Xadago

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

  



2 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Xadago 50 mg film-coated tablets 

Xadago 100 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Xadago 50 mg film-coated tablets 

 

Each film-coated tablet contains safinamide methansulfonate equivalent to 50 mg safinamide.  

 

Xadago 100 mg film-coated tablets 

 

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) 

 

Xadago 50 mg film-coated tablets 

 

Orange to copper, round, biconcave, film-coated tablet of 7 mm diameter with metallic gloss, 

embossed with the strength “50” on one side of the tablet. 

 

Xadago 100 mg film-coated tablets 

 

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 safinamide 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.  

 



3 

Hepatic impairment 

Safinamide 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 safinamide 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. 

Safinamide should be taken with water. 

Safinamide 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, safinamide 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 

safinamide 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 safinamide. 

 

At least 7 days must elapse between discontinuation of safinamide and initiation of treatment with 

MAO inhibitors or pethidine (see section 4.3 and 4.5). 

 

When safinamide is co-administered with products that are BCRP substrates, please refer to the SmPC 

for that particular medicinal product. 

Hepatic impairment 

 

Caution should be exercised when initiating treatment with safinamide in patients with moderate 

hepatic impairment. In case patients progress from moderate to severe hepatic impairment, treatment 

with  safinamide should be stopped (see sections 4.2, 4.3 and 5.2).  

 

Potential for retinal degeneration in patients with prior history of retinal disease  

 

Safinamide should not be administered to patients with ophthalmological history that would put them 

at increased risk for potential retinal effects (e.g., family history of hereditary retinal disease, or history 

of uveitis) see sections 4.3 and 5.3. 

 



4 

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 

Safinamide 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 safinamide 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 safinamide 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 safinamide 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 safinamide 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 safinamide. 

 

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. 

 

 



5 

In vivo and in vitro pharmacokinetic drug interactions 

 

Safinamide may transiently inhibit BCRP in vitro. In drug-drug-interaction studies in human, a weak 

interaction was observed with rosuvastatin (AUC increase between 1.25 and 2.00 fold) but no 

significant interaction was found with diclofenac.  

It is recommended to monitor patients when safinamide is taken with medicinal products that are 

BCRP substrates (e.g., rosuvastatin, pitavastatin, pravastatin, ciprofloxacin, methotrexate, topotecan, 

diclofenac or glyburide) and to refer to their SmPCs to determine if a dose adjustment is needed. 

 

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%.  

 

Safinamide inhibits OCT1 in vitro at clinically relevant portal vein concentrations. Therefore, caution 

is necessary when safinamide is taken concomitantly with medicinal products that are OCT1 substrates 

and have a tmax similar to safinamide (2 hours) (e.g. metformin, aciclovir, ganciclovir) as exposure to 

these substrates might be increased as a consequence. 

 

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 

 

Safinamide should not be given to women of childbearing potential unless adequate contraception is 

practiced.  

 

Pregnancy  

 

There are no or limited amount of data from the use of safinamide in pregnant women. Studies in 

animals have shown reproductive toxicity (see section 5.3). Xadago is not recommended during 

pregnancy and in women of childbearing potential not using contraception. 

 

 

Breast-feeding 

 

Available pharmacodynamic/toxicological data in animals have shown excretion of safinamide in milk 

(for details see 5.3).  

A risk for the breast-fed child cannot be excluded. Xadago should not be used during breast-feeding. 

 

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). 

 



6 

4.7 Effects on ability to drive and use machines 
 

Somnolence and dizziness may occur during safinamide treatment, therefore  patients should be 

cautioned about using hazardous machines, including motor vehicles, until they are reasonably certain 

that safinamide does not affect them adversely. 

 

4.8 Undesirable effects 
 

Summary of the safety profile 

 

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.  

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 reactions 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, 

Compulsions, 

delirium, 



7 

System Organ 

Class 

Very 

common 

Common Uncommon Rare 

abnormal dreams, 

anxiety, 

confusional state, 

affect lability, 

libido increased, 

psychotic disorder, 

restlessness, 

sleep disorder 

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, 

Peptic ulcer, 

retching, 

upper gastrointestinal 

haemorrhage 



8 

System Organ 

Class 

Very 

common 

Common Uncommon Rare 

salivary hypersecretion, 

gastrooesophageal reflux 

disease, 

aphthous stomatitis 

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 

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, 



9 

System Organ 

Class 

Very 

common 

Common Uncommon Rare 

abnormal, 

urine analysis abnormal, 

blood pressure increased, 

blood pressure decreased, 

ophthalmic diagnostic 

procedures abnormal 

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 dreactions 

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 the national reporting system 

listed in Appendix V. 

