GILENYA 0.5 MG

Israel - English - Ministry of Health

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Active ingredient:
FINGOLIMOD AS HYDROCHLORIDE
Available from:
NOVARTIS ISRAEL LTD
ATC code:
L04AA27
Pharmaceutical form:
HARD CAPSULE
Composition:
FINGOLIMOD AS HYDROCHLORIDE 0.5 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
NOVARTIS PHARMA STEIN AG, SWITZERLAND
Therapeutic group:
FINGOLIMOD
Therapeutic area:
FINGOLIMOD
Therapeutic indications:
Gilenya is indicated for the treatment of patients with relapsing forms of multiple sclerosis ( MS ) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.
Authorization number:
145 78 33270 00
Authorization date:
2016-03-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

20-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

17-08-2016

PATIENT PACKAGE INSERT IN

ACCORDANCE WITH THE PHARMACISTS’

REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a

doctor’s prescription only

Gilenya 0.5 mg

Hard Capsules

The active ingredient

Each capsule contains:

Fingolimod (as hydrochloride) 0.5 mg

Inactive ingredients:

See section 6 ‘Further Information’.

Read this leaflet carefully in its entirety

before using the medicine. This leaflet

contains concise information about the medicine.

If you have further questions, refer to the doctor

or pharmacist.

The medicine has been prescribed for the

treatment of your ailment. Do not pass it on to

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

you that their ailment is similar.

This medicine is not intended for children and

adolescents under the age of 18.

Taking the first dose:

After taking the first dose of Gilenya, observation

by a health care professional is required for 6

hours.

This recommendation also applies if you are

resuming treatment after interrupting treatment

with Gilenya.

The full instructions regarding taking the

first dose are detailed in the section ‘Special

warnings regarding use of the medicine’.

1. WHAT IS THE MEDICINE INTENDED

FOR?

Gilyena is indicated for the treatment of patients

with relapsing forms of multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease

that affects the central nervous system (CNS),

particularly how the brain and spinal cord work.

In MS, inflammation destroys the protective

sheath (called myelin) around the nerves in

the CNS, and stops the nerves from working

properly (demyelination).

The exact cause of MS is unknown. An abnormal

response by the body’s immune system is

thought to play an important part in the process

which damages the CNS.

People with MS experience repeated bouts

(relapses) of nervous system symptoms that

reflect inflammation within the CNS. Symptoms

may vary from patient to patient but typically

involve: walking difficulties, numbness,

vision problems and problems with balance.

The symptoms of a relapse may disappear

completely when the relapse is over but some

problems may remain. This form of the disease

is called relapsing MS, or relapsing-remitting

In some cases, the symptoms gradually increase

between relapses, indicating transition to another

form of MS - secondary progressive MS.

The medicine does not cure MS, but it helps

reduce the number of relapses and slow the

build-up of irreversible physical problems

(disability progression) caused by the disease.

Mechanism of action:

The medicine influences the way the body’s

immune system works, the ability of some white

blood cells to move freely within the body and

stops the cells that cause inflammation from

reaching the brain. This reduces the nerve

damage caused by the immune system as well

as the clinical symptoms.

The medicine may also have a direct and

beneficial effect on certain brain cells (neural

cells) involved in repairing or slowing down the

disease damage.

In clinical studies, the medicine has been shown

to significantly cut down the number of attacks

and in addition, to reduce the number of severe

relapses and relapses that must be treated in

hospital, to prolong the time without relapses

and to decrease the percentage of patients who

have a progression of disability.

Therapeutic group:

Sphingosine-1-phosphate (S1-P) receptor

modulator.

If you have any questions about how the

medicine works or why it has been prescribed

for you, ask your doctor.

2. BEFORE USING THE MEDICINE

x

Do not use the medicine:

If during the last 6 months you have suffered

from

myocardial

infarction,

unstable

angina, stroke or transient ischemic attack,

decompensated heart failure requiring

hospitalization or class III or IV heart failure

If you suffer from high degree atrioventricular

(AV) block or sick sinus syndrome, not

including patients with a pacemaker

If you have a baseline QTc interval ≥500 ms

If you are being treated with Class Ia or Class

III anti-arrhythmic medicines

If you are allergic (hypersensitive) to

fingolimod or any of the other ingredients

of Gilenya listed in section 6 ‘Further

information’

If you think you may be allergic, ask your

doctor for advice

Special warnings regarding use of the

medicine:

Taking the first dose:

After taking the first dose of Gilenya, observation

by a health care professional is required for 6

hours.

Before starting treatment with Gilenya, an ECG

check is required to check the health of the

heart. A second ECG check is required at the

end of the 6-hour observation period following

administration of the first dose of Gilenya.

Your heart rate and blood pressure will also be

checked hourly by a health care professional

during the 6-hour observation period.

In case of an abnormal ECG recording or slow

heart rate at the end of the 6-hour observation

period, you may be observed longer and

even overnight if necessary by a health care

professional.

This recommendation also applies if you are

resuming treatment after interrupting treatment

with Gilenya, depending on the length of the

interruption and the duration of time you were

treated (see section ‘Stopping treatment’.)

Checking the health of the heart is particularly

important if any of the following cases applies

to you.

Your doctor may decide not to use Gilenya, but,

if your doctor thinks that Gilenya is good for

you, he/she may first refer you to a cardiologist

(doctor specializing in heart disease). You may

also be monitored overnight by a healthcare

professional after taking the first dose of

Gilenya, beyond the 6 hours required for all

patients.

!

Tell your doctor before taking Gilenya:

if you have an irregular or abnormal

heartbeat, a severe heart disease,

uncontrolled high blood pressure, a

history of stroke or other diseases

related to blood vessels in the brain, if

when you sleep you are severely affected

by an inability to breathe (sleep apnea

that is not treated), if you are at risk for,

or if you have heart rhythm disturbances

(called QTc prolongation or abnormal ECG

heart tracing). Your doctor may decide not to

use Gilenya if you have or have had one of

these conditions.

if you are taking medicines for an

irregular heartbeat such as quinidine,

procainamide, amiodarone or sotalol (see

section ‘Taking other medicines’).

if you suffer from a slow heart rate, if

at the start of treatment with Gilenya

you are taking medicines that slow your

heart rate or if you have a history of

sudden loss of consciousness (fainting).

Your doctor may decide not to use Gilenya or

may refer you first to a cardiologist to switch

to medicines that do not slow your heart rate

or to decide on a proper observation after

taking the first dose of Gilenya.

At the beginning of treatment, Gilenya can

cause the heart rate to slow down. Gilenya can

also cause an irregular heartbeat, especially

after the first dose. Irregular heartbeat usually

returns to normal in less than one day. Slow

heart rate usually returns to normal values

within one month.

If your heart rate slows down after your first

dose, you may feel dizzy or tired, or may be

consciously aware of your heartbeat.

If your heart rate slows down too much or your

blood pressure drops, you may need treatment

right away. In this case, you will be monitored

overnight by a healthcare professional and the

same observation process that took place for

your first dose of Gilenya will also apply for your

second dose.

If any of the following applies to you, tell your

doctor before taking Gilenya:

if you have no history of chickenpox

or have not been vaccinated against

varicella zoster virus. The doctor will test

the status of the antibody against this virus

and may decide to vaccinate you if you do

not have antibodies to this virus. In this case,

you will start Gilenya treatment one month

after the full course of the vaccination is

completed.

if you have a lowered immune response

(due to a disease or medicines that suppress

the immune system, detailed in the section

‘Taking other medicines’). You may get

infections more easily or an infection you

already have may get worse. Gilenya lowers

the white blood cell count (particularly the

lymphocyte count). White blood cells fight

infection. While you are taking Gilenya (and

for up to 2 months after you stop taking it),

you may get infections more easily.

if you have an infection, tell your doctor

before you take Gilenya. An infection that

you already have may get worse. Infections

could be serious and sometimes life-

threatening. Before you start taking Gilenya,

you will have a white blood cells test to

ensure that there is no impediment to starting

treatment. During your treatment with

How long to take Gilenya

Do not stop the treatment or change your dose

without talking with your doctor.

If you have questions about how long to

take Gilenya, talk to your doctor or your

pharmacist.

If you take more Gilenya than you should

or if you have taken a first dose of Gilenya

by mistake

If you take a dose higher than required or if

you took the first dose of Gilenya by mistake,

contact your doctor right away.

Your doctor may decide to observe you with

heart rate and blood pressure measurements

every hour, to run ECGs and he may even

decide to monitor you overnight.

If you took an overdose, or if a child has

accidentally swallowed the medicine, refer

immediately to a doctor or proceed to a hospital

emergency room, and bring the package of the

medicine with you.

If you forget to take Gilenya

If you forget a dose, take the next dose as

planned. Do not take a double dose to make

up for a forgotten dose.

If you have been taking Gilenya for less than

2 weeks and you forget to take a dose for one

day, contact your doctor right away. Your doctor

may decide to observe you at the time you take

the next dose.

Stopping treatment

Adhere to the treatment as recommended by

the doctor.

Even if there is an improvement in your health,

do not stop treatment or change your dosage

without consulting the doctor.

The medicine will stay in your body for up to

2 months after you stop taking it. Your white

blood cell count (lymphocyte count) may also

remain low during this time and the side effects

described in this leaflet may still occur.

Female patients should read the section

‘Pregnancy and breast-feeding’.

The recommendation regarding taking the first

dose is applicable also if you stop taking Gilenya

for one day or more during the first 2 weeks of

treatment or if you stop taking Gilenya for more

than 2 weeks after your first month of Gilenya

treatment or if you stop treatment for more

than 7 days during the third and fourth weeks

of treatment. In these cases, the initial effect

on your heart rate may occur again. When you

restart Gilenya treatment, your doctor may

decide to monitor your heart rate and blood

pressure every hour, to run ECGs or to keep

you under monitoring overnight.

Do not take medicines in the dark! Check

the label and the dose each time you take a

medicine.

Wear glasses if you need them.

If you have further questions regarding the

use of the medicine, consult a doctor or

pharmacist.

4. SIDE EFFECTS

As with all medicines, the use of Gilenya may

cause side effects in some users, although not

everybody gets them. Do not be alarmed by

the list of side effects. You may not suffer from

any of them.

Side effects may occur with certain frequencies,

which are defined as follows:

Very

common:

affects more than 1 in 10

patients

Common:

affects between 1 and 10 in

every 100 patients

Uncommon:

affects between 1 and 10 in

every 1,000 patients

Rare:

affects between 1 and 10 in

every 10,000 patients

Frequency

unknown:

frequency cannot be

estimated from the available

data

Gilenya, if you think you have an infection,

have a fever, feel like you have the flu, or

have a headache accompanied by stiff neck,

sensitivity to light, nausea, and/or confusion

(these may be symptoms of meningitis),

contact your doctor right away. If you believe

your MS is getting worse (e.g. weakness or

visual changes) or if you notice any new or

unusual symptoms, talk to your doctor as

soon as possible, because these may be the

symptoms of a rare brain disorder caused by

infection and called progressive multifocal

leukoencephalopathy (PML).

if you plan to receive a vaccine. You

should not receive certain types of vaccines

(live attenuated vaccines) during and for up

to 2 months after treatment with Gilenya (see

section ‘Taking other medicines’).

if you have or have had visual disturbances

or other signs of swelling in the central

vision area (macula) at the back of the

eye (a condition known as macular

edema), inflammation or infection of

the eye (uveitis) or if you have diabetes.

Your doctor may want you to undergo an eye

examination before you start treatment with

Gilenya and at regular intervals after the start

of Gilenya treatment. The macula is a small

area of the retina at the back of the eye,

which enables you to see shapes, colors, and

details clearly and sharply (central vision).

Gilenya may cause swelling in the macula and

it usually happens during the first 4 months of

treatment. The chance of developing macular

edema is higher if you have diabetes or have

had an inflammation of the eye called uveitis.

Macular edema can cause some of the same

vision symptoms as an MS attack (optic

neuritis). Be sure to tell the doctor about any

changes in vision. The doctor may want you

to undergo an eye examination particularly if

the center of your vision becomes blurred or

has shadows, if you develop a blind spot in the

center of your vision, or if you have problems

seeing colors or fine details.

if you have liver problems you will have

a blood test to check your liver function

before you start taking Gilenya. Gilenya may

affect your liver function. You will probably

not notice any symptoms but if you notice

yellowing of your skin or the whites of your

eyes, abnormally dark urine or unexplained

nausea, vomiting and tiredness during your

treatment, tell your doctor straight away. Your

doctor may carry out blood tests to check your

liver function and may consider stopping

Gilenya treatment if your liver problem is

serious.

Tell your doctor straight away, if you suffer

from any of following symptoms or diseases

during your treatment with Gilenya:

A condition called posterior reversible

encephalopathy syndrome (PRES) has been

rarely reported in MS patients treated with

Gilenya. Symptoms may include sudden onset of

severe headache, confusion, seizures and vision

changes. Tell your doctor, if you experience

any of these symptoms during your treatment

with Gilenya.

A type of skin cancer called basal cell carcinoma

(BCC) has been reported in MS patients treated

with Gilenya. Talk to your doctor if you notice

any skin nodules (e.g. shiny pearly nodules),

patches or open sores that do not heal within

weeks (these may be signs of BCC).

!

Taking other medicines

If you are taking or have recently taken

other medicines, including non-prescription

medicines and food supplements, tell the

doctor or pharmacist. In particular if you are

taking or have recently taken:

Medicines for an irregular heartbeat such

as quinidine, procainamide, amiodarone or

sotalol. The doctor may decide not to use

Gilenya if you take these medicines due to a

possible added effect on irregular heartbeat.

Medicines that slow down heartbeat

such as atenolol (called beta-blockers), such

as verapamil, diltiazem or ivabradine (called

calcium channel blockers) or digoxin. Your

doctor may decide not to use Gilenya or may

refer you first to a cardiologist to change your

medicines due to a possible added effect on

slowing down heartbeat in the first days of

beginning treatment with Gilenya.

Medicines that prolong the QT interval such

as citalopram, chlorpromazine, haloperidol,

methadone, erythromycin.

Medicines that suppress or modulate

the immune system including other

medicines used to treat MS such as

beta-interferon,

glatiramer

acetate,

natalizumab,

mitoxantrone,

dimethyl

fumarate, teriflunomide, alemtuzumab or

corticosteroids due to a possible added effect

on the immune system.

Vaccines. If you need to receive a vaccine,

seek your doctor’s advice first. During and for

up to 2 months after treatment with Gilenya,

administration of some vaccines containing

live virus (live attenuated vaccines) may

result in infection that the vaccination should

prevent, while others may not work well.

Check with your doctor or pharmacist.

!

Taking Gilenya with food

You can take Gilenya with or without food.

!

Older people (over 65 years old)

Experience with Gilenya in older people is

limited. Talk to your doctor if you have any

concerns.

!

Children and adolescents (under 18 years

old)

Gilenya is not intended for use in children and

adolescents, as it has not been studied in MS

patients aged under 18.

!

Pregnancy and breast-feeding

You should avoid becoming pregnant

while taking Gilenya or in the two months

after you stop taking it because of the risk

of harm to the fetus. Talk with your doctor

about the associated risks and about reliable

methods of birth control that you should use

during treatment and for 2 months after you

stop treatment.

Tell your doctor if you are pregnant, think you

might be pregnant, or are trying to become

pregnant.

If you do become pregnant while taking

Gilenya, tell your doctor right away. You

and your doctor will decide what is best for you

and your baby.

You should not breast-feed while you are

taking Gilenya. Gilenya can pass into breast

milk and there is a risk of serious side effects for

a breast-fed baby. Talk with your doctor before

breast-feeding while you take Gilenya.

Ask your doctor or pharmacist for advice before

taking any medicine, if you are pregnant or

breast-feeding.

!

Driving and using machines

Your doctor will tell you whether your illness

allows you to drive vehicles and use machines

safely. Gilenya is not expected to affect your

ability to drive and use machines.

3. HOW

SHOULD

YOU

USE

THE

MEDICINE?

Always use according to the doctor’s instructions.

Check with the doctor or pharmacist if you are

uncertain.

Tests and follow-up

Before you start taking Gilenya,

you will have a

white blood cells

test

Before you start taking Gilenya, you will have a

blood test to check your liver function.

Dosage

The dosage and manner of treatment will

be determined by the doctor only. The usual

dosage is generally:

One capsule per day (0.5 mg fingolimod).

Do not exceed the recommended dose.

How and when to take Gilenya

Take Gilenya once a day, with half a glass of

water.

Taking Gilenya at the same time each day

will help you remember when to take your

medicine.

Some side effects could be or could become

serious

If you experience any of the following effects,

refer to your doctor immediately:

Common side effects:

Bronchitis with symptoms such as coughing

with phlegm, chest pain, fever

Shingles (herpes zoster) with symptoms such

as blisters, burning, itching or pain of the

skin, typically on the upper part of the body

or the face. Other symptoms may be fever

and weakness in the early stages of infection,

followed by numbness, itching or red patches

with severe pain

Slow heartbeat (bradycardia)

A type of skin cancer called basal cell

carcinoma (BCC) which often appears as a

pearly nodule, though it can also take other

forms

Uncommon side effects:

Pneumonia with symptoms such as fever,

cough, difficulty breathing

Macular edema (swelling in the central vision

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

symptoms such as shadows or blind spot in the

center of the vision, blurred vision, problems

seeing colors or details

Rare side effects:

A condition called posterior reversible

encephalopathy syndrome (PRES). Symptoms

may include sudden onset of severe headache,

confusion, seizures and vision changes

Side effects of unknown frequency:

Serious irregularity in heartbeat that is

temporary and that returns to normal during

the 6-hour observation period

Allergic reactions, including symptoms of

rash or itchy hives (urticaria), swelling of lips,

tongue or face, which are likely to occur on

the day you start Gilenya treatment

A rare and severe infection called progressive

multifocal leukoencephalopathy (PML) with

symptoms that may be similar to MS symptoms

and may include muscle weakness, cognitive

dysfunction, headache, speech/visual

difficulties, seizures, sensory impairment/

loss, walking or coordination disturbances.

Cryptococcal infections (a type of fungal

infection), including cryptococcal meningitis

with symptoms such as headache accompanied

by stiff neck, sensitivity to light, nausea and/

or confusion

Other side effects

If any of the following effects affects you

severely, refer to your doctor:

Very common side effects:

Infection from flu virus with symptoms such as

tiredness, chills, sore throat, joints or muscles

pain, fever

Feeling of pressure or pain in the cheeks and

forehead (sinusitis)

Headache

Diarrhea

Back pain

Blood testing showing higher levels of liver

enzymes

Cough

Common side effects:

Ringworm, a fungal infection of the skin (tinea

versicolor)

Dizziness

Severe headache often accompanied by

nausea, vomiting and sensitivity to light

(migraine)

Weakness

Itchy, red, burning rash (eczema)

Itchy skin

Blood fat (triglycerides) level increased

Breathlessness

Abnormal lung function test results starting

after one month of treatment, remaining

stable after that and reversible after treatment

discontinuation

Blurred vision (see also the information on

macular edema in section ‘Warnings’ and

‘Side effects that could be serious’, above)

Hypertension. Gilenya may cause a mild

increase in blood pressure

Low level of white blood cells (lymphopenia,

leukopenia)

Side effects of unknown frequency:

Nausea

If a side effect occurs, if any of the side effects

worsens or if you suffer from a side effect

not mentioned in the leaflet, consult with the

doctor.

Reporting of side effects

Side effects can be reported to the Ministry of

Health via the online form for reporting side

effects that can be found on the Ministry of

Health homepage www.health.gov.il

following

link:

https://forms.

gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE

STORED?

Avoid poisoning! This medicine, and any other

medicine, should be kept in a safe place out of

the reach and sight of children and/or infants

in order to avoid poisoning. Do not induce

vomiting unless explicitly instructed to do so

by the doctor.

Do not use the medicine after the expiry

date (exp. date) appearing on the package.

The expiry date refers to the last day of that

month.

Store the medicine below 25°C.

Store in the original package, protect from

moisture.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine

also contains:

Gelatin, mannitol, titanium dioxide (E171),

magnesium stearate, yellow iron oxide (E172),

printing ink (black, yellow).

What does the medicine look like and what

are the contents of the package

Gilenya is supplied as hard capsules for oral

use.

The hard capsules have a white opaque body

with two radial bands imprinted in yellow and

a bright yellow opaque cap with FTY 0.5 mg

imprinted in black.

Contents of the capsules: White to almost white

powder.

Package sizes: 7 or 28 capsules. (Not all package

sizes may be marketed).

Registration Holder and address:

Novartis Israel Ltd., 36 Shacham St., Petach-

Tikva.

Manufacturer and address:

Novartis Pharma Stein AG, Stein, Switzerland,

For Novartis Pharma AG, Basel, Switzerland.

This leaflet was checked and approved by the

Ministry of Health in August 2015.

Registration number of the medicine

in the National Drug Registry of the Ministry

of Health:

Gilenya 0.5 mg - 145 78 33270

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ﻊﻄﻘﻤﻟﺍ ﻞﻴﻄﺗ ﻲﺘﻟﺍ ﺔﻳﻭﺩﻷﺍ

.ﻦﻴﺴﻴﻣﻭﺮﺘﻳﺭﺇ ،ﻥﻭﺩﺎﺘﻴﻣ ،ﻝﻭﺪﻳﺮﻴﭘﻮﻟﺎﻫ ،ﻦﻳﺯﺎﻣﻭﺮﭘﺭﻮﻠﻛ ﻲﻓ ﺎﻤﺑ ﺔﻋﺎﻨﻤﻟﺍ ﺯﺎﻬﺠﻟ ﺔﻤﻈﻨﻣ ﻭﺃ ﺔﺤﺑﺎﻛ ﺔــﻳﻭﺩﺃ

ﻞﺜﻣ ﺩﺪﻌﺘﻤﻟﺍ ﺐﻠﺼﺘﻟﺍ ﺝﻼﻌﻟ ﻯﺮــﺧﺃ ﺔــﻳﻭﺩﺃ ﻚــﻟﺫ ،ﺏﺎﻣﻭﺰﻴﻟﺎﺗﺎﻧ ،ﺕﺎﺘﻴﺳﺃ ﺮﻴﻣﺍﺮﻴﺗﻼﭼ ،ﻥﻭﺮﻴﻓﺮﺘﻧﺇ ـ ﺎﺘﻴﺑ ،ﺪﻴﻣﻮﻧﻮﻠﻔﻳﺮﻴﺗ ،ﺕﺍﺭﺎﻣﻮﻓ ﻞﻴﺘﻴﻤﻳﺩ ،ﻥﻭﺮﺘﻧﺎﺴﻛﻮﺘﻴﻣ ﺔﻴﻧﺎﻜﻣﺇ ﺐﺒﺴﺑ ﺕﺍﺪﻴﺋﻭﺮﻴﺘﺳﻮﻜﻴﺗﺭﻮﻛ ﻭﺃ ﺏﺎﻣﻭﺯﻮﺘﻤﻴﻟﺃ .ﺔﻋﺎﻨﻤﻟﺍ ﺯﺎﻬﺟ ﻰﻠﻋ ﻲﻓﺎﺿﺇ ﺮﻴﺛﺄﺗ ﺙﻭﺪﺣ ﻲﻘﻠﺘﻟ

ﻻﻭﺍ ﻪﺟﻮﺗ ،ﺡﺎﻘﻟ ﻲﻘﻠﺘﻟ ﺔﺟﺎﺤﺑ ﺖﻨﻛ ﺍﺫﺇ .ﺕﺎﺣﺎﻘﻟ

ﺪﻌﺑ ﻦﻳﺮﻬﺷ ﻰﺘﺣﻭ ﺝﻼﻌﻟﺍ ﻝﻼﺧ .ﻚﺒﻴﺒﻃ ﻦﻣ ﺓﺭﺎﺸﺘﺳﺇ ﺔﻳﻭﺎﺤﻟﺍ ﺔﻨﻴﻌﻣ ﺕﺎﺣﺎﻘﻟ ﺀﺎﻄﻋﺇ ﻥﺇ ، ﺎﻴﻨﻴﻠﻴﭼ ـﺑ ﺝﻼﻌﻟﺍ ﺙﻮﻠﺘﻟﺍ ﺐﺒﺴﺗ ﺪﻗ (ﺔﻴﺣ ﺔﻔﻌﻀﻣ ﺕﺎﺣﺎﻘﻟ) ﻲﺣ ﺱﻭﺮﻴﭬ ﺕﺎﺣﺎﻘﻟ ﻥﺃ ﻦﻴﺣ ﻲﻓ ،ﺡﺎﻘﻠﻟﺍ ﻪﻌﻨﻤﻳ ﻥﺃ ﺽﺮﺘﻔﻤﻟﺍ ﻦﻣ ﻱﺬﻟﺍ ﻦﻣ ﺡﺎﻀﻴﺘﺳﻹﺍ ﺐﺠﻳ .ﺪﻴﺟ ﻞﻜﺸﺑ ﻞﻤﻌﺗ ﻻ ﺪﻗ ﻯﺮﺧﺃ .ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﺐﻴﺒﻄﻟﺍ ﻡﺎﻌﻄﻟﺍﻭ ﺎﻴﻨﻴﻠﻴﭼ ﻝﺎﻤﻌﺘﺳﺇ

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.ﻡﺎﻌﻃ ﻥﻭﺪﺑ ﻭﺃ ﻊﻣ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺗ ﻥﺎﻜﻣﻹﺎﺑ (ﺔﻨﺳ ٦٥ ﺮﻤﻋ ﻕﻮﻓ) ﻦﻴﻨﺴﻤﻟﺍ ﻦﻴﺠﻟﺎﻌﻤﻟﺍ

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ﻦﻴﻨﺴﻤﻟﺍ ﺹﺎﺨﺷﻷﺍ ﻯﺪﻟ ﺎﻴﻨﻴﻠﻴﭼ ـﺑ ﺝﻼﻌﻟﺍ ﻲﻓ ﺔﺑﺮﺠﺘﻟﺍ ﻥﺇ .ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﺐﺠﻳ ،ﻚﺸﻟﺍ ﺔﻟﺎﺣ ﻲﻓ .ﺓﺩﻭﺪﺤﻣ ﻲﻫ (ﺔﻨﺳ ١٨ ﺮﻤﻋ ﻥﻭﺩ) ﻦﻴﻘﻫﺍﺮﻤﻟﺍﻭ ﻝﺎﻔﻃﻷﺍ

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ﻦﻴﻘﻫﺍﺮﻤﻟﺍﻭ ﻝﺎﻔﻃﻷﺍ ﻯﺪﻟ ﺝﻼﻌﻠﻟ ﺺﺼﺨﻣ ﺮﻴﻏ ﺎﻴﻨﻴﻠﻴﭼ ﺭﺎﻤﻋﺄﺑ ﺩﺪﻌﺘﻤﻟﺍ ﺐﻠﺼﺘﻟﺍ ﻰﺿﺮﻣ ﻯﺪﻟ ﻩﺭﺎﺒﺘﺧﺇ ﻢﺘﻳ ﻢﻟ ﻪﻧﻷ .ﺔﻨﺳ ١٨ ﻦﻣ ﻞﻗﺃ ﻉﺎﺿﺭﻹﺍﻭ ﻞﻤﺤﻟﺍ

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ﻭﺃ ﺎﻴﻨﻴﻠﻴﭼ ﻝﺎﻤﻌﺘﺳﺇ ﺀﺎﻨﺛﺃ ﻞﻤﺤﻟﺍ ﻦﻋ ﻉﺎﻨﺘﻣﻹﺍ ﺐﺠﻳ ﺮﻃﺎﺨﻤﻟﺍ ﺐﺒﺴﺑ ﻝﺎﻤﻌﺘﺳﻹﺍ ﻦﻋ ﻚﻔﻗﻮﺗ ﺪﻌﺑ ﻦﻳﺮﻬﺷ ﺓﺪﻤﻟ ﺔﻃﻮﻨﻤﻟﺍ ﺮﻃﺎﺨﻤﻟﺍ ﻝﻮﺣ ﺐﻴﺒﻄﻟﺍ ﻱﺮﻴﺸﺘﺳﺇ .ﻦﻴﻨﺠﻟﺍ ﺭﺮﻀﺘﻟ ﻝﻼﺧ ﻞﻤﺤﻟﺍ ﻊﻨﻤﻟ ﺔﻗﻮﺛﻮﻣ ﻞﺋﺎﺳﻭ ﻝﺎﻤﻌﺘﺳﺇ ﻝﻮﺣﻭ ﻚﻟﺬﺑ .ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺪﻌﺑ ﻦﻳﺮﻬﺷ ﺓﺪﻤﻟﻭ ﺝﻼﻌﻟﺍ ﻚﻧﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ ﻪﻧﺃ ﻦﻴﻨﻈﺗ ﻭﺃ ،ﻞﻣﺎﺣ ﺖﻨﻛ ﺍﺫﺇ ﺐﻴﺒﻄﻟﺍ ﻲﻐﻠﺑ .ﻞﻤﺤﻟﺍ ﻦﻴﻟﻭﺎﺤﺗ ﺖﻨﻛ ﺍﺫﺇ ﻭﺃ ،ﻞﻣﺎﺣ ﺝﻼﻌﻟﺍ ﺀﺎﻨﺛﺃ ﻚﻟﺫ ﻦﻣ ﻢﻏﺮﻟﺍ ﻰﻠﻋ

ﻼﻣﺎﺣ ﺖﺤﺒﺻﺃ ﺍﺫﺇ ﺐﻴﺒﻄﻟﺍﻭ ﺖﻧﺃ .

ﻻﺎﺣ ﺐﻴﺒﻄﻟﺍ ﻍﻼﺑﺇ ﺐﺠﻴﻓ ﺎﻴﻨﻴﻠﻴﭼ ـﺑ .ﻚﻌﻴﺿﺮﻟﻭ ﻚﻟ ﻞﻀﻓﻷﺍ ﺎﻣ ﻥﺍﺭﺮﻘﺗ ﺎﻴﻨﻴﻠﻴﭼ ـﻟ ﻦﻜﻤﻳ .ﺎﻴﻨﻴﻠﻴﭼ ﻝﺎﻤﻌﺘﺳﺇ ﺀﺎﻨﺛﺃ ﻉﺎﺿﺭﻹﺍ ﺯﻮﺠﻳﻻ ﺽﺍﺮﻋﺃ ﺙﻭﺪﺤﻟ ﺓﺭﻮﻄﺧ ﻙﺎﻨﻫﻭ ﻡﻷﺍ ﺐﻴﻠﺣ ﻰﻟﺇ ﻞﻘﺘﻨﻳ ﻥﺃ .ﺔﻋﺎﺿﺮﻟﺍ ﻦﻣ ﻯﺬﻐﺘﻳ ﻱﺬﻟﺍ ﻊﻴﺿﺮﻠﻟ ﺓﺮﻴﻄﺧ ﺔﻴﺒﻧﺎﺟ ﺝﻼﻌﻟﺍ ﺀﺎﻨﺛﺃ ﻉﺎﺿﺭﻹﺎﺑ ﻲﻣﻮﻘﺗ ﻥﺃ ﻞﺒﻗ ﺐﻴﺒﻄﻟﺍ ﻱﺮﻴﺸﺘﺳﺇ .ﺎﻴﻨﻴﻠﻴﭼ ـﺑ ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﺐﺠﻴﻓ ،ﺔﻌﺿﺮﻣ ﻭﺃ ﻞﻤﺤﻟﺍ ﺓﺮﺘﻓ ﻲﻓ ﺖﻨﻛ ﺍﺫﺇ .ﺀﺍﻭﺩ ﻱﺃ ﻝﻭﺎﻨﺗ ﻞﺒﻗ ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﺕﺎﻨﻛﺎﻤﻟﺍ ﻝﺎﻤﻌﺘﺳﺇﻭ ﺔﻗﺎﻴﺴﻟﺍ

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ﺕﺎﺒﻛﺮﻤﻟﺍ ﺔﻗﺎﻴﺴﺑ ﻚﻟ ﺢﻤﺴﻳ ﻚﺿﺮﻣ ﻥﺎﻛ ﺍﺫﺇ ﻚﺒﻴﺒﻃ ﻚﻐﻠﺒﻳ ﺮﺛﺆﻳ ﻥﺃ ﻊﻗﻮﺘﻤﻟﺍ ﺮﻴﻏ ﻦﻣ .ﻦﻣﺁ ﻞﻜﺸﺑ ﺕﺎﻨﻛﺎﻤﻟﺍ ﻝﺎﻤﻌﺘﺳﺇﻭ .ﺕﺎﻨﻛﺎﻤﻟﺍ ﻝﺎﻤﻌﺘﺳﺇﻭ ﺔﻗﺎﻴﺴﻟﺍ ﻰﻠﻋ ﺓﺭﺪﻘﻟﺍ ﻰﻠﻋ ﺎﻴﻨﻴﻠﻴﭼ ؟ﺀﺍﻭﺪﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ ﺔﻴﻔﻴﻛ (٣ ﻚﻴﻠﻋ .

ﺎﻤﺋﺍﺩ ﺐﻴﺒﻄﻟﺍ ﺕﺎﻤﻴﻠﻌﺗ ﺐﺴﺣ ﻝﺎﻤﻌﺘﺳﻹﺍ ﺐﺠﻳ

ﺎﻘﺛﺍﻭ ﻦﻜﺗ ﻢﻟ ﺍﺫﺇ ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﺐﻴﺒﻄﻟﺍ ﻦﻣ ﺡﺎﻀﻴﺘﺳﻹﺍ ﺔﻌﺑﺎﺘﻤﻟﺍﻭ ﺹﻮﺤﻔﻟﺍ ﺕﺎﻳﺮﻜﻟ ﺺﺤﻓ ﺯﺎﺘﺠﺗ ﻑﻮﺳ ،ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺘﺑ ﺃﺪﺒﺗ ﻥﺃ ﻞﺒﻗ .ﺾﻴﺒﻟﺍ ﻡﺪﻟﺍ ﺺﺤﻔﻟ ﻡﺩ ﺺﺤﻓ ﺯﺎﺘﺠﺗ ﻑﻮﺳ ،ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺘﺑ ﺃﺪﺒﺗ ﻥﺃ ﻞﺒﻗ .ﺪﺒﻜﻟﺍ ﻒﺋﺎﻇﻭ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﺐﻴﺒﻄﻟﺍ ﻞﺒﻗ ﻦﻣ ﻥﺍﺩﺪﺤﻳ ﺝﻼﻌﻟﺍ ﺔﻘﻳﺮﻃﻭ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ :ﻲﻫ ﺓﺩﺎﻋ ﺔﻳﺩﺎﻴﺘﻋﻹﺍ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ .ﻂﻘﻓ .(ﺩﻮﻤﻴﻟﻮﭽﻨﻴﻓ ﻎﻠﻣ ٠٫٥) ﻡﻮﻴﻟﺍ ﻲﻓ ﺓﺪﺣﺍﻭ ﺔﻟﻮﺴﺒﻛ .ﺎﻬﺑ ﻰﺻﻮﻤﻟﺍ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﺯﻭﺎﺠﺘﺗ ﻻ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺘﺗ ﻒﻴﻛﻭ ﻰﺘﻣ ﻦﻣ ﺱﺄﻛ ﻒﺼﻧ ﻊﻣ ،ﻡﻮﻴﻟﺍ ﻲﻓ ﺓﺪﺣﺍﻭ ﺓﺮﻣ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺗ ﺐﺠﻳ ﺪﻋﺎﺴﻳ ﻡﻮﻳ ﻞﻛ ﻦﻣ ﺔﻋﺎﺴﻟﺍ ﺲﻔﻨﺑ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺗ ﻥﺇ .ﺀﺎﻤﻟﺍ .ﺀﺍﻭﺪﻟﺍ ﻝﻭﺎﻨﺗ ﺐﺠﻳ ﻰﺘﻣ ﺮﻛﺬﺘﻟﺍ ﻰﻠﻋ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺗ ﺓﺮﺘﻓ ﻥﻭﺪﺑ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﺮﻴﻴﻐﺗ ﻭﺃ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺯﻮﺠﻳ ﻻ ﺓﺮﺘﻓ ﻝﻮﺣ ﺔﻠﺌﺳﺃ ﻚﻳﺪﻟ ﺕﺮﻓﻮﺗ ﺍﺫﺇ.ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﺐﺠﻳ ،ﺎﻴﻨﻴﻠﻴﭼ ـﺑ ﺝﻼﻌﻟﺍ .ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﻝﻭﺎﻨﺗ ﻭﺃ ﺏﻮﻠﻄﻤﻟﺍ ﻦﻣ ﺮﺜﻛﺃ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺗ ﺄﻄﺨﻟﺎﺑ ﻰﻟﻭﻷﺍ ﺔﻋﺮﺠﻟﺍ ﺍﺫﺇ ﻭﺃ ﺏﻮﻠﻄﻤﻟﺍ ﻦﻣ ﺮﺒﻛﺃ ﺔﻋﺮﺟ ﺖﻟﻭﺎﻨﺗ ﺍﺫﺇ ،ﺄﻄﺨﻟﺎﺑ ﺎﻴﻨﻴﻠﻴﭼ ﻦﻣ ﻰﻟﻭﻷﺍ ﺔﻋﺮﺠﻟﺍ ﺖﻟﻭﺎﻨﺗ

ﻻﺎﺣ ﺐﻴﺒﻄﻟﺍ ﻰﻟﺇ ﻪﺟﻮﺘﻟﺍ ﺐﺠﻳ ﻊﻣ ﺔﺒﻗﺍﺮﻣ ﺀﺍﺮﺟﺈﺑ ﺐﻴﺒﻄﻟﺍ ﺭﺮﻘﻳ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ ،ﺔﻋﺎﺳ ﻞﻜﺑ ﻡﺪﻟﺍ ﻂﻐﺿﻭ ﺐﻠﻘﻟﺍ ﻢﻈﻧ ﺱﺎﻴﻗ

) ﺐﻠﻘﻠﻟ ﻲﺋﺎﺑﺮﻬﻜﻟﺍ ﻂﻴﻄﺨﺘﻟﺍ ﺹﻮﺤﻓ .ﻞﻴﻠﻟﺍ ﺔﻠﻴﻃ ﺔﺒﻗﺍﺮﻣ ﻞﺑ ﻻ ،ﺀﺍﻭﺪﻟﺍ ﻦﻣ ﺄﻄﺨﻟﺎﺑ ﻞﻔﻃ ﻊﻠﺑ ﺍﺫﺇ ﻭﺃ ﺔﻃﺮﻔﻣ ﺔﻋﺮﺟ ﺖﻟﻭﺎﻨﺗ ﺍﺫﺇ ﻰﻔﺸﺘﺴﻤﻟﺍ ﻲﻓ ﺉﺭﺍﻮﻄﻟﺍ ﺔﻓﺮﻏ ﻰﻟﺇ ﻭﺃ ﺐﻴﺒﻄﻟﺍ ﻰﻟﺇ

ﻻﺎﺣ ﻪﺟﻮﺗ .ﻚﻌﻣ ﺀﺍﻭﺪﻟﺍ ﺔﺒﻠﻋ ﺮﻀﺣﺃﻭ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺗ ﺖﻴﺴﻧ ﺍﺫﺇ ﺎﻤﻛ ﺔﻣﺩﺎﻘﻟﺍ ﺔﻋﺮﺠﻟﺍ ﻝﻭﺎﻨﺗ ﺐﺠﻴﻓ ،ﺔﻋﺮﺟ ﻝﻭﺎﻨﺗ ﺖﻴﺴﻧ ﺍﺫﺇ ﻦﻋ ﺾﻳﻮﻌﺘﻠﻟ ﺔﻔﻋﺎﻀﻣ ﺔﻋﺮﺟ ﻝﻭﺎﻨﺗ ﺯﻮﺠﻳ ﻻ .ﻂﻄﺨﻣ ﻮﻫ ﻦﻣ ﻞﻗﻷ ﺎﻴﻨﻴﻠﻴﭼ ـﺑ ﺞﻟﺎﻌﺘﺗ ﺖﻨﻛ ﺍﺫﺇ.ﺔﻴﺴﻨﻤﻟﺍ ﺔﻋﺮﺠﻟﺍ ﻍﻼﺑﺇ ﺐﺠﻳ ،ﺪﺣﺍﻭ ﻡﻮﻳ ﻝﻼﺧ ﺔﻋﺮﺟ ﻝﻭﺎﻨﺗ ﺖﻴﺴﻧﻭ ﻦﻴﻋﻮﺒﺳﺃ ﺀﺍﺮﺟﺈﺑ ﺐﻴﺒﻄﻟﺍ ﺭﺮﻘﻳ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ .ﻱﺭﻮﻓ ﻞﻜﺸﺑ ﺐﻴﺒﻄﻟﺍ .ﺔﻣﺩﺎﻘﻟﺍ ﺔﻋﺮﺠﻟﺍ ﻝﻭﺎﻨﺗ ﺀﺎﻨﺛﺃ ﺔﺒﻗﺍﺮﻣ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ .ﺐﻴﺒﻄﻟﺍ ﻪﺑ ﻰﺻﻭﺃ ﺎﻤﻛ ﺝﻼﻌﻟﺍ ﻰﻠﻋ ﺔﺒﻇﺍﻮﻤﻟﺍ ﺐﺠﻳ ﻥﻭﺪﺑ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﺮﻴﻴﻐﺗ ﻭﺃ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺯﻮﺠﻳ ﻻ ﻚﺘﻟﺎﺣ ﻰﻠﻋ ﻦﺴﺤﺗ ﺃﺮﻃ ﻮﻟﻭ ﻰﺘﺣ ،ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﻒﻗﻮﺘﻟﺍ ﺪﻌﺑ ﻦﻳﺮﻬﺷ ﻰﺘﺣ ﻢﺴﺠﻟﺍ ﻲﻓ ﺀﺍﻭﺪﻟﺍ ﻰﻘﺒﻳ .ﺔﻴﺤﺼﻟﺍ ﺀﺎﻀﻴﺒﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺧ ﺩﺍﺪﻌﺗ ﻰﻘﺒﻳ ﻥﺃ

ﺎﻀﻳﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ .ﺝﻼﻌﻟﺍ ﻦﻋ ﺙﺪﺤﺗ ﺪﻗﻭ ﺓﺮﺘﻔﻟﺍ ﻩﺬﻫ ﻝﻼﺧ

ﺎﻀﻔﺨﻨﻣ (ﺕﺎﻳﻭﺎﻔﻤﻠﻟﺍ ﺩﺍﺪﻌﺗ) .ﻥﻵﺍ ﻰﺘﺣ ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﻲﻓ ﺖﻔﺻﻭ ﻲﺘﻟﺍ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ .«ﻉﺎﺿﺭﻹﺍﻭ ﻞﻤﺤﻟﺍ» ﺓﺮﻘﻓ ﺓﺀﺍﺮﻗ ﺐﺠﻳ ،ﺕﺎﺠﻟﺎﻌﻤﻟﺍ ﺀﺎﺴﻨﻠﻟ ﻰﺘﺣ ﺔﻤﺋﺎﻗ ﻲﻫ ﻰﻟﻭﻷﺍ ﺔﻋﺮﺠﻟﺍ ﻝﻭﺎﻨﺘﻟ ﺔﺒﺴﻨﻟﺎﺑ ﺔﻴﺻﻮﺘﻟﺍ ﻥﺇ ﻝﻼﺧ ﺮﺜﻛﺃ ﻭﺃ ﺪﺣﺍﻭ ﻡﻮﻳ ﺓﺮﺘﻔﻟ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺗ ﻦﻋ ﺖﻔﻗﻮﺗ ﻮﻟﻭ ﺎﻴﻨﻴﻠﻴﭼ ﻝﻭﺎﻨﺗ ﻦﻋ ﺖﻔﻗﻮﺗ ﺍﺫﺇ ﻭﺃ ﺝﻼﻌﻠﻟ ﻦﻴﻟﻭﻷﺍ ﻦﻴﻋﻮﺒﺳﻷﺍ ﺎﻴﻨﻴﻠﻴﭼ ـﺑ ﺝﻼﻌﻠﻟ ﻝﻭﻷﺍ ﺮﻬﺸﻟﺍ ﺪﻌﺑ ﻦﻴﻋﻮﺒﺳﺃ ﻦﻣ ﺮﺜﻛﺃ ﺓﺮﺘﻔﻟ ﻉﻮﺒﺳﻷﺍ ﻝﻼﺧ ﻡﺎﻳﺃ ﺔﻌﺒﺳ ﻦﻣ ﺮﺜﻛﻷ ﺝﻼﻌﻟﺍ ﻦﻋ ﺖﻔﻗﻮﺗ ﺍﺫﺇ ﻭﺃ ﻲﻟﻭﻷﺍ ﺮﻴﺛﺄﺘﻟﺍ ﻥﺇ ،ﺕﻻﺎﺤﻟﺍ ﻩﺬﻫ ﻲﻓ .ﺝﻼﻌﻠﻟ ﻊﺑﺍﺮﻟﺍﻭ ﺚﻟﺎﺜﻟﺍ ﺝﻼﻌﻟﺍ ﺃﺪﺒﺗ ﺎﻣﺪﻨﻋ .ﺔﻴﻧﺎﺛ ﺙﺪﺤﻳ ﻥﺃ ﻦﻜﻤﻳ ﺐﻠﻘﻟﺍ ﻢﻈﻧ ﻰﻠﻋ ﺔﺒﻗﺍﺮﻣ ﺐﻴﺒﻄﻟﺍ ﺭﺮﻘﻳ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻤﻓ ،ﺪﻳﺪﺟ ﻦﻣ ﺎﻴﻨﻴﻠﻴﭼ ـﺑ ﺹﻮﺤﻓ ﻱﺮﺠﻳ ﻥﺃﻭ ،ﺔﻋﺎﺳ ﻞﻜﺑ ﻡﺪﻟﺍ ﻂﻐﺿﻭ ﺐﻠﻘﻟﺍ ﻢﻈﻧ ﺔﺒﻗﺍﺮﻤﻟﺍ ﺖﺤﺗ ﻚﺋﺎﻘﺑﺇ ﻭﺃ ﺐﻠﻘﻠﻟ ﻲﺋﺎﺑﺮﻬﻜﻟﺍ ﻂﻴﻄﺨﺘﻟﺍ .ﻞﻴﻠﻟﺍ ﻝﺍﻮﻃ ﻊﺑﺎﻃ ﺺﻴﺨﺸﺗ ﺐﺠﻳ !ﺔﻤﺘﻌﻟﺍ ﻲﻓ ﺔﻳﻭﺩﻷﺍ ﻝﻭﺎﻨﺗ ﺯﻮﺠﻳ ﻻ ﺎﻬﻴﻓ ﻝﻭﺎﻨﺘﺗ ﺓﺮﻣ ﻞﻛ ﻲﻓ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﻦﻣ ﺪﻛﺄﺘﻟﺍﻭ ﺀﺍﻭﺪﻟﺍ .ﻚﻟﺫ ﺮﻣﻷﺍ ﻡﺰﻟ ﺍﺫﺇ ﺔﻴﺒﻄﻟﺍ ﺕﺍﺭﺎﻈﻨﻟﺍ ﻊﺿ .ﺀﺍﻭﺩ ﺮﺸﺘﺳﺇ ،ﺀﺍﻭﺪﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ ﻝﻮﺣ ﺔﻴﻓﺎﺿﺇ ﺔﻠﺌﺳﺃ ﻚﻳﺪﻟ ﺕﺮﻓﻮﺗ ﺍﺫﺇ .ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﺐﻴﺒﻄﻟﺍ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ (٤ ﺔﻴﺒﻧﺎﺟ

ﺎﺿﺍﺮﻋﺃ ﺐﺒﺴﻳ ﺪﻗ ﺎﻴﻨﻴﻠﻴﭼ ﻝﺎﻤﻌﺘﺳﺇ ﻥﺇ ،ﺀﺍﻭﺩ ﻞﻜﺑ ﺎﻤﻛ ﻯﺪﻟ ﺎﻬﺛﻭﺪﺣ ﻡﺪﻋ ﻦﻣ ﻢﻏﺮﻟﺍ ﻰﻠﻋ ،ﻦﻴﻠﻤﻌﺘﺴﻤﻟﺍ ﺾﻌﺑ ﺪﻨﻋ ﺰﺋﺎﺠﻟﺍ ﻦﻣ ،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺔﻤﺋﺎﻗ ﻦﻣ ﺶﻫﺪﻨﺗ ﻻ .ﻊﻴﻤﺠﻟﺍ .ﺎﻬﻨﻣ

ﺎﻳﺃ ﻲﻧﺎﻌﺗ ﻻﺃ ﻑﺮﻌﻣ ﻦﻴﻌﻣ ﻉﻮﻴﺸﺑ ﺙﺪﺤﺗ ﻥﺃ ﻦﻜﻤﻳ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ :ﻲﻠﻳ ﺎﻤﻛ ﺪﻗ ﻭﺃ ﺓﺮﻴﻄﺧ ﻥﻮﻜﺗ ﻥﺃ ﻦﻜﻤﻳ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺾﻌﺑ :ﺓﺮﻴﻄﺧ ﺢﺒﺼﺗ ﺐﻴﺒﻄﻟﺍ ﺔﻌﺟﺍﺮﻣ ﺐﺠﻳ ،ﺔﻴﻟﺎﺘﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺈﺑ ﺕﺮﻌﺷ ﺍﺫﺇ

:

ﻻﺎﺣ :ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻞﺜﻣ ﺽﺍﺮﻋﺃ ﻊﻣ (

Bronchitis

) ﺕﺎﺒﺼﻘﻟﺍ ﺏﺎﻬﺘﻟﺇ

ﺔﻧﻮﺨﺳ ،ﺭﺪﺼﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﻢﻐﻠﺑ ﻊﻣ ﻝﺎﻌﺳ ﻞﺜﻣ ﺽﺍﺮﻋﺃ ﻊﻣ (

herpes zoster

) ﺔﻘﻄﻨﻤﻟﺍ ﺔﻟﻮﺒﻘﻋ

ﻢﺴﻘﻟﺍ ﻲﻓ ،ﺪﻠﺠﻟﺍ ﻲﻓ ﻢﻟﺃ ﻭﺃ ﺔﻜﺣ ،ﺔﻗﺮﺣ ،ﺕﻼﺼﻳﻮﺣ ﺽﺍﺮﻋﺃ ﺙﺪﺤﺗ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ .ﻪﺟﻮﻟﺍ ﻭﺃ ﻢﺴﺠﻠﻟ ﻱﻮﻠﻌﻟﺍ ،ﺙﻮﻠﺘﻠﻟ ﺓﺮﻜﺒﻤﻟﺍ ﻞﺣﺍﺮﻤﻟﺍ ﻲﻓ ﻒﻌﺿﻭ ﺔﻧﻮﺨﺳ ﻦﻣ ﻯﺮﺧﺃ ﺪﻳﺪﺷ ﻢﻟﺃ ﻊﻣ ﺀﺍﺮﻤﺣ ﻊﻘﺑ ﻭﺃ ﺔﻜﺣ ،ﺭﺪﺧ ﺎﻫﺪﻌﺑ ﻦﻣﻭ

bradycardia

) ﺐﻠﻘﻟﺍ ﻢﻈﻧ ﺆﻃﺎﺒﺗ

ﺎﻳﻼﺨﻟﺍ ﻥﺎﻃﺮﺳ ﻰﻤﺴﻳ ﻱﺬﻟﺍ ﺪﻠﺠﻟﺍ ﻥﺎﻃﺮﺳ ﻦﻣ ﻉﻮﻧ

ﻱﺬﻟﺍ (

basal cell

carcinoma, BCC

) ﺔﻳﺪﻋﺎﻘﻟﺍ ،ﺓﺆﻟﺆﻠﻟﺍ ﻪﺒﺸﺗ ﺓﺮﻴﻐﺻ ﺔﻠﺘﻜﻛ ﺔﺑﺭﺎﻘﺘﻣ ﻥﺎﻴﺣﺃ ﻲﻓ ﻭﺪﺒﻳ ﻯﺮﺧﺃ ﻝﺎﻜﺷﺄﺑ ﻭﺪﺒﻳ ﺪﻗ ﻪﻨﻜﻟ :ﺔﻌﺋﺎﺷ ﺮﻴﻏ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺕﺎﺑﻮﻌﺻ ،ﻝﺎﻌﺳ ،ﺔﻧﻮﺨﺳ ﻞﺜﻣ ﺽﺍﺮﻋﺃ ﻊﻣ ﻦﻴﺘﺋﺮﻟﺍ ﺏﺎﻬﺘﻟﺇ

ﺔﻴﺴﻔﻨﺗ ﺔﻳﺰﻛﺮﻤﻟﺍ ﺔﻳﺅﺮﻟﺍ ﺔﻘﻄﻨﻣ ﻲﻓ ﺥﺎﻔﺘﻧﺇ) ﺔﻴﻌﻘﺑ ﺔﻣﺫﻭ

ﻞﺜﻣ ﺽﺍﺮﻋﺃ ﻊﻣ (ﻦﻴﻌﻠﻟ ﻲﻔﻠﺨﻟﺍ ﻢﺴﻘﻟﺍ ﻲﻓ ﺔﻴﻜﺒﺸﻠﻟ ،ﺔﻴﺑﺎﺒﺿ ﺔﻳﺅﺭ ،ﺔﻳﺅﺮﻟﺍ ﺰﻛﺮﻣ ﻲﻓ ﺀﺎﻴﻤﻋ ﺔﻌﻘﺑ ﻭﺃ ﻞﻴﻠﻇ ﺀﺎﻴﺷﻷﺍ ﻭﺃ ﻥﺍﻮﻟﻷﺍ ﺔﻳﺅﺭ ﻲﻓ ﻞﻛﺎﺸﻣ :ﺓﺭﺩﺎﻧ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ

posterior

re v e r s i b l e

ﻰﻤﺴﺗ ﺔــﻟﺎــﺣ

ﻦﻜﻤﻳ .

encephalopathy syndrome (PRES

،ﻙﺎﺒﺗﺭﺇ ،ﺪﻳﺪﺷ ﻉﺍﺪﺼﻟ ﺔﺌﺟﺎﻔﻣ ﺔﻳﺍﺪﺑ ﺽﺍﺮﻋﻷﺍ ﻞﻤﺸﺗ ﻥﺃ ﺔﻳﺅﺮﻟﺍ ﻲﻓ ﺕﺍﺮﻴﻐﺗﻭ ﺕﺎﺟﻼﺘﺧﺇ :ﻑﻭﺮﻌﻣ ﺮﻴﻏ ﻉﻮﻴﺸﺑ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺩﻮﻌﻳﻭ ﺖﻗﺆﻣ ﺮﺒﺘﻌﻳ ﻱﺬﻟﺍ ﺾﺒﻨﻟﺍ ﻲﻓ ﺮﻴﻄﺧ ﻡﺎﻈﺘﻧﺇ ﻡﺪﻋ

ﺖﺴﻟﺍ ﺕﺍﺫ ﺔﺒﻗﺍﺮﻤﻟﺍ ﺓﺮﺘﻓ ﻝﻼﺧ ﻢﻴﻠﺴﻟﺍ ﻪﻌﺿﻭ ﻰﻟﺇ ﺕﺎﻋﺎﺳ ﻙﺎﺣ ﻯﺮﺷ ﻭﺃ ﺢﻔﻃ ﺽﺍﺮﻋﺃ ﻞﻤﺸﺗ ،ﺔﻴﺴﺴﺤﺗ ﻞﻌﻓ ﺩﻭﺩﺭ

،ﻪﺟﻮﻟﺍ ﻭﺃ ﻥﺎﺴﻠﻟﺍ ،ﻦﻴﺘﻔﺸﻟﺍ ﺥﺎﻔﺘﻧﺇ ،(

hives

،ﻯﺮﺷ) ﺕﺃﺪﺑ ﻱﺬﻟﺍ ﻡﻮﻴﻟﺍ ﻲﻓ ﺙﺪﺤﺗ ﻥﺃ ﻞﻤﺘﺤﻤﻟﺍ ﻦﻣ ﻱﺬﻟﺍ .ﺎﻴﻨﻴﻠﻴﭼ ـﺑ ﺝﻼﻌﻟﺍ ﻪﻴﻓ

progressive multifocal

ﻰﻤﺴﻳ ﺭﺩﺎﻧﻭ ﺮﻴﻄﺧ ﺙﻮﻠﺗ

ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ ﻭﺫ

leukoencephalopathy (PML

ﺩﺪﻌﺘﻤﻟﺍ ﺐﻠﺼﺘﻟﺍ ﺽﺍﺮﻋﺄﺑ ﺔﻬﻴﺒﺷ ﻥﻮﻜﺗ ﻥﺃ ﻦﻜﻤﻳ ﻲﻓ ﻞﻠﺧ ،ﺕﻼﻀﻌﻟﺍ ﻲﻓ ﻒﻌﺿ ﻞﻤﺸﺗ ﻥﺃ ﺎﻬﻧﺄﺷ ﻦﻣﻭ /ﻖﻄﻨﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ،ﻉﺍﺪﺻ ،ﻲﻏﺎﻣﺪﻟﺍ ﻲﻔﻴﻇﻮﻟﺍ ﺀﺍﺩﻷﺍ ﺕﺎﺑﺍﺮﻄﺿﺇ ،ﺲﺤﻟﺍ ﻲﻓ ﻞﻠﺧ/ﻥﺍﺪﻘﻓ ،ﺕﺎﺟﻼﺘﺧﺇ ،ﺔﻳﺅﺮﻟﺍ .(ﺔﻛﺮﺤﻟﺍ ﻖﻴﺴﻨﺗ) ﻖﻴﺴﻨﺘﻟﺍ ﻭﺃ ﻲﺸﻤﻟﺍ ﻲﻓ ،(ﻱﺮﻄﻔﻟﺍ ﺙﻮﻠﺘﻟﺍ ﻦﻣ ﻉﻮﻧ) ﺔﻴﻔﺨﻟﺍ ﺓﺭﻮﻜﻤﻟﺎﺑ ﺕﺎﺛﻮﻠﺗ

ﺽﺍﺮﻋﺃ ﻊﻣ ﺔﻴﻔﺨﻟﺍ ﺕﺍﺭﻮﻜﻤﻟﺎﺑ ﺎﻳﺎﺤﺴﻟﺍ ﺏﺎﻬﺘﻟﺇ ﻞﻤﺸﻳ ﺔﻴﺳﺎﺴﺣ ،ﺔﺒﻗﺮﻟﺍ ﻲﻓ ﺐﻠﺼﺘﺑ ﻖﻓﺍﺮﺘﻳ ﻱﺬﻟﺍ ﻉﺍﺪﺻ ﻞﺜﻣ ﻙﺎﺒﺗﺭﺇ ﻭﺃ/ﻭ ﻥﺎﻴﺜﻏ ،ﺀﻮﻀﻠﻟ ﺔﻴﻓﺎﺿﺇ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ،ﺪﻳﺪﺷ ﻞﻜﺸﺑ ﺔﻴﻟﺎﺘﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻦﻣ ﺓﺪﺣﺍﻭ ﻚﻴﻠﻋ ﺕﺮﺛﺃ ﺍﺫﺇ :ﺐﻴﺒﻄﻟﺍ ﻊﺟﺍﺭ

ﺍﺪﺟ ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ،ﺓﺮﻳﺮﻌﺸﻗ ،ﻕﺎﻫﺭﺇ ﻞﺜﻣ ﺽﺍﺮﻋﺃ ﻊﻣ ﺍﺰﻧﺇﻮﻠﻔﻧﻹﺍ ﺱﻭﺮﻴﭭﺑ ﺙﻮﻠﺗ

ﺔﻧﻮﺨﺳ ،ﺔﻴﻠﻀﻋ ﻭﺃ ﺔﻴﻠﺼﻔﻣ ﻡﻻﺁ ،ﺓﺮﺠﻨﺤﻟﺍ ﻲﻓ ﻢﻟﺃ ﺏﺎﻬﺘﻟﺇ) ﻦﻴﺒﺠﻟﺍﻭ ﻦﻳﺪﺨﻟﺍ ﻲﻓ ﻢﻟﺃ ﻭﺃ ﻂﻐﻀﺑ ﺭﻮﻌﺸﻟﺍ

(ﺔﻴﻔﻧﻷﺍ ﺏﻮﻴﺠﻟﺍ ﻉﺍﺪﺻ

ﻝﺎﻬﺳﺇ

ﺮﻬﻈﻟﺍ ﻲﻓ ﻢﻟﺃ

ﺪﺒﻜﻟﺍ ﺕﺎﻤﻳﺰﻧﻹ ﻰﻠﻋﺃ ﺕﺎﻳﻮﺘﺴﻣ ﺮﻬﻈﺗ ﻡﺩ ﺹﻮﺤﻓ

ﻝﺎﻌﺳ

:ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺮﻄﻓ) ﺪﻠﺠﻠﻟ ﻱﺮﻄﻓ ﺙﻮﻠﺗ ،(

ringworm

) ﺮﻓﺎﻇﻷﺍ ﺮﻄﻓ

tinea versicolor

ﺲﻤﺸﻟﺍ ﺭﺍﻭﺩ

ﺀﻮﻀﻠﻟ ﺔﻴﺳﺎﺴﺣﻭ ﺆﻴﻘﺗ ،ﻥﺎﻴﺜﻐﺑ

ﺎﺒﻟﺎﻏ ﻖﻓﺍﺮﺘﻳ ﺪﻳﺪﺷ ﻉﺍﺪﺻ

(ﺔﻘﻴﻘﺷ) ﻒﻌﺿ

(ﺎﻤﻳﺰﻛﺇ) ﻕﺭﺎﺣ ،ﺮﻤﺣﺃ ،ﻙﺎﺣ ﺢﻔﻃ

ﺪﻠﺠﻟﺍ ﻲﻓ ﺔﻜﺣ

(ﺕﺍﺪﻳﺮﻴﺴﻴﻠﭽﻳﺮﺗ) ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﺤﺸﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ

ﺲﻔﻨﺘﻟﺍ ﺔﻠﻗ

ﺪﻌﺑ ﺃﺪﺒﺗ ﺔﻟﺎﺣ ،ﻦﻴﺘﺋﺮﻟﺍ ﻒﺋﺎﻇﻭ ﺺﺤﻓ ﻲﻓ ﺓﺫﺎﺷ ﺞﺋﺎﺘﻧ

ﺲﻜﻌﻠﻟ ﺔﻠﺑﺎﻗﻭ ﻚﻟﺫ ﺪﻌﺑ ﺔﺘﺑﺎﺛ ﻰﻘﺒﺗ ،ﺝﻼﻌﻟﺍ ﻦﻣ ﺪﺣﺍﻭ ﺮﻬﺷ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺪﻌﺑ ﺔﻴﻌﻘﺒﻟﺍ ﺔﻣﺫﻮﻟﺍ ﻦﻋ ﺕﺎﻣﻮﻠﻌﻤﻟﺍ

ﺎﻀﻳﺃ ﺮﻈﻧﺃ) ﺔﻴﺑﺎﺒﺿ ﺔﻳﺅﺭ

ﻲﺘﻟﺍ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ» ﻲﻓﻭ «ﺕﺍﺮﻳﺬﺤﺗ» ﺓﺮﻘﻓ ﻲﻓ

ﺎﻘﺑﺎﺳ ،«ﺓﺮﻴﻄﺧ ﻥﻮﻜﺗ ﻥﺃ ﻦﻜﻤﻳ

ﺎﻋﺎﻔﺗﺭﺇ ﺐﺒﺴﻳ ﻥﺃ ﺎﻴﻨﻴﻠﻴﭼ ﻥﺄﺷ ﻦﻣ .ﻡﺪﻟﺍ ﻂﻐﺿ ﻉﺎﻔﺗﺭﺇ

ﻡﺪﻟﺍ ﻂﻐﺿ ﻲﻓ

ﺎﻄﻴﺴﺑ ،ﺕﺎﻳﻭﺎﻔﻤﻠﻟﺍ ﺔﻠﻗ) ﺀﺎﻀﻴﺒﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺧ ﺔﺒﺴﻧ ﺽﺎﻔﺨﻧﺇ

(ﺾﻴﺒﻟﺍ ﺕﺎﻳﺮﻜﻟﺍ ﺔﻠﻗ :ﻑﻭﺮﻌﻣ ﺮﻴﻏ ﻉﻮﻴﺸﺑ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻥﺎﻴﺜﻏ

،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻤﻗﺎﻔﺗ ﺍﺫﺇ ،ﻲﺒﻧﺎﺟ ﺽﺮﻋ ﺮﻬﻇ ﺍﺫﺃ ،ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﻲﻓ ﺮﻛﺬﻳ ﻢﻟ ﻲﺒﻧﺎﺟ ﺽﺮﻋ ﻦﻣ ﻲﻧﺎﻌﺗ ﺎﻣﺪﻨﻋ ﻭﺃ .ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﻚﻴﻠﻋ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻦﻋ ﻍﻼﺑﻹﺍ ﺔﻄﺳﺍﻮﺑ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻮﻟ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻦﻋ ﻍﻼﺑﻹﺍ ﻥﺎﻜﻣﻹﺎﺑ ﻲﻓ ﺩﻮﺟﻮﻤﻟﺍ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻦﻋ ﻍﻼﺑﻺﻟ ﺮﺷﺎﺒﻤﻟﺍ ﺝﺫﻮﻤﻨﻟﺍ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻊﻗﻮﻤﻟ ﺔﻴﺴﻴﺋﺮﻟﺍ ﺔﺤﻔﺼﻟﺍ

www.health.gov.il

https://forms.

:ﻂﺑﺍﺮﻟﺍ ﺢﻔﺼﺗ ﻖﻳﺮﻃ ﻦــﻋ ﻭﺃ

gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.gov.il

؟ﺀﺍﻭﺪﻟﺍ ﻦﻳﺰﺨﺗ ﺔﻴﻔﻴﻛ (٥ ﻥﺎﻜﻣ ﻲﻓ ﺀﺍﻭﺩ ﻞﻛﻭ ﺀﺍﻭﺪﻟﺍ ﺍﺬﻫ ﻆﻔﺣ ﺐﺠﻳ !ﻢﻤﺴﺘﻟﺍ ﺐﻨﺠﺗ ﻭﺃ/ﻭ ﻝﺎﻔﻃﻷﺍ ﺔﻳﺅﺭ ﻝﺎﺠﻣﻭ ﻱﺪﻳﺃ ﻝﻭﺎﻨﺘﻣ ﻦﻋ

ﺍﺪﻴﻌﺑ ﻖﻠﻐﻣ ﺆﻴﻘﺘﻟﺍ ﺐﺒﺴﺗ ﻻ .ﻢﻤﺴﺘﻟﺎﺑ ﻢﻬﺘﺑﺎﺻﺇ ﻱﺩﺎﻔﺘﻟ ﻚﻟﺫﻭ ،ﻊﺿﺮﻟﺍ .ﺐﻴﺒﻄﻟﺍ ﻦﻣ ﺔﺤﻳﺮﺻ ﺕﺎﻤﻴﻠﻌﺗ ﻥﻭﺪﺑ

exp.

) ﺔﻴﺣﻼﺼﻟﺍ ﺦﻳﺭﺎﺗ ﺀﺎﻀﻘﻧﺇ ﺪﻌﺑ ﺀﺍﻭﺪﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ ﺯﻮﺠﻳ ﻻ ﺦﻳﺭﺎﺗ ﺮﻴﺸﻳ .ﺔﺒﻠﻌﻟﺍ ﺮﻬﻇ ﻰﻠﻋ ﺮﻬﻈﻳ ﻱﺬﻟﺍ (

date

.ﺮﻬﺸﻟﺍ ﺲﻔﻧ ﻦﻣ ﺮﻴﺧﻷﺍ ﻡﻮﻴﻟﺍ ﻰﻟﺇ ﺔﻴﺣﻼﺼﻟﺍ .ﺔﻳﻮﺌﻣ ﺔﺟﺭﺩ ٢٥ ﻥﻭﺩ ﺀﺍﻭﺪﻟﺍ ﻦﻳﺰﺨﺗ ﺐﺠﻳ ﻦﻣ ﻪﺘﻳﺎﻤﺣ ﺐﺠﻳ ،ﺔﻴﻠﺻﻷﺍ ﺔﺒﻠﻌﻟﺍ ﻲﻓ ﻦﻳﺰﺨﺘﻟﺍ ﺐﺠﻳ .ﺔﺑﻮﻃﺮﻟﺍ ﺔﻴﻓﺎﺿﺇ ﺕﺎﻣﻮﻠﻌﻣ (٦

ﺎﻀﻳﺃ ﺔﻟﺎﻌﻔﻟﺍ ﺓﺩﺎﻤﻠﻟ ﺔﻓﺎﺿﻹﺎﺑ ﺀﺍﻭﺪﻟﺍ ﻱﻮﺘﺤﻳ ﺔﺒﻠﻌﻟﺍ ﻯﻮﺘﺤﻣ ﻮﻫ ﺎﻣﻭ ﺀﺍﻭﺪﻟﺍ ﻭﺪﺒﻳ ﻒﻴﻛ ﺔﻴﺳﺎﻗ ﺕﻻﻮﺴﺒﻛ ﻞﻜﺷ ﻰﻠﻋ ﻕﻮﺴﻣ ﺎﻴﻨﻴﻠﻴﭼ ﺀﺍﻭﺪﻟﺍ ﺔﻴﺳﺎﻘﻟﺍ ﺕﻻﻮﺴﺒﻜﻠﻟ .(ﻢﻔﻟﺍ ﻖﻳﺮﻃ ﻦﻋ) ﻱﻮﻤﻔﻟﺍ ﻝﺎﻤﻌﺘﺳﻺﻟ ﺮﻔﺻﺃ ﺀﺎﻄﻏﻭ ﺮﻔﺻﻷﺎﺑ ﻦ

ﻴﻄﺧ ﻪﻴﻠﻋ ﻉﻮﺒﻄﻣ ﻢﺗﺎﻗ ﺾﻴﺑﺃ ﻢﺴﺟ .ﺩﻮﺳﻷﺎﺑ

FTY 0.5 mg

ﻪﻴﻠﻋ ﻉﻮﺒﻄﻣ ﻢﺗﺎﻗ ﺢﺗﺎﻓ ﺾﻴﺑﻸﻟ ﻞﺋﺎﻣ ﻰﻟﺇ ﺾﻴﺑﺃ ﻥﻮﻠﺑ ﻕﻮﺤﺴﻣ :ﺕﻻﻮﺴﺒﻜﻟﺍ ﻯﻮﺘﺤﻣ

ﺎﺒﻳﺮﻘﺗ

ﻮﺴﺗ ﻻﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ).ﺔﻟﻮﺴﺒﻛ ٢٨ ﻭﺃ ٧ :ﺐﻠﻌﻟﺍ ﻡﺎﺠﺣﺃ .(ﺐﻠﻌﻟﺍ ﻡﺎﺠﺣﺃ ﺔﻓﺎﻛ ،.ﺽ.ﻡ ﻞﻴﺋﺍﺮﺳﺇ ﺲﻴﺗﺭﺎﭬﻮﻧ :ﻪﻧﺍﻮﻨﻋﻭ ﺯﺎﻴﺘﻣﻹﺍ ﺐﺣﺎﺻ .ﺎﭭﻜﺗ ـ ﺢﺘﻴﭘ ،٣٦ ﻡﺎﺣﺎﺷ ﻉﺭﺎﺷ ،ﻲﺟ ﻲﻳﺍ ﻦﻳﺎﺘﺷ ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ :ﻪﻧﺍﻮﻨﻋﻭ ﺞﺘﻨﻤﻟﺍ ﻢﺳﺇ ﺍﺮﺴﻳﻮﺳ ،ﻦﻳﺎﺘﺷ ﺍﺮﺴﻳﻮﺳ ،ﻝﺯﺎﺑ ،ﻲﺟ ﻲﻳﺍ ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ :ﻞﺟﺃ ﻦﻣ ﺺﺤ

ﻓ ﺎﻫﺍﻮﺘﺤﻣﻭ ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﺔﻐﻴﺻ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﺕﺮﻗﺃ ٢٠١٥ ﺏﺁ :ﺦﻳﺭﺎﺗ ﻲﻓ ﺺﺧ

ﺭﻭ ﺓﺭﺍﺯﻭ ﻲﻓ ﻲﻣﻮﻜﺤﻟﺍ ﺔﻳﻭﺩﻷﺍ ﻞﺠﺳ ﻲﻓ ﺀﺍﻭﺪﻟﺍ ﻞﺠﺳ ﻢﻗﺭ :ﺔﺤﺼﻟﺍ ١٤٥ ٧٨ ٣٣٢٧٠ ـ ﻎﻠﻣ ٠٫٥ ﺎﻴﻨﻴﻠﻴﭼ ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﺔﻏﺎﻴﺻ ﺖﻤﺗ ،ﺓﺀﺍﺮﻘﻟﺍ ﻦﻳﻮﻬﺗﻭ ﺔﻟﻮﻬﺳ ﻞﺟﺃ ﻦﻣ ﺺﺼﺨﻣ ﺀﺍﻭﺪﻟﺍ ﻥﺈﻓ ،ﻚﻟﺫ ﻦﻣ ﻢﻏﺮﻟﺍ ﻰﻠﻋ .ﺮﻛﺬﻤﻟﺍ ﺔﻐﻴﺼﺑ .ﻦﻴﺴﻨﺠﻟﺍ ﻼﻜﻟ ﺔﻌﺋﺎﺷ

ﺍﺪﺟ ١٠ ﻞﻜﻟ ١ ﺞ

ﻟﺎﻌﻣ ﻦﻣ ﺮﺜﻛﺃ ﻰﻠﻋ ﺮﺛﺆﺗ ﻦﻴﺠ

ﻟﺎﻌﻣ :ﺔﻌﺋﺎﺷ ١٠٠ ﻞﻜﻟ ﻦﻴﺠ

ﻟﺎﻌﻣ ١٠ ﻰﺘﺣ ١ ﻰﻠﻋ ﺮﺛﺆﺗ

ﻟﺎﻌﻣ :ﺔﻌﺋﺎﺷ ﺮﻴﻏ ١٠٠٠ ﻞﻜﻟ ﻦﻴﺠ

ﻟﺎﻌﻣ ١٠ ﻰﺘﺣ ١ ﻰﻠﻋ ﺮﺛﺆﺗ

ﻟﺎﻌﻣ :ﺓﺭﺩﺎﻧ ﻞﻜﻟ ﻦﻴﺠ

ﻟﺎﻌﻣ ١٠ ﻰﺘﺣ ١ ﻰﻠﻋ ﺮﺛﺆﺗ

ﻟﺎﻌﻣ ١٠٠٠٠ ﺮﻴﻏ ﻉﻮﻴﺷ :ﻑﻭﺮﻌﻣ ﻦﻣ ﻉﻮﻴﺸﻟﺍ ﻯﺪﻣ ﻢﻴﻴﻘﺗ ﻦﻜﻤﻳ ﻻ ﺓﺮﻓﻮﺘﻤﻟﺍ ﺕﺎﻴﻄﻌﻤﻟﺍ

Gelatin, mannitol, titanium dioxide (E171),

magnesium stearate, yellow iron oxide

(E172), printing ink (black, yellow).

GIL API AUG15 CL V7

CDS 2015-PSB/GLC-767-s 180815

EU SmPC 140715

ע עבקנ הז ןולע טמרופ

"

ואו קדבנ ונכותו תואירבה דרשמ י ודי לע רש

טסוגוא

2015

1

Trade name

GILENYA

0.5 mg, hard capsules

2

Description and composition

Pharmaceutical form

Hard capsules

Active substance

Each capsule contains 0.5 mg fingolimod (as hydrochloride)

Fingolimod hydrochloride is a synthetic analogue of sphingosine. The chemical designation is

2-amino-2[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride. Its molecular formula is

C19H33NO2-HCl and it has a molecular weight of 343.93.

Fingolimod hydrochloride is a white to almost white crystalline powder which is freely

soluble in water.

Active moiety

Fingolimod

Excipients

Mannitol, Magnesium stearate, Titanium dioxide, Gelatin, Yellow iron oxide, Printing ink

(black, yellow).

3

Indications

Gilenya is indicated for the treatment of patients with relapsing forms of multiple sclerosis

(MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of

physical disability.

4

Dosage and administration

General target population

The recommended dose of Gilenya is one 0.5 mg capsule taken orally once daily, which can

be taken with or without food. If a dose is missed, treatment should be continued with the next

dose as planned.

Before initiating treatment with Gilenya, a recent complete blood count (CBC) (i.e. within 6

months or after discontinuation of prior therapy) should be available. Assessments of CBC are

also recommended periodically during treatment, at month 3 and at least yearly thereafter, and

in case of signs of infection. Absolute lymphocyte count <0.2x10

/l, if confirmed, should lead

to treatment interruption until recovery, because in clinical studies, fingolimod treatment was

interrupted in patients with absolute lymphocyte count <0.2x10

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

initiation of treatment with Gilenya. In the absence of clinical symptoms, liver transaminases

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should be monitored at Months 1, 3, 6, 9 and 12 on therapy and periodically thereafter. If liver

transaminases rise above 5 times the ULN, more frequent monitoring should be instituted,

including serum bilirubin and alkaline phosphatase (ALP) measurement. With repeated

confirmation of liver transaminases above 5 times the ULN, treatment with Gilenya should be

interrupted and only re-commenced once liver transaminase values have normalised.

For recommendations related to switching patients from other disease modifying therapies to

Gilenya, see section 6 Warnings and precautions: Prior treatment with immunosuppressive or

immune-modulating therapies.

First Dose Monitoring

Initiation of Gilenya treatment results in a decrease in heart rate (see 6 Warnings and

Precautions and 11 Clinical Pharmacology). After the first dose of Gilenya, the heart rate

decrease starts within an hour and the Day 1 nadir generally occurs within approximately 6

hours, although the nadir can be observed up to 24 hours after the first dose in some patients.

first

dose

Gilenya

should

administered

setting

which

resources

appropriately manage symptomatic bradycardia are available. In order to assess patient

response to the first dose of fingolimod, observe all patients for 6 hours for signs and

symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain in all

patients an electrocardiogram prior to dosing, and at the end of the observation period.

Additional observation should be instituted until the finding has resolved in the following

situations:

If the heart rate 6 hours post-dose is <45 bpm

Or if the heart rate 6 hours post-dose is at the lowest value post-dose (suggesting that

the maximum pharmacodynamic effect on the heart may not have occurred)

Or if the ECG 6-hours post-dose shows new onset second degree or higher AV block

Should post-dose symptomatic bradycardia occur, initiate appropriate management, begin

continuous ECG monitoring, and continue observation until the symptoms have resolved.

Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous

overnight ECG monitoring in a medical facility should be instituted, and the first dose

monitoring strategy should be repeated after the second dose of Gilenya.

Patients with some pre-existing conditions (e.g., ischemic heart disease, history of myocardial

infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history

of symptomatic bradycardia, history of recurrent syncope, uncontrolled hypertension, severe

untreated sleep apnea, AV block, sino-atrial heart block) may poorly tolerate the Gilenya-

induced bradycardia, or experience serious rhythm disturbances after the first dose of Gilenya.

Prior to treatment with Gilenya, these patients should have a cardiac evaluation by a physician

appropriately trained to conduct such evaluation, and, if treated with Gilenya, should be

monitored overnight with continuous ECG in a medical facility after the first dose. Gilenya is

contraindicated in patients who in the last 6 months experienced myocardial infarction,

unstable

angina,

stroke,

transient

ischemic

attack

(TIA),

decompensated

heart

failure

requiring hospitalization or Class III/IV heart failure) (see 5 Contraindications).

Since initiation of Gilenya treatment results in decreased heart rate and may prolong the QT

interval, patients with a prolonged QT interval (>450 msec males, >470 msec females) before

dosing

during

hour

observation,

additional

risk

prolongation

(e.g.,

hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy

with QT prolonging drugs with a known risk of Torsades de pointes (e.g., citalopram,

chlorpromazine, haloperidol, methadone, erythromycin): advice from a cardiologist should be

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sought and the patients should be monitored overnight with continuous ECG in a medical

facility (see 8 Interactions).

Experience with Gilenya is limited in patients receiving concurrent therapy with drugs that

slow heart rate (e.g., beta blockers, heart-rate lowering calcium channel blockers such as

diltiazem or verapamil, or digoxin). Because the initiation of Gilenya treatment is also

associated with slowing of the heart rate, concomitant use of these drugs during Gilenya

initiation may be associated with severe bradycardia or heart block. The possibility to switch

to non-heart-rate lowering drugs should be evaluated by the physician prescribing the heart-

rate

lowering

drug

before

initiating

Gilenya.

patients

cannot

switch,

overnight

continuous ECG monitoring after the first dose is recommended (see 8 Interactions).

Clinical data indicate effects of Gilenya on heart rate are maximal after the first dose although

milder effects on heart rate may persist for, on average, 2-4 weeks after initiation of therapy at

which time heart rate generally returns to baseline. Physicians should continue to be alert to

patient reports of cardiac symptoms.

Re-initiation of Therapy Following Discontinuation

If Gilenya therapy is discontinued for more than 14 days, after the first month of treatment,

the effects on heart rate and AV conduction may recur on reintroduction of Gilenya treatment

and the same precautions (first dose monitoring) as for initial dosing should apply. Within the

first 2 weeks of treatment, first dose procedures are recommended after interruption of one

day or more, during week 3 and 4 of treatment first dose procedures are recommended after

treatment interruption of more than 7 days.

Dosing in special populations

Renal impairment

No Gilenya dose adjustments are needed in patients with renal impairment (see section 11

Clinical pharmacology).

Hepatic impairment

Gilenya

dose

adjustments

needed

patients

with

mild

moderate

hepatic

impairment. Gilenya should be used with caution in patients with severe hepatic impairment

(Child-Pugh class C) (see section 11 Clinical pharmacology).

Pediatrics patients

Gilenya is not indicated for use in pediatric patients (see section 11 Clinical pharmacology).

Geriatrics patients

Gilenya should be used with caution in patients aged 65

years

and over (see section

11 Clinical pharmacology).

Ethnicity

No Gilenya dose adjustments are needed based on ethnic origin (see section 11 Clinical

pharmacology).

Gender

Gilenya

dose

adjustments

needed

based

gender

(see

section

Clinical

pharmacology).

Diabetic patients

Gilenya should be used with caution in patients with diabetes mellitus due to a potential

increased risk of macular edema (see section 6 Warnings and precautions).

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5

Contraindications

Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke,

TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure)

History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV)

block or sick sinus syndrome, unless patient has a functioning pacemaker

Baseline QTc interval ≥500 ms

Treatment with Class Ia or Class III anti-arrhythmic drugs

Known hypersensitivity to fingolimod, or to any of the excipients

6

Warnings and precautions

Infections

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

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

lymphocytes in lymphoid tissues (see section 11 Clinical pharmacology).

The immune system effects (see section 11 Clinical pharmacology) of Gilenya may increase

risk

infections,

including

opportunistic

infections

(see

section

Adverse

drug

reactions). Before initiating treatment with Gilenya, a recent complete blood count (CBC) (i.e.

within 6 months or after discontinuation of prior therapy) should be available (see section 4

Dosage and administration).

Initiation of treatment with Gilenya should be delayed in patients with severe active infection

until resolution. Effective diagnostic and therapeutic strategies should be employed in patients

with symptoms of infection while on therapy. Because elimination of fingolimod after

discontinuation of Gilenya may take up to two months, vigilance for infection should be

continued throughout this period (see below: Stopping Gilenya therapy).

Anti-neoplastic,

immune-modulating

immunosuppressive

therapies

(including

corticosteroids) should be co-administered with caution due to the risk of additive immune

system

effects.

Specific

decisions

dosage

duration

treatment

with

corticosteroids should be based on clinical judgment. Co-administration of a short course of

corticosteroids (up to 5 days as per study protocols) did not increase the overall rate of

infection in patients treated with fingolimod in the Phase III clinical trials, compared to

placebo. Based on these data, short courses of corticosteroids (up to 5 days) can be used in

combination with Gilenya (see section 7 Adverse drug reactions and section 8 Interactions).

Patients receiving Gilenya should be instructed to report symptoms of infections to their

physician. Suspension of treatment with Gilenya should be considered if a patient develops a

serious infection, and consideration of benefit-risk should be undertaken prior to re-initiation

of therapy.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in the post-

marketing setting (see section 7 Adverse drug reactions). PML is an opportunistic infection

caused by JC virus, which may be fatal or result in severe disability. Physicians should be

vigilant for clinical symptoms or MRI findings that may be suggestive of PML. If PML is

suspected, Gilenya treatment should be suspended until PML has been excluded.

Isolated cases of cryptococcal meningitis have been reported in the post-marketing setting

(see section 7 Adverse drug reactions). Patients with symptoms and signs consistent with

cryptococcal

meningitis

should

undergo

prompt

diagnostic

evaluation.

cryptococcal

meningitis is diagnosed, appropriate treatment should be initiated.

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Patients need to be assessed for their immunity to varicella (chickenpox) prior to Gilenya

treatment. It is recommended that patients without a health care professional confirmed

history of chickenpox or documentation of a full course of vaccination with varicella vaccine

undergo antibody testing to varicella zoster virus (VZV) before initiating Gilenya therapy. A

full

course

vaccination

antibody-negative

patients

with

varicella

vaccine

recommended prior to commencing treatment with Gilenya (see section 7 Adverse drug

reactions). Initiation of treatment with Gilenya should be postponed for 1 month to allow full

effect of vaccination to occur.

Vaccination

Vaccination may be less effective during and for up to two months after stopping treatment

with Gilenya (see below: Stopping Gilenya therapy). The use of live attenuated vaccines

should be avoided (see section 8 Interactions).

Macular edema

Macular edema (see section 7 Adverse drug reactions) with or without visual symptoms has

been reported in 0.5% of patients treated with Gilenya 0.5 mg, occurring predominantly in the

first 3-4 months of therapy. An ophthalmic evaluation is therefore recommended 3-4 months

after treatment initiation. If patients report visual disturbances at any time while on Gilenya

therapy, an evaluation of the fundus, including the macula, should be carried out.

Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of

macular edema (see section 7 Adverse drug reactions). Gilenya has not been studied in

multiple

sclerosis

patients

with

concomitant

diabetes

mellitus.

recommended

that

multiple sclerosis patients with diabetes mellitus or a history of uveitis undergo an ophthalmic

evaluation prior to initiating Gilenya therapy and have follow-up evaluations while receiving

Gilenya therapy.

Continuation of Gilenya in patients with macular edema has not been evaluated. A decision

on whether or not Gilenya therapy should be discontinued needs to take into account the

potential benefits and risks for the individual patient.

Bradyarrhythmia and Atrio-ventricular Blocks

Because of a risk for bradyarrhythmia and atrio-ventricular (AV) blocks, patients should be

monitored during Gilenya treatment initiation (see 4 Dosage and Administration).

Reduction in heart rate

After the first dose of Gilenya, the heart rate decrease starts within an hour. On Day 1, the

maximal decline in heart rate generally occurs within 6 hours and recovers, although not to

baseline levels, by 8-10 hours post dose. Because of physiological diurnal variation, there is a

second period of heart rate decrease within 24 hours after the first dose. In some patients,

heart rate decrease during the second period is more pronounced than the decrease observed in

the first 6 hours. Heart rates below 40 beats per minute were rarely observed. Adverse

reactions of symptomatic bradycardia following the first dose were reported in 0.5% of

patients receiving Gilenya 0.5 mg, but in no patient on placebo. Patients who experienced

bradycardia

were

generally

asymptomatic,

some

patients

experienced

hypotension,

dizziness, fatigue, palpitations, and chest pain that usually resolved within the first 24 hours of

treatment.

Following the second dose, a further decrease in heart rate may occur when compared to the

heart rate prior to the second dose, but this change is of a smaller magnitude than that

observed following the first dose. With continued dosing, the heart rate returns to baseline

within one month of chronic treatment.

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Atrio-ventricular blocks

Initiation of Gilenya treatment has been associated with atrio-ventricular conduction delays,

usually first-degree atrio-ventricular blocks (prolonged PR interval on electrocardiogram).

Second-degree atrio-ventricular blocks, usually Mobitz type

I (Wenckebach) have been

observed in less than 0.2% of patients receiving Gilenya 0.5 mg in clinical trials. The

conduction abnormalities typically were transient, asymptomatic, usually did not require

treatment and resolved within the first 24-hours on treatment (see section 7 Adverse drug

reactions).

Post-marketing experience

In the post-marketing setting, third degree AV block and AV block with junctional escape

have been observed during the first-dose six-hour observation period following the first dose

of Gilenya. Isolated delayed onset events, including transient asystole and unexplained death,

have

occurred

within

hours

first

dose.

These

events

were

confounded

concomitant medications and/or pre-existing disease, and the relationship to

Gilenya is

uncertain. Cases of syncope were also reported after the first dose of Gilenya.

Gilenya has not been studied in patients with arrhythmias requiring treatment with Class Ia

(e.g. quinidine, procainamide) or Class III anti-arrhythmic drugs (e.g., amiodarone, sotalol).

Class Ia and Class III anti-arrhythmic drugs have been associated with cases of Torsades de

Pointes in patients with bradycardia. Since initiation of Gilenya treatment results in decreased

heart rate, Gilenya should not be used concomitantly with these drugs.

Liver function

Increased hepatic enzymes, mostly alanine aminotransaminase (ALT) elevation, have been

reported in multiple sclerosis patients treated with Gilenya. In clinical trials, a 3-fold or

greater elevation in ALT occurred in 8.0% of patients treated with Gilenya 0.5 mg and the

drug was discontinued if the elevation exceeded a 5-fold increase. Recurrence of ALT

elevations occurred upon re-challenge in some patients, supporting a relationship to the drug.

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

initiation of treatment with Gilenya (see section 4 Dosage and administration).

Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained

nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during

treatment,

should

have

liver

enzymes

checked

Gilenya

should

discontinued

significant liver injury is confirmed (see section 7 Adverse drug reactions: Liver function).

Although there are no data to establish that patients with preexisting liver disease are at

increased risk to develop elevated liver function test (LFT) values when taking Gilenya,

caution should be exercised when using Gilenya in patients with a history of significant liver

disease.

Posterior reversible encephalopathy syndrome

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

0.5 mg dose in clinical trials and in the post-marketing setting (see section 7 Adverse drug

reactions). Symptoms reported included sudden onset of severe headache, nausea, vomiting,

altered

mental

status,

visual

disturbances

seizure.

Symptoms

PRES

usually

reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis

and treatment may lead to permanent neurological sequelae. If PRES is suspected, Gilenya

should be discontinued.

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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 in order to avoid an additive immune effect whilst at the

same time minimizing risk of disease reactivation. Before initiating treatment with Gilenya, a

recent CBC (i.e. after discontinuation of prior therapy) should be available to ensure any

immune effects of such therapies (e.g. cytopenia) have resolved.

Beta interferon, glatiramer acetate or dimethyl fumarate

Gilenya

generally

started

immediately

after

discontinuation

beta

interferon,

glatiramer acetate or dimethyl fumarate.

Natalizumab or teriflunomide

Due to the long half-life of natalizumab or teriflunomide, caution regarding potential additive

immune effects is required when switching patients from these therapies to Gilenya. A careful

case-by-case

assessment

regarding

timing

initiation

Gilenya

treatment

recommended.

Elimination of natalizumab usually takes up to 2-3 months following discontinuation.

Teriflunomide is also eliminated slowly from the plasma. Without an accelerated elimination

procedure, clearance of teriflunomide from plasma can take several months to up to 2-years.

An accelerated elimination procedure is described in the teriflunomide product information.

Alemtuzumab

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

product

information,

initiating

treatment

with

Gilenya

after

alemtuzumab

recommended unless the benefits of Gilenya treatment clearly outweigh the risks for the

individual patient.

Basal cell carcinoma

Basal cell carcinoma (BCC) has been reported in patients receiving Gilenya (see section

7 Adverse drug reactions). Vigilance for BCC is warranted.

Stopping therapy

If a decision is made to stop treatment with Gilenya, the physician needs to be aware that

fingolimod remains in

the blood and has pharmacodynamic

effects,

such as decreased

lymphocyte counts, for up to two months following the last dose. Lymphocyte counts

typically return to the normal range within 1-2 months of stopping therapy (see section

11 Clinical

pharmacology).

Starting

other

therapies

during

this

interval

will

result

concomitant

exposure

fingolimod.

immunosuppressants

soon

after

discontinuation of Gilenya may lead to an additive effect on the immune system and therefore

caution should be applied.

7

Adverse drug reactions

Summary of the safety profile

The safety population of Gilenya is derived from two Phase III placebo-controlled clinical

trials and one Phase III active-controlled clinical trial in patients with relapsing remitting

multiple sclerosis. It includes a total of 2,431 patients on Gilenya (0.5 or 1.25 mg dose).

Study D2301 (FREEDOMS) was a 2-year placebo-controlled clinical study in 854 multiple

sclerosis patients treated with fingolimod (placebo: 418). Study D2309 (FREEDOMS II) was

a 2-year placebo-controlled clinical study in 728 multiple sclerosis patients treated with

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fingolimod (placebo: 355). In the pooled data from these two studies the most serious adverse

drug reactions (ADRs) for the 0.5 mg recommended therapeutic dose were infections, macular

edema and transient atrio-ventricular blocks on treatment initiation. The most frequent ADRs

(incidence ≥10%) at the 0.5 mg dose were headache, hepatic enzyme increased, diarrhoea,

cough, influenza, sinusitis and back pain. The most frequent adverse event reported for

Gilenya 0.5 mg at an incidence greater than 1% leading to treatment interruption was ALT

elevations (2.2%).

The ADRs for fingolimod in Study D2302 (TRANSFORMS), a 1-year controlled study using

interferon

beta-1a

comparator

patients

with

multiple

sclerosis

treated

with

fingolimod, were generally similar to placebo-controlled studies, taking into account the

differences in study duration.

Tabulated summary of adverse drug reactions

Table 7-1 presents the frequency of ADRs reported in the pooled analysis of the placebo-

controlled studies FREEDOMS and FREEDOMS II.

ADRs are listed according to MedDRA system organ class. Frequencies were defined as

follows: 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

7-1

Tabulated summary of adverse drug reactions

Primary system organ class

Preferred Term

Placebo

N=773

%

Fingolimod

0.5mg

N=783

%

Frequency

range for the

0.5 mg dose

Infections

Influenza

65 (8.4)

89 (11.4)

very common

Sinusitis

64 (8.3)

85 (10.9)

very common

Bronchitis

35 (4.5)

64 (8.2)

common

Herpes zoster

7 (0.9)

16 (2.0)

common

Tinea versicolor

3 (0.4)

14 (1.8)

common

Pneumonia

1 (0.1)

7 (0.9)

uncommon

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

Basal cell carcinoma

5 (0.6)

14 (1.8)

common

Cardiac Disorders

Bradycardia

7 (0.9)

20 (2.6)

common

Nervous system disorders

Headache

175 (22.6)

192 (24.5)

very common

Dizziness

65 (8.4)

69 (8.8)

common

Migraine

28 (3.6)

45 (5.7)

common

Posterior reversible

encephalopathy syndrome

(PRES)

0 (0.0)

0 (0.0)

rare*

Gastrointestinal disorders

Diarrhea

74 (9.6)

99 (12.6)

very common

General disorders and administration site conditions

Asthenia

6 (0.8)

15 (1.9)

common

Musculoskeletal and connective tissue disorders

Back pain

69 (8.9)

78 (10.0)

very common

Skin and subcutaneous tissue disorders

Eczema

15 (1.9)

21 (2.7)

common

Pruritus

17 (2.2)

21 (2.7)

common

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Primary system organ class

Preferred Term

Placebo

N=773

%

Fingolimod

0.5mg

N=783

%

Frequency

range for the

0.5 mg dose

Investigations

Hepatic enzyme increased

(increased ALT, GGT, AST)

32 (4.1)

119 (15.2)

Very common

Blood triglycerides increased

7 (0.9)

16 (2.0)

common

Respiratory, thoracic and mediastinal disorders

Cough

87 (11.3)

96 (12.3)

very common

Dyspnoea

54 (7.0)

71 (9.1)

common

Eye disorders

Vision blurred

19 (2.5)

33 (4.2)

common

Macular edema

3 (0.4)

4 (0.5)

uncommon

Vascular disorders

Hypertension

28 (3.6)

63 (8.0)

common

Blood and lymphatic system disorders

Lymphopenia

2 (0.3)

53 (6.8)

common

Leucopenia

1 (0.1)

17 (2.2)

common

*Not reported in Study FREEDOMS, FREEDOMS II and TRANSFORMS. The frequency category was based on

an estimated exposure of approximately 10, 000 patients to fingolimod in all clinical trials.

Adverse

drug

reactions

from

spontaneous

reports

and

literature

cases

(frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with

Gilenya via spontaneous case reports and literature cases. Because these reactions are reported

voluntarily from a population of uncertain size, it is not possible to reliably estimate their

frequency which is therefore categorized as not known. Adverse drug reactions are listed

according to system organ classes.

Table

7-2

Adverse drug reactions from spontaneous reports and literature

(frequency not known)

Immune system disorders

Hypersensitivity reactions, including rash, urticaria and angioedema upon treatment initiation

Gastrointestinal disorders

Nausea

Infections

In multiple sclerosis clinical trials, the overall rate of infections (65.1%) at the 0.5 mg dose

was similar to placebo. However, bronchitis, herpes zoster and pneumonia, were more

common in Gilenya treated patients. Serious infections occurred at a rate of 1.6% in the

fingolimod 0.5 mg group versus 1.4% in the placebo group.

There have been very rare fatal cases of VZV infections in the context of prolonged

concomitant corticosteroid use (more than 5 days) for treatment of multiple sclerosis relapses,

however, a causal relationship between the concomitant treatment and fatal outcome has not

been established. Co-administration of a short course of corticosteroids (up to 5 days as per

study

protocols)

increase

overall

rate

infection

patients

treated

with

fingolimod in the Phase III clinical trials, compared to placebo (see section 6 Warnings and

precautions and section 8 Interactions).

There have been very rare cases of other herpes viral infections with fatal outcome. However,

a causal relationship with Gilenya has not been established.

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In the post-marketing setting cases of infections with opportunistic pathogens, such as viral

(e.g.

VZV,

causing

PML,

HSV),

fungal

(e.g.

cryptococci

including

cryptococcal

meningitis) or bacterial (e.g. atypical mycobacterium), have been reported (see section 6

Warnings and precautions).

Macular edema

In clinical trials, macular edema occurred in 0.5% of patients treated with the recommended

Gilenya dose of 0.5 mg and in 1.1% of patients treated with the higher 1.25 mg dose.

The majority of cases in multiple sclerosis clinical trials occurred within the first 3-4 months

of therapy. Some patients presented with blurred vision or decreased visual acuity, but others

were asymptomatic and diagnosed on routine ophthalmic examination. The macular edema

generally

improved

resolved

spontaneously

after

drug

discontinuation.

risk

recurrence after re-challenge has not been evaluated.

Macular edema incidence is increased in multiple sclerosis patients with a history of uveitis

(approximately 20% with a history of uveitis vs 0.6% without a history of uveitis).

Gilenya has not been tested in multiple sclerosis patients with diabetes mellitus. In renal

transplant clinical studies where patients with diabetes mellitus were included, therapy with

Gilenya 2.5 mg and 5 mg resulted in a 2-fold increase in the incidence of macular edema.

Multiple sclerosis patients with diabetes mellitus are therefore expected to be at a higher risk

for macular edema (see section 6 Warnings and precautions).

Bradyarrhythmia

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

associated with atrio-ventricular conduction delays (see section 6 Warnings and precautions).

In multiple sclerosis clinical trials the mean maximum decrease in heart rate after the first

dose intake was seen 4 - 5 hours post-dose, with a decline in the mean heart rate, as measured

by pulse, of 8 beats per minute for Gilenya 0.5 mg. The second dose may result in a slight

further decrease. Heart rates below 40 beats per minute were rarely observed in patients on

Gilenya 0.5 mg. Heart rate returned to baseline within 1 month of chronic dosing.

In the multiple sclerosis clinical program first-degree atrio-ventricular block (prolonged PR

interval on electrocardiogram) was detected following drug initiation in 4.7% of patients on

Gilenya 0.5 mg, in 2.8% of patients on intramuscular interferon beta-1a IM and in 1.6% of

patients on placebo. Second degree atrio-ventricular block was detected in less than 0.2 %

patients on Gilenya 0.5 mg.

The conduction abnormalities observed both in clinical trials and post-marketing were

typically transient, asymptomatic and resolved within 24 hours on treatment. Although most

patients did not require medical intervention, in clinical trials, in rare cases, they required

treatment with atropine or isoproterenol.

Blood pressure

In multiple sclerosis clinical trials Gilenya 0.5 mg was associated with a mild increase of

approximately 1 mmHg on average in mean arterial pressure manifesting after approximately

month

treatment

initiation.

This

increase

persisted

with

continued

treatment.

Hypertension was reported in 6.5% of patients on Gilenya 0.5 mg and in 3.3 % of patients on

placebo.

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Liver function

Increased hepatic enzymes (mostly ALT elevation) have been reported in multiple sclerosis

patients treated with Gilenya. In clinical trials, 8.0% and 1.8% of patients treated with Gilenya

0.5mg experienced an asymptomatic elevation in serum levels of ALT of ≥3x ULN and ≥5x

ULN, respectively, compared with corresponding figures in the placebo group of 1.9% and

0.9% respectively. The majority of elevations occurred within 6-9 months. ALT levels

returned to normal within approximately 2 months after discontinuation of Gilenya. In the few

patients who experienced ALT elevations of ≥5x ULN and who continued on Gilenya

therapy, the ALT levels returned to normal within approximately 5 months (see section 6

Warnings and precautions).

Respiratory System

Minor dose-dependent 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

fingolimod treatment starting at month 1 and remaining stable thereafter. At month 24, the

reduction from baseline values in percent of predicted FEV

was 2.7% for fingolimod 0.5 mg

and 1.2% for placebo, a difference that resolved after treatment discontinuation. For DLCO

the reductions at month 24 were 3.3% for fingolimod 0.5 mg and 2.7% for placebo.

Vascular events

In phase III clinical trials, rare cases of peripheral arterial occlusive disease occurred in

patients treated with Gilenya at higher doses (1.25 or 5.0 mg). Rare cases of ischemic and

hemorrhagic strokes have also been reported at the 0.5 mg dose in clinical trials and in the

post-marketing setting although a causal relationship has not been established.

Lymphomas

There have been cases of lymphoma in clinical studies and the post-marketing setting. The

cases reported were heterogeneous in nature, including B-cell and T-cell lymphomas. The

relationship to Gilenya remains uncertain.

Haemophagocytic syndrome

Very rare cases of haemophagocytic syndrome (HPS) with fatal outcome have been reported

in patients treated with fingolimod in the context of an infection. HPS is a rare condition that

has been described in association with infections, immunosuppression and a variety of

autoimmune

diseases.

causal

relationship

between

Gilenya

been

established.

Reporting of suspected adverse reactions

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic

@moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL).

8

Interactions

Pharmacodynamic interactions

Anti-neoplastic,

immune

modulating

immunosuppressive

therapies

(including

corticosteroids) should be co-administered with caution due to the risk of additive immune

system effects. Specific decisions as to the dosage and duration of concomitant treatment with

corticosteroids should be based on clinical judgment. Co-administration of a short course of

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corticosteroids (up to 5 days as per study protocols) did not increase the overall rate of

infection in patients treated with fingolimod in the Phase III clinical trials, compared to

placebo (see sections 6 Warnings and precautions and 7 Adverse drug reactions).

Caution should also be applied when switching patients from long-acting therapies with

immune effects such as natalizumab, teriflunomide or mitoxantrone (see section 6 Warnings

and precautions: Prior treatment with immunosuppressive or immune-modulating therapies).

When fingolimod is used with atenolol, there is an additional 15% reduction in heart rate upon

fingolimod initiation, an effect not seen with diltiazem. Treatment with Gilenya should not be

initiated in patients receiving beta blockers, heart rate lowering calcium channel blockers

(such as verapamil, diltiazem or ivabradine), or other substances which may decrease heart

rate (e.g. digoxin) because of the potential additive effects on heart rate. If treatment with

Gilenya 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

(should last overnight) (see section 6 Warnings and precautions).

QT prolonging drugs: Gilenya has not been studied in patients treated with drugs that prolong

the QT interval. Drugs that prolong the QT interval have been associated with cases of

torsades de pointes in patients with bradycardia. Since initiation of Gilenya treatment results

in decreased heart rate and may prolong the QT interval, patients on QT prolonging drugs

with a known risk of Torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol,

methadone, erythromycin) should be monitored overnight with continuous ECG in a medical

facility (see 4 Dosage and Administration and 6 Warnings and Precautions).

During and for up to two months after treatment with Gilenya vaccination may be less

effective. The use of live attenuated vaccines may carry the risk of infection and should

therefore be avoided (see sections 7 Adverse drug reactions and 6 Warnings and precautions).

Pharmacokinetic interactions

Fingolimod is primarily cleared via cytochrome P450 4F2 (CYP4F2) and possibly other

CYP4F isoenzymes. In vitro studies in hepatocytes indicated that CYP3A4 may contribute to

fingolimod metabolism in the case of strong induction of CYP3A4.

Potential

of

fingolimod

and

fingolimod-phosphate

to

inhibit

the

metabolism

of

co-medications.

In vitro inhibition studies using pooled human liver microsomes and specific metabolic probe

substrates demonstrated that fingolimod and fingolimod-phosphate have little or no capacity

to inhibit the activity of CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 (fingolimod only)). Therefore,

fingolimod and fingolimod-phosphate are unlikely to reduce the clearance of drugs that are

mainly cleared through metabolism by the major CYP isoenzymes.

Potential

of

fingolimod

and

fingolimod-phosphate

to

induce

its

own

and/or

the

metabolism of co-medications.

Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2,

and ABCB1 (P-gp) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19,

and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or

activity of the different CYP enzymes and ABCB1 with respect to the vehicle control.

Therefore, no clinically relevant induction of the tested CYP enzymes or ABCB1 (P-gp) by

fingolimod is expected at therapeutic concentrations. In vitro experiments did not provide an

indication of CYP induction by fingolimod-phosphate.

Potential of fingolimod and fingolimod-phosphate to inhibit the active transport of co-

medications

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Based on in vitro data, fingolimod as well as fingolimod-phosphate are not expected to inhibit

the uptake of co-medications and/or biologics transported by the organic anion transporting

polypeptides

(OATP1B1,

OATP1B3)

sodium

taurocholate

transporting polypeptide (NTCP). Similarly, they are not expected to inhibit the efflux of co-

medications and/or biologics transported by the breast cancer resistance protein (BCRP), the

bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2) or P-

glycoprotein (P-gp) at therapeutic concentrations.

Oral contraceptives

The co-administration of fingolimod 0.5 mg daily with oral contraceptives (ethinylestradiol

and levonorgestrel) did not elicit any change in oral contraceptive exposure. Fingolimod and

fingolimod-phosphate

exposure

were

consistent

with

those

from

previous

studies.

interaction

studies

have

been

performed

with

oral

contraceptives

containing

other

progestagens, however an effect of fingolimod on their exposure is not expected.

Cyclosporine

The pharmacokinetics of single-dose fingolimod were not altered during co-administration

with cyclosporine at steady-state, nor were cyclosporine steady-state pharmacokinetics altered

by single-dose, or multi-dose (28 days) fingolimod administration. These data indicate that

fingolimod is unlikely to reduce or increase the clearance of drugs mainly cleared by CYP3A4

and that inhibition of CYP3A4 is unlikely to reduce the clearance of fingolimod. Potent

inhibition

transporters

P-gp,

MRP2

OATP1B1

does

influence

fingolimod

disposition.

Ketoconazole

The co-administration of ketoconazole 200 mg twice daily at steady-state and a single dose of

fingolimod 5 mg led to a modest increase in the AUC of fingolimod and fingolimod-

phosphate (1.7-fold increase) by inhibition of CYP4F2.

Isoproterenol, atropine, atenolol and diltiazem

Single-dose

fingolimod

fingolimod-phosphate

exposure

altered

administered

isoproterenol

atropine.

Likewise,

single-dose

pharmacokinetics

fingolimod and fingolimod-phosphate and the steady-state pharmacokinetics of both atenolol

and diltiazem were unchanged during the co-administration of the latter two drugs with

fingolimod.

Carbamazepine

The co-administration of carbamazepine 600 mg twice daily at steady-state and a single dose

of fingolimod 2 mg had a weak effect on the AUC of fingolimod and fingolimod-phosphate,

decreasing both by approximately 40%. The clinical relevance of this decrease is unknown.

Population pharmacokinetics analysis of potential drug-drug interactions

A population pharmacokinetics evaluation performed in multiple sclerosis patients did not

provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6

inhibitors) on fingolimod or fingolimod-phosphate concentrations. In addition, the following,

commonly prescribed substances had no clinically relevant effect (≤20%) on fingolimod or

fingolimod-phosphate

concentrations:

baclofen,

gabapentin,

oxybutynin,

amantadine,

modafinil, amitriptyline, pregabalin, corticosteroids and oral contraceptives.

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Laboratory tests

Since fingolimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid

organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte

subset status of a patient treated with Gilenya.

Laboratory tests requiring the use of circulating mononuclear cells require larger blood

volumes due to reduction in the number of circulating lymphocytes.

9

Women of child-bearing potential, pregnancy, breast-

feeding and fertility

Women of childbearing potential

Before initiation of Gilenya treatment, women of childbearing potential should be counselled

on the potential for a serious risk to the fetus and the need for effective contraception during

treatment with Gilenya. Since it takes approximately 2 months to eliminate the compound

from the body after stopping treatment (see section 6 Warnings and precautions) the potential

risk to the fetus may persist and contraception should be pursued during this period.

Pregnancy

The use of Gilenya in women who are or may become pregnant should only be considered if

the potential benefit justifies the potential risk to the fetus (see above: Women of childbearing

potential).

Animal studies have shown reproductive toxicity including fetal loss and organ defects,

notably persistent truncus arteriosus and ventricular septal defect (see section 13 Non-clinical

safety data). Furthermore, the receptor affected by fingolimod (sphingosine-1-phosphate

receptor) is known to be involved in vascular formation during embryogenesis. At the present

time it is not known whether cardiovascular malformations will be found in humans. There

are very limited data from the use of fingolimod in pregnant women. In clinical trials, 20

pregnancies were reported in patients exposed to fingolimod at the time of diagnosis of

pregnancy, but data are too limited to draw conclusions on the safety of Gilenya in pregnancy.

Labor and delivery

There are no data on the effects of fingolimod on labor and delivery.

Breast-feeding

Fingolimod is excreted in the milk of treated animals during lactation. Because of the

potential for serious adverse drug reactions to fingolimod in nursing infants, women receiving

Gilenya should not breast feed.

Fertility

Data from preclinical studies does not suggest that fingolimod would be associated with an

increased risk of reduced fertility.

Male reproductive toxicity

Available data do not suggest that Gilenya would be associated with an increased risk of

male-mediated fatal toxicity.

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10

Overdosage

Single doses up to 80-fold the recommended dose (0.5 mg) were well tolerated in healthy

volunteers. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was

clinically consistent with small airway reactivity.

Fingolimod can induce bradycardia. The decline in heart rate usually starts within one hour of

the first dose, and is maximal within 6 hours. There have been reports of slow atrioventricular

conduction with isolated reports of transient, spontaneously resolving complete AV block (see

Section 6 Warnings and precautions and section 7 Adverse drug reactions).

In case of Gilenya overdosage, observe patients overnight with continuous ECG monitoring in

a medical facility, and obtain regular measurements of blood pressure (see section 4 Dosage

and administration and section 6 Warnings and precautions).

Neither dialysis nor plasma exchange would result in meaningful removal of fingolimod from

the body.

11

Clinical pharmacology

ATC code: L04AA27

Mechanism of action

Fingolimod is a sphingosine-1-phosphate receptor modulator. Fingolimod is metabolized by

sphingosine kinase to the active metabolite fingolimod-phosphate. Fingolimod-phosphate

binds at low nanomolar concentrations to sphingosine-1-phosphate (S1P) receptors 1, 3, and 4

located on lymphocytes, and readily crosses the blood brain barrier to bind to S1P receptors 1,

3, and 5 located on neural cells in the central nervous system (CNS). By acting as a functional

antagonist

S1PR

lymphocytes,

fingolimod-phosphate

blocks

capacity

lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of

lymphocytes. This redistribution reduces the infiltration of pathogenic lymphocytes, including

pro-inflammatory

Th17

cells,

into

(CNS)

where

they

would

involved

nerve

inflammation and nervous tissue damage.

Animal studies and in vitro experiments indicate that fingolimod may also exert beneficial

effects in multiple sclerosis via interaction with S1P receptors on neural cells. Fingolimod

penetrates the CNS, in both humans and animals, and has been shown to reduce astrogliosis,

demyelination and neuronal loss. Further, fingolimod treatment increases the levels of brain

derived neurotropic factor (BDNF) in the cortex, hippocampus and striatum of the brain to

support neuronal survival and improve motor functions.

Pharmacodynamic properties

Immune system

Effects on immune cell numbers in the blood. Within 4-6 hours after the first dose of

fingolimod 0.5 mg, the lymphocyte count decreases to approximately 75% of baseline. With

continued daily dosing, the lymphocyte count continues to decrease over a two week period,

reaching a nadir count of approximately 500 cells/μL or approximately 30% of baseline.

Eighteen percent of patients reached a nadir of < 200 cells/μL on at least one occasion. Low

lymphocyte counts are maintained with chronic daily dosing. The majority of T and B

lymphocytes regularly traffic through lymphoid organs and these are the cells mainly affected

fingolimod.

Approximately

15-20%

lymphocytes

have

effector

memory

phenotype, cells that are important for peripheral immune surveillance. Since this lymphocyte

subset

typically

does

traffic

lymphoid

organs

affected

fingolimod.

Peripheral

lymphocyte

count

increases

evident

within

days

stopping

fingolimod

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treatment and typically normal counts are reached within one to two months. Chronic

fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of

baseline. Monocytes are unaffected by fingolimod.

Heart rate and rhythm

Fingolimod causes a transient reduction in heart rate and atrio-ventricular conduction upon

treatment initiation (see section 7 Adverse drug reactions). The maximum decline in heart rate

is seen in the first 6 hours post-dose, with 70% of the negative chronotropic effect achieved

on the first day. Heart rate progressively returns to baseline values within one month of

chronic treatment.

Autonomic responses of the heart, including diurnal variation of heart rate and response to

exercise, are not affected by fingolimod treatment.

With initiation of fingolimod treatment there is an increase in atrial premature contractions,

but there is no increased rate of atrial fibrillation/flutter, ventricular arrhythmias or ectopy.

Fingolimod treatment is not associated with a decrease in cardiac output.

The decrease in heart rate induced by fingolimod can be reversed by atropine, isoprenaline or

salmeterol.

Potential to prolong the QT interval

In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a

negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in

a prolongation of QTcI, with the upper boundary of the 90% CI ≤13.0 msec. There is no dose

exposure-response

relationship

fingolimod

QTcI

prolongation.

There

consistent signal of increased incidence of QTcI outliers, either absolute or change from

baseline, associated with fingolimod treatment. In the multiple sclerosis studies, there was no

clinically relevant prolongation of the QT interval.

Pulmonary function

Fingolimod treatment with single or multiple doses of 0.5 and 1.25 mg for two weeks is not

associated with a detectable increase in airway resistance as measured by FEV

and forced

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

25-75

However, single fingolimod doses ≥5 mg (10-fold the recommended dose) are associated with

a dose-dependent increase in airway resistance. Fingolimod treatment with multiple doses of

0.5, 1.25 or 5 mg is not associated with impaired oxygenation or oxygen desaturation with

exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod

treatment have a normal bronchodilator response to inhaled β-agonists.

Pharmacokinetic properties

Absorption

Fingolimod absorption is slow (t

of 12-16 hours) and extensive (

85%, based on the

amount of radioactivity excreted in urine and the amount of metabolites in feces extrapolated

to infinity). The apparent absolute oral bioavailability is high (93%).

Food intake does not alter C

or exposure (AUC) of fingolimod or fingolimod-phosphate.

Therefore

Gilenya

taken

without

regard

meals

(see

section

Dosage

administration).

Steady-state

blood

concentrations

reached

within

2 months

once-daily

administration and steady-state levels are approximately 10-fold greater than with the initial

dose.

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Distribution

Fingolimod highly distributes in red blood cells, with the fraction in blood cells of 86%.

Fingolimod-phosphate

smaller

uptake

blood

cells

<17%.

Fingolimod

fingolimod-phosphate

highly

protein

bound

(>99.7%).

Fingolimod

fingolimod-

phosphate protein binding is not altered by renal or hepatic impairment.

Fingolimod is extensively distributed to body tissues with a volume of distribution of about

1200

260 L. A study in four healthy subjects who received a single intravenous dose of

radioiodolabeled fingolimod demonstrated that fingolimod penetrates into the brain. In a study

in 13 male multiple sclerosis patients who received Gilenya 0.5 mg/day at steady-state, the

amount of fingolimod (and fingolimod-phosphate) in seminal ejaculate was more than 10,000

times lower than the dose administered (0.5 mg).

Metabolism

The biotransformation of fingolimod in humans occurs by three main pathways; by reversible

stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-

phosphate, by oxidative biotransformation catalyzed mainly by CYP4F2 and possibly other

CYP4F isoenzymes and subsequent fatty acid-like degradation to inactive metabolites, and by

formation of pharmacologically inactive non-polar ceramide analogs of fingolimod.

Following

single

oral

administration

fingolimod,

major

fingolimod-related

components in blood, as judged from their contribution to the AUC up to 816 hours post-dose

total

radiolabeled

components,

fingolimod

itself

(23.3%),

fingolimod-phosphate

(10.3%), and inactive metabolites (M3 carboxylic acid metabolite (8.3%), M29 ceramide

metabolite (8.9%) and M30 ceramide metabolite (7.3%)).

Elimination

Fingolimod blood clearance is 6.3

2.3 L/h, and the average apparent terminal half-life (t

) is

6-9 days. Blood levels of fingolimod-phosphate decline in parallel with fingolimod in the

terminal phase yielding similar half-lives for both.

After oral administration, about 81% of the dose is slowly excreted in the urine as inactive

metabolites. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the

major components in the feces with amounts representing less than 2.5% of the dose each.

After 34 days, the recovery of the administered dose is 89%.

Linearity

Fingolimod

fingolimod-phosphate

concentrations

increase

apparent

dose

proportional manner after multiple once daily doses of fingolimod 0.5 mg or 1.25 mg.

Special populations

Renal dysfunction

Severe renal impairment increases fingolimod C

and AUC by 32% and 43%, respectively,

and fingolimod-phosphate C

and AUC by 25% and 14%, respectively. The apparent

elimination half-life is unchanged for both analytes. No Gilenya dose adjustments are needed

in patients with renal impairment.

Hepatic dysfunction

The pharmacokinetics of single-dose fingolimod (1 or 5 mg), when assessed in subjects with

mild, moderate and severe hepatic impairments (Child-Pugh class A, B, and C), showed no

change on fingolimod C

max,

but an increase in AUC by 12%, 44% and 103%, respectively.

The apparent elimination half-life is unchanged in mild hepatic impairment but is prolonged

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by 49-50% in moderate and severe hepatic impairment. In patients with severe hepatic

impairment (Child-Pugh class C), fingolimod-phosphate C

was decreased by 22% and

AUC increased by 38%. The pharmacokinetics of fingolimod-phosphate were not evaluated in

patients with mild or moderate hepatic impairment. Although hepatic impairment elicited

changes in the disposition of fingolimod and fingolimod-phosphate, the magnitude of these

changes suggests that the fingolimod dose does not need to be adjusted in mild or moderate

hepatic impaired patients (Child-Pugh class A and B). Fingolimod should be used with

caution in patients with severe hepatic impairment (Child-Pugh class C).

Pediatrics

The safety and efficacy of Gilenya in pediatric patients below the age of 18 have not been

studied. Gilenya is not indicated for use in pediatric patients.

Geriatrics

The mechanism for elimination and results from population pharmacokinetics suggest that

dose adjustment would not be necessary in elderly patients. However, clinical experience in

patients aged above 65 years is limited.

Ethnicity

The effects of ethnic origin on fingolimod and fingolimod phosphate pharmacokinetics are not

of clinical relevance.

Gender

Gender has no influence on fingolimod and fingolimod-phosphate pharmacokinetics.

12

Clinical studies

The efficacy of Gilenya has been demonstrated in two studies that evaluated once-daily doses

of Gilenya 0.5 mg and 1.25 mg in patients with relapsing-remitting multiple sclerosis. Both

studies included patients who had experienced at least 2 clinical relapses during the 2 years

prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization,

and had an Expanded Disability Status Scale (EDSS) between 0 to 5.5. A third study targeting

the same patient population was completed after registration of Gilenya.

Study D2301 (FREEDOMS)

Study D2301 (FREEDOMS) was a 2-year randomized, double-blind, placebo-controlled

Phase III study in patients with relapsing-remitting multiple sclerosis who had not received

any interferon-beta or glatiramer acetate for at least the previous 3 months and had not

received natalizumab for at least the previous 6 months. Neurological evaluations were

performed at screening, every 3 months and at time of suspected relapse. MRI evaluations

were performed at screening, Month 6, Month 12 and Month 24. The primary endpoint was

the annualized relapse rate (ARR).

Median age was 37 years, median disease duration was 6.7 years and median EDSS score at

baseline was 2.0. Patients were randomized to receive Gilenya 0.5 mg (n=425), Gilenya

1.25 mg (n=429) or placebo (n=418) for up to 24 months. Median time on study drug was 717

days on 0.5 mg, 715 days on 1.25 mg and 718.5 days on placebo.

The annualized relapse rate was significantly lower in patients treated with Gilenya than in

patients

received

placebo.

secondary

endpoint

time

3-month

confirmed disability progression as measured by at least a 1-point increase from baseline in

EDSS (0.5 point increase for patients with baseline EDSS of 5.5) sustained for 3 months.

Time to onset of 3-month confirmed disability progression was significantly delayed with

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Gilenya treatment compared to placebo. There were no significant differences between the

0.5 mg and the 1.25 mg doses on either endpoint.

The results for this study are shown in Table 12-1 and Figures 12-1 and 12-2.

Table 12-1

Clinical and MRI results of Study FREEDOMS

Gilenya 0.5 mg

Gilenya 1.25 mg

Placebo

Clinical endpoints

N=425

N=429

N=418

Annualized relapse rate (primary

endpoint)

0.18

(p<0.001*)

0.16

(p<0.001*)

0.40

Relative reduction (percentage)

Percent of patients remaining relapse-free

at 24 months

70.4

(p<0.001*)

74.7

(p<0.001*)

45.6

Risk of disability progression

Hazard ratio (95% CI)

(3-month confirmed)

0.70 (0.52, 0.96)

(p=0.024*)

0.68 (0.50, 0.93)

(p=0.017*)

Hazard ratio (95% CI)

(6-month confirmed)

0.63 (0.44, 0.90)

(p=0.012*)

0.60 (0.41, 0.86)

(p=0.006*)

MRI endpoints

Number of new or newly enlarging T2

lesions

n=370

n=337

n=339

Median (mean) number over 24 months

0.0 (2.5)

(p<0.001*)

0.0 (2.5)

(p<0.001*)

5.0 (9.8)

Number of Gd-enhancing lesions

n=369 (Month 24)

n=343 (Month 24)

n=332 (Month 24)

Median (mean) number at

Month 6

Month 12

Month 24

0.0 (0.2)

0.0 (0.2)

0.0 (0.2)

(p<0.001* at each

timepoint)

0.0 (0.3)

0.0 (0.3)

0.0 (0.2)

(p<0.001* at each

timepoint)

0.0 (1.3)

0.0 (1.1)

0.0 (1.1)

Percent change in T2 lesion total volume

n=368

n= 343

n=339

Median (mean) % change over 24 months

-1.7 (10.6)

(p<0.001*)

-3.1 (1.6)

(p<0.001*)

8.6 (33.8)

Change in T1 hypointense lesion volume

n=346

n=317

n=305

Median (mean) % change

over 24 months

0.0 (8.8)

(p=0.012*)

-0.2 (12.2)

(p=0.015*)

1.6 (50.7.)

Percent change in brain volume

n=357

n=334

n=331

Median (mean) % change

over 24 months

-0.7 (-0.8)

(p<0.001*)

-0.7 (-0.9)

(p<0.001*)

-1.0 (-1.3)

All analyses of clinical endpoints were intent-to treat. MRI analyses used the evaluable dataset.

* Indicates statistical significance vs. placebo at two-sided 0.05 level.

Determination of p-values: aggregate ARR by negative binomial regression adjusting for treatment, pooled country,

number of relapses in previous 2 years and baseline EDSS; percentage of patients maintaining relapse-free logistic

regression adjusted for treatment, country, number of relapses in previous 2 years, and baseline EDSS; time to 3-

month/6-month confirmed disability progression by Cox’s proportional hazards model adjusted for treatment, pooled

country, baseline EDSS, and age; new/newly enlarging T2 lesions by negative binomial regression adjusted for

treatment and pooled country; Gd-enhancing lesions by rank ANCOVA adjusted for treatment, pooled country, and

baseline number of Gd-enhancing lesions; and % change in lesion and brain volume by rank ANCOVA adjusted for

treatment, pooled country, and corresponding baseline value.

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Figure ‎12-1

Kaplan-Meier plot of time to first confirmed relapse up to Month 24–

Study FREEDOMS (ITT population)

Figure 12-2

Cumulative plot of time to 3-month confirmed disability progression –

Study FREEDOMS (ITT population)

Patients who completed Study FREEDOMS (D2301) had the option to enter a dose-blinded

extension study D2301E1. 920 patients from the core study entered the extension and were all

treated with fingolimod (n=331 continued on 0.5 mg, 289 continued on 1.25 mg, 155 switched

from placebo to 0.5 mg and 145 switched from placebo to 1.25 mg). 811 of these patients

(88.2%) had at least 18 months follow-up in the extension phase. The maximum cumulative

duration of exposure to fingolimod 0.5 mg (core + extension study) was 1,782 days.

Placebo

Fingolimod 0.5 mg

Time to first relapse (days)

Percentage (%) of patients without confirmed relapse

Fingolimod 1.25 mg

Fingolimod 1.25 mg

Fingolimod 0.5 mg

Days on study

Percentage (%) of patients with 3-m confirmed

progression

Placebo

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At Month 24 of the extension study, patients who received placebo in the core study had

reductions in ARR of 55% after switching to fingolimod 0.5 mg (ARR ratio 0.45,95% CI 0.32

to 0.62, p<0.001). The ARR for patients who were treated with fingolimod 0.5 mg in the core

study remained low during the extension study (ARR of 0.10 in the extension study).

Study D2309 (FREEDOMS II)

Study D2309 (FREEDOMS II) had a design similar to that of Study D2301 (FREEDOMS): it

was a 2-year randomized, double-blind, placebo-controlled Phase III study in patients with

relapsing-remitting multiple sclerosis who had not received any interferon-beta or glatiramer

acetate for at least the previous 3 months and had not received any natalizumab for at least the

previous 6 months. Neurological evaluations were performed at screening, every 3 months

and at time of suspected relapse. MRI evaluations were performed at screening, Month 6,

Month 12 and Month 24. The primary endpoint was the annualized relapse rate (ARR).

Median age was 40.5 years, median disease duration was 8.9 years and median EDSS score at

baseline was 2.5. Patients were randomized to receive Gilenya 0.5 mg (n=358) or Gilenya

1.25 mg (n=370), or placebo (n=355) for up to 24 months.

Median time on study drug was 719 days on 0.5 mg and 719 days on placebo. Patients

randomized to the fingolimod 1.25 mg dose arm were switched in a blinded manner to receive

fingolimod 0.5 mg when results of Study 2301 became available and confirmed a better

benefit/risk profile of the lower dose. The dose was switched in 113 patients (30.5%) in this

dose arm, median time on fingolimod 1.25 mg in this arm was 496.1 days and 209.8 days on

fingolimod 0.5 mg.

The annualized relapse rate was significantly lower in patients treated with Gilenya than in

patients who received placebo. The first key secondary endpoint was change from baseline in

brain volume. Loss of brain volume was significantly less with Gilenya treatment compared to

placebo. The other key secondary endpoint was the time to 3-month confirmed disability

progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point

increase for patients with baseline EDSS of 5.5) sustained for 3 months. The risk of disability

progression for Gilenya and placebo groups was not statistically different.

There were no significant differences between the 0.5 mg and the 1.25 mg doses on any of the

endpoints.

The results for this study are shown in Table 12-2 and Figures 12-3.

Table

12-2

Clinical and MRI results of Study FREEDOMS II

Gilenya 0.5 mg

Gilenya 1.25 mg

Placebo

Clinical endpoints

N=358

N=370

N=355

Annualized relapse rate (primary

endpoint)

0.21

(p<0.001*)

0.20

(p<0.001*)

0.40

Relative reduction (percentage)

Percent of patients remaining relapse-free

at 24 months

71.5

(p<0.001*)

73.2

(p<0.001*)

52.7

Risk of disability progression

Hazard ratio (95% CI)

(3-month confirmed)

0.83 (0.61, 1.12)

(p=0.227)

0.72 (0.53, 0.99)

(p=0.041*)

Hazard ratio (95% CI)

(6-month confirmed)

0.72 (0.48, 1.07)

(p=0.113)

0.72 (0.48, 1.08)

(p=0.101)

MRI endpoints

Percent change in brain volume

n=266

n=247

n=249

Median (mean) % change over

24 months

-0.7 (-0.9)

(p<0.001*)

-0.6 (-0.6)

(p<0.001*)

-1.0 (-1.3)

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Gilenya 0.5 mg

Gilenya 1.25 mg

Placebo

Number of new or newly enlarging T2

lesions

n=264

n=245

n=251

Median (mean) number over 24

months

0.0 (2.3)

(p<0.001*)

0.0 (1.6)

(p<0.001*)

4.0 (8.9)

Number of Gd-enhancing lesions

n=269 (Month 24)

n=251 (Month 24)

n=256 (Month 24)

Median (mean) number at

Month 6

Month 12

Month 24

0.0 (0.2)

0.0 (0.2)

0.0 (0.4)

(p<0.001* at each

timepoint)

0.0 (0.2)

0.0 (0.2)

0.0 (0.2)

(p<0.001* at each

timepoint)

0.0 (1.1)

0.0 (1.3)

0.0 (1.2)

Percent change in T2 lesion total volume

n=262

n= 242

n=247

Median (mean) % change over 24

months

-7.1 (13.7)

(p<0.001*)

-10.1 (-7.7)

(p<0.001*)

0.8 (25.1)

Change in T1 hypointense lesion volume

n=225

n=209

n=209

Median (mean) % change over

24 months

-9.9 (12.6)

(p=0.372)

-10.9 (-4.7)

(p=0.205)

-8.5 (26.4.)

All analyses of clinical endpoints were intent-to treat. MRI analyses used the evaluable dataset.

* Indicates statistical significance vs. placebo at two-sided 0.05 level.

Determination of p-values: aggregate ARR by negative binomial regression adjusted for treatment, pooled country, number of

relapses in previous 2 years and baseline EDSS; percentage of patients maintaining relapse-free logistic regression adjusted for

treatment, country, number of relapses in previous 2 years, and baseline EDSS; time to 3-month/6-month confirmed disability

progression by Cox’s proportional hazards model adjusted for treatment, pooled country, baseline EDSS, and age; new/newly

enlarging T2 lesions by negative binomial regression adjusted for treatment and pooled country; Gd-enhancing lesions by rank

ANCOVA adjusted for treatment, pooled country, and baseline number of Gd-enhancing lesions; and % change in lesion and

brain volume by rank ANCOVA adjusted for treatment, pooled country, and corresponding baseline value.

Additional analyses revealed that results in the overall population were not significant due to false positive progressions in the

subgroup of patients with baseline EDSS=0 (n=62, 8.7% of study population). In patients with EDSS>0 (n=651; 91.3% of study

population), fingolimod 0.5 mg demonstrated a clinically relevant and statistically significant reduction compared to placebo

(HR= 0.70; CI (0.50, 0.98); p=0.040), consistent with study FREEDOMS.

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Figure

12-3

Kaplan-Meier plot of time to first confirmed relapse up to Month 24 –

Study FREEDOMS II (ITT population)

Study D2302 (TRANSFORMS)

Study D2302 (TRANSFORMS) was a 1-year randomized, double-blind, double-dummy,

active-controlled (interferon beta-1a, 30 micrograms, intramuscular, once weekly) Phase III

study in patients with relapsing-remitting multiple sclerosis who had not received natalizumab

in the previous 6 months. Prior therapy with interferon-beta or glatiramer acetate up to the

time of randomization was permitted.

Neurological evaluations were performed at screening, every 3 months and at the time of

suspected relapses. MRI evaluations were performed at screening and at Month 12. The

primary endpoint was the annualized relapse rate.

Median age was 36 years, median disease duration was 5.9 years and median EDSS score at

baseline was 2.0. Patients were randomized to receive Gilenya 0.5 mg (n=431) or 1.25 mg

(n=426) or interferon beta-1a 30 micrograms via the intramuscular route once weekly (n=435)

for up to 12 months. Median time on study drug was 365 days on Gilenya 0.5 mg, 354 days

on Gilenya 1.25 mg and 361 days on interferon beta-1a.

The annualized relapse rate was significantly lower in patients treated with Gilenya than in

patients who received interferon beta-1a IM. There was no significant difference between the

Gilenya 0.5 mg and 1.25 mg doses. The key secondary endpoints were number of new or

newly enlarging T2 lesions and time to onset of 3-month confirmed disability progression as

measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for those

with baseline EDSS of 5.5) sustained for 3 months. The number of new or newly enlarging T2

lesions was significantly lower in patients treated with Gilenya than in patients who received

interferon beta-1a IM. There was no significant difference in the time to 3-month confirmed

Time to first relapse (days)

Percentage of patients without confirmed relapse

Fingolimod 0.5 mg

Fingolimod 1.25 mg

Placebo

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disability progression between Gilenya and interferon beta-1a IM-treated patients at 1 year.

There were no significant differences between the 0.5 mg and 1.25 mg doses for either

endpoint.

The results for this study are shown in Table 12-3 and Figure 12-4.

Table 12-3

Clinical and MRI results of Study TRANSFORMS

Gilenya 0.5 mg

Gilenya 1.25 mg

Interferon beta-1a

IM, 30 mcg,

Clinical endpoints

N=429

N=420

N=431

Annualized relapse rate (primary

endpoint)

0.16

(p<0.001*)

0.20

(p<0.001*)

0.33

Relative reduction (percent)

Percent of patients remaining relapse-free

at 12 months

82.5

(p<0.001*)

80.5

(p<0.001*)

70.1

Risk of disability progression

Hazard ratio (95% CI)

(3-month confirmed)

0.71 (0.42, 1.21)

(p=0.209)

0.85 (0.51, 1.42)

(p=0.543)

MRI endpoints

Number of new or newly enlarging T2

lesions

n=380

n=356

n=365

Median (mean) number

over

12 months

0.0 (1.7)

(p=0.004*)

1.0 (1.5)

(p<0.001*)

1.0 (2.6)

Number of Gd-enhancing lesions

n=374

n=352

n=354

Median (mean) number

at 12

months

0.0 (0.2)

(p<0.001*)

0.0 (0.1)

(p<0.001*)

0.0 (0.5)

Percent change in brain volume

n=368

n=345

n=359

Median (mean) % change

over

12 months

-0.2 (-0.3)

(p<0.001*)

-0.2 (-0.3)

(p<0.001*)

-0.4 (-0.5)

All analyses of clinical endpoints were intent-to treat. MRI analyses used the evaluable dataset.

* Indicates statistical significance vs. Interferon beta-1a IM at two-sided 0.05 level.

Determination of p-values: aggregate ARR by negative binomial regression adjusting for treatment, country, number of

relapses in previous 2 years and baseline EDSS; percentage of patients maintaining relapse-free logistic regression

adjusted for treatment, country, number of relapses in previous 2 years, and baseline EDSS; risk of disability

progression by Cox’s proportional hazards model adjusted for treatment, country, baseline EDSS, and age; new/newly

enlarging T2 lesions by negative binomial regression adjusted for treatment, country, number of relapses in previous 2

years and baseline EDSS; Gd-enhancing lesions by rank ANCOVA adjusted for treatment, country, and baseline

number of Gd-enhancing lesions; and % change in brain volume by Wilcoxon rank sum test.

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Figure ‎12-4

Kaplan-Meier plot for time to first confirmed relapse up to Month 12 –

Study TRANSFORMS (ITT population)

Patients who completed Study TRANSFORMS (D2302) had the option to enter a dose-

blinded extension. 1,030 patients from the core study entered the extension (Study D2302E1)

and were treated with fingolimod (n=357 continued on 0.5 mg, 330 continued on 1.25 mg,

167 switched from interferon beta-1a to 0.5 mg and 176 switched from interferon beta-1a to

1.25 mg). 882 of these patients (85.9%) had at least 12 months follow-up in the extension

phase. The maximum cumulative duration of exposure to fingolimod 0.5 mg (core + extension

study) was 1,594 days.

At Month 12 of the extension study, patients who received interferon beta-1a i.m. in the core

study had relative reductions in ARR of 30% after switching to fingolimod 0.5 mg (ARR

ratio=0.70, p=0.06). The ARR for patients who were treated with fingolimod 0.5 mg in the

core study was low during the combined core and extension study (ARR of 0.18 up to Month.

The pooled results of studies D2301 (FREEDOMS) and D2302 (TRANSFORMS) showed a

consistent reduction in the annualized relapse rate with Gilenya compared to comparator in

subgroups

defined

gender,

age,

prior

multiple

sclerosis

therapy,

disease

activity

disability levels at baseline.

13

Non-clinical safety data

The preclinical safety profile of fingolimod was assessed in mice, rats, dogs and monkeys.

The major target organs were the lymphoid system (lymphopenia and lymphoid atrophy),

lungs (increased weight, smooth muscle hypertrophy at the bronchio-alveolar junction), and

heart (negative chronotropic effect, increase in blood pressure, perivascular changes and

myocardial degeneration) in several species; blood vessels (vasculopathy) in rats only; and

pituitary, forestomach, liver, adrenals, gastrointestinal tract and nervous system at high doses

only (often associated with signs of general toxicity) in several species.

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of

fingolimod up to the maximum tolerated dose of 2.5 mg/kg, representing an approximate

Percentage (%) of patients without confirmed relapse

Time to first relapse (days)

Fingolimod 0.5 mg

Fingolimod 1.25 mg

Interferon Beta-1a

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50-fold margin based on human systemic exposure (AUC) at the 0.5 mg dose. However, in a

2-year mouse study, an increased incidence of malignant lymphoma was seen at doses of 0.25

mg/kg and higher, representing an approximate 6-fold margin based on human systemic

exposure (AUC) at a daily dose of 0.5 mg.

Fingolimod was not mutagenic in an Ames test and in a L5178Y mouse lymphoma cell line in

vitro. No clastogenic effects were seen in vitro in V79 Chinese hamster lung cells. Fingolimod

induced numerical (polyploidy) chromosomal aberrations in V79 cells at concentrations of 3.7

mcg/mL and above. Fingolimod was not clastogenic in the in vivo micronucleus tests in mice

and rats.

Fingolimod had no effect on sperm count or motility, nor on fertility in male and female rats

up to the highest dose tested (10 mg/kg), representing an approximate 150-fold margin based

on human systemic exposure (AUC) at a daily dose of 0.5 mg.

Fingolimod was teratogenic in the rat when given at doses of 0.1 mg/kg or higher. The most

common fetal visceral malformations included persistent truncus arteriosus and ventricular

septum defect. An increase in post-implantation loss was observed in rats at 1 mg/kg and

higher and a decrease in viable fetuses at 3 mg/kg. Fingolimod was not teratogenic in the

rabbit, where an increased embryo-fetal mortality was seen at doses of 1.5 mg/kg and higher,

and a decrease in viable fetuses as well as fetal growth retardation at 5 mg/kg.

In rats, F1 generation pup survival was decreased in the early postpartum period at doses that

did not cause maternal toxicity. However, F1 body weights, development, behavior, and

fertility were not affected by treatment with fingolimod. In a toxicity study in juvenile rats, no

additional

target

organs

toxicity

were

observed

compared

adult

rats.

Repeated

stimulations with

Keyhole

Limpet Hemocyanin (KLH) showed a moderately decreased

response during the treatment period, but fully functional immune reactions at the end of an 8

week recovery period.

Fingolimod was excreted in the milk of treated animals during lactation. Fingolimod and its

metabolites crossed the placental barrier in pregnant rabbits.

14

Pharmaceutical information

Incompatibilities

Not applicable

Special Precautions for storage

Do not store above 25°C; protect from moisture

Gilenya must be kept out of the reach and sight of children.

Instructions for use and handling

No special requirements

Special precautions for disposal

No special requirements

Manufacturer:

Novartis Pharma Stein AG, Stein, Switzerland

For: Novartis Pharma AG, Basel, Switzerland

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Registration Holder:

Novartis Israel Ltd., 36 Shacham St., Petach-Tikva

העדוה

לע

הרמחה

(

עדימ

)תוחיטב ןולעב

אפורל ןכדועמ(

05.2013

)

:ךיראת

טסוגואב

2015

םש

רישכת

:תילגנאב

Gilenya 0.5 mg

רפסמ

:םושירה

33270

םש

לעב

:םושירה סיטרבונ

לארשי

מ"עב ספוט

הז

דעוימ

טוריפל

תורמחהה

!דבלב

רוחש טסקט

רשואמ טסקט

יתחת וק םע טסקט

ןולעל טסקט תפסוה רשואמה

הצוח וק םע טסקט

ןולעהמ טסקט תקיחמ רשואמה

בוהצב ןמוסמה טסקט

הרמחה תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Warnings and

precautions

Cases of progressive multifocal

leukoencephalopathy (PML) have been

reported in the post-marketing setting (see

section 7 Adverse drug reactions). PML is

an opportunistic infection caused by JC

virus, which may be fatal or result in

severe disability. Physicians should be

vigilant for clinical symptoms or MRI

findings that may be suggestive of PML.

If PML is suspected, Gilenya treatment

should be suspended until PML has been

excluded

Adverse drug

reactions

Adverse drug reactions from

spontaneous reports and literature

cases (frequency not known)

Infections

In the post-marketing setting cases of

infections with opportunistic pathogens,

such as viral (e.g. VZV, JCV, HSV),

fungal (e.g. cryptococci including

cryptococcal meningitis) or bacterial (e.g.

atypical mycobacterium), have been

reported (see section 6 Warnings and

precautions).

Adverse drug reactions from

spontaneous reports and literature

cases (frequency not known)

Gastrointestinal disorders: Nausea

Infections

In the post-marketing setting cases of

infections with opportunistic pathogens,

such as viral (e.g. VZV, JCV causing

PML, HSV), fungal (e.g. cryptococci

including cryptococcal meningitis) or

bacterial (e.g. atypical mycobacterium),

have been reported (see section 6

Warnings and precautions).

העדוה

לע

הרמחה

(

עדימ

)תוחיטב ןולעב

ןכרצל ןכדועמ(

05.2013

)

:ךיראת

טסוגואב

2015

םש

רישכת

:תילגנאב

Gilenya 0.5 mg

רפסמ

:םושירה

[

33270

]

םש

לעב

:םושירה סיטרבונ

המראפ

ססיורס

ייא

י'ג ספוט

הז

דעוימ

טוריפל

תורמחהה

!דבלב

רוחש טסקט

רשואמ טסקט

יתחת וק םע טסקט

ןולעל טסקט תפסוה רשואמה

הצוח וק םע טסקט

ןולעהמ טסקט תקיחמ רשואמה

בוהצב ןמוסמה טסקט

הרמחה תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח תורהזא

תודחוימ תועגונה

שומישל הפורתב םא

דחא

םיבצמהמ

םיאבה

עגונ ,ךילא שי

עדיל

תא

אפורה

ינפל תליטנ

:הינליג

םא

שי

ךל

רומא ,םוהיז

תאז

אפורל ינפל

התאש

לטונ

הינליג

םוהיז םייק

לולע

םימוהיז .רימחהל

םילולע תויהל

םייניצר

םיתיעלו

ינכסמ

.םייח ינפל

התאש

ליחתמ

תליטנב

הינליג

רובעת

תקידב

תוירודכ

םד

תונבל

לע תנמ

אדול

ןיאש

העינמ

ליחתהל .לופיטב ךלהמב

לופיטה

הינליגב

,

םא

התא

בשוח

שיש

ךל

,םוהיז םא

שי ךל

,םוח םא

שי

ךל

השגרה

לש

תעפש וא

םא

שי

ךל

באכ

שאר

הוולמה ראווצב

תושיגר ,השקונ

הליחב ,רואל וא/ו

לובלב

הלא(

םייושע

תויהל םינימסת

לש

תקלד

םורק

,)חומה שי ץעוויהל

אפורב

.דימ םא

דחא

םיבצמהמ

םיאבה

עגונ ,ךילא שי

עדיל

תא

אפורה

ינפל תליטנ

:הינליג

םא

שי

ךל

רומא ,םוהיז

תאז

אפורל ינפל

התאש

לטונ

הינליג

םוהיז םייק

לולע

םימוהיז .רימחהל

םילולע תויהל

םייניצר

םיתיעלו

ינכסמ

.םייח ינפל

התאש

ליחתמ

תליטנב

הינליג

רובעת

תקידב

תוירודכ

םד

תונבל

לע תנמ

אדול

ןיאש

העינמ

ליחתהל .לופיטב ךלהמב

לופיטה

הינליגב

,

םא

התא

בשוח

שיש

ךל

,םוהיז םא

שי ךל

,םוח םא

שי

ךל

השגרה

לש

תעפש וא

םא

שי

ךל

באכ

שאר

הוולמה ראווצב

תושיגר ,השקונ

הליחב ,רואל וא/ו

לובלב

הלא(

םייושע

תויהל םינימסת

לש

תקלד

םורק

,)חומה שי ץעוויהל

אפורב

.דימ

םא

התא

שיגרמ

תשרטהש

הצופנה

הרימחמ

לשמל(

השלוח

וא

םייוניש

וא )הייארב

םא

התא

ןיחבמ

םינימסתב

םהשלכ

םישדח

וא

אל

הנפ ,םיליגר

אפורל

ךלש

םדקהב

ירשפאה

ןוויכמ

הלאש

םייושע

תויהל

םינימסתה

לש

הערפה

תיחומ

הרידנ

תמרגנה

לע

ידי

םוהיז

תארקנו

progressive multifocal

leukoencephalopathy (PML)

תועפות

יאוול תועפות

יאוול

תוחיכשב

אל

העודי

ןוכדע

חוסינה

תשקבל

ףגא

:תוחקורה םוהיז

רומח

רידנו

ארקנה

progressive

multifocal leukoencephalopathy

(PML)

לעב ,

םינימסת

םילוכיש

תויהל

םימוד

ינימסתל

תשרט

הצופנ

םייושעו

לולכל

תשלוח

דוקפת ,םירירש

ילכש

באכ ,יוקל

םיישק ,שאר

יוקיל/ןדבוא ,םיסוכרפ ,הייאר/רובידב תוערפה ,יתשוחת

הכילהב

וא

היצנידרואוק

םואית(

.)העונת

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