptic ulcer, retching, upper gastrointestinal haemorrhage
Hepatobiliary disorders				Hyperbilirubinaemia
Skin and subcutaneous tissue disorders			Hyperhidrosis, pruritus generalised, photosensitivity reaction, erythema	Alopecia, blister, dermatitis contact, dermatosis, ecchymosis, lichenoid keratosis, night sweats, pain of skin, pigmentation disorder, psoriasis, seborrhoeic dermatitis
Musculoskeletal and connective tissue disorders			Back pain, arthralgia, muscle spasms, muscle rigidity, pain in extremity, muscular weakness, sensation of heaviness	Ankylosing spondylitis, flank pain, joint swelling, musculoskeletal pain, myalgia, neck pain, osteoarthritis, synovial cyst
Renal and urinary disorders			Nocturia, dysuria	Micturition urgency, polyuria, pyuria, urinary hesitation
Reproductive system and breast disorders			Erectile dysfunction	Benign prostatic hyperplasia, breast disorder, breast pain
General disorders and administration site conditions			Fatigue, asthenia, gait disturbance, oedema peripheral, pain, feeling hot	Drug effect decreased, drug intolerance, feeling cold, malaise, pyrexia, xerosis
Investigations			Weight decreased, weight increased, blood creatine phosphokinase increased, blood triglycerides increased, blood glucose increased, blood urea increased, blood alkaline phosphatase increased, blood bicarbonate increased, blood creatinine increased, electrocardiogram QT prolonged, liver function test abnormal, urine analysis abnormal, blood pressure increased, blood pressure decreased, ophthalmic diagnostic procedures abnormal	Blood calcium decreased, blood potassium decreased, blood cholesterol decreased, body temperature increased, cardiac murmur, cardiac stress test abnormal, haematocrit decreased, haemoglobin decreased, international normalised ratio decreased, lymphocyte count decreased, platelet count decreased, very low density lipoprotein increased
Injury, poisoning and procedural complications		Fall	Foot fracture	Contusion, fat embolism, head injury, mouth injury, skeletal injury
Social circumstances				Gambling

Description of selected Adverse Drug Reactions (ADRs)
Dyskinesia was the most common adverse reaction reported in safinamide patients when used in combination with L-dopa alone or in combination with other PD treatments. Dyskinesia occurred early in treatment, was rated “severe”, led to discontinuation in very few patients (approx. 1.5%), and did not require reduction of dose in any patient.
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: Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
In one patient suspected of consuming more than the daily prescribed dose of 100 mg for one month, symptoms of confusion, sleepiness, forgetfulness and dilated pupils were reported. These symptoms resolved on discontinuing the medicinal product, without sequelae.
The expected pattern of events or symptoms following intentional or accidental overdose with Xadago would be those related to its pharmacodynamic profile: MAO-B inhibition with activity-dependent inhibition of Na+ channels. The symptoms of an excessive MAO-B inhibition (increase in dopamine level) could include hypertension, postural hypotension, hallucinations, agitation, nausea, vomiting, and dyskinesia.
There is no known antidote to safinamide or any specific treatment for safinamide overdose. If an important overdose occurs, Xadago treatment should be discontinued and supportive treatment should be administered as clinically indicated.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: {Not yet assigned}, ATC code: {Not yet assigned}.
Mechanism of action
Safinamide acts through both dopaminergic and non-dopaminergic mechanisms of action. Safinamide is a highly selective and reversible MAO-B inhibitor causing an increase in extracellular levels of dopamine in the striatum. Safinamide is associated with state-dependent inhibition of voltage-gated sodium (Na+) channels, and modulation of stimulated release of glutamate. To what extent the non-dopaminergic effects contribute to the overall effect has not been established.
Pharmacodynamic effects
Population PK models developed from studies in patients with Parkinson's disease indicate that the pharmacokinetic and pharmacodynamics effects of safinamide were not dependent on age, gender, weight, renal function and exposure to levodopa, indicating that dose adjustments will not be required based on these variables.
Pooled analyses of adverse event data from placebo controlled studies in Parkinson's disease patients indicate that the concomitant administration of safinamide together with a broad category of commonly used medicinal products in this patient population (antihypertensive, beta-blockers cholesterol lowering, non-steroidal anti-inflammatory medicinal products, proton pump inhibitors, antidepressants, etc.) was not associated with an increased risk for adverse events. Studies were not stratified for co-medication, and no randomized interaction studies were performed for these medicinal products.
