SPRYCEL 100 MG

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

SPRYCEL 20 mg

Film-coated tablets

SPRYCEL 50 mg

Film-coated tablets

SPRYCEL 70 mg

Film-coated tablets

SPRYCEL 100 mg

Film-coated tablets

The active ingredient and its quantity:

Each film-coated tablet contains: dasatinib 20 mg, dasatinib 50 mg,

dasatinib 70 mg, dasatinib 100 mg

For the list of inactive ingredients, please see section 6 and ‘Important

information about some of this medicine’s ingredients ‘ in section 2.

Read this leaflet carefully in its entirety before using the medicine.

This leaflet contains concise information about the medicine. If you have

further questions, refer to the doctor or pharmacist.

This medicine has been prescribed to treat your ailment. Do not pass it on to

others. It may harm them even if it seems to you that their ailment is similar.

SPRYCEL is not intended for use in children and adolescents under 18 years

of age. There is limited experience with use of SPRYCEL in this age group.

1.

WHAT IS THE MEDICINE INTENDED FOR?

SPRYCEL is a medicine intended for the treatment of adults:

Newly

diagnosed

patients

suffering

from

Philadelphia

chromosome-

positive chronic myeloid leukemia )CML(, at the chronic phase.

Patients with chronic myeloid leukemia )CML( at the chronic, accelerated

or blast phase with resistance or intolerance to prior treatment, including

prior treatment with imatinib mesilate.

Patients

with

Philadelphia

chromosome-positive

acute

lymphoblastic

leukemia (ALL( and patients with lymphoid blast-phase chronic myeloid

leukemia (CML) with resistance or intolerance to prior treatment.

Therapeutic group: protein kinase inhibitors.

2.

BEFORE USING THE MEDICINE

Do not use the medicine if:

You are sensitive )allergic( to the active ingredient )dasatinib( or to any

of the other ingredients of the medicine (see section 6).

If you could be allergic, ask your doctor for advice.

Special warnings regarding use of the medicine

Before treatment with SPRYCEL tell your doctor or pharmacist if:

You are taking medicines to thin your blood or prevent clots (see the section

‘Drug interactions’).

You have liver or heart problems, or used to have them.

You start having difficulty breathing, chest pain, or a cough when

taking SPRYCEL, refer to the doctor. This may be a sign of fluid retention

in the lungs or chest (which can be more common in patients aged 65 and

older) or due to changes in the blood vessels supplying the lungs.

You have ever had or currently have hepatitis B infection. This is because

SPRYCEL 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.

You experience bruising, bleeding, fever, fatigue and confusion during

the treatment with SPRYCEL, contact your doctor. These may be signs

of damage to blood vessels known as thrombotic microangiopathy (TMA).

Tests and follow-up:

Your doctor will regularly monitor your condition to check whether SPRYCEL

is having the desired effect. You will also have blood tests regularly while you

are taking SPRYCEL.

Children and adolescents:

SPRYCEL is not intended for use in children and adolescents under 18 years

old. There is limited experience with the use of SPRYCEL in this age group.

Drug interactions

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

non-prescription

medicines

and

nutritional

supplements,

tell

the

doctor or pharmacist.

SPRYCEL is primarily cleared by the liver. Certain medicines may interfere

with the effect of SPRYCEL when taken together.

Do not take the following medicines together with SPRYCEL:

ketoconazole and itraconazole – these are antifungal medicines

erythromycin, clarithromycin and telithromycin – these are antibiotics

ritonavir – this is an antiviral medicine

phenytoin, carbamazepine, phenobarbital – for treatment of epilepsy

rifampicin – this is a treatment for tuberculosis

famotidine and omeprazole – these are medicines that block stomach acid

St. John’s wort – a herbal-based preparation to treat depression (also

known as Hypericum perforatum)

Do not take medicines that neutralise stomach acid (antacids such as

aluminium hydroxide or magnesium hydroxide to treat heartburn) in the

2 hours before or 2 hours after taking SPRYCEL.

Tell your doctor if you are taking medicines to thin the blood or prevent clots.

Use of the medicine and food

The medicine can be taken with or without food.

Do not take the medicine with grapefruit or grapefruit juice.

Pregnancy and breastfeeding

If you are pregnant or think you may be pregnant, tell your doctor

immediately.

Do not take SPRYCEL during pregnancy unless clearly necessary. Your doctor

will discuss with you the potential risk of taking SPRYCEL during pregnancy.

Both men and women taking SPRYCEL must consult their doctor regarding

the use of effective contraception during the course of treatment.

If you are breastfeeding, tell your doctor. You should stop breastfeeding

while you are taking SPRYCEL.

Driving and use of machines

Take special care when driving or using machines in case you experience

side effects such as dizziness and blurred vision.

Important information about some of this medicine’s ingredients

SPRYCEL contains lactose. If you have been told by your doctor that you

have an intolerance to certain sugars, talk to your doctor before taking the

medicine.

3.

HOW SHOULD YOU USE THE MEDICINE?

SPRYCEL will only be prescribed to you by a doctor with experience in treating

leukemia. Always use SPRYCEL according to the doctor’s instructions. Check

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

treatment regimen of this product. SPRYCEL is intended for adults.

The dosage and treatment regimen will be determined by the doctor only.

Take the medicine in accordance with the dosage and duration determined

by your doctor. Depending on how you respond to the treatment, the doctor

will update you regarding the need for a higher or lower dosage of SPRYCEL,

or even stopping treatment briefly. For higher or lower doses, you may need

to take combinations of the different tablet strengths.

Do not exceed the recommended dose.

How long to take SPRYCEL

Take SPRYCEL daily until your doctor tells you to stop. Make sure you take

SPRYCEL for as long as it is prescribed.

Take the medicine at the same time every day.

Swallow the tablets whole. Do not crush, cut or chew the tablets (in order to

maintain dosing consistency and minimise the risk of skin exposure). Do not

disperse the tablets (as the exposure in patients receiving a dispersed tablet

is lower than in those swallowing a whole tablet).

You cannot be sure you will receive the correct dose if you crush, cut, chew

or disperse the tablets.

The medicine can be taken with or without food. Do not take the medicine

with grapefruit or grapefruit juice.

If you are also taking antacids )to treat heartburn(, such as medicines that

contain aluminium hydroxide or magnesium hydroxide, take the antacids no

less than two hours before or two hours after SPRYCEL.

Special handling instructions for SPRYCEL:

It is unlikely that the SPRYCEL tablets will get broken. But if they do, persons

other than the patient should use gloves when handling SPRYCEL.

Tests and follow-up:

Blood tests to monitor treatment progress should be carried out during the

course of treatment with this medicine.

If you took an overdose or if a child accidentally swallowed the medicine,

immediately refer to a doctor or proceed to a hospital emergency room and

bring the package of the medicine with you.

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 your doctor.

Adhere to the treatment regimen recommended by the doctor.

If you stop taking the medicine

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

without consulting the doctor.

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

you take medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine, consult the

doctor or pharmacist.

4.

SIDE EFFECTS

As with any medicine, use of SPRYCEL 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.

Contact your doctor immediately if the following effects, that can be signs

of severe side effects, occur:

having chest pain, difficulty breathing, coughing and fainting

unexpected bleeding or bruising without having an injury

having blood in your vomit, stools or urine, or having black stools

having signs of infection such as fever and severe chills

having fever, sore mouth or throat, blistering or peeling of your skin and/or

mucous membranes

Additional side effects:

Very common side effects (effects that occur in more than 1 in 10 users):

Infections )including bacterial, viral, and fungal infections(

Heart and lungs: shortness of breath

Digestive problems: diarrhea, nausea, vomiting

Skin, hair, eye, general: skin rash, fever, swelling around the face, hands

and feet, headache, feeling tired or weak, bleeding

Pain: pain in the muscles )during or after discontinuing treatment(, tummy

(abdominal) pain

Tests may show: low blood platelet count, low white blood cell count

)neutropenia(, anemia, fluid around the lungs

Common side effects (effects that occur in up to 1 in 10 users):

Infections: pneumonia, herpes virus infection )including cytomegalovirus

- CMV(, upper respiratory tract infection, serious infection of the blood or

tissues (including uncommon cases with fatal outcomes)

Heart and lungs: palpitations, irregular heartbeat, congestive heart failure,

weak heart muscle, high blood pressure, increased blood pressure in the

lungs, cough

Digestive problems: appetite disturbances, taste disturbance, bloated

or distended tummy )abdomen(, inflammation of the colon, constipation,

heartburn, mouth ulceration, weight increase, weight decrease, gastritis

Skin, hair, eye, general: skin tingling, itching, dry skin, acne, inflammation

of the skin, persistent noise in ears, hair loss, excessive perspiration, visual

disorder (including blurred vision and disturbed vision(, dry eye, bruise,

depression, insomnia, flushing, dizziness, contusion )bruising(, anorexia,

somnolence, generalized oedema

Pain: pain in joints, muscular weakness, chest pain, pain around hands

and feet, chills, stiffness in muscles and joints, muscle spasm

Tests may show: fluid around the heart, fluid in the lungs, arrhythmia,

febrile neutropenia, gastrointestinal bleeding, high uric acid levels in the

blood

Uncommon side effects (effects that occur in up to 1 in 100 users):

Heart and lungs: heart attack )including fatal outcome(, inflammation of

the lining (fibrous sack) surrounding the heart, irregular heartbeat, chest

pain due to lack of blood supply to the heart )angina(, low blood pressure,

narrowing of airway that may cause breathing difficulties, asthma, increased

blood pressure in the arteries of the lungs, blood clots

Digestive

problems:

inflammation

pancreas,

peptic

ulcer,

inflammation of the food pipe, swollen tummy )abdomen(, tear in the skin

of the anal canal, difficulty in swallowing, inflammation of the gallbladder,

blockage of bile ducts, gastro-esophageal reflux )a condition where acid

and other stomach contents come back up into the throat)

Skin, hair, eye, general: allergic reaction including tender, red lumps on the

skin )erythema nodosum(, anxiety, confusion, mood swings, lower sexual

drive, fainting, tremor, inflammation of the eye which causes redness or

pain, a skin disease characterized by red, tender, well-defined blotches with

the sudden onset of fever and raised white blood cell count (neutrophilic

dermatosis(, loss of hearing, sensitivity to light, visual impairment, increased

eye tearing, disturbance in skin color, inflammation of fatty tissue under the

skin, skin ulcer, blistering of the skin, nail disorder, hair disorder, hand-

foot disorder, renal failure, urinary frequency, breast enlargement in men,

menstrual disorder, general weakness and discomfort, low thyroid function,

losing balance while walking, osteonecrosis )a disease of reduced blood

flow to the bones, which can cause bone loss and bone death(, arthritis,

skin swelling anywhere in the body

Pain: inflammation of vein which can cause redness, tenderness and

swelling, inflammation of the tendon

Brain: loss of memory

Tests may show: abnormal blood test results and possibly impaired

kidney function caused by removal of tumor waste products (tumor lysis

syndrome(, low levels of albumin in the blood, low levels of lymphocytes )a

type of white blood cell( in the blood, high level of cholesterol in the blood,

swollen lymph nodes, bleeding in the brain, irregularity of the electrical

activity of the heart, enlarged heart, inflammation of the liver, protein in

the urine, raised creatine phosphokinase )an enzyme mainly found in the

heart, brain, and skeletal muscles(, raised troponin )an enzyme mainly

found in tissues such as the heart and skeletal muscles(, raised gamma-

glutamyl-transferase )an enzyme mainly found in the liver)

Rare side effects (effects that occur in up to 1 in 1,000 users):

Heart

and

lungs:

enlargement

right

ventricle

heart,

inflammation of the heart muscle, collection of various conditions resulting

from blockage of blood supply to the heart muscle (acute coronary

syndrome(, cardiac arrest )stopping of blood flow from the heart(, coronary

heart disease, inflammation of the tissue covering the heart and lungs,

blood clots )in deep veins(, blood clots in the lungs

Digestive problems: loss of vital nutrients such as protein from your

digestive tract, bowel obstruction, anal fistula )an abnormal opening from

the anus to the skin around the anus(, impairment of kidney function,

diabetes

Skin, hair, eye, general: convulsions, inflammation of the optic nerve that

may cause complete or partial loss of vision, blue-purple mottling of the

skin, abnormally high thyroid function, inflammation of the thyroid gland,

ataxia )coordination disorder(, difficulty walking, miscarriage, inflammation

of the skin blood vessels, skin fibrosis

Brain: stroke, temporary episode of neurologic dysfunction caused by

impaired blood flow, facial nerve paralysis, dementia

Additional side effects whose frequency is not known (cannot be

estimated from the available data):

Inflammation of the lungs

Bleeding in the stomach or bowels that can cause death

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

hepatitis B in the past (a liver infection)

A reaction with fever, blisters on the skin, and ulceration of the mucous

membranes

Disease of the kidneys with symptoms including oedema and abnormal

laboratory test results such as protein in the urine and low protein level in

the blood

Damage to blood vessels known as thrombotic microangiopathy )TMA(,

including decreased red blood cell count, decreased platelets, and formation

of blood clots.

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

experience a side effect not mentioned in this leaflet, consult your doctor.

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

link: “Reporting of side effects from drug treatment”, which can be 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://sideeffects.health.gov.il

5.

HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine and any other medicine must be stored in

a closed place out of the reach and sight of children and/or infants to avoid

poisoning. Do not induce vomiting unless explicitly instructed to do so by

a doctor!

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

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

Storage conditions:

Store below 25°C. Do not refrigerate or freeze. Keep the bottle tightly closed.

After first opening can be used for 12 months, but no later than the expiry

date that appears on the package.

Do not discard medicines via wastewater or household waste. Ask the

pharmacist how to dispose of medicines no longer in use. These measures

will help protect the environment.

6.

FURTHER INFORMATION

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

lactose monohydrate; cellulose, microcrystalline; croscarmellose sodium;

hydroxypropyl cellulose; magnesium stearate; Opadry white, YS-1-18177-A

The tablet contains lactose.

SPRYCEL 20 mg - Each film-coated tablet contains 27.0 mg of lactose

monohydrate.

SPRYCEL 50 mg - Each film-coated tablet contains 67.5 mg of lactose

monohydrate.

SPRYCEL 70 mg - Each film-coated tablet contains 94.5 mg of lactose

monohydrate.

SPRYCEL 100 mg - Each film-coated tablet contains 135.0 mg of lactose

monohydrate.

What the medicine looks like and the contents of the package:

SPRYCEL 20 mg:

The film-coated tablet is white to off-white, biconvex, round with “BMS”

debossed on one side and “527” on the other side.

The package contains a bottle with 60 film-coated tablets.

SPRYCEL 50 mg:

The film-coated tablet is white to off-white, biconvex, oval with “BMS”

debossed on one side and “528” on the other side.

The package contains a bottle with 60 film-coated tablets.

SPRYCEL 70 mg:

The film-coated tablet is white to off-white, biconvex, round with “BMS”

debossed on one side and “524” on the other side.

The package contains a bottle with 60 film-coated tablets.

SPRYCEL 100 mg:

The film-coated tablet is white to off-white, biconvex, oval with “BMS 100”

debossed on one side and “852” on the other side.

The package contains a bottle with 30 film-coated tablets.

License holder and address: Bristol-Myers Squibb )Israel( Ltd., 18 Aharon

Bart St., P.O. Box 3361, Kiryat Arye, Petach Tikva, 4951448.

Manufacturer and address: Bristol-Myers Squibb Company, Princeton,

New Jersey, 08543, USA.

This leaflet was revised in August 2020.

Registration numbers of the medicine in the National Drug Registry of

the Ministry of Health:

SPRYCEL 20 mg: 140-30-31919

SPRYCEL 50 mg: 140-31-31920

SPRYCEL 70 mg: 140-32-31921

SPRYCEL 100 mg: 143-90-33125

DOR-SPR-PIL-0720-17

:)لمعتسم 100 نيب نم 1 ىتح ىدل رهظت ضارعأ( ةعئاش ريغ ةيبناج ضارعأ

يذلا (fibrous sack) يطاخملا ءاشغلا باهتلا ،)ةتيمم جئاتن لمشي اذهو( ةيبلق ةبون :ناتئرلاو بلقلا مد طغض ،)ةحبذ( بلقلل مدلا ديوزت يف صقن ببسب ردصلا يف ملأ ،بلقلا مظن ماظتنا مدع ،بلقلاب طيحي يف ديازتم مد طغض ،وبر ،سفنت تابوعص ىلإ يدؤت نأ نكمم يتلا ةيئاوهلا يراجملا قيضت ،ضفخنم ةيومد تارثخت ،نيتئرلا نييارش

ةانقلا دلج يف قزمت ،نطبلا خافتنا ،ءيرملا يف باهتلا ،ةي

م ةحرق ،سايركنبلا باهتلا :مضهلا يف لكاشم (reflux( يئيرم يدعم دادترا ،ةيوارفصلا تاونقلا دادسنا ،ةرارملا باهتلا ،علبلا يف ةبوعص ،ةيجرشلا )قلحلا لخاد ىلإ ةدعملا تايوتحم يقابو ضامحلأا اهيف دوعت يتلا ةلاح يهو(

ىمامح( دلجلا ىلع ةساسحو ءارمح لتك لمشي يسسحت لعف در :ةماع ضارعأو نويعلا ،رعشلا ،دلجلا ،ةيسنجلا ةبغرلا يف ضافخنا ،جازملا يف تاريغت ،كابترا ،قلق ،)erythema nodosum - ةدقع ،ةساسح ،ءارمح عقبب زيمتي يدلج ضرم ،ا

ملأ وأ ا

رارمحا ببسي يذلا نيعلا باهتلا ،ةفجر ،ءامغإ neutrophilic( ءاضيبلا مدلا ايلاخ دادعت يف عافتراو ةنوخسل ئجافم روهظب قفارتت

اديج ةحضاو ،دلجلا نول ريغت ،عمدلل دئاز زارفإ ،ةيؤرلا يف للخ ،ءوضلل ةيساسح ،عمسلا نادقف ،)dermatosis ،رعشلا يف ريغت ،رفاظلأا يف ريغت ،دلجلا يف تلاصيوح ،دلجلا حرقت ،دلجلا تحت يمحشلا جيسنلا باهتلا ىدل ردصلا مخضت ،لوبتلا راركت ،يولك روصق ،)hand-foot disorder( لجر – دي ةمزلاتم ،يشملا ءانثأ نزاوتلا نادقف ،ةيقردلا ةدغلا روصق ،ماع جاعزناو فعض ،ثمطلا يف بارطضا ،لاجرلا تومو نادقف ىلإ يدؤي نأ نكمم يذلا ،ماظعلل ضفخنم مد قفدت ضرم – osteonecrosis( مظعلا رخن مسجلا نم ةفلتخم نكامأب دلجلا خافتنا ،لصافملا باهتلا ،)مظعلا

رتولا باهتلا ،خافتناو ةيساسح ،ا

رارمحا ببسي دق يذلا يديرو باهتلا :ملأ

ةركاذلا نادقف :غامدلا

يف للخ كانه نوكي نأ لمتحملا نمو ةميلس ريغ مد تاصوحف جئاتن :ن

ّ

يب

ُ

ت نأ تاصوحفلا نأش نم ةضفخنم بسن ،)tumour lysis syndrome( مرولا تلاضف داعبلإ ةجيتن ىلكلل يفيظولا ءادلأا ةبسن عافترا ،مدلا يف )ءاضيبلا مدلا ايلاخ نم عون( تايوافمللا نم ةضفخنم بسن ،مدلا يف نيموبللأا نم مخضت ،بلقلل يئابرهكلا طاشنلا ماظتنا مدع ،يغامد فزن ،ةيوافمللا ددغلا خافتنا ،مدلا يف لورتسلوكلا يسيئر لكشب دوجوم ميزنإ( زانيكوفسوف نيتايرك ميزنإ عافترا ،لوبلا يف نيتورب ،دبكلا باهتلا ،بلقلا يسيئر لكشب دوجوم ميزنإ( نينوپورتلا عافترا ،)يمظعلا لكيهلا تلاضع يفو ،غامدلا يف ،بلقلا يف ميزنإ( زاريفسنارت - ليماتﻮلچ - اماچ عافترا ،)يمظعلا لكيهلا تلاضعو بلقلا ةلضع لثم ةجسنلأا يف )دبكلا يف يسيئر لكشب دوجوم :)لمعتسم 1,000 نيب نم 1 ىتح ىدل رهظت ضارعأ( ةردان ةيبناج ضارعأ

يف دادسنا ةجيتن ثدحت ةفلتخم تلااح ،بلقلا ةلضع باهتلا ،بلقلل نميلأا نيطبلا مخضت :ناتئرلاو بلقلا ،)بلقلا نم مدلا قفدت فقوت( ةيبلق ةتكس ،)acute coronary syndrome( بلقلا ةلضعل مدلا ديوزت تارثخ ،)ةقيمعلا ةدرولأا يف( ةيومد تارثخ ،نيتئرلاو بلقلا فلغي يذلا جيسنلا باهتلا ،يجات يبلق ضرم نيتئرلا يف ةيومد

روسان ،ءاعملأا دادسنا ،مضهلا زاهج نم نيتوربلا لثم ةيرورض ةيذغم داوم نادقف :مضهلا يف لكاشم فئاظو ررضت ،)جرشلا ةحتفل طيحملا دلجلا هاجتاب جرشلا ةحتف يف ةميلس ريغ ةحتف( جرشلا ةحتف يف يركس ،ىلكلا

وأ لماك نادقفل يدؤي دق يذلا ةيؤرلا بصع باهتلا ،تاجنشت :ةماع ضارعأو نويعلا ،رعشلا ،دلجلا ةدغلا باهتلا ،ةيقردلا ةدغلا طاشن طرف ،يجسفنبلا ىلإ لئام - قرزلأا ىلإ لئام دلجلا نول ،ةيؤرلل يئزج ةبدن ،دلجلا يف ةيومدلا ةيعولأا باهتلا ،ضاهجإ ،يشملا ةبوعص ،)قيسنتلا يف بارطضا( حنرت ،ةيقردلا دلجلا يف ةيفيل

،هجولا بصع يف للش ،مدلا قفدت يف للخ ةجيتن يبصعلا يفيظولا ءادلأا يف تقؤم للاتخا ،ةتكس :غامدلا (dementia( فرخ :)ةدوجوملا تامولعملا نم اهريدقت نكمي لا( ةفورعم ريغ اهعويش ةبسن ةيفاضإ ةيبناج ضارعأ

نيتئرلا باهتلا

ةافولل يدؤي دق يذلا ءاعملأا يف وأ ةدعملا يف فيزن

يف B دبكلا باهتلا سوريﭬ نم تيناع اذإ ،B دبكلا باهتلا سوريڤب ثولتلا )Reactivation( راركت )دبكلا يف ثولت( يضاملا

ةيطاخملا ةيشغلأا حرقتو ،دلجلا ىلع تلاصيوح ،ةنوخسب بوحصم لعف در

ىوتسمو لوبلا يف نيتورب دوجو لثم ةذاش ةيربخم تاصوحف جئاتنو ةمذو لمشت ضارعأ عم ىلك ضرم مدلا يف ضفخنم نيتورب

thrombotic microangiopathy

[ ي

راث

خلا ة

قيق

دلا

ةيعو

لأا للاتعا مساب فورعملا ةيومدلا ةيعولأا يف ررض .ةيومد تارثخت ن

وكتو حئافصلا يف ضافخنا ،ءارمحلا مدلا تايرك دادعت يف ضافخنا لمشي يذلا ،](TMA) يف ةروكذم ريغ ة

ّ

يبناج ضارعأ نم تيناع اذإ وأ ة

ّ

يبناجلا ضارعلأا دحأ مقافت اذإ ،يبناج ضرع رهظ اذإ .بيبطلا ةراشتسا كيلع ،ةرشنلا ضارعأ نع غيلبت

"

طبارلا ىلع طغضلا ةطساوب ةحصلا ةرازول ةيبناج ضارعأ نع غيلبتلا ناكملإاب (www.health.gov.il) ةحصلا ةرازول ةيسيئرلا ةحفصلا ىلع دوجوملا ،

"

يئاود جلاع بقع ةيبناج :طبارلا لوخد قيرط نع وأ ،ةيبناج ضارعأ نع غيلبتلل رشابملا جذومنلل كهجوي يذلا

https://sideeffects.

health.gov.il

؟ءاودلا نيزخت ةيفيك .5

ةيؤر لاجمو يديأ لوانتم نع

اديعب قلغم ناكم يف رخآ ءاود لكو ءاودلا اذه ظفح بجي !ممستلا بنجت !بيبطلا نم ةحيرص تاميلعت نودب ؤيقتلا ببست لا .ممستلا بنجتت اذكهو ،عضرلا وأ/و لافطلأا

خيرات ريشي .ةبلعلا ىلع رهظي يذلا )exp. date( ةيحلاصلا خيرات ءاضقنا دعب ءاودلا لامعتسا زوجي لا .رهشلا سفن نم ريخلأا مويلا ىلإ ةيحلاصلا :نيزختلا طورش

ةقلغم ةنينقلا ظفح بجي .ديمجتلا وأ داربلا يف ءاودلا عضو زوجي لا .25°C ـلا تحت نيزختلا بجي .ديج لكشب

هيلا راشملا ةيحلاصلا ءاهتنا خيرات زواجتي لاأ ىلع .

ارهش 12 ةدمل لامعتسلاا ناكملإاب لولأا حتفلا دعب .ةبلعلا رهظ ىلع

ديق دعت مل ةيودأ نم صلختلا ةيفيك نع يلديصلا لأسا .ةمامقلل وأ يراجملا ىلإ ةيودلأا يمر زوجي لا .ةئيبلا ىلع ظافحلا يف دعاست لئاسولا هذه .لامعتسلاا ةيفاضإ تامولعم .6

:

ً

اضيأ ةلاعفلا ةداملل ةفاضلإاب ءاودلا يوتحي

lactose monohydrate; cellulose, microcrystalline; croscarmellose sodium;

hydroxypropyl cellulose; magnesium stearate; Opadry white, YS-1-18177-A

.زوتكلا ىلع صرقلا يوتحي .تارديهونوم زوتكلا غلم 27.0 یلع يوتحي يلطم صرق لك - غلم 20 لسياﺮﭙس .تارديهونوم زوتكلا غلم 67.5 یلع يوتحي يلطم صرق لك - غلم 50 لسياﺮﭙس .تارديهونوم زوتكلا غلم 94.5 یلع يوتحي يلطم صرق لك - غلم 70 لسياﺮﭙس .تارديهونوم زوتكلا غلم 135.0 یلع يوتحي يلطم صرق لك - غلم 100 لسياﺮﭙس :ةبلعلا ىوتحم وه امو ءاودلا ودبي فيك :غلم 20 لسياﺮﭙس لئام ضيبأ( تياو-فوأ ىتح ضيبأ هنول ،نيبناجلا نم بدحم ،ريدتسم صرق نع ةرابع وه يلطملا صرقلا .يناثلا بناجلا نم "527" -و دحاو بناج نم "BMS" صرقلا ىلع عوبطم .)يدامرلل

ايلطم

اصرق 60 اهيفو ةنينق ىلع ةبلعلا يوتحت

DOR-SPR-PIL-0720-17

:غلم 50 لسياﺮﭙس لئام ضيبأ( تياو-فوأ ىتح ضيبأ هنول ،نيبناجلا نم بدحم ،يوضيب صرق نع ةرابع وه يلطملا صرقلا .يناثلا بناجلا نم "528" -و دحاو بناج نم "BMS" صرقلا ىلع عوبطم .)يدامرلل

ايلطم

اصرق 60 اهيفو ةنينق ىلع ةبلعلا يوتحت :غلم 70 لسياﺮﭙس لئام ضيبأ( تياو فوأ ىتح ضيبأ هنول ،نيبناجلا نم بدحم ،ريدتسم صرق نع ةرابع وه يلطملا صرقلا .يناثلا بناجلا نم "524" -و دحاو بناج نم "BMS" صرقلا ىلع عوبطم .)يدامرلل

ايلطم

اصرق 60 اهيفو ةنينق ىلع ةبلعلا يوتحت :غلم 100 لسياﺮﭙس لئام ضيبأ( تياو-فوأ ىتح ضيبأ هنول ،نيبناجلا نم بدحم ،يوضيب صرق نع ةرابع وه يلطملا صرقلا .يناثلا بناجلا نم "852" -و دحاو بناج نم "BMS 100" صرقلا ىلع عوبطم .)يدامرلل

ايلطم

اصرق 30 اهيفو ةنينق ىلع ةبلعلا يوتحت .ب.ص ،18 تراب نوراهأ عراش ، .ض.م )ليئارسإ( بيوكس سريام-لوتسيرب :هناونعو زايتملإا بحاص .4951448 ،اڤكت حتيپ ،هيرأ تايرك ،3361 ةدحتملا تايلاولا ،08543 ،يسريج وين ،نوتسنيرپ ،ينپاموك بيوكس سريام-لوتسيرب :هناونعو جتنملا .ةيكيرملاا .2020 بآ يف ةرشنلا هذه ريرحت

ّ

مت :ةحصلا ةرازو يف

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يمسرلا ةيودلأا لجس يف ءاودلا ليجست ماقرأ

140-30-31919 :غلم 20 لسياﺮﭙس

140-31-31920 :غلم 50 لسياﺮﭙس

140-32-31921 :غلم 70 لسياﺮﭙس

143-90-33125 :غلم 100 لسياﺮﭙس ءاودلا نإف ،كلذ نم مغرلا ىلع .ركذملا ةغيصب ةرشنلا هذه ةغايص تمت ،ةءارقلا نيوهتو ةلوهس لجأ نم .نيسنجلا لاكل صصخم

1.

NAME OF THE MEDICINAL PRODUCT

SPRYCEL 20 mg

,

50 mg, 70 mg,100 mg

film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg , 50 mg, 70 mg, 100 mg dasatinib (as monohydrate).

Excipients with known effect

Each Sprycel 20mg film-coated tablet contains 27 .0 mg of lactose monohydrate.

Each Sprycel 50mg film-coated tablet contains 67.5 mg of lactose monohydrate.

Each Sprycel 70mg film-coated tablet contains 94.5 mg of lactose monohydrate.

Each Sprycel 100mg film-coated tablet contains 135.0 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet).

SPRYCEL 20 mg film coated tablets: White to off-white, biconvex, round film-coated tablet with

“BMS” debossed on one side and "527" on the other side.

SPRYCEL 50 mg film coated tablets: White to off-white, biconvex, oval film-coated tablet with

“BMS” debossed on one side and "528" on the other side.

SPRYCEL 70 mg : film coated tablets White to off-white, biconvex, round film-coated tablet with

“BMS” debossed on one side and "524" on the other side.

SPRYCEL 100 mg : film coated tablets White to off-white, biconvex, oval film-coated tablet with

“BMS 100” debossed on one side and “852” on the other side

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

SPRYCEL is indicated for the treatment of adult patients with:

newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia

(CML) in the chronic phase.

chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including

imatinib mesilate.

Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or

intolerance to prior therapy.

4.2

Posology and method of administration

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

leukaemia.

Posology

The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily.

The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase)

CML or Ph+ ALL is 140 mg once daily. (see section 4.4).

Treatment duration

In clinical studies, treatment with SPRYCEL was continued until disease progression or until no

longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the

achievement of a cytogenetic or molecular response [including complete cytogenetic response (CCyR),

major molecular response (MMR) and MR4.5] has not been investigated.

To achieve the recommended dose, SPRYCEL is available as 20 mg, 50 mg, 70 mg and

mg film-

coated tablets. Dose increase or reduction is recommended based on patient response and tolerability.

Dose escalation

In clinical studies in adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic

phase CML) or 180 mg once daily (advanced phase CML or Ph+ ALL) was allowed in patients who

did not achieve a haematologic or cytogenetic response at the recommended starting dose.

Dose adjustment for adverse reactions

Myelosuppression

In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or

discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate.

Haematopoietic growth factor has been used in patients with resistant myelosuppression.

Guidelines for dose modifications are summarised in Table 1.

Table 1:

Dose adjustments for neutropaenia and thrombocytopaenia in adults

Adults with chronic phase

(starting dose 100 mg once

daily)

ANC < 0.5 x 10

/Land/or

platelets < 50 x 10

Stop treatment until ANC ≥ 1.0 x 10

and platelets ≥ 50 x 10

/ L.

Resume treatment at the original

starting dose.

If platelets < 25 x 10

/L and/or

recurrence of ANC < 0.5 x 10

/L for

> 7 days, repeat step 1 and resume

treatment at a reduced dose of 80 mg

once daily for second episode. For third

episode, further reduce dose to 50 mg

once daily (for newly diagnosed

patients) or discontinue (for patients

resistant or intolerant to prior therapy

including imatinib).

Adults with accelerated and

blast phase CML and

Ph+ ALL

(starting dose 140 mg once

daily)

ANC < 0.5 x 10

and/or

platelets < 10 x 10

Check if cytopaenia is related to

leukaemia (marrow aspirate or biopsy).

If cytopaenia is unrelated to leukaemia,

stop treatment until ANC ≥ 1.0 x 10

and platelets ≥ 20 x 10

/L and resume

at the original starting dose.

If recurrence of cytopaenia, repeat step

1 and resume treatment at a reduced

dose of 100 mg once daily (second

episode) or 80 mg once daily (third

episode).

If cytopaenia is related to leukaemia,

consider dose escalation to 180 mg

once daily.

ANC: absolute neutrophil count

Non-haematologic adverse reactions

If a moderate, grade 2, non-haematologic adverse reaction develops with dasatinib, treatment should

be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be

resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse

reaction. If a severe grade 3 or 4, non-haematological adverse reaction develops with dasatinib,

treatment must be withheld until the adverse reaction has resolved. Thereafter, treatment can be

resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction. For

patients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once daily

with further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. For

patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to

100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, is

recommended.

Pleural effusion:

If a pleural effusion is diagnosed, dasatinib should be interrupted until patient is examined,

asymptomatic or has returned to baseline. If the episode does not improve within approximately one

week, a course of diuretics or corticosteroids or both concurrently should be considered (see sections

4.4 and 4.8). Following resolution of the first episode, reintroduction of dasatinib at the same dose

level should be considered .Following resolution of a subsequent episode, dasatinib at one dose level

reduction should be reintroduced .Following resolution of a severe (grade 3 or 4) episode, treatment

can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse

reaction.

Special populations

Paediatric population

The safety and efficacy of SPRYCEL in children and adolescents below 18 years of age have not yet

been established. No data are available (see section 5.1).

Elderly

No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No

specific dose recommendation is necessary in elderly.

Hepatic impairment

Patients with mild, moderate or severe hepatic impairment may receive the recommended starting

dose. However, SPRYCEL should be used with caution in patients with hepatic impairment (see

section 5.2).

Renal impairment

No clinical studies were conducted with SPRYCEL in patients with decreased renal function (the study

in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine

concentration > 3 times the upper limit of the normal range, and studies in patients with chronic phase

CML with resistance or intolerance to prior imatinib therapy excluded patients with serum creatinine

concentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib

and its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renal

insufficiency.

Method of administration

SPRYCEL must be administered orally.

The film-coated tablets must not be crushed, cut or chewed in order to maintain dosing consistency and

minimise the risk of dermal exposure; they must be swallowed whole. Film coated tablets should not

be dispersed as the exposure in patients receiving a dispersed tablet is lower than in those swallowing

a whole tablet. SPRYCEL can be taken with or without a meal and should be taken consistently either

in the morning or in the evening.

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

Clinically relevant interactions

Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a

potential for interaction with other concomitantly administered medicinal products that are

metabolised primarily by or modulate the activity of CYP3A4 (see section 4.5).

Concomitant use of dasatinib and medicinal products or substances that potently inhibit CYP3A4 (e.g.

ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may

increase exposure to dasatinib. Therefore, in patients receiving dasatinib, coadministration of a potent

CYP3A4 inhibitor is not recommended (see section 4.5).

Concomitant use of dasatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone,

phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing Hypericum

perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially

increasing the risk of therapeutic failure. Therefore, in patients receiving dasatinib, coadministration of

alternative medicinal products with less potential for CYP3A4 induction should be selected (see

section 4.5).

Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4

substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substrates

of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil

or ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5).

The concomitant use of dasatinib and a histamine-2 (H

) antagonist (e.g. famotidine), proton pump

inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure

to dasatinib. Thus, H

antagonists and proton pump inhibitors are not recommended and aluminium

hydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hours

following the administration of dasatinib (see section 4.5).

Special populations

Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or

severe hepatic impairment may receive the recommended starting dose (see section 5.2). Due to the

limitations of this clinical study, caution is recommended when administering dasatinib to patients with

hepatic impairment.

Important adverse reactions

Myelosuppression

Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Their

occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in

chronic phase CML. In patients with advanced phase CML or Ph+ ALL, complete blood counts

should be performed weekly for the first 2 months, and then monthly thereafter, or as clinically

indicated. In patients with chronic phase CML, complete blood counts should be performed every 2

weeks for 12 weeks, then every 3

months thereafter or as clinically indicated. Myelosuppression is

generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction

(see sections 4.2 and 4.8).

Bleeding

In patients with chronic phase CML (n=548), 5 patients (1%) receiving dasatinib had grade 3 or 4

haemorrhage. In clinical studies in patients with advanced phase CML receiving the recommended

dose of SPRYCEL (n=304), severe central nervous system (CNS) haemorrhage occurred in 1% of

patients. One case was fatal and was associated with Common Toxicity Criteria (CTC) grade 4

thrombocytopaenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 6% of patients with

advanced phase CML and generally required treatment interruptions and transfusions. Other grade 3 or

4 haemorrhage occurred in 2% of patients with advanced phase CML. Most bleeding related adverse

reactions in these patients were typically associated with grade 3 or 4 thrombocytopaenia (see

section 4.8). Additionally, in vitro and in vivo platelet assays suggest that SPRYCEL treatment

reversibly affects platelet activation.

Caution should be exercised if patients are required to take medicinal products that inhibit platelet

function or anticoagulants.

Fluid retention

Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newly

diagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 13 patients (5%) in the

dasatinib-treatment group and in 2 patients (1%) in the imatinib-treatment group after a minimum of

60 months follow-up (see section 4.8). In all SPRYCEL treated patients with chronic phase CML,

severe fluid retention occurred in 32 patients (6%) receiving SPRYCEL at the recommended dose

(n=548). In clinical studies in patients with advanced phase CML or Ph+ ALL receiving SPRYCEL at

the recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, including

grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. In these

patients grade 3 or 4 pulmonary oedema and pulmonary hypertension were each reported in 1% of

patients.

Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should

be evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen

therapy. Fluid retention adverse reactions were typically managed by supportive care measures that

include diuretics and short courses of steroids (see sections 4.2 and 4.8). Patients aged 65 years and

older are more likely than younger patients to experience pleural effusion, dyspnoea, cough,

pericardial effusion and congestive heart failure, and should be monitored closely.

Pulmonary arterial hypertension (PAH)

PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been

reported in association with dasatinib treatment (see section 4.8). In these cases, PAH was reported

after initiation of dasatinib therapy, including after more than one year of treatment.

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to

initiating dasatinib therapy. An echocardiography should be performed at treatment initiation in every

patient presenting symptoms of cardiac disease and considered in patients with risk factors for cardiac

or pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should be

evaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung

infiltration. In accordance with recommendations for management of non-haematologic adverse

reactions (see section 4.2) the dose of dasatinib should be reduced or therapy interrupted during this

evaluation. If no explanation is found, or if there is no improvement with dose reduction or

interruption, the diagnosis of PAH should be considered. The diagnostic approach should follow

standard practice guidelines. If PAH is confirmed, dasatinib should be permanently discontinued.

Follow up should be performed according to standard practice guidelines. Improvements in

haemodynamic and clinical parameters have been observed in dasatinib-treated patients with PAH

following cessation of dasatinib therapy.

QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT

Interval) (see section 5.3). In 258 dasatinib-treated patients and 258 imatinib-treated patients with a

minimum of 60 months follow-up in the Phase III study in newly diagnosed chronic phase CML, 1

patient (< 1%) in each group had QTc prolongation reported as an adverse reaction. The median

changes in QTcF from baseline were 3.0 msec in dasatinib-treated patients compared to 8.2 msec in

imatinib-treated patients. One patient (< 1%) in each group experienced a QTcF > 500 msec. In

865 patients with leukaemia treated with dasatinib in Phase II clinical studies, the mean changes from

baseline in QTc interval using Fridericia's method (QTcF) were 4 - 6 msec; the upper 95% confidence

intervals for all mean changes from baseline were < 7 msec (see section 4.8).

Of the 2,182 patients with resistance or intolerance to prior imatinib therapy who received dasatinib in

clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one of these

patients (1%) experienced a QTcF > 500 msec.

Dasatinib should be administered with caution to patients who have or may develop prolongation of

QTc. These include patients with hypokalaemia or hypomagnesaemia, patients with congenital long

QT syndrome, patients taking anti-arrhythmic medicinal products or other medicinal products which

lead to QT prolongation, and cumulative high dose anthracycline therapy. Hypokalaemia or

hypomagnesaemia should be corrected prior to dasatinib administration.

Cardiac adverse reactions

Dasatinib was studied in a randomised clinical study of 519 patients with newly diagnosed CML in

chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of

congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT

prolongation and myocardial infarction (including fatal) were reported in patients taking dasatinib.

Cardiac adverse reactions were more frequent in patients with risk factors or a history of cardiac

disease. Patients with risk factors (e.g. hypertension, hyperlipidaemia, diabetes) or a history of cardiac

disease (e.g. prior percutaneous coronary intervention, documented coronary artery disease) should be

monitored carefully for clinical signs or symptoms consistent with cardiac dysfunction such as chest

pain, shortness of breath, and diaphoresis.

If these clinical signs or symptoms develop, physicians are advised to interrupt dasatinib

administration and consider the need for alternative CML specific treatment. After resolution, a

functional assessment should be performed prior to resuming treatment with dasatinib. Dasatinib may

be resumed at the original dose for mild/moderate adverse reactions (≤ grade 2) and resumed at a dose

level reduction for severe adverse reactions (≥ grade 3) (see section 4.2). Patients continuing treatment

should be monitored periodically.

Patients with uncontrolled or significant cardiovascular disease were not included in the clinical

studies.

Thrombotic microangiopathy (TMA)

BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA),

including individual case reports for SPRYCEL (see section 4.8). If laboratory or clinical findings

associated with TMA occur in a patient receiving SPRYCEL, treatment with SPRYCEL should be

discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-

ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated

in conjunction with low ADAMTS13 activity, treatment with SPRYCEL should not be resumed.

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 SPRYCEL. 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

SPRYCEL 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).

Severe Dermatologic Reactions

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome

and erythema multiforme, have been reported in patients treated with SPRYCEL. Discontinue

permanently in patients who experience a severe mucocutaneous reaction during treatment if no

other

etiology can be identified.

Excipients

Lactose

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of

galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this

medicinal product.

4.5

Interaction with other medicinal products and other forms of interaction

Active substances that may increase dasatinib plasma concentrations

In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and

medicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole,

erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to

dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4

inhibitor is not recommended (See section 4.2).

At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on

the basis of in vitro experiments. No studies have been performed to evaluate dasatinib interaction

with other protein-bound medicinal products. The potential for displacement and its clinical relevance

are unknown.

Active substances that may decrease dasatinib plasma concentrations

When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a

potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicinal products that

induce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, phenobarbital or herbal

preparations containing Hypericum perforatum, also known as St. John´s Wort) may also increase

metabolism and decrease dasatinib plasma concentrations. Therefore, concomitant use of potent

CYP3A4 inducers with dasatinib is not recommended. In patients in whom rifampicin or other

CYP3A4 inducers are indicated, alternative medicinal products with less enzyme induction potential

should be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is

allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of

dexamethasone, which is not likely to be clinically meaningful.

Histamine-2 antagonists and proton pump inhibitors

Long-term suppression of gastric acid secretion by H

antagonists or proton pump inhibitors (e.g.

famotidine and omeprazole) is likely to reduce dasatinib exposure. In a single-dose study in healthy

subjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL reduced

dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg dose

of SPRYCEL 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of

dasatinib by 43% and the C

of dasatinib by 42%. The use of antacids should be considered in place

of H

antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy (see section 4.4).

Antacids

Non-clinical data demonstrate that the solubility of dasatinib is pH-dependent. In healthy subjects, the

concomitant use of aluminium hydroxide/magnesium hydroxide antacids with SPRYCEL reduced the

AUC of a single dose of SPRYCEL by 55% and the C

by 58%. However, when antacids were

administered 2 hours prior to a single dose of SPRYCEL, no relevant changes in dasatinib

concentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or

2 hours following SPRYCEL (see section 4.4).

Active substances that may have their plasma concentrations altered by dasatinib

Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4

substrate. In a study in healthy subjects, a single 100 mg dose of dasatinib increased AUC and C

exposure to simvastatin, a known CYP3A4 substrate, by 20 and 37% respectively. It cannot be

excluded that the effect is larger after multiple doses of dasatinib. Therefore, CYP3A4 substrates

known to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide, quinidine,

bepridil or ergot alkaloids [ergotamine, dihydroergotamine]) should be administered with caution in

patients receiving dasatinib (see section 4.4).

In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

Both sexually active men and women of childbearing potential should use effective methods of

contraception during treatment.

Pregnancy

Based on human experience, dasatinib is suspected to cause congenital malformations including neural

tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy.

Studies in animals have shown reproductive toxicity (see section 5.3).

SPRYCEL should not be used during pregnancy unless the clinical condition of the woman requires

treatment with dasatinib. If SPRYCEL is used during pregnancy, the patient must be informed of the

potential risk to the foetus.