 

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 

Safinamide 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, safinamide treatment should be discontinued and supportive treatment 

should be administered as clinically indicated.  

 

 

5 PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Anti-Parkinson-Drugs, monoamine oxidase -B inhibitors, ATC code: 

N04BD03.  

 

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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


10 

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 safinamide 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 medicinal products, 

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 



11 

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) 

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  

<0.000

1 

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 

<0.000

1 
 0.0028 0.0003  

<0.000

1 

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  

<0.000

1 



12 

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) 

(a) Daily targeted dose, (b) Mean (SD), (c) analysis population (mITT); MMRM model for change 

from Baseline to Endpoint includes treatment, region, and visit as fixed effects, and baseline value as 

a covariate; (d) target dose of 100 mg/day; (e) analysis population (mITT); data are presented as the 

number (percentage) of patients in each group meeting the responder definition (f) chi-square test of 

the odds ratio of the treatment groups compared to placebo using a logistic regression model, with 

fixed effects for treatment and country. 

SE Standard Error, SD Standard deviation, LSM Least Square Mean, LS Diff. Least Square 

Difference vs Placebo  

mITT Population: Study 016/018 - Placebo (n=212), safinamide 50 mg/day (n=217) and 100 mg/day 

(n=216), and SETTLE - Placebo (n=270), safinamide 50-100 mg/day (n=273).  

 

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 



13 

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).  

 



14 

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 

Macrogol (6000) 

Titanium dioxide (E171) 

Iron oxide red (E172) 

Mica (E555) 

 



15 

6.2 Incompatibilities 
 

Not applicable 

 

6.3 Shelf life 
 

4 years  

 

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 
 

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)  
 

Xadago 50 mg film-coated tablets 

 

EU/1/14/984/001 

EU/1/14/984/002 

EU/1/14/984/003 

EU/1/14/984/004 

EU/1/14/984/005 

 

Xadago 100 mg film-coated tablets 

 

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 

Date of latest renewal: 

 

mailto:info.zambonspa@zambongroup.com


16 

 

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. 

  

http://www.ema.europa.eu/


17 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 



18 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Catalent Germany Schorndorf GmbH 

Steinbeisstrasse 2 

D-73614 Schorndorf 

Germany 

 

Zambon S.p.A. 

Via della Chimica, 9 

36100 Vicenza 

Italy 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

 Periodic Safety Update Reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached.  

  



19 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



20 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

  



21 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON –film-coated tablets 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Xadago 50 mg film-coated tablets  

safinamide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains safinamide methansulfonate equivalent to 50 mg safinamide. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

14 film-coated tablets 

28 film-coated tablets 

30 film-coated tablets 

90 film-coated tablets 

100 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP  

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 



22 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Zambon S.p.A. 

Via Lillo del Duca 10 

20091 Bresso (MI) - Italy 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/14/984/001 

EU/1/14/984/002 

EU/1/14/984/003 

EU/1/14/984/004 

EU/1/14/984/005 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

xadago 50 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 

  



23 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Xadago 50 mg tablets 

safinamide 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Zambon S.p.A. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 

  



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON – film-coated tablets 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Xadago 100 mg film-coated tablets 

safinamide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains safinamide methansulfonate equivalent to 100 mg safinamide.  

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

14 film-coated tablets 

28 film-coated tablets 

30 film-coated tablets 

90 film-coated tablets 

100 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 



25 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Zambon S.p.A. 