Clinical efficacy
Studies in mid- to late-stage PD patients
The efficacy of Xadago as add-on treatment in mid-to late-stage PD (LSPD) patients with motor fluctuations, currently receiving L-dopa alone or in combination with other PD medications, was evaluated in two double-blind, placebo-controlled studies: Study SETTLE (Study 27919; 50-100 mg/day; 24 weeks), and Study 016/018 (50 and 100 mg/day; 2-year, double-blind, placebo-controlled study).
The primary efficacy parameter was the change from baseline to endpoint in 'ON Time without troublesome dyskinesia'.
Secondary efficacy parameters included OFF Time, UPDRS II and III (Unified Parkinson's Disease Rating Scale – sections II and III), and CGI-C (Clinical Global Impression of Change)
Both the SETTLE and 016/018 studies indicated significant superiority of safinamide, compared to placebo, at the target doses of 50 and 100 mg/day for the primary, and selected secondary, efficacy variables, as summarized in the table below. The effect on ON Time was maintained at the end of the 24-month double-blind treatment period for both safinamide doses as compared to placebo.

Study	016 (24 weeks)			016/018 (2 years)			27919 (SETTLE) (24 weeks)
Dose (mg/day) (a)	Placebo	Safinamide		Placebo	Safinamide		Placebo	Safin-amide
		50	100		50	100		50-100 (d)
Randomized	222	223	224	222	223	224	275	274
Age (years) (b)	59.4 (9.5)	60.1 (9.7)	60.1 (9.2)	59.4 (9.5)	60.1 (9.7)	60.1 (9.2)	62.1 (9.0)	61.7 (9.0)
PD Duration (years) (b)	8.4 (3.8)	7.9 (3.9)	8.2 (3.8)	8.4 (3.8)	7.9 (3.9)	8.2 (3.8)	9.0 (4.9)	8.9 (4.4)
ON time without troublesome dyskinesia (hrs) (c)
Baseline (b)	9.3 (2.2)	9.4 (2.2)	9.6 (2.5)	9.3 (2.2)	9.4 (2.2)	9.6 (2.5)	9.1 (2.5)	9.3 (2.4)
Change LSM (SE)	0.5 (0.2)	1.0 (0.2)	1.2 (0.2)	0.8 (0.2)	1.4 (0.2)	1.5 (0.2)	0.6 (0.1)	1.4 (0.1)
LS Diff vs Placebo		0.5	0.7		0.6	0.7		0.9
95% CI		[0.1, 0.9]	[0.3, 1.0]		[0.1, 1.0]	[0.2, 1.1]		[0.6, 1.2]
p-value		0.0054	0.0002		0.0110	0.0028		<0.0001
OFF time (hrs) (c)
Baseline (b)	5.3 (2.1)	5.2 (2.0)	5.2 (2.2)	5.3 (2.1)	5.2 (2.2)	5.2 (2.1)	5.4 (2.0)	5.3 (2.0)
Change LSM (SE)	-0.8 (0.20)	-1.4 (0.20)	-1.5 (0.20)	-1.0 (0.20)	-1.5 (0.19)	-1.6 (0.19)	-0.5 (0.10)	-1.5 (0.10)
LS Diff vs Placebo		-0.6	-0.7		-0.5	-0.6		-1.0
95% CI		[-0.9, -0.3]	[-1.0, -0.4]		[-0.8, -0.2]	[-0.9, -0.3]		[-1.3, -0.7]
p-value		0.0002	<0.0001		0.0028	0.0003		<0.0001
UPDRS III (c)
Baseline (b)	28.6 (12.0)	27.3 (12.8)	28.4 (13.5)	28.6 (12.0)	27.3 (12.8)	28.4 (13.5)	23.0 (12.8)	22.3 (11.8)
Change LSM (SE)	-4.5 (0.83)	-6.1 (0.82)	-6.8 (0.82)	-4.4 (0.85)	-5.6 (0.84)	-6.5 (0.84)	-2.6 (0.34)	-3.5 (0.34)
LS Diff vs Placebo		-1.6	-2.3		-1.2	-2.1		-0.9
95% CI		[-3.0, -0.2]	[-3.7, -0.9]		[-2.6, 0.2]	[-3.5, -0.6]		[-1.8, 0.0]
p-value		0.0207	0.0010		0.0939	0.0047		0.0514
UPDRS II (c)
Baseline (b)	12.2 (5.9)	11.8 (5.7)	12.1 (5.9)	12.2 (5.9)	11.8 (5.7)	12.1 (5.9)	10.4 (6.3)	10.0 (5.6)
Change LSM (SE)	-1.2 (0.4)	-1.9 (0.4)	-2.3 (0.4)	-1.4 (0.3)	-2.0 (0.3)	-2.5 (0.3)	-0.8 (0.2)	-1.2 (0.2)
LS Diff vs Placebo		-0.7	-1.1		-0.6	-1.1		-0.4
95% CI		[-1.3, -0.0]	[-1.7, -0.5]		[-1.3, 0.0]	[-1.8, -0.4]		[-0.9, 0.0]
p-value		0.0367	0.0007		0.0676	0.0010		0.0564
Responder analyses (post-hoc) (e) n(%)
ON time increase ≥60 minutes	93 (43.9)	119 (54.8)	121 (56.0)	100 (47.2)	125 (57.6)	117 (54.2)	116 (42.5)	152 (56.3)
p-value		0.0233	0.0122		0.0308	0.1481		0.0013
≥60 minutes increase ON time and decrease in OFF time and ≥ 30% improvement UPDRS III	32 (15.1)	52 (24.0)	56 (25.9)	28 (13.2)	43 (19.8)	42 (19.4)	24 (8.8)	49 (18.1)
