TASIGNA 150 MG

Israel - English - Ministry of Health

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Active ingredient:
NILOTINIB AS HYDROCHLORIDE MONOHYDRATE
Available from:
NOVARTIS ISRAEL LTD
ATC code:
L01XE08
Pharmaceutical form:
CAPSULES
Composition:
NILOTINIB AS HYDROCHLORIDE MONOHYDRATE 150 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
NOVARTIS PHARMA STEIN AG, SWITZERLAND
Therapeutic group:
NILOTINIB
Therapeutic area:
NILOTINIB
Therapeutic indications:
Treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase. .
Authorization number:
145 84 33271 00
Authorization date:
2016-03-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

15-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

01-11-2018

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

TASIGNA

®

150 MG

TASIGNA

®

200 MG

Capsules

Capsules

Each capsule contains:

Each capsule contains:

Nilotinib as hydrochloride

Nilotinib as hydrochloride

monohydrate 150 mg

monohydrate 200 mg

Inactive ingredients: See “Important information about some of the

medicine’s ingredients” section, listed under section 2, and also section

6 “Further information”.

Read this package insert carefully in its entirety before using this

medicine. This leaflet contains concise information about the medicine.

If you have further questions, refer to the doctor or pharmacist.

Keep this leaflet. You may need to read it again.

This 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.

There is no experience with use of Tasigna in children and adolescents

(below the age of 18).

1. WHAT IS THE MEDICINE INTENDED FOR?

Tasigna 150 mg and Tasigna 200 mg are used:

For treatment of adult patients with newly diagnosed Philadelphia

chromosome positive chronic myeloid leukemia - Ph+ CML in the

chronic phase.

Tasigna 200 mg only is used:

For treatment of patients with Philadelphia chromosome positive chronic

myeloid leukemia - Ph+ CML in the chronic or accelerated phase, who

are resistant to or who experienced significant toxicity during treatment

with imatinib.

Tasigna is used to treat a type of leukemia called Philadelphia

chromosome positive chronic myeloid leukemia (Ph+ CML).

CML is a cancer of the blood which causes the body to produce too many

abnormal white blood cells.

In CML patients, a change in the genetic material (DNA) triggers a signal

which causes the body to produce too many abnormal white blood cells.

Tasigna blocks this signal and stops the production of these cells.

Therapeutic group: Antineoplastic.

If you have any question about how Tasigna works or why this medicine

has been prescribed for you, refer to your doctor.

2. BEFORE USING THE MEDICINE:

Follow all the doctor’s instructions carefully. They may differ from the

general information contained in this leaflet.

X

Do not use the medicine:

If you have an allergy (hypersensitivity) to nilotinib or to any of the other

ingredients of the medicine listed in section 6 “Further information”.

If you think you may be allergic, inform the doctor before taking

Tasigna.

Special warnings regarding use of the medicine:

Before treatment with Tasigna, inform your doctor if any of the following

apply to you:

∙ If you have had prior cardiovascular events such as a heart attack,

chest pain (angina), problems with the blood supply to your brain

(stroke), or problems with the blood flow to your leg (claudication) or

if you have risk factors for cardiovascular disease such as high blood

pressure (hypertension), diabetes, or problems with the level of fats

in your blood (lipid disorders).

∙ If you have a heart disorder such as an abnormal electrical signal

called “prolongation of the QT interval”.

∙ If you are being treated with medicines that affect the heart rate

(anti-arrhythmics) or the liver (see below “If you are taking, or have

recently taken, other medicines”).

∙ If you suffer from lack of potassium or magnesium.

∙ If you have a liver or pancreas disorder.

∙ If you have symptoms such as easy bruising, feeling tired or short of

breath or recurrent infections.

∙ If you underwent surgery for removal of your entire stomach

(gastrectomy).

∙ If you have ever had or might have a hepatitis B infection. Tasigna

could cause hepatitis B to become active again, which can be fatal

in some cases. Patients will be carefully checked by their doctor for

signs of this infection before treatment is started.

!

During treatment with Tasigna

Refer to your doctor immediately if you faint (lose consciousness),

or have irregular heartbeats during treatment with this medicine, as

these may occur due to a serious heart condition. Prolongation of the

QT interval or irregular heartbeats may lead to sudden death.

Uncommon cases of sudden death have been reported in patients

treated with Tasigna.

Refer to your doctor immediately if you have sudden heart palpitations,

severe muscle weakness or paralysis, seizures or sudden changes in

your thinking or level of alertness, since this may be a sign of the rapid

breakdown of cancer cells called “tumor lysis syndrome”. Rare cases of

tumor lysis syndrome have been reported in patients taking Tasigna

Refer to your doctor immediately if you develop chest pain or

discomfort, numbness or weakness, problems with walking or speech,

pain, discoloration or a cold sensation in one of the limbs since this

may be a sign of a cardiovascular event. Severe cardiovascular events

including problems with blood flow to the leg (peripheral arterial

occlusive disease), ischemic heart disease and problems with blood

supply to the brain (ischemic cerebrovascular disease) have been

reported in patients taking Tasigna. Your doctor should monitor the

level of fats (lipids) and sugar in your blood before initiating treatment

with Tasigna and during the treatment.

If you develop swelling of the feet or hands, generalized swelling or

rapid weight gain, tell your doctor since these may be signs of severe

fluid retention. Uncommon cases of severe fluid retention have been

reported in patients taking Tasigna.

Tests and follow-up:

During treatment with this medicine, tests should be performed regularly,

including blood tests. These tests will monitor:

∙ the amount of blood cells (white blood cells, red blood cells and

platelets) in the body to see how Tasigna is being tolerated.

∙ pancreas and liver function in the body to see how Tasigna is being

tolerated.

∙ electrolytes in the body (potassium, magnesium). These are important

in the functioning of the heart.

∙ the level of sugar and fats in the blood.

The heart rate will also be checked using a machine that measures the

electrical activity of the heart (a test called “ECG”).

Your doctor will regularly monitor your treatment and decide whether

you should continue taking Tasigna.

If you are told to stop taking this medicine, your doctor will carefully

continue to monitor your CML and may instruct you to resume taking

Tasigna if necessary, depending on your condition.

Refer to the doctor with any question regarding how Tasigna works or

why it was prescribed for you.

!

If you are taking, or have recently taken, other medicines,

including non-prescription medicines and nutritional supplements,

tell the doctor or pharmacist in order to prevent risks or inefficacy arising

from drug interactions. Tasigna may interfere with other medicines. In

particular, inform the doctor or pharmacist if you are taking:

∙ Anti-arrhythmics - used to treat irregular heart rate;

∙ Chloroquine, halofantrine, clarithromycin, haloperidol, methadone,

moxifloxacin - medicines that may have an unwanted effect on the

function of the heart;

∙ Ketoconazole, itraconazole, voriconazole, clarithromycin, Telithromycin –

used to treat infections;

∙ Ritonavir – a medicine for the treatment of AIDS (HIV) from the

“antiprotease” group;

∙ Carbamazepine, phenobarbital, phenytoin - used to treat epilepsy;

∙ Rifampicin - used to treat tuberculosis;

∙ St. John’s Wort – a herbal product used to treat depression and other

conditions (also known as Hypericum perforatum);

∙ Midazolam – used to relieve states of anxiety before surgery;

∙ Alfentanil and fentanyl - used to treat pain and as a sedative before

or during surgery or medical procedures;

∙ Cyclosporine, sirolimus and tacrolimus - medicines that suppress the

“self-defense” capability of the body and ability to fight infections and

are usually used to prevent the rejection of transplanted organs such

as liver, heart and kidney;

∙ Dihydroergotamine and ergotamine - used to treat dementia;

∙ Lovastatin, simvastatin - used to treat high levels of fats in blood;

∙ Warfarin - used to treat blood coagulation disorders (such as blood

clots and thrombosis);

∙ Astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil.

During treatment with Tasigna avoid taking these medicines. If you

are taking one or more of these medicines, the doctor may prescribe

alternative medicines for you.

In addition, inform the doctor or pharmacist before taking Tasigna if

you are taking antacids (medicines for treatment of heartburn). These

medications need to be taken separately from Tasigna:

∙ Antacids called H2 blockers, which decrease the production of acidity

in the stomach - should be taken approximately 10 hours before and,

approximately 2 hours, after you take Tasigna.

∙ Antacids such as those containing aluminium hydroxide, magnesium

hydroxide and simethicone, which neutralize high acidity of the

stomach - should be taken approximately 2 hours before or 2 hours

after taking Tasigna.

You should inform your doctor if you are already taking Tasigna and

you are prescribed a new medicine, including non-prescription medicines,

that you have not taken previously during Tasigna treatment.

!

Use of Tasigna and food

Do not take the medicine with food. Food may enhance the

absorption of Tasigna and therefore increase its amount in the blood,

possibly to a harmful level.

Do not drink grapefruit juice or eat grapefruit. It may increase the

amount of Tasigna in the blood, possibly to a harmful level.

!

Elderly people (patients from 65 years and over)

Tasigna can be used by people aged 65 years and over at the same

dosages as for other adults.

!

Pregnancy and breast-feeding

It is not recommended to use Tasigna during pregnancy unless clearly

necessary. If you are pregnant or think that you may be pregnant, inform

the doctor who will discuss with you whether you can use this medicine

during pregnancy.

Women of child-bearing age must use highly effective contraception

while using Tasigna and for 2 full weeks after ending treatment.

Do not breast-feed during treatment with Tasigna. Inform your doctor

if you are breast-feeding.

If you are pregnant or breast-feeding, think you are pregnant or planning

to become pregnant, consult with the doctor or pharmacist before taking

this medicine.

!

Driving and use of machines

If you experience side effects (such as dizziness or visual disorders)

that can affect the ability to drive safely or use any tools or machines

after taking this medicine, you should refrain from these activities until

the effect has passed.

!

Important information about some of the medicine’s

ingredients

The preparation contains lactose (milk sugar). If you know that you are

lactose intolerant, inform the doctor before taking Tasigna.

Each 150 mg Tasigna capsule contains approximately 117 mg lactose

monohydrate.

Each 200 mg Tasigna capsule contains approximately 156 mg lactose

monohydrate.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use the preparation according to the doctor’s instructions. Check

with the doctor or pharmacist if you are not sure about the dosage and

treatment regimen of the preparation.

The dosage and the treatment regimen will be determined by

the doctor only. The usual dosage is generally:

Adult patients with newly diagnosed Ph+ CML: 2 capsules of 150 mg

twice daily (300 mg twice daily).

For patients with Ph+ CML in the chronic or accelerated phase who are

resistant to or who experienced significant toxicity during treatment with,

imatinib: 2 capsules of 200 mg twice daily (400 mg twice daily).

Your doctor may prescribe a lower dosage depending on your response

to treatment.

Do not exceed the recommended dose.

When to take Tasigna:

Take the capsules:

∙ twice a day (approximately every 12 hours)

∙ at least 2 hours after eating any food

∙ then wait at least 1 hour before eating again

If you have questions about when to take the medicine, talk to your

doctor or pharmacist.

Taking the medicine at the same time each day will help you remember

when to take your capsules.

How to take Tasigna:

Swallow the capsules whole with water.

Do not consume any food together with the capsules.

Do not open the capsules unless you are unable to swallow the

capsules whole.

In this case you may mix the contents of each capsule in one teaspoon

of applesauce (pureed apple) and take it immediately. Do not use more

than one teaspoon of applesauce for each capsule and do not use any

food other than applesauce.

Duration of treatment:

Continue taking the medicine every day as long as your doctor instructs

you to; this is a long-term treatment. Your doctor will regularly monitor

your condition to check that the treatment is having the desired

effect.

The doctor will consider stopping the treatment with Tasigna according

to specific criteria.

If you have questions regarding how long to take Tasigna, consult your

doctor or pharmacist.

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.

Medical treatment may be necessary.

If you forgot to take this medicine at the required time, do not

take a double dose. Take the next dose at the regular time and consult

the doctor.

Adhere to the treatment as recommended by the doctor.

Even if there is an improvement in your health, do not stop

treatment with the medicine without consulting the doctor.

Stopping treatment with the medicine without a doctor’s recommendation

places you at risk for worsening of your illness which may come with

life-threatening consequences. Be sure to discuss with your doctor, nurse

and/or pharmacist if you are considering stopping Tasigna.

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

each time you take medicine. Wear glasses if you need them.

If your doctor recommended discontinuation of Tasigna

treatment

Your doctor will regularly monitor your treatment by a certain diagnostic

test and will decide if you should continue taking this medicine.

If you have been told to stop taking Tasigna, your doctor will continue to

carefully monitor your CML, before, during and after stopping treatment

and may instruct you to resume taking Tasigna if necessary, depending

on your condition.

If you have further questions regarding use of the medicine,

consult the doctor or pharmacist.

4. SIDE EFFECTS:

As with any medicine, use of Tasigna may cause side effects in some

users. Do not be alarmed when reading the list of side effects. You

may not suffer from any of them. Most of the side effects are mild to

moderate, and will generally disappear after a few days to a few weeks

after starting treatment.

Some side effects can be serious. Contact the doctor immediately

in the following cases:

These side effects are common (may affect up to 1 in 10 patients),

uncommon (may affect up to 1 in 100 patients) or were reported at

unknown frequencies (can not be estimated from the existing data).

∙ Rapid weight gain, swelling of hands, ankles, feet or face (signs of

water retention)

∙ Chest pain, high blood pressure, irregular heart rate, blue discoloration

of the lips, tongue or skin (signs of heart disorders)

∙ Difficulty breathing, cough, wheezing with or without fever, swelling

of legs and feet (signs of lung disorders)

∙ Fever, easy bruising, frequent infections (signs of blood disorders)

∙ Weakness or paralysis of limbs or face, difficulty speaking, severe

headache, seeing, hearing or feeling things that are not there (signs

of nervous system disorders)

∙ Thirst, dry skin, irritability, dark urine, decreased urine output (signs

of kidney disorders)

Blurred vision, loss of vision, blood in the eyes (signs of eye disorders)

∙ Swelling and pain in one part of the body (signs of clotting within a

vein)

∙ Abdominal pain, nausea, vomiting of blood, black stools, constipation,

swollen abdomen (signs of gastrointestinal disorders)

∙ Severe upper abdominal pain (a sign of inflammation of pancreas)

∙ Yellow skin and eyes, nausea, loss of appetite, dark-colored urine

(signs of liver disorders)

∙ Rash, painful red lumps, pain in joints and muscles (signs of skin

disorders)

∙ Excessive thirst, high urine output, increased appetite with weight

loss, tiredness (signs of high level of sugar in the blood)

∙ Fast heartbeats, bulging eyes, weight loss, swelling at front of the

neck (signs of overactive thyroid gland)

∙ Nausea, shortness of breath, irregular heartbeats, clouding of urine,

tiredness and/or joint discomfort with abnormal laboratory test results

(such as an increase in potassium, uric acid and phosphorous levels

and decrease in calcium levels in the blood)

∙ Pain, discomfort, weakness or cramping in leg muscles, which may

be due to decreased blood flow, ulcers on the legs and arms that

heal slowly or not at all and noticeable changes in color (blueness or

paleness) or temperature (coolness) of the legs and arms, as these

symptoms could be signs of artery blockage in the affected limb (leg

or arm) and digits (toes and fingers).

∙ Recurrence (reactivation) of hepatitis B infection when you have had

hepatitis B in the past.

If you experience any of these side effects, tell your doctor

immediately.

Additional side effects:

Very common side effects (may affect more than 1 in 10 patients):

Diarrhea; headache; tiredness; muscle pain; itching, rash, nausea;

vomiting; hair loss; high blood level of bilirubin (liver function); high

blood level of lipase (pancreas function); muscle pain, musculoskeletal

pains, pain in extremities, pain in joints, bone pain, and back pains with

discontinuation of Tasigna treatment.

If one of the effects mentioned above affects you severely, tell your

doctor.

Common side effects (may affect up to 1 in 10 patients): Hives (urticaria);

abdominal discomfort, stomach discomfort after meals, flatulence, swelling

or bloating of the abdomen; bone pain, joint pain, muscle spasms; pain

including back pain, neck pain and pain in extremities, pain or discomfort

in the side of the body; eye irritation, swelling, discharge, itching or

redness, dry eyes (signs of eye disorders); skin redness, dry skin, acne,

skin wart, decreased skin sensitivity; weight increase or decrease, loss of

appetite, disturbed sense of taste; insomnia, depression, anxiety; night

sweats, increased sweating, hot flushes; dizziness, generally feeling

unwell, spinning sensation; tingling or numbness; voice disturbance;

nose bleed; frequent urine output; palpitations.

If one of the effects mentioned above affects you severely, tell your

doctor.

Uncommon side effects (may affect up to 1 in 100 patients): Increased

skin sensitivity, skin pain; eyelid swelling; dry mouth, sore throat, mouth

sores; heartburn; breast pain; increased appetite; attention disorder;

difficulty and pain upon urinating, exaggerated sense of needing to

urinate; inability to achieve or maintain an erection; breast enlargement

in men; flu-like symptoms, muscle weakness; trembling; decreased

sharpness of vision; severe headache occasionally accompanied by

nausea, vomiting, sensitivity to light; visual disturbances; vaginal or

oral thrush; joint and muscle stiffness; loss of consciousness; weight

gain; feeling body temperature change (including feeling hot, feeling

cold); thickened patches of red/silver skin (signs of psoriasis); teeth

sensitivity.

If one of the effects mentioned above affects you severely, tell your

doctor.

The following side effects were reported at unknown frequencies

(can not be estimated from the existing data):

Confusion, spatial disorientation, memory loss, disturbed mood, lack of

energy; bacterial skin infection; blister, skin cyst, oily skin, thinning of

skin, dark patches of skin, skin discoloration; bleeding, tender or enlarged

gums; runny or stuffy nose, sneezing; reddening and/or swelling and

possibly peeling of the palms of the hands and soles of the feet (named

hand-foot syndrome); increased sensitivity of the eyes or skin to light;

eye pain or redness, pain, itching of eyelids; difficulty hearing, ear pain,

noises (ringing) in the ears; swollen and painful joints (gout); blood in

urine, urinary incontinence, abnormal urine color; hemorrhoids; feeling

of hardening in the breasts, nipple swelling, heavy periods; symptoms of

restless legs syndrome (an urge to move one part of the body, usually

the leg, in order to stop uncomfortable sensations).

If the effects mentioned above affect you severely, notify the doctor.

During treatment with Tasigna you may have abnormal blood test results,

e.g., low level of blood cells (white blood cells, red blood cells, platelets),

high blood level of lipase or amylase (pancreas function), high blood level

of bilirubin (liver function), high blood level of creatinine (kidney function),

low or high blood level of insulin (a hormone regulating blood sugar level),

low or high blood sugar level, high level of fats in the blood.

If one of the effects mentioned above affects you, follow your doctor’s

advice.

If a side effect occurs, if one of the side effects worsens or

if you suffer from a side effect not mentioned in this leaflet,

consult with the doctor.

Side effects can be reported to the Ministry of Health by clicking on

the link “Report Side Effects of Drug Treatment” found on the Ministry

of Health homepage (www.health.gov.il) that directs you to the online

form for reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formTyp

e=AdversEffectMedic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine and any other medicine must be kept

in a closed place out of the reach of children and/or infants 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. Expiry date refers to the last day of that month.

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Do not use a package that is damaged or shows signs of tampering.

Keep out of the reach and sight of children.

6. FURTHER INFORMATION:

In addition to the active ingredient, the medicine also contains:

Lactose monohydrate, Crospovidone, Poloxamer 188, Silica colloidal,

anhydrous/Colloidal silicon dioxide, Magnesium stearate.

Tasigna 150 mg capsule shell: Gelatin, Titanium dioxide (E171), Iron

oxide yellow (E172), Iron oxide red (E172), and Printing ink: black.

Qualitative composition of printing ink: Shellac, Iron oxide black, n-butyl

alcohol, purified water, propylene glycol, dehydrated ethanol, isopropyl

alcohol, ammonium hydroxide.

Tasigna 200 mg capsule shell: Gelatin, Titanium dioxide (E171), Iron

oxide yellow (E172), Printing ink: red.

Qualitative composition of printing ink a: Shellac, dehydrated alcohol,

isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia

solution, Iron oxide red (E172), potassium hydroxide, purified water.

Qualitative composition of printing ink b: Shellac, Iron oxide red (E172),

Iron oxide black (E172), n-butyl alcohol, purified water, titanium

dioxide (E171), propylene glycol, industrial methylated spirit, isopropyl

alcohol.

The printing ink used is ‘Printing ink a’ or alternatively ‘Printing ink b’.

Each 150 mg Tasigna capsule contains approximately 117 mg lactose

monohydrate.

Each 200 mg Tasigna capsule contains approximately 156 mg lactose

monohydrate.

What does the medicine look like and what are the contents

of the package:

A monthly package of Tasigna 150 mg contains 112 capsules. The

monthly package contains 4 weekly packs.

A 10-day pack of Tasigna 200 mg contains 40 capsules and a monthly

package contains 120 capsules. The monthly package contains 3

10-day packs.

Tasigna 150 mg capsules: White to yellowish powder in red, opaque,

size 1 capsules, with black axial imprint “NVR”/“BCR”.

Tasigna 200 mg capsules: White to yellowish powder in light yellow,

opaque, size 0 capsules, with red axial imprint “NVR”/“TKI”.

Registration Holder and address:

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

Manufacturer and address:

Novartis Pharma Stein A.G., Stein, Switzerland for Novartis Pharma

A.G., Basel, Switzerland.

This leaflet was checked and approved by the Ministry of Health in

September 2018.

Drug Registration Number in the National Drug Registry of the

Ministry of Health:

Tasigna 150 mg: 145 84 33271

Tasigna 200 mg: 138 17 31681

SH TAS APL SEP18 V12 CL COR OCT18 CL

SH TAS APL SEP18 V12 CL COR OCT18 CL

:ﺎﻨﭽﯿﺳﺎﺗ ﻝﻭﺎﻨﺗ ﺐﺠﻳ ﻰﺘﻣ :ﺕﻻﻮﺴﺒﻜﻟﺍ ﻝﻭﺎﻨﺗ ﺐﺠﻳ (ﺔﻋﺎﺳ ١٢ ﻞﻛ ﻲﻟﺍﻮﺣ) ﻡﻮﻴﻟﺍ ﻲﻓ ﻦﻴﺗﺮﻣ ∙ ﻡﺎﻌﻃ ﻱﺃ ﻞﻛﺃ ﺪﻌﺑ ﻞﻗﻷﺍ ﻰﻠﻋ ﻦﻴﺘﻋﺎﺳ ∙ ﺔﻴﻧﺎﺛ ﻞﻛﻷﺍ ﻞﺒﻗ ﻞﻗﻷﺍ ﻰﻠﻋ ﺔﻋﺎﺳ ﺭﺎﻈﺘﻧﻹﺍ ﻢﺛ ﻦﻣﻭ ∙ ﻝﻭﺎﻨﺗ ﻥﺇ.ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ،ﺀﺍﻭﺪﻟﺍ ﻝﻭﺎﻨﺗ ﺐﺠﻳ ﻰﺘﻣ ﻝﻮﺣ ﺔﻠﺌﺳﺃ ﺔﻳﺃ ﻚﻳﺪﻟ ﺕﺮﻓﻮﺗ ﺍﺫﺇ .ﻚﺑ ﺔﺻﺎﺨﻟﺍ ﺕﻻﻮﺴﺒﻜﻟﺍ ﻝﻭﺎﻨﺗ ﺮﻛﺬﺗ ﻰﻠﻋ ﻙﺪﻋﺎﺴﻳ ﻡﻮﻳ ﻞﻛ ﺔﻋﺎﺴﻟﺍ ﺲﻔﻨﺑ ﺀﺍﻭﺪﻟﺍ :ﺎﻨﭽﯿﺳﺎﺗ ﻝﻭﺎﻨﺗ ﺔﻴﻔﻴﻛ .ﺀﺎﻤﻟﺍ ﻊﻣ ﻞﻣﺎﻜﻟﺍ ﺎﻬﻠﻜﺸﺑ ﺕﻻﻮﺴﺒﻜﻟﺍ ﻊﻠﺑ ﺐﺠﻳ .ﺕﻻﻮﺴﺒﻜﻟﺍ ﻊﻣ ﺔﻳﻮﺳ ﻡﺎﻌﻃ ﻱﺃ ﻙﻼﻬﺘﺳﺇ ﺯﻮﺠﻳ ﻻ ﺎﻬﻠﻜﺸﺑ ﺕﻻﻮﺴﺒﻜﻟﺍ ﻊﻠﺑ ﻙﺭﻭﺪﻘﻤﺑ ﻦﻜﻳ ﻢﻟ ﺍﺫﺇ ﻻﺇ ،ﺕﻻﻮﺴﺒﻜﻟﺍ ﺢﺘﻓ ﺯﻮﺠﻳ ﻻ .ﻞﻣﺎﻜﻟﺍ ﺱﻭﺮﻬﻤﻟﺍ ﺡﺎﻔﺘﻟﺍ ﻦﻣ ﺓﺪﺣﺍﻭ ﺔﻘﻌﻠﻣ ﻊﻣ ﺔﻟﻮﺴﺒﻛ ﻞﻛ ﻯﻮﺘﺤﻣ ﻂﻠﺧ ﻥﺎﻜﻣﻹﺎﺑ ﺔﻟﺎﺤﻟﺍ ﻩﺬﻫ ﻲﻓ ﺔﻟﻮﺴﺒﻛ ﻞﻜﻟ ﺱﻭﺮﻬﻤﻟﺍ ﺡﺎﻔﺘﻟﺍ ﻦﻣ ﺓﺪﺣﺍﻭ ﺔﻘﻌﻠﻣ ﻦﻣ ﺮﺜﻛﺃ ﻞﻤﻌﺘﺴﺗ ﻻ.

ﻻﺎﺣ ﻝﻭﺎﻨﺘﻟﺍﻭ .ﺱﻭﺮﻬﻤﻟﺍ ﺡﺎﻔﺘﻟﺍ ﺍﺪﻋ ﺮﺧﺁ ﻡﺎﻌﻃ ﻱﺃ ﻻﻭ :ﺝﻼﻌﻟﺍ ﺓﺮﺘﻓ .ﺪﻣﻷﺍ ﻞﻳﻮﻃ ﻮﻫ ﺝﻼﻌﻟﺍ ﺍﺬﻫ ،ﺐﻴﺒﻄﻟﺍ ﻙﺎﺻﻭﺃ ﺎﻤﻟﺎﻄﻟ ﻡﻮﻳ ﻞﻛ ﺀﺍﻭﺪﻟﺍ ﻝﻭﺎﻨﺗ ﺔﻠﺻﺍﻮﻣ ﺐﺠﻳ ﺱﺭﺪﻳ .ﻪﻓﺪﻫ ﻖﻘﺤﻳ ﺝﻼﻌﻟﺍ ﻥﺃ ﻦﻣ ﺪﻛﺄﺘﻠﻟ ﻚﻟﺫﻭ ﻢﻈﺘﻨﻣ ﻞﻜﺸﺑ ﻚﺘﻟﺎﺣ ﺔﻌﺑﺎﺘﻤﺑ ﻚﺒﻴﺒﻃ ﻡﻮﻘﻳ ﺓﺮﺘﻔﻟﺍ ﻝﻮﺣ ﺔﻠﺌﺳﺃ ﻚﻳﺪﻟ ﺕﺮﻓﻮﺗ ﺍﺫﺇ .ﺔﻨﻴﻌﻣ ﺮﻴﻳﺎﻌﻤﻟ

ﺎﻘﻓﻭ ﺎﻨﭽﯿﺳﺎﺗ ـﺑ ﺝﻼﻌﻟﺍ ﻑﺎﻘﻳﺇ ﺐﻴﺒﻄﻟﺍ .ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﺐﺠﻳ ،ﺎﻨﭽﯿﺳﺎﺗ ﻝﻭﺎﻨﺗ ﺎﻬﻴﻓ ﺐﺟﺍﻮﻟﺍ ﺔﻴﻨﻣﺰﻟﺍ ﺐﻴﺒﻄﻟﺍ ﻰﻟﺇ

ﻻﺎﺣ ﻪﺟﻮﺗ ،ﺀﺍﻭﺪﻟﺍ ﻦﻣ ﺄﻄﺨﻟﺎﺑ ﻞﻔﻃ ﻊﻠﺑ ﺍﺫﺇ ﻭﺃ ﺔﻃﺮﻔﻣ ﺔﻋﺮﺟ ﺖﻟﻭﺎﻨﺗ ﺍﺫﺇ ﺝﺎﺘﺤﻳ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ .ﺀﺍﻭﺪﻟﺍ ﺔﺒﻠﻋ ﻚﻌﻣ ﺮﻀﺣﺃﻭ ﻰﻔﺸﺘﺴﻤﻟﺍ ﻲﻓ ﺉﺭﺍﻮﻄﻟﺍ ﺔﻓﺮﻐﻟ ﻭﺃ

ﺎﻴﺒﻃ

ﺎﺟﻼﻋ ﺮﻣﻷﺍ ﻝﻭﺎﻨﺗ .ﺔﻔﻋﺎﻀﻣ ﺔﻋﺮﺟ ﻝﻭﺎﻨﺗ ﺯﻮﺠﻳ ﻻ ،ﺏﻮﻠﻄﻤﻟﺍ ﺖﻗﻮﻟﺍ ﻲﻓ ﺀﺍﻭﺪﻟﺍ ﺍﺬﻫ ﻝﻭﺎﻨﺗ ﺖﻴﺴﻧ ﺍﺫﺇ .ﺐﻴﺒﻄﻟﺍ ﺮﺸﺘﺳﺇﻭ ﻱﺩﺎﻴﺘﻋﻹﺍ ﺖﻗﻮﻟﺍ ﻲﻓ ﺔﻣﺩﺎﻘﻟﺍ ﺔﻋﺮﺠﻟﺍ .ﺐﻴﺒﻄﻟﺍ ﻪﺑ ﻰﺻﻭﺃ ﺎﻤﻛ ﺝﻼﻌﻟﺍ ﻰﻠﻋ ﺔﺒﻇﺍﻮﻤﻟﺍ ﺐﺠﻳ ﻰﻠﻋ ﻦﺴﺤﺗ ﺃﺮﻃ ﻮﻟﻭ ﻰﺘﺣ ،ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺍ ﻥﻭﺪﺑ ﺀﺍﻭﺪﻟﺎﺑ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺯﻮﺠﻳ ﻻ .ﺔﻴﺤﺼﻟﺍ ﻚﺘﻟﺎﺣ ﻢﻗﺎﻔﺗ ﺓﺭﻮﻄﺨﻟ

ﺎﺿﺮﻌﻣ ﻚﻠﻌﺠﺗ ﺐﻴﺒﻄﻟﺍ ﻦﻣ ﺔﻴﺻﻮﺗ ﻥﻭﺪﺑ ﺀﺍﻭﺪﻟﺍ ﺍﺬﻬﺑ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﻥﺇ ﻚﺘﺸﻗﺎﻨﻣ ﻦﻣ ﺪﻛﺄﺗ .ﺓﺎﻴﺤﻟﺍ ﻰﻠﻋ

ﺍﺮﻄﺧ ﻞﻜﺸﺗ ﺕﺎﻴﻋﺍﺪﺗ ﻪﻟ ﻥﻮﻜﺗ ﺪﻗ ﻱﺬﻟﺍ ﺮﻣﻷﺍ ﻚﺿﺮﻣ .ﺎﻨﭽﯿﺳﺎﺗ ﻝﻭﺎﻨﺗ ﻦﻋ ﻒﻗﻮﺘﻟﺎﺑ ﺮﻜﻔﺗ ﺖﻨﻛ ﺍﺫﺇ ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ/ﻭ ﺔﺿﺮﻤﻤﻟﺍ ،ﺐﻴﺒﻄﻠﻟ ﻲﺋﺍﻭﺪﻟﺍ ﺭﺍﺪﻘﻤﻟﺍ ﻦﻣ ﺪﻛﺄﺘﻟﺍﻭ ﺀﺍﻭﺪﻟﺍ ﻊﺑﺎﻃ ﺺﻴﺨﺸﺗ ﺐﺠﻳ !ﺔﻤﺘﻌﻟﺍ ﻲﻓ ﺔﻳﻭﺩﻷﺍ ﻝﻭﺎﻨﺗ ﺯﻮﺠﻳ ﻻ .ﻚﻟﺫ ﺮﻣﻷﺍ ﻡﺰﻟ ﺍﺫﺇ ﺔﻴﺒﻄﻟﺍ ﺕﺍﺭﺎﻈﻨﻟﺍ ﻊﺿ .ﺀﺍﻭﺩ ﺎﻬﻴﻓ ﻝﻭﺎﻨﺘﺗ ﺓﺮﻣ ﻞﻛ ﻲﻓ .ﺎﻨﭽﯿﺳﺎﺗ ـﺑ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺎﺑ ﻚﺒﻴﺒﻃ ﻰﺻﻭﺃ ﺍﺫﺇ ﺭﺮﻘﻳﻭ ﻦﻴﻌﻣ ﻲﺼﻴﺨﺸﺗ ﺺﺤﻓ ﺀﺍﺮﺟﺇ ﺔﻄﺳﺍﻮﺑ ﻚﺟﻼﻌﻟ ﺔﻌﺑﺎﺘﻣ ﻢﻈﺘﻨﻣ ﻞﻜﺸﺑ ﻚﺒﻴﺒﻃ ﻱﺮﺠﻳ ،ﺎﻨﭽﯿﺳﺎﺗ ﻝﻭﺎﻨﺗ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﻚﻴﻠﻋ ﻥﺄﺑ ﻚﻟ ﻞﻴﻗ ﺍﺫﺇ .ﺀﺍﻭﺪﻟﺍ ﺍﺬﻫ ﻝﻭﺎﻨﺗ ﺔﻠﺻﺍﻮﻣ ﻚﻴﻠﻋ ﺍﺫﺇ ﺎﻤﻴﻓ ﻝﻭﺎﻨﺘﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺪﻌﺑﻭ ﻝﻼﺧ ،ﻞﺒﻗ ﻚﻟﺫﻭ ﺹﺮﺤﺑ ﻚﻳﺪﻟ

ـﻟﺍ ﺽﺮﻣ ﺔﺒﻗﺍﺮﻣ ﻚﺒﻴﺒﻃ ﻞﺻﺍﻮﻳ .ﻚﺘﻟﺎﺤﻟ

ﺎﻘﻓﻭ ،ﺔﺟﺎﺤﻟﺍ ﺖﻋﺩ ﺍﺫﺇ ﺎﻨﭽﯿﺳﺎﺗ ﻝﻭﺎﻨﺗ ﺓﺩﻭﺎﻌﻤﺑ ﻙﺪﺷﺮﻳ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣﻭ .ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﺐﻴﺒﻄﻟﺍ ﺮﺸﺘﺳﺍ ،ﺀﺍﻭﺪﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ ﻝﻮﺣ ﺔﻴﻓﺎﺿﺇ ﺔﻠﺌﺳﺃ ﻚﻳﺪﻟ ﺕﺮﻓﻮﺗ ﺍﺫﺇ :ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ (٤ .ﻦﻴﻠﻤﻌﺘﺴﻤﻟﺍ ﺾﻌﺑ ﺪﻨﻋ ﺔﻴﺒﻧﺎﺟ

ﺎﺿﺍﺮﻋﺃ ﺐﺒﺴﻳ ﺪﻗ ﺎﻨﭽﯿﺳﺎﺗ ﻝﺎﻤﻌﺘﺳﺇ ﻥﺇ ،ﺀﺍﻭﺩ ﻞﻜﺑ ﺎﻤﻛ .ﺎﻬﻨﻣ

ﺎﻳﺃ ﻲﻧﺎﻌﺗ ﻻﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ .ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺔﻤﺋﺎﻗ ﻦﻣ ﺶﻫﺪﻨﺗ ﻻ ﺓﺪﻋ ﻰﺘﺣ ﻡﺎﻳﺃ ﺓﺪﻋ ﺪﻌﺑ ﺓﺩﺎﻋ ﻝﻭﺰﺗﻭ ،ﺔﻟﺪﺘﻌﻣ ﻰﺘﺣ ﺔﻔﻴﻔﻃ ﻲﻫ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺔﻴﺒﻟﺎﻏ ﻥﺇ .ﺝﻼﻌﻟﺍ ﺀﺪﺑ ﻦﻣ ﻊﻴﺑﺎﺳﺃ ﻲﻓ ﺐﻴﺒﻄﻟﺍ ﻰﻟﺇ ﻝﺎﺤﻟﺍ ﻲﻓ ﻪﺟﻮﺘﻟﺍ ﺐﺠﻳ .ﺓﺮﻴﻄﺧ ﻥﻮﻜﺗ ﺪﻗ ﺔﻨﻴﻌﻣ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ :ﺔﻴﻟﺎﺘﻟﺍ ﺕﻻﺎﺤﻟﺍ ﺔﻌﺋﺎﺷ ﺮﻴﻏ ،(ﻦﻴﺠﻟﺎﻌﺘﻣ ١٠ ﻦﻴﺑ ﻦﻣ ١ ﻰﺘﺣ ﻰﻠﻋ ﺮﺛﺆﺗ ﺪﻗ) ﺔﻌﺋﺎﺷ ﻲﻫ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻚﻠﺗ ﻦﻜﻤﻳ ﻻ) ﻑﻭﺮﻌﻣ ﺮﻴﻏ ﻉﻮﻴﺸﺑ ﺎﻬﻨﻋ ﻎﻠ

ﺑ ﻭﺃ (ﺞﻟﺎﻌﺘﻣ ١٠٠ ﻦﻴﺑ ﻦﻣ ١ ﻰﺘﺣ ﻰﻠﻋ ﺮﺛﺆﺗ ﺪﻗ) .(ﺓﺮﻓﻮﺘﻤﻟﺍ ﺕﺎﻣﻮﻠﻌﻤﻟﺍ ﻦﻣ ﻢﻴﻴﻘﺘﻟﺍ ﺕﺎﻣﻼﻋ) ﻪﺟﻮﻟﺍ ﻭﺃ ﻦﻴﻣﺪﻘﻟﺍ ﻲﺘﺣﺍﺭ ،ﻦﻴﻠﺣﺎﻜﻟﺍ ،ﻦﻳﺪﻴﻟﺍ ﺥﺎﻔﺘﻧﺇ ،ﻥﺯﻮﻟﺍ ﻲﻓ ﻊﻳﺮﺳ ﺩﺎﻳﺩﺯﺇ ∙ (ﺀﺎﻤﻟﺍ ﺱﺎﺒﺘﺣﻹ ﻥﺎﺴﻠﻟﺍ ،ﻦﻴﺘﻔﺸﻟﺍ ﻕﺎﻗﺭﺯﺇ ،ﺐﻠﻘﻟﺍ ﻢﻈﻧ ﻡﺎﻈﺘﻧﺇ ﻡﺪﻋ ،ﻊﻔﺗﺮﻣ ﻡﺩ ﻂﻐﺿ ،ﺭﺪﺼﻟﺍ ﻲﻓ ﻢﻟﺃ ∙ (ﺐﻠﻘﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﺪﻠﺠﻟﺍ ﻭﺃ ﻲﺘﺣﺍﺭﻭ ﻦﻴﻠﺟﺮﻟﺍ ﺥﺎﻔﺘﻧﺇ ،ﺔﻧﻮﺨﺳ ﻥﻭﺪﺑ ﻭﺃ ﻊﻣ ﺮﻴﻔﺻ ،ﻝﺎﻌﺳ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺔﺑﻮﻌﺻ ∙ (ﻦﻴﺘﺋﺮﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﻦﻴﻣﺪﻘﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﺓﺭﺮﻜﺘﻣ ﺕﺎﺛﻮﻠﺗ ،ﺔﻟﻮﻬﺴﺑ (ﺕﺎﻣﺪﻛ) ﺕﺎﺑﺎﺻﺇ ﺭﻮﻬﻇ ،ﺔﻧﻮﺨﺳ ∙ (ﻡﺪﻟﺍ ﺯﺎﻬﺟ ﻉﺎﻤﺳ ،ﺔﻳﺅﺭ ،ﺪﻳﺪﺷ ﻉﺍﺪﺻ ،ﻖﻄﻨﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ،ﻪﺟﻮﻟﺍ ﻭﺃ ﻑﺍﺮﻃﻷﺍ ﻞﻠﺷ ﻭﺃ ﻡﺎﻋ ﻒﻌﺿ

(ﻲﺒﺼﻌﻟﺍ ﺯﺎﻬﺠﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﺓﺩﻮﺟﻮﻣ ﺮﻴﻏ ﺀﺎﻴﺷﺄﺑ ﺭﻮﻌﺸﻟﺍ ﻭﺃ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﻝﻮﺒﻟﺍ ﺝﺎﺘﻧ ﺺﻗﺎﻨﺗ ،ﻦﻛﺍﺩ ﻝﻮﺑ ،ﻂﺨﺳ ،ﺪﻠﺠﻟﺍ ﻑﺎﻔﺟ ،ﺶﻄﻋ ∙ (ﻰﻠﻜﻟﺍ (ﻦﻴﻌﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﻦﻴﻨﻴﻌﻟﺍ ﻞﺧﺍﺩ ﻡﺩ ،ﺔﻳﺅﺮﻟﺍ ﻥﺍﺪﻘﻓ ،ﺔﻳﺅﺮﻟﺍ ﺵﻮﺸﺗ ∙ (ﺪﻳﺭﻮﻟﺍ ﻞﺧﺍﺩ ﺔﻳﻮﻣﺩ ﺓﺮﺜﺨﻟ ﺕﺎﻣﻼﻋ) ﻢﺴﺠﻟﺍ ﻦﻣ ﺓﺪﺣﺍﻭ ﺔﻘﻄﻨﻣ ﻲﻓ ﻢﻟﺃﻭ ﺥﺎﻔﺘﻧﺇ ∙ ﺕﺎﻣﻼﻋ) ﻦﻄﺒﻟﺍ ﻲﻓ ﺔﺨﻔﻧ ،ﻙﺎﺴﻣﺇ ،ﺩﻮﺳﺃ ﺯﺍﺮﺑ ،ﻱﻮﻣﺩ ﺆﻴﻘﺗ ،ﻥﺎﻴﺜﻏ ،ﻦﻄﺒﻟﺍ ﻲﻓ ﻡﻻﺁ ∙ (ﻲﻤﻀﻬﻟﺍ ﺯﺎﻬﺠﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ (ﺱﺎﻳﺮﻜﻨﺒﻟﺍ ﺏﺎﻬﺘﻟﻹ ﺔﻣﻼﻋ) ﻦﻄﺒﻟﺍ ﻰﻠﻋﺃ ﻲﻓ ﺪﻳﺪﺷ ﻢﻟﺃ ∙ ﺕﺎﻣﻼﻋ) ﻥﻮﻠﻟﺍ ﻦﻛﺍﺩ ﻝﻮﺑ ،ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﻥﺍﺪﻘﻓ ،ﻥﺎﻴﺜﻏ ،ﻦﻴﻨﻴﻌﻟﺍﻭ ﺪﻠﺠﻟﺍ ﺭﺍﺮﻔﺻﺇ ∙ (ﺪﺒﻜﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﺕﻼﻀﻌﻟﺍﻭ ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﻡﻻﺁ ،ﺀﺍﺮﻤﺣﻭ ﺔﻤﻟﺆﻣ ﺕﺎﻣﺪﻛ ،ﺢﻔﻃ ∙ (ﺪﻠﺠﻟﺍ ﻕﺎﻫﺭﺇ ،ﻥﺯﻮﻟﺍ ﺺﻗﺎﻨﺘﺑ ﻖﻓﺍﺮﺘﺗ ﻲﺘﻟﺍ ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﺓﺩﺎﻳﺯ ،ﻝﻮﺒﻟﺍ ﺝﺎﺘﻧ ﺓﺩﺎﻳﺯ ،ﺪﺋﺍﺯ ﺶﻄﻋ ∙ (ﻡﺪﻟﺍ ﻲﻓ ﺮﻜﺴﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﻹ ﺕﺎﻣﻼﻋ) ﺕﺎﻣﻼﻋ) ﻖﻨﻌﻟﺍ ﺔﻣﺪﻘﻣ ﺥﺎﻔﺘﻧﺇ ،ﻥﺯﻮﻟﺍ ﺺﻗﺎﻨﺗ ،ﻦﻴﻨﻴﻌﻟﺍ ﻅﻮﺤﺟ ،ﺐﻠﻘﻟﺍ ﺕﺎﺑﺮﺿ ﻉﺮﺴﺗ ∙

[thyroid]

ﺔﻴﻗﺭﺪﻟﺍ ﺓﺪﻐﻟﺍ ﻁﺎﺸﻧ ﻁﺮﻔﻟ ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﺝﺎﻋﺰﻧﺇ ﻭﺃ/ﻭ ﻕﺎﻫﺭﺇ ،ﺮﻜﻋ ﻝﻮﺑ ،ﺔﻤﻈﺘﻨﻣ ﺮﻴﻏ ﺐﻠﻗ ﺕﺎﺑﺮﺿ ،ﺲﻔﻨﺗ ﻖﻴﺿ ،ﻥﺎﻴﺜﻏ ∙ ﻝﻮﺒﻟﺍ ﺾﻤﺣ ،ﻡﻮﻴﺳﺎﺗﻮﭙﻟﺍ ﺐﺴﻧ ﻉﺎﻔﺗﺭﺇ ﻞﺜﻣ) ﺔﻤﻴﻠﺳ ﺮﻴﻏ ﺔﻳﺮﺒﺨﻣ ﺹﻮﺤﻔﺑ ﻖﻓﺍﺮﺘﻳ (ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﻴﺴﻟﺎﻜﻟﺍ ﺐﺴﻧ ﺺﻗﺎﻨﺗﻭ ﺭﻮﻔﺳﻮﻔﻟﺍﻭ ﺺﻗﺎﻨﺗ ﺀﺍﺮﺟ ﻥﻮﻜﺗ ﻥﺃ ﻦﻜﻤﻳ ﻲﺘﻟﺍ ﻦﻴﻠﺟﺮﻟﺍ ﻲﻓ ﺔﻴﻠﻀﻋ ﺕﺎﺼﻠﻘﺗ ﻭﺃ ﻒﻌﺿ ،ﺝﺎﻋﺰﻧﺇ ،ﻢﻟﺃ ∙ ﺕﺍﺮﻴﻐﺗﻭ

ﺍﺪﺑﺃ ﻰﻔﺸﺗ ﻻ ﻭﺃ ﺀﻂﺒﺑ ﻰﻔﺸﺗ ﻲﺘﻟﺍ ﻦﻳﺪﻴﻟﺍﻭ ﻦﻴﻠﺟﺮﻟﺍ ﻲﻓ ﺕﺎﺣﺮﻘﺗ ،ﻡﺪﻟﺍ ﻥﺎﻳﺮﺟ ﻩﺬﻫ ﻥﻷ ﻦﻳﺪﻴﻟﺍﻭ ﻦﻴﻠﺟﺮﻟﺍ (ﺓﺩﻭﺮﺑ) ﺓﺭﺍﺮﺣ ﺔﺟﺭﺩ ﻲﻓ ﻭﺃ (ﺏﻮﺤﺷ ﻭﺃ ﻕﺎﻗﺭﺯﺇ) ﻥﻮﻟ ﻲﻓ ﺔﺤﺿﺍﻭ ﻲﻓﻭ (ﺪﻳ ﻭﺃ ﻞﺟﺭ) ﺮﺛﺄﺘﻤﻟﺍ ﻑﺮﻄﻟﺍ ﻲﻓ ﻥﺎﻳﺮﺷ ﺩﺍﺪﺴﻧﻹ ﺕﺎﻣﻼﻋ ﻥﻮﻜﺗ ﻥﺃ ﻦﻜﻤﻳ ﺽﺍﺮﻋﻷﺍ .(ﻦﻳﺪﻴﻟﺍ ﻊﺑﺎﺻﺃﻭ ﻦﻴﻠﺟﺮﻟﺍ ﻊﺑﺎﺻﺃ) ﻊﺑﺎﺻﻷﺍ ﻲﻓ ﺖﻴﻧﺎﻋ ﺍﺫﺇ (

ﺪﺒﻜﻟﺍ ﺏﺎﻬﺘﻟﺇ)

ﻲﺳﻭﺮﻴﭭﻟﺍ ﺪﺒﻜﻟﺍ ﺏﺎﻬﺘﻟﺇ (ﻂﻴﺸﻨﺗ ﺓﺩﺎﻋﺇ) ﺓﺩﻮﻋ

ﺪﺒﻜﻟﺍ ﺏﺎﻬﺘﻟﺇ)

ﻲﺳﻭﺮﻴﭭﻟﺍ ﺪﺒﻜﻟﺍ ﺏﺎﻬﺘﻟﺇ ﻦﻣ ﻲﺿﺎﻤﻟﺍ .ﻱﺭﻮﻓ ﻞﻜﺸﺑ ﺐﻴﺒﻄﻟﺍ ﻎﻠﺑ ،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻚﻠﺗ ﻯﺪﺣﺇ ﻦﻣ ﻚﺗﺎﻧﺎﻌﻣ ﻝﺎﺣ ﻲﻓ :ﺔﻴﻓﺎﺿﺇ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ؛ﻝﺎﻬﺳﺇ :(ﻦﻴﺠﻟﺎﻌﺘﻣ ١٠ ﻦﻴﺑ ﻦﻣ ١ ﻦﻣ ﺮﺜﻛﺃ ﻰﻠﻋ ﺮﺛﺆﺗ ﺪﻗ) ﹰ ﺍﺪﺟ ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻴﺑﻭﺮﻴﻠﻴﺒﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ ؛ﺮﻌﺸﻟﺍ ﻂﻗﺎﺴﺗ ؛ﺆﻴﻘﺗ ؛ﻥﺎﻴﺜﻏ ،ﺢﻔﻃ ،ﺔﻜﺣ ؛ﺔﻴﻠﻀﻋ ﻡﻻﺁ ؛ﻕﺎﻫﺭﺇ ؛ﻉﺍﺪﺻ ﻡﻻﺁ ؛(ﺱﺎﻳﺮﻜﻨﺒﻠﻟ ﻲﻔﻴﻇﻮﻟﺍ ﺀﺍﺩﻷﺍ) ﺯﺎﭙﯿﻠﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ ؛(ﺪﺒﻜﻠﻟ ﻲﻔﻴﻇﻮﻟﺍ ﺀﺍﺩﻷﺍ) ﻡﺪﻟﺍ ﻲﻓ ﻡﺎﻈﻌﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﻡﻻﺁ ،ﻑﺍﺮﻃﻷﺍ ﻲﻓ ﻡﻻﺁ ،ﺔﻴﻠﻜﻴﻬﻟﺍ ﺕﻼﻀﻌﻟﺍ ﻲﻓ ﻡﻻﺁ ،ﺔﻴﻠﻀﻋ .ﺎﻨﭽﯿﺳﺎﺗ ـﺑ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺪﻨﻋ ﺮﻬﻈﻟﺍ ﻲﻓ ﻡﻻﺁﻭ .ﻚﺒﻴﺒﻃ ﻎﻠﺑ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻚﻴﻠﻋ ﺮﺛﺆﺗ

ﺎﻔﻧﺁ ﺕﺮﻛﺫ ﻲﺘﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻧﺎﻛ ﺍﺫﺇ ؛(

urticaria

) ﻯﺮﺷ :(ﻦﻴﺠﻟﺎﻌﺘﻣ ١٠ ﻦﻴﺑ ﻦﻣ ١ ﻰﺘﺣ ﻰﻠﻋ ﺮﺛﺆﺗ ﺪﻗ) ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻭﺃ ﺔﺨﻔﻧ ،ﺕﺍﺯﺎﻏ ،ﻡﺎﻌﻄﻟﺍ ﺕﺎﺒﺟﻭ ﺪﻌﺑ ﺓﺪﻌﻤﻟﺍ ﻲﻓ ﺝﺎﻋﺰﻧﺈﺑ ﺭﻮﻌﺸﻟﺍ ،ﻦﻄﺒﻟﺍ ﻲﻓ ﺝﺎﻋﺰﻧﺇ ﻲﻓ ﻢﻟﺃ ﻞﻤﺸﻳ ﻢﻟﺃ ؛ﺔﻴﻠﻀﻋ ﺕﺎﺼﻠﻘﺗ ،ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﻡﺎﻈﻌﻟﺍ ﻲﻓ ﻢﻟﺃ ؛ﻦﻄﺒﻟﺍ ﺥﺎﻔﺘﻧﺇ ،ﺥﺎﻔﺘﻧﺇ ؛ﻦﻴﻌﻟﺍ ﺞﻴﻬﺗ ؛ﻢﺴﺠﻟﺍ ﺐﻧﺎﺟ ﻲﻓ ﺝﺎﻋﺰﻧﺇ ﻭﺃ ﻢﻟﺃ ،ﻑﺍﺮﻃﻷﺍ ﻲﻓ ﻢﻟﺃﻭ ﻖﻨﻌﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﺮﻬﻈﻟﺍ ﻑﺎﻔﺟ ،ﺪﻠﺠﻟﺍ ﺭﺍﺮﻤﺣﺇ ؛(ﻦﻴﻌﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﻦﻴﻨﻴﻌﻟﺍ ﻑﺎﻔﺟ ،ﺭﺍﺮﻤﺣﺇ ﻭﺃ ﺔﻜﺣ ،ﺯﺍﺮﻓﺇ ﻥﺍﺪﻘﻓ ،ﻥﺯﻮﻟﺍ ﺺﻗﺎﻨﺗ ﻭﺃ ﺓﺩﺎﻳﺯ ؛ﺪﻠﺠﻟﺍ ﺔﻴﺳﺎﺴﺣ ﺺﻗﺎﻨﺗ ،ﺪﻠﺠﻟﺍ ﻲﻓ ﻞﻴﻟﺂﺛ ،ﺏﺎﺒﺸﻟﺍ ﺐﺣ ،ﺪﻠﺠﻟﺍ ﺕﺎﺒﻫ ،ﺪﺋﺍﺯ ﻕﺮﻌﺗ ،ﻲﻠﻴﻟ ﻕﺮﻌﺗ ؛ﻖﻠﻗ ،ﺏﺎﺌﺘﻛﺇ ؛ﻕﺭﺃ ؛ﻕﺍﺬﻤﻟﺍ ﺔﺳﺎﺣ ﻲﻓ ﺏﺍﺮﻄﺿﺇ ،ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ؛ﻑﺎﻋﺭ ؛ﺕﻮﺼﻟﺍ ﻲﻓ ﺏﺍﺮﻄﺿﺇ ؛ﺭﺪﺧ ﻭﺃ ﺰﺧﻭ ؛ﺔﺧﻭﺪﺑ ﺭﻮﻌﺸﻟﺍ ،ﺪﻴﺟ ﺮﻴﻏ ﻡﺎﻋ ﺭﻮﻌﺷ ،ﺭﺍﻭﺩ ؛ﺮﺤﻟﺍ .ﺐﻠﻘﻠﻟ ﺔﻌﻳﺮﺳ ﺕﺎﺑﺮﺿ ؛ﻝﻮﺒﺘﻟﺍ ﺭﺍﺮﻜﺗ .ﻚﺒﻴﺒﻃ ﻎﻠﺑ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻚﻴﻠﻋ ﺮﺛﺆﺗ

ﺎﻔﻧﺁ ﺕﺮﻛﺫ ﻲﺘﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻧﺎﻛ ﺍﺫﺇ ﺔﻴﺳﺎﺴﺣ ﺓﺩﺎﻳﺯ :(ﺞﻟﺎﻌﺘﻣ ١٠٠ ﻦﻴﺑ ﻦﻣ ١ ﻰﺘﺣ ﻰﻠﻋ ﺮﺛﺆﺗ ﺪﻗ) ﺔﻌﺋﺎﺷ ﺮﻴﻏ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻲﻓ ﺕﺎﺣﺮﻘﺗ ،ﺓﺮﺠﻨﺤﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﻢﻔﻟﺍ ﻑﺎﻔﺟ ؛ﻦﻴﻨﻔﺠﻟﺍ ﺥﺎﻔﺘﻧﺇ ؛ﺪﻠﺠﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﺪﻠﺠﻟﺍ ﻢﻟﺃﻭ ﺔﺑﻮﻌﺻ ؛ﺀﺎﻐﺻﻹﺍ ﻲﻓ ﺏﺍﺮﻄﺿﺇ ؛ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﺓﺩﺎﻳﺯ ؛ﻦﻴﻳﺪﺜﻟﺍ ﻲﻓ ﻡﻻﺁ ؛ﻥﺎﻗﺮﺣ ؛ﻢﻔﻟﺍ ﻰﻠﻋ ﻅﺎﻔﺤﻟﺍ ﻭﺃ ﻖﻴﻘﺤﺗ ﻰﻠﻋ ﺓﺭﺪﻘﻟﺍ ﻡﺪﻋ ؛ﻝﻮﺒﺘﻠﻟ ﺔﺟﺎﺤﻟﺎﺑ ﻪﻴﻓ ﻎﻟﺎﺒﻣ ﺭﻮﻌﺷ ،ﻝﻮﺒﺘﻟﺍ ﺀﺎﻨﺛﺃ ﻒﻌﺿ ،ﺍﺰﻧﺇﻮﻠﻔﻧﻹﺍ ﻪﺒﺸﺗ ﺽﺍﺮﻋﺃ ؛ﻝﺎﺟﺮﻟﺍ ﻯﺪﻟ ﺭﺪﺼﻟﺍ ﻢﺨﻀﺗ ؛ﻲﻠﺳﺎﻨﺘﻟﺍ ﺐﻴﻀﻘﻟﺍ ﺏﺎﺼﺘﻧﺇ ﺔﻴﺳﺎﺴﺣ ،ﺆﻴﻘﺗ ،ﻥﺎﻴﺜﻐﺑ

ﺎﻧﺎﻴﺣﺃ ﻖﻓﺍﺮﺘﻳ ﺪﻳﺪﺷ ﻉﺍﺪﺻ ؛ﺔﻳﺅﺮﻟﺍ ﺓﺪﺣ ﺺﻗﺎﻨﺗ ؛ﺔﻔﺟﺭ ؛ﺕﻼﻀﻌﻟﺍ ؛ﺕﻼﻀﻌﻟﺍﻭ ﻞﺻﺎﻔﻤﻟﺍ ﺐﻠﺼﺗ ؛ﻢﻔﻟﺍ ﻭﺃ ﻞﺒﻬﻤﻟﺍ ﻲﻓ ﻱﺮﻄﻓ ﺙﻮﻠﺗ ؛ﺔﻳﺅﺮﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﺇ ؛ﺀﻮﻀﻠﻟ ﺭﻮﻌﺸﻟﺍ ،ﺔﻧﻮﺨﺴﺑ ﺭﻮﻌﺸﻟﺍ ﻞﻤﺸﻳ) ﺮﻴﻐﺘﺗ ﻢﺴﺠﻟﺍ ﺓﺭﺍﺮﺣ ﻥﺄﺑ ﺭﻮﻌﺸﻟﺍ ؛ﻥﺯﻮﻟﺍ ﺓﺩﺎﻳﺯ ؛ﻲﻋﻮﻟﺍ ﻥﺍﺪﻘﻓ .ﻥﺎﻨﺳﻷﺍ ﺔﻴﺳﺎﺴﺣ ؛(ﺔﻴﻓﺪﺼﻟﺍ ﺀﺍﺪﻟ ﺕﺎﻣﻼﻋ) ﻲﻀﻓ/ﺮﻤﺣﺃ ﺪﻠﺟ ﻦﻣ ﺔﻜﻴﻤﺳ ﻊﻘﺑ ؛(ﺓﺩﻭﺮﺒﺑ .ﻚﺒﻴﺒﻃ ﻎﻠﺑ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻚﻴﻠﻋ ﺮﺛﺆﺗ

ﺎﻔﻧﺁ ﺕﺮﻛﺫ ﻲﺘﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻧﺎﻛ ﺍﺫﺇ ﻦﻣ ﻢﻴﻴﻘﺘﻟﺍ ﻦﻜﻤﻳ ﻻ) ﻑﻭﺮﻌﻣ ﺮﻴﻏ ﻉﻮﻴﺸﺑ ﺔﻴﻟﺎﺘﻟﺍ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺙﻭﺪﺣ ﻦﻋ ﻎﻠ

،ﺔﻴﺴﻔﻨﻟﺍ ﺔﻟﺎﺤﻟﺍ ﺭﺍﺮﻘﺘﺳﺇ ﻡﺪﻋ ،ﺓﺮﻛﺍﺬﻟﺍ ﻥﺍﺪﻘﻓ ،ﺀﻼﺨﻟﺍ ﻥﺎﻫﻮﺗ ،ﻙﺎﺒﺗﺭﺇ :(ﺓﺮﻓﻮﺘﻤﻟﺍ ﺕﺎﻣﻮﻠﻌﻤﻟﺍ ،ﺪﻠﺠﻟﺍ ﻖﻗﺮﺗ ،ﻲﻨﻫﺩ ﺪﻠﺟ ،ﺪﻠﺠﻟﺍ ﻲﻓ ﺔﺴﻴﻛ ،ﺕﻼﺼﻳﻮﺣ ؛ﺪﻠﺠﻟﺍ ﻲﻓ ﻲﻣﻮﺛﺮﺟ ﺙﻮﻠﺗ ؛ﺔﻳﻮﻴﺤﻟﺍ ﺔﻠﻗ ﺩﺍﺪﺴﻧﺇ ﻭﺃ ﺢﺷﺭ ؛ﺔﺜﻠﻟﺍ ﻢﺨﻀﺗ ﻭﺃ ﺔﻴﺳﺎﺴﺣ ،ﻑﺰﻧ ؛ﺪﻠﺠﻟﺍ ﻥﻮﻟ ﺮﻴﻐﺗ ،ﺪﻠﺠﻟﺍ ﻰﻠﻋ ﺔﻨﻛﺍﺩ ﻊﻘﺑ ﻦﻴﻣﺪﻘﻟﺍﻭ ﻦﻳﺪﻴﻟﺍ ﻲﺘﺣﺍﺭ ﻲﻓ ﺮﺸﻘﺗ ﺙﺪﺤﻳ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣﻭ ﺥﺎﻔﺘﻧﺇ ﻭﺃ/ﻭ ﺭﺍﺮﻤﺣﺇ ؛ﺱﺎﻄﻋ ؛ﻒﻧﻷﺍ ﺭﺍﺮﻤﺣﺇ ﻭﺃ ﻢﻟﺃ ؛ﺀﻮﻀﻠﻟ ﺪﻠﺠﻟﺍ ﻭﺃ ﻦﻴﻨﻴﻌﻟﺍ ﺔﻴﺳﺎﺴﺣ ﺓﺩﺎﻳﺯ ؛(

hand-foot

ﺔﻣﺯﻼﺘﻣ ﻰﻤﺴﺗ) (ﻦﻴﻨﻃ) ﺞﻴﺠﺿ ،ﻦﻴﻧﺫﻷﺍ ﻲﻓ ﻢﻟﺃ ،ﻊﻤﺴﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ؛ﻦﻴﻨﻔﺠﻟﺍ ﻲﻓ ﺔﻜﺣ ،ﻢﻟﺃ ،ﻦﻴﻌﻟﺍ ﻢﻜﺤﺘﻟﺍ ﻡﺪﻋ ،ﻝﻮﺒﻟﺍ ﻲﻓ ﻡﺩ ؛(

gout

ﺱﺮﻘﻨﻟﺍ ﺀﺍﺩ) ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﻢﻟﺃﻭ ﺥﺎﻔﺘﻧﺇ ؛ﻦﻴﻧﺫﻷﺍ ﻲﻓ ،ﻦﻴﺘﻤﻠﺤﻟﺍ ﺥﺎﻔﺘﻧﺇ ،ﻦﻴﻳﺪﺜﻟﺍ ﻲﻓ ﺓﻭﺎﺴﻘﺑ ﺭﻮﻌﺸﻟﺍ ؛ﺮﻴﺳﺍﻮﺑ ؛ﻝﻮﺒﻠﻟ ﻱﺩﺎﻋ ﺮﻴﻏ ﻥﻮﻟ ،ﻝﻮﺒﺘﻟﺍ ﻰﻠﻋ ،ﻢﺴﺠﻟﺍ ﻦﻣ ﺪﺣﺍﻭ ﺀﺰﺟ ﻚﻳﺮﺤﺗ ﻲﻓ ﺔﺒﻏﺮﻟﺍ) ﻦﻴﻗﺎﺴﻟﺍ ﻞﻤﻠﻤﺘﻟ ﺽﺍﺮﻋﺃ ؛ﺓﺪﻳﺪﺷ ﺔﻴﺜﻤﻃ ﺕﺍﺭﻭﺩ .(ﺝﺎﻋﺰﻧﻹﺎﺑ ﺭﻮﻌﺸﻟﺍ ﻑﺎﻘﻳﺇ ﻞﺟﺃ ﻦﻣ ﻚﻟﺫﻭ ،ﺓﺩﺎﻋ ﻞﺟﺮﻟﺍ .ﺐﻴﺒﻄﻟﺍ ﻡﻼﻋﺇ ﻚﻴﻠﻋ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻚﻴﻠﻋ ﺮﺛﺆﺗ

ﺎﻔﻧﺁ ﺕﺮﻛﺫ ﻲﺘﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻧﺎﻛ ﺍﺫﺇ ﻞﺜﻣ ﺔﻤﻴﻠﺳ ﺮﻴﻏ ﻚﻳﺪﻟ ﻡﺪﻟﺍ ﺹﻮﺤﻓ ﺞﺋﺎﺘﻧ ﻥﻮﻜﺗ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ ،ﺎﻨﭽﯿﺳﺎﺗ ـﺑ ﺝﻼﻌﻟﺍ ﺓﺮﺘﻓ ﻝﻼﺧ ،(ﺔﻳﻮﻣﺪﻟﺍ ﺕﺎﺤﻴﻔﺼﻟﺍ ،ﺀﺍﺮﻤﺤﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺧ ،ﺀﺎﻀﻴﺒﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺧ) ﻡﺪﻟﺍ ﺎﻳﻼﺧ ﻯﻮﺘﺴﻣ ﺽﺎﻔﺨﻧﺇ ﻦﻴﺑﻭﺮﻴﻠﻴﺒﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ ،(ﺱﺎﻳﺮﻜﻨﺒﻠﻟ ﻲﻔﻴﻇﻮﻟﺍ ﺀﺍﺩﻷﺍ) ﻡﺪﻟﺍ ﻲﻓ ﺯﻼﻴﻣﻷﺍ ﻭﺃ ﺯﺎﭙﯿﻠﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ ،(ﻰﻠﻜﻠﻟ ﻲﻔﻴﻇﻮﻟﺍ ﺀﺍﺩﻷﺍ) ﻡﺪﻟﺍ ﻲﻓ ﻦﻴﻨﻴﺗﺎﻳﺮﻜﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ ،(ﺪﺒﻜﻠﻟ ﻲﻔﻴﻇﻮﻟﺍ ﺀﺍﺩﻷﺍ) ﻡﺪﻟﺍ ﻲﻓ ﺽﺎﻔﺨﻧﺇ ،(ﻡﺪﻟﺍ ﻲﻓ ﺮﻜﺴﻟﺍ ﺐﺴﻧ ﻢﻈﻨﻳ ﻥﻮﻣﺭﻮﻫ) ﻡﺪﻟﺍ ﻲﻓ ﻦﻴﻟﻮﺴﻧﻹﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ ﻭﺃ ﺽﺎﻔﺨﻧﺇ .ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﺤﺸﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ ،ﻡﺪﻟﺍ ﻲﻓ ﺮﻜﺴﻟﺍ ﺔﺒﺴﻧ ﻉﺎﻔﺗﺭﺇ ﻭﺃ .ﻚﺒﻴﺒﻃ ﺓﺭﻮﺸﻤﺑ ﺪﻴﻘﺘﻓ ،ﻚﻴﻠﻋ ﺮﺛﺆﺗ

ﺎﻔﻧﺁ ﺕﺮﻛﺫ ﻲﺘﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻧﺎﻛ ﺍﺫﺇ ﺽﺮﻋ ﻦﻣ ﻲﻧﺎﻌﺗ ﺎﻣﺪﻨﻋ ﻭﺃ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻤﻗﺎﻔﺗ ﺍﺫﺇ ،ﻲﺒﻧﺎﺟ ﺽﺮﻋ ﺮﻬﻇ ﺍﺫﺇ .ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﻚﻴﻠﻋ ،ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﻲﻓ ﺮﻛﺬﻳ ﻢﻟ ﻲﺒﻧﺎﺟ ﻦﻋ ﻎﻴﻠﺒﺗ» ﻂﺑﺍﺮﻟﺍ ﻰﻠﻋ ﻂﻐﻀﻟﺍ ﺔﻄﺳﺍﻮﺑ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻮﻟ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻋ ﻎﻴﻠﺒﺘﻟﺍ ﻥﺎﻜﻣﻹﺎﺑ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻊﻗﻮﻤﻟ ﺔﻴﺴﻴﺋﺮﻟﺍ ﺔﺤﻔﺼﻟﺍ ﻰﻠﻋ ﺩﻮﺟﻮﻤﻟﺍ «ﻲﺋﺍﻭﺩ ﺝﻼﻋ ﺐﻘﻋ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ،ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻋ ﻎﻴﻠﺒﺘﻠﻟ ﺮﺷﺎﺒﻤﻟﺍ ﺝﺫﻮﻤﻨﻟﺍ ﻰﻟﺇ ﻚﻬﺟﻮﻳ ﻱﺬﻟﺍ

(www.health.gov.il

:ﻂﺑﺍﺮﻟﺍ ﺢﻔﺼﺗ ﻖﻳﺮﻃ ﻦﻋ ﻭﺃ ؟ﺀﺍﻭﺪﻟﺍ ﻦﻳﺰﺨﺗ ﺔﻴﻔﻴﻛ (٥ ﻱﺪﻳﺃ ﻝﻭﺎﻨﺘﻣ ﻦﻋ

ﺍﺪﻴﻌﺑ ﻖﻠﻐﻣ ﻥﺎﻜﻣ ﻲﻓ ﺮﺧﺁ ﺀﺍﻭﺩ ﻞﻛﻭ ﺀﺍﻭﺪﻟﺍ ﺍﺬﻫ ﻆﻔﺣ ﺐﺠﻳ !ﻢﻤﺴﺘﻟﺍ ﺐﻨﺠﺗ ﺔﺤﻳﺮﺻ ﺕﺎﻤﻴﻠﻌﺗ ﻥﻭﺪﺑ ﺆﻴﻘﺘﻟﺍ ﺐﺒﺴﺗ ﻻ .ﻢﻤﺴﺘﻟﺎﺑ ﻢﻬﺘﺑﺎﺻﺇ ﻱﺩﺎﻔﺘﻟ ﻚﻟﺫﻭ ،ﻊﺿﺮﻟﺍ ﻭﺃ/ﻭ ﻝﺎﻔﻃﻷﺍ ﺮﻬﻈﻳ ﻱﺬﻟﺍ (

exp.date

) ﺔﻴﺣﻼﺼﻟﺍ ﺦﻳﺭﺎﺗ ﺀﺎﻀﻘﻧﺇ ﺪﻌﺑ ﺀﺍﻭﺪﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ ﺯﻮﺠﻳ ﻻ .ﺐﻴﺒﻄﻟﺍ ﻦﻣ .ﺮﻬﺸﻟﺍ ﺲﻔﻧ ﻦﻣ ﺮﻴﺧﻷﺍ ﻡﻮﻴﻟﺍ ﻰﻟﺇ ﺔﻴﺣﻼﺼﻟﺍ ﺦﻳﺭﺎﺗ ﺮﻴﺸﻳ .ﺔﺒﻠﻌﻟﺍ ﺮﻬﻇ ﻰﻠﻋ .ﺔﻳﻮﺌﻣ ﺔﺟﺭﺩ ٣٠ ﻦﻋ ﺪﻳﺰﺗ ﺓﺭﺍﺮﺣ ﺔﺟﺭﺪﺑ ﻦﻳﺰﺨﺘﻟﺍ ﺯﻮﺠﻳ ﻻ ،ﺔﺑﻮﻄﻌﻣ ﺔﺒﻠﻋ ﻝﺎﻤﻌﺘﺳﺇ ﺯﻮﺠﻳ ﻻ .ﺔﺑﻮﻃﺮﻟﺍ ﻦﻣ ﻪﺘﻳﺎﻤﺤﻟ ﻚﻟﺫﻭ ،ﺔﻴﻠﺻﻷﺍ ﺔﺒﻠﻌﻟﺍ ﻲﻓ ﻦﻳﺰﺨﺘﻟﺍ ﺐﺠﻳ .ﻝﺎﻔﻃﻷﺍ ﺔﻳﺅﺭ ﻝﺎﺠﻣﻭ ﻱﺪﻳﺃ ﻝﻭﺎﻨﺘﻣ ﻦﻋ

ﺍﺪﻴﻌﺑ ﻆﻔﺤﻟﺍ ﺐﺠﻳ .ﺭﺮﻀﻟ ﺕﺎﻣﻼﻋ ﺎﻬﻴﻠﻋ ﻭﺃ :ﺔﻴﻓﺎﺿﺇ ﺕﺎﻣﻮﻠﻌﻣ (٦

ﺎﻀﻳﺃ ﺔﻟﺎﻌﻔﻟﺍ ﺓﺩﺎﻤﻠﻟ ﺔﻓﺎﺿﻹﺎﺑ ﺀﺍﻭﺪﻟﺍ ﻱﻮﺘﺤﻳ .ﺕﺍﺭﺪﻴﻫﻮﻧﻮﻣ ﺯﻮﺘﻜﻟ ﻎﻠﻣ ١١٧ ﻲﻟﺍﻮﺣ ﻰﻠﻋ ﻎﻠﻣ ١٥٠ ﺎﻨﭽﯿﺳﺎﺗ ﻦﻣ ﺔﻟﻮﺴﺒﻛ ﻞﻛ ﻱﻮﺘﺤﺗ .ﺕﺍﺭﺪﻴﻫﻮﻧﻮﻣ ﺯﻮﺘﻜﻟ ﻎﻠﻣ ١٥٦ ﻲﻟﺍﻮﺣ ﻰﻠﻋ ﻎﻠﻣ ٢٠٠ ﺎﻨﭽﯿﺳﺎﺗ ﻦﻣ ﺔﻟﻮﺴﺒﻛ ﻞﻛ ﻱﻮﺘﺤﺗ ﻎﻠﻣ ١٥٠ ﺎﻨﭽﯿﺳﺎﺗ ﻦﻣ ﺔﻳﺮﻬﺸﻟﺍ ﺔﺒﻠﻌﻟﺍ ﻱﻮﺘﺤﺗ :ﺔﺒﻠﻌﻟﺍ ﻯﻮﺘﺤﻣ ﻮﻫ ﺎﻣﻭ ﺀﺍﻭﺪﻟﺍ ﻭﺪﺒﻳ ﻒﻴﻛ .ﺔﻴﻋﻮﺒﺳﺃ ﺐﻠﻋ ٤ ﻰﻠﻋ ﻱﻮﺘﺤﺗ ﺔﻳﺮﻬﺸﻟﺍ ﺔﺒﻠﻌﻟﺍ .ﺔﻟﻮﺴﺒﻛ ١١٢ ﻰﻠﻋ ﺔﻳﺮﻬﺸﻟﺍ ﺔﺒﻠﻌﻟﺍ ﻱﻮﺘﺤﺗﻭ ﺔﻟﻮﺴﺒﻛ ٤٠ ﻰﻠﻋ ﻎﻠﻣ ٢٠٠ ﺎﻨﭽﯿﺳﺎﺗ ﻦﻣ ﻡﺎﻳﺃ ١٠ ـﻟ ﺔﺒﻠﻌﻟﺍ ﻱﻮﺘﺤﺗ .ﻡﺎﻳﺃ ١٠ ـﻟ ﺐﻠﻋ ٣ ﻰﻠﻋ ﻱﻮﺘﺤﺗ ﺔﻳﺮﻬﺸﻟﺍ ﺔﺒﻠﻌﻟﺍ .ﺔﻟﻮﺴﺒﻛ ١٢٠ ﻰﻠﻋ ﻥﻮﻟ ﺕﺍﺫ ﺔﻤﺗﺎﻗ ﺕﻻﻮﺴﺒﻛ ﻦﻤﺿ ﺮﻔﺻﻸﻟ ﻞﺋﺎﻣ ﺾﻴﺑﺃ ﻕﻮﺤﺴﻣ :ﻎﻠﻣ ١٥٠ ﺎﻨﭽﯿﺳﺎﺗ ﺕﻻﻮﺴﺒﻛ

NVR»/«BCR

» ﺭﻮﺤﻤﻟﺍ ﻰﻠﻋ ﺩﻮﺳﻷﺎﺑ ﺔﻋﺎﺒﻃ ﺎﻬﻴﻠﻋﻭ

ﻢﺠﺤﺑ ،ﺮﻤﺣﺃ ﻥﻮﻟ ﺕﺍﺫ ﺔﻤﺗﺎﻗ ﺕﻻﻮﺴﺒﻛ ﻦﻤﺿ ﺮﻔﺻﻸﻟ ﻞﺋﺎﻣ ﺾﻴﺑﺃ ﻕﻮﺤﺴﻣ :ﻎﻠﻣ ٢٠٠ ﺎﻨﭽﯿﺳﺎﺗ ﺕﻻﻮﺴﺒﻛ

NVR»/«TKI

» ﺭﻮﺤﻤﻟﺍ ﻰﻠﻋ ﺮﻤﺣﻷﺎﺑ ﺔﻋﺎﺒﻃ ﺎﻬﻴﻠﻋﻭ

ﻢﺠﺤﺑ ،ﺢﺗﺎﻓ ﺮﻔﺻﺃ .ﺎﭭﻜﺗ ـ ﺢﺘﻴﭘ ،٣٦ ﻡﺎﺣﺎﺷ ﻉﺭﺎﺷ ،.ﺽ.ﻡ ﻞﻴﺋﺍﺮﺳﺇ ﺲﻴﺗﺭﺎﭬﻮﻧ :ﻪﻧﺍﻮﻨﻋﻭ ﺯﺎﻴﺘﻣﻹﺍ ﺐﺣﺎﺻ ﻞﺟﺃ ﻦﻣ ﺍﺮﺴﻳﻮﺳ ،ﻦﻳﺎﻄﺷ ،ﻲﺟ ﻲﻳﺍ ﻦﻳﺎﻄﺷ ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ :ﻪﻧﺍﻮﻨﻋﻭ ﺞﺘﻨﻤﻟﺍ ﻢﺳﺇ .ﺍﺮﺴﻳﻮﺳ ،ﻝﺯﺎﺑ ،ﻲﺟ ﻲﻳﺍ ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ .٢٠١٨ ﻝﻮﻠﻳﺃ:ﺦﻳﺭﺎﺗ ﻲﻓ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻞﺒﻗ ﻦﻣ ﺖﺼﺧ

ﺭﻭ ﺖﺼﺤ

ﻓ ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ :ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻲﻓ ﻲﻣﻮﻜﺤﻟﺍ ﺔﻳﻭﺩﻷﺍ ﻞﺠﺳ ﻲﻓ ﺀﺍﻭﺪﻟﺍ ﻞﺠﺳ ﻢﻗﺭ ١٤٥ ٨٤ ٣٣٢٧١ :ﻎﻠﻣ١٥٠ ﺎﻨﭽﯿﺳﺎﺗ ١٣٨ ١٧ ٣١٦٨١ :ﻎﻠﻣ٢٠٠ ﺎﻨﭽﯿﺳﺎﺗ ﻦﻣ ﻢﻏﺮﻟﺍ ﻰﻠﻋ .ﺮﻛﺬﻤﻟﺍ ﺔﻐﻴﺼﺑ ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﺔﻏﺎﻴﺻ ﺖﻤﺗ ،ﺓﺀﺍﺮﻘﻟﺍ ﻦﻳﻮﻬﺗﻭ ﺔﻟﻮﻬﺳ ﻞﺟﺃ ﻦﻣ .ﻦﻴﺴﻨﺠﻟﺍ ﻼﻜﻟ ﺺﺼﺨﻣ ﺀﺍﻭﺪﻟﺍ ﻥﺈﻓ ،ﻚﻟﺫ

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?form

Type=AdversEffectMedic@moh.gov.il

Lactose monohydrate, Crospovidone, Poloxamer 188, Silica colloidal,

anhydrous/Colloidal silicon dioxide, Magnesium stearate.

Tasigna 150 mg capsule shell: Gelatin, Titanium dioxide (E171), Iron oxide

yellow (E172), Iron oxide red (E172) and Printing ink: black.

Qualitative composition of printing ink: Shellac, Iron oxide black, n-butyl

alcohol, purified water, propylene glycol, dehydrated ethanol, isopropyl

alcohol, ammonium hydroxide.

Tasigna 200 mg capsule shell: Gelatin, Titanium dioxide (E171), Iron

oxide yellow (E172), Printing ink: red.

Qualitative composition of printing ink a: Shellac, dehydrated alcohol,

isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution,

Iron oxide red (E172), potassium hydroxide, purified water.

Qualitative composition of printing ink b: Shellac, Iron oxide red (E172), Iron

oxide black (E172), n-butyl alcohol, purified water, titanium dioxide (E171),

propylene glycol, industrial methylated spirit, isopropyl alcohol.

The printing ink used is ‘Printing ink a’ or alternatively ‘Printing ink b’.

TAS API SEP18 V11 CL EU SmPC 11.2017

The format of this leaflet was determined by the Ministry of Health and its content was checked

and approved by it in September 2018.

1.

NAME OF THE MEDICINAL PRODUCT

Tasigna 150mg capsules

Tasigna 200 mg capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Tasigna 150mg capsules

One capsule contains 150 mg nilotinib (as hydrochloride monohydrate).

Excipient with known effect

One capsule contains 117.08 mg lactose monohydrate.

Tasigna 200mg capsules

One capsule contains 200 mg nilotinib (as hydrochloride monohydrate).

Excipient with known effect

One capsule contains 156.11 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsule

Tasigna 150mg capsules

White to yellowish powder in red opaque capsules, size 1 with black axial imprint “NVR/BCR”.

Tasigna 200mg capsules

White to yellowish powder in light yellow opaque capsules, size 0 with red axial imprint “NVR/TKI”.

TAS API SEP18 V11 CL EU SmPC 11.2017

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Tasigna 150mg and 200mg are indicated for the treatment of adult patients with newly diagnosed

Philadelphia chromosome positive chronic myeloid leukaemia (CML) in the chronic phase.

Tasigna 200mg

only

is indicated also for the treatment of Philadelphia chromosome positive chronic

myeloid leukaemia (Ph+CML) in chronic phase or accelerated phase in patients resistant to or

experiencing significant toxicity during treatment with imatinib.

4.2

Posology and method of administration

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients

with CML.

Posology

Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity

occurs.

If a dose is missed the patient should not take an additional dose, but take the usual prescribed next

dose.

Posology for Philadelphia chromosome positive CML adult patients

The recommended dose of Tasigna is:

300 mg twice daily in newly diagnosed patients with CML in the chronic phase,

400 mg twice daily in patients with chronic or accelerated phase CML with resistance or

intolerance to prior therapy with imatinib.

For a dose of 300 mg twice daily, 150 mg capsules are available. For a dose of 400 mg once daily (see

dose adjustments below), 200 mg capsules are available.

Philadelphia chromosome positive

CML patients in chronic phase who have been treated with

nilotinib as first-line therapy and who achieved a sustained deep molecular response (MR4.5)

Discontinuation of treatment may be considered in eligible Philadelphia chromosome positive (Ph+)

CML patients in chronic phase who have been treated with nilotinib at 300 mg twice daily for a

minimum of 3 years if a deep molecular response

is sustained for a minimum of one year immediately

prior to discontinuation of therapy. Discontinuation of nilotinib therapy should be initiated by a

physician experienced in the treatment of patients with CML (see sections 4.4 and 5.1).

Eligible patients who discontinue nilotinib therapy must have their BCR-ABL transcript levels and

complete blood count with differential monitored monthly for one year, then every 6 weeks for the

second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be

performed with a quantitative diagnostic test validated to measure molecular response levels on the

International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS).

For patients who lose MR4 (MR4=BCR-ABL/ABL ≤0.01%IS) but not MMR (MMR=BCR-

ABL/ABL ≤0.1%IS) during the treatment-free phase, BCR-ABL transcript levels should be monitored

every 2 weeks until BCR-ABL levels return to a range between MR4 and MR4.5. Patients who

maintain BCR-ABL levels between MMR and MR4 for a minimum of 4 consecutive measurements

can return to the original monitoring schedule.

TAS API SEP18 V11 CL EU SmPC 11.2017

Patients who lose MMR must re-initiate treatment within 4 weeks of when loss of remission is known

to have occurred. Nilotinib therapy should be re-initiated at 300 mg twice daily or at a reduced dose

level of 400 mg once daily if the patient had a dose reduction prior to discontinuation of therapy.

Patients who re-initiate nilotinib therapy should have their BCR-ABL transcript levels monitored

monthly until MMR is re-established and every 12 weeks thereafter (see section 4.4).

Philadelphia chromosome positive CML patients in chronic phase who have achieved a sustained

deep molecular response (MR 4.5) on nilotinib following prior imatinib therapy

Discontinuation of treatment may be considered in eligible Philadelphia chromosome positive (Ph+)

CML patients in chronic phase who have been treated with nilotinib for a minimum of 3 years if a

deep molecular response is sustained for a minimum of one year immediately prior to discontinuation

of therapy. Discontinuation of nilotinib therapy should be initiated by a physician experienced in the

treatment of patients with CML (see sections 4.4 and 5.1).

Eligible patients who discontinue nilotinib therapy must have their BCR-ABL transcript levels and

complete blood count with differential monitored monthly for one year, then every 6 weeks for the

second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be

performed with a quantitative diagnostic test validated to measure molecular response levels on the

International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS).

Patients with confirmed loss of MR4 (MR4= BCR-ABL/ABL ≤0.01%IS) during the treatment-free

phase (two consecutive measures separated by at least 4 weeks showing loss of MR4) or loss of major

molecular response (MMR=BCR-ABL/ABL ≤0.1%IS) must re-initiate treatment within 4 weeks of

when loss of remission is known to have occurred. Nilotinib therapy should be re-initiated at either

300 mg or 400 mg twice daily. Patients who re-initiate nilotinib therapy should have their BCR-ABL

transcript levels monitored monthly until previous major molecular response or MR4 level is re-

established and every 12 weeks thereafter (see section 4.4).

Dose adjustments or modifications

Tasigna may need to be temporarily withheld and/or dose reduced for haematological toxicities

(neutropenia, thrombocytopenia) that are not related to the underlying leukaemia (see Table 1).

Table 1

Dose adjustments for neutropenia and thrombocytopenia

Adult patients with

Newly diagnosed

chronic phase CML

at 300 mg twice

daily

imatinib-resistant or

intolerant CML in

chronic phase at

400 mg twice daily

ANC* <1.0 x 10

/l and/or platelet

counts <50 x 10

Treatment with nilotinib must be interrupted

and blood count monitored.

Treatment must be resumed within 2 weeks

at prior dose if ANC >1.0 x 10

/l and/or

platelets >50 x 10

If blood counts remain low, a dose reduction

to 400 mg once daily may be required.

Adult patients with

Imatinib-resistant or

intolerant CML in

accelerated phase at

400 mg twice daily

ANC* <0.5 x 10

/l and/or platelet

counts <10 x 10

Treatment with nilotinib must be interrupted

and blood count monitored.

Treatment must be resumed within 2 weeks

at prior dose if ANC >1.0 x 10

/l and/or

platelets >20 x 10

If blood counts remain low, a dose reduction

to 400 mg once daily may be required.

*ANC = absolute neutrophil count

TAS API SEP18 V11 CL EU SmPC 11.2017

If clinically significant moderate or severe non-haematological toxicity develops, dosing should be

interrupted, and patients should be monitored and treated accordingly. If the prior dose was 300 mg

twice daily in adult newly diagnosed patients with CML in the chronic phase, or 400 mg twice daily

in adult patients with imatinib-resistant or intolerant CML in chronic or accelerated phase, dosing

may be resumed at 400 mg once daily in adult patients once the toxicity has resolved. If the prior dose

was 400 mg once daily in adult patients, treatment should be discontinued. If clinically appropriate,

re-escalation of the dose to the starting dose of 300 mg twice daily in adult newly diagnosed patients

with CML in the chronic phase or to 400 mg twice daily in adult patients with imatinib-resistant or

intolerant CML in chronic or accelerated phase should be considered.

Elevated serum lipase: For Grade 3-4 serum lipase elevations, doses in adult patients should be

reduced to 400 mg once daily or interrupted. Serum lipase levels should be tested monthly or as

clinically indicated (see section 4.4).

Elevated bilirubin and hepatic transaminases: For Grade 3-4 bilirubin and hepatic transaminase

elevations in adult patients, doses should be reduced to 400 mg once daily or interrupted. Bilirubin

and hepatic transaminases levels should be tested monthly or as clinically indicated.

Special populations

Elderly

Approximately 12% of subjects in the Phase III study in patients with newly diagnosed CML in

chronic phase and approximately 30% of subjects in the Phase II study in patients with imatinib-

resistant or intolerant CML in chronic phase and accelerated phase were 65 years of age or over. No

major differences were observed for safety and efficacy in patients ≥65 years of age as compared to

adults aged 18 to 65 years.

Renal impairment

Clinical studies have not been performed in patients with impaired renal function.

Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not

anticipated in patients with renal impairment.

Hepatic impairment

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Dose adjustment is not

considered necessary in patients with hepatic impairment. However, patients with hepatic impairment

should be treated with caution (see section 4.4).

Cardiac disorders

In clinical studies, patients with uncontrolled or significant cardiac disease (e.g. recent myocardial

infarction, congestive heart failure, unstable angina or clinically significant bradycardia) were

excluded. Caution should be exercised in patients with relevant cardiac disorders (see section 4.4).

Increases in total serum cholesterol levels have been reported with nilotinib therapy (see section 4.4).

Lipid profiles should be determined prior to initiating nilotinib therapy, assessed at month 3 and 6

after initiating therapy and at least yearly during chronic therapy.

Increases in blood glucose levels have been reported with nilotinib therapy (see section 4.4). Blood

glucose levels should be assessed prior to initiating nilotinib therapy and monitored during treatment.

Paediatric population

The safety and efficacy of Tasigna in children from birth to less than 18 years have not yet been

established. Therefore, its use in paediatric patients is not recommended due to a lack of data on

TAS API SEP18 V11 CL EU SmPC 11.2017

safety and efficacy.

Method of administration

Tasigna should be taken twice daily approximately 12 hours apart and must not be taken with food.

The capsules should be swallowed whole with water. No food should be consumed for 2 hours before

the dose is taken and no food should be consumed for at least one hour after the dose is taken.

For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one

teaspoon of apple sauce (puréed apple) and should be taken immediately. Not more than one teaspoon

of apple sauce and no food other than apple sauce must be used (see sections 4.4 and 5.2).

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

Myelosuppression

Treatment with nilotinib is associated with (National Cancer Institute Common Toxicity Criteria

grade 3-4) thrombocytopenia, neutropenia and anaemia.

Occurrence is more frequent in patients with

imatinib-resistant or intolerant CML, in particular in patients with accelerated-phase CML. Complete

blood counts should be performed every two weeks for the first 2 months and then monthly thereafter,

or as clinically indicated. Myelosuppression was generally reversible and usually managed by

withholding Tasigna temporarily or dose reduction (see section 4.2).

QT prolongation

Nilotinib has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval

on the surface ECG in a concentration-dependent manner in adult.

In the Phase III study in patients with newly diagnosed CML in chronic phase receiving 300 mg

nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state

was 6 msec. No patient had a QTcF >480 msec. No episodes of torsade de pointes were observed.

In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated

phase receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF

interval at steady state was 5 and 8 msec, respectively. QTcF of >500 msec was observed in <1% of

these patients. No episodes of torsade de pointes were observed in clinical studies.

In a healthy volunteer study with exposures that were comparable to the exposures observed in

patients, the time-averaged mean placebo-subtracted QTcF change from baseline was 7 msec

(CI ± 4 msec). No subject had a QTcF >450 msec. Additionally, no clinically relevant arrhythmias

were observed during the conduct of the trial. In particular, no episodes of torsade de pointes

(transient or sustained) were observed.

Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken with

strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT, and/or

food (see section 4.5). The presence of hypokalaemia and hypomagnesaemia may further enhance this

effect. Prolongation of the QT interval may expose patients to the risk of fatal outcome.

Tasigna should be used with caution in patients who have or who are at significant risk of developing

TAS API SEP18 V11 CL EU SmPC 11.2017

prolongation of QTc, such as those:

with congenital long QT prolongation

with uncontrolled or significant cardiac disease including recent myocardial infarction,

congestive heart failure, unstable angina or clinically significant bradycardia.

taking anti-arrhythmic medicinal products or other substances that lead to QT prolongation.

Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended

prior to initiating nilotinib therapy and as clinically indicated. Hypokalemia or hypomagnesemia must

be corrected prior to TASIGNA administration and potassium and magnesium blood levels should be

monitored

periodically

during

therapy,

particularly

patients

risk

these

electrolyte

abnormalities.

Sudden death

Uncommon cases (0.1 to 1%) of sudden deaths have been reported in patients with imatinib-resistant

or intolerant CML in chronic phase or accelerated phase with a past medical history of cardiac disease

or significant cardiac risk factors. Co-morbidities in addition to the underlying malignancy were also

frequently present as were concomitant medicinal products. Ventricular repolarisation abnormalities

may have been contributory factors. No cases of sudden death were reported in the Phase III study in

newly diagnosed patients with CML in chronic phase.

Fluid retention and oedema

Severe forms of fluid retention such as pleural effusion, pulmonary oedema, and pericardial effusion

were uncommonly (0.1 to 1%) observed in a Phase III study of newly diagnosed CML patients.

Similar events were observed in post-marketing reports. Unexpected, rapid weight gain should be

carefully investigated. If signs of severe fluid retention appear during treatment with nilotinib, the

aetiology should be evaluated and patients treated accordingly (see section 4.2 for instructions on

managing non-haematological toxicities).

Cardiovascular events

Cardiovascular events were reported in a randomised Phase III study in newly diagnosed CML

patients and observed in post-marketing reports. In this clinical study with a median on-therapy time

of 60.5 months, Grade 3-4 cardiovascular events included peripheral arterial occlusive disease (1.4%

and 1.1% at 300 mg and 400 mg nilotinib twice daily, respectively), ischaemic heart disease (2.2%

and 6.1% at 300 mg and 400 mg nilotinib twice daily, respectively) and ischaemic cerebrovascular

events (1.1% and 2.2% at 300 mg and 400 mg nilotinib twice daily, respectively). Patients should be

advised to seek immediate medical attention if they experience acute signs or symptoms of

cardiovascular events. The cardiovascular status of patients should be evaluated and cardiovascular

risk factors monitored and actively managed during nilotinib therapy according to standard guidelines.

Appropriate therapy should be prescribed to manage cardiovascular risk factors (see section 4.2 for

instructions on managing non-haematological toxicities).

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these

patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or

fulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with nilotinib

Experts in liver

disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients

with positive hepatitis B serology (including those with active disease) and for patients who test

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positive for HBV infection during treatment. Carriers of HBV who require treatment with nilotinib

should be closely monitored for signs and symptoms of active HBV infection throughout therapy and

for several months following termination of therapy (see section 4.8).

Special monitoring of Ph+ CML patients in chronic phase who have achieved a sustained deep

molecular response

Eligibility for discontinuation of treatment

Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or

e14a2/b3a2, can be considered for treatment discontinuation. Patients must have typical BCR-ABL

transcripts to allow quantitation of BCR-ABL, evaluation of the depth of molecular response, and

determination of a possible loss of molecular remission after discontinuation of treatment with

nilotinib.

Monitoring of patients who have discontinued therapy

Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation

must be performed with a quantitative diagnostic test validated to measure molecular response levels

with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS). BCR-ABL transcript levels must

be assessed prior to and during treatment discontinuation (see sections 4.2 and 5.1).

Loss of major molecular response (MMR=BCR-ABL/ABL ≤0.1%IS) or confirmed loss of MR4 (two

consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL

≤0.01%IS)) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to

have occurred. Molecular relapse can occur during the treatment-free phase, and long-term outcome

data are not yet available. It is therefore crucial to perform frequent monitoring of BCR-ABL

transcript levels and complete blood count with differential in order to detect possible loss of

remission (see section 4.2). For patients who fail to achieve MMR after three months of treatment

re-initiation, BCR-ABL kinase domain mutation testing should be performed.

Laboratory tests and monitoring

Blood lipids

In a Phase III study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mg

nilotinib twice daily showed a Grade 3-4 elevation in total cholesterol; no Grade 3-4 elevations were

however observed in the 300 mg twice daily dose group (see section 4.8). It is recommended that the

lipid profiles be determined before initiating treatment with nilotinib, assessed at month 3 and 6 after

initiating therapy and at least yearly during chronic therapy (see section 4.2). If a HMG-CoA

reductase inhibitor (a lipid-lowering agent) is required, please refer to section 4.5 before initiating

treatment since certain HMG-CoA reductase inhibitors are also metabolised by the CYP3A4 pathway.

Blood glucose

In a Phase III study in newly diagnosed CML patients, 6.9% and 7.2% of the patients treated with

400 mg nilotinib and 300 mg nilotinib twice daily, respectively, showed a Grade 3-4 elevation in

blood glucose. It is recommended that the glucose levels be assessed before initiating treatment with

Tasigna and monitored during treatment, as clinically indicated (see section 4.2). If test results

warrant therapy, physicians should follow their local standards of practice and treatment guidelines.

Interactions with other medicinal products

The administration of Tasigna with agents that are strong CYP3A4 inhibitors (including, but not

limited to, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) should

be avoided. Should treatment with any of these agents be required, it is recommended that nilotinib

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therapy be interrupted if possible (see section 4.5). If transient interruption of treatment is not

possible, close monitoring of the individual for prolongation of the QT interval is indicated (see

sections 4.2, 4.5 and 5.2).

Concomitant use of nilotinib with medicinal products that are potent inducers of CYP3A4 (e.g.

phenytoin, rifampicin, carbamazepine, phenobarbital and St. John’s Wort) is likely to reduce exposure

to nilotinib to a clinically relevant extent. Therefore, in patients receiving nilotinib, co-administration

of alternative therapeutic agents with less potential for CYP3A4 induction should be selected (see

section 4.5).

Food effect

The bioavailability of nilotinib is increased by food. Tasigna must not be taken in conjunction with

food (see sections 4.2 and 4.5) and should be taken 2 hours after a meal. No food should be consumed

for at least one hour after the dose is taken. Grapefruit juice and other foods that are known to inhibit

CYP3A4 should be avoided. For patients who are unable to swallow capsules, the content of each

capsule may be dispersed in one teaspoon of apple sauce and should be taken immediately. Not more

than one teaspoon of apple sauce and no food other than apple sauce must be used (see section 5.2).

Hepatic impairment

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose

administration of 200 mg of nilotinib resulted in increases in AUC of 35%, 35% and 19% in subjects

with mild, moderate and severe hepatic impairment, respectively, compared to a control group of

subjects with normal hepatic function. The predicted steady-state C

of nilotinib showed an increase

of 29%, 18% and 22%, respectively. Clinical studies have excluded patients with alanine

transaminase (ALT) and/or aspartate transaminase (AST) >2.5 (or >5, if related to disease) times the

upper limit of the normal range and/or total bilirubin >1.5 times the upper limit of the normal range.

Metabolism of nilotinib is mainly hepatic. Patients with hepatic impairment might therefore have

increased exposure to nilotinib and should be treated with caution (see section 4.2).

Serum lipase

Elevation in serum lipase has been observed. Caution is recommended in patients with previous

history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, nilotinib

therapy should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis.

Total gastrectomy

The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see section 5.2).

More frequent follow-up of these patients should be considered.

Tumour lysis syndrome

Due to possible occurrence of tumour lysis syndrome (TLS) correction of clinically significant

dehydration and treatment of high uric acid levels are recommended prior to initiating nilotinib

therapy (see section 4.8).

Lactose

Tasigna capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the

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

TAS API SEP18 V11 CL EU SmPC 11.2017

4.5

Interaction with other medicinal products and other forms of interaction

Tasigna may be given in combination with haematopoietic growth factors such as erythropoietin or

granulocyte colony-stimulating factor (G-CSF) if clinically indicated. It may be given with

hydroxyurea or anagrelide if clinically indicated.

Nilotinib is mainly metabolised in the liver and is also a substrate for the multi-drug efflux pump,

P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed

nilotinib may be influenced by substances that affect CYP3A4 and/or P-gp.

Substances that may increase nilotinib serum concentrations

Concomitant administration of nilotinib with imatinib (a substrate and moderator of P-gp and

CYP3A4), had a slight inhibitory effect on CYP3A4 and/or P-gp. The AUC of imatinib was increased

by 18% to 39%, and the AUC of nilotinib was increased by 18% to 40%. These changes are unlikely

to be clinically important.

The exposure to nilotinib in healthy subjects was increased 3-fold when co-administered with the

strong CYP3A4 inhibitor ketoconazole. Concomitant treatment with strong CYP3A4 inhibitors,

including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin,

should therefore be avoided (see section 4.4). Increased exposure to nilotinib might also be expected

with moderate CYP3A4 inhibitors. Alternative concomitant medicinal products with no or minimal

CYP3A4 inhibition should be considered.

Substances that may decrease nilotinib serum concentrations

Rifampicin, a potent CYP3A4 inducer, decreases nilotinib C

by 64% and reduces nilotinib AUC by

80%. Rifampicin and nilotinib should not be used concomitantly.

The concomitant administration of other medicinal products that induce CYP3A4 (e.g. phenytoin,

carbamazepine, phenobarbital and St. John’s Wort) is likewise likely to reduce exposure to nilotinib

to a clinically relevant extent. In patients for whom CYP3A4 inducers are indicated, alternative agents

with less enzyme induction potential should be selected.

Nilotinib has pH dependent solubility, with lower solubility at higher pH. In healthy subjects

receiving esomeprazole at 40 mg once daily for 5 days, gastric pH was markedly increased, but

nilotinib absorption was only decreased modestly (27% decrease in C

and 34% decrease in

AUC0-∞). Nilotinib may be used concurrently with esomeprazole or other proton pump inhibitors as

needed.

In a healthy subjects study, no significant change in nilotinib pharmacokinetics was observed when a

single 400 mg dose of nilotinib was administered 10 hours after and 2 hours before famotidine.

Therefore, when the concurrent use of a H2 blocker is necessary, it may be administered

approximately 10 hours before and approximately 2 hours after the dose of Tasigna.

In the same study as above, administration of an antacid (aluminium hydroxide/magnesium

hydroxide/simethicone) 2 hours before or after a single 400 mg dose of nilotinib also did not alter

nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately

2 hours before or approximately 2 hours after the dose of Tasigna.

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Substances that may have their systemic concentration altered by nilotinib

In vitro

, nilotinib is a relatively strong inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and

UGT1A1, with Ki value being lowest for CYP2C9 (Ki=0.13 microM).

A single-dose drug-drug interaction study in healthy volunteers with 25 mg warfarin, a sensitive

CYP2C9 substrate, and 800 mg nilotinib did not result in any changes in warfarin pharmacokinetic

parameters or warfarin pharmacodynamics measured as prothrombin time (PT) and international

normalised ratio (INR). There are no steady-state data. This study suggests that a clinically

meaningful drug-drug interaction between nilotinib and warfarin is less likely up to a dose of 25 mg

of warfarin. Due to lack of steady-state data, control of warfarin pharmacodynamic markers (INR or

PT) following initiation of nilotinib therapy (at least during the first 2 weeks) is recommended.

In CML patients, nilotinib administered at 400 mg twice daily for 12 days increased the systemic

exposure (AUC and C

) of oral midazolam (a substrate of CYP3A4) 2.6-fold and 2.0-fold,

respectively. Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other

medicinal products primarily metabolised by CYP3A4 (e.g. certain HMG-CoA reductase inhibitors)

may be increased when co-administered with nilotinib. Appropriate monitoring and dose adjustment

may be necessary for medicinal products that are CYP3A4 substrates and have a narrow therapeutic

index (including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl,

sirolimus and tacrolimus) when co-administered with nilotinib.

Anti-arrhythmic medicinal products and other substances that may prolong the QT interval

Nilotinib should be used with caution in patients who have or may develop prolongation of the QT

interval, including those patients taking anti-arrhythmic medicinal products such as amiodarone,

disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QT

prolongation such as chloroquine, halofantrine, clarithromycin, haloperidol, methadone and

moxifloxacin (see section 4.4).

Food interactions

The absorption and bioavailability of nilotinib are increased if it is taken with food, resulting in a

higher serum concentration (see sections 4.2, 4.4 and 5.2). Grapefruit juice and other foods that are

known to inhibit CYP3A4 should be avoided.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

/Contraception

Women of childbearing potential have to use highly effective contraception during treatment with

nilotinib and for up to two weeks after ending treatment.

Pregnancy

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

animals have shown reproductive toxicity (see section 5.3). Tasigna should not be used during

pregnancy unless the clinical condition of the woman requires treatment with nilotinib. If it is used

during pregnancy, the patient must be informed of the potential risk to the foetus.

If a woman who is being treated with nilotinib is considering pregnancy, treatment discontinuation

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may be considered based on the eligibility criteria for discontinuing treatment as described in

sections 4.2 and 4.4. There is a limited amount of data on pregnancies in patients while attempting

treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be

informed of a potential need to re-initiate nilotinib treatment during pregnancy (see sections 4.2 and

4.4).

Breast-feeding

It is unknown whether nilotinib is excreted in human milk. Available toxicological data in animals

have shown excretion of nilotinib in milk (see section 5.3). A risk to the newborns/infants cannot be

excluded. Tasigna should not be used during breast-feeding.

Fertility

Animal studies did not show an effect on fertility in male and female rats (see section 5.3).

4.7

Effects on ability to drive and use machines

Tasigna has no or negligible influence on the ability to drive and use machines. However, it is

recommended that patients experiencing dizziness, fatigue, visual impairment or other undesirable

effects with a potential impact on the ability to drive or use machines safely should refrain from these

activities as long as the undesirable effects persist (see section 4.8).

4.8

Undesirable effects

Summary of the safety profile

The data described below reflect exposure to nilotinib in a total of 737 adult patients from a

randomised Phase III study in patients with newly diagnosed Ph+ CML in chronic phase treated at the

recommended dose of 300 mg twice daily (n=279) and from an open-label multicentre Phase II study

in adult patients with imatinib-resistant or intolerant CML in chronic phase (n=321) and accelerated

phase (n=137) treated at the recommended dose of 400 mg twice daily. Safety information from two

Tasigna treatment discontinuation studies is also provided.

In adult patients with newly diagnosed CML in chronic phase

The median duration of exposure was 60.5 months (range 0.1-70.8 months).

The most frequent (≥10%) non-haematological adverse reactions were rash, pruritus, headache,

nausea, fatigue, alopecia, myalgia and upper abdominal pain. Most of these adverse reactions were

mild to moderate in severity. Constipation, dry skin, asthenia, muscle spasms, diarrhoea, arthralgia,

abdominal pain, vomiting and peripheral oedema were observed less commonly (<10% and ≥5%)

were of mild to moderate severity, manageable and generally did not require dose reduction.

Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (18%),

neutropenia (15%) and anaemia (8%). Biochemical adverse drug reactions include alanine

aminotransferase increased (24%), hyperbilirubinaemia (16%), aspartate aminotransferase increased

(12%), lipase increased (11%), blood bilirubin increased (10%), hyperglycaemia (4%),

hypercholesterolaemia (3%) and hypertriglyceridaemia (<1%). Pleural and pericardial effusions,

regardless of causality, occurred in 2% and <1% of patients, respectively, receiving nilotinib 300 mg

twice daily. Gastrointestinal haemorrhage, regardless of causality, was reported in 3% of these

patients.

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The change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient

had an absolute QTcF >500 msec while on the study medicinal product. QTcF increase from baseline

exceeding 60 msec was observed in <1% of patients while on the study medicinal product. No sudden

deaths or episodes of torsade de pointes (transient or sustained) were observed. No decrease from

baseline in mean left ventricular ejection fraction (LVEF) was observed at any time during treatment.

No patient had a LVEF of <45% during treatment nor an absolute reduction in LVEF of more than

15%.

Discontinuation due to adverse drug reactions was observed in 10% of patients.

In adult patients with imatinib-resistant or intolerant CML in chronic phase and accelerated phase

The data described below reflect exposure to nilotinib in 458 adult patients in an open-label

multicentre Phase II study in patients with imatinib-resistant or intolerant CML in chronic phase

(n=321) and accelerated phase (n=137) treated at the recommended dose of 400 mg twice daily.

The most frequent (≥10%) non-haematological drug-related adverse events were rash, pruritus,

nausea, fatigue, headache, vomiting, myalgia, constipation and diarrhoea. Most of these adverse

events were mild to moderate in severity. Alopecia, muscle spasms, decreased appetite, arthralgia,

abdominal pain, bone pain, peripheral oedema, asthenia, upper abdominal pain, dry skin, erythema

and pain in extremity were observed less commonly (<10% and ≥5%) and have been of mild to

moderate severity (Grade 1 or 2). Discontinuation due to adverse drug reactions was observed in 16%

of chronic phase and 10% of accelerated phase patients.

Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (31%),

neutropenia (17%) and anaemia (14%). Pleural and pericardial effusions as well as complications of

fluid retention occurred in <1% of patients receiving Tasigna. Cardiac failure was observed in <1% of

patients. Gastrointestinal and CNS haemorrhage were reported in 1% and <1% of patients,

respectively.

QTcF exceeding 500 msec was observed in <1% of patients. No episodes of torsade de pointes

(transient or sustained) were observed.

Tabulated list of adverse reactions

The adverse reactions are ranked under heading of frequency using the following convention: very

common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to

<1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within

each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Most frequently reported adverse reactions in Tasigna clinical studies

Non-haematological adverse reactions (excluding laboratory abnormalities) that are reported in at

least 5% of the patients in Tasigna clinical studies that serve as the basis for the approved indications

are shown in Table 2.

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Table 2

Non-haematological adverse reactions (≥5% of all patients)

Newly diagnosed CML-CP

300 mg twice daily

n=279

Imatinib-resistant or intolerant

CML-CP and CML-AP

400 mg twice daily

n=458

60-month analysis

24-month analysis

System organ

class/

Adverse

reaction

Frequency

All

grades

Grade

3-4

Frequency

All

grades

Grade

3-4

CML-

CP

n=321

Grade

3-4

CML-

AP

n=137

Grade

3-4

%

%

%

%

%

%

Metabolism and nutrition disorders

Decreased

appetite **

Common

Common

<1

<1

Nervous system disorders

Headache

Very

common

Very

common

<1

Gastrointestinal disorders

Nausea

Very

common

<1

Very

common

<1

<1

<1

Constipation

Common

Very

common

<1

<1

Diarrhoea

Common

<1

Very

common

<1

Vomiting

Common

Very

common

<1

<1

Upper

abdominal pain

Very

common

Common

<1

<1

Abdominal

pain

Common

Common

<1

<1

<1

Dyspepsia

Common

Common

Skin and subcutaneous tissue disorders

Rash

Very

common

<1

Very

common

Pruritus

Very

common

<1

Very

common

<1

<1

Alopecia

Very

common

Common

Dry skin

Common

Common

Erythema

Common

Common

<1

<1

Musculoskeletal and connective tissue disorders

Myalgia

Very

common

<1

Very

common

<1

<1

<1

Muscle spasms

Common

Common

<1

<1

Arthralgia

Common

<1

Common

<1

Bone pain

Common

Common

<1

<1

Pain in

extremity

Common

<1

Common

<1

<1

<1

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General disorders and administration site conditions

Fatigue

Very

common

Very

common

<1

Asthenia

Common

<1

Common

<1

<1

Oedema

peripheral

Common

Common

* Percentages are rounded to integer for presentation in this table. However, percentages with one

decimal precision are used to identify terms with a frequency of at least 5% and to classify terms

according to frequency categories.

**Also includes preferred term anorexia

The following adverse reactions were reported in adult patients in the Tasigna clinical studies which

serve as a basis for the approved indications at a frequency of less than 5%. For laboratory

abnormalities, very common adverse reactions not included in Table 2 are also reported. These

adverse reactions are included based on clinical relevance.

Infections and infestations:

Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis,

rhinitis).

Uncommon: pneumonia, urinary tract infection, gastroenteritis, bronchitis, herpes virus infection,

candidiasis (including oral candidiasis).

Not known: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis, hepatitis B reactivation.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Common: skin papilloma.

Not known: oral papilloma, paraproteinaemia.

Blood and lymphatic system disorders:

Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia.

Uncommon: thrombocythaemia, leukocytosis.

Immune system disorders:

Not known: hypersensitivity.

Endocrine disorders

Uncommon: hyperthyroidism, hypothyroidism.

Not known: hyperparathyroidism secondary, thyroiditis.

Metabolism and nutrition disorders:

Very common: hypophosphataemia (including blood phosphorus decreased).

Common: electrolyte imbalance (including hypomagnesaemia, hyperkalaemia, hypokalaemia,

hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia), diabetes mellitus,

hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia.

Uncommon: dehydration, increased appetite, gout, dyslipidaemia.

Not known: hyperuricaemia, hypoglycaemia, appetite disorder.

Psychiatric disorders:

Common: depression, insomnia, anxiety.

Not known: disorientation, confusional state, amnesia, dysphoria.

Nervous system disorders:

Common: dizziness, peripheral neuropathy, hypoaesthesia, paraesthesia.

Uncommon: intracranial haemorrhage, ischaemic stroke, transient ischaemic attack, cerebral

TAS API SEP18 V11 CL EU SmPC 11.2017

infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention,

hyperaesthesia.

Not known: cerebrovascular accident, brain oedema, optic neuritis, lethargy, dysaesthesia, restless

legs syndrome, basilar artery stenosis.

Eye disorders:

Common: eye haemorrhage, periorbital oedema, eye pruritus, conjunctivitis, dry eye (including

xerophthalmia).

Uncommon: visual impairment, vision blurred, conjunctival haemorrhage, visual acuity reduced,

eyelid oedema, photopsia, hyperaemia (scleral, conjunctival, ocular), eye irritation.

Not known: papilloedema, chorioretinopathy, diplopia, photophobia, eye swelling, blepharitis, eye

pain, conjunctivitis allergic, ocular surface disease.

Ear and labyrinth disorders:

Common: vertigo.

Not known: hearing impaired, ear pain, tinnitus.

Cardiac disorders:

Common: angina pectoris, arrhythmia (including atroventricular block, cardiac flutter, extrasystoles,

tachycardia, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged.

Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur,

pericardial effusion, cyanosis.

Not known: ventricular dysfunction, pericarditis, ejection fraction decreased, diastolic dysfunction.

Vascular disorders:

Common: hypertension, flushing, peripheral artery stenosis.

Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication,

arterial stenosis limb, haematoma, arteriosclerosis.

Not known: shock haemorrhagic, hypotension, thrombosis.

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea, dyspnoea exertional, epistaxis, cough, dysphonia.

Uncommon: pulmonary oedema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy,

pharyngolaryngeal pain, throat irritation.

Not known: pulmonary hypertension, wheezing, oropharyngeal pain.

Gastrointestinal disorders:

Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence.

Uncommon: gastrointestinal haemorrhage, melaena, mouth ulceration, gastroesophageal reflux,

stomatitis, oesophageal pain, dry mouth, gastritis, sensitivity of teeth.

Not known: gastrointestinal ulcer perforation, retroperitoneal haemorrhage, haematemesis, gastric

ulcer, oesophagitis ulcerative, subileus, enterocolitis, haemorrhoids, hiatus hernia, rectal

haemorrhage, gingivitis.

Hepatobiliary disorders:

Very common: hyperbilirubinaemia (including blood bilirubin increased).

Common: hepatic function abnormal.

Uncommon: hepatotoxicity, toxic hepatitis, jaundice.

Not known: cholestasis, hepatomegaly.

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Skin and subcutaneous tissue disorders:

Common: night sweats, eczema, urticaria, hyperhidrosis, contusion, acne, dermatitis (including

allergic, exfoliative and acneiform).

Uncommon: exfoliative rash, drug eruption, skin pain, ecchymosis, swelling face.

Not known: erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysaesthesia

syndrome, petechiae, photosensitivity, blister, dermal cysts, sebaceous hyperplasia, skin atrophy, skin

discolouration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis, psoriasis.

Musculoskeletal and connective tissue disorders:

Common: musculoskeletal chest pain, musculoskeletal pain, back pain, flank pain, neck pain,

muscular weakness.

Uncommon: musculoskeletal stiffness, joint swelling.

Not known: arthritis.

Renal and urinary disorders:

Common: pollakiuria.

Uncommon: dysuria, micturition urgency, nocturia.

Not known: renal failure, haematuria, urinary incontinence, chromaturia.

Reproductive system and breast disorders:

Uncommon: breast pain, gynaecomastia, erectile dysfunction.

Not known: breast induration, menorrhagia, nipple swelling.

General disorders and administration site conditions:

Common: chest pain (including non-cardiac chest pain), pain, pyrexia, chest discomfort, malaise.

Uncommon: face oedema, gravitational oedema, influenza-like illness, chills, feeling body

temperature change (including feeling hot, feeling cold).

Not known: localised oedema.

Investigations:

Very common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase

increased, lipoprotein cholesterol (including low density and high density) increased, total cholesterol

increased, blood triglycerides increased.

Common: haemoglobin decreased, blood amylase increased, blood alkaline phosphatase increased,

gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased,

weight increased, blood insulin increased, globulins decreased.

Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood urea increased.

Not known: troponin increased, blood bilirubin unconjugated increased, blood insulin decreased,

insulin C-peptide decreased, blood parathyroid hormone increased.

Clinically relevant or severe abnormalities of routine haematological or biochemistry laboratory

values in adult patients are presented in Table 3.

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Table 3

Grade 3-4 laboratory abnormalities

Newly diagnosed

CML-CP

300 mg twice

daily

Imatinib-resistant or intolerant

CML-CP and CML-AP

400 mg twice daily

n=279

(%)

CML-CP

n=321

(%)

CML-AP

n=137

(%)

Haematological parameters

Myelosuppression

- Neutropenia

- Thrombocytopenia

- Anaemia

Biochemistry parameters

- Elevated creatinine

<1

- Elevated lipase

- Elevated SGOT (AST)

- Elevated SGPT (ALT)

- Hypophosphataemia

- Elevated bilirubin (total)

- Elevated glucose

- Elevated cholesterol (total)

- Elevated triglycerides

*Percentages with one decimal precision are used and rounded to integer for presentation in this table

**Parameters not collected

Treatment discontinuation in Ph+ CML patients in chronic phase who have achieved a sustained deep

molecular response

After discontinuation of nilotinib therapy within the framework of attempting TFR, patients may

experience musculoskeletal symptoms more frequently than before treatment discontinuation, e.g.,

myalgia, pain in extremity, arthralgia, bone pain, spinal pain or musculoskeletal pain.

In a Phase II clinical study with newly diagnosed patients with Ph+ CML in chronic phase (N=190),

musculoskeletal symptoms were reported within a year of Tasigna discontinuation in 24.7% versus

16.3% within the previous year on nilotinib treatment.

In a Phase II clinical study with patients with Ph+ CML in chronic phase on nilotinib treatment and

previously treated with imatinib (N=126), musculoskeletal symptoms were reported within a year of

discontinuation in 42.1% versus 14.3% within the previous year on nilotinib treatment

Description of selected adverse reactions

Sudden death

Uncommon cases (0.1 to 1%) of sudden deaths have been reported in Tasigna clinical trials and/or

compassionate use programs in patients with imatinib-resistant or intolerant CML in chronic phase or

accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors (see

section 4.4).

Hepatitis B reactivation

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Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in

acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see

section 4.4).

Post-marketing experience

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

spontaneous case reports, literature cases, expanded access programmes, and clinical studies other

than the global registration trials. Since these reactions are reported voluntarily from a population of

uncertain size, it is not always possible to reliably estimate their frequency or establish a causal

relationship to nilotinib exposure.

Frequency rare: Cases of tumour lysis syndrome have been reported in patients treated with nilotinib.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

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

Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go

v.il

4.9

Overdose

Isolated reports of intentional overdose with nilotinib were reported, where an unspecified number of

Tasigna capsules were ingested in combination with alcohol and other medicinal products. Events

included neutropenia, vomiting and drowsiness. No ECG changes or hepatotoxicity were reported.

Outcomes were reported as recovered.

In the event of overdose, the patient should be observed and appropriate supportive treatment given.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE08

Mechanism of action

Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both

in cell lines and in primary Philadelphia-chromosome positive leukaemia cells. The substance binds

with high affinity to the ATP-binding site in such a manner that it is a potent inhibitor of wild-type

BCR-ABL and maintains activity against 32/33 imatinib-resistant mutant forms of BCR-ABL. As a

consequence of this biochemical activity, nilotinib selectively inhibits the proliferation and induces

apoptosis in cell lines and in primary Philadelphia-chromosome positive leukaemia cells from CML

patients. In murine models of CML, as a single agent nilotinib reduces tumour burden and prolongs

survival following oral administration.

Pharmacodynamic effects

Nilotinib has little or no effect against the majority of other protein kinases examined, including Src,

TAS API SEP18 V11 CL EU SmPC 11.2017

except for the PDGF, KIT and Ephrin receptor kinases, which it inhibits at concentrations within the

range achieved following oral administration at therapeutic doses recommended for the treatment of

CML (see Table 4).

Table 4

Kinase profile of nilotinib (phosphorylation IC

50

nM)

BCR-ABL

PDGFR

Clinical efficacy

Clinical studies in newly diagnosed CML in chronic phase

An open-label, multicentre, randomised Phase III study was conducted to determine the efficacy of

nilotinib versus imatinib in 846 adult patients with cytogenetically confirmed newly diagnosed

Philadelphia chromosome positive CML in the chronic phase. Patients were within six months of

diagnosis and were previously untreated, with the exception of hydroxyurea and/or anagrelide.

Patients were randomised 1:1:1 to receive either nilotinib 300 mg twice daily (n=282), nilotinib

400 mg twice daily (n=281) or imatinib 400 mg once daily (n=283). Randomisation was stratified by

Sokal risk score at the time of diagnosis.

Baseline characteristics were well balanced between the three treatment arms. Median age was

47 years in both nilotinib arms and 46 years in the imatinib arm, with 12.8%, 10.0% and 12.4% of

patients were ≥65 years of age in the nilotinib 300 mg twice daily, nilotinib 400 mg twice daily and

imatinib 400 mg once daily treatment arms, respectively. There were slightly more male than female

patients (56.0%, 62.3% and 55.8%, in the nilotinib 300 mg twice daily, 400 mg twice daily and

imatinib 400 mg once daily arm, respectively). More than 60% of all patients were Caucasian and

25% of all patients were Asian.

The primary data analysis time point was when all 846 patients completed 12 months of treatment (or

discontinued earlier). Subsequent analyses reflect when patients completed 24, 36, 48, 60 and

72 months of treatment (or discontinued earlier). The median time on treatment was approximately

70 months in the nilotinib treatment groups and 64 months in the imatinib group. The median actual

dose intensity was 593 mg/day for nilotinib 300 mg twice daily, 772 mg/day for nilotinib 400 mg

twice daily and 400 mg/day for imatinib 400 mg once daily. This study is ongoing.

The primary efficacy endpoint was major molecular response (MMR) at 12 months. MMR was

defined as ≤0.1% BCR-ABL/ABL% by international scale (IS) measured by RQ-PCR, which

corresponds to a ≥3 log reduction of BCR-ABL transcript from standardised baseline. The MMR rate

at 12 months was statistically significantly higher for nilotinib 300 mg twice daily compared to

imatinib 400 mg once daily (44.3% versus 22.3%, p<0.0001). The rate of MMR at 12 months, was

also statistically significantly higher for nilotinib 400 mg twice daily compared to imatinib 400 mg

once daily (42.7% versus 22.3%, p<0.0001).

The rates of MMR at 3, 6, 9 and 12 months were 8.9%, 33.0%, 43.3% and 44.3% for nilotinib 300 mg

twice daily, 5.0%, 29.5%, 38.1% and 42.7% for nilotinib 400 mg twice daily and 0.7%, 12.0%, 18.0%

and 22.3% for imatinib 400 mg once daily.

The MMR rate at 12, 24, 36, 48, 60 and 72 months is presented in Table 5.

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Table 5

MMR rate

Nilotinib

mg twice daily

n=282

Nilotinib

400 mg twice daily

n=281

Imatinib

400 mg once daily

n=283

MMRat 12 months

Response (95% CI)

44.3

(38.4; 50.3)

42.7

(36.8; 48.7)

22.3 (17.6; 27.6)

MMR at 24 months

Response (95% CI)

61.7

(55.8; 67.4)

59.1

(53.1; 64.9)

37.5 (31.8; 43.4)

MMR at 36 months

2

Response (95% CI)

58.5

(52.5; 64.3)

57.3

(51.3; 63.2)

38.5 (32.8; 44.5)

MMR at 48 months

3

Response (95% CI)

59.9

(54.0; 65.7)

55.2 (49.1; 61.1)

43.8 (38.0; 49.8)

MMR at 60 months

4

Response (95% CI)

62.8 (56.8; 68.4)

61.2 (55.2; 66.9)

49.1 (43.2; 55.1)

MMR at 72 months

5

Response (95% CI)

52.5 (46.5; 58.4)

57.7 (51.6; 63.5)

41.7 (35.9; 47.7)

Cochran-Mantel-Haenszel (CMH) test p-value for response rate (vs. imatinib 400 mg) <0.0001

Only patients who were in MMR at a specific time point are included as responders for that time

point. A total of 199 (35.2%) of all patients were not evaluable for MMR at 36 months (87 in the

nilotinib 300 mg twice daily group and 112 in the imatinib group) due to missing/unevaluable PCR

assessments (n=17), atypical transcripts at baseline (n=7), or discontinuation prior to the 36-month

time point (n=175).

Only patients who were in MMR at a specific time point are included as responders for that time

point. A total of 305 (36.1%) of all patients were not evaluable for MMR at 48 months (98 in the

nilotinib 300 mg BID group, 88 in the nilotinib 400 mg BID group and 119 in the imatinib group) due

to missing/unevaluable PCR assessments (n=18), atypical transcripts at baseline (n=8), or

discontinuation prior to the 48-month time point (n=279).

Only patients who were in MMR at a specific time point are included as responders for that time

point. A total of 322 (38.1%) of all patients were not evaluable for MMR at 60 months (99 in the

nilotinib 300 mg twice daily group, 93 in the nilotinib 400 mg twice daily group and 130 in the

imatinib group) due to missing/unevaluable PCR assessments (n=9), atypical transcripts at baseline

(n=8) or discontinuation prior to the 60-month time point (n=305).

Only patients who were in MMR at a specific time point are included as responders for that time

point. A total of 395 (46.7%) of all patients were not evaluable for MMR at 72 months (130 in the

nilotinib 300 mg twice daily group, 110 in the nilotinib 400 mg twice daily group and 155 in the

imatinib group) due to missing/unevaluable PCR assessments (n=25), atypical transcripts at baseline

(n=8) or discontinuation prior to the 72-month time point (n=362).

MMR rates by different time points (including patients who achieved MMR at or before those time

points as responders) are presented in the cumulative incidence of MMR (see Figure 1).

TAS API SEP18 V11 CL EU SmPC 11.2017

Figure 1

Cumulative incidence of MMR

For all Sokal risk groups, the MMR rates at all time points remained consistently higher in the two

nilotinib groups than in the imatinib group.

In a retrospective analysis, 91% (234/258) of patients on nilotinib 300 mg twice daily achieved BCR-

ABL levels ≤10% at 3 months of treatment compared to 67% (176/264) of patients on imatinib

400 mg once daily. Patients with BCR-ABL levels ≤10% at 3 months of treatment show a greater

overall survival at 72 months compared to those who did not achieve this molecular response level

(94.5% vs. 77.1% respectively [p=0.0005]).

Based on the Kaplan-Meier analysis of time to first MMR the probability of achieving MMR at

different time points was higher for both nilotinib at 300 mg and 400 mg twice daily compared to

imatinib 400 mg once daily (HR=2.17 and stratified log-rank p<0.0001 between nilotinib 300 mg

twice daily and imatinib 400 mg once daily, HR=1.88 and stratified log-rank p<0.0001 between

nilotinib 400 mg twice daily and imatinib 400 mg once daily).

The proportion of patients who had a molecular response of ≤0.01% and ≤0.0032% by IS at different

time points are presented in Table 6 and the proportion of patients who had a molecular response of

≤0.01% and ≤0.0032% by IS by different time points are presented in Figures 2 and 3. Molecular

responses of ≤0.01% and ≤0.0032% by IS correspond to a ≥4 log reduction and ≥4.5 log reduction,

respectively, of BCR-ABL transcripts from a standardised baseline.

Months since randomisation

Cumulative incidence of MMR, %

By 1 year

By 2 years

By 3 years

By 4 years

By 5 years

55%; P < .0001

71%; P < .0001

73%; P < .0001

76%; P < .0001

77%; P < .0001

61%;

P < .0001

70%; P < .0001

73%; P < .0001

77%; P < .0001

51%;

P < .0001

Nilotinib 300 mg twice daily (n = 282)

Nilotinib 400 mg twice daily (n = 281)

Imatinib 400 mg once daily (n = 283)

By 6 years

79%; P < .0001

77%; P < .0001

TAS API SEP18 V11 CL EU SmPC 11.2017

Table 6

Proportions of patients who had molecular response of ≤0.01% (4 log reduction)

and ≤0.0032% (4.5 log reduction)

Nilotinib

300 mg twice daily

n=282

Nilotinib

400 mg twice daily

n=281

Imatinib

400 mg once daily

n=283

≤0.01%

≤0.0032%

≤0.01%

≤ 0.0032%

≤0.01%

≤0.0032%

At 12 months

11.7

At 24 months

24.5

12.4

22.1

10.2

At 36 months

29.4

13.8

23.8

12.1

14.1

At 48 months

33.0

16.3

29.9

17.1

19.8

10.2

At 60 months

47.9

32.3

43.4

29.5

31.1

19.8

At 72 months

44.3

31.2

45.2

28.8

27.2

18.0

Figure 2

Cumulative incidence of molecular response of ≤0.01% (4-log reduction)

Cumulative incidence of MR

4

(BCR-ABL ≤0.01% on the international scale), %

39%; P < .0001

50%; P < .0001

56%; P < .0001

66%; P < .0001

33%;

P < .0001

44%;

P < .0001

50%; P < .0001

63%;

P < .0001

67%; P < .0001

65%; P < .0001

20%; P < .0001

15%; P = .0004

Months since randomisation

Nilotinib 300 mg twice daily (n = 282)

Nilotinib 400 mg twice daily (n = 281)

Imatinib 400 mg once daily (n = 283)

By 1 year

By 2 years

By 3 years

By 4 years

By 5 years

By 6 years

TAS API SEP18 V11 CL EU SmPC 11.2017

Figure 3

Cumulative incidence of molecular response of ≤0.0032% (4.5 log reduction)

Based on Kaplan-Meier estimates of the duration of first MMR, the proportions of patients who were

maintaining response for 72 months among patients who achieved MMR were 92.5% (95% CI:

88.6-96.4%) in the nilotinib 300 mg twice daily group, 92.2% (95% CI: 88.5-95.9%) in the nilotinib

400 mg twice daily group and 88.0% (95% CI: 83.0-93.1%) in the imatinib 400 mg once daily group.

Complete cytogenetic response (CCyR) was defined as 0% Ph+ metaphases in the bone marrow based

on a minimum of 20 metaphases evaluated. Best CCyR rate by 12 months (including patients who

achieved CCyR at or before the 12 month time point as responders) was statistically higher for both

nilotinib 300 mg and 400 mg twice daily compared to imatinib 400 mg once daily, see Table 7.

CCyR rate by 24 months (includes patients who achieved CCyR at or before the 24 month time point

as responders) was statistically higher for both the nilotinib 300 mg twice daily and 400 mg twice

daily groups compared to the imatinib 400 mg once daily group.

25%; P < .0001

32%; P < .0001

40%; P < .0001

54%; P < .0001

19%;

P = .0006

28%;

P = .0003

37%;

P = .0002

52%;

P < .0001

56%; P < .0001

55%; P < .0001

11%; P < .0001

7%; P < .0001

Cumulative incidence of MR

4.5

(BCR-ABL ≤0.0032% on the international scale), %

Nilotinib 300 mg twice daily (n = 282)

Nilotinib 400 mg twice daily (n = 281)

Imatinib 400 mg once daily (n = 283)

Months since randomisation

By 1 year

By 2 years

By 3 years

By 4 years

By 5 years

By 6 years

TAS API SEP18 V11 CL EU SmPC 11.2017

Table 7

Best CCyR rate

Nilotinib

300 mg twice daily

n=282

Nilotinib

400 mg twice daily

n=281

Imatinib

400 mg once daily

n=283

By 12 months

Response (95% CI)

80.1 (75.0; 84.6)

77.9 (72.6; 82.6)

65.0 (59.2; 70.6)

No response

19.9

22.1

35.0

CMH test p-value for response rate

(versus imatinib 400 mg once

daily)

<0.0001

0.0005

By 24 months

Response (95% CI)

86.9 (82.4; 90.6)

84.7 (79.9; 88.7)

77.0 (71.7; 81.8)

No response

13.1

15.3

23.0

CMH test p-value for response rate

(versus imatinib 400 mg once

daily)

0.0018

0.0160

Based on Kaplan-Meier estimates, the proportions of patients who were maintaining response for

72 months among patients who achieved CCyR were 99.1% (95% CI: 97.9-100%) in the nilotinib

300 mg twice daily group, 98.7% (95% CI: 97.1-100%) in the nilotinib 400 mg twice daily group and

97.0% (95% CI: 94.7-99.4%) in the imatinib 400 mg once daily group.

Progression to accelerated phase (AP) or blast crisis (BC) on treatment is defined as the time from the

date of randomisation to the first documented disease progression to accelerated phase or blast crisis

or CML-related death. Progression to accelerated phase or blast crisis on treatment was observed in a

total of 17 patients: 2 patients on nilotinib 300 mg twice daily, 3 patients on nilotinib 400 mg twice

daily and 12 patients on imatinib 400 mg once daily. The estimated rates of patients free from

progression to accelerated phase or blast crisis at 72 months were 99.3%, 98.7% and 95.2%,

respectively (HR=0.1599 and stratified log-rank p=0.0059 between nilotinib 300 mg twice daily and

imatinib once daily, HR=0.2457 and stratified log-rank p=0.0185 between nilotinib 400 mg twice

daily and imatinib once daily). No new events of progression to AP/BC were reported on-treatment

since the 2-year analysis.

Including clonal evolution as a criterion for progression, a total of 25 patients progressed to

accelerated phase or blast crisis on treatment by the cut-off date (3 in the nilotinib 300 mg twice daily

group, 5 in the nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group).

The estimated rates of patients free from progression to accelerated phase or blast crisis including

clonal evolution at 72 months were 98.7%, 97.9% and 93.2%, respectively (HR=0.1626 and stratified

log-rank p=0.0009 between nilotinib 300 mg twice daily and imatinib once daily, HR=0.2848 and

stratified log-rank p=0.0085 between nilotinib 400 mg twice daily and imatinib once daily).

A total of 55 patients died during treatment or during the follow-up after discontinuation of treatment.

(21 in the nilotinib 300 mg twice daily group, 11 in the nilotinib 400 mg twice daily group and 23 in

the imatinib 400 mg once daily group). Twenty-six (26) of these 55 deaths were related to CML (6 in

the nilotinib 300 mg twice daily group, 4 in the nilotinib 400 mg twice daily group and 16 in the

imatinib 400 mg once daily group). The estimated rates of patients alive at 72 months were 91.6%,

95.8% and 91.4%, respectively (HR=0.8934 and stratified log-rank p=0.7085 between nilotinib

300 mg twice daily and imatinib, HR=0.4632 and stratified log-rank p=0.0314 between nilotinib

400 mg twice daily and imatinib). Considering only CML-related deaths as events, the estimated rates

of overall survival at 72 months were 97.7%, 98.5% and 93.9%, respectively (HR=0.3694 and

stratified log-rank p=0.0302 between nilotinib 300 mg twice daily and imatinib, HR=0.2433 and

TAS API SEP18 V11 CL EU SmPC 11.2017

stratified log-rank p=0.0061 between nilotinib 400 mg twice daily and imatinib).

Clinical studies in imatinib-resistant or intolerant CML in chronic phase and accelerated phase

An open-label, uncontrolled, multicentre Phase II study was conducted to determine the efficacy of

nilotinib in patients with imatinib resistant or intolerant CML with separate treatment arms for

chronic and accelerated phase disease. Efficacy was based on 321 CP patients and 137 AP patients

enrolled. Median duration of treatment was 561 days for CP patients and 264 days for AP patients

(see Table 8). Tasigna was administered on a continuous basis (twice daily 2 hours after a meal and

with no food for at least one hour after administration) unless there was evidence of inadequate

response or disease progression. The dose was 400 mg twice daily and dose escalation to 600 mg

twice daily was allowed.

Table 8

Duration of exposure with nilotinib

Chronic phase

n=321

Accelerated phase

n=137

Median duration of therapy in days

(25th-75th percentiles)

(196-852)

(115-595)

Resistance to imatinib included failure to achieve a complete haematological response (by 3 months),

cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of

disease after a previous cytogenetic or haematological response. Imatinib intolerance included

patients who discontinued imatinib because of toxicity and were not in major cytogenetic response at

time of study entry.

Overall, 73% of patients were imatinib-resistant, while 27% were imatinib-intolerant. The majority of

patients had a long history of CML that included extensive prior treatment with other antineoplastic

agents, including imatinib, hydroxyurea, interferon, and some had even failed organ transplant

(Table 9). The median highest prior imatinib dose had been 600 mg/day. The highest prior imatinib

dose was

600 mg/day in 74% of all patients, with 40% of patients receiving imatinib doses

800 mg/day.

Table 9

CML disease history characteristics

Chronic phase

(n=321)

Accelerated phase

(n=137)*

Median time since diagnosis in months

(range)

(5–275)

(2–298)

Imatinib

Resistant

Intolerant without MCyR

226 (70%)

95 (30%)

109 (80%)

27 (20%)

Median time of imatinib treatment in

days

(25th-75

percentiles)

(519-1,488)

(424-1,497)

Prior hydroxyurea

Prior interferon

Prior bone marrow transplant

* Missing information on imatinib-resistant/intolerant status for one patient.

The primary endpoint in the CP patients was major cytogenetic response (MCyR), defined as

elimination (CCyR, complete cytogenetic response) or significant reduction to <35% Ph+ metaphases

(partial cytogenetic response) of Ph+ haematopoietic cells. Complete haematological response (CHR)

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in CP patients was evaluated as a secondary endpoint. The primary endpoint in the AP patients was

overall confirmed haematological response (HR), defined as either a complete haematological

response, no evidence of leukaemia or return to chronic phase.

Chronic phase

The MCyR rate in 321 CP patients was 51%. Most responders achieved their MCyR rapidly within

3 months (median 2.8 months) of starting nilotinib treatment and these were sustained. The median

time to achieve CCyR was just past 3 months (median 3.4 months). Of the patients who achieved

MCyR, 77% (95% CI: 70% - 84%) were maintaining response at 24 months. Median duration of

MCyR has not been reached. Of the patients who achieved CCyR, 85% (95% CI: 78% - 93%) were

maintaining response at 24 months. Median duration of CCyR has not been reached. Patients with a

CHR at baseline achieved a MCyR faster (1.9 versus 2.8 months). Of CP patients without a baseline

CHR, 70% achieved a CHR, median time to CHR was 1 month and median duration of CHR was

32.8 months. The estimated 24-month overall survival rate in CML-CP patients was 87%.

Accelerated phase

The overall confirmed HR rate in 137 AP patients was 50%. Most responders achieved a HR early

with nilotinib treatment (median 1.0 months) and these have been durable (median duration of

confirmed HR was 24.2 months). Of the patients who achieved HR, 53% (95% CI: 39% - 67%) were

maintaining response at 24 months. MCyR rate was 30% with a median time to response of

2.8 months. Of the patients who achieved MCyR, 63% (95% CI: 45% - 80%) were maintaining

response at 24 months. Median duration of MCyR was 32.7 months. The estimated 24-month overall

survival rate in CML-AP patients was 70%.

The rates of response for the two treatment arms are reported in Table 10.

Table 10

Response in CML

(Best response rate)

Chronic phase

Accelerated phase

Intolerant

(n=95)

Resistant

(n=226)

Total

(n=321)

Intolerant

(n=27)

Resistant

(n=109)

Total*

(n=137)

Haematological

Response (%)

Overall (95%CI)

Complete

Return to CP

87 (74-94)

65 (56-72)

(63-76)

48 (29-68)

51 (42-61)

50 (42-59)

Cytogenetic

Response (%)

Major (95%CI)

Complete

Partial

57 (46-67)

49 (42-56)

51 (46-57)

33 (17-54)

29 (21-39)

30 (22-38)

NEL = no evidence of leukaemia/marrow response

114 CP patients had a CHR at baseline and were therefore not assessable for complete

haematological response

* Missing information on imatinib-resistant/intolerant status for one patient.

Efficacy data in patients with CML-BC are not yet available. Separate treatment arms were also

included in the Phase II study to investigate Tasigna in a group of CP and AP patients who had been

extensively pre-treated with multiple therapies including a tyrosine kinase inhibitor agent in addition

to imatinib. Of these patients 30/36 (83%) were treatment resistant not intolerant. In 22 CP patients

TAS API SEP18 V11 CL EU SmPC 11.2017

evaluated for efficacy nilotinib induced a 32% MCyR rate and a 50% CHR rate. In 11 AP patients,

evaluated for efficacy, treatment induced a 36% overall HR rate.

After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54%

of accelerated phase CML patients who were evaluated for mutations. Tasigna demonstrated efficacy

in patients harboring a variety of BCR-ABL mutations associated with imatinib resistance, except

T315I.

Treatment discontinuation in Ph+ CML patients in chronic phase who have been treated with

nilotinib as first-line therapy and who have achieved a sustained deep molecular response

In an open-label, single-arm study, 215 adult patients with Ph+ CML in chronic phase treated with

nilotinib in first-line for ≥2 years who achieved MR4.5 as measured with the MolecularMD MRDx™

BCR-ABL test were enrolled to continue nilotinib treatment for additional 52 weeks (nilotinib

consolidation phase). 190 of 215 patients (88.4%) entered the TFR phase after achieving a sustained

deep molecular response during the consolidation phase, defined by the following criteria:

the 4 last quarterly assessments (taken every 12 weeks) were at least MR4 (BCR-ABL/ABL

≤0.01% IS), and maintained for one year

the last assessment being MR4.5 (BCR-ABL/ABL ≤0.0032% IS)

no more than two assessments falling between MR4 and MR4.5 (0.0032% IS < BCR-

ABL/ABL ≤0.01% IS).

The primary endpoint was the percentage of patients in MMR at 48 weeks after starting the TFR

phase (considering any patient who required re-initiation of treatment as non-responder). Of the

190 patients who entered the TFR phase, 98 patients (51.6% [95% CI: 44.2, 58.9]) were in MMR at

48 weeks.

Eighty-eight patients (46.3%) discontinued the TFR phase due to loss of MMR, and 1 (0.5%), 1

(0.5%), and 3 patients (1.6%) due to death from unknown cause, physician decision and subject

decision, respectively. Among these 88 patients, 86 patients restarted nilotinib treatment and

2 patients permanently discontinued the study. Eighty-five of these 86 patients (98.8%) regained

MMR, (one patient discontinued study permanently due to subject decision) and 76 patients (88.4%)

regained MR4.5 by the time of the cut-off date.

The Kaplan-Meier (KM) estimated median time on nilotinib treatment to regain MMR and MR4.5

was 7.9 weeks (95% CI: 5.1, 8.0) and 13.1 weeks (95% CI: 12.3, 15.7), respectively. The KM

estimated MMR and MR4.5 rates at 24 weeks of re-initiation were 98.8 % (95% CI: 94.2, 99.9) and

90.9 % (95% CI: 83.2, 96.0), respectively.

The KM estimate of median treatment-free survival (TFS) has not yet been reached (Figure 4); 99 of

190 patients (52.1%) did not have a TFS event.

TAS API SEP18 V11 CL EU SmPC 11.2017

Figure 4

Kaplan-Meier estimate of treatment-free survival after start of TFR (full analysis

set)

Treatment discontinuation in CML patients in chronic phase who have achieved a sustained deep

molecular response on nilotinib treatment following prior imatinib therapy

In an open-label, single-arm study, 163 adult patients with Ph+ CML in chronic phase taking tyrosine

kinase inhibitors (TKIs) for ≥3 years (imatinib as initial TKI therapy for more than 4 weeks without

documented MR4.5 on imatinib at the time of switch to nilotinib, then switched to nilotinib for at

least two years), and who achieved MR4.5 on nilotinib treatment as measured with the MolecularMD

MRDx™ BCR-ABL test were enrolled to continue nilotinib treatment for additional 52 weeks

(nilotinib consolidation phase). 126 of 163 patients (77.3%) entered the TFR phase after achieving a

sustained deep molecular response during the consolidation phase, defined by the following criterion:

The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5

(BCR-ABL/ABL ≤0.0032% IS) during one year.

The primary endpoint was the proportion of patients without confirmed loss of MR4.0 or loss of

MMR within 48 weeks following treatment discontinuation. Of the 126 patients who entered the TFR

phase, 73 patients (57.9%, [95% CI: 48.8, 66.7]) had no loss of MMR, no confirmed loss of MR4.0,

and no re-initiation of nilotinib within 48 weeks.

Among the 53 patients who discontinued the TFR phase due to confirmed loss of MR4.0 or loss of

MMR, 51 patients restarted nilotinib and 2 patients discontinued the study. Forty-eight of these

51 patients (94.1%) regained MR4.0 and 47 patients (92.2%) regained MR4.5 by the time of the

cut-off date.

The Kaplan-Meier (KM) estimated median time on nilotinib to regain MR4.0 and MR4.5 was

12.0 weeks (95% CI: 8.3, 12.7) and 13.1 weeks (95% CI: 12.4, 16.1), respectively. The KM estimated

MR4.0 and MR4.5 rates at 48 weeks of re-initiation were 100.0% (95% CI: not estimated) and 94.8%

(95% CI: 85.1, 99.0), respectively.

The median TFS has not yet been reached (Figure 5); 74 of 126 patients (58.7%) did not have a TFS

event.

Pat Evt Cen

190 91 99

Censored observations

Treatment-free Survival (%)

Time since TFR (weeks)

0:91

1:91

12:91

38:91

90:89

190:0

At risk : Events

108:81

120:70

165:25

TAS API SEP18 V11 CL EU SmPC 11.2017

Figure 5

Kaplan-Meier estimate of treatment-free survival after start of TFR (full analysis

set)

5.2

Pharmacokinetic properties

Absorption

Peak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib absorption

following oral administration was approximately 30%. The absolute bioavailability of nilotinib has

not been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability

of nilotinib capsule is approximately 50%. In healthy volunteers, C

and area under the serum

concentration-time curve (AUC) of nilotinib are increased by 112% and 82%, respectively, compared

to fasting conditions when Tasigna is given with food. Administration of Tasigna 30 minutes or

2 hours after food increased bioavailability of nilotinib by 29% or 15%, respectively (see sections 4.2,

4.4 and 4.5).

Nilotinib absorption (relative bioavailability) might be reduced by approximately 48% and 22% in

patients with total gastrectomy and partial gastrectomy, respectively.

Distribution

The blood-to-plasma ratio of nilotinib is 0.71. Plasma protein binding is approximately 98% on the

basis of

in vitro

experiments.

Biotransformation

Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is

the main circulating component in the serum. None of the metabolites contribute significantly to the

pharmacological activity of nilotinib. Nilotinib is primarily metabolised by CYP3A4, with possible

minor contribution from CYP2C8.

Censored observations

Treatment-free Survival (%)

126:0

107:19

76:49

74:51

61:52

36:52

14:52

1:52

0:52

Time since TFR (weeks)

At risk : Events

TAS API SEP18 V11 CL EU SmPC 11.2017

Elimination

After a single dose of radiolabelled nilotinib in healthy subjects, more than 90% of the dose was

eliminated within 7 days, mainly in faeces (94% of the dose). Unchanged nilotinib accounted for 69%

of the dose.

The apparent elimination half-life estimated from the multiple-dose pharmacokinetics with daily

dosing was approximately 17 hours. Inter-patient variability in nilotinib pharmacokinetics was

moderate to high.

Linearity/non-linearity

Steady-state nilotinib exposure was dose-dependent, with less than dose-proportional increases in

systemic exposure at dose levels higher than 400 mg given as once-daily dosing. Daily systemic

exposure to nilotinib with 400 mg twice-daily dosing at steady state was 35% higher than with 800 mg

once-daily dosing. Systemic exposure (AUC) of nilotinib at steady state at a dose level of 400 mg

twice daily was approximately 13.4% higher than at a dose level of 300 mg twice daily. The average

nilotinib trough and peak concentrations over 12 months were approximately 15.7% and 14.8% higher

following 400 mg twice-daily dosing compared to 300 mg twice daily. There was no relevant increase

in exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily.

Steady-state conditions were essentially achieved by day 8. An increase in serum exposure to nilotinib

between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for

twice-daily dosing.

Bioavailability/bioequivalence studies

Single-dose administration of 400 mg nilotinib, using 2 capsules of 200 mg whereby the content of

each capsule was dispersed in one teaspoon of apple sauce, was shown to be bioequivalent with a

single-dose administration of 2 intact capsules of 200 mg.

5.3

Preclinical safety data

Nilotinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity,

reproductive toxicity, phototoxicity and carcinogenicity (rats and mice) studies.

Nilotinib did not have effects on CNS or respiratory functions.

In vitro

cardiac safety studies

demonstrated a preclinical signal for QT prolongation, based upon block of hERG currents and

prolongation of the action potential duration in isolated rabbit hearts by nilotinib. No effects were

seen in ECG measurements in dogs or monkeys treated for up to 39 weeks or in a special telemetry

study in dogs.

Repeated-dose toxicity studies in dogs of up to 4 weeks’ duration and in cynomolgus monkeys of up

to 9 months’ duration revealed the liver as the primary target organ of toxicity of nilotinib. Alterations

included increased alanine aminotransferase and alkaline phosphatase activity and histopathology

findings (mainly sinusoidal cell or Kupffer cell hyperplasia/hypertrophy, bile duct hyperplasia and

periportal fibrosis). In general the changes in clinical chemistry were fully reversible after a four-week

recovery period and the histological alterations showed partial reversibility. Exposures at the lowest

dose levels at which the liver effects were seen were lower than the exposure in humans at a dose of

800 mg/day. Only minor liver alterations were seen in mice or rats treated for up to 26 weeks. Mainly

reversible increases in cholesterol levels were seen in rats, dogs and monkeys.

Genotoxicity studies in bacterial

in vitro

systems and in mammalian

in vitro

in vivo

systems with

TAS API SEP18 V11 CL EU SmPC 11.2017

and without metabolic activation did not reveal any evidence for a mutagenic potential of nilotinib.

In the 2-year rat carcinogenicity study, the major target organ for non-neoplastic lesions was the

uterus (dilatation, vascular ectasia, endothelial cell hyperplasia, inflammation and/or epithelial

hyperplasia). There was no evidence of carcinogenicity upon administration of nilotinib at 5, 15 and

40 mg/kg/day. Exposures (in terms of AUC) at the highest dose level represented approximately 2x to

3x human daily steady-state exposure (based on AUC) to nilotinib at the dose of 800 mg/day.

In the 26-week Tg.rasH2 mouse carcinogenicity study, in which nilotinib was administered at 30, 100

and 300 mg/kg/day, skin papillomas/carcinomas were detected at 300 mg/kg, representing

approximately 30 to 40 times (based on AUC) the human exposure at the maximum approved dose of

800 mg/day (administered as 400 mg twice daily). The No-Observed-Effect-Level for the skin

neoplastic lesions was 100 mg/kg/day, representing approximately 10 to 20 times the human exposure

at the maximum approved dose of 800 mg/day (administered as 400 mg twice daily). The major target

organs for non-neoplastic lesions were the skin (epidermal hyperplasia), the growing teeth

(degeneration/atrophy of the enamel organ of upper incisors and inflammation of the

gingiva/odontogenic epithelium of incisors) and the thymus (increased incidence and/or severity of

decreased lymphocytes).

Nilotinib did not induce teratogenicity, but did show embryo- and foetotoxicity at doses that also

showed maternal toxicity. Increased post-implantation loss was observed in both the fertility study,

which involved treatment of both males and females, and the embryotoxicity study, which involved

treatment of females. Embryo-lethality and foetal effects (mainly decreased foetal weights, premature

fusion of the facial bones (fused maxilla/zygomatic) visceral and skeletal variations) in rats and

increased resorption of foetuses and skeletal variations in rabbits were present in the embryotoxicity

studies. In a pre- and postnatal development study in rats, maternal exposure to nilotinib caused

reduced pup body weight with associated changes in physical development parameters as well as

reduced mating and fertility indices in the offspring. Exposure to nilotinib in females at No-Observed-

Adverse-Effect-Levels was generally less or equal to that in humans at 800 mg/day.

In a juvenile development study, nilotinib was administered via oral gavage to juvenile rats from the

first week post partum through young adult (day 70 post partum) at doses of 2, 6 and 20 mg/kg/day.

Besides standard study parameters, evaluations of developmental landmarks, CNS effects, mating and

fertility were performed. Based on a reduction in body weight in both genders and a delayed preputial

separation in males (which may be associated with the reduction in weight), the No-Observed-Effect-

Level in juvenile rats was considered to be 6 mg/kg/day. The juvenile animals did not exert increased

sensitivity to nilotinib relative to adults. In addition, the toxicity profile in juvenile rats was

comparable to that observed in adult rats.

No effects on sperm count/motility or on fertility were noted in male and female rats up to the highest

tested dose, approximately 5 times the recommended dosage for humans.

Nilotinib was shown to absorb light in the UV-B and UV-A range, is distributed into the skin and

showed a phototoxic potential

in vitro

, but no effects have been observed

in vivo

. Therefore the risk

that nilotinib causes photosensitisation in patients is considered very low.

TAS API SEP18 V11 CL EU SmPC 11.2017

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tasigna 150mg capsules

Capsule content: Lactose monohydrate, Crospovidone, Poloxamer 188, Silica colloidal anhydrous,

Magnesium stearate.

Capsule shell: Gelatin, Titanium dioxide (E171), Iron oxide red, (E172), Iron oxide yellow (E172).

Printing ink, black: Shellac, Iron oxide black, N-butyl alcohol, Purified water, Propylene glycol,

Dehydrated ethanol, Isopropyl alcohol, Ammonium hydroxide.

Tasigna 200mg capsules

Capsule content: Lactose monohydrate, Crospovidone, Poloxamer 188, Silica colloidal anhydrous,

Magnesium stearate

Capsule shell: Gelatin, Titanium dioxide (E171), Iron oxide yellow (E172)

Printing ink, red:

Printing ink a: Shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol,

strong ammonia solution, Iron oxide red (E172), potassium hydroxide, purified water.

Printing ink b: Shellac, Iron oxide red (E172), Iron oxide black (E172), n-butyl alcohol,

purified

water,

titanium

dioxide

(E171),

propylene

glycol,

industrial

methylated

spirit,

isopropyl alcohol.

The printing ink used is ‘Printing ink a’ or alternatively ‘Printing ink b’.

6.2

Incompatibilities

Not applicable.

6.3 Shelf life

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

6.4

Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from moisture.

6.5

Nature and contents of container

PVC/PVDC/Alu blisters.

Tasigna 150mg is available in the following pack sizes:

Unit packs containing 28 capsules.

Multipacks containing 112 (4 packs of 28) capsules

Tasigna 200mg is available in the following pack sizes:

Unit packs containing 40 capsules.

Multipacks containing 120 (3 packs of 28) capsules

TAS API SEP18 V11 CL EU SmPC 11.2017

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MANUFACTURER

Novartis Pharma Stein AG., Stein, Switzerland

For Novartis Pharma Ag., Basel, Switzerland

8. REGISTRATION HOLDER

Novartis Israel Ltd.

36 Shacham st.,

Petah-Tikva

רבוטקוא

2018

/דבכנ ה/אפור חקור ,ה

/

,ה/דבכנ ת

:ןודנה

Tasigna 150mg and 200mg, capsules

הנגיסט

150

ו ג"מ

-

200

תולוספק ,ג"מ

רישכתה םי

ושר ןודנבש םימ

יוותהל לארשיב תו

אבה תו

Tasigna 150mg and 200mg are indicated for the treatment of adult patients with newly

diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) in the

chronic phase.

Tasigna 200mg

only

is indicated also for the treatment of Philadelphia chromosome positive chronic

myeloid leukaemia (Ph+CML) in chronic phase or accelerated phase in patients resistant to or

experiencing significant toxicity during treatment with imatinib.

:ליעפה ביכרמה

Nilotinib (as hydrochloride monohydrate)

ןונימ רטשמב םייוניש לע םכעידוהל וננוצרב

-

Treatment-free remission (TFR)

םינוכדע לעו

ב םיפסונ ןולע ו אפורל

ב

רישכתה לש ןכרצל ןולע .ןודנב םי

) םיאבה םידומעב םיפרוצמ םייונישה ןומיס םע םינכדועמה םינולעה

ןותחת ו

,ףסוותהש עדימ הצוח וק

עדימ ,רסוהש בוהצב השגדה

.(הרמחה

לע םיספדומ םלבקל ןתינו ,תואירבה דרשמ רתאבש תופורתה רגאמב םוסרפל וחלשנ םינולעה

.םושירה לעבל הינפ ידי

,הכרבב

ןילטיג הנלי

הנוממ תחקור

.מ"עב לארשי סיטרבונ

םחש 'חר

חתפ ןולטמ תיירק

הוקת

.ד.ת

7759

חתפ

הוקת

49250

:ןופלט

03-9201111

:סקפ

03-9229230

Novartis Israel Ltd.

36 Shaham St., Kiryat Matalon, Petach-Tikva

P.O.B 7759, Petach Tikva 49250, Israel

Tel: 972-3-9201111 Fax: 972-3-9229230

אפורל ןולע

The format of this leaflet was determined by the Ministry of Health and its content was checked

September 2018

September 2016

and approved by it in

1.

NAME OF THE MEDICINAL PRODUCT

Tasigna 150mg capsules

Tasigna 200 mg capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Tasigna 150mg capsules

One hard capsule contains 150 mg nilotinib (as hydrochloride monohydrate).

Excipient(s) with known effect

One hard capsule contains 117.08 mg lactose (as monohydrate).

Tasigna 200mg capsules

One capsule contains 200 mg nilotinib (as hydrochloride monohydrate).

Excipient(s) with known effect

One capsule contains 156.11 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsule

Tasigna 150mg capsules

White to yellowish powder in red opaque hard gelatin capsules, size 1 with black axial imprint

“NVR/BCR”.

Tasigna 200mg capsules

White to yellowish powder in light yellow opaque hard gelatin capsules, size 0 with red axial imprint

“NVR/TKI”.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Tasigna 150mg and 200mg are indicated for the treatment of adult patients with newly diagnosed

Philadelphia chromosome positive chronic myeloid leukaemia (CML) in the chronic phase.

Tasigna 200mg

only

is indicated also for the treatment of Philadelphia chromosome positive chronic

myeloid leukaemia (Ph+CML) in chronic phase or accelerated phase in patients resistant to or

experiencing significant toxicity during treatment with imatinib.

4.2

Posology and method of administration

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients

with CML.

Posology

Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity

occurs.

If a dose is missed the patient should not take an additional dose, but take the usual prescribed next

dose.

Posology for Philadelphia chromosome positive CML adult patients

The recommended dose of Tasigna is:

300 mg twice daily in newly diagnosed patients with CML in the chronic phase,

400 mg twice daily in patients with chronic or accelerated phase CML with resistance or

intolerance to prior therapy with imatinib.

Treatment should be continued as long as the patient continues to benefit.

For a dose of 300 mg twice daily, 150 mg capsules are available. For a dose of 400 mg once daily (see

dose adjustments below), 200 mg capsules are available.

If a dose is missed the patient should not take an additional dose, but take the usual prescribed next

dose.

Philadelphia chromosome positive

CML patients in chronic phase who have been treated with

nilotinib as first-line therapy and who achieved a sustained deep molecular response (MR4.5)

Discontinuation of treatment may be considered in eligible Philadelphia chromosome positive (Ph+)

CML patients in chronic phase who have been treated with nilotinib at 300 mg twice daily for a

minimum of 3 years if a deep molecular response

is sustained for a minimum of one year immediately

prior to discontinuation of therapy. Discontinuation of nilotinib therapy should be initiated by a

physician experienced in the treatment of patients with CML (see sections 4.4 and 5.1).

Eligible patients who discontinue nilotinib therapy must have their BCR-ABL transcript levels and

complete blood count with differential monitored monthly for one year, then every 6 weeks for the

second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be

performed with a quantitative diagnostic test validated to measure molecular response levels on the

International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS).

For patients who lose MR4 (MR4=BCR-ABL/ABL ≤0.01%IS) but not MMR (MMR=BCR-ABL/ABL

≤0.1%IS) during the treatment-free phase, BCR-ABL transcript levels should be monitored every

2 weeks until BCR-ABL levels return to a range between MR4 and MR4.5. Patients who maintain

BCR-ABL levels between MMR and MR4 for a minimum of 4 consecutive measurements can return to

the original monitoring schedule.

Patients who lose MMR must re-initiate treatment within 4 weeks of when loss of remission is known

to have occurred. Nilotinib therapy should be re-initiated at 300 mg twice daily or at a reduced dose

level of 400 mg once daily if the patient had a dose reduction prior to discontinuation of therapy.

Patients who re-initiate nilotinib therapy should have their BCR-ABL transcript levels monitored

monthly until MMR is re-established and every 12 weeks thereafter (see section 4.4).

Philadelphia chromosome positive CML patients in chronic phase who have achieved a sustained

deep molecular response (MR 4.5) on nilotinib following prior imatinib therapy

Discontinuation of treatment may be considered in eligible Philadelphia chromosome positive (Ph+)

CML patients in chronic phase who have been treated with nilotinib for a minimum of 3 years if a deep

molecular response is sustained for a minimum of one year immediately prior to discontinuation of

therapy. Discontinuation of nilotinib therapy should be initiated by a physician experienced in the

treatment of patients with CML (see sections 4.4 and 5.1).

Eligible patients who discontinue nilotinib therapy must have their BCR-ABL transcript levels and

complete blood count with differential monitored monthly for one year, then every 6 weeks for the

second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be

performed with a quantitative diagnostic test validated to measure molecular response levels on the

International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS).

Patients with confirmed loss of MR4 (MR4= BCR-ABL/ABL ≤0.01%IS) during the treatment-free

phase (two consecutive measures separated by at least 4 weeks showing loss of MR4) or loss of major

molecular response (MMR=BCR-ABL/ABL ≤0.1%IS) must re-initiate treatment within 4 weeks of

when loss of remission is known to have occurred. Nilotinib therapy should be re-initiated at either

300 mg or 400 mg twice daily. Patients who re-initiate nilotinib therapy should have their BCR-ABL

transcript levels monitored monthly until previous major molecular response or MR4 level is re-

established and every 12 weeks thereafter (see section 4.4).

Dose adjustments or modifications

Tasigna may need to be temporarily withheld and/or dose reduced for haematological toxicities

(neutropenia, thrombocytopenia) that are not related to the underlying leukaemia (see Table 1).

Table 1

Dose adjustments for neutropenia and thrombocytopenia

Adult patients with

Newly diagnosed

chronic phase CML

at 300 mg twice

daily

imatinib-resistant or

intolerant CML in

chronic phase at

400 mg twice daily

ANC* <1.0 x 10

/l and/or platelet

counts <50 x 10

Treatment with nilotinibTasigna must be

interrupted and blood count monitored.

Treatment must be resumed within 2 weeks

at prior dose if ANC >1.0 x 10

/l and/or

platelets >50 x 10

If blood counts remain low, a dose reduction

to 400 mg once daily may be required.

Adult patients with

Imatinib-resistant or

intolerant CML in

accelerated phase at

400 mg twice daily

ANC* <0.5 x 10

/l and/or platelet

counts <10 x 10

Treatment with nilotinibTasigna must be

interrupted and blood count monitored.

Treatment must be resumed within 2 weeks at

prior dose if ANC >1.0 x 10

/l and/or

platelets >20 x 10

If blood counts remain low, a dose reduction

to 400 mg once daily may be required.

*ANC = absolute neutrophil count

If clinically significant moderate or severe non-haematological toxicity develops, dosing should be

interrupted, and patients should be monitored and treated accordingly. If the prior dose was 300 mg

twice daily in adult newly diagnosed patients with CML in the chronic phase, or 400 mg twice daily in

adult patients with imatinib-resistant or intolerant CML in chronic or accelerated phase, dosing and

may be resumed at 400 mg once daily in adult patients once the toxicity has resolved. If the prior dose

was 400 mg once daily in adult patients, treatment should be discontinued. If clinically appropriate, re-

escalation of the dose to the starting dose of 300 mg twice daily in adult newly diagnosed patients with

CML in the chronic phase or to 400 mg twice daily in adult patients with imatinib-resistant or intolerant

CML in chronic phase andor accelerated phase should be considered.

Elevated serum lipase: For Grade 3-4 serum lipase elevations, doses in adult patients should be reduced

to 400 mg once daily or interrupted. Serum lipase levels should be tested monthly or as clinically

indicated (see section 4.4).

Elevated bilirubin and hepatic transaminases: For Grade 3-4 bilirubin and hepatic transaminase

elevations in adult patients, doses should be reduced to 400 mg once daily or interrupted. Bilirubin and

hepatic transaminases levels should be tested monthly or as clinically indicated.

Special populations

Elderly

Approximately 12% of subjects in the Phase III study in patients with newly diagnosed CML in chronic

phase and approximately 30% of subjects in the Phase II study in patients with imatinib-resistant or

intolerant CML in chronic phase and accelerated phase were 65 years of age or over. No major

differences were observed for safety and efficacy in patients ≥65 years of age as compared to adults

aged 18 to 65 years.

Renal impairment

Clinical studies have not been performed in patients with impaired renal function.

Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not

anticipated in patients with renal impairment.

Hepatic impairment

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Dose adjustment is not

considered necessary in patients with hepatic impairment. However, patients with hepatic impairment

should be treated with caution (see section 4.4).

Cardiac disorders

In clinical studies, patients with uncontrolled or significant cardiac disease (e.g. recent myocardial

infarction, congestive heart failure, unstable angina or clinically significant bradycardia) were

excluded. Caution should be exercised in patients with relevant cardiac disorders (see section 4.4).

Increases in total serum cholesterol levels have been reported with nilotinibTasigna therapy (see section

4.4). Lipid profiles should be determined prior to initiating nilotinibTasigna therapy, assessed at

month 3 and 6 after initiating therapy and at least yearly during chronic therapy.

Increases in blood glucose levels have been reported with nilotinib Tasigna therapy (see section 4.4).

Blood glucose levels should be assessed prior to initiating nilotinibTasigna therapy and monitored

during treatment.

Paediatric population

The safety and efficacy of Tasigna in children from birth to less than 18 years have not yet been

established. Therefore, its use in paediatric patients is not recommended due to a lack of data on safety

and efficacy.

Method of administration

Tasigna should be taken twice daily approximately 12 hours apart and must not be taken with food. The

capsules should be swallowed whole with water. No food should be consumed for 2 hours before the

dose is taken and no food should be consumed for at least one hour after the dose is taken.

For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one

teaspoon of apple sauce (puréed apple) and should be taken immediately. Not more than one teaspoon

of apple sauce and no food other than apple sauce must be used (see sections 4.4 and 5.2).

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

Myelosuppression

Treatment with nilotinibTasigna is associated with (National Cancer Institute Common Toxicity

Criteria grade 3-4) thrombocytopenia, neutropenia and anaemia.

Occurrence is more frequent in

patients with imatinib-resistant or intolerant CML, in particular in patients with accelerated-phase

CML. Complete blood counts should be performed every two weeks for the first 2 months and then

monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually

managed by withholding Tasigna temporarily or dose reduction (see section 4.2).

QT prolongation

NilotinibTasigna has been shown to prolong cardiac ventricular repolarisation as measured by the QT

interval on the surface ECG in a concentration-dependent manner in adult.

In the Phase III study in patients with newly diagnosed CML in chronic phase receiving 300 mg

nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was

6 msec. No patient had a QTcF >480 msec. No episodes of torsade de pointes were observed.

In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase

receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval

at steady state was 5 and 8 msec, respectively. QTcF of >500 msec was observed in <1% of these

patients. No episodes of torsade de pointes were observed in clinical studies.

In a healthy volunteer study with exposures that were comparable to the exposures observed in patients,

the time-averaged mean placebo-subtracted QTcF change from baseline was 7 msec (CI ± 4 msec). No

subject had a QTcF >450 msec. Additionally, no clinically relevant arrhythmias were observed during

the conduct of the trial. In particular, no episodes of torsade de pointes (transient or sustained) were

observed.

Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken with

strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT, and/or

food (see section 4.5). The presence of hypokalaemia and hypomagnesaemia may further enhance this

effect. Prolongation of the QT interval may expose patients to the risk of fatal outcome.

Tasigna should be used with caution in patients who have or who are at significant risk of developing

prolongation of QTc, such as those:

with congenital long QT prolongation

with uncontrolled or significant cardiac disease including recent myocardial infarction,

congestive heart failure, unstable angina or clinically significant bradycardia.

taking anti-arrhythmic medicinal products or other substances that lead to QT prolongation.

Concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to

prolong QT should be avoided.

Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended

prior to initiating therapy with nilotinibTASIGNA therapy and should be repeated after 7 days and as

as clinically indicated. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA

administration and potassium and magnesium blood levels should be monitored periodically during

therapy, particularly in patients at risk for these electrolyte abnormalities.

Sudden death

Uncommon cases (0.1 to 1%) of sudden deaths have been reported in patients with imatinib-resistant or

intolerant CML in chronic phase or accelerated phase with a past medical history of cardiac disease or

significant cardiac risk factors. Co-morbidities in addition to the underlying malignancy were also

frequently present as were concomitant medicinal products. Ventricular repolarisation abnormalities

may have been contributory factors. No cases of sudden death were reported in the Phase III study in

newly diagnosed patients with CML in chronic phase.

Fluid retention and oedema

Severe forms of fluid retention such as pleural effusion, pulmonary oedema, and pericardial effusion

were uncommonly (0.1 to 1%) observed in a Phase III study of newly diagnosed CML patients. Similar

events were observed in post-marketing reports. Unexpected, rapid weight gain should be carefully

investigated. If signs of severe fluid retention appear during treatment with nilotinib, the aetiology

should be evaluated and patients treated accordingly (see section 4.2 for instructions on managing non-

haematological toxicities).

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these

patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or

fulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with

Tasigna.

Experts in liver

disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients

with positive hepatitis B serology (including those with active disease) and for patients who test

positive for HBV infection during treatment. Carriers of HBV who require treatment with

Tasigna

should be closely monitored for signs and symptoms of active HBV infection throughout therapy and

for several months following termination of therapy (see section 4.8).

Cardiovascular events

Cardiovascular events were reported in a randomised Phase III study in newly diagnosed CML patients

and observed in post-marketing reports. In this clinical study with a median on-therapy time of

60.5 months, Grade 3-4 cardiovascular events included peripheral arterial occlusive disease (1.4% and

1.1% at 300 mg and 400 mg nilotinib twice daily, respectively), ischaemic heart disease (2.2% and

6.1% at 300 mg and 400 mg nilotinib twice daily, respectively) and ischaemic cerebrovascular events

(1.1% and 2.2% at 300 mg and 400 mg nilotinib twice daily, respectively). Patients should be advised

to seek immediate medical attention if they experience acute signs or symptoms of cardiovascular

events. The cardiovascular status of patients should be evaluated and cardiovascular risk factors

monitored and actively managed during nilotinibTasigna therapy according to standard guidelines.

Appropriate therapy should be prescribed to manage cardiovascular risk factors (see section 4.2 for

instructions on managing non-haematological toxicities).

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these

patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or

fulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with nilotinib

Tasigna.

Experts

in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in

patients with positive hepatitis B serology (including those with active disease) and for patients who

test positive for HBV infection during treatment. Carriers of HBV who require treatment with

nilotinib

Tasigna

should be closely monitored for signs and symptoms of active HBV infection

throughout therapy and for several months following termination of therapy (see section 4.8).

Special monitoring of Ph+ CML patients in chronic phase who have achieved a sustained deep

molecular response

Eligibility for discontinuation of treatment

Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or

e14a2/b3a2, can be considered for treatment discontinuation. Patients must have typical BCR-ABL

transcripts to allow quantitation of BCR-ABL, evaluation of the depth of molecular response, and

determination of a possible loss of molecular remission after discontinuation of treatment with

nilotinib.

Monitoring of patients who have discontinued therapy

Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation

must be performed with a quantitative diagnostic test validated to measure molecular response levels

with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS). BCR-ABL transcript levels must

be assessed prior to and during treatment discontinuation (see sections 4.2 and 5.1).

Loss of major molecular response (MMR=BCR-ABL/ABL ≤0.1%IS) or confirmed loss of MR4 (two

consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL

≤0.01%IS)) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to

have occurred. Molecular relapse can occur during the treatment-free phase, and long-term outcome

data are not yet available. It is therefore crucial to perform frequent monitoring of BCR-ABL transcript

levels and complete blood count with differential in order to detect possible loss of remission (see

section 4.2). For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-

ABL kinase domain mutation testing should be performed

Laboratory tests and monitoring

Blood lipids

In a Phase III study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mg

nilotinib twice daily showed a Grade 3-4 elevation in total cholesterol; no Grade 3-4 elevations were

however observed in the 300 mg twice daily dose group (see section 4.8). It is recommended that the

lipid profiles be determined before initiating treatment with nilotinibTasigna, assessed at month 3 and 6

after initiating therapy and at least yearly during chronic therapy (see section 4.2). If a HMG-CoA

reductase inhibitor (a lipid-lowering agent) is required, please refer to section 4.5 before initiating

treatment since certain HMG-CoA reductase inhibitors are also metabolised by the CYP3A4 pathway.

Blood glucose

In a Phase III study in newly diagnosed CML patients, 6.9% and 7.2% of the patients treated with

400 mg nilotinib and 300 mg nilotinib twice daily, respectively, showed a Grade 3-4 elevation in blood

glucose. It is recommended that the glucose levels be assessed before initiating treatment with Tasigna

and monitored during treatment, as clinically indicated (see section 4.2). If test results warrant therapy,

physicians should follow their local standards of practice and treatment guidelines.

Interactions with other medicinal products

The administration of Tasigna with agents that are strong CYP3A4 inhibitors (including, but not

limited to, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) should be

avoided. Should treatment with any of these agents be required, it is recommended that

nilotinib

therapy with Tasigna be interrupted if possible (see section 4.5). If transient interruption of treatment is

not possible, close monitoring of the individual for prolongation of the QT interval is indicated (see

sections 4.2, 4.5 and 5.2).

Concomitant use of nilotinibTasigna with medicinal products that are potent inducers of CYP3A4 (e.g.

phenytoin, rifampicin, carbamazepine, phenobarbital and St. John’s Wort) is likely to reduce exposure

to nilotinib to a clinically relevant extent. Therefore, in patients receiving nilotinibTasigna, co-

administration of alternative therapeutic agents with less potential for CYP3A4 induction should be

selected (see section 4.5).

Food effect

The bioavailability of nilotinib is increased by food. Tasigna must not be taken in conjunction with

food (see sections 4.2 and 4.5) and should be taken 2 hours after a meal. No food should be consumed

for at least one hour after the dose is taken. Grapefruit juice and other foods that are known to inhibit

CYP3A4 should be avoided. For patients who are unable to swallow capsules, the content of each

capsule may be dispersed in one teaspoon of apple sauce and should be taken immediately. Not more

than one teaspoon of apple sauce and no food other than apple sauce must be used (see section 5.2).

Hepatic impairment

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose

administration of 200 mg of nilotinib resulted in increases in AUC of 35%, 35% and 19% in subjects

with mild, moderate and severe hepatic impairment, respectively, compared to a control group of

subjects with normal hepatic function. The predicted steady-state C

of nilotinib showed an increase

of 29%, 18% and 22%, respectively. Clinical studies have excluded patients with alanine transaminase

(ALT) and/or aspartate transaminase (AST) >2.5 (or >5, if related to disease) times the upper limit of

the normal range and/or total bilirubin >1.5 times the upper limit of the normal range. Metabolism of

nilotinib is mainly hepatic. Patients with hepatic impairment might therefore have increased exposure to

nilotinib and should be treated with caution (see section 4.2).

Serum lipase

Elevation in serum lipase has been observed. Caution is recommended in patients with previous history

of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms,

nilotinib

therapyTasigna should be interrupted and appropriate diagnostic measures considered to exclude

pancreatitis.

Total gastrectomy

The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see section 5.2).

More frequent follow-up of these patients should be considered.

Tumour lysis syndrome

Due to possible occurrence of tumour lysis syndrome (TLS) correction of clinically significant

dehydration and treatment of high uric acid levels are recommended prior to initiating nilotinib therapy

with Tasigna (see section 4.8).

Lactose

Tasigna capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the

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

4.5

Interaction with other medicinal products and other forms of interaction

Tasigna may be given in combination with haematopoietic growth factors such as erythropoietin or

granulocyte colony-stimulating factor (G-CSF) if clinically indicated. It may be given with hydroxyurea

or anagrelide if clinically indicated.

Nilotinib is mainly metabolised in the liver and is also a substrate for the multi-drug efflux pump,

P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed

nilotinib may be influenced by substances that affect CYP3A4 and/or P-gp.

Substances that may increase nilotinib serum concentrations

Concomitant administration of nilotinib with imatinib (a substrate and moderator of P-gp and

CYP3A4), had a slight inhibitory effect on CYP3A4 and/or P-gp. The AUC of imatinib was increased

by 18% to 39%, and the AUC of nilotinib was increased by 18% to 40%. These changes are unlikely to

be clinically important.

The exposure to nilotinib in healthy subjects was increased 3-fold when co-administered with the

strong CYP3A4 inhibitor ketoconazole. Concomitant treatment with strong CYP3A4 inhibitors,

including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin, should

therefore be avoided (see section 4.4). Increased exposure to nilotinib might also be expected with

moderate CYP3A4 inhibitors. Alternative concomitant medicinal products with no or minimal

CYP3A4 inhibition should be considered.

Substances that may decrease nilotinib serum concentrations

Rifampicin, a potent CYP3A4 inducer, decreases nilotinib C

by 64% and reduces nilotinib AUC by

80%. Rifampicin and nilotinib should not be used concomitantly.

The concomitant administration of other medicinal products that induce CYP3A4 (e.g. phenytoin,

carbamazepine, phenobarbital and St. John’s Wort) is likewise likely to reduce exposure to nilotinib to

a clinically relevant extent. In patients for whom CYP3A4 inducers are indicated, alternative agents

with less enzyme induction potential should be selected.

Nilotinib has pH dependent solubility, with lower solubility at higher pH. In healthy subjects receiving

esomeprazole at 40 mg once daily for 5 days, gastric pH was markedly increased, but nilotinib

absorption was only decreased modestly (27% decrease in C

and 34% decrease in AUC0-∞).

Nilotinib may be used concurrently with esomeprazole or other proton pump inhibitors as needed.

In a healthy subjects study, no significant change in nilotinib pharmacokinetics was observed when a

single 400 mg dose of nilotinib

Tasigna was administered 10 hours after and 2 hours before famotidine.

Therefore, when the concurrent use of a H2 blocker is necessary, it may be administered approximately

10 hours before and approximately 2 hours after the dose of Tasigna.

In the same study as above, administration of an antacid (aluminium hydroxide/magnesium

hydroxide/simethicone) 2 hours before or after a single 400 mg dose of nilotinibTasigna also did not

alter nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered

approximately 2 hours before or approximately 2 hours after the dose of Tasigna.

Substances that may have their systemic concentration altered by nilotinib

In vitro

, nilotinib is a relatively strong inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and

UGT1A1, with Ki value being lowest for CYP2C9 (Ki=0.13 microM).

A single-dose drug-drug interaction study in healthy volunteers with 25 mg warfarin, a sensitive

CYP2C9 substrate, and 800 mg nilotinib did not result in any changes in warfarin pharmacokinetic

parameters or warfarin pharmacodynamics measured as prothrombin time (PT) and international

normalised ratio (INR). There are no steady-state data. This study suggests that a clinically meaningful

drug-drug interaction between nilotinib and warfarin is less likely up to a dose of 25 mg of warfarin.

Due to lack of steady-state data, control of warfarin pharmacodynamic markers (INR or PT) following

initiation of nilotinib therapy (at least during the first 2 weeks) is recommended.

In CML patients, nilotinib administered at 400 mg twice daily for 12 days increased the systemic

exposure (AUC and C

) of oral midazolam (a substrate of CYP3A4) 2.6-fold and 2.0-fold,

respectively. Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other

drugs medicinal products primarily metabolised by CYP3A4 (e.g. certain HMG-CoA reductase

inhibitors) may be increased when co-administered with nilotinib. Appropriate monitoring and dose

adjustment may be necessary for drugs medicinal products that are CYP3A4 substrates and have a

narrow therapeutic index (including but not limited to alfentanil, cyclosporine, dihydroergotamine,

ergotamine, fentanyl, sirolimus and tacrolimus) when co-administered with nilotinib.

Anti-arrhythmic medicinal products and other substances that may prolong the QT interval

Concomitant use of anti-arrhythmic medicines (including, but not limited to amiodarone, disopyramide,

procainamide, quinidine and sotalol) and other drugs that may prolong the QT interval (including, but

not limited to chloroquine, halofantrine, clarithromycin, haloperidol methadone, moxifloxacin, bepridil

and pimozide) should be avoided (see section 4.4).

Anti-arrhythmic medicinal products and other substances that may prolong the QT interval

Nilotinib should be used with caution in patients who have or may develop prolongation of the QT

interval, including those patients taking anti-arrhythmic medicinal products such as amiodarone,

disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QT

prolongation such as chloroquine, halofantrine, clarithromycin, haloperidol, methadone and

moxifloxacin (see section 4.4).

Food interactions

The absorption and bioavailability of nilotinibTasigna are increased if it is taken with food, resulting in

a higher serum concentration (see sections 4.2, 4.4 and 5.2). Grapefruit juice and other foods that are

known to inhibit CYP3A4 should be avoided.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

/Contraception

Women of childbearing potential have to use highly effective contraception during treatment with

nilotinib

Tasigna and for up to two weeks after ending treatment.

Pregnancy

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

have shown reproductive toxicity (see section 5.3). Tasigna should not be used during pregnancy unless

the clinical condition of the woman requires treatment with nilotinib. If it is used during pregnancy, the

patient must be informed of the potential risk to the foetus.

If a woman who is being treated with nilotinib is considering pregnancy, treatment discontinuation may

be considered based on the eligibility criteria for discontinuing treatment as described in sections 4.2

and 4.4. There is a limited amount of data on pregnancies in patients while attempting treatment-free

remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a

potential need to re-initiate nilotinib treatment during pregnancy (see sections 4.2 and 4.4).

Breast-feeding

It is unknown whether nilotinib is excreted in human milk. Available toxicological data in animals have

shown excretion of nilotinib in milk (see section 5.3). A risk to the newborns/infants cannot be

excluded. Tasigna should not be used during breast-feeding.

Fertility

Animal studies did not show an effect on fertility in male and female rats (see section 5.3).

4.7

Effects on ability to drive and use machines

Tasigna has no or negligible influence on the ability to drive and use machines. However, it is

recommended that Patients patients experiencing dizziness, fatigue, visual impairment or other

undesirable effects with a potential impact on the ability to drive or use machines safely should refrain

from these activities as long as the undesirable effects persist (see section 4.8).

4.8

Undesirable effects

Summary of the safety profile

The data described below reflect exposure to nilotinibTasigna in a total of 717737 adult patients from a

randomised Phase III study in patients with newly diagnosed Ph+ CML in chronic phase treated at the

recommended dose of 300 mg twice daily (n=279) and from an open-label multicentre Phase II study in

adult patients with imatinib-resistant or intolerant CML in chronic phase (n=321) and accelerated phase

(n=137) treated at the recommended dose of 400 mg twice daily. Safety information from two Tasigna

treatment discontinuation studies is also provided.

In adult patients with newly diagnosed CML in chronic phase

The median duration of exposure was 60.5 months (range 0.1-70.8 months).

The most frequent (≥10%) non-haematological adverse reactions were rash, pruritus, headache, nausea,

fatigue, alopecia, myalgia and upper abdominal pain. Most of these adverse reactions were mild to

moderate in severity. Constipation, dry skin, asthenia, muscle spasms, diarrhoea, arthralgia, abdominal

pain, vomiting and peripheral oedema were observed less commonly (<10% and ≥5%) were of mild to

moderate severity, manageable and generally did not require dose reduction.

Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (18%),

neutropenia (15%) and anaemia (8%). Biochemical adverse drug reactions include alanine

aminotransferase increased (24%), hyperbilirubinaemia (16%), aspartate aminotransferase increased

(12%), lipase increased (11%), blood bilirubin increased (10%), hyperglycaemia (4%),

hypercholesterolaemia (3%) and hypertriglyceridaemia (<1%). Pleural and pericardial effusions,

regardless of causality, occurred in 2% and <1% of patients, respectively, receiving nilotinibTasigna

300 mg twice daily. Gastrointestinal haemorrhage, regardless of causality, was reported in 3% of these

patients.

The change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient

had an absolute QTcF >500 msec while on the study medicinal product. QTcF increase from baseline

exceeding 60 msec was observed in <1% of patients while on the study medicinal product. No sudden

deaths or episodes of torsade de pointes (transient or sustained) were observed. No decrease from

baseline in mean left ventricular ejection fraction (LVEF) was observed at any time during treatment.

No patient had a LVEF of <45% during treatment nor an absolute reduction in LVEF of more than

15%.

Discontinuation due to adverse drug reactions was observed in 10% of patients.

In adult patients with imatinib-resistant or intolerant CML in chronic phase and accelerated phase

The data described below reflect exposure to nilotinibTasigna in 458 adult patients in an open-label

multicentre Phase II study in patients with imatinib-resistant or intolerant CML in chronic phase

(n=321) and accelerated phase (n=137) treated at the recommended dose of 400 mg twice daily.

The most frequent (≥10%) non-haematological drug-related adverse events were rash, pruritus, nausea,

fatigue, headache, vomiting, myalgia, constipation and diarrhoea. Most of these adverse events were

mild to moderate in severity. Alopecia, muscle spasms, decreased appetite, arthralgia, abdominal pain,

bone pain, peripheral oedema, asthenia, upper abdominal pain, dry skin, erythema and pain in extremity

were observed less commonly (<10% and ≥5%) and have been of mild to moderate severity (Grade 1

or 2). Discontinuation due to adverse drug reactions was observed in 16% of chronic phase and 10% of

accelerated phase patients.

Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (31%),

neutropenia (17%) and anaemia (14%). Pleural and pericardial effusions as well as complications of

fluid retention occurred in <1% of patients receiving Tasigna. Cardiac failure was observed in <1% of

patients. Gastrointestinal and CNS haemorrhage were reported in 1% and <1% of patients,

respectively.

QTcF exceeding 500 msec was observed in <1% of patients. No episodes of torsade de pointes

(transient or sustained) were observed.

Tabulated list of adverse reactions

The adverse reactions are ranked under heading of frequency using the following convention: very

common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to

<1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within

each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Most frequently reported adverse reactions in Tasigna clinical studies

Non-haematological adverse reactions (excluding laboratory abnormalities) that are reported in at least

5% of the patients in Tasigna clinical studies that serve as the basis for the approved indications are

shown in Table 2. These are ranked under heading of frequency; with the most frequent appearing first,

using one decimal precision for percentages and the following convention: very common (≥1/10) or

common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order

of decreasing seriousness.

Table 2

Non-haematological adverse reactions (≥5% of all patients)

Newly diagnosed CML-CP

300 mg twice daily

n=279

Imatinib-resistant or intolerant

CML-CP and CML-AP

400 mg twice daily

n=458

60-month analysis

24-month analysis

System organ

class/

Adverse

reaction

Frequency

All

grades

Grade

3-4

Frequency

All

grades

Grade

3-4

CML-

CP

n=321

Grade

3-4

CML-

AP

n=137

Grade

3-4

%

%

%

%

%

%

Metabolism and nutrition disorders

Decreased

appetite **

Common

Common

<1

<1

Nervous system disorders

Headache

Very

common

Very

common

<1

Gastrointestinal disorders

Nausea

Very

common

<1

Very

common

<1

<1

<1

Constipation

Common

Very

common

<1

<1

Diarrhoea

Common

<1

Very

common

<1

Vomiting

Common

Very

common

<1

<1

Upper

abdominal pain

Very

common

Common

<1

<1

Abdominal pain

Common

Common

<1

<1

<1

Dyspepsia

Common

Common

Skin and subcutaneous tissue disorders

Rash

Very

common

<1

Very

common

Pruritus

Very

common

<1

Very

common

<1

<1

Alopecia

Very

common

Common

Dry skin

Common

Common

Erythema

Common

Common

<1

<1

Musculoskeletal and connective tissue disorders

Myalgia

Very

common

<1

Very

common

<1

<1

<1

Muscle spasms

Common

Common

<1

<1

Arthralgia

Common

<1

Common

<1

Bone pain

Common

Common

<1

<1

Pain in

extremity

Common

<1

Common

<1

<1

<1

General disorders and administration site conditions

Fatigue

Very

common

Very

common

<1

Asthenia

Common

<1

Common

<1

<1

Oedema

peripheral

Common

Common

* Percentages are rounded to integer for presentation in this table. However, percentages with one

decimal precision are used to identify terms with a frequency of at least 5% and to classify terms

according to frequency categories.

**Also includes preferred term anorexia

The following adverse reactions were reported in adult patients in the Tasigna clinical studies which

serve as a basis for the approved indications at a frequency of less than 5%. For laboratory

abnormalities, very common adverse reactions events (

1/10) not included in Table 2 are also reported.

These adverse reactions are included based on clinical relevance. and ranked in order of decreasing

seriousness within each category using the following convention: very common (≥1/10), common

(≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), not known (cannot be estimated from the

available data).

Infections and infestations:

Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis).

Uncommon: pneumonia, urinary tract infection, gastroenteritis, bronchitis, herpes virus infection,

candidiasis (including oral candidiasis).

Not known: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis, hepatitis B reactivation.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Common: skin papilloma.

Not known: oral papilloma, paraproteinaemia.

Blood and lymphatic system disorders:

Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia.

Uncommon: thrombocythaemia, leukocytosis.

Immune system disorders:

Not known: hypersensitivity.

Endocrine disorders

Uncommon: hyperthyroidism, hypothyroidism.

Not known: hyperparathyroidism secondary, thyroiditis.

Metabolism and nutrition disorders:

Very common: hypophosphataemia (including blood phosphorus decreased).

Common: electrolyte imbalance (including hypomagnesaemia, hyperkalaemia, hypokalaemia,

hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia), diabetes mellitus,

hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia.

Uncommon: dehydration, increased appetite, gout, dyslipidaemia.

Not known: hyperuricaemia, hypoglycaemia, appetite disorder.

Psychiatric disorders:

Common: depression, insomnia, anxiety.

Not known: disorientation, confusional state, amnesia, dysphoria.

Nervous system disorders:

Common: dizziness, peripheral neuropathy, hypoaesthesia, paraesthesia.

Uncommon: intracranial haemorrhage, ischaemic stroke, transient ischaemic attack, cerebral infarction,

migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperaesthesia.

Not known: cerebrovascular accident, brain oedema, optic neuritis, lethargy, dysaesthesia, restless legs

syndrome, basilar artery stenosis.

Eye disorders:

Common: eye haemorrhage, periorbital oedema, eye pruritus, conjunctivitis, dry eye (including

xerophthalmia).

Uncommon: visual impairment, vision blurred, conjunctival haemorrhage, visual acuity reduced, eyelid

oedema, photopsia, hyperaemia (scleral, conjunctival, ocular), eye irritation.

Not known: papilloedema, chorioretinopathy, diplopia, photophobia, eye swelling, blepharitis, eye pain,

conjunctivitis allergic, ocular surface disease.

Ear and labyrinth disorders:

Common: vertigo.

Not known: hearing impaired, ear pain, tinnitus.

Cardiac disorders:

Common: angina pectoris, arrhythmia (including atroventricular block, cardiac flutter, extrasystoles,

tachycardia, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged.

Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur,

pericardial effusion, cyanosis.

Not known: ventricular dysfunction, pericarditis, ejection fraction decreased, diastolic dysfunction.

Vascular disorders:

Common: hypertension, flushing, peripheral artery stenosis.

Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial

stenosis limb, haematoma, arteriosclerosis.

Not known: shock haemorrhagic, hypotension, thrombosis.

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea, dyspnoea exertional, epistaxis, cough, dysphonia.

Uncommon: pulmonary oedema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy,

pharyngolaryngeal pain, throat irritation.

Not known: pulmonary hypertension, wheezing, oropharyngeal pain.

Gastrointestinal disorders:

Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence.

Uncommon: gastrointestinal haemorrhage, melaena, mouth ulceration, gastroesophageal reflux,

stomatitis, oesophageal pain, dry mouth, gastritis, sensitivity of teeth.

Not known: gastrointestinal ulcer perforation, retroperitoneal haemorrhage, haematemesis, gastric

ulcer, oesophagitis ulcerative, subileus, enterocolitis, haemorrhoids, hiatus hernia, rectal haemorrhage,

gingivitis.

Hepatobiliary disorders:

Very common: hyperbilirubinaemia (including blood bilirubin increased).

Common: hepatic function abnormal.

Uncommon: hepatotoxicity, toxic hepatitis, jaundice.

Not known: cholestasis, hepatomegaly.

Skin and subcutaneous tissue disorders:

Common: night sweats, eczema, urticaria, hyperhidrosis, contusion, acne, dermatitis (including allergic,

exfoliative and acneiform).

Uncommon: exfoliative rash, drug eruption, skin pain, ecchymosis, swelling face.

Not known: erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysaesthesia

syndrome, petechiae, photosensitivity, blister, dermal cysts, sebaceous hyperplasia, skin atrophy, skin

discolouration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis, psoriasis.

Musculoskeletal and connective tissue disorders:

Common: musculoskeletal chest pain, musculoskeletal pain, back pain, flank pain, neck pain, muscular

weakness.

Uncommon: musculoskeletal stiffness, joint swelling.

Not known: arthritis.

Renal and urinary disorders:

Common: pollakiuria.

Uncommon: dysuria, micturition urgency, nocturia.

Not known: renal failure, haematuria, urinary incontinence, chromaturia.

Reproductive system and breast disorders:

Uncommon: breast pain, gynaecomastia, erectile dysfunction.

Not known: breast induration, menorrhagia, nipple swelling.

General disorders and administration site conditions:

Common: chest pain (including non-cardiac chest pain), pain, pyrexia, chest discomfort, malaise.

Uncommon: face oedema, gravitational oedema, influenza-like illness, chills, feeling body temperature

change (including feeling hot, feeling cold).

Not known: localised oedema.

Investigations:

Very common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase

increased, lipoprotein cholesterol (including low density and high density) increased, total cholesterol

increased, blood triglycerides increased.

Common: haemoglobin decreased, blood amylase increased, blood alkaline phosphatase increased,

gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased,

weight increased, blood insulin increased, globulins decreased.

Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood urea increased.

Not known: troponin increased, blood bilirubin unconjugated increased, blood insulin decreased,

insulin C-peptide decreased, blood parathyroid hormone increased.

Clinically relevant or severe abnormalities of routine haematological or biochemistry laboratory values

In adult patients are presented in Table 3.

Table 3

Grade 3-4 laboratory abnormalities

Newly diagnosed

CML-CP

300 mg twice

daily

Imatinib-resistant or intolerant

CML-CP and CML-AP

400 mg twice daily

n=279

(%)

CML-CP

n=321

(%)

CML-AP

n=137

(%)

Haematological parameters

Myelosuppression

- Neutropenia

- Thrombocytopenia

- Anaemia

Biochemistry parameters

- Elevated creatinine

<1

- Elevated lipase

- Elevated SGOT (AST)

- Elevated SGPT (ALT)

- Hypophosphataemia

- Elevated bilirubin (total)

- Elevated glucose

- Elevated cholesterol (total)

- Elevated triglycerides

*Percentages with one decimal precision are used and rounded to integer for presentation in this table

**Parameters not collected

Treatment discontinuation in Ph+ CML patients in chronic phase who have achieved a sustained deep

molecular response

After discontinuation of nilotinib therapy within the framework of attempting TFR, patients may

experience musculoskeletal symptoms more frequently than before treatment discontinuation, e.g.,

myalgia, pain in extremity, arthralgia, bone pain, spinal pain or musculoskeletal pain.

In a Phase II clinical study with newly diagnosed patients with Ph+ CML in chronic phase (N=190),

musculoskeletal symptoms were reported within a year of Tasigna discontinuation in 24.7% versus

16.3% within the previous year on nilotinib treatment.

In a Phase II clinical study with patients with Ph+ CML in chronic phase on nilotinib treatment and

previously treated with imatinib (N=126), musculoskeletal symptoms were reported within a year of

discontinuation in 42.1% versus 14.3% within the previous year on nilotinib treatment

Description of selected adverse reactions

Sudden death

Uncommon cases (0.1 to 1%) of sudden deaths have been reported in Tasigna clinical trials and/or

compassionate use programs in patients with imatinib-resistant or intolerant CML in chronic phase or

accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors (see

section 4.4).

Hepatitis B reactivation

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in

acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see

section 4.4).

Post-marketing experience

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

spontaneous case reports, literature cases, expanded access programmes, and clinical studies other than

the global registration trials. Since these reactions are reported voluntarily from a population of

uncertain size, it is not always possible to reliably estimate their frequency or establish a causal

relationship to nilotinib exposure.

Frequency rare: Cases of tumour lysis syndrome have been reported in patients treated with

Tasignanilotinib

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

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

Regulation by using an online form

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

4.9

Overdose

Isolated reports of intentional overdose with nilotinib were reported, where an unspecified number of

Tasigna capsules were ingested in combination with alcohol and other medicinal products. Events

included neutropenia, vomiting and drowsiness. No ECG changes or hepatotoxicity were reported.

Outcomes were reported as recovered.

In the event of overdose, the patient should be observed and appropriate supportive treatment given.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE08

Mechanism of action

Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in

cell lines and in primary Philadelphia-chromosome positive leukaemia cells. The substance binds with

high affinity to the ATP-binding site in such a manner that it is a potent inhibitor of wild-type BCR-

ABL and maintains activity against 32/33 imatinib-resistant mutant forms of BCR-ABL. As a

consequence of this biochemical activity, nilotinib selectively inhibits the proliferation and induces

apoptosis in cell lines and in primary Philadelphia-chromosome positive leukaemia cells from CML

patients. In murine models of CML, as a single agent nilotinib reduces tumour burden and prolongs

survival following oral administration.

Pharmacodynamic effects

Nilotinib has little or no effect against the majority of other protein kinases examined, including Src,

except for the PDGF, KIT and Ephrin receptor kinases, which it inhibits at concentrations within the

range achieved following oral administration at therapeutic doses recommended for the treatment of

CML (see Table 4).

Table 4

Kinase profile of nilotinib (phosphorylation IC

50

nM)

BCR-ABL

PDGFR

Clinical efficacy

Clinical studies in newly diagnosed CML in chronic phase

An open-label, multicentre, randomised Phase III study was conducted to determine the efficacy of

nilotinib versus imatinib in 846 adult patients with cytogenetically confirmed newly diagnosed

Philadelphia chromosome positive CML in the chronic phase. Patients were within six months of

diagnosis and were previously untreated, with the exception of hydroxyurea and/or anagrelide. Patients

were randomised 1:1:1 to receive either nilotinib 300 mg twice daily (n=282), nilotinib 400 mg twice

daily (n=281) or imatinib 400 mg once daily (n=283). Randomisation was stratified by Sokal risk score

at the time of diagnosis.

Baseline characteristics were well balanced between the three treatment arms. Median age was 47 years

in both nilotinib arms and 46 years in the imatinib arm, with 12.8%, 10.0% and 12.4% of patients were

≥65 years of age in the nilotinib 300 mg twice daily, nilotinib 400 mg twice daily and imatinib 400 mg

once daily treatment arms, respectively. There were slightly more male than female patients (56.0%,

62.3% and 55.8%, in the nilotinib 300 mg twice daily, 400 mg twice daily and imatinib 400 mg once

daily arm, respectively). More than 60% of all patients were Caucasian and 25% of all patients were

Asian.

The primary data analysis time point was when all 846 patients completed 12 months of treatment (or

discontinued earlier). Subsequent analyses reflect when patients completed 24, 36, 48, 60 and

72 months of treatment (or discontinued earlier). The median time on treatment was approximately

70 months in the nilotinib treatment groups and 64 months in the imatinib group. The median actual

dose intensity was 593 mg/day for nilotinib 300 mg twice daily, 772 mg/day for nilotinib 400 mg twice

daily and 400 mg/day for imatinib 400 mg once daily. This study is ongoing.

The primary efficacy endpoint was major molecular response (MMR) at 12 months. MMR was defined

as ≤0.1% BCR-ABL/ABL% by international scale (IS) measured by RQ-PCR, which corresponds to a

≥3 log reduction of BCR-ABL transcript from standardised baseline. The MMR rate at 12 months was

statistically significantly higher for nilotinib 300 mg twice daily compared to imatinib 400 mg once

daily (44.3% versus 22.3%, p<0.0001). The rate of MMR at 12 months, was also statistically

significantly higher for nilotinib 400 mg twice daily compared to imatinib 400 mg once daily (42.7%

versus 22.3%, p<0.0001).

The rates of MMR at 3, 6, 9 and 12 months were 8.9%, 33.0%, 43.3% and 44.3% for nilotinib 300 mg

twice daily, 5.0%, 29.5%, 38.1% and 42.7% for nilotinib 400 mg twice daily and 0.7%, 12.0%, 18.0%

and 22.3% for imatinib 400 mg once daily.

The MMR rate at 12, 24, 36, 48, 60 and 72 months is presented in Table 5.

Table 5

MMR rate

TasignaNilotinib

mg twice daily

n=282

NilotinibTasigna

400 mg twice daily

n=281

Imatinib

400 mg once daily

n=283

MMRat 12 months

Response (95% CI)

44.3

(38.4; 50.3)

42.7

(36.8; 48.7)

22.3 (17.6; 27.6)

MMR at 24 months

Response (95% CI)

61.7

(55.8; 67.4)

59.1

(53.1; 64.9)

37.5 (31.8; 43.4)

MMR at 36 months

2

Response (95% CI)

58.5

(52.5; 64.3)

57.3

(51.3; 63.2)

38.5 (32.8; 44.5)

MMR at 48 months

3

Response (95% CI)

59.9

(54.0; 65.7)

55.2 (49.1; 61.1)

43.8 (38.0; 49.8)

MMR at 60 months

4

Response (95% CI)

62.8 (56.8; 68.4)

61.2 (55.2; 66.9)

49.1 (43.2; 55.1)

MMR at 72 months

5

Response (95% CI)

52.5 (46.5; 58.4)

57.7 (51.6; 63.5)

41.7 (35.9; 47.7)

Cochran-Mantel-Haenszel (CMH) test p-value for response rate (vs. imatinib 400 mg) <0.0001

Only patients who were in MMR at a specific time point are included as responders for that time

point. A total of 199 (35.2%) of all patients were not evaluable for MMR at 36 months (87 in the

nilotinib 300 mg twice daily group and 112 in the imatinib group) due to missing/unevaluable PCR

assessments (n=17), atypical transcripts at baseline (n=7), or discontinuation prior to the 36-month time

point (n=175).

Only patients who were in MMR at a specific time point are included as responders for that time

point. A total of 305 (36.1%) of all patients were not evaluable for MMR at 48 months (98 in the

nilotinib 300 mg BID group, 88 in the nilotinib 400 mg BID group and 119 in the imatinib group) due

to missing/unevaluable PCR assessments (n=18), atypical transcripts at baseline (n=8), or

discontinuation prior to the 48-month time point (n=279).

Only patients who were in MMR at a specific time point are included as responders for that time

point. A total of 322 (38.1%) of all patients were not evaluable for MMR at 60 months (99 in the

nilotinib 300 mg twice daily group, 93 in the nilotinib 400 mg twice daily group and 130 in the imatinib

group) due to missing/unevaluable PCR assessments (n=9), atypical transcripts at baseline (n=8) or

discontinuation prior to the 60-month time point (n=305).

Only patients who were in MMR at a specific time point are included as responders for that time

point. A total of 395 (46.7%) of all patients were not evaluable for MMR at 72 months (130 in the

nilotinib 300 mg twice daily group, 110 in the nilotinib 400 mg twice daily group and 155 in the

imatinib group) due to missing/unevaluable PCR assessments (n=25), atypical transcripts at baseline

(n=8) or discontinuation prior to the 72-month time point (n=362).

MMR rates by different time points (including patients who achieved MMR at or before those time

points as responders) are presented in the cumulative incidence of MMR (see Figure 1).

Figure 1

Cumulative incidence of MMR

For all Sokal risk groups, the MMR rates at all time points remained consistently higher in the two

nilotinib groups than in the imatinib group.

In a retrospective analysis, 91% (234/258) of patients on nilotinib 300 mg twice daily achieved BCR-

ABL levels ≤ 10% at 3 months of treatment compared to 67% (176/264) of patients on imatinib 400 mg

once daily. Patients with BCR-ABL levels ≤ 10% at 3 months of treatment show a greater overall

survival at 72 months compared to those who did not achieve this molecular response level (94.5% vs.

77.1% respectively [p=0.0005]).

Based on the Kaplan-Meier analysis of time to first MMR the probability of achieving MMR at

different time points was higher for both nilotinib at 300 mg and 400 mg twice daily compared to

imatinib 400 mg once daily (HR=2.17 and stratified log-rank p<0.0001 between nilotinib 300 mg twice

daily and imatinib 400 mg once daily, HR=1.88 and stratified log-rank p<0.0001 between nilotinib

400 mg twice daily and imatinib 400 mg once daily).

The proportion of patients who had a molecular response of ≤0.01% and ≤0.0032% by IS at different

time points are presented in Table 6 and the proportion of patients who had a molecular response of

≤0.01% and ≤0.0032% by IS by different time points are presented in Figures 2 and 3. Molecular

responses of ≤0.01% and ≤0.0032% by IS correspond to a ≥4 log reduction and ≥4.5 log reduction,

respectively, of BCR-ABL transcripts from a standardised baseline.

Months Since since Randomisationrandomisation

Cumulative Incidence incidence of

MMR, %

By

1 year

By

2 years

By

3 years

By

4 years

By

5 years

55%; P < .0001

71%; P < .0001

73%; P < .0001

76%; P < .0001

77%; P < .0001

61%;

P < .0001

70%; P < .0001

73%; P < .0001

77%; P < .0001

51%;

P < .0001

NilotinibTasigna 300 mg twice daily (n =

282)

NilotinibTasigna 400 mg twice daily (n =

281)

Imatinib 400 mg once daily (n = 283)

By

6 years

79%; P < .0001

77%; P < .0001

Table 6

Proportions of patients who had molecular response of ≤0.01% (4 log reduction) and

≤0.0032% (4.5 log reduction)

NilotinibTasigna

300 mg twice daily

n=282

NilotinibTasigna

400 mg twice daily

n=281

Imatinib

400 mg once daily

n=283

≤0.01%

≤0.0032%

≤0.01%

≤ 0.0032%

≤0.01%

≤0.0032%

At 12 months

11.7

At 24 months

24.5

12.4

22.1

10.2

At 36 months

29.4

13.8

23.8

12.1

14.1

At 48 months

33.0

16.3

29.9

17.1

19.8

10.2

At 60 months

47.9

32.3

43.4

29.5

31.1

19.8

At 72 months

44.3

31.2

45.2

28.8

27.2

18.0

Figure 2

Cumulative incidence of molecular response of ≤0.01% (4-log reduction)

Cumulative iIncidence of MR

4

(BCR-ABL ≤0.01% on the iInternational

Scalescale), %

39%; P < .0001

50%; P < .0001

56%; P < .0001

66%; P < .0001

33%;

P < .0001

44%;

P < .0001

50%; P < .0001

63%;

P < .0001

67%; P < .0001

65%; P < .0001

20%; P < .0001

15%; P = .0004

Months Since since Randomisation randomisation

NilotinibTasigna 300 mg twice daily (n = 282)

NilotinibTasigna 400 mg twice daily (n =

281)

Imatinib 400 mg once daily (n = 283)

By

1 year

By

2 years

By

3 years

By

4 years

By

5 years

By

6 years

Figure 3

Cumulative incidence of molecular response of ≤0.0032% (4.5 log reduction)

Based on Kaplan-Meier estimates of the duration of first MMR, the proportions of patients who were

maintaining response for 72 months among patients who achieved MMR were 92.5% (95% CI:

88.6-96.4%) in the nilotinib 300 mg twice daily group, 92.2% (95% CI: 88.5-95.9%) in the nilotinib

400 mg twice daily group and 88.0% (95% CI: 83.084.2-93.194.0%) in the imatinib 400 mg once daily

group.

Complete cytogenetic response (CCyR) was defined as 0% Ph+ metaphases in the bone marrow based

on a minimum of 20 metaphases evaluated. Best CCyR rate by 12 months (including patients who

achieved CCyR at or before the 12 month time point as responders) was statistically higher for both

nilotinib 300 mg and 400 mg twice daily compared to imatinib 400 mg once daily, see Table 7.

CCyR rate by 24 months (includes patients who achieved CCyR at or before the 24 month time point as

responders) was statistically higher for both the nilotinib 300 mg twice daily and 400 mg twice daily

groups compared to the imatinib 400 mg once daily group.

25%; P < .0001

32%; P < .0001

40%; P < .0001

54%; P < .0001

19%;

P = .0006

28%;

P = .0003

37%;

P = .0002

52%;

P < .0001

56%; P < .0001

55%; P < .0001

11%; P < .0001

7%; P < .0001

Cumulative Incidence incidence of MR

4.5

(BCR-ABL ≤0.0032% on the International

international Scalescale), %

NilotinibTasigna 300 mg twice daily (n = 282)

NilotinibTasigna 400 mg twice daily (n = 281)

Imatinib 400 mg once daily (n = 283)

Months Since since

Randomisationrandomisation

By

1 year

By

2 years

By

3 years

By

4 years

By

5 years

By

6 years

Table 7

Best complete cytogenetic response (CCyR) rate

Tasigna

(nNilotinib)

300 mg twice daily

n=282

Tasigna

(Nnilotinib)

400 mg twice daily

n=281

Glivec (Iimatinib)

400 mg once daily

n=283

By 12 months

Response (95% CI)

80.1 (75.0; 84.6)

77.9 (72.6; 82.6)

65.0 (59.2; 70.6)

No response

19.9

22.1

35.0

CMH test p-value for response rate

(versus imatinib 400 mg once daily)

<0.0001

0.0005

By 24 months

Response (95% CI)

86.9 (82.4; 90.6)

84.7 (79.9; 88.7)

77.0 (71.7; 81.8)

No response

13.1

15.3

23.0

CMH test p-value for response rate

(versus imatinib 400 mg once daily)

0.0018

0.0160

Based on Kaplan-Meier estimates, the proportions of patients who were maintaining response for

72 months among patients who achieved CCyR were 99.1% (95% CI: 97.9-100%) in the nilotinib

300 mg twice daily group, 98.7% (95% CI: 97.1-100%) in the nilotinib 400 mg twice daily group and

97.0% (95% CI: 94.7-99.4%) in the imatinib 400 mg once daily group.

Progression to accelerated phase (AP) or blast crisis (BC) on treatment is defined as the time from the

date of randomisation to the first documented disease progression to accelerated phase or blast crisis or

CML-related death. Progression to accelerated phase or blast crisis on treatment was observed in a total

of 17 patients: 2 patients on nilotinib 300 mg twice daily, 3 patients on nilotinib 400 mg twice daily and

12 patients on imatinib 400 mg once daily. The estimated rates of patients free from progression to

accelerated phase or blast crisis at 72 months were 99.3%, 98.7% and 95.2%, respectively (HR=0.1599

and stratified log-rank p=0.0059 between nilotinib 300 mg twice daily and imatinib once daily,

HR=0.2457 and stratified log-rank p=0.0185 between nilotinib 400 mg twice daily and imatinib once

daily). No new events of progression to AP/BC were reported on-treatment since the 2-year analysis.

Including clonal evolution as a criterion for progression, a total of 25 patients progressed to accelerated

phase or blast crisis on treatment by the cut-off date (3 in the nilotinib 300 mg twice daily group, 5 in

the nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group). The estimated

rates of patients free from progression to accelerated phase or blast crisis including clonal evolution at

72 months were 98.7%, 97.9% and 93.2%, respectively (HR=0.1626 and stratified log-rank p=0.0009

between nilotinib 300 mg twice daily and imatinib once daily, HR=0.2848 and stratified log-rank

p=0.0085 between nilotinib 400 mg twice daily and imatinib once daily).

A total of 55 patients died during treatment or during the follow-up after discontinuation of treatment.

(21 in the nilotinib 300 mg twice daily group, 11 in the nilotinib 400 mg twice daily group and 23 in the

imatinib 400 mg once daily group). Twenty-six (26) of these 55 deaths were related to CML (6 in the

nilotinib 300 mg twice daily group, 4 in the nilotinib 400 mg twice daily group and 16 in the imatinib

400 mg once daily group). The estimated rates of patients alive at 72 months were 91.6%, 95.8% and

91.4%, respectively (HR=0.8934 and stratified log-rank p=0.7085 between nilotinib 300 mg twice

daily and imatinib, HR=0.4632 and stratified log-rank p=0.0314 between nilotinib 400 mg twice daily

and imatinib). Considering only CML-related deaths as events, the estimated rates of overall survival at

72 months were 97.7%, 98.5% and 93.9%, respectively (HR=0.3694 and stratified log-rank p=0.0302

between nilotinib 300 mg twice daily and imatinib, HR=0.2433 and stratified log-rank p=0.0061

between nilotinib 400 mg twice daily and imatinib).

Clinical studies in imatinib-resistant or intolerant CML in chronic phase and accelerated phase

An open-label, uncontrolled, multicentre Phase II study was conducted to determine the efficacy of

Tasigna nilotinib in patients with imatinib resistant or intolerant CML with separate treatment arms for

chronic and accelerated phase disease. Efficacy was based on 321 CP patients and 137 AP patients

enrolled. Median duration of treatment was 561 days for CP patients and 264 days for AP patients (see

Table 8). Tasigna was administered on a continuous basis (twice daily 2 hours after a meal and with no

food for at least one hour after administration) unless there was evidence of inadequate response or

disease progression. The dose was 400 mg twice daily and dose escalation to 600 mg twice daily was

allowed.

Table 8

Duration of exposure with

nilotinib

Tasigna

Chronic phase

n=321

Accelerated phase

n=137

Median duration of therapy in days

(25th-75th percentiles)

(196-852)

(115-595)

Resistance to imatinib included failure to achieve a complete haematological response (by 3 months),

cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of

disease after a previous cytogenetic or haematological response. Imatinib intolerance included patients

who discontinued imatinib because of toxicity and were not in major cytogenetic response at time of

study entry.

Overall, 73% of patients were imatinib-resistant, while 27% were imatinib-intolerant. The majority of

patients had a long history of CML that included extensive prior treatment with other antineoplastic

agents, including imatinib, hydroxyurea, interferon, and some had even failed organ transplant

(Table 9). The median highest prior imatinib dose had been 600 mg/day. The highest prior imatinib

dose was

600 mg/day in 74% of all patients, with 40% of patients receiving imatinib doses

800 mg/day.

Table 9

CML disease history characteristics

Chronic phase

(n=321)

Accelerated phase

(n=137)*

Median time since diagnosis in months

(range)

(5–275)

(2–298)

Imatinib

Resistant

Intolerant without MCyR

226 (70%)

95 (30%)

109 (80%)

27 (20%)

Median time of imatinib treatment in

days

(25th-75

percentiles)

(519-1,488)

(424-1,497)

Prior hydroxyurea

Prior interferon

Prior bone marrow transplant

* Missing information on imatinib-resistant/intolerant status for one patient.

The primary endpoint in the CP patients was major cytogenetic response (MCyR), defined as

elimination (CCyR, complete cytogenetic response) or significant reduction to <35% Ph+ metaphases

(partial cytogenetic response) of Ph+ haematopoietic cells. Complete haematological response (CHR)

in CP patients was evaluated as a secondary endpoint. The primary endpoint in the AP patients was

overall confirmed haematological response (HR), defined as either a complete haematological response,

no evidence of leukaemia or return to chronic phase.

Chronic Phasephase

The MCyR rate in 321 CP patients was 51%. Most responders achieved their MCyR rapidly within

3 months (median 2.8 months) of starting nilotinibTasigna treatment and these were sustained. The

median time to achieve CCyR was just past 3 months (median 3.4 months). Of the patients who

achieved MCyR, 77% (95% CI: 70% - 84%) were maintaining response at 24 months. Median duration

of MCyR has not been reached. Of the patients who achieved CCyR, 85% (95% CI: 78% - 93%) were

maintaining response at 24 months. Median duration of CCyR has not been reached. Patients with a

CHR at baseline achieved a MCyR faster (1.9 versus 2.8 months). Of CP patients without a baseline

CHR, 70% achieved a CHR, median time to CHR was 1 month and median duration of CHR was

32.8 months. The estimated 24-month overall survival rate in CML-CP patients was 87%.

Accelerated Phasephase

The overall confirmed HR rate in 137 AP patients was 50%. Most responders achieved a HR early with

nilotinibTasigna treatment (median 1.0 months) and these have been durable (median duration of

confirmed HR was 24.2 months). Of the patients who achieved HR, 53% (95% CI: 39% - 67%) were

maintaining response at 24 months. MCyR rate was 30% with a median time to response of 2.8 months.

Of the patients who achieved MCyR, 63% (95% CI: 45% - 80%) were maintaining response at

24 months. Median duration of MCyR was 32.7 months. The estimated 24-month overall survival rate

in CML-AP patients was 70%.

The rates of response for the two treatment arms are reported in Table 10.

Table 10

Response in CML

(Best Response

response rRate)

Chronic Phasephase

Accelerated Phasephase

Intolerant

(n=95)

Resistant

(n=226)

Total

(n=321)

Intolerant

(n=27)

Resistant

(n=109)

Total*

(n=137)

Haematological

Response (%)

Overall (95%CI)

Complete

Return to CP

87 (74-94)

65 (56-72)

(63-76)

48 (29-68)

51 (42-61)

50 (42-59)

Cytogenetic

Response (%)

Major (95%CI)

Complete

Partial

57 (46-67)

49 (42-56)

51 (46-57)

33 (17-54)

29 (21-39)

30 (22-38)

NEL = no evidence of leukaemia/marrow response

114 CP patients had a CHR at baseline and were therefore not assessable for complete haematological

response

* Missing information on imatinib-resistant/intolerant status for one patient.

Efficacy data in patients with CML-BC are not yet available. Separate treatment arms were also

included in the Phase II study to investigate Tasigna in a group of CP and AP patients who had been

extensively pre-treated with multiple therapies including a tyrosine kinase inhibitor agent in addition to

imatinib. Of these patients 30/36 (83%) were treatment resistant not intolerant. In 22 CP patients

evaluated for efficacy nilotinibTasigna induced a 32% MCyR rate and a 50% CHR rate. In 11 AP

patients, evaluated for efficacy, treatment induced a 36% overall HR rate.

After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54%

of accelerated phase CML patients who were evaluated for mutations. Tasigna demonstrated efficacy

in patients harboring a variety of BCR-ABL mutations associated with imatinib resistance, except

T315I.

Treatment discontinuation in Ph+ CML patients in chronic phase who have been treated with nilotinib

as first-line therapy and who have achieved a sustained deep molecular response

In an open-label, single-arm study, 215 adult patients with Ph+ CML in chronic phase treated with

nilotinib in first-line for ≥2 years who achieved MR4.5 as measured with the MolecularMD MRDx™

BCR-ABL test were enrolled to continue nilotinib treatment for additional 52 weeks (nilotinib

consolidation phase). 190 of 215 patients (88.4%) entered the TFR phase after achieving a sustained

deep molecular response during the consolidation phase, defined by the following criteria:

the 4 last quarterly assessments (taken every 12 weeks) were at least MR4 (BCR-ABL/ABL

≤0.01% IS), and maintained for one year

the last assessment being MR4.5 (BCR-ABL/ABL ≤0.0032% IS)

no more than two assessments falling between MR4 and MR4.5 (0.0032% IS < BCR-ABL/ABL

≤0.01% IS).

The primary endpoint was the percentage of patients in MMR at 48 weeks after starting the TFR phase

(considering any patient who required re-initiation of treatment as non-responder). Of the 190 patients

who entered the TFR phase, 98 patients (51.6% [95% CI: 44.2, 58.9]) were in MMR at 48 weeks.

Eighty-eight patients (46.3%) discontinued the TFR phase due to loss of MMR, and 1 (0.5%), 1

(0.5%), and 3 patients (1.6%) due to death from unknown cause, physician decision and subject

decision, respectively. Among these 88 patients, 86 patients restarted nilotinib treatment and 2 patients

permanently discontinued the study. Eighty-five of these 86 patients (98.8%) regained MMR, (one

patient discontinued study permanently due to subject decision) and 76 patients (88.4%) regained

MR4.5 by the time of the cut-off date.

The Kaplan-Meier (KM) estimated median time on nilotinib treatment to regain MMR and MR4.5 was

7.9 weeks (95% CI: 5.1, 8.0) and 13.1 weeks (95% CI: 12.3, 15.7), respectively. The KM estimated

MMR and MR4.5 rates at 24 weeks of re-initiation were 98.8 % (95% CI: 94.2, 99.9) and 90.9 %

(95% CI: 83.2, 96.0), respectively.

The KM estimate of median treatment-free survival (TFS) has not yet been reached (Figure 4); 99 of

190 patients (52.1%) did not have a TFS event.

Figure 4

Kaplan-Meier estimate of treatment-free survival after start of TFR (full analysis

set)

Pat Evt Cen

190 91 99

Censored observations

Treatment-free Survival (%)

Time Since since TFR

0:91

1:91

12:91

38:91

90:89

190:0

At risk : Events

108:81

120:70

165:25

Treatment discontinuation in CML patients in chronic phase who have achieved a sustained deep

molecular response on nilotinib treatment following prior imatinib therapy

In an open-label, single-arm study, 163 adult patients with Ph+ CML in chronic phase taking tyrosine

kinase inhibitors (TKIs) for ≥3 years (imatinib as initial TKI therapy for more than 4 weeks without

documented MR4.5 on imatinib at the time of switch to nilotinib, then switched to nilotinib for at least

two years), and who achieved MR4.5 on nilotinib treatment as measured with the MolecularMD

MRDx™ BCR-ABL test were enrolled to continue nilotinib treatment for additional 52 weeks

(nilotinib consolidation phase). 126 of 163 patients (77.3%) entered the TFR phase after achieving a

sustained deep molecular response during the consolidation phase, defined by the following criterion:

The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5

(BCR-ABL/ABL ≤0.0032% IS) during one year.

The primary endpoint was the proportion of patients without confirmed loss of MR4.0 or loss of MMR

within 48 weeks following treatment discontinuation. Of the 126 patients who entered the TFR phase,

73 patients (57.9%, [95% CI: 48.8, 66.7]) had no loss of MMR, no confirmed loss of MR4.0, and no

re-initiation of nilotinib within 48 weeks.

Among the 53 patients who discontinued the TFR phase due to confirmed loss of MR4.0 or loss of

MMR, 51 patients restarted nilotinib and 2 patients discontinued the study. Forty-eight of these

51 patients (94.1%) regained MR4.0 and 47 patients (92.2%) regained MR4.5 by the time of the

cut-off date.

The Kaplan-Meier (KM) estimated median time on nilotinib to regain MR4.0 and MR4.5 was

12.0 weeks (95% CI: 8.3, 12.7) and 13.1 weeks (95% CI: 12.4, 16.1), respectively. The KM estimated

MR4.0 and MR4.5 rates at 48 weeks of re-initiation were 100.0% (95% CI: not estimated) and 94.8%

(95% CI: 85.1, 99.0), respectively.

The median TFS has not yet been reached (Figure 5); 74 of 126 patients (58.7%) did not have a TFS

event.

Figure 5

Kaplan-Meier estimate of treatment-free survival after start of TFR (Ffull analysis

set)

Censored observations

Treatment-free Survival (%)

126:0

107:19

76:49

74:51

61:52

36:52

14:52

1:52

0:52

Time Since since TFR

At risk : Events

5.2

Pharmacokinetic properties

Absorption

Peak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib absorption

following oral administration was approximately 30%. The absolute bioavailability of nilotinib has not

been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability of

nilotinib capsule is approximately 50%. In healthy volunteers, C

and area under the serum

concentration-time curve (AUC) of nilotinib are increased by 112% and 82%, respectively, compared

to fasting conditions when Tasigna is given with food. Administration of Tasigna 30 minutes or 2 hours

after food increased bioavailability of nilotinib by 29% or 15%, respectively (see sections 4.2, 4.4 and

4.5).

Nilotinib absorption (relative bioavailability) might be reduced by approximately 48% and 22% in

patients with total gastrectomy and partial gastrectomy, respectively.

Distribution

The blood-to-plasma ratio of nilotinib is 0.71. Plasma protein binding is approximately 98% on the

basis of

in vitro

experiments.

Biotransformation

Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is

the main circulating component in the serum. None of the metabolites contribute significantly to the

pharmacological activity of nilotinib. Nilotinib is primarily metabolised by CYP3A4, with possible

minor contribution from CYP2C8.

Elimination

After a single dose of radiolabelled nilotinib in healthy subjects, more than 90% of the dose was

eliminated within 7 days, mainly in faeces (94% of the dose). Unchanged nilotinib accounted for 69%

of the dose.

The apparent elimination half-life estimated from the multiple-dose pharmacokinetics with daily dosing

was approximately 17 hours. Inter-patient variability in nilotinib pharmacokinetics was moderate to

high.

Linearity/non-linearity

Steady-state nilotinib exposure was dose-dependent, with less than dose-proportional increases in

systemic exposure at dose levels higher than 400 mg given as once-daily dosing. Daily systemic

exposure to nilotinib with 400 mg twice-daily dosing at steady state was 35% higher than with 800 mg

once-daily dosing. Systemic exposure (AUC) of nilotinib at steady state at a dose level of 400 mg twice

daily was approximately 13.4% higher than at a dose level of 300 mg twice daily. The average nilotinib

trough and peak concentrations over 12 months were approximately 15.7% and 14.8% higher following

400 mg twice-daily dosing compared to 300 mg twice daily. There was no relevant increase in

exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily.

Steady-state conditions were essentially achieved by day 8. An increase in serum exposure to nilotinib

between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for

twice-daily dosing.

Bioavailability/bioequivalence studies

Single-dose administration of 400 mg nilotinib, using 2 capsules of 200 mg whereby the content of

each capsule was dispersed in one teaspoon of apple sauce, was shown to be bioequivalent with a

single-dose administration of 2 intact capsules of 200 mg.

5.3

Preclinical safety data

Nilotinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive

toxicity, phototoxicity and carcinogenicity (rats and mice) studies.

Nilotinib did not have effects on CNS or respiratory functions.

In vitro

cardiac safety studies

demonstrated a preclinical signal for QT prolongation, based upon block of hERG currents and

prolongation of the action potential duration in isolated rabbit hearts by nilotinib. No effects were seen

in ECG measurements in dogs or monkeys treated for up to 39 weeks or in a special telemetry study in

dogs.

Repeated-dose toxicity studies in dogs of up to 4 weeks’ duration and in cynomolgus monkeys of up to

9 months’ duration revealed the liver as the primary target organ of toxicity of nilotinib. Alterations

included increased alanine aminotransferase and alkaline phosphatase activity and histopathology

findings (mainly sinusoidal cell or Kupffer cell hyperplasia/hypertrophy, bile duct hyperplasia and

periportal fibrosis). In general the changes in clinical chemistry were fully reversible after a four-week

recovery period and the histological alterations showed partial reversibility. Exposures at the lowest

dose levels at which the liver effects were seen were lower than the exposure in humans at a dose of

800 mg/day. Only minor liver alterations were seen in mice or rats treated for up to 26 weeks. Mainly

reversible increases in cholesterol levels were seen in rats, dogs and monkeys.

Genotoxicity studies in bacterial

in vitro

systems and in mammalian

in vitro

in vivo

systems with

and without metabolic activation did not reveal any evidence for a mutagenic potential of nilotinib.

In the 2-year rat carcinogenicity study, the major target organ for non-neoplastic lesions was the uterus

(dilatation, vascular ectasia, endothelial cell hyperplasia, inflammation and/or epithelial hyperplasia).

There was no evidence of carcinogenicity upon administration of nilotinib at 5, 15 and 40 mg/kg/day.

Exposures (in terms of AUC) at the highest dose level represented approximately 2x to 3x human daily

steady-state exposure (based on AUC) to nilotinib at the dose of 800 mg/day.

In the 26-week Tg.rasH2 mouse carcinogenicity study, in which nilotinib was administered at 30, 100

and 300 mg/kg/day, skin papillomas/carcinomas were detected at 300 mg/kg, representing

approximately 30 to 40 times (based on AUC) the human exposure at the maximum approved dose of

800 mg/day (administered as 400 mg twice daily). The No-Observed-Effect-Level for the skin

neoplastic lesions was 100 mg/kg/day, representing approximately 10 to 20 times the human exposure

at the maximum approved dose of 800 mg/day (administered as 400 mg twice daily). The major target

organs for non-neoplastic lesions were the skin (epidermal hyperplasia), the growing teeth

(degeneration/atrophy of the enamel organ of upper incisors and inflammation of the

gingiva/odontogenic epithelium of incisors) and the thymus (increased incidence and/or severity of

decreased lymphocytes).

Nilotinib did not induce teratogenicity, but did show embryo- and foetotoxicity at doses that also

showed maternal toxicity. Increased post-implantation loss was observed in both the fertility study,

which involved treatment of both males and females, and the embryotoxicity study, which involved

treatment of females. Embryo-lethality and foetal effects (mainly decreased foetal weights, premature

fusion of the facial bones (fused maxilla/zygomatic) visceral and skeletal variations) in rats and

increased resorption of foetuses and skeletal variations in rabbits were present in the embryotoxicity

studies. In a pre- and postnatal development study in rats, maternal exposure to nilotinib caused

reduced pup body weight with associated changes in physical development parameters as well as

reduced mating and fertility indices in the offspring. Exposure to nilotinib in females at No-Observed-

Adverse-Effect-Levels was generally less or equal to that in humans at 800 mg/day.

In a juvenile development study, nilotinib was administered via oral gavage to juvenile rats from the

first week post partum through young adult (day 70 post partum) at doses of 2, 6 and 20 mg/kg/day.

Besides standard study parameters, evaluations of developmental landmarks, CNS effects, mating and

fertility were performed. Based on a reduction in body weight in both genders and a delayed preputial

separation in males (which may be associated with the reduction in weight), the No-Observed-Effect-

Level in juvenile rats was considered to be 6 mg/kg/day. The juvenile animals did not exert increased

sensitivity to nilotinib relative to adults. In addition, the toxicity profile in juvenile rats was comparable

to that observed in adult rats.

No effects on sperm count/motility or on fertility were noted in male and female rats up to the highest

tested dose, approximately 5 times the recommended dosage for humans.

Nilotinib was shown to absorb light in the UV-B and UV-A range, is distributed into the skin and

showed a phototoxic potential

in vitro

, but no effects have been observed

in vivo

. Therefore the risk

that nilotinib causes photosensitisation in patients is considered very low.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tasigna 150mg capsules

Capsule content: Lactose monohydrate, Crospovidone, Poloxamer 188, Silica colloidal anhydrous,

Magnesium stearate.

Capsule shell: Gelatin, Titanium dioxide (E171), Iron oxide red, (E172), Iron oxide yellow (E172).

Printing ink, black: Shellac, Iron oxide black, N-butyl alcohol, Purified water, Propylene glycol,

Dehydrated ethanol, Isopropyl alcohol, Ammonium hydroxide.

Tasigna 200mg capsules

Capsule content: Lactose monohydrate, Crospovidone, Poloxamer 188, Silica colloidal anhydrous,

Magnesium stearate

Capsule shell: Gelatin, Titanium dioxide (E171), Iron oxide yellow (E172)

Printing ink, red:

Printing ink a: Shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol,

strong ammonia solution, Iron oxide red (E172), potassium hydroxide, purified water.

Printing ink b: Shellac, Iron oxide red (E172), Iron oxide black (E172), n-butyl alcohol,

purified

water,

titanium

dioxide

(E171),

propylene

glycol,

industrial

methylated

spirit,

isopropyl alcohol.

The printing ink used is ‘Printing ink a’ or alternatively ‘Printing ink b’.

6.2

Incompatibilities

Not applicable.

6.3 Shelf life

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

6.43

Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from moisture.

6.45

Nature and contents of container

PVC/PVDC/Alu blisters.

Tasigna 150mg is available in the following pack sizes:

Unit packs containing 28 capsules.

Multipacks containing 112 (4 packs of 28) capsules

Tasigna 200mg is available in the following pack sizes:

Unit packs containing 40 capsules.

Multipacks containing 120 (3 packs of 28) capsules

Not all pack sizes may be marketed.

6.56

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.No special requirements for disposal.

7.

MANUFACTURER

Novartis Pharma Stein AG., Stein, Switzerland

For Novartis Pharma Ag., Basel, Switzerland

8. REGISTRATION LICENSE HOLDER

Novartis Israel Ltd.

36 Shacham st.,

Petah-Tikva

ל ןולע ןכרצ

ו"משתה (םירישכת) םיחקורה תונקת יפל ןכרצל ןולע

-

1986

דבלב אפור םשרמ יפ לע תקוושמ הפורתה

הנגיסט

150

תוסומכ ג"מ

הנגיסט

200

תוסומכ ג"מ

:הליכמ הסומכ לכ

לכורדיהכ ביניטולינ דירו טארדיהונומ

ג"מ

Nilotinib as hydrochloride

monohydrate 150 mg

:הליכמ הסומכ לכ

דירולכורדיהכ ביניטולינ טארדיהונומ

ג"מ

Nilotinib as hydrochloride

monohydrate 200 mg

:םיליעפ יתלב םירמוח

האר

ףיעס

"

הפורתה לש םיביכרמהמ קלח לע בושח עדימ

"

תחת עיפומה

ףיעס

,ןכ ומכו ףיעס

."ףסונ עדימ"

.הפורתב שמתשת םרטב ופוס דע ןולעה תא ןויעב ארק

תולאש ךל שי םא .הפורתה לע יתיצמת עדימ ליכמ הז ןולע .חקורה לא וא אפורה לא הנפ ,תופסונ

.ןולעה תא רומש

.בוש וב אורקל ךרטצתו ןכתי

תוא ריבעהל ןיא .ךתלחמב לופיטל המשרנ וז הפורת םתלחמ יכ ךל הארנ םא וליפא םהל קיזהל הלולע איה .םירחאל ה .המוד

ליגל תחתמ) םירגבתמבו םידליב הנגיסט לש שומישב ןויסינ ןי

1

.

?הפורתה תדעוימ המל

תארקנה הימקול לש גוסב לופיטל תשמשמ הנגיסט

Philadelphia chromosome positive chronic myeloid leukemia

Ph+CML

.םיניקת םניאש םינבל םד יאת ידמ רתוי רצייל ףוגל םרוגה םדה ןטרס וניה

ילוחב

) יתשרותה רמוחב יוניש ,

תותיא ליעפמ

םרוגה

תמסוח הנגיסט .םיניקת אל םינבל םד יאת רצייל ףוגל .ולא םיאת לש רוצייה תא תרצועו הז תותיא

הנגיסט

הנגיסטו ג"מ

ג"מ

תושמשמ

פיט יבויח היפלדליפ םוזומורכ םע תינורכ תידיאולאימ הימקול םע הנושארל ונחבוא רשא םירגובמ םילוחב לו

Philadelphia chromosome positive chronic myeloid leukemia - Ph+ CML

.ינורכה בלשב

הנגיסט

ג"מ דבלב

תשמשמ

םוזומורכ םע תינורכ תידיאולאימ הימקול םע םילוחב לופיט

יבויח היפלדליפ

Philadelphia chromosome positive

Ph+ CML

chronic myeloid leukemia

,ץאומה וא ינורכה בלשב ( םילוחב

ווחש וא םידימע

תיתועמשמ תוליער .ביניטמיא םע לופיטה ךלהמב

תארקנה הימקול לש גוסב לופיטל תשמשמ הנגיסט

c myeloid leukemia

Philadelphia chromosome positive chroni

.םיניקת םניאש םינבל םד יאת ידמ רתוי רצייל ףוגל םרוגה םדה ןטרס וניה

ילוחב

) יתשרותה רמוחב יוניש ,

םרוגה תותיא ליעפמ

תמסוח הנגיסט .םיניקת אל םינבל םד יאת רצייל ףוגל .ולא םיאת לש רוצייה תא תרצועו הז תותיא

טיופרת הצובק :תי

יטסלפואניטנא

םא

ךל שי לכ לאש

לע

ןפוא

לש הלועפה הנגיסט וא

המשרנ וז הפורת עודמ ךל

הנפ

אפורל

ךלש

2

.

ל

ב שומיש ינפ הפורת

:

רחא תוריהזב בוקעל שי לכ אפורה תוארוה .הז ןולעב עיפומה יללכה עדימהמ תונוש תויהל תויושע ןה .

ליגב םירגובמ םישנ

שמתשהל םילוכי הלעמו .םירגובמה ראש ומכ הנמ התואב הנגיסטב

X

:הפורתב שמתשהל ןיא

ל וא ביניטולינל (רתי תושיגר) היגרלא ךל שי םא לכ םיעיפומה הפורתה יביכרממ דחא ףיעסב

"ףסונ עדימ"

יגרלא תויהל לולע התאש רובס ךנה םא

אפורה תא עדייל שי לוטיל ילבמ

תליטנ ינפ

.הנגיסט

ונה תודחוימ תורהזא :הפורתב שומישל תועג

מ דחא םא

םיפיעס םיאבה ךלש אפורה תא עדי ,ךילע לח ינפל

תליטנ

הנגיסט

חומל םדה תקפסא םע תויעב ,(הקועת) הזחב באכ ,בל ףקתה תמגודכ םימדוק םייבבל םיעוריא ךל ויה םא הלחמל ןוכיס ימרוג ךל שי םא וא (העילצ) ךלש לגרל םדה תמירזב תויעב וא ,(ץבש) ךלש ץחל תמגודכ תיבבל

ץחל רתי) הובג םד

.(םינמוש תוערפה) םדב םינמושה תמר םע תויעב וא ,תרכוס ,(םד

ךל שי םא בלב הערפה

ןוגכ

ילמשח תוא ןיקת אל

ה חוורמ לש הכראה" יורקה

"

םא ךנה תופורתב לפוטמ

) בלה בצק לע תועיפשמה

תופורת יטנא

וא (תוימתירא

דבכה לע

האר) םא" ןלהל

חקול התא

הנורחאל תחקל םא וא

("תורחא תופורת

םא .םויזנגמב וא ןגלשאב רוסחממ לבוס ךנה

ךל שי םא דבכב הערפה

וא .בלבלב

םימוהיז וא המישנ רצוק וא תופייע תשגרה ,תולקב (תורובח) םיעצפ תעפוה ןוגכ םינימסת ךל שי םא .םירזוח

םא מוטקרטסג) האולמב הביקה תרסהל חותינ תרבע .(הי

תיפיגנ דבכ תקלד ךל שיו ןכתי וא םעפ יא ךל התייה םא

סיטיטפה

תקלדל םורגל הלולע הנגיסט .( תיפיגנ דבכ

סיטיטפה)

בוש הליעפל ךופהל (

םילפוטמ .םימיוסמ םירקמב תוומל םורגל לולעה רבד , לע הדיפקב וקדבי

לחתה ינפל וז תקלד לש םינמיס רותיאל םהלש אפורה ידי .לופיטה ת

םא

ךלש אפורה תא עדי ,ךיבגל ןוכנ ל"נה םירבדהמ דחא

הנגיסטב לופיט ךלהמב !

תידיימ הנפ

ךלש אפורל וא ,(הרכה דבאמ) ףלעתמ ךנהש הרקמב ךל שי םא ךלהמב תורידס אל בל תומיעפ לופיטה הנגיסטב

וז הפורת

ןכש ש ןכתי ולא

בקע ושחרתי ה חוורמ תכראה .בלב תיניצר היעב

יא וא .ימואתפ תוומל ליבוהל םילולע בלה תומיעפב תורידס

.הנגיסטב ולפוטש םילוחב ימואתפ תוומ לש םיחיכש אל םירקמ וחווד

ךלש אפורל תידיימ הנפ

,קותיש וא הרומח םירירש תשלוח ,(תויצטיפלפ) תוימואתפ בל תוקיפד ךל שי םא הבישחב םיימואתפ םייוניש וא םיסוכרפ

ע תמרב וא יאת לש ריהמ קוריפל ןמיס תויהל לולע הז ןכש ,תונר "לודיגה קוריפ תנומסת" יורקה ןטרס

tumor lysis syndrome

לודיגה קוריפ תנומסת לש םירידנ םירקמ .(

tumor lysis syndrome

.הנגיסט םילטונה םילפוטמב וחווד (

תידיימ הנפ

ךלש אפורל

יא וא הזחב באכ חתפמ התאש הרקמב

תוחונ רסוח ,

,השלוח וא השוח

תויעב עוריא לש ןמיס תויהל לולע הז ןכש ,םייפגה תחאב רוק תשוחת וא עבצב יוניש ,באכ ,רובידב וא הכילהב םירלוקסווידרק םיעוריא .ירלוקסווידרק םייניצר םירומח הלחמ) לגרל םדה תמירז םע תויעב םיללוכה תלחמ ,(םיירפירפ םיקרוע לש תיתמיסח

תימכסיא בל

ילכ לש תימכסיא הלחמ) חומל םדה תקפסא םע תויעבו

רכוסהו (םידיפיל) םינמושה תומר תא רטנל ךירצ ךלש אפורה .הנגיסט םילטונה םילפוטמב וחווד (חומב םדה .לופיטה ךלהמבו הנגיסטב לופיטה תליחת ינפל םדב

יהמ היילע וא תיללכ תוחיפנ ,םיידי וא םיילגרה תופכב תוחיפנ חתפמ התא םא ןכש ךלש אפורל רפס ,לקשמב הר וחווד הרומח םילזונ תריגא לש םיחיכש אל םירקמ .הרומח םילזונ תריגאל םינמיס תויהל םילולע הלא .הנגיסט םילטונה םילפוטמב

:בקעמו תוקידב

ורטני ולא תוקידב .םד תוקידב ללוכ רידס ןפואב תוקידב עצבל שי וז הפורתב לופיטה תפוקתב

תא תומכ

דה יאת (תויסטו םימודא םד יאת ,םינבל םד יאת) ם

.תלבסנ הנגיסט דציכ תוארל ידכ ףוגב

דבכהו בלבלה ידוקפת ףוגב תוארל ידכ דציכ הנגיסט

תלבסנ

וגב םיטילורטקלא

.בלה דוקפתב תובישח ילעב ולא ;(םויזנגמ ,ןגלשא)

.םדב םינמושהו רכוסה תמר

דדומ רשא רישכמ תועצמאב םג קדביי בלה בצק .(".ג.ק.א" תארקנה הקידב) בלה לש תילמשחה תוליעפה תא

לוטיל ךישמהל ךילע םאה טילחיו רידס ןפואב ךלופיט רחא בקעמ עצבי ךלש אפורה הנגיסט

לוטיל קיספהל ךל רמאנ םא וז הפורת ה תלחמ תא הדיפקב רטנל ךישמי ךלש אפורה ,

החניו ןכתיו ךלש היהי םא הנגיסט לוטיל רוזחל ךתוא

.ךבצמל םאתהב ,ךרוצ

אפורל תונפל שי ,ךרובע המשרנ עודמ וא תלעופ הנגיסט דציכ יבגל הלאש לכב

חקול התא םא !

,

הנורחאל תחקל םא וא

,

ךכ לע רפס ,הנוזת יפסותו םשרמ אלל תופורת ללוכ תורחא תופורת יא וא םינוכיס עונמל ידכ חקורל וא אפורל

ןיב תובוגתמ םיעבונה תוליעי

ויתפורת

םע שגנתהל היושע הנגיסט .תורחא תופורת יל שי דחוימב

:חקול התא םא חקורה וא אפורה תא עד

יטנא תופורת

תוימתירא

רידס אל בל בצקב לופיטל תושמשמה

סקולפיסקומ ,ןודתמ ,לודירפולאה ,ןיצימורתירלק ,ןירטנפולה ,ןיווקורולכ

ןיצ

םורגל תולולעה תופורת ע היוצר אל העפשהל בלה דוקפת ל

ןיצימורתילט ,ןיצימורתירלק ,לוזאנוקירוו ,לוזאנוקארטיא ,לוזאנוקוטק

םימוהיזב לופיטל תושמשמה

ריבאנוטיר

) סדייאב לופיטל הפורת

(HIV

"תוזאטורפיטנא"ה תצובקמ

ןיאוטינפ ,לאטיבראבונפ ,ןיפזאמאבראק

היספליפאב לופיטל תושמשמה

ןיציפמאפיר

ופיטל שמשמה תפחשב ל

St. John's Wort

םשב םג עודי) םיפסונ םיבצמבו ןואכידב לופיטל שמשמה יחמצ רישכת םוקירפיה םוטארופרפ

םלוזאדימ

חותינ ינפל הדרח יבצמ לע הלקהל שמשמה

לינטנפו לינטנפלא

וא חותינ ךלהמב וא ינפל המדרה רמוחכו באכב לופיטל םישמשמה תולועפ תויאופר ר םיכילה םייאופ

סומילורקטו סומילוריס ,ןירופסולקיצ

המיחלו ףוגה לש "תימצע הנגה" תלוכי תא םיאכדמה םירישכת םישמשמו םימוהיזב ללכ ךרדב םיתעל

הילכו בל ,דבכ ןוגכ םילתשומ םירביא לש הייחד תעינמל

ןימטוגראו ןימטוגראורדיהיד

היצנמדב לופיטל תושמשמה

ןיטטסבמיס ,ןיטטסבול

תושמשמה

םדב םינמוש לש תוהובג תומרב לופיטל

ןיראפר

םד תשירק תוערפהב לופיטל שמשמה

(תקקפ וא םד ישירק ןוגכ)

.לידירפב ,ןידיניוק ,דיזומיפ ,דירפאסיצ ,ןידאנפרט ,לוזימטסא

רתמ רתוי וא תחא לטונ ךנהו הדימב .ולא תופורת תליטנמ ענמיהל שי הנגיסטב לופיטה ךלהמב ןכתי ,ולא תופו .תויפולח תופורת ךל םושרי אפורה יכ

לופיטל תופורת) הצמוח ירתוס לטונ ךנה םא הנגיסט תליטנ ינפל חקורה וא אפורה תא עדייל שי ,ףסונב :הנגיסטמ דרפנב ולא תופורת לוטיל שי .(תברצב

ימסוח םיארקנה הצמוח ירתוס

הביקב תויצמוחה רוציי תא םיתיחפמה

םיכירצ כ חקליהל

תועש .הנגיסט תליטנ ירחא םייתעשכו ינפל

ורדיה םוינימולא םיליכמה ולא ןוגכ הצמוח ירתוס

ורדיה םויזנגמ ,דיס

םילרטנמה ןוקיטמיסו דיס הביקב ההובג תויצמוח

.הנגיסט תליטנ ירחא םייתעש וא ינפל םייתעשכ חקליהל םיכירצ

אפורה תא עדייל שי ט לטונ רבכ ךנה םא הנגיס

,םשרמ אלל תופורת ללוכ ,השדח הפורת ךל םימשורו הדימב .הנגיסטב לופיטה ךלהמב רבעב תלטנ אלש

!

ב שומיש הנגיסט ןוזמו

.לכוא םע הפורתה תא לוטיל ןיא

לולע ןוזמ

ןכלו הנגיסט לש הגיפסה תא ריבגהל

םדב התומכ תא תולעהל

ןכתי .הקיזמ המרל דע

וא תוילוכשא ץימ תותשל ןיא המרל ןכתי ,םדב הנגיסט לש תומכה תא תולעהל לולע רבדה .תילוכשא לוכאל .הקיזמ

) םישישק !

יאליגמ םילפוטמ

65

(הלעמו

הל ןתי

יאליגב םישנאב הנגיסטב שמ

םירגובמ ראשב ומכ םינונימ םתואב הלעמו

!

הקנהו ןוירה

ךרוצ םייק םא אלא ,ןוירה ךלהמב הנגיסטב שמתשהל ץלמומ אל

הב ךניה םא .רורב

ךניהש תבשוח וא ןויר הב

שמתשהל ילכות םאה ךמיע ןודיש אפורה תא יעדי ,ןויר הנגיסטב

וז הפורת

.ןוירהה ךלהמב

ליגב םישנ ןוירפ

תוירופ

הנגיסטב שומישה ךלהמב רתויב םיליעי העינמ יעצמאב שמתשהל תובייח

ךשמבו לופיטה םות רחאל םיאלמ םייעובש

קינהל ןיא המב .הקינימ ךניה םא ךלש אפורה תא יעדי .הנגיסטב לופיטה ךל

תבשוח ,הקינימ וא ןוירהב תא םא ןוירהל סנכיהל הלוכי ךניהש ןוירהב תאש

ןוירה תננכתמ וא

ץעוויהל שי הפורת תליטנ ינפל חקורב וא אפורב וז

!

הגיהנ תונוכמב שומישו

וערפה וא תרוחרחס ןוגכ) יאוול תועפותב שח ךנה םא גוהנל תלוכיה לע עיפשהל תולולעה (הייארב ת החטיבב וא םילכ ליעפהל

תונוכמ תליטנ רחאל הנגיסט וז הפורת

.תרבוע העפשההש דע ולא תויוליעפמ ענמיהל שי

הפורתה לש םיביכרמהמ קלח לע בושח עדימ !

יא ךל שיש עדוי ךנה םא .(בלח רכוס) זוטקל ליכמ רישכתה

תא עדי ,זוטקלל תוליבס תליטנ ינפל אפורה .הנגיסט

הנגיסט לש הסומכ לכ

כ הליכמ ג"מ

.טארדיהונומ זוטקל ג"מ

הנגיסט לש הסומכ לכ

כ הליכמ ג"מ

.טארדיהונומ זוטקל ג"מ

3

.

?הפורתב שמתשת דציכ

דימ שמתשהל שי

דימת רישכתב חוטב ךניא םא חקורה וא אפורה םע קודבל ךילע .אפורה תוארוה יפל

עגונב .רישכתב לופיטה ןפואו ןונימל

לע ועבקי לופיטה ןפואו ןונימה

-

.דבלב אפורה ידי לבוקמה ןונימה

אוה ללכ ךרדב

:

הנושארל ונחבוא רשא םירגובמ םילוחב

םע

Ph+ CML

לש תוסומכ

) םויב םיימעפ ג"מ

םיימעפ ג"מ (םויב

םע םילוחב

Ph+ CML

ץאומה וא ינורכה בלשב

ילוחב

לופיטה ךלהמב תיתועמשמ תוליער ווחש וא םידימע ביניטמיא םע

לש תוסומכ

) םויב םיימעפ ג"מ

(םויב םיימעפ ג"מ

.לופיטל ךתבוגתל םאתהב רתוי ךומנ ןונימ םושרל יושע ךלש אפורה

.תצלמומה הנמה לע רובעל ןיא

לוטיל יתמ

הנגיסט

:

:תוסומכה תא לוטיל שי

עב) םויב םיימעפ לכ ךר

(תועש

םייתעש תוחפל ןוזמ לכ לש הליכא רחאל

ינפל העש תוחפל ןיתמהל זאו תינשב םילכואש

.חקורל וא ךלש אפורל הנפ ,הפורתה תא לוטיל יתמ יבגל תולאש ךל שי םא

.ךלש תוסומכה תא לוטיל רוכזל ךל רוזעת םוי לכב העשה התואב הפורתה תליטנ

לוטיל דציכ

:הנגיסט

תא עולבל שי

.םימ םע ןתומלשב תוסומכה

תוסומכה םע דחי והשלכ לכוא ךורצל ןיא

ןכ םא אלא ,תוסומכה תא חותפל ןיא .ןתומלשב תוסומכה תא עולבל ךתלוכיב ןיא

תיפכב הסומכ לכ לש ןכותה תא בברעל ןתינ הז הרקמב תחא

.דימ לוטילו (םיחופת תיחמ) םיחופת קסר לש יחמ לש תחא תיפכמ רתויב שמתשת לא תיחמל טרפ רחא ןוזמ םושב אלו הסומכ לכ רובע םיחופת ת .םיחופת

:לופיטה ךשמ

אפורה .ךורא חווטל לופיט והז ,ךל הרומ אפורה דוע לכ םוי לכ הפורתה תא לוטילו ךישמהל שי ךלש בוקעי רידס ןפואב .ודעי תא גישמ לופיטהש קודבל ידכ ךבצמ ירחא

לוקשי אפור לופיטה תקספה הנגיסטב לע

םינוירטירק יפ

יוסמ

.םימ

ךשמ יבגל תולאש שיו הדימב לוטיל שיש ןמזה

אפורב ץעוויהל שי ,הנגיסט

.חקורב וא

:בקעמו תוקידב

ורטני ולא תוקידב .םד תוקידב ללוכ רידס ןפואב תוקידב עצבל שי וז הפורתב לופיטה תפוקתב

תא תומכ

(תויסטו םימודא םד יאת ,םינבל םד יאת) םדה יאת

וגב

ךלש .תלבסנ הנגיסט דציכ תוארל ידכ

דבכהו בלבלה ידוקפת ךפוגב תוארל ידכ דציכ הנגיסט

תלבסנ

םיטילורטקלא ךפוגב בלה דוקפתב תובישח ילעב ולא ;(םויזנגמ ,ןגלשא)

ךלש

םינמושהו רכוסה תמר ךמדב

בלה בצק ךלש ) בלה לש תילמשחה תוליעפה תא דדומ רשא רישכמ תועצמאב םג קדביי תארקנה הקידב .(".ג.ק.א"

אפורל תונפל שי ,ךרובע המשרנ עודמ וא תלעופ הנגיסט דציכ יבגל הלאש לכב

תלטנ םא רתי תנמ ,הפורתה ןמ דלי עלב תועטב םא וא תא אבהו םילוחה תיב לש ןוימ רדחל וא אפורל דימ הנפ ךתיא הפורתה תזירא .יאופר לופיטב ךרוצ היהיו ןכתי .

רת לוטיל תחכש םא הפו

וז ה ןמזב שורד

ץעוויהו ליגרה ןמזב האבה הנמה תא חק .הלופכ הנמ לוטיל ןיא .אפורב

י

לע ץלמוהש יפכ לופיטב דימתהל ש

-

.אפורה ידי

ךתואירב בצמב רופיש לח םא םג

,

לופיטה תא קיספהל ןיא אפורה םע תוצעייתה אלל הפורתב

לופיט תקספה הנגיסטב וז הפורתב א המש אפור תצלמה אלל הלולעש ךלש הלחמה תרמחהל ןוכיס תחת ךתו תא קיספהל לקוש התא םא חקור וא/ו תוחא ,אפור םע ןד התא יכ אדו .םייח תונכסמ תוכלשה םע תויהל .הנגיסט

א

הנמהו תיוותה קודבל שי !ךשוחב תופורת לוטיל ןי םעפ לכב

.הפורת לטונ ךנהש

ךנה םא םייפקשמ בכרה .םהל קוקז

ב

ו הדימ אפורה ךלש

ה

הנגיסטב לופיטה תקספה לע ץילמ

ךלש אפורה

בקעמ עצב

רחא רידס ןפואב ךלופיט

ידי י"

תנחבאמ הקידב יוסמ

תמ

טילחיו

םאה ךילע לוטיל ךישמהל וז הפורת

רטנל ךישמי ךלש אפורה ,הנגיסט לוטיל קיספהל ךל רמאנ םא

הדיפקב

תא תלחמ

ךלש ךלהמב ,ינפל ןכתיו הליטנה תקספה ירחאו

.ךבצמל םאתהב ,ךרוצ היהי םא הנגיסט לוטיל רוזחל ךתוא החניו

.חקורב וא אפורב ץעוויה ,הפורתב שומישל עגונב תופסונ תולאש ךל שי םא

4

.

:יאוול תועפות

ארקמל להבית לא .םישמתשמהמ קלחב יאוול תועפותל םורגל לולע הנגיסטב שומישה ,הפורת לכב ומכ אלו ןכתי .יאוולה תועפות תמישר

ךרדבו ,תונותמ דע תולק ןה יאוולה תועפות בור .ןהמ תחא ףאמ לובסת .לופיטה תליחתמ תועובש רפסמ דע םימי רפסמ ירחא תומלענ ללכ

.תורומח תויהל תולולע תומיוסמ יאוול תועפות שי תונפל

:םיאבה םירקמב אפורל דימ

תוחיכש ןניה ולא יאוול תועפות

דע לע עיפשהל תולולע

ךותמ

) תוחיכש אל ,(םילפוטמ

עיפשהל תולולע לע דע

דע

ךותמ

וחוודש וא (םילפוטמ עדימה ךותמ ךירעהל ןתינ אל) העודי הניאש תוחיכשב (םייקה םידדוב םילוח יבגל

תוערפהל םינמיס) רועה וא ןושלה ,םייתפשה לש הלחכה ,רידס אל בל בצק ,הובג םד ץחל ,הזחב באכ (בלב

הריהמ היילע

(םימ תריצא לש םינמיס) םינפב וא םיילגרה תופכב ,םיילוסרקב ,םיידיב תוחיפנ ,לקשמב

תוערפהל םינמיס) רועה וא ןושלה ,םייתפשה לש הלחכה ,רידס אל בל בצק ,הובג םד ץחל ,הזחב באכ (בלב

ו םיילגרב תוחיפנ ,םוח אלל וא םע םיפוצפצ ,לועיש ,המישנב ישוק

ערפהל םינמיס) םיילגר תופכ תו (תואירב

(םדה תכרעמב תוערפהל םינמיס) םיפוכת םימוהיז ,תולקב (תורובח) םיעצפ תעפוה ,םוח

לש השוחת וא העימש ,הייאר ,רומח שאר באכ ,רוביד יישק ,םינפה לש וא םייפגה לש קותיש וא השלוח (םיבצעה תכרעמב תוערפהל םינמיס) םיאצמנ םניאש םירבד

ןתש ,תונזגר ,שבי רוע ,ןואמיצ (תוילכב תוערפהל םינמיס) ןתשה תקופתב הדירי ,ההכ

(ןיעב תוערפהל םינמיס) םייניעה ךותב םד ,הייאר ןדבוא ,תשטשוטמ הייאר

(דירו ךותב םד שירקל םינמיס) ףוגה לש דחא רוזאב באכו תוחיפנ

תכרעמב תוערפהל םינמיס) ןטבה לש תוחיפנ ,תוריצע ,הרוחש האוצ ,םד תאקה ,הליחב ,ןטב יבאכ (לוכיעה

(בלבלב תקלדל ןמיס) הנוילע ןטבב רומח באכ

(דבכב תוערפהל םינמיס) ההכ עבצב ןתש ,ןובאית דוביא ,הליחב ,םיבוהצ םייניעו רוע

(רועב תוערפהל םינמיס) םירירשו םיקרפ יבאכ ,תומודאו תובאוכ תורובח ,החירפ

מ תתחפהב הוולמה ןובאיתב היילע ,ההובג ןתש תקופת ,רבגומ ןואמיצ המרל םינמיס) תופייע ,לקש (םדב רכוס לש ההובג

לש רתי תוליעפל םינמיס) ראווצה תמדקב תוחיפנ ,לקשמב הדירי ,תוטלוב םייניע ,תוריהמ בל תומיעפ ([דיאורית] סירתה תטולב

יא וא/ו תופייע ,רוכע ןתש ,תורידס אל בל תומיעפ ,המישנ רצוק ,הליחב

הוולמה םיקרפמב תוחונ הדבעמ תוקידבב ןדיסה תומרב הדיריו ןחרזו תירוא הצמוח ,ןגלשאה תומרב היילע ןוגכ) תוניקת אל (םדב

באכ

יא

,תוחונ השלוח

וא

יצוויכ

רירש

םיילגרב

,םדה תמירזב הדירי בקע תויהל םילוכיש םיביכ

םיידיבו םיילגרב םיאפרנה

טאל

וא

ללכב

אל

םייונישו

םיארנ עבצב

הלחכה) וא

ןורוויח

וא

הרוטרפמטב

תורירק

םיידיהו םיילגרה לש ןכש םינימסת

מיס תויהל םילוכי ולא םינ

יסח לש תמ

קרוע

פגב

תועבצאבו (די וא לגר) תעפשומה

(םיידיה תועבצאו תונוהב)

תיפיגנ דבכ תקלד לש (לועפש) הרזח

סיטיטפה)

תיפיגנ דבכ תקלדמ רבעב תלבס םא

סיטיטפה)

חא הווח התא םא ,ולא יאוול תועפותמ ת חווד

אפורל

ןפואב

ידיימ

.

:תופסונ יאוול תועפות

ת

) דואמ תוחיכש יאוול תועפו מ רתוי לע עיפשהל תולולע

ךותמ

(םילפוטמ

:

לושלש

שאר באכ

תופייע

םירירש יבאכ

הליחב ,החירפ ,דרג

האקה

רעיש תרישנ

(דבכ דוקפת) םדב ןיבוריליב לש ההובג המר

(בלבל דוקפת) זאפיל לש ההובג המר

ירירש יבאכ

,דלשה רירשב םיבאכ ,םייפג יבאכ

באכ ,םיקרפמ יבאכ ו תומצעב בג יבאכ

.הנגיסטב לופיטה תקספה םע

.ךלש אפורל רפס ,רומח ןפואב ךילע העיפשמ ליעל וניוצש תועפותהמ תחא םא

) תוחיכש יאוול תועפות לע עיפשהל תולולע דע ןיב

לכ ךותמ

(םילפוטמ

:

(הירקיטרוא) תדפרס

יא

יא תשגרה ,ןטבב תוחונ

ןטבב תוחפנתה וא תוחיפנ ,םיזג ,תוחורא רחאל הביקב תוחונ

,תומצעב באכ םירירש תויוצווכתה ,םיקרפמב באכ

יא וא באכ ,םייפגב באכו ראווצב באכ ,בג באכ ללוכה באכ

דצב תוחונ ףוגה

(ןיעב תוערפהל םינמיס) תושבי םייניע ,תוימומדא וא דרג ,השרפה ,תוחיפנ ,ןיעב יוריג

,רועב םדוא רועה תושיגרב הדירי ,רועב תלבי ,הנקא ,רועב שבוי

שוחב הערפה ,ןובאית ןדבוא ,לקשמב הדירי וא היילע םעטה

הדרח ,ןואכיד ,הניש ידודנ

םוח ילג ,תרבגומ העזה ,הליל תועזה

אל תיללכ השגרה ,תרוחרח רורחס תשגרה ,הבוט

השוחת רסוח וא ץוצקע

לוקב הערפה

ףאהמ םומיד

ןתש ןתמב תופיכת

בל תוקיפד .תוריהמ

.ךלש אפורל רפס ,רומח ןפואב ךילע העיפשמ ליעל וניוצש תועפותהמ תחא םא

) תוחיכש אל יאוול תועפות לע עיפשהל תולולע תוחפ דע

לכמ ךותמ

(םילפוטמ

:

תושיגרב היילע רועב באכ ,רועה

םייפעפעב תוחיפנ

הפב םיעצפ ,ןורג באכ ,הפב שבוי

תברצ

םיידשב םיבאכ

היילע ןובאיתב

בשק תערפה

ןתש ןתמב ךרוצ לש תמזגומ השוחת ,ןתש ןתמ ןמזב באכו ישוק

עיגהל תלוכי רסוח הפקיז קיזחהל וא

םירבגב הזחה תלדגה

ייומד םינימסת

םירירש תשלוח ,תעפש

דער

תודחב הדירי הייאר

רואל תושיגר ,האקה ,הליחבב םיתעל הוולמה רומח שאר באכ

הייאר תוערפה

לש יתיירטפ םוהיז הפה וא קיתרנה

םירירשו םיקרפמ תושקונ

הרכה ןדבוא

לקשמב היילע

ללוכ) הנתשמ ףוגה םוחש השגרה (רוק תשגרה ,םוח תשגרה

םיבועמ םימתכ (סיזאירוספ לש םינמיס) ףוסכ/םודא רוע לש

.םיינישב תושיגר

.ךלש אפורל רפס ,רומח ןפואב ךילע העיפשמ ליעל וניוצש תועפותהמ תחא םא

ב וחווד תואבה יאוולה תועפות ) העודי הניאש תוחיכש :(םייקה עדימה ךותמ ךירעהל ןתינ אל דואמ טעמ :הנגיסטב ולפוטש םילוח

תואצמתה רסוח ,לובלב היגרנא רסוח ,רערועמ חור בצמ ,ןורכז דוביא ,בחרמב

רועב יקדייח םוהיז

רועה עבצ יוניש ,רועב םיהכ םימתכ ,רועה לש תוקקדיה ,ינונמש רוע ,רועב הטסיצ ,תיחופלש

,םומיד תולדגומ וא תושיגר םייכינח

תויושטעתה ,םותס ףא וא תלזנ

תופכב ףוליק ןכתיו תוחיפנ וא/ו המדאה םיידיה

תנומסת ארקנ) םיילגרהו

foot

hand

רואל רועה וא םייניעה לש רתי תושיגר

תוימומדא וא באכ םייפעפעב דרג ,באכ ,ןיעב

םיינזואב (םילוצלצ) םישער ,םיינזוא באכ ,העימש יישק

םיחופנ םיקרפמ ] טואג) םיבאוכו

([ןודגש

ליגר וניאש ןתש עבצ ,ןתש ןתמב הטילש רסוח ,ןתשב םד

חט םירו

לש השוחת םישק תסו ירוזחמ ,תומטפב תוחיפנ ,םיידשב תושקתה

זיזהל ףחד) החונמה תורסח םיילגר לש םינימסת ,ףוגה לש דחא קלח

.(תוחונ רסוח לש תושוחת קיספהל תנמ לע ,לגרה ללכ ךרדב

.אפורה תא עדייל ךילע ,הרומח הרוצב ךילע תועיפשמ ליעל וניוצש תועפותה םא

ופיטה ךלהמב יאת) הכומנ םד יאת תמר ןוגכ תוניקת ןניאש םד תוקידב תואצות ךל ויהי יכ ןכתי ,הנגיסטב ל וא זאפיל לש ההובג המר ,(םד תויסט ,םימודא םד יאת ,םינבל םד

המר ,(בלבל דוקפת) םדב זאלימ ומנ המר ,(תוילכ דוקפת) םדב ןיניטארק לש ההובג המר ,(דבכ דוקפת) םדב ןיבוריליב לש ההובג וא הכ המר ,םדב רכוס לש ההובג וא הכומנ המר ,(םדב רכוס תומר תסוומה ןומרוה) ןילוסניא לש םדב ההובג .םדב םינמוש לש ההובג

.ךלש אפורה תצע רחא בוקע ,ךילע העיפשמ ליעל וניוצש תועפותהמ תחא םא

ל תעפותמ לבוס התאש וא הרימחמ יאוולה תועפותמ תחא םא ,יאוול תעפות העיפוה םא אלש יאוו הרכזוה הניוצ ןולעב

הז .אפורה םע ץעייתהל ךילע ,

רושיקה לע הציחל תועצמאב תואירבה דרשמל יאוול תועפות לע חוודל ןתינ

לופיט בקע יאוול תועפות לע חוויד יתפורת

רתא לש תיבה ףדב אצמנש

) תואירבה דרשמ

www.health.gov.il

לע חווידל ןווקמה ספוטל הנפמה

th.gov.il

www.heal

תואירבה דרשמ (

ע וא ,יאוול תועפות

הסינכ י

רושיקל

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

@moh.gov.il

5

.

?הפורתה תא ןסחאל ךיא

דלי לש םדי גשיהל ץוחמ רוגס םוקמב רומשל שי תרחא הפורת לכו וז הפורת !הלערה ענמ תוקונית וא/ו םי לעו

ידי

.הלערה ענמת ךכ

.אפורהמ תשרופמ הארוה אלל האקהל םורגת לא

) הגופתה ךיראת ירחא הפורתב שמתשהל ןיא

exp. date

סחייתמ הגופתה ךיראת .הזיראה יבג לע עיפומה ( .שדוח ותוא לש ןורחאה םויל

ל לעמ ןסחאל ןיא

°30

וחלמ ןגהל ידכ ,תירוקמה הזיראב ןסחאל שי

.הלבח לש םינמיס תלעב וא ,המוגפ הזיראב שמתשהל ןיא

.םידלי לש םתייאר הדשו םדי גשיהמ קחרה רומשל שי

6

.

:ףסונ עדימ

:םג הליכמ הפורתה ליעפה רמוחה לע ףסונ

Lactose

monohydrate,

Crospovidone,

Poloxamer

188,

Silica

colloidal,

anhydrous/

Colloidal silicon dioxide,

Magnesium stearate.

Tasigna 150 mg capsule shell: Gelatin, Titanium dioxide (E171), Iron oxide yellow

(E172), Iron oxide red (E172) and Printing ink: black.

Qualitative composition of printing ink: Shellac, Iron oxide black, n-butyl alcohol, purified

water, propylene glycol, dehydrated ethanol, isopropyl alcohol, ammonium hydroxide.

Tasigna 200 mg capsule shell: Gelatin, Titanium dioxide (E171), Iron oxide yellow

(E172), Printing ink: red, .

Iron oxide, black (E 172).

Qualitative composition of printing ink a: Shellac, dehydrated alcohol, isopropyl alcohol,

butyl alcohol, propylene glycol, strong ammonia solution, Iron oxide red (E172), potassium

hydroxide, purified water.

Qualitative composition of printing ink b: Shellac, Iron oxide red (E172), Iron oxide black

(E172), n-butyl alcohol, purified water, titanium dioxide (E171), propylene glycol, industrial

methylated spirit, isopropyl alcohol.

The printing ink used is ‘Printing ink a’ or alternatively ‘Printing ink b’.

הנגיסט לש הסומכ לכ

כ הליכמ ג"מ

.טארדיהונומ זוטקל ג

הנגיסט לש הסומכ לכ

כ הליכמ ג"מ

.טארדיהונומ זוטקל ג"מ

:הזיראה ןכות המו הפורתה תיארנ דציכ

הנגיסט לש תישדוח הזירא

הליכמ ג"מ

הליכמ תישדוחה הזיראה .תוסומכ

.תויעובש תוזירא

ל הזירא

הנגיסט לש םימי

הליכמ ג"מ

תוסומכ

הליכמ תישדוח הזיראו

הליכמ תישדוחה הזיראה .תוסומכ

ל תוזירא

.םימי

הנגיסט תוסומכ

תוסומכב הבהבהצ דע הנבל הקבא :ג"מ תומוטא תוחישק ןיטל'ג םודא עבצב

םוטא לדוגב ,

םע " ריצה לע הרוחש העבטה

"/"

."

הנגיסט תוסומכ

ומכב הבהבהצ דע הנבל הקבא :ג"מ תוס תומוטא תוחישק ןיטל'ג

ריהב בוהצ עבצב

םוטא לדוגב ,

" ריצה לע המודא העבטה םע

"/"

."

:ותבותכו םושירה לעב

םחש 'חר ,מ"עב לארשי סיטרבונ

חתפ ,

.הווקת

:ותבותכו ןרציה םש

י'ג ייא ןייטש המראפ סיטרבונ

לזב

ץיווש ןייטש

ץיווש

זב ,י'ג ייא המראפ סיטרבונ רובע .ץיווש ,ל

.רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ

לע רשואו קדבנ הז ןולע

:ךיראתב תואירבה דרשמ ידי

רבמטפס

2016

רבמטפס

2018

:תואירבה דרשמב יתכלממה תופורתה סקנפב הפורתה םושיר 'סמ

הנגיסט

:ג"מ

145 84 33271

הנגיסט

:ג"מ

138 17 31681

של .םינימה ינש ינבל תדעוימ הפורתה ,תאז ףא לע .רכז ןושלב חסונ הז ןולע ,האירקה תלקהלו תוטשפה ם

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