Via Lillo del Duca 10 

20091 Bresso (MI) - Italy 

 

 

12. 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 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

xadago 100 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 

  



26 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Xadago 100 mg tablets 

safinamide 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Zambon S.p.A. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 

  



27 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

  



28 

Package leaflet: Information for the patient 

 

Xadago 50 mg film-coated tablets 

Xadago 100 mg film-coated tablets 

safinamide 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  

- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 
in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Xadago is and what it is used for  

2. What you need to know before you take Xadago 

3. How to take Xadago 

4. Possible side effects  

5. How to store Xadago 

6. Contents of the pack and other information 

 

 

1. What Xadago is and what it is used for 

 

Xadago is a medicine that contains the active substance safinamide. It acts to increase the level of a 

substance called dopamine in the brain, which is involved in the control of movement and is present in 

reduced amounts in the brain of patients with Parkinson’s disease. Xadago is used for the treatment of 

Parkinson’s disease in adults.  

 

In mid- to late-stage patients experiencing sudden switches between being “ON” and able to move and 

being “OFF” and having difficulties moving about, Xadago is added to a stable dose of the medicine 

called levodopa alone or in combination with other medicines for Parkinson’s disease. 

 

 

2. What you need to know before you take Xadago 

 

Do not take Xadago 
- If you are allergic to safinamide or any of the other ingredients of this medicine (listed in 

section 6).  

- If you are taking any of the following medicines: 
- Monoamine oxidase (MAO) inhibitors such as selegiline, rasagiline, moclobemide, 

phenelzine, isocarboxazid, tranylcypromine (e.g. for treatment of Parkinson’s disease or 

depression, or used for any other condition).  

- Pethidine (a strong pain killer).  
You must wait at least 7 days after stopping Xadago treatment before starting treatment with 

MAO inhibitors or pethidine. 

- If you have been told that you have severe liver problems  
- If you have an eye condition which might put you at risk of potential damage to your retina (the 

light sensitive layers at the back of your eyes), e.g. albinism (lack of pigment in your skin and 

eyes), retinal degeneration (loss of cells from light sensitive layer at the back of the eye), or 

uveitis (inflammation inside of the eye), inherited retinopathy (inherited disorders of the vision), 

or severe progressive diabetic retinopathy (a progressive decrease of the vision due to diabetes). 

 



29 

Warnings and precautions  
Talk to your doctor before taking Xadago  

- If  you have liver problems  
- Patients and carers should be made aware that certain compulsive behaviours such as 

compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, 

impulsive behaviour and compulsive spending or buying have been reported with other 

medicines for Parkinson’s disease.  

- Uncontrollable jerky movements may occur or worsen when Xadago is used together with 
levodopa.  

 

Children and adolescents 

Xadago is not recommended for use in children and adolescents, below 18 years old due to the lack of 

data on safety and efficacy in this population. 

 

Other medicines and Xadago 

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other 

medicines. Ask your doctor for advice before taking any of the following medicines together with 

Xadago:  

- Cold or cough remedies containing dextromethorphan, ephedrine or pseudoephedrine 
- Medicines called selective serotonin reuptake inhibitors (SSRIs) typically used to treat anxiety 

disorders, and some personality disorders (e.g. fluoxetine or fluvoxamine) 

- Medicines called serotonin–norepinephrine reuptake inhibitors (SNRIs), used in the treatment of 
major depression and other mood disorders, such as venlafaxine 

- Medicines for high cholesterol such as rosuvastatin, pitavastatin, pravastatin 
- Fluoroquinolone antibiotic such as ciprofloxacin 
- Medicines that affect the immune system such as methotrexate  
- Medicines to treat metastatic carcinoma such as topotecan 
- Medicine to treat pain and inflammation such as diclofenac 
- Medicines to treat type 2 diabetes such as glyburide, metformin 
- Medicines to treat virus infection such as aciclovir, ganciclovir 
  

Pregnancy and breast-feeding 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor for advice before taking this medicine.  

 

Pregnancy  

Xadago should not be used during pregnancy or by women of childbearing potential not practicing 

adequate contraception. 

 

Breast Feeding 

Xadago is likely to be excreted in breast milk. Xadago should not be used during breast-feeding. 

 

Driving and using machines 
Somnolence and dizziness may occur during safinamide treatment; you should be cautious about 

operating hazardous machines or driving, until you are reasonably certain that Xadago does not affect 

you in any way.  

 

Ask your doctor for advice prior to driving or using machines. 

 

 

3. How to take Xadago 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 

sure. 

 

http://en.wikipedia.org/wiki/Anxiety_disorder
http://en.wikipedia.org/wiki/Anxiety_disorder
http://en.wikipedia.org/wiki/Personality_disorder


30 

The recommended starting dose of Xadago is one 50 mg tablet that may be increased to one 100 mg 

tablet, taken once daily preferably in the morning by mouth with water. Xadago may be taken with or 

without food.  

 

If you suffer from moderately reduced liver function, you should not take more than 50 mg a day; your 

doctor will advise if this applies to you. 

 

If you take more Xadago than you should 
If you have taken too many Xadago tablets, you may develop raised blood pressure, anxiety, 

confusion, forgetfulness, sleepiness, lightheadedness; feel sick or be sick; dilated pupils or develop 

involuntary jerky movements. Contact your doctor immediately and take the Xadago pack with you.  

 

If you forget to take Xadago  
Do not take a double dose to make up for a forgotten dose. Skip the missed dose and take the next 

dose at the time you normally take it.  

 

If you stop taking Xadago 
Do not stop taking Xadago without first talking to your doctor.  

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them.  

Seek medical advice in case of hypertensive crisis (very high blood pressure, collapse), neuroleptic 

malignant syndrome (confusion, sweating, muscle rigidity, hyperthermia, increase level of enzyme 

creatine kinase in your blood), serotonin syndrome (confusion, hypertension, muscle stiffness, 

hallucinations), and hypotension. 

 

The following side effects have been reported in patients at a mid- to late-stage of Parkinson’s disease 

(patients taking safinamide as add-on to levodopa alone or in combination with other medicines for 

Parkinson’s disease): 

 

Common (may affect up to 1 in 10 people): insomnia, difficulty in performing voluntary movements, 

feeling sleepy, dizziness, headache, worsening of Parkinson’s disease, clouding of the lens of the eye, 

fall in blood pressure when rising to a standing position, nausea, falling.  

 

Uncommon (may affect up to 1 in 100 people): urine infection, skin cancer, low iron in your blood, 

low white cell count, red blood cell abnormality, decreased appetite, high fat in blood, increased 

appetite, high blood sugar, seeing things that are not there, feeling sad, abnormal dreams, fear and 

worry, confusional state, mood swings , increased interest in sex, abnormal thinking and perception, 

restlessness, sleep disorder, numbness, unsteadiness, loss of sensation, sustained abnormal muscle 

contraction, head discomfort, difficulty in speaking, fainting, memory impairment, blurring of vision, 

blind spot, double vision, aversion to light, disorders of the light sensitive layer at the back of your 

eye, redness of the eyes, increased pressure in the eye, sensation of room spinning, feeling of heart 

beating, fast heartbeat, irregular heartbeat, slowed heartbeat , high blood pressure, low blood pressure, 

veins that have become large and twisted, cough, difficult breathing, runny nose, constipation, 

heartburn, vomiting, dry mouth, diarrhoea, abdominal pain, burning stomach, wind, feeling full, 

drooling, mouth ulcer, sweating, itching, sensitive to light, redness of the skin, back pain, joint pain, 

cramps, stiffness, pain in legs or arms, muscle weakness, sensation of heaviness, increased urination at 

night, pain upon urination, difficulty in having sex in males, fatigue, feeling weak, unsteady walking, 

swelling of your feet, pain, feeling hot, weight loss, weight gain, abnormal blood tests, high fat in your 

blood, increased sugar in your blood, abnormal ECG, liver function test abnormal, abnormal urine 

tests, blood pressure decreased, blood pressure increased, abnormal eye test, fracture of your foot.  

 

Rare (may affect up to 1 in 1000 people): pneumonia, skin infection, sore throat, nasal allergy, tooth 

infection, viral infection, non-cancerous skin conditions/growth, white blood cell abnormalities, severe 



31 

loss of weight and weakness, increased potassium in blood, uncontrollable urges, clouding of 

consciousness, disorientation, wrong perception of images, reduced interest in sex, thoughts that you 

cannot get rid of, feeling that someone is out to get you, premature ejaculation, uncontrollable urge to 

sleep, fear of social situations, thoughts of suicide, clumsiness, easily distracted, loss of taste, 

weak/slow reflexes, radiating pain in the legs, continuous desire to move your legs, feeling sleepy, eye 

abnormalities, progressive diminution of vision due to diabetes, increased tears, night blindness, cross 

eyed, heart attack, tightening/narrowing of blood vessel, severe high blood pressure, tightening of the 

chest, difficulty in speaking, difficulty in/painful swallowing, peptic ulcer, retching, stomach bleeding, 

jaundice, loss of hair, blister, skin allergy, skin conditions, bruising, scaly skin, night sweats, pain of 

skin, discolouration of the skin, psoriasis, flaky skin, inflammation of spinal joints due to an 

autoimmune disorder, pain in your sides, swelling of joints, musculoskeletal pain, muscular pain, neck 

pain, joint pain, cyst in the joint, uncontrollable urge to urinate, increased urination, passing of pus 

cells in urine, urinary hesitation, prostate problem, breast pain, drug effect decreased, drug intolerance, 

feeling cold, feeling unwell, fever, dryness of skin, eye and mouth, abnormal blood tests, heart 

murmur, abnormal heart tests, bruising/swelling after injury, blood vessel blockage due to fat, head 

injury, mouth injury, skeletal injury, gambling. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects, you can help provide more information on the safety 

of this medicine. 

 

 

5. How to store Xadago 

 

Keep this medicine out of the sight and reach of children.  

 

Do not use this medicine after the expiry date which is stated on the carton and blister after “EXP”  

The expiry date refers to the last day of that month.  

 

This medicine does not require any special storage conditions. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment.  

 

 

6. Contents of the pack and other information 

 

What Xadago contains  

- The active substance is safinamide. Each tablet contains 50 mg or 100 mg of safinamide (as 
methansulfonate).  

- The other ingredients are: 
- Tablet core: microcrystalline cellulose, crospovidone type A, magnesium stearate, silica 

colloidal anhydrous  

- Tablet coating: hypromellose, macrogol (6000), titanium dioxide (E171), iron oxide red 
(E172), mica (E555). 

 

What Xadago looks like and contents of the pack 

Xadago 50 mg are orange to copper, round, biconcave film-coated tablets of 7 mm diameter with 

metallic gloss, embossed with “50” on one side of the tablet. 

 

Xadago 100 mg are orange to copper, round, biconcave film-coated tablets 9 mm diameter with 

metallic gloss, embossed with “100” on one side of the tablet.  

 

Xadago is supplied in packs containing 14, 28, 30, 90 or 100 film coated tablets. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


32 

Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder  

 

Zambon S.p.A. 

Via Lillo del Duca 10 

20091 Bresso (MI) 

Italy 

Tel: +39 02665241 

Fax: +39 02 66501492 

Email: info.zambonspa@zambongroup.com 

 

Manufacturer 

 

Catalent Germany Schorndorf GmbH 

Steinbeisstrasse 2 

D- 73614 Schorndorf 

Germany 

 

Zambon S.p.A. 

Via della Chimica, 9 

36100 Vicenza 

Italy 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien/ 

Luxembourg/Luxemburg 

Zambon N.V./S.A.  

Tél/Tel: + 32 2 777 02 00 

 

France 

Zambon France S.A. 

Tél: + 33 (0)1 58 04 41 41 

 

България/Česká republika/Eesti/Ελλάδα/ 

Hrvatska/Ireland/Ísland/Κύπρος/Latvija/ 

Lietuva/Magyarország/Malta/Polska/ 

România/Slovenija/Slovenská republika 

Zambon S.p.A. 

Teл./Tel/Τηλ/Sími: + 39 02665241 

 

United Kingdom 

Profile Pharma Limited 

Tel: + 44 (0) 800 0288 942 

 

Italia 

Zambon Italia S.r.l. 

Tel: + 39 02665241 

 

Danmark/Norge/Suomi/Finland/Sverige 

Zambon Sweden, Filial of Zambon Nederland B.V. 

Tlf/Puh/Tel: + 47 815 300 30 

 

Nederland 

Zambon Nederland B.V. 

Tel: + 31 (0)33 450 4370 

 

Deutschland/Österreich 

Zambon GmbH 

Tel: 00800 92626633 

 

Portugal 

Zambon - Produtos Farmacêuticos, Lda. 

Tel: + 351 217 600 952 / 217 600 954 

España 

Zambon, S.A.U. 

Tel: + 34 93 544 64 00 

 

 

This leaflet was last revised in . 

 

Other sources of information 

 

mailto:info.zambonspa@zambongroup.com


33 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET