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Xadago (safinamide methanesulfonate) – Summary of product characteristics - N04B

Updated on site: 10-Oct-2017

Medication nameXadago
ATC CodeN04B
Substancesafinamide methanesulfonate
ManufacturerZambon SpA

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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

4.1Therapeutic 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.

4.2Posology 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.

4.3Contraindications

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).

4.4Special 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.

4.5Interaction 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.

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.

4.6Fertility, 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).

4.7Effects 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.

4.8Undesirable 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

Very

Common

Uncommon

Rare

Class

common

 

 

 

Infections and

 

 

Urinary tract infection

Bronchopneumonia,

infestations

 

 

 

furuncle,

 

 

 

 

nasopharyngitis,

 

 

 

 

pyoderma,

 

 

 

 

rhinitis,

 

 

 

 

tooth infection,

 

 

 

 

viral infection

Neoplasms benign,

 

 

Basal cell carcinoma

Acrochordon,

malignant and

 

 

 

melanocytic naevus,

unspecified (incl

 

 

 

seborrhoeic keratosis,

cysts and polyps)

 

 

 

skin papilloma

Blood and

 

 

Anaemia,

Eosinophilia,

lymphatic system

 

 

leukopenia,

lymphopenia

disorders

 

 

red blood cell

 

 

 

 

abnormality

 

Metabolism and

 

 

Decreased appetite,

Cachexia,

nutrition disorders

 

 

hypertriglyceridaemia,

hyperkalaemia

 

 

 

increased appetite,

 

 

 

 

hypercholesterolaemia,

 

 

 

 

hyperglycaemia,

 

Psychiatric

 

Insomnia

Hallucination,

Compulsions,

disorders

 

 

depression,

delirium,

 

 

 

abnormal dreams,

disorientation,

 

 

 

anxiety,

illusion,

 

 

 

confusional state,

impulsive behaviour,

 

 

 

affect lability,

loss of libido,

 

 

 

libido increased,

obsessive thoughts,

 

 

 

psychotic disorder,

paranoia,

 

 

 

restlessness,

premature ejaculation,

 

 

 

sleep disorder

sleep attacks,

 

 

 

 

social phobia,

 

 

 

 

suicidal ideation

Nervous system

 

Dyskinesia

Paraesthesia,

Coordination abnormal,

disorders

 

somnolence,

balance disorder,

disturbance in attention,

 

 

dizziness,

hypoaesthesia,

dysgeusia,

 

 

headache,

dystonia,

hyporeflexia,

 

 

Parkinson's

head discomfort,

radicular pain,

 

 

disease

dysarthria,

Restless Legs Syndrome,

 

 

 

syncope,

sedation

 

 

 

cognitive disorder

 

Eye disorders

 

Cataract

Vision blurred,

Amblyopia,

 

 

 

scotoma,

chromatopsia,

 

 

 

diplopia,

diabetic retinopathy,

 

 

 

photophobia,

erythropsia,

 

 

 

retinal disorder,

eye haemorrhage,

 

 

 

conjunctivitis,

eye pain,

 

 

 

glaucoma

eyelid oedema,

 

 

 

 

hypermetropia,

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Class

common

 

 

 

 

 

 

 

keratitis,

 

 

 

 

lacrimation increased,

 

 

 

 

night blindness,

 

 

 

 

papilloedema,

 

 

 

 

presbyopia,

 

 

 

 

strabismus

Ear and labyrinth

 

 

Vertigo

 

disorders

 

 

 

 

Cardiac disorders

 

 

Palpitations,

Myocardial infarction

 

 

 

tachycardia,

 

 

 

 

sinus bradycardia,

 

 

 

 

arrhythmia

 

Vascular disorders

 

Orthostatic

Hypertension,

Arterial spasm,

 

 

hypotension

hypotension,

arteriosclerosis,

 

 

 

varicose vein

hypertensive crisis

Respiratory,

 

 

Cough,

Bronchospasm,

thoracic and

 

 

dyspnoea,

dysphonia,

mediastinal

 

 

rhinorrhoea

oropharyngeal pain,

disorders

 

 

 

oropharyngeal spasm

Gastrointestinal

 

Nausea

Constipation,

Peptic ulcer,

disorders

 

 

dyspepsia,

retching,

 

 

 

vomiting,

upper gastrointestinal

 

 

 

dry mouth,

haemorrhage

 

 

 

diarrhoea,

 

 

 

 

abdominal pain,

 

 

 

 

gastritis,

 

 

 

 

flatulence,

 

 

 

 

abdominal distension,

 

 

 

 

salivary hypersecretion,

 

 

 

 

gastrooesophageal reflux

 

 

 

 

disease,

 

 

 

 

aphthous stomatitis

 

Hepatobiliary

 

 

 

Hyperbilirubinaemia

disorders

 

 

 

 

Skin and

 

 

Hyperhidrosis,

Alopecia,

subcutaneous

 

 

pruritus generalised,

blister,

tissue disorders

 

 

photosensitivity reaction,

dermatitis contact,

 

 

 

erythema

dermatosis,

 

 

 

 

ecchymosis,

 

 

 

 

lichenoid keratosis,

 

 

 

 

night sweats,

 

 

 

 

pain of skin,

 

 

 

 

pigmentation disorder,

 

 

 

 

psoriasis,

 

 

 

 

seborrhoeic dermatitis

Musculoskeletal

 

 

Back pain,

Ankylosing spondylitis,

and connective

 

 

arthralgia,

flank pain,

tissue disorders

 

 

muscle spasms,

joint swelling,

 

 

 

muscle rigidity,

musculoskeletal pain,

 

 

 

pain in extremity,

myalgia,

 

 

 

muscular weakness,

neck pain,

 

 

 

sensation of heaviness

osteoarthritis,

 

 

 

 

synovial cyst

System Organ

Very

Common

Uncommon

Rare

Class

common

 

 

 

Renal and urinary

 

 

Nocturia,

Micturition urgency,

disorders

 

 

dysuria

polyuria, pyuria,

 

 

 

 

urinary hesitation

Reproductive

 

 

Erectile dysfunction

Benign prostatic

system and breast

 

 

 

hyperplasia,

disorders

 

 

 

breast disorder,

 

 

 

 

breast pain

General disorders

 

 

Fatigue,

Drug effect decreased,

and administration

 

 

asthenia,

drug intolerance,

site conditions

 

 

gait disturbance,

feeling cold,

 

 

 

oedema peripheral,

malaise,

 

 

 

pain,

pyrexia,

 

 

 

feeling hot

xerosis

Investigations

 

 

Weight decreased,

Blood calcium decreased,

 

 

 

weight increased,

blood potassium

 

 

 

blood creatine

decreased,

 

 

 

phosphokinase increased,

blood cholesterol

 

 

 

blood triglycerides

decreased,

 

 

 

increased,

body temperature

 

 

 

blood glucose increased,

increased,

 

 

 

blood urea increased,

cardiac murmur,

 

 

 

blood alkaline phosphatase

cardiac stress test

 

 

 

increased,

abnormal,

 

 

 

blood bicarbonate

haematocrit decreased,

 

 

 

increased,

haemoglobin decreased,

 

 

 

blood creatinine increased,

international normalised

 

 

 

electrocardiogram QT

ratio decreased,

 

 

 

prolonged,

lymphocyte count

 

 

 

liver function test

decreased,

 

 

 

abnormal,

platelet count decreased,

 

 

 

urine analysis abnormal,

very low density

 

 

 

blood pressure increased,

lipoprotein increased

 

 

 

blood pressure decreased,

 

 

 

 

ophthalmic diagnostic

 

 

 

 

procedures abnormal

 

Injury, poisoning

 

Fall

Foot fracture

Contusion,

and procedural

 

 

 

fat embolism,

complications

 

 

 

head injury,

 

 

 

 

mouth injury,

 

 

 

 

skeletal injury

Social

 

 

 

Gambling

circumstances

 

 

 

 

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 the national reporting system listed in Appendix V.

4.9Overdose

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

5.1Pharmacodynamic 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 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

 

 

 

016/018

 

27919 (SETTLE)

 

 

(24 weeks)

 

(2 years)

 

(24 weeks)

Dose (mg/day) (a)

 

 

Safinamide

 

 

Safinamide

 

Safin-

 

Placebo

 

Placebo

 

Placebo

amide

 

 

 

 

 

 

 

 

 

 

50-100

 

 

 

 

 

 

(d)

 

 

 

 

 

 

 

 

 

 

Randomized

 

 

Age (years) (b)

59.4

 

60.1

60.1

59.4

 

60.1

60.1

62.1

61.7

 

(9.5)

 

(9.7)

(9.2)

(9.5)

 

(9.7)

(9.2)

(9.0)

(9.0)

PD Duration (years)

8.4 (3.8)

 

7.9 (3.9)

8.2

8.4 (3.8)

 

7.9

8.2

9.0 (4.9)

8.9

(b)

 

(3.8)

 

(3.9)

(3.8)

(4.4)

 

 

 

 

 

 

ON time without troublesome dyskinesia (hrs) (c)

 

 

 

 

 

 

Baseline (b)

9.3 (2.2)

 

9.4 (2.2)

9.6

9.3 (2.2)

 

9.4

9.6

9.1 (2.5)

9.3

 

 

(2.5)

 

(2.2)

(2.5)

(2.4)

 

 

 

 

 

 

 

Change LSM (SE)

0.5 (0.2)

 

1.0 (0.2)

1.2

0.8 (0.2)

 

1.4

1.5

0.6 (0.1)

1.4

 

 

(0.2)

 

(0.2)

(0.2)

(0.1)

 

 

 

 

 

 

 

LS Diff vs Placebo

 

 

0.5

0.7

 

 

0.6

0.7

 

0.9

 

 

 

[0.1, 0.9]

[0.3,

 

 

[0.1,

[0.2,

 

[0.6,

95% CI

 

 

1.0]

 

 

1.0]

1.1]

 

1.2]

 

 

 

 

 

 

 

 

 

0.0054

0.0002

 

 

0.0110

0.0028

 

<0.000

p-value

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OFF time (hrs) (c)

 

 

 

 

 

 

 

 

 

 

Baseline (b)

5.3 (2.1)

 

5.2 (2.0)

5.2

5.3 (2.1)

 

5.2

5.2

5.4 (2.0)

5.3

 

 

(2.2)

 

(2.2)

(2.1)

(2.0)

 

 

 

 

 

 

 

Change LSM (SE)

-0.8

 

-1.4

-1.5

-1.0

 

-1.5

-1.6

-0.5

-1.5

 

(0.20)

 

(0.20)

(0.20)

(0.20)

 

(0.19)

(0.19)

(0.10)

(0.10)

LS Diff vs Placebo

 

 

-0.6

-0.7

 

 

-0.5

-0.6

 

-1.0

 

 

 

[-0.9,

[-1.0,

 

 

[-0.8,

[-0.9,

 

[-1.3,

95% CI

 

 

-0.3]

-0.4]

 

 

-0.2]

-0.3]

 

-0.7]

 

 

 

0.0002

<0.0001

 

 

0.0028

0.0003

 

<0.000

p-value

 

 

 

 

 

 

 

 

 

 

 

 

 

 

UPDRS III (c)

 

 

 

 

 

 

 

 

 

 

Baseline (b)

28.6

 

27.3

28.4

28.6

 

27.3

28.4

23.0

22.3

 

(12.0)

 

(12.8)

(13.5)

(12.0)

 

(12.8)

(13.5)

(12.8)

(11.8)

Change LSM (SE)

-4.5

 

-6.1

-6.8

-4.4

 

-5.6

-6.5

-2.6

-3.5

 

(0.83)

 

(0.82)

(0.82)

(0.85)

 

(0.84)

(0.84)

(0.34)

(0.34)

LS Diff vs Placebo

 

 

-1.6

-2.3

 

 

-1.2

-2.1

 

-0.9

Study

 

 

 

016/018

 

27919 (SETTLE)

 

 

(24 weeks)

 

(2 years)

 

(24 weeks)

Dose (mg/day) (a)

 

 

Safinamide

 

Safinamide

 

Safin-

 

Placebo

 

Placebo

Placebo

amide

 

 

 

 

 

 

 

 

 

 

50-100

 

 

 

 

 

 

 

 

 

 

 

 

(d)

 

 

 

 

 

 

 

 

 

 

 

 

 

[-3.0,

 

[-3.7,

 

[-2.6,

[-3.5,

 

[-1.8,

95% CI

 

 

-0.2]

 

-0.9]

 

0.2]

-0.6]

 

0.0]

p-value

 

 

0.0207

 

0.0010

 

0.0939

0.0047

 

0.0514

UPDRS II (c)

 

 

 

 

 

 

 

 

 

 

Baseline (b)

12.2

 

11.8

 

12.1

12.2

11.8

12.1

10.4

10.0

 

(5.9)

 

(5.7)

 

(5.9)

(5.9)

(5.7)

(5.9)

(6.3)

(5.6)

Change LSM (SE)

-1.2

 

-1.9

 

-2.3

-1.4

-2.0

-2.5

-0.8

-1.2

 

(0.4)

 

(0.4)

 

(0.4)

(0.3)

(0.3)

(0.3)

(0.2)

(0.2)

LS Diff vs Placebo

 

 

-0.7

 

-1.1

 

-0.6

-1.1

 

-0.4

 

 

 

[-1.3,

 

[-1.7,

 

[-1.3,

[-1.8,

 

[-0.9,

95% CI

 

 

-0.0]

 

-0.5]

 

0.0]

-0.4]

 

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

(43.9)

 

(54.8)

 

(56.0)

(47.2)

(57.6)

(54.2)

(42.5)

(56.3)

p-value

 

 

0.0233

 

0.0122

 

0.0308

0.1481

 

0.0013

≥60 minutes increase

 

 

 

 

 

 

 

 

 

 

ON time and decrease

 

52 (24.0)

 

28 (13.2)

24 (8.8)

in OFF time and ≥ 30%

 

 

(15.1)

 

 

(25.9)

(19.8)

(19.4)

(18.1)

improvement UPDRS

 

 

 

 

 

 

 

 

 

 

III

 

 

 

 

 

 

 

 

 

 

p-value

 

 

0.0216

 

0.0061

 

0.0671

0.0827

 

0.0017

CGI-C: patients who

 

 

 

 

 

were much/very much

 

72 (33.2)

 

46 (21.7)

26 (9.5)

(19.8)

 

 

(36.1)

(28.6)

(29.6)

(24.4)

improved

 

 

 

 

 

 

 

 

 

 

 

 

 

0.0017

 

0.0002

 

0.0962

0.0575

 

<0.000

p-value (f)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(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.

5.2Pharmacokinetic 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).

5.3Preclinical 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

6.1List 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)

6.2Incompatibilities

Not applicable

6.3Shelf life

36 months

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

PVC/PVDC/Aluminium blister packs of 14, 28, 30, 90 and 100 tablets.

Not all pack sizes may be marketed.

6.6Special 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

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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