p-value		0.0216	0.0061		0.0671	0.0827		0.0017
CGI-C: patients who were much/very much improved	42 (19.8)	72 (33.2)	78 (36.1)	46 (21.7)	62 (28.6)	64 (29.6)	26 (9.5)	66 (24.4)
p-value (f)		0.0017	0.0002		0.0962	0.0575		<0.0001

Paediatric population
The pharmacodynamic effects of safinamide have not been assessed in children and adolescents.
5.2 Pharmacokinetic properties
Absorption
Safinamide absorption is rapid after single and multiple oral dosing, reaching Tmax in the time range 1.8-2.8 h after dosing under fasting conditions. Absolute bioavailability is high (95%), showing that safinamide is almost completely absorbed after oral administration and first pass metabolism is negligible. The high absorption classifies safinamide as a highly permeable substance.
Distribution
The volume of distribution (Vss) is approximately 165 L which is 2.5-fold of body volume indicating extensive extravascular distribution of safinamide. Total clearance was determined to be 4.6 L/h classifying safinamide as a low clearance substance.
Plasma protein binding of safinamide is 88-90%.
Biotransformation
In humans, safinamide is almost exclusively eliminated via metabolism (urinary excretion of unchanged safinamide was <10%) mediated principally through high capacity amidases, that have not yet been characterized. In vitro experiments indicated that inhibition of amidases in human hepatocytes led to complete suppression of the NW-1153 formation. Amidase present in blood, plasma, serum, simulated gastric fluid and simulated intestinal fluid as well as human carboxylesterases hCE-1 and hCE-2 are not responsible for the biotransformation of safinamide to NW-1153. The amidase FAAH was able to catalyse the formation of NW-1153 at low rates only. Therefore, other amidases are likely to be involved in the conversion to NW-1153. Safinamide's metabolism is not dependent on Cytochrome P450 (CYP) based enzymes.
Metabolite structure elucidation revealed three metabolic pathways of safinamide. The principal pathway involves hydrolytic oxidation of the amide moiety leading to the primary metabolite 'safinamide acid' (NW-1153). Another pathway involves oxidative cleavage of the ether bond forming 'O-debenzylated safinamide' (NW-1199). Finally the 'N-dealkylated acid' (NW-1689) is formed by oxidative cleavage of the amine bond of either safinamide (minor) or the primary safinamide acid metabolite (NW-1153) (major). The 'N-dealkylated acid' (NW-1689) undergoes conjugation with glucuronic acid yielding its acyl glucuronide. None of these metabolites are pharmacologically active.
Safinamide does not appear to significantly induce or inhibit enzymes at clinically relevant systemic concentrations. In vitro metabolism studies have indicated that there is no meaningful induction or inhibition of cytochrome P450, CYP2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A3/5 at concentrations which are relevant (Cmax of free safinamide 0.4 µM at 100 mg/day) in man. Dedicated drug-drug interaction studies performed with ketoconazole, L-dopa and CYP1A2 and CYP3A4 substrates (caffeine and midazolam), did not detect any clinically significant effects on the pharmacokinetics of safinamide, or L-dopa, caffeine and midazolam.
A mass balance study showed that the plasma AUC0-24h of the unchanged 14C-safinamide accounted for approximately 30% of the total radioactivity AUC0-24h, indicative of an extensive metabolism.
Transporters
Preliminary in vitro studies have shown that safinamide is not a substrate for the transporters P-gp, BCRP, OAT1B1, OAT1B3, OATP1A2 or OAT2P1. Metabolite NW-1153 is not a substrate for OCT2, or OAT1, but it is substrate for OAT3. This interaction has the potential to reduce the clearance of NW-1153 and increase its exposure; however the systemic exposure of NW-1153 is low (1/10 of parent safinamide), and as it is metabolised to secondary and tertiary metabolites, it is unlikely to be of any clinical relevance.
Safinamide transiently inhibits BCRP in the small intestine (see section 4.5). . At concentrations of 50µM, safinamide inhibited OATP1A2 and OATP2P1. The relevant plasma concentrations of safinamide are substantially lower, therefore a clinically relevant interaction with co-administered substrates of these transporters is unlikely. NW-1153 is not an inhibitor of OCT2, MATE1, or MATE2-K up to concentrations of 5µM.
Linearity/non-linearity
The pharmacokinetics of safinamide are linear after single and repeated doses. No time-dependency was observed.
Elimination
Safinamide undergoes almost complete metabolic transformation (<10% of the administered dose was found unchanged in urine). Substance-related radioactivity was largely excreted in urine (76%) and only to a low extent in faeces (1.5%) after 192 hours. The terminal elimination half-life of total radioactivity was approximately 80 hours.
The elimination half-life of safinamide is 20-30 hours. Steady-state is reached within one week.
Patients with hepatic impairment
Safinamide exposure in patients with mild hepatic disease increased marginally (30% in AUC), while in patients with moderate hepatic impairment exposure increased by approximately 80% (see section 4.2).
Patients with renal impairment
Moderate or severe renal impairment did not alter the exposure to safinamide, compared to healthy subjects (see section 4.2).
5.3 Preclinical safety data
Retinal degeneration was observed in rodents after repeated safinamide dosing resulting in systemic exposure below the anticipated systemic exposure in patients given the maximal therapeutic dose. No retinal degeneration was noted in monkeys despite higher systemic exposure than in rodents or in patients at the maximum human dose.
Long-term studies in animals have shown convulsions (1.6 to 12.8 times human clinical exposure, based on plasma AUC). Liver hypertrophy and fatty changes were seen only in rodent livers at exposures similar to humans. Phospholipidosis was seen mainly in the lungs in rodents (at exposures similar to humans) and monkeys (at exposures greater than 12 fold higher than human).
Safinamide did not present genotoxic potential in in vivo and in several in vitro systems using bacteria or mammalian cells.
The results obtained from carcinogenicity studies in mice and rats showed no evidence of tumorigenic potential related to safinamide at systemic exposures up to 2.3 to 4.0 times respectively, the anticipated systemic exposure in patients given the maximal therapeutic dose.
Fertility studies in female rats showed reduced number of implantations and corpora lutea at exposures in excess of 3 times the anticipated human exposure. Male rats showed minor abnormal morphology and reduced speed of sperm cells at exposures in excess of 1.4 times the anticipated human exposure. Male rat fertility was not affected.
In embryo-foetal developmental studies in rats and rabbits malformations were induced at safinamide exposures 2 and 3-fold above human clinical exposure, respectively. The combination of safinamide with levodopa/carbidopa resulted in additive effects in the embryo-foetal development studies with a higher incidence of foetal skeletal abnormalities than seen with either treatment alone.
In a pre- and postnatal developmental rat study, pup mortality, absence of milk in the stomach and neonatal hepatotoxicity were observed at dose levels similar to the anticipated clinical exposure. Toxic effects on the liver and accompanying symptoms as yellow/orange skin and skull, in pups exposed to safinamide during lactation are mediated mainly via in utero exposure, whereas exposure via the mother's milk had only a minor influence.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Crospovidone type A
Magnesium stearate
Silica, colloidal anhydrous
Film-coating
Hypromellose
Polyethylene glycol 6000
Titanium dioxide (E171)
Iron oxide red (E172)
Mica (E555)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVDC/Aluminium blister packs of 14, 28, 30, 90 and 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7. Marketing authorisation holder
Zambon S.p.A.
Via Lillo del Duca 10
20091 Bresso (MI) - Italy
Tel: +39 02 665241
Fax: +39 02 66501492
Email: info.zambonspa@zambongroup.com
8. Marketing authorisation number(s)
EU/1/14/984/006
EU/1/14/984/007
EU/1/14/984/008
EU/1/14/984/009
EU/1/14/984/010
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 24 February 2015
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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Xadago 50mg film-coated tablets（https://www.medicines.org.uk/emc/medicine/31916）
Xadago 100mg film-coated tablets（https://www.medicines.org.uk/emc/medicine/31917）
Zambon XADAGO® (SAFINAMIDE) in Belgium for patients with mid-to late stage Parkinson’s disease
•Zambon today announces the availability and reimbursement in Belgium of Xadago® (safinamide) as an add-on to levodopa alone or in combination with other Parkinson’s disease (PD) medications in mid-to late stage PD.
•Safinamide is a new chemical entity with a dopaminergic and non dopaminergic action, providing a balanced control of motor symptoms and motor complications
2016 - Zambon S.p.A., an international pharmaceutical company strongly committed to the central nervous system (CNS) therapeutic area, and its partner Newron Pharmaceuticals S.p.A. (“Newron”) (SIX: NWRN), a biopharmaceutical company focused on the development of novel therapies for patients with diseases of the central nervous system (CNS) and pain, today announced the launch of Xadago® (safinamide) in Belgium for the treatment of mid- to late stage Parkinson’s disease (PD). Following the launch in Switzerland, Germany, Spain and Italy, Xadago® (safinamide) is now available in Belgium as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other PD therapies for mid-to late-stage fluctuating patients.
Safinamide is a new chemical entity with a dopaminergic and non-dopaminergic action, providing a balanced control of motor symptoms and motor complications.
Prof. Patrick Santens, from University Hospital Ghent commented “Thanks to its unique dual dopaminergic and non-dopaminergic mode of action, including the modulation of altered glutamatergic neurotransmission, Xadago® (safinamide) has the potential to become a long awaited treatment alternative for our patients suffering from idiopathic Parkinson’s disease with motor fluctuations”.
Maurizio Castorina, CEO of Zambon SpA said: “We are glad to see health authorities across Europe approving the reimbursement of Xadago® (safinamide) for PD patients. Patients in Belgium will now have access to an innovative add-on treatment option that has shown meaningful and long lasting improvements on motor symptoms and good ON Time without troublesome dyskinesia, in addition to a well-tolerated profile”.
About Xadago® (safinamide)
Safinamide is a new chemical entity with a unique mode of action including selective and reversible MAO-B-inhibition and blocking of voltage dependent sodium channels which leads to modulation of abnormal glutamate release. Clinical trials have established its efficacy in controlling motor symptoms and motor complications in the short term, maintaining this effect over 2 years. Results from 24 month double-blind controlled studies suggest that safinamide shows statistically significant effects on motor fluctuations (ON/OFF time) without increasing the risk of developing troublesome dyskinesia. This effect may be related to its dual mechanism acting on both the dopaminergic and the glutamatergic pathways. Safinamide is a once-daily dose and has no diet restrictions due to its high MAO-B/MAO-A selectivity. Zambon has the rights to develop and commercialize Xadago® globally, excluding Japan and other key territories where Meiji Seika has the rights to develop and commercialize the compound. The rights to develop and commercialize Xadago® in the USA have been granted to US WorldMeds, by Zambon.
About Parkinson’s disease
PD is the second most common chronic progressive neurodegenerative disorder in the elderly after Alzheimer’s disease, affecting 1-2% of individuals aged ≥ 65 years worldwide. The prevalence of the PD market is expected to grow in the next years due to the increase in the global population and advancements in healthcare that contribute to an aging population at increased risk for PD. The diagnosis of PD is mainly based on observational criteria of muscular rigidity, resting tremor, or postural instability in combination with bradykinesia. As the disease progresses, symptoms become more severe. Early-stage patients are more easily managed on L-dopa. L-dopa remains as the most effective treatment for PD, and over 75% of the patients with PD receive L-dopa. However, long term treatment with L-dopa leads to seriously debilitating motor fluctuations, i.e. phases of normal functioning (ON-time) and decreased functioning (OFF-time). Furthermore, as a result of the use of high doses of L-dopa with increasing severity of the disease, many patients experience involuntary movements known as L-dopa-Induced Dyskinesia (LID). As the disease progresses, more drugs are used as an add-on to what the patient already takes, and the focus is to treat symptoms while managing LID and the “off-time” effects of L-dopa. Most current therapies target the dopaminergic system that is implicated in the pathogenesis of PD, and most current treatments act by increasing dopaminergic transmission that leads to amelioration of motor symptoms.