Breast-feeding

There is insufficient/limited information on the excretion of dasatinib in human or animal breast milk.

Physico-chemical and available pharmacodynamic/toxicological data on dasatinib point to excretion in

breast milk and a risk to the suckling child cannot be excluded.

Breast-feeding should be stopped during treatment with SPRYCEL.

Fertility

In animal studies, the fertility of male and female rats was not affected by treatment with dasatinib (see

section 5.3). Physicians and other healthcare providers should counsel male patients of appropriate age

about possible effects of SPRYCEL on fertility, and this counseling may include consideration of semen

deposition.

4.7

Effects on ability to drive and use machines

SPRYCEL has minor influence on the ability to drive and use machines. Patients should be advised

that they may experience adverse reactions such as dizziness or blurred vision during treatment with

dasatinib. Therefore, caution should be recommended when driving a car or operating machines.

4.8

Undesirable effects

Summary of the safety profile

The data described below reflect the exposure to SPRYCEL at all doses tested in clinical studies

(N=2,712) , including 324 patients with newly diagnosed chronic phase CML and 2,388 patients with

imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL. In the 2,712 patients

with either chronic phase CML, advanced phase CML or Ph+ ALL, the median duration of therapy

was 19.2 months (range 0to 93.2 months).

In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of

therapy was approximately 60 months . The median duration of therapy in 1,618 patients with chronic

phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1,094

patients with advanced phase CML or Ph+ ALL, was 6.2 months (range 0 to 93.2 months).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the overall

population of 2,712 SPRYCEL treated subjects, 520 (19%) experienced adverse reactions leading to

treatment discontinuation.

Tabulated list of adverse reactions

The following adverse reactions, excluding laboratory abnormalities, were reported in patients in

SPRYCEL clinical studies and post-marketing experience (Table 2). These reactions are presented by

system organ class and by frequency. Frequencies are defined as: 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); not known

(cannot be estimated from available post-marketing data).

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

Table 2:

Tabulated summary of adverse reactions

Infections and infestations

Very common

infection (including bacterial, viral, fungal, non-specified)

Common

pneumonia (including bacterial, viral, and fungal), upper respiratory tract

infection/inflammation, herpes virus infection, (including cytomegalovirus -

CMV), enterocolitis infection, sepsis (including uncommon cases with fatal

outcomes)

Not known

hepatitis B reactivation

Blood and lymphatic system disorders

Very Common

myelosuppression (including anaemia, neutropaenia, thrombocytopaenia)

Common

febrile neutropaenia

Uncommon

lymphadenopathy, lymphopaenia

Rare

aplasia pure red cell

Immune system disorders

Uncommon

hypersensitivity (including erythema nodosum)

Endocrine disorders

Uncommon

Hypothyroidism

Rare

hyperthyroidism, thyroiditis

Metabolism and nutrition disorders

Common

appetite disturbances

, hyperuricaemia

Uncommon

tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia

Rare

diabetes mellitus

Psychiatric disorders

Common

depression, insomnia

Uncommon

anxiety, confusional state, affect lability, libido decreased

Nervous system disorders

Very common

Headache

Common

neuropathy (including peripheral neuropathy), dizziness, dysgeusia,

somnolence

Uncommon

CNS bleeding*

, syncope, tremor, amnesia, balance disorder

Rare

cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis,

VIIth nerve paralysis, dementia, ataxia

Eye disorders

Common

visual disorder (including visual disturbance, vision blurred, and visual acuity

reduced), dry eye

Uncommon

visual impairment, conjunctivitis, photophobia, lacrimation increased

Ear and labyrinth disorders

Common

Tinnitus

Uncommon

hearing loss, vertigo

Cardiac disorders

Common

congestive heart failure/cardiac dysfunction*

, pericardial effusion*, arrhythmia

(including tachycardia), palpitations

Uncommon

myocardial infarction (including fatal outcome)*, electrocardiogram QT

prolonged*, pericarditis, ventricular arrhythmia (including ventricular

tachycardia), angina pectoris, cardiomegaly, electrocardiogram T wave

abnormal, troponin increased

Rare

cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest,

electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis

Not known

atrial fibrillation/atrial flutter

Vascular disorders

Very common

haemorrhage*

Common

hypertension, flushing

Uncommon

hypotension, thrombophlebitis, thrombosis

Rare

deep vein thrombosis, embolism, livedo reticularis

Not Known

thrombotic microangiopathy

Respiratory, thoracic and mediastinal disorders

Very common

pleural effusion*, dyspnoea

Common

pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis,

cough

Uncommon

pulmonary arterial hypertension, bronchospasm, asthma

Rare

pulmonary embolism, acute respiratory distress syndrome

Not known

interstitial lung disease

Gastrointestinal disorders

Very common

diarrhoea, vomiting, nausea, abdominal pain

Common

gastrointestinal bleeding*, colitis (including neutropaenic colitis), gastritis,

mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal

distension, constipation, oral soft tissue disorder

Uncommon

pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer,

oesophagitis, ascites*, anal fissure, dysphagia, gastroesophageal reflux disease

Rare

protein-losing gastroenteropathy, ileus, anal fistula

Not known

fatal gastrointestinal haemorrhage*

Hepatobiliary disorders

Uncommon

hepatitis, cholecystitis, cholestasis

Skin and subcutaneous tissue disorders

Very common

skin rash

Common

alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria,

hyperhidrosis

Uncommon

neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis,

skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia

syndrome, hair disorder

Rare

leukocytoclastic vasculitis, skin fibrosis

Not known

Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal pain

Common

arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle

spasm

Uncommon

rhabdomyolysis, osteonecrosis, muscle inflammation, tendonitis, arthritis

Renal and urinary disorders

Uncommon

renal impairment (including renal failure), urinary frequency, proteinuria

Not known

nephrotic syndrome

Pregnancy, puerperium and perinatal conditions

Rare

Abortion

Reproductive system and breast disorders

Uncommon

gynecomastia, menstrual disorder

General disorders and administration site conditions

Very common

peripheral oedema

, fatigue, pyrexia, face oedema

Common

asthenia, pain, chest pain, generalised oedema*

, chills

Uncommon

malaise, other superficial oedema

Rare

gait disturbance

Investigations

Common

weight decreased, weight increased

Uncommon

blood creatine phosphokinase increased, gamma-glutamyltransferase increased

Injury, poisoning, and procedural complications

Common

Contusion

Includes decreased appetite, early satiety, increased appetite.

Includes central nervous system haemorrhage, cerebral haematoma, cerebral haemorrhage, extradural haematoma,

haemorrhage intracranial, haemorrhagic stroke, subarachnoid haemorrhage, subdural haematoma, and subdural

haemorrhage.

Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventricular

dysfunction, cardiac failure,cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy,