MAYZENT 0.25 MG

Israel - English - Ministry of Health

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Active ingredient:
SIPONIMOD AS FUMARIC ACID
Available from:
NOVARTIS ISRAEL LTD
ATC code:
L04AA42
Pharmaceutical form:
FILM COATED TABLETS
Composition:
SIPONIMOD AS FUMARIC ACID 0.25 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
NOVARTIS PHARMA STEIN AG, SWITZERLAND
Therapeutic area:
SIPONIMOD
Therapeutic indications:
Mayzent is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease, and active secondary progressive disease, in adults.
Authorization number:
165 54 36195 00
Authorization date:
2020-10-26

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

01-04-2021

Patient Information leaflet Patient Information leaflet - Hebrew

01-04-2021

Read the complete document

.ةيداعلا ةعرجلاب جلاعلا ىلإ لقتنت فوس ،6 ـلا مويلا يف عم حابصلا يف صارقلأا لوانت نسحتس

ي ،جلاعلا نم ىلولأا 6 ـلا مايلأا يف .ماعط نود نم وأ جلاعلا ةعرج (غلم 2 تنزيام نم دحاو صرق( مويلا يف ةرم غلم 2 يه ةعبتملا ةعرجلا .ماعط نود نم وأ عم تنزيام نم صارقأ 4) طقف مويلا يف ةرم غلم 1 لوانت كبيبط كنم بلطي دق ككفي كمسج نأ جلاعلا ءدب لبق مدلا صحف رهظأ اذإ كلذو ،)غلم 0.25 تفلن .)2 لصفلا يف "ةعباتملاو تاصوحفلا" رظنا( رثكأ ءطبب تنزيام صارقأ 5 لوانت نإف ،كمسج يف ءطبب ككفتي ءاودلا ناك اذإ هنأ ىلإ كهابتنا ام قفو ةرياعملا ةرتف نم سماخلا مويلا يف غلم 0.25 ةعرجب تنزيام نم .كل انمآ نوكي ،هلاعأ ءاج .اهب ىصوملا ةعرجلا زواجت زوجي لا لوانتلا ةقيرط .ءاملا عم صرقلا لوانت كيلع .طقف يومفلا لامعتسلال

دعم تنزيام .صارقلأا غضم/رطش/قحس لوح تامولعم كانه تسيل أطخلا قيرط نع ىلعأ ةعرج تلوانت اذإ تلوانت اذإ وأ ،أطخلا قيرط نع تنزيام صارقأ نم ربكأ ةيمك تلوانت اذإ ةوبعلا نم لادب جلاعلا ةوبع نم كب صاخلا لولأا صرقلا أطخلا قيرط نع ةجاحب كنأ كبيبط ررقي نأ ل

متح

ي .كبيبط ىلإ هجوت ،)ةرياعملا ةوبع( ةيلولأا .ةعباتمل عوضخلا ىلإ ىلإ وأ بيبطلا ىلإ اروف

جوت ،أطخلا قيرط نع ءاودلا نم لفط علتبا اذإ .ءاودلا ة

وبع كعم ا

حطصم ىفشتسملل ةعباتلا ئراوطلا ةفرغ ءاودلا ل

ُ

وانت تيسن اذإ ،كتعرج لوانت مايلأا دحأ يف تيسن اذإ ،جلاعلا نم ىلولأا 6 ـلا مايلأا للاخ .ةيلاتلا ةعرجلا لوانتت نأ لبق كبيبط ىلإ هجوت يف ديدج نم جلاعلا ءدب كيلع .ةديدج ةرياعم ةوبع بيبطلا كل فصيس .1 مويلا عباسلا مويلا( جلاعلا نم ةيداعلا ةعرجلا عبتت تنأو كتعرج لوانت تيطخت اذإ .كركذت روف ةعرجلا لوانت ،)ا

دعاصف عباتو ،ةيسنملا ةعرجلا

َّ

طخت ،ةيلاتلا كتعرج لوانتل ابيرقت ناولأا نآ اذإ نع اضيوعت ةفعاضم ةعرج لوانت كل زوجي لا .داتعملاك ءاودلا لوانت .ةيسنملا ةعرجلا كبيبط ىلإ هجوت ،رثكأو مايأ 4 ةدمل لاتتم لكشب تنزيام لوانت تيسن اذإ ،ةديدج ةرياعم ةوبع كبيبط كل فصي فوس .ةيلاتلا ةعرجلا لوانتت نأ لبق .1 مويلا يف ديدج نم جلاعلا ءدب كيلع نوكي فوسو .بيبطلا تايصوت قفو جلاعلا ىلع ةموادملا كيلع جلاعلا اذه نع فقوتلا كل زوجي لا ،ةيحصلا كتلاح ىلع نسحت أرط اذإ ىتح .بيبطلا ةراشتسا نود نم يئاودلا ءاودلا ل

ُ

وانت نع تفقوت اذإ .لاوأ كبيبط ةراشتسا نود كتعرج ر

يغت لا وأ تنزيام لوانت نع فقوتت لا نأ ل

متح

ي .جلاعلا نع فقوتلا دعب مايأ 10 ىتح كمسج يف تنزيام لظي ىتح اضفخنم كيدل )Lymphocytes( ءاضيبلا مدلا ايلاخ دادعت لظي ضارعلأا ثدحت نأ ل

متح

ي .تنزيام لوانت نع فقوتلا دعب عيباسأ 3-4 ضارعلأا" لصفلا رظنا( ةرتفلا هذه للاخ ةرشنلا هذه يف ةفوصوملا ةيبناجلا .)"ةيبناجلا ذنم مايأ 4 نم رثكأ رورم دعب اددجم تنزيامب جلاعلا كيلع نيعتي ناك اذإ ءدب كيلعو ،ةديدج ةرياعم ةوبع بيبطلا كل فصيس ،هلوانت نع تفقوت نأ .1 مويلا يف ديدج نم جلاعلا فاقيإ دعب مقافت كيدل ددعتملا بلصتلا نأ دقتعت تنك اذإ اروف كبيبط ربخأ .تنزيامب جلاعلا نمو ءاودلا ة

ّ

وبع ىلع قصلملا نم ق

ّ

قحت !ملاظلا يف ةيودلأا لوانت عنم

ُ

ي

اذإ ةي

ّ

بطلا تارا

ّ

ظنلا عض .ءاود اهيف لوانتت ة

ّ

رم

ّ

لك يف ة

ّ

يئاودلا ةعرجلا .اهيلإ ةجاحب تنك وأ بيبطلا ر

ِ

شتسا ،ءاودلا لامعتساب ق

ّ

لعتت ىرخأ ةلئسأ

َ

كيدل تناك اذإ .يلديصلا

.

ةيبناجلا ضارعلأا ضعب ىدل ةيبناج ا

ضارعأ تنزيام لامعتسا ب

بسي نأ نكمي ،ةيودلأا عيمجك

لاأ لمتحملا نمف .ة

يبناجلا ضارعلأا ةمئاق ةءارق دنع عزفت لا .نيم

دختسملا .اهنم

يأ نم يناعت ةريطخ نوكت دق ةيبناج ضارعأ كانه نيلمعتسم 1-10 ىدل رهظت ضارعأ ( common ( ةعئاش ةيبناج ضارعأ :100 لصأ نم

ضارعأ( رمحأ دلج ىلع رهظت ،لئاسب ةئيلم ةريغص تلاصيوح عم حفط دق يذلا ( Herpes zoster( يقاطنلا سبرهلا ىعدت ةيسوريف ىودع )اداح نوكي

ثيح )BCC( ةيدعاقلا ايلاخلا ناطرس ىعدي دلجلا ناطرس نم عون رهظي دق هنأ ريغ ،ؤلؤللاب ةهيبش تءاوتن لكش ىلع ةبيرق نايحأ يف رهظي ىرخأ لاكشأب

تايوافمللا ةلق( ىودعلا ةجيتن مفلا يف تاحرقت وأ/و ةرجنحلا يف ملأ ،ىمح ))مدلا يف تايوافمللا ددع ضافخنا(

تابون ،تاجلاتخا

،ةيؤرلا زكرم يف ءايمع ةعقب وأ لظ ةيؤر لثم ةيؤرلا يف تابارطضا ةمذو ضارعأ( ليصافت وأ ناولأ ةيؤرب زيمتت لكاشم ،ةيؤرلا ش

وشت )نيعلا نم يفلخلا ءزجلا يف ةيكبشلا ةعقب يف مروت يه يتلا ،ةيعقب

atrioventricular ) ينيطب ينيذأ راصحإ( ةمظتنم ريغ بلق مظن ةريتو

(( block

(Bradycardia) ةئيطب بلق مظن ةريتو .ضارعلأا هذه دحأب ترعش اذإ اروف بيبطلا ىلإ هجوتلا بجي اهراشتنا ةريتو ددح

ُ

ت مل ضارعأ( ةفورعم ريغ اهتريتو ةيبناج ضارعأ )دعب

اياحسلا باهتلا كلذ يف امب )تايفختسملاب ةيرطف ىودع( ةيرطف ىودع عادص لثم ضارعأ عم )cryptococcal meningitis( تايفختسملاب كابترا وأ نايثغ ،ءوضلل ةيساسح ،ةبقرلا س

بيت عم

ة

ّ

يفاضإ ةيبناج ضارعأ .هاندأ ةروكذملا ةيبناجلا ضارعلأا ىلع ىرخلأا ةيبناجلا ضارعلأا لمتشت .يلديصلا وأ بيبطلا ربخأ ،ةيبناجلا ضارعلأا هذه دحأ مقافت اذإ رثكأ ىدل رهظت ضارعأ ) very common ) ادج ةعئاش ةيبناج ضارعأ :ةرشع لصأ نم لمعتسم نم

عادص

،عادصلا لثم ضارعأ انايحأ هقفارت ،)مدلا طغض عافترا( عفترم مد طغض ةخودلاو

دبكلا تاميزنإ تايوتسم عافترا ىلإ مدلا تاصوحف جئاتن ريشت نيلمعتسم 1-10 ىدل رهظت ضارعأ ) common ( ةعئاش ةيبناج ضارعأ :100 لصأ نم

ةديدج )Moles) تاماش

ةخود

مسجلا يف يدارإ لا نافجر

لاهسإ

نايثغ

نيمدقلا يتحار وأ نيديلا يتفك يف ملأ

)ةيطيحم ةمذو( نيمدقلا يتحار وأ نيقاسلا ،نيلحاكلا ،نيديلا يتفك مروت

ءايعإ ،فعض

ءادلأا يف ضافخنا ىلإ ريشت يتلا نيتئرلا ءادأ جئاتن تيناع اذإ وأ ،ةيبناجلا ضارعلأا نم

ٌّ

يأ مقافت اذإ ،يبناج ضراع رهظ اذإ .بيبطلا ةراشتسا كيلع ،ةرشنلا يف ر

َ

كذ

ُ

ي مل

ّ

يبناج ض

ِ

راع نم غلابلإا" طبار ىلع طغضلا ربع ةيبناجلا ضارعلأاب ة

حصلا ةرازو غلابإ نكمي ةيسيئرلا ةحفصلا يف دوجوملا ،"يئاودلا جلاعلا ببسب ةيبناجلا ضارعلأا نع ةرامتسا ىلإ كهجوي يذلا )

www.health.gov.

) ة

حصلا ةرازو عقومل :طبارلا ىلإ لوخدلا ربع وأ ةيبناجلا ضارعلأا نع غلابلإل تنرتنلإا ىلع

.https://sideeffects.health.gov.il

5

.

؟ءاودلا نيزخت ةيفيك

ديعب ،قلغم ناكم يف ،رخآ ءاود

لكو ،ءاودلا اذه ظفح بجي ! ممستلا ب

نجت

مستلا ب

نجتت اذكهو ،لافطلأا وأ/و دلاولأا ةيؤر لاجمو يديأ لوانتم نع .بيبطلا نم ةحيرص تاميلعت نود ؤيقتلا ببست لا رهاظلا )exp. date( ةيحلاصلا ءاهتنا خيرات دعب ءاودلا لامعتسا زوجي لا .رهشلا سفن نم ريخلأا مويلا ىلإ بسن

ي ة

يحلاصلا ءاهتنا خيرات .ةوبعلا ىلع :نيزختلا طورش . 25° C نم ىلعأ ةرارح ةجردب نيزختلا زوجي لا .ررض تاملاع اهيلع وأ ةررضتم ةوبعلا نأ تظحلا اذإ ءاودلا لامعتسا عنم

.ةيلزنملا تايافنلا ةلس يف وأ يحصلا فرصلا هايم يف ةيودلأا نم صلختت لا .لامعتسلاا ديق دعت مل يتلا ةيودلأا نم صلختلا كيلع فيك يلديصلا لأسا .ةئيبلا ةيامح يف ريبادتلا هذه دعاست

6

.

ة

ّ

يفاضإ تامولعم :ىلع ا

ً

ضيأ ءاودلا يوتحي ،ةلا

ّ

عفلا ةداملا ىلإ ةفاضإ :غلم 2 و غلم 0.25 تنزيام صرق ةاون

lactose

monohydrate,

cellulose

microcrystalline/

microcrystalline

cellulose,

crospovidone

)type

glycerol dibehenate/glyceryl behenate, silica colloidal

DOR-May-PIL-0221-07 MAY APL FEB21 V2

DOR-May-PIL-0221-07 MAY APL FEB21 V2

Patient leaflet in accordance with the Pharmacists’

Regulations (Preparations) - 1986

This medicine is dispensed with a doctor’s prescription only

Mayzent 0.25 mg

Mayzent 2 mg

Film-coated tablets

Active ingredient

siponimod 0.25 mg (as siponimod fumaric acid) in each film-

coated tablet

siponimod 2 mg (as siponimod fumaric acid( in each film-

coated tablet

Inactive ingredients and allergens in this medicine: See section

2 under ‘Important information about some of this medicine’s

ingredients’ and section 6 ‘Additional information’.

Read the entire leaflet carefully before you start using

this medicine. This leaflet contains concise information

about this medicine. If you have any further questions, consult

your doctor or pharmacist.

This medicine has been prescribed to treat you. Do not pass

it on to others. It may harm them, even if it seems to you that

their medical condition is similar to yours.

In addition to the patient leaflet, Mayzent also has a

Patient/Caregiver Guide and a Pregnancy Reminder Card.

These guides contain important safety information that you

should know of before you start and during your treatment

with Mayzent and which you should follow. Read the

Patient/Caregiver

Guide

Pregnancy

Reminder

Card as well as the patient leaflet before you start taking

this medicine. Keep the guides in case you need to read

them again.

1. What is this medicine intended for?

Mayzent is intended for the treatment of adults with relapsing

forms of multiple

sclerosis )MS( including relapsing-remitting

disease )RRMS(, and active secondary progressive disease

(SPMS).

Therapeutic group: immunosuppressants, selective

immunosuppressants.

Active disease in secondary progressive multiple sclerosis

is when there are relapses or when magnetic resonance

imaging (MRI) results show signs of inflammation.

Mayzent helps to protect the central nervous system )CNS(

from attacks by the body’s own immune system. It does this

- making some white blood cells (called lymphocytes) less

able to move freely within the body.

- stopping the white blood cells (lymphocytes) from reaching

the brain and spinal cord.

This reduces nerve damage caused by SPMS and as a result

Mayzent helps to slow down the effects of the disease activity

)such as worsening disability, brain lesions, and relapses(.

2. Before using this medicine

Do not use this medicine if:

you are sensitive )allergic( to siponimod, peanuts, soya or

any of the other ingredients in this medicine (see ‘Important

information about some of this medicine’s ingredients’ as

well as section 6 ‘Additional information’).

you have an immunodeficiency syndrome.

you have ever had progressive multifocal

leukoencephalopathy or cryptococcal meningitis.

you have an active cancer.

you have severe liver problems.

in the last 6 months, you have had a heart attack, unstable

angina, stroke or certain types of heart failure.

you have certain types of irregular or abnormal heartbeat

)arrhythmia( and you do not have a pacemaker.

If your blood tests show that your body cannot break

down this medicine well enough, do not take it )see ‘Tests

and follow-up’(.

you are pregnant or could become pregnant and are not

using effective contraception.

Special warnings about using this medicine

Before treatment with Mayzent, tell your doctor if:

you have an infection or if your immune system does not work

properly (for example due to a disease or to medicines that

suppress the immune system; see also ‘Drug interactions’).

you have never had chickenpox and have not been vaccinated

against it. You may be at a high risk of complications if you

develop chickenpox during Mayzent treatment. Your doctor

may want to vaccinate you against chickenpox before you

start treatment.

you are planning to have any vaccinations. Your doctor will

advise you on this )see ‘Drug interactions’(.

you have ever had, or have, difficulties with your vision )in

particular a condition called macular edema) or an infection

or inflammation of the eye )uveitis(. Your doctor may want

you to have eye examinations before you start treatment

and regularly while you are on treatment. Mayzent can

cause a swelling in the macula (the area of the eye that

enables you to see shapes, colors and details( known as

macular edema. Your chance of developing macular edema

is higher if you have had it before or if you have ever had an

inflammation of the eye )uveitis(.

you have diabetes. The chance of developing macular

edema )see above( is higher in patients with diabetes.

you have ever had any of the following conditions )even if

you are receiving treatment for them(: severe heart disease,

irregular or abnormal heartbeat )arrhythmia(, stroke or other

disease related to the blood vessels in the brain, a slow

heart rate, fainting, disturbance of heart rhythm )indicated

by abnormal ECG ]electrocardiogram[ results(.

you have severe breathing problems when sleeping (sleep

apnea).

you have high blood pressure that cannot be controlled by

medicines. Your blood pressure will need to be checked

regularly.

you have ever had liver problems. Your doctor may want

to perform blood tests to check your liver function before

prescribing Mayzent.

you could become pregnant, because using siponimod

during pregnancy can harm the unborn baby. Before you

start treatment, your doctor will explain the risks and ask you

to do a pregnancy test to ensure that you are not pregnant.

You must use effective contraception during treatment and

up to 10 days after stopping treatment )see ‘Pregnancy,

breastfeeding and fertility’).

If any of the above applies to you, tell your doctor before

taking Mayzent.

Look out for the following while taking Mayzent

If you get any of the following while taking Mayzent, tell your

doctor immediately because it could be serious:

if you have an infection. Mayzent lowers the number of

white blood cells in your blood. White blood cells fight

infection, so you may get infections more easily while you

are taking Mayzent )and up to 3 to 4 weeks after you stop

taking it). These infections could be serious and possibly

even life-threatening.

if you think your MS is getting worse or if you notice any

new or unusual symptoms. A very rare brain infection

called progressive multifocal leukoencephalopathy )PML(

used during pregnancy, there is a risk of harm to the unborn

baby. If you are a woman of childbearing age, your doctor

will inform you about this risk before you start treatment with

Mayzent and will ask you to do a pregnancy test in order

to ensure that you are not pregnant. You must use effective

contraception while taking Mayzent and for at least 10 days

after you stop taking it to avoid becoming pregnant. Ask your

doctor about reliable methods of contraception.

If you do become pregnant while taking Mayzent, tell your

doctor straight away. Your doctor will decide to stop treatment

(see ‘If you stop taking this medicine’ in section 3(. Specialized

pre-natal monitoring will be performed.

Do not breastfeed while you are taking Mayzent. It is not

known if Mayzent and its main breakdown products pass into

breast milk.

Fertility

The impact of Mayzent on fertility in humans has not been

studied.

Driving and using machines

Your doctor will tell you whether your illness allows you to

drive vehicles and use machines safely. Mayzent has no

effect or a negligible effect on your ability to drive and use

machines when you are treated with your regular dose. At the

start of treatment you may occasionally feel dizzy. On your

first day of treatment with Mayzent, therefore, you should not

drive and should not use machines.

Important information about some of this medicine’s

ingredients

Mayzent contains lactose and soya lecithin

If you have been told by your doctor that you have an

intolerance to some sugars, contact your doctor before taking

this medicine.

If you are sensitive )allergic( to peanuts or soya, do not use

this medicine.

3. How to use this medicine?

Treatment with Mayzent will be overseen by a doctor who is

experienced in the treatment of MS.

Always use this medicine according to your doctor’s instructions.

Check with your doctor or pharmacist if you are not sure

about your dose or about how to take this medicine.

Only your doctor will determine your dose and how you should

take this medicine. The usual recommended dosage is:

Starting treatment

You will be given a starter pack called a titration pack, with

which your dose will be gradually increased over 5 days.

Follow the instructions on the pack )see also the ‘Titration

pack’ table).

The purpose of the titration phase is to reduce the risk of side

effects on your heart at the start of treatment.

Your doctor will monitor you closely at the start of treatment if

you are at risk of your heartbeat becoming slower or irregular.

Titration pack

Day

Dose

Number of Mayzent

0.25 mg tablets to take

Day 1

0.25 mg

1 tablet

Day 2

0.25 mg

1 tablet

Day 3

0.5 mg

2 tablets

Day 4

0.75 mg

3 tablets

Day 5

1.25 mg

5 tablets

On day 6, you will switch to your regular treatment dose.

On the first 6 days of treatment, it is recommended that you

take the tablets in the morning with or without food.

Treatment dose

The recommended dose is 2 mg once daily (one tablet of

2 mg Mayzent( with or without food.

Your doctor may instruct you to take only 1 mg once daily (four

0.25 mg Mayzent tablets( if the blood test performed before

the start of treatment showed that your body breaks down

Mayzent more slowly )see ‘Tests and follow-up’ in section 2).

If slow breakdown applies to you, note that it is nevertheless

safe for you to take five 0.25 mg Mayzent tablets on day 5 of

the titration period as indicated above.

Do not exceed the recommended dose.

How to take this medicine

Mayzent is for oral use only. Take the tablet with water.

There is no information about crushing/splitting/chewing the

tablets.

If you have accidentally taken a higher dose

If you have accidentally taken too many Mayzent tablets, or

if you take your first tablet from the treatment pack instead

of the starter pack (titration pack( by mistake, contact your

doctor straight away. Your doctor may decide to keep you

under observation.

child

accidentally

swallowed

some

medicine,

immediately see a doctor or go to a hospital emergency room

and bring the medicine package with you.

If you forget to take the medicine

During the first 6 days of treatment, if you have forgotten to

take your dose on one day, contact your doctor before you

take the next dose.

Your doctor will prescribe a new titration pack. You will have

to restart your treatment at day 1.

If you miss a dose when you are on the regular treatment

dose (day 7 onwards(, take the missed dose as soon as you

remember.

If it is almost time for your next dose, skip the missed dose

and continue as usual. Do not take a double dose to make up

for a forgotten dose.

If you forget to take Mayzent for 4 or more days in a row,

contact your doctor before you take the next dose. Your

doctor will prescribe a new titration pack and you will have to

restart treatment at day 1.

Adhere to the treatment as recommended by your doctor.

Even if your health improves, do not stop taking this medicine

without consulting your doctor.

If you stop taking this medicine

Do not stop taking Mayzent or change your dose without

talking to your doctor first.

Mayzent will stay in your body for up to 10 days after you

stop treatment. Your white blood cell )lymphocyte( count

may remain low for up to 3 to 4 weeks after you stop taking

Mayzent. The side effects described in this leaflet may still

occur during this period (see the section ‘Side effects’).

If you have to restart Mayzent more than 4 days after you

stopped taking it, your doctor will prescribe a new titration

pack and you will have to restart treatment at day 1.

Tell your doctor straight away if you think your MS worsens

after you have stopped treatment with Mayzent.

Do not take medicines in the dark! Check the label and

dose every time you take medicine. Wear glasses if you

need them.

If you have any further questions about using this medicine,

consult your doctor or pharmacist.

. Side effects

Like with all medicines, using Mayzent may cause side effects

in some users. Do not be alarmed by this list of side effects;

you may not experience any of them.

Some side effects could be serious

Common side effects (affect 1-10 in 100 users):

rash with small fluid-filled blisters, appearing on reddened

skin )symptoms of a viral infection called herpes zoster that

can be severe(

a type of skin cancer called basal cell carcinoma (BCC)

which often appears as a pearly nodule, though it can also

take other forms

fever, sore throat and/or mouth ulcers due to infection

(lymphopenia ]reduced number of lymphocytes in your

blood[(

convulsions, fits

visual disturbances such as a shadow or a blind spot in the

center of vision, blurred vision, problems seeing colors or

details )symptoms of macular edema, which is a swelling in

the macular area of the retina at the back of the eye)

irregular heartbeat )atrioventricular block(

slow heartbeat (bradycardia)

If you get any of these side effects, tell your doctor straight

away.

Side effects of unknown frequency (the frequency of

these effects has not been established yet)

cryptococcal infections )a type of fungal infection(, including

cryptococcal meningitis with symptoms such as headache

together

with

stiff

neck,

sensitivity

light,

nausea

confusion

Additional side effects

Additional side effects include those listed below. If any of

these side effects become severe, tell your doctor or

pharmacist.

Very common side effects (affect more than 1 in 10 users)

headache

high blood pressure )hypertension(, sometimes with symptoms

such as headache and dizziness

blood test results showing increased liver enzyme levels

Common side effects (affect 1-10 in 100 users):

new moles

dizziness

involuntary shaking of the body )tremor(

diarrhea

nausea

pain in hands or feet

swollen hands, ankles, legs or feet (peripheral edema)

weakness, exhaustion

lung function test results showing decreased function

If you experience any side effect, if any side effect gets

worse, or if you experience a side effect not mentioned

in this leaflet, consult your doctor.

You can report side effects to the Ministry of Health by

following the link ‘Reporting Side Effects of Drug Treatment’

on the Ministry of Health home page (www.health.gov.il)

which links to an online form for reporting side effects. You

can also use this link: https://sideeffects.health.gov.il.

5. How to store the medicine?

Prevent poisoning! To prevent poisoning, keep this, and all

other medicines, in a closed place, out of the reach and sight

of children and/or infants. Do not induce vomiting unless

explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry date (exp. date)

which is stated on the package. The expiry date refers to the

last day of that month.

Storage conditions:

Do not store above 25°C. Do not use this medicine if you

notice that the pack is damaged or shows signs of tampering.

throw

away

medicines

wastewater

household waste. Ask your pharmacist how to throw away

medicines you no longer use. These measures will help

protect the environment.

6. Additional information

In addition to the active ingredient, this medicine also

contains:

Mayzent 0.25 mg and 2 mg tablet core:

lactose monohydrate, cellulose microcrystalline/microcrystalline

cellulose,

crospovidone )type A(, glycerol dibehenate/glyceryl

behenate, silica colloidal anhydrous/colloidal silica dixide.

Mayzent 0.25 mg tablet coating:

polyvinyl alcohol-part hydrolyzed, titanium dioxide )E171(,

talc, lecithin )soya( )E322(, xanthan gum, iron oxide red

)E172(, black iron oxide )E172(.

Mayzent 2 mg tablet coating:

polyvinyl alcohol-part hydrolyzed, titanium dioxide )E171(,

talc, lecithin )soya( )E322(, xanthan gum, iron oxide yellow

)E172(, iron oxide red )E172(.

What the medicine looks like and contents of the pack

Mayzent 0.25 mg - pale red, round, bevel-edged film-coated

tablets with no score line and with the company logo on one

side and “T” on the other side.

Mayzent 0.25 mg film-coated tablets are available in the

following packages:

- Titration pack (as wallet) containing 12 tablets

- Pack of 120 tablets

Mayzent 2 mg - pale yellow, round, bevel-edged film-coated

tablets with no score line and with the company logo on one

side and “II” on the other side.

Mayzent 2 mg film-coated tablets are available in packs of

28 tablets.

Registration holder and importer name and address:

Novartis Israel Ltd., P.O.B 7126, Tel Aviv.

Revised in February 2021 according to MOH guidelines.

Registration number of the medicine in the Ministry of

Health’s National Drug Registry:

Mayzent 0.25 mg: 165-54-36195

Mayzent 2 mg: 165-55-36196

can cause symptoms similar to SPMS. PML can occur in

patients taking medicines like Mayzent and other medicines

used for treating MS.

if you have fever, feel like you have flu or have a headache

together with a stiff neck, sensitivity to light, nausea or

confusion. These may be symptoms of a type of meningitis

caused by a fungal infection (cryptococcal meningitis).

if you have changes in your vision, for example if the center

of your vision becomes blurred or has shadows, a blind spot

develops in the center of your vision, or you have problems

seeing colors or fine detail. These could be symptoms

of macular edema. You may not notice any symptoms in

the early stages of macular edema, and it can cause the

same visual symptoms as an MS attack (optic neuritis).

Your doctor may want you to have an eye examination 3 or

4 months after starting treatment and possibly again later. If

macular edema is confirmed, your doctor may advise you to

stop Mayzent treatment.

if you have symptoms such as sudden onset of severe

headache, confusion, seizures and vision changes. These

may be symptoms of a condition called posterior reversible

encephalopathy syndrome (PRES).

have

symptoms

such

unexplained

nausea,

vomiting, abdominal pain, tiredness, yellowing of the skin or

whites of the eyes or abnormally dark urine. These may be

symptoms of liver problems.

if you notice skin nodules )e.g., shiny, pearly nodules(,

patches or open sores that do not heal within weeks.

Slow heart rate (bradycardia) and irregular heartbeat

During the first days of treatment, Mayzent can cause the

heart rate to slow down )bradycardia(. You may not feel

anything or you may feel dizzy or tired. It may also cause your

heartbeat to become irregular at the beginning of treatment.

If anything indicates that you may be at higher risk of

experiencing these effects, your doctor may decide to monitor

your condition more closely at the start of treatment, refer you

first to a heart specialist )cardiologist(, or choose not to give

you Mayzent.

Skin cancer

Cases of skin cancer have been reported in MS patients

treated with Mayzent. Talk to your doctor straight away if you

notice any skin nodules (e.

g., shiny pearly nodules(, patches

or open sores that do not heal within weeks.

Symptoms of skin cancer may include abnormal growth or

changes of skin tissue )e.g., unusual moles( with a change

in color, shape or size over time. Before you start taking

Mayzent, a skin examination is required to check whether you

have any skin nodules. Your doctor will also carry out regular

skin examinations during your treatment with Mayzent. If you

develop problems with your skin, your doctor may refer you

to a dermatologist, who after consultation may decide that it

is important to see you on a regular basis.

Exposure to the sun and protection against the sun

Mayzent weakens your immune system. This may increase

your risk of developing skin cancer. You should limit your

exposure to the sun and UV rays by:

wearing appropriate protective clothing.

regularly applying sunscreen with a high degree of UV

protection.

Worsening of MS after stopping Mayzent treatment

Do not stop taking Mayzent or change your dose without

talking to your doctor first.

Tell your doctor straight away if you think your MS worsens

after you have stopped treatment with Mayzent )see ‘If you

stop taking this medicine’ in section 3).

Elderly patients (65 years of age and above)

Mayzent had not been studied in patients aged 65 years and

above. Talk to your doctor if you have any concerns.

Children and adolescents

This medicine is not intended for children and adolescents

below 18 years of age. There are no data available on

safety and efficacy of use of this medicine in children and

adolescents below 18 years of age.

Tests and follow-up

How quickly this medicine is broken down )metabolized( in

the body varies from patient to patient and different people

therefore require different doses. Your doctor will perform a

blood test before you start treatment to determine which dose

is best for you. In rare cases, the test result may indicate that

Mayzent is not right for you.

Your blood may also be tested before the start of treatment

and periodically during treatment to check the white blood cell

count. Your doctor may need to stop or reduce your Mayzent

dose if the white blood cell count is too low.

Before the start of treatment your blood will also be tested to

check how well your liver is working.

Drug interactions

If you are taking or have recently taken other medicines,

including

nonprescription

medications

and

dietary

supplements, tell your doctor or pharmacist. Particularly

if you are taking:

medicines for an irregular heartbeat, such as amiodarone,

procainamide, quinidine or sotalol. Your doctor may decide

not to prescribe Mayzent because it could intensify the

effect on irregular heartbeat.

medicines that slow down the heartbeat, such as diltiazem

or verapamil )which belong to a group of medicines called

calcium

channel

blockers(,

digoxin

ivabradine.

Your

doctor may refer you to a heart specialist, as your medicines

may need to be changed because Mayzent may also slow

down your heartbeat in the first days of treatment. If you are

taking a beta-blocker, such as atenolol or propranolol, your

doctor may ask you to temporarily stop your beta-blocker

treatment until you have reached your full daily dose of

Mayzent.

medicines

that

affect

immune

system,

such

chemotherapy, immunosuppressants or other medicines

to treat MS. Your doctor may ask you to stop taking these

medicines

to avoid an increased effect on the immune system.

vaccines. If you need to have a vaccination, talk to your

doctor first. During and for up to 4 weeks after stopping

treatment with Mayzent, you should not be given certain

types

vaccines

)called

live

attenuated

vaccines(

they could trigger the infection that they were supposed

to prevent )see ‘Before treatment with Mayzent, tell your

doctor if’ in section 2).

fluconazole

certain

other

medicines

increase

the levels of Mayzent in the blood and taking them in

combination with Mayzent is not recommended. Your doctor

will advise you on this.

carbamazepine and certain other medicines can lower the

levels of Mayzent in your blood and can therefore stop it

from working properly. Your doctor will advise you on this.

modafinil and certain other medicines can lower the levels

of Mayzent in the blood of certain patients and can therefore

stop it from working properly. Your doctor will advise you on

this if this is relevant for you.

phototherapy with UV radiation or PUVA photochemotherapy.

UV therapy during Mayzent treatment may increase your

risk of developing skin cancer.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, may be pregnant or are

planning to have a baby, ask your doctor or pharmacist for

advice before taking this medicine.

Do not use Mayzent during pregnancy, if you are trying to

become pregnant or if you are a woman of childbearing age

and you are not using effective contraception. If Mayzent is

anhydrous/colloidal silicon dioxide.

:غلم 0.25 تنزيام صرق ءلاط

polyvinyl alcohol-part hydrolyzed, titanium dioxide )E171(,

talc, lecithin )soya( )E322(, xanthan gum, iron oxide red

)E172(, black iron oxide )E172).

:غلم 2 تنزيام صرق ءلاط

polyvinyl alcohol-part hydrolyzed, titanium dioxide )E171(,

talc, lecithin )soya( )E322(, xanthan gum, iron oxide yellow

)E172(, iron oxide red )E172(.

ة

ّ

وبعلا يوحت اذامو ءاودلا ودبي فيك ةريدتسم ،رطشلل رطخ نود ،بحاش رمحأ اهنول ة

يلطم صارقأ - غلم 0.25 تنزيام .رخلآا بناجلا يف " T " و ،دحاو بناج يف ةكرشلا راعش اهيلعو ،ةردحنم فارطأ عم :ةيلاتلا تاوبعلا يف ق

وس

ت ،ة

يلطم صارقأ - غلم 0.25 تنزيام اصرق 12 ىلع يوتحت )ةظفحم ةوبعك( ةرياعم ةوبع - اصرق 120 اهيف ةوبع - عم ةريدتسم ،رطشلل رطخ نود ،بحاش رفصأ اهنول ة

يلطم صارقأ - غلم 2 تنزيام .رخلآا بناجلا يف " II " و ،دحاو بناج يف ةكرشلا راعش اهيلعو ،ةردحنم فارطأ .اصرق 28 ىلع يوتحت تاوبع نمض ق

وست ،ة

يلطم صارقأ غلم 2 تنزيام :هناونعو دروتسملاو ليجستلا بحاص مسا .بيبأ لت ،7126 ب.ص ،.ض.م ليئارسإ سيتراڨون .ةحصلا ةرازو تاميلعت قفو 2021 طابش يف اهريرحت مت :ةحصلا ةرازو يف يمسرلا ةيودلأا لجس يف ءاودلا ليجست مقر 165-54-36195 :غلم 0.25 تنزيام 165-55-36196 :غلم 2 تنزيام لاكل

دعم ءاودلاف اذه عم

كذملا ةغيصب

صنلا درو اهليهستو ةرشنلا هذه ةءارق طيسبتل .نيسنجلا

Read the complete document

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EU SmPC01.2021

1.

NAME OF THE MEDICINAL PRODUCT

Mayzent 0.25 mg

Mayzent 2 mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Mayzent 0.25 mg, film-coated tablets

Each film-coated tablet contains siponimod fumaric acid equivalent to 0.25 mg siponimod.

Excipient with known effect

Each tablet contains 62.197 mg lactose monohydrate and 0.092 mg lecithin (soya).

Mayzent 2 mg, film-coated tablets

Each film-coated tablet contains siponimod fumaric acid equivalent to 2 mg siponimod.

Excipient with known effect

Each tablet contains 60.251 mg lactose monohydrate and 0.092 mg lecithin (soya).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

Mayzent 0.25 mg, film-coated tablets

Pale red, unscored, round, biconvex, bevelled-edged film-coated tablet of approximately 6.1 mm

diameter with company logo on one side and “

” on the other side.

Mayzent 2 mg, film-coated tablets

Pale yellow, unscored, round, biconvex, bevelled-edged film-coated tablet of approximately 6.1 mm

diameter with company logo on one side and “

” on the other side.

4.

CLINICAL PARTICULARS

Patient/Caregiver Guide and Pregnancy Reminder Card

The marketing of Mayzent is subject to a risk management plan (RMP) including

‘Patient/Caregiver Guide’ and ‘Pregnancy Reminder Card’. These cards emphasize important

safety information that the patient should be aware of before and during treatments. Please

explain to the patient the need to review the card/s before starting treatment.

Physician’s Checklist

This product is marketed with Physician’s Checklist providing important safety information.

Please ensure you are familiar with this material as it contains important safety information.

4.1

Therapeutic indications

Mayzent is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include

relapsing-remitting disease, and active secondary progressive disease, in adults.

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EU SmPC01.2021

4.2

Posology and method of administration

Treatment with siponimod should be initiated and supervised by a physician experienced in the

management of multiple sclerosis.

Before initiation of treatment, patients must be genotyped for CYP2C9 to determine their CYP2C9

metaboliser status (see sections 4.4, 4.5 and 5.2).

In patients with a CYP2C9*3*3 genotype, siponimod should not be used (see sections 4.3, 4.4 and

5.2).

In patients with a CYP2C9*2*3 or *1*3 genotype, the recommended maintenance dose is 1 mg taken

once daily (four tablets of 0.25 mg) (see sections 4.4 and 5.2).

The recommended maintenance dose of siponimod in all other CYP2C9 genotype patients is 2 mg.

Mayzent is taken once daily.

Posology

Treatment initiation

Treatment has to be started with a titration pack that lasts for 5 days. Treatment starts with 0.25 mg

once daily on days 1 and 2, followed by once-daily doses of 0.5 mg on day 3, 0.75 mg on day 4, and

1.25 mg on day 5, to reach the patient’s prescribed maintenance dose of siponimod starting on day 6

(see Table 1).

During the first 6 days of treatment initiation the recommended daily dose should be taken once daily

in the morning with or without food.

Table 1

Dose titration regimen to reach maintenance dosage

Titration

Titration dose

Titration regimen

Dose

Day 1

0.25 mg

1 x 0.25 mg

TITRATION

Day 2

0.25 mg

1 x 0.25 mg

Day 3

0.5 mg

2 x 0.25 mg

Day 4

0.75 mg

3 x 0.25 mg

Day 5

1.25 mg

5 x 0.25 mg

Day 6

2 mg

1 x 2 mg

MAINTENANCE

In patients with CYP2C9*2*3 or *1*3 genotype, the recommended maintenance dose is 1 mg

taken once daily (4 x 0.25 mg) (see above and sections 4.4 and 5.2). Additional exposure of

0.25 mg on day 5 does not compromise patient safety.

Missed dose(s) during treatment initiation

During the first 6 days of treatment, if a titration dose is missed on one day treatment needs to be

re-initiated with a new titration pack.

Missed dose after day 6

If a dose is missed, the prescribed dose should be taken at the next scheduled time; the next dose

should not be doubled.

Re-initiation of maintenance therapy after treatment interruption

If maintenance treatment is interrupted for 4 or more consecutive daily doses, siponimod needs to be

re-initiated with a new titration pack.

Special populations

Elderly

Siponimod has not been studied in patients aged 65 years and above. Clinical studies included patients

up to the age of 61 years. Siponimod should be used with caution in the elderly due to insufficient data

MAY API FEB21 V2

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EU SmPC01.2021

on safety and efficacy (see section 5.2).

Renal impairment

Based on clinical pharmacology studies, no dose adjustment is needed in patients with renal

impairment (see section 5.2).

Hepatic impairment

Siponimod must not be used in patients with severe hepatic impairment (Child-Pugh class C) (see

section 4.3). Although no dose adjustment is needed in patients with mild or moderate hepatic

impairment, caution should be exercised when initiating treatment in these patients (see sections 4.4

and 5.2).

Paediatric population

Mayzent is not indicated for children and adolescents under 18 years old.

The safety and efficacy of siponimod in children and adolescents aged 0 to 18 years have not yet been

established. No data are available.

Method of administration

Oral use. Siponimod is taken with or without food.

The film-coated tablets should be swallowed whole with water.

4.3

Contraindications

Hypersensitivity to the active substance, or to peanut, soya or any of the excipients listed in

section 6.1.

Immunodeficiency syndrome.

History of progressive multifocal leukoencephalopathy or cryptococcal meningitis.

Active malignancies.

Severe liver impairment (Child-Pugh class C).

Patients who in the previous 6 months had a myocardial infarction (MI), unstable angina

pectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring

inpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure (see

section 4.4).

Patients with a history of second-degree Mobitz type II atrioventricular (AV) block,

third-degree AV block, sino-atrial heart block or sick-sinus syndrome, if they do not wear a

pacemaker (see section 4.4).

Patients homozygous for CYP2C9*3 (CYP2C9*3*3) genotype (poor metaboliser).

During pregnancy and in women of childbearing potential not using effective contraception (see

sections 4.4 and 4.6).

4.4

Special warnings and precautions for use

Infections

Risk of infections

A core pharmacodynamic effect of siponimod is a dose-dependent reduction of the peripheral

lymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration of

lymphocytes in lymphoid tissues (see section 5.1).

The immune system effects of siponimod may increase the risk of infections (see section 4.8).

Before initiating treatment, a recent complete blood count (CBC) (i.e. within last 6 months or after

discontinuation of prior therapy) should be available. Assessments of CBC are also recommended

periodically during treatment. Absolute lymphocyte counts <0.2 x 10

/l, if confirmed, should lead to

dose reduction to 1 mg, because in clinical studies siponimod dose was reduced in patients with

absolute lymphocyte counts <0.2 x 10

/l. Confirmed absolute lymphocyte counts <0.2 x 10

/l in a

MAY API FEB21 V2

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EU SmPC01.2021

patient already receiving siponimod 1 mg should lead to interruption of siponimod therapy until the

level reaches 0.6 x 10

/l when re-initiation of siponimod can be considered.

Initiation of treatment should be delayed in patients with severe active infection until resolution.

Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count,

may persist for up to 3 to 4 weeks after discontinuation, vigilance for infection should be continued

throughout this period (see below section “Stopping siponimod therapy”).

Patients should be instructed to report symptoms of infection to their physician promptly. Effective

diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while

on therapy. Suspension of treatment with siponimod should be considered if a patient develops a

serious infection.

A case of cryptococcal meningitis (CM) has been reported for siponimod. Cases of CM have been

reported for another sphingosine 1-phosphate (S1P) receptor modulator. Patients with symptoms and

signs consistent with CM should undergo prompt diagnostic evaluation. Siponimod treatment should

be suspended until CM has been excluded. If CM is diagnosed, appropriate treatment should be

initiated.

No cases of progressive multifocal leukoencephalopathy (PML) have been reported for siponimod in

the development programme; however, they have been reported for another S1P receptor modulator.

Physicians should be vigilant for clinical symptoms or magnetic resonance imaging (MRI) findings

that may be suggestive of PML. If PML is suspected, siponimod treatment should be suspended until

PML has been excluded.

Cases of herpes viral infection (including one case of reactivation of varicella zoster virus [VZV]

infection leading to varicella zoster meningitis) have been reported in the siponimod development

programme. Patients without a physician-confirmed history of varicella or without documentation of a

full course of vaccination against VZV should be tested for antibodies to VZV before starting

siponimod (see below section “Vaccination”).

Vaccination

A full course of vaccination with varicella vaccine is recommended for antibody-negative patients

prior to commencing treatment with siponimod, following which initiation of treatment should be

postponed for 1 month to allow the full effect of vaccination to occur (see section 4.8).

The use of live attenuated vaccines should be avoided while patients are taking siponimod and for

4 weeks after stopping treatment (see section 4.5).

Vaccinations may be less effective if administered during siponimod treatment. Discontinuation of

treatment 1 week prior to planned vaccination until 4 weeks after is recommended. When stopping

siponimod therapy for vaccination, the possible return of disease activity should be considered (see

below section “Stopping siponimod therapy”).

Concomitant treatment with anti-neoplastic, immune-modulating or immunosuppressive therapies

Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids)

should be co-administered with caution due to the risk of additive immune system effects during such

therapy (see section 4.5).

Macular oedema

Macular oedema with or without visual symptoms was more frequently reported on siponimod (1.8%)

than on placebo (0.2%) in the phase III clinical study (see section 4.8). The majority of cases occurred

within the first 3-4 months of therapy. An ophthalmological evaluation is therefore recommended

3-4 months after treatment initiation. As cases of macular oedema have also occurred on longer-term

treatment, patients should report visual disturbances at any time while on siponimod therapy and an

evaluation of the fundus, including the macula, is recommended.

MAY API FEB21 V2

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EU SmPC01.2021

Siponimod therapy should not be initiated in patients with macular oedema until resolution.

Siponimod should be used with caution in patients with a history of diabetes mellitus, uveitis or

underlying/co-existing retinal disease due to a potential increase in the risk of macular oedema (see

section 4.8). It is recommended that these patients should undergo an ophthalmological evaluation

prior to initiating therapy and regularly while receiving siponimod therapy to detect macular oedema.

Continuation of siponimod therapy in patients with macular oedema has not been evaluated. It is

recommended that siponimod be discontinued if a patient develops macular oedema. A decision on

whether or not siponimod should be re-initiated after resolution needs to take into account the

potential benefits and risks for the individual patient.

Bradyarrhythmia

Reduction in heart rate

Initiation of siponimod treatment results in a transient decrease in heart rate (see sections 4.8 and 5.1),

and a titration scheme to reach the maintenance dose on day 6 is therefore applied at the start of

treatment (see section 4.2).

After the first titration dose, the heart rate decrease starts within one hour and the day 1 decline is

maximal at approximately 3 to 4 hours. With continued up-titration, further heart rate decreases are

seen on subsequent days, with maximal decrease from day 1 (baseline) reached on day 5 to 6. The

highest daily post-dose decrease in absolute hourly mean heart rate is observed on day 1, with the

pulse declining on average 5 to 6 beats per minute (bpm). Post-dose declines on the following days are

less pronounced. With continued dosing heart rate starts increasing after day 6 and reaches placebo

levels within 10 days after treatment initiation.

Heart rates below 40 bpm were rarely observed. Patients who experienced bradycardia were generally

asymptomatic. A few patients experienced mild to moderate symptoms including dizziness and

non-cardiac chest pain, which resolved within 24 hours without intervention (see section 4.8). If

necessary, the decrease in heart rate induced by siponimod can be reversed by parenteral doses of

atropine or isoprenaline.

Atrioventricular conduction

Initiation of siponimod treatment has been associated with transient atrioventricular conduction delays

that follow a similar temporal pattern to the observed decrease in heart rate during dose titration. The

atrioventricular conduction delays manifested in most of the cases as first-degree atrioventricular (AV)

blocks (prolonged PR interval on electrocardiogram). In clinical studies, second-degree AV blocks,

usually Mobitz type I (Wenckebach), have been observed in less than 1.7% of patients at the time of

treatment initiation. The conduction abnormalities typically were transient, asymptomatic, resolved

within 24 hours and did not require discontinuation of treatment.

Treatment initiation recommendation in patients with certain pre-existing cardiac conditions

As a precautionary measure, patients with the following cardiac conditions should be observed for a

period of 6 hours after the first dose of siponimod for signs and symptoms of bradycardia (see also

section 4.3):

sinus bradycardia (heart rate <55 bpm),

history of first- or second-degree [Mobitz type I] AV block,

history of myocardial infarction, or

history of heart failure (patients with NYHA class I and II).

In these patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at

the end of the observation period. If post-dose bradyarrhythmia or conduction-related symptoms occur

or if ECG 6 hours post-dose shows new onset second-degree or higher AV block or QTc ≥500 msec,

appropriate management should be initiated and observation continued until the symptoms/findings

have resolved. If pharmacological treatment is required, monitoring should be continued overnight and

6-hour monitoring should be repeated after the second dose.

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Due to the risk of serious cardiac rhythm disturbances or significant bradycardia, siponimod

should

not be used

in patients with:

history of symptomatic bradycardia or recurrent syncope,

uncontrolled hypertension, or

severe untreated sleep apnoea.

In such patients, treatment with siponimod should be considered only if the anticipated benefits

outweigh the potential risks, and advice from a cardiologist should be sought prior to initiation of

treatment in order to determine the most appropriate monitoring strategy.

A thorough QT study demonstrated no significant direct QT-prolonging effect and siponimod is not

associated with an arrhythmogenic potential related to QT prolongation. Initiation of treatment may

result in decreased heart rate and indirect prolongation of the QT interval during the titration phase.

Siponimod was not studied in patients with significant QT prolongation (QTc >500 msec) or who

were treated with QT-prolonging medicinal products. If treatment with siponimod is considered in

patients with pre-existing significant QT prolongation or who are already being treated with

QT-prolonging medicinal products with known arrhythmogenic properties, advice from a cardiologist

should be sought prior to initiation of treatment in order to determine the most appropriate monitoring

strategy during treatment initiation.

Siponimod has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g.

quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products.

Class Ia and class III antiarrhythmic medicinal products have been associated with cases of torsades de

pointes in patients with bradycardia. Since initiation of treatment results in decreased heart rate,

siponimod should not be used concomitantly with these medicinal products during treatment initiation.

Experience is limited in patients receiving concurrent therapy with heart-rate-lowering calcium

channel blockers (such as verapamil or diltiazem) or other substances that may decrease heart rate

(e.g. ivabradine or digoxin) as these medicinal products were not studied in patients receiving

siponimod in clinical studies. Concomitant use of these substances during treatment initiation may be

associated with severe bradycardia and heart block. Because of the potential additive effect on heart

rate, treatment with siponimod should generally not be initiated in patients who are concurrently

treated with these substances (see section 4.5). In such patients, treatment with siponimod should be

considered only if the anticipated benefits outweigh the potential risks.

If concomitant treatment with one of the above substances is considered during initiation of treatment

with siponimod, advice from a cardiologist should be sought regarding the switch to a

non-heart-rate-lowering medicinal product or appropriate monitoring for treatment initiation.

Bradyarrhythmic effects are more pronounced when siponimod is added to beta-blocker therapy. For

patients receiving a stable dose of beta blocker, the resting heart rate should be considered before

introducing treatment. If the resting heart rate is >50 bpm under chronic beta-blocker treatment,

siponimod can be introduced. If resting heart rate is ≤50 bpm, then beta-blocker treatment should be

interrupted until the baseline heart rate is >50 bpm. Treatment with siponimod can then be initiated

and treatment with beta blocker can be re-initiated after siponimod has been up-titrated to the target

maintenance dose (see section 4.5).

Liver function

Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before

initiation of treatment with siponimod.

In the phase III clinical study, alanine aminotransferase (ALT) or aspartate aminotransferase (AST)

three times the upper limit of normal (ULN) was observed in 5.6% of patients treated with siponimod

2 mg compared to 1.5% of patients who received placebo (see section 4.8). In clinical studies

treatment was discontinued if the elevation exceeded a 3-fold increase and the patient showed

symptoms related to hepatic function or if the elevation exceeded a 5-fold increase. In the phase III

clinical study, 1% of all discontinuations met one of these criteria.

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Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes checked

and siponimod

should be discontinued if significant liver injury is confirmed. Resumption of therapy

will be dependent on whether or not another cause of liver injury is determined and on the benefits to

the patient of resuming therapy versus the risks of recurrence of liver dysfunction.

Although there are no data to establish that patients with pre-existing liver disease are at increased risk

of developing elevated liver function test values when taking siponimod, caution should be exercised

in patients with a history of significant liver disease.

Cutaneous neoplasms

In study A2304, basal cell carcinoma was the most common neoplasm and was reported with a similar

incidence in the siponimod 2 mg (1.01%, 12 patients) and placebo (1.23%, 7 patients) groups.

However, additional cases in patients treated with siponimod have been reported with longer exposure

(see section 4.8). Other skin malignancies, including melanoma, have also been reported in patients

treated with siponimod and in patients on long-term therapy with another S1P modulator.

Skin examination is recommended for all patients at treatment initiation, and then every 6 to12 months

taking into consideration clinical judgement. Patients should be advised to promptly report any

suspicious skin lesions to their physician. Patients treated with siponimod should be cautioned against

exposure to sunlight without protection. These patients should not receive concomitant phototherapy

with UV-B radiation or PUVA-photochemotherapy.

Unexpected neurological or psychiatric symptoms/signs

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported for another

sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for siponimod

in the development programme. However, should a patient on siponimod

treatment develop any

unexpected neurological or psychiatric symptoms/signs (e.g. cognitive deficits, behavioural changes,

cortical visual disturbances or any other neurological cortical symptoms/signs or any symptom/sign

suggestive of an increase in intracranial pressure) or accelerated neurological deterioration, a complete

physical and neurological examination should promptly be scheduled and MRI should be considered.

Prior treatment with immunosuppressive or immune-modulating therapies

When switching from other disease-modifying therapies, the half-life and mode of action of the other

therapy must be considered to avoid an additive immune effect whilst at the same time minimising the

risk of disease reactivation. A peripheral lymphocyte count (CBC) is recommended prior to initiating

siponimod to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved.

Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its

product information, initiating treatment with siponimod after alemtuzumab is not recommended.

Siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer

acetate.

Blood pressure effects

Patients with hypertension uncontrolled by medication were excluded from participation in clinical

studies and special care is indicated if patients with uncontrolled hypertension are treated with

siponimod.

Hypertension was more frequently reported in patients on siponimod (12.6%) than in those given

placebo (9.0%) in the phase III clinical study in patients with secondary progressive multiple sclerosis

(SPMS). Treatment with siponimod resulted in an increase of systolic and diastolic blood pressure

starting early after treatment initiation, reaching maximum effect after approximately 6 months of

treatment (systolic 3 mmHg, diastolic 1.2 mmHg) and staying stable thereafter. The effect persisted

with continued treatment.

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Blood pressure should be regularly monitored during treatment with siponimod.

CYP2C9 genotype

Before initiation of treatment with siponimod, patients should be genotyped for CYP2C9 to determine

their CYP2C9 metaboliser status (see section 4.2). Patients homozygous for CYP2C9*3

(CYP2C9*3*3 genotype: approximately 0.3 to 0.4% of the population) should not be treated with

siponimod. Use of siponimod in these patients results in substantially elevated siponimod plasma

levels. The recommended maintenance dose is 1 mg daily in patients with a CYP2C9*2*3 genotype

(1.4-1.7% of the population) and in patients with a *1*3 genotype (9-12% of the population) to avoid

increased exposure to siponimod (see sections 4.2 and 5.2).

Women of childbearing potential

Due to risk for the foetus, siponimod is contraindicated during pregnancy and in women of

childbearing potential not using effective contraception. Before initiation of treatment, women of

childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test

and must use effective contraception during treatment and for at least 10 days after treatment

discontinuation (see sections 4.3 and 4.6).

Stopping siponimod therapy

Severe exacerbation of disease, including disease rebound, has been rarely reported after

discontinuation of another S1P receptor modulator. The possibility of severe exacerbation of disease

after stopping siponimod treatment should be considered. Patients should be observed for relevant

signs of possible severe exacerbation or return of high disease activity upon siponimod discontinuation

and appropriate treatment should be instituted as required.

After siponimod therapy has been stopped, siponimod remains in the blood for up to 10 days. Starting

other therapies during this interval will result in concomitant exposure to siponimod.

In the vast majority (90%) of SPMS patients, lymphocyte counts return to the normal range within

10 days of stopping therapy. However, residual pharmacodynamic effects, such as lowering effects on

peripheral lymphocyte count, may persist for up to 3-4 weeks after the last dose. Use of

immunosuppressants within this period may lead to an additive effect on the immune system and

therefore caution should be exercised for 3 to 4 weeks after the last dose.

Interference with haematological testing

Since siponimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs,

peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a

patient treated with siponimod. Laboratory tests involving the use of circulating mononuclear cells

require larger blood volumes due to reduction in the number of circulating lymphocytes.

Excipients

The tablets contain soya lecithin. Patients who are hypersensitive to peanut or soya should not take

siponimod (see section 4.3).

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total

lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5

Interaction with other medicinal products and other forms of interaction

Antineoplastic, immune-modulating or immunosuppressive therapies

Siponimod has not been studied in combination with antineoplastic, immune-modulating or

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immunosuppressive therapies. Caution should be exercised during concomitant administration due to

the risk of additive immune effects during such therapy and in the weeks after administration of any of

these medicinal products is stopped (see section 4.4).

Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its

product information, initiating treatment with siponimod after alemtuzmab is not recommended unless

the benefits of treatment clearly outweigh the risks for the individual patient (see section 4.4).

Anti-arrhythmic medicinal products, QT-prolonging medicinal products, medicinal products that may

decrease heart rate

During treatment initiation siponimod should not be concomitantly used in patients receiving class Ia

(e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) anti-arrhythmic medicinal

products, QT-prolonging medicinal products with known arrhythmogenic properties,

heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances that

may decrease heart rate (e.g. ivabradine or digoxin) because of the potential additive effects on heart

rate (see section 4.4). No data are available for concomitant use of these medicinal products with

siponimod. Concomitant use of these substances during treatment initiation may be associated with

severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment

with siponimod should generally not be initiated in patients who are concurrently treated with these

substances (see section 4.4). If treatment with siponimod is considered, advice from a cardiologist

should be sought regarding the switch to non-heart-rate-lowering medicinal products or appropriate

monitoring for treatment initiation.

Beta blockers

Caution should be exercised when siponimod is initiated in patients receiving beta blockers due to the

additive effects on lowering heart rate (see section 4.4). Beta-blocker treatment can be initiated in

patients receiving stable doses of siponimod.

The negative chronotropic effect of co-administration of siponimod and propranolol was evaluated in

a dedicated pharmacodynamic/safety study. The addition of propranolol on top of siponimod

pharmacokinetic/pharmacodynamic steady state had less pronounced negative chronotropic effects

(less than additive) in comparison to addition of siponimod on top of propranolol

pharmacokinetic/pharmacodynamic steady state (additive HR effect).

Vaccination

The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided

during siponimod treatment and for up to 4 weeks after treatment (see section 4.4).

During and for up to 4 weeks after treatment with siponimod vaccinations may be less effective. The

efficacy of vaccination is not considered to be compromised if siponimod treatment is paused 1 week

prior to vaccination until 4 weeks after (see section 4.4).

Potential of other medicinal products to affect siponimod pharmacokinetics

Siponimod is metabolised primarily by cytochrome P450 2C9 (CYP2C9) (79.3%) and to a lesser

extent by cytochrome P450 3A4 (CYP3A4) (18.5%). CYP2C9 is a polymorphic enzyme and the

drug-drug interaction (DDI) effect in the presence of CYP3A or CYP2C9 perpetrator drugs is

predicted to be dependent on the CYP2C9 genotype.

CYP2C9 and CYP3A4 inhibitors

Because of a significant increase in exposure to siponimod, concomitant use of siponimod and

medicinal products that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not

recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual

inhibitor (e.g. fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate moderate

or strong CYP3A4 inhibitor.

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The co-administration of fluconazole (moderate CYP2C9/strong CYP3A4 inhibitor) 200 mg daily at

steady state and a single dose of siponimod 4 mg in healthy volunteers with a CYP2C9*1*1 genotype

led to a 2-fold increase in the area under the curve (AUC) of siponimod. According to evaluation of

the drug interaction potential using physiologically based pharmacokinetic (PBPK) modelling, a

maximum of a 2-fold increase in the AUC of siponimod is predicted across genotypes with any type of

CYP3A4 and CYP2C9 inhibitors except for patients with a CYP2C9*2*2 genotype. In CYP2C9*2*2

patients, a 2.7-fold increase in the AUC of siponimod is expected in the presence of moderate

CYP2C9/CYP3A4 inhibitors.

CYP2C9 and CYP3A4 inducers

Siponimod may be combined with most types of CYP2C9 and CYP3A4 inducers. However, because

of an expected reduction in siponimod exposure, the appropriateness and possible benefit of the

treatment should be considered when siponimod is combined:

with strong CYP3A4/moderate CYP2C9 inducers (e.g. carbamazepine) in all patients regardless

of genotype

with moderate CYP3A4 inducers (e.g. modafinil) in patients with a CYP2C9*1*3 or *2*3

genotype.

A significant reduction of siponimod exposure (by up to 76% and 51%, respectively) is expected

under these conditions according to evaluation of the drug interaction potential using PBPK

modelling. The co-administration of siponimod 2 mg daily in the presence of 600 mg daily doses of

rifampin (strong CYP3A4 and moderate CYP2C9 inducer) decreased siponimod AUC

tau,ss

and C

max,ss

by 57% and 45%, respectively, in CY2C9*1*1 subjects.

Oral contraceptives

Co-administration with siponimod did not reveal clinically relevant effects on the pharmacokinetics

and pharmacodynamics of the combined ethinylestradiol and levonorgestrel oral contraceptive.

Therefore the efficacy of the investigated oral contraceptive was maintained under siponimod

treatment.

No interaction studies have been performed with oral contraceptives containing other progestagens,

however an effect of siponimod on the efficacy of oral contraceptives is not expected.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Siponimod is contraindicated in women of childbearing potential not using effective contraception

(see section 4.3). Therefore, before initiation of treatment in women of childbearing potential a

negative pregnancy test result must be available and counselling should be provided regarding serious

risk to the foetus. Women of childbearing potential must use effective contraception during treatment

and for at least ten days following the last dose of siponimod (see section 4.4).

Specific measures are also included in the Physician Education Pack. These measures must be

implemented before siponimod is prescribed to female patients and during treatment.

When stopping siponimod therapy for planning a pregnancy, the possible return of disease activity

should be considered (see section 4.4).

Pregnancy

There are no or limited amount of data available from the use of siponimod in pregnant women.

Animal studies have demonstrated siponimod-induced embryotoxicity and foetotoxicity in rats and

rabbits and teratogenicity in rats, including embryo-foetal deaths and skeletal or visceral

malformations at exposure levels comparable to the human exposure at the daily dose of 2 mg (see

section 5.3). In addition, clinical experience with another sphingosine-1-phosphate receptor modulator

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indicated a 2-fold higher risk of major congenital malformations when administered during pregnancy

compared with the rate observed in the general population.

Consequently, siponimod is contraindicated during pregnancy (see section 4.3). Siponimod should be

stopped at least 10 days before a pregnancy is planned (see section 4.4). If a woman becomes pregnant

while on treatment, siponimod must be discontinued. Medical advice should be given regarding the

risk of harmful effects to the foetus associated with treatment and ultrasonography examinations

should be performed.

Breast-feeding

It is unknown whether siponimod or its major metabolites are excreted in human milk. Siponimod and

its metabolites are excreted in the milk of rats. Siponimod should not be used during breast-feeding.

Fertility

The effect of siponimod on human fertility has not been evaluated. Siponimod had no effect on male

reproductive organs in rats and monkeys or on fertility parameters in rats.

4.7

Effects on ability to drive and use machines

Siponimod has no or negligible influence on the ability to drive and use machines. However, dizziness

may occasionally occur when initiating therapy with siponimod. Therefore, patients should not drive

or use machines during the first day of treatment initiation with siponimod (see section 4.4).

4.8

Undesirable effects

Summary of the safety profile

The most common adverse drug reactions are headache (15%) and hypertension (12.6%).

Tabulated list of adverse reactions

Within each system organ class, the adverse drug reactions are ranked by frequency, with the most

frequent reactions first. In addition, the corresponding frequency category for each adverse drug

reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10);

uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 2

Tabulated list of adverse reactions

Infections and infestations

Common

Herpes zoster

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Common

Melanocytic naevus

Basal cell carcinoma

Blood and lymphatic system disorders

Common

Lymphopenia

Nervous system disorders

Very common

Headache

Common

Dizziness

Seizure

Tremor

Eye disorders

Common

Macular oedema

Cardiac disorders

Common

Bradycardia

Atrioventricular block (first and second degree)

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Vascular disorders

Very common

Hypertension

Gastrointestinal disorders

Common

Nausea

Diarrhoea

Musculoskeletal and connective tissue disorders

Common

Pain in extremity

General disorders and administration site conditions

Common

Oedema peripheral

Asthenia

Investigations

Very common

Liver function test increased

Common

Pulmonary function test decreased

Description of selected adverse reactions

Infections

In the phase III clinical study in patients with SPMS the overall rate of infections was comparable

between the patients on siponimod and those on placebo (49.0% versus 49.1%, respectively).

However, an increase in the rate of herpes zoster infections was reported on siponimod (2.5%)

compared to placebo (0.7%). In the extension part of the phase III clinical study, a case of

cryptococcal meningitis (CM) has been reported (see section 4.4).

Macular oedema

Macular oedema was more frequently reported in patients receiving siponimod (1.8%) than in those

given placebo (0.2%). Although the majority of cases occurred within 3 to 4 months of commencing

siponimod, cases were also reported in patients treated with siponimod for more than 6 months (see

section 4.4). Some patients presented with blurred vision or decreased visual acuity, but others were

asymptomatic and diagnosed on routine ophthalmological examination. The macular oedema

generally improved or resolved spontaneously after discontinuation of treatment. The risk of

recurrence after re-challenge has not been evaluated.

Bradyarrhythmia

Initiation of siponimod treatment results in a transient decrease in heart rate and may also be

associated with atrioventricular conduction delays (see section 4.4). Bradycardia was reported in 6.2%

of patients treated with siponimod compared to 3.1% on placebo and AV block in 1.7% of patients

treated with siponimod compared to 0.7% on placebo (see section 4.4).

The maximum decline in heart rate is seen in the first 6 hours post-dose.

A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase and

plateaued at doses ≥5 mg. Bradyarrhythmic events (AV blocks and sinus pauses) were detected with a

higher incidence under siponimod treatment compared to placebo.

Most AV blocks and sinus pauses occurred above the therapeutic dose of 2 mg, with notably higher

incidence under non-titrated conditions compared to dose titration conditions.

The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline.

Liver function tests

Increased hepatic enzymes (mostly ALT elevation) have been reported in MS patients treated with

siponimod. In the phase III study in patients with SPMS, liver function test increases were more

frequently observed in patients on siponimod (11.3%) than in those on placebo (3.1%), mainly due to

liver transaminase (ALT/AST) and GGT elevations. The majority of elevations occurred within

6 months of starting treatment. ALT levels returned to normal within approximately 1 month after

discontinuation of siponimod (see section 4.4).

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Blood pressure

Hypertension was more frequently reported in patients on siponimod (12.6%) than in those given

placebo (9.0%) in the phase III clinical study in patients with SPMS. Treatment with siponimod

resulted in an increase of systolic and diastolic blood pressure starting early after treatment initiation,

reaching maximum effect after approximately 6 months of treatment (systolic 3 mmHg, diastolic

1.2 mmHg) and staying stable thereafter. The effect persisted with continued treatment.

Seizures

Seizures were reported in 1.7% of patients treated with siponimod compared to 0.4% on placebo in the

phase III clinical study in patients with SPMS.

Respiratory effects

Minor reductions in forced expiratory volume in 1 second (FEV

) and in the diffusing capacity of the

lung for carbon monoxide (DLCO) values were observed with siponimod treatment. At months 3 and

6 of treatment in the phase III clinical study in patients with SPMS, mean changes from baseline in

in the siponimod group were -0.1 L at each time point, with no change in the placebo group.

These observations were slightly higher (approximately 0.15 L mean change from baseline in FEV

) in

patients with respiratory disorders such as chronic obstructive pulmonary disease (COPD) or asthma

treated with siponimod. On chronic treatment, this reduction did not translate into clinically significant

adverse events and was not associated with an increase in reports of cough or dyspnoea (see

section 5.1).

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. Any suspected

adverse events should be reported to the Ministry of Health according to the National Regulation by

using an online form https://sideeffects.health.gov.il/.

4.9

Overdose

In healthy subjects, the single maximum tolerated dose was determined to be 25 mg based upon the

occurrence of symptomatic bradycardia after single doses of 75 mg. A few subjects received

unintended doses of up to 200 mg daily for 3 to 4 days and experienced asymptomatic mild to

moderate transient elevations of liver function tests.

One patient (with a history of depression) who took 84 mg siponimod experienced a slight elevation in

liver transaminases.

If the overdose constitutes first exposure to siponimod or occurs during the dose titration phase of

siponimod it is important to observe for signs and symptoms of bradycardia, which could include

overnight monitoring. Regular measurements of pulse rate and blood pressure are required and

electrocardiograms should be performed (see sections 4.2 and 4.4).

There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would

result in meaningful removal of siponimod from the body.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code:

L04AA42

Mechanism of action

Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds selectively to

two out of five G-protein-coupled receptors (GPCRs) for S1P, namely S1P1 and S1P5. By acting as a

functional antagonist on S1P1 receptors on lymphocytes, siponimod prevents egress from lymph

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nodes. This reduces the recirculation of T cells into the central nervous system (CNS) to limit central

inflammation.

Pharmacodynamic effects

Reduction of the peripheral blood lymphocytes

Siponimod induces a dose-dependent reduction of the peripheral blood lymphocyte count within

6 hours of the first dose, due to the reversible sequestration of lymphocytes in lymphoid tissues.

With continued daily dosing, the lymphocyte count continues to decrease, reaching a nadir median

(90% CI) lymphocyte count of approximately 0.560 (0.271-1.08) cells/nL in a typical CYP2C9*1*1 or

*1*2 non-Japanese SPMS patient, corresponding to 20-30% of baseline. Low lymphocyte counts are

maintained with daily dosing.

In the vast majority (90%) of SPMS patients, lymphocyte counts return to the normal range within

10 days of stopping therapy. After stopping siponimod treatment residual lowering effects on

peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose.

Heart rate and rhythm

Siponimod causes a transient reduction in heart rate and atrioventricular conduction on treatment

initiation (see sections 4.4 and 4.8), which is mechanistically related to the activation of

G-protein-coupled inwardly rectifying potassium (GIRK) channels via S1P1 receptor stimulation

leading to cellular hyperpolarisation and reduced excitability. Due to its functional antagonism at S1P1

receptors, initial titration of siponimod successively desensitises GIRK channels until the maintenance

dose is reached.

Potential to prolong the QT interval

The effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod on cardiac

repolarisation were investigated in a thorough QT study. The results did not suggest an

arrhythmogenic potential related to QT prolongation with siponimod. Siponimod increased the

placebo-corrected baseline-adjusted mean QTcF (ΔΔQTcF) by more than 5 ms, with a maximum

mean effect of 7.8 ms (2 mg) and 7.2 ms (10 mg), respectively, at 3 h post-dose. The upper bound of

the one-sided 95% CI for the ΔΔQTcF at all time points remained below 10 ms. Categorical analysis

revealed no treatment-emergent QTc values above 480 ms, no QTc increases from baseline of more

than 60 ms and no corrected or uncorrected QT/QTc value exceeded 500 ms.

Pulmonary function

Siponimod treatment with single or multiple doses for 28 days is not associated with clinically

relevant increases in airway resistance as measured by forced expiratory volume in 1 second (FEV

and forced expiratory flow (FEF) during expiration of 25 to 75% of the forced vital capacity

(FEF

25-75%

). A slight trend of reduced FEV

was detected at non-therapeutic single doses (>10 mg).

Multiple doses of siponimod were associated with mild to moderate changes in FEV

and FEF

25-75%

which were not dose- and daytime-dependent and were not associated with any clinical signs of

increased airway resistance.

Clinical efficacy and safety

The efficacy of siponimod has been investigated in a phase III study evaluating once-daily doses of

2 mg in patients with SPMS.

Study A2304 (EXPAND) in SPMS

Study A2304 was a randomised, double-blind, placebo-controlled, event and follow-up duration

driven, phase III study in patients with SPMS who had documented evidence of progression in the

prior 2 years in the absence or independent of relapses, no evidence of relapse in the 3 months prior to

study enrolment and with a median Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 at

study entry. The median EDSS was 6.0 at baseline. Patients above 61 years of age were not included.

With regard to disease activity, features characteristic of inflammatory activity in SPMS can be

relapse- or imaging-related (i.e. Gd-enhancing T1 lesions or active [new or enlarging] T2 lesions).

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Patients were randomised 2:1 to receive either once-daily siponimod 2 mg or placebo. Clinical

evaluations were performed at screening and every 3 months and at the time of relapse. MRI

evaluations were performed at screening and every 12 months.

The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP)

determined as at least a 1-point increase from baseline in EDSS (0.5 point increase for patients with

baseline EDSS of 5.5 or more) sustained for 3 months. Key secondary endpoints were time to 3-month

confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25W) and change

from baseline in T2 lesion volume. Additional secondary endpoints included time to 6-month CDP,

percent brain volume change and measures of inflammatory disease activity (annualised relapse rate,

MRI lesions). Change in cognitive processing speed on Symbol Digit Modality Test score was an

exploratory endpoint.

Study duration was variable for individual patients (median study duration was 21 months,

range: 1 day to 37 months).

The study involved randomisation of 1,651 patients to either siponimod 2 mg (N=1,105) or placebo

(N=546); 82% of patients treated with siponimod and 78% of placebo-treated patients completed the

study. Median age was 49 years, median disease duration was 16 years and median EDSS score was

6.0 at baseline. 64% of patients had no relapses in the 2 years prior to study entry and 76% had no

gadolinium (Gd)-enhancing lesions on their baseline MRI scan. 78% of patients had been previously

treated with a therapy for their MS.

Time to onset of 3-month and 6-month CDP was significantly delayed for siponimod, with reduction

in risk of 3-month CDP by 21% compared to placebo (hazard ratio [HR] 0.79, p=0.0134) and

reduction in risk of 6-month CDP by 26% compared to placebo (HR 0.74, p=0.0058).

Figure 1

Patients with 3- and 6-month CDP based on EDSS-Kaplan-Meier curves (full

analysis set, study A2304)

Number of patients at risk

Placebo (N=546)

Percentage of subjects with 3-month CDP

Percentage of subjects with 6-month CDP

Siponimod (N=1099)

Study month

Siponimod

Placebo

0

10

20

30

40

50

0

10

20

30

40

50

0

6

12

18

24

30

36

42

0

6

12

18

24

30

36

42

Hazard ratio: 0.79, p=0.0134; (95% Cl: 0.65,

0.95); risk reduction: 21%

Hazard ratio: 0.74, p=0.0058; (95%

Cl: 0.60, 0.92); risk reduction: 26%

Study month

1099

Number of patients at risk

Siponimod

Placebo

1099

Time to 3-month CDP versus placebo

(Primary endpoint)

Time to 6-month CDP versus placebo

MAY API FEB21 V2

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EU SmPC01.2021

Table 3

Clinical and MRI results of study A2304

Endpoints

A2304 (EXPAND)

Siponimod 2 mg

(n=1,099)

Placebo

(n=546)

Clinical endpoints

Primary efficacy endpoint:

Proportion of patients with 3-month confirmed

disability progression (primary endpoint)

26.3%

31.7%

Risk reduction

21% (p=0.0134)

Proportion of patients with 3-month confirmed

20% increase in timed 25-foot walk test

39.7%

41.4%

Risk reduction

6% (p=0.4398)

Proportion of patients with 6-month confirmed

disability progression

19.9%

25.5%

Risk reduction

[(p=0.0058)]

Annualised relapse rate (ARR)

0.071

0.152

Rate reduction

[(p<0.0001)]

MRI endpoints

Change from baseline in T2 lesion volume

+184 mm

+879 mm

Difference in T2 lesion volume change

-695 mm

(p<0.0001)

Percentage brain volume change relative to

baseline (95% CI)

-0.497%

-0.649%

Difference in percentage brain volume change

0.152%

[(p=0.0002)]

Average cumulative number of Gd-enhancing T1

weighted lesions (95% CI)

0.081

0.596

Rate reduction

[(p<0.0001)]

Proportion of patients with 4-point worsening in

Symbol Digit Modality Test

16.0%

20.9%

Risk reduction

[(p=0.0163)]

From Cox modelling for time to progression

From a model for recurrent events

Average over month 12 and month 24

Up to month 24

Confirmed at 6 months

[Nominal p-value for endpoints not included in the hierarchical testing and not adjusted for

multiplicity]

Non-confirmatory p-value; hierarchical testing procedure terminated before reaching endpoint

Results from the study showed a variable but consistent risk reduction in the time to 3- and 6-month

CDP with siponimod compared to placebo in subgroups defined based on gender, age, pre-study

relapse activity, baseline MRI disease activity, disease duration and disability levels at baseline.

In the subgroup of patients (n=779) with active disease (defined as patients with relapse in the 2 years

prior to the study and/or presence of Gd-enhancing T1 lesions at baseline) the baseline characteristics

were similar to the overall population. Median age was 47 years, median disease duration was 15 years

and median EDSS score at baseline was 6.0.

Time to onset of 3-month and 6-month CDP was significantly delayed in siponimod-treated patients

with active disease, by 31% compared to placebo (hazard ratio [HR] 0.69; 95% CI: 0.53, 0.91) and by

37% compared to placebo (HR 0.63; 95% CI: 0.47, 0.86), respectively. The ARR (confirmed relapses)

was reduced by 46% (ARR ratio 0.54; 95% CI: 0.39, 0.77) compared to placebo. The relative rate

reduction of cumulative number of Gd-enhancing T1 weighted lesions over 24 months was 85% (rate

ratio 0.155; 95% CI: 0.104, 0.231) compared to placebo. The differences in T2 lesion volume change

and in percentage of brain volume change (average over months 12 and 24) compared to placebo

were -1163 mm

(95% CI: -1484, -843 mm

) and 0.141% (95% CI: 0.020, 0.261%), respectively.

MAY API FEB21 V2

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EU SmPC01.2021

Figure 2

Patients with

3- and 6-month CDP based on EDSS-Kaplan-Meier curves –

Subgroup with active SPMS (full analysis set, study A2304)

In the subgroup of patients (n=827) without signs and symptoms of disease activity (defined as

patients without relapse in the 2 years prior to the study and without presence of Gd-enhancing T1

lesions at baseline), effects on 3-month and 6-month CDP were small (risk reductions were 7% and

13%, respectively).

5.2

Pharmacokinetic properties

Absorption

The time (T

) to reach maximum plasma concentrations (C

) after multiple oral administration of

siponimod is about 4 hours (range: 2 to 12 hours). Siponimod absorption is extensive (≥70%, based on

the amount of radioactivity excreted in urine and the amount of metabolites in faeces extrapolated to

infinity). The absolute oral bioavailability of siponimod is approximately 84%. For 2 mg siponimod

given once daily over 10 days, a mean C

of 30.4 ng/ml and mean AUC

of 558 h*ng/ml were

observed on day 10. Steady state was reached after approximately 6 days of multiple once-daily

administration of siponimod.

Despite a delay in T

to 8 hours after a single dose, food intake had no effect on the systemic

exposure of siponimod (C

and AUC), therefore siponimod may be taken without regard to meals

(see section 4.2).

Distribution

Siponimod is distributed to body tissues with a moderate mean volume of distribution of 124 litres.

The siponimod fraction found in plasma is 68% in humans. Siponimod readily crosses the blood-brain

barrier. Protein binding of siponimod is >99.9% in healthy subjects and in patients with hepatic or

renal impairment.

Biotransformation

Siponimod is extensively metabolised, mainly by cytochrome P450 2C9 (CYP2C9) (79.3%), and to a

Number of patients at risk

Placebo (N=263)

Percentage of patients with 3-month CDP

Percentage of patients with 6-month CDP

Siponimod (N=516)

Study month

Siponimod

Placebo

0

10

20

30

40

0

10

20

30

40

0

6

12

18

24

30

36

42

0

6

12

18

24

30

36

Study month

Number of patients at risk

Siponimod

Placebo

Time to 3-month CDP versus placebo

(Primary endpoint)

Time to 6-month CDP versus placebo

42

50

Hazard ratio: 0.69 (95% Cl: 0.53,

0.91); risk reduction: 31%

Hazard ratio: 0.63 (95% Cl: 0.47,

0.86); risk reduction: 37%

MAY API FEB21 V2

Page 18 of 22

EU SmPC01.2021

lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%).

The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the

clinical effect and the safety of siponimod in humans.

In vitro

investigations indicated that siponimod and its major systemic metabolites M3 and M17 do

not show any clinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg once

daily for all investigated CYP enzymes and transporters, and do not necessitate clinical investigation.

CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative

metabolism pathways to overall elimination. PBPK modelling indicates a differential CYP2C9

genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9

metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on

siponimod exposure is anticipated (see section 4.5).

Elimination

An apparent systemic clearance (CL/F) of 3.11 l/h was estimated in MS patients. The apparent

elimination half-life of siponimod is approximately 30 hours.

Siponimod is eliminated from the systemic circulation mainly due to metabolism and subsequent

biliary/faecal excretion. Unchanged siponimod was not detected in urine.

Linearity

Siponimod concentration increases in an apparent dose proportional manner after multiple once-daily

doses of siponimod 0.3 mg to 20 mg.

Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing and

steady-state levels are approximately 2- to 3-fold greater than after the initial dose. An up-titration

regimen is used to reach the clinically therapeutic dose of 2 mg siponimod after 6 days and

4 additional days of dosing are required to reach the steady-state plasma concentrations.

Characteristics in specific groups or special populations

CYP2C9 genotype

The CYP2C9 genotype influences siponimod CL/F. Two population pharmacokinetic analyses

indicated that CYP2C9*1*1 and *1*2 subjects behave as extensive metabolisers, *2*2 and *1*3

subjects as intermediate metabolisers and *2*3 and *3*3 subjects as poor metabolisers. Compared to

CYP2C9*1*1 subjects, individuals with the CYP2C9*2*2, *1*3, *2*3 and *3*3 genotypes have 20%,

35-38%, 45-48% and 74% smaller CL/F values, respectively. Siponimod exposure is therefore

approximately 25%, 61%, 91% and 284% higher in CYP2C9*2*2, *1*3, *2*3 and *3*3 subjects,

respectively, as compared to *1*1 subjects (see Table 4) (see sections 4.2 and 4.4).

MAY API FEB21 V2

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EU SmPC01.2021

Table 4

CYP2C9 genotype effect on siponimod CL/F and systemic exposure

CYP2C9

genotype

Frequency in

Caucasians

Estimated CL/F

(L/h)

% of

CYP2C9*1*1

CL/F

% exposure

increase versus

CYP2C9*1*1

Extensive metabolisers

CYP2C9*1*1

62-65

3.1-3.3

CYP2C9*1*2

20-24

3.1-3.3

99-100

Intermediate metabolisers

CYP2C9*2*2

2.5-2.6

CYP2C9*1*3

9-12

1.9-2.1

62-65

Poor metabolisers

CYP2C9*2*3

1.4-1.7

1.6-1.8

52-55

CYP2C9*3*3

0.3-0.4

Elderly

Results from population pharmacokinetics suggest that dose adjustment is not necessary in elderly

patients (age 65 years and above). No patients over 61 years of age were enrolled in clinical studies.

Siponimod should be used with caution in the elderly (see section 4.2).

Gender

Results from population pharmacokinetics suggest that gender-based dose adjustment is not necessary.

Race/Ethnicity

The single-dose pharmacokinetic parameters were not different between Japanese and Caucasian

healthy subjects, indicating absence of ethnic sensitivity on the pharmacokinetics of siponimod.

Renal impairment

No siponimod dose adjustments are needed in patients with mild, moderate or severe renal

impairment. Mean siponimod half-life and C

(total and unbound) were comparable between

subjects with severe renal impairment and healthy subjects. Total and unbound AUCs were only

slightly increased (by 23 to 33%) compared to healthy subjects. The effects of end-stage renal disease

or haemodialysis on the pharmacokinetics of siponimod have not been studied. Due to the high plasma

protein binding (>99.9%) of siponimod, haemodialysis is not expected to alter the total and unbound

siponimod concentration and no dose adjustments are anticipated based on these considerations.

Hepatic impairment

Siponimod must not be used in patients with severe hepatic impairment (see section 4.3). No dose

adjustments for siponimod are needed in patients with mild or moderate hepatic impairment. The

unbound siponimod pharmacokinetics AUC is 15% and 50% higher in subjects with moderate and

severe hepatic impairment, respectively, in comparison with healthy subjects for the 0.25 mg single

dose studied. The mean half-life of siponimod was unchanged in hepatic impairment.

5.3

Preclinical safety data

In repeat-dose toxicity studies in mice, rats and monkeys, siponimod markedly affected the lymphoid

system (lymphopenia, lymphoid atrophy and reduced antibody response), which is consistent with its

primary pharmacological activity at S1P1 receptors (see section 5.1).

Dose-limiting toxicities in animal species were nephrotoxicity in mice, body weight development in

rats and adverse CNS and gastrointestinal effects in monkeys. The main target organs of toxicity in

rodents included the lung, liver, thyroid, kidney and uterus/vagina. In monkeys, effects on muscle and

skin were additionally observed. These toxicities developed at more than 30-fold higher systemic

siponimod levels than the AUC-based human exposure at the maintenance dose of 2 mg/day.

Siponimod did not exert any phototoxic or dependence potential and was not genotoxic

in vitro

in

vivo

MAY API FEB21 V2

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EU SmPC01.2021

Carcinogenicity

In carcinogenicity investigations, siponimod induced lymphoma, haemangioma and

haemangiosarcoma in mice, whereas follicular adenoma and carcinoma of the thyroid gland were

identified in male rats. These tumour findings were either regarded as mouse-specific or attributable to

metabolic liver adaptations in the particularly sensitive rat species and are of questionable human

relevance.

Fertility and reproductive toxicity

Siponimod did not affect male and female fertility in rats up to the highest dose tested, representing an

approximate 19-fold safety margin based on human systemic exposure (AUC) at a daily dose of 2 mg.

The receptor affected by siponimod (sphinosine-1-phosphate receptor) is known to be involved in

vascular formation during embryogenesis.

In embryofoetal development studies conducted in rats and rabbits, siponimod induced embryotoxic

effects in the absence of maternal toxicity. In both species, prenatal mortality was increased. While in

rats a higher number of foetuses with external, skeletal and visceral malformations (e.g. cleft palate

and misshapen clavicles, cardiomegaly and oedema) were noted, in rabbit foetuses skeletal and

visceral variations were predominantly observed.

In the prenatal and postnatal development study performed in rats, there was in increased number of

dead (stillborn or found dead before postnatal day 4) and malformed pups (male pups with urogenital

malformations and/or decreased anogenital distance; pups of both sexes with oedema, swollen soft

cranium, or flexed hindlimbs).

The exposure levels (AUC) at the respective NOAELs for embryofoetal (rats and rabbits) and

pre/postnatal (rats) development were below the human systemic exposure (AUC) at a daily dose of

2 mg and consequently no safety margin exists.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Mayzent 0.25 mg, film-coated tablets

Tablet core

Lactose monohydrate

Cellulose microcrystalline / Microcrystalline cellulose

Crospovidone (type A)

Glycerol dibehenate / Glyceryl behenate

Silica colloidal anhydrous / Colloidal silicon dioxide

Tablet coating

Polyvinyl alcohol – part hydrolyzed

Titanium dioxide (E171)

Talc

Lecithin (Soya) (E322)

Xanthan gum

Iron oxide, red (E172)

Ferrosoferric oxide / Black iron oxide (E172)

MAY API FEB21 V2

Page 21 of 22

EU SmPC01.2021

Mayzent 2 mg, film-coated tablets

Tablet core

Lactose monohydrate

Cellulose microcrystalline / Microcrystalline cellulose

Crospovidone (type A)

Glycerol dibehenate / Glyceryl behenate

Silica colloidal anhydrous / Colloidal silicon dioxide

Tablet coating

Polyvinyl alcohol – part hydrolyzed

Titanium dioxide (E171)

Talc

Lecithin (Soya) (E322)

Xanthan gum

Iron oxide, yellow (E172)

Iron oxide, red (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Special precautions for storage

Do not store above 25°C.

6.5

Nature and contents of container

Mayzent 0.25 mg film-coated tablets

Titration packs of 12 film-coated tablets in PA/Alu/PVC-Alu blister in wallet.

Packs of 120 film-coated tablets in PA/Alu/PVC-Alu blisters.

Mayzent 2 mg film-coated tablets

Packs of 28 film-coated tablets in PA/Alu/PVC -

Alu blisters.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

MAY API FEB21 V2

Page 22 of 22

EU SmPC01.2021

7.

REGISTRATION HOLDER AND IMPORTER

Novartis Israel Ltd., POB 7126, Tel-Aviv

8.

REGISTRATION NUMBER(S)

Mayzent 0.25 mg: 165-54-36195

Mayzent 2 mg: 165-55-36196

Revise on February 2021 according to MOH’s guidelines.

Read the complete document

Novartis Israel Ltd.

6 Totzeret Ha’arets St.

P.O.B 7126, Tel Aviv, Israel

Tel: 972-3-9201123 Fax: 972-3-9229331

לארשי סיטרבונ

מ"עב

'חר ץראה תרצות

.ד.ת

7126

ביבא לת

:ןופלט

03-9201123

:סקפ

03-9229331

רבמצד

2020

,ה/דבכנ ה/אפור ,ה/דבכנ ת/חקור

:ןודנה

Mayzent 0.25 mg, Mayzent 2 mg

coated tablets

Film

שדח רישכת

שדח רישכת לש ומושיר לע םכעידוהל םישקבמ ונא

םינונימ ינשב

טנזיימ

0.25

ג"מ

טנזיימו

ג"מ

יוותהל לארשיב םושר רישכתה

אבה

MAYZENT is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to

include relapsing-remitting disease, and active secondary progressive disease, in adults.

כר

ליעפה

Siponimod (as fumaric acid) 0.25 mg, 2 mg

ולעה

אפורל ןכרצל ןולעהו חלשנ

לבקל ןתינו ,תואירבה דרשמ רתאבש תופורתה רגאמ

ספדומ םי

לע

הינפ ידי .םושירה לעבל

,הכרבב

'ץיבודיוד ינור

הנוממ תחקור

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