Sutent

Evrópusambandið - enska - EMA (European Medicines Agency)

Kauptu það núna

Upplýsingar fylgiseðill PIL
Vara einkenni SPC
Opinber matsskýrsla PAR
Virkt innihaldsefni:
sunitinib
Fáanlegur frá:
Pfizer Limited
ATC númer:
L01XE04
INN (Alþjóðlegt nafn):
sunitinib
Meðferðarhópur:
Antineoplastic agents,
Lækningarsvæði:
Gastrointestinal Stromal Tumors, Carcinoma, Renal Cell, Neuroendocrine Tumors
Ábendingar:
Gastrointestinal stromal tumour (GIST), Sutent is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) in adults after failure of imatinib mesilate treatment due to resistance or intolerance.Metastatic renal cell carcinoma (MRCC), Sutent is indicated for the treatment of advanced/metastatic renal cell carcinoma (MRCC) in adults.Pancreatic neuroendocrine tumours (pNET), Sutent is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours with disease progression in adults., Experience with Sutent as first-line treatment is limited (see section 5.1).,
Vörulýsing:
Revision: 38
Leyfisstaða:
Authorised
Leyfisnúmer:
EMEA/H/C/000687
Leyfisdagur:
2006-07-19
EMEA númer:
EMEA/H/C/000687

Skjöl

Opinber matsskýrsla Opinber matsskýrsla - búlgarska
Opinber matsskýrsla Opinber matsskýrsla - tékkneska
Opinber matsskýrsla Opinber matsskýrsla - eistneska
Opinber matsskýrsla Opinber matsskýrsla - lettneska
Opinber matsskýrsla Opinber matsskýrsla - litháíska
Opinber matsskýrsla Opinber matsskýrsla - ungverska
Opinber matsskýrsla Opinber matsskýrsla - maltneska
Opinber matsskýrsla Opinber matsskýrsla - hollenska
Opinber matsskýrsla Opinber matsskýrsla - portúgalska
Opinber matsskýrsla Opinber matsskýrsla - rúmenska
Opinber matsskýrsla Opinber matsskýrsla - slóvakíska
Opinber matsskýrsla Opinber matsskýrsla - slóvenska
Samantekt á eiginleikum vöru Samantekt á eiginleikum vöru - norskt bókmál
Opinber matsskýrsla Opinber matsskýrsla - króatíska

B. PACKAGE LEAFLET

Package leaflet: Information for the user

Sutent 12.5 mg hard capsules

Sutent 25 mg hard capsules

Sutent 37.5 mg hard capsules

Sutent 50 mg hard capsules

sunitinib

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

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

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor. This includes any possible side effects not listed

in this leaflet. See section 4.

What is in this leaflet

What Sutent is and what it is used for

What you need to know before you take Sutent

How to take Sutent

Possible side effects

How to store Sutent

Contents of the pack and other information

1.

What Sutent is and what it is used for

Sutent contains the active substance sunitinib, which is a protein kinase inhibitor. It is

used to treat

cancer by preventing the activity of a special group of proteins which are known to be involved in the

growth and spread of cancer cells.

Sutent is used to treat adults with the following types of cancer:

Gastrointestinal stromal tumour (GIST), a type of cancer of the stomach and bowel, where

imatinib (another anticancer medicine) no longer works or you cannot take imatinib.

Metastatic renal cell carcinoma (MRCC), a type of kidney cancer that has spread to other parts

of the body.

Pancreatic neuroendocrine tumours (pNET) (tumours of the hormone-producing cells in the

pancreas) that have progressed or cannot be removed with surgery.

If you have any questions about how Sutent works or why this medicine has been prescribed for you,

ask your doctor.

2.

What you need to know before you take Sutent

Do not take Sutent:

If you are allergic to sunitinib or any of the other ingredients of Sutent (listed in section 6).

Warnings and precautions

Talk to your doctor before taking Sutent:

-

If you have high blood pressure.

Sutent can raise blood pressure. Your doctor may check your

blood pressure during treatment with Sutent, and you may be treated with medicines to reduce

the blood pressure, if needed.

If you have or have had blood disease, bleeding problems, or bruising.

Treatment with

Sutent may lead to a higher risk of bleeding or lead to changes in the number of certain cells in

the blood which may lead to

anaemia or affect the ability of your blood to clot. If you are taking

warfarin or acenocoumarole, medicines which thin the blood to prevent blood clots, there may

be a greater risk of bleeding. Tell your doctor if you have any bleeding while on treatment with

Sutent.

If you have heart problems.

Sutent can cause heart problems. Tell your doctor if you feel very

tired, are short of breath, or have swollen feet and ankles.

If you have abnormal heart rhythm changes.

Sutent can cause abnormality of your heart

rhythm. Your doctor may obtain electrocardiograms to evaluate for these problems during your

treatment with Sutent. Tell your doctor if you feel dizzy, faint, or have abnormal heartbeats

while taking Sutent.

If you have had a recent problem with blood clots in your veins and/or arteries (types of

blood vessels), including stroke, heart attack, embolism, or thrombosis.

Call your doctor

immediately if you get symptoms such as chest pain or pressure, pain in your arms, back, neck

or jaw, shortness of breath, numbness or weakness on 1 side of your body, trouble talking,

headache, or dizziness while on treatment with Sutent.

If you have or have had an aneurysm

(enlargement and weakening of a blood vessel wall) or a

tear in a blood vessel wall.

If you have or have had damage to the smallest blood vessels known as thrombotic

microangiopathy (TMA).

Tell your doctor if you develop fever, fatigue, tiredness, bruising,

bleeding, swelling, confusion, vision loss, and seizures.

If you have thyroid glands problems.

Sutent can cause thyroid gland problems. Tell your

doctor if you get tired more easily, generally feel colder than other people, or your voice

deepens whilst taking Sutent. Your thyroid function should be checked before you take Sutent

and regularly while you are taking it. If your thyroid gland is not producing enough thyroid

hormone, you may be treated with thyroid hormone replacement.

-

If you have or have had pancreatic or gallbladder disorders.

Tell your doctor if you develop

any of the following signs and symptoms: pain in the area of the stomach (upper abdomen),

nausea, vomiting, and fever. These may be caused by inflammation of the pancreas

gallbladder.

If you have or have had liver problems.

Tell your doctor if you develop any of the following

signs and symptoms of liver problems during Sutent treatment: itching, yellow eyes or skin, dark

urine, and pain or discomfort in the right upper stomach area. Your doctor should do blood tests

to check your liver function before and during treatment with Sutent, and as clinically indicated.

If you have or have had kidney problems.

Your doctor will monitor your kidney function.

If you are going to have surgery or if you had an operation recently.

Sutent may affect the

way your wounds heal. You will usually be taken off Sutent if you are having an operation.

Your doctor will decide when to start Sutent again.

You may be advised to have a dental check-up before you start treatment with Sutent.

If you have or have had pain in the mouth, teeth and/or jaw, swelling or sores inside the

mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth, tell your

doctor and dentist immediately.

If you need to undergo an invasive dental treatment or dental surgery, tell your dentist that

you are being treated with Sutent in particular when you are also receiving or have received

intravenous bisphosphonates. Bisphosphonates are medicines used to prevent bone

complications that may have been given for another medical condition.

If you have or have had skin and subcutaneous tissue disorders.

While you are on this

medicine "pyoderma gangrenosum" (painful skin ulceration) or “necrotising fasciitis” (rapidly

spreading infection of the skin/soft tissue that may be life-threatening) may occur. Contact your

doctor immediately if symptoms of infection occur around a skin injury, including fever, pain,

redness, swelling, or drainage of pus or blood. This event is generally reversible after sunitinib

discontinuation. Severe skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis,

erythema multiforme) have been reported with the use of sunitinib, appearing initially as reddish

target-like spots or circular patches often with central blisters on the trunk. The rash may

progress to widespread blistering or peeling of the skin and may be life-threatening. If you

develop a rash or these skin symptoms, seek immediate advice from a doctor.

If you have or have had seizures.

Notify your doctor as soon as possible if you have high

blood pressure, headache, or loss of sight.

If you have diabetes.

Blood sugar levels in diabetic patients should be checked regularly in

order to assess if antidiabetic medicine’s dosage needs to be adjusted to minimise the risk of low

blood sugar. Notify your doctor as soon as possible if you experience any signs and symptoms

of low blood sugar (fatigue, palpitations, sweating, hunger and loss of consciousness).

Children and adolescents

Sutent is not recommended for people aged under 18.

Other medicines and Sutent

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other

medicines, including medicines obtained without a prescription and even those not prescribed.

Some medicines can affect the levels of Sutent in your body. You should inform your doctor if you are

taking medicines containing the following active substances:

ketoconazole, itraconazole – used to treat fungal infections

erythromycin, clarithromycin, rifampicin –used to treat infections

ritonavir –used to treat HIV

dexamethasone – a corticosteroid used for various conditions (such as allergic/breathing

disorders or skin diseases)

phenytoin, carbamazepine, phenobarbital – used to treat epilepsy and other neurological

conditions

herbal preparations containing St. John’s Wort (

Hypericum perforatum

) – used to treat

depression and anxiety

Sutent with food and drink

You should avoid drinking grapefruit juice while on treatment with Sutent.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

If you might get pregnant, you should use a reliable method of contraception during treatment with

Sutent.

If you are breast-feeding, tell your doctor. You should not breast-feed during treatment with Sutent.

Driving and using machines

If you experience dizziness or you feel unusually tired, take special care when driving or using

machines.

3.

How to take Sutent

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not

sure.

Your doctor will prescribe a dose that is right for you, depending on the type of cancer to be treated. If

you are being treated for:

GIST or MRCC: the usual dose is 50 mg once daily taken for 28 days (4 weeks), followed by

14 days (2 weeks) of rest (no medicine), in 6-week cycles.

pNET: the usual dose is 37.5 mg once daily without a rest period.

Your doctor will determine the appropriate dose you need to take, as well as if and when you need to

stop treatment with Sutent.

Sutent can be taken with or without food.

If you take more Sutent

than you should

If you have accidentally taken too many capsules, talk to your doctor straight away. You may require

medical attention.

If you forget to take Sutent

Do not take a double dose to make up for a forgotten dose.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You must immediately contact your doctor if you experience any of those serious side effects (see also

What you need to know before you take Sutent

Heart problems.

Tell your doctor if you feel very tired,

are short of breath, or have swollen feet and

ankles. These may be symptoms of heart problems that may include heart failure and heart muscle

problems (cardiomyopathy).

Lung or breathing problems.

Tell your doctor if you develop cough, chest pain, sudden onset of

shortness of breath, or coughing up blood. These may be symptoms of a condition called pulmonary

embolism that occurs when blood clots travel to your lungs.

Kidney disorders.

Tell your doctor if you experience

altered frequency or absence of urination which

may be symptoms of kidney failure.

Bleeding.

Tell your doctor if you have any of these symptoms or a serious bleeding problem during

treatment with Sutent: painful, swollen stomach (abdomen); vomiting blood; black, sticky stools;

bloody urine; headache or change in your mental status; coughing up of blood or bloody sputum from

the lungs or airway.

Tumour destruction leading to hole in the intestine.

Tell your doctor if you have severe abdominal

pain, fever, nausea, vomiting, blood in your stool, or changes in bowel habits.

Other side effects with Sutent may include:

Very common: may affect more than 1 in 10 people

Reduction in the number of platelets, red blood cells and/or white blood cells (e.g. neutrophils).

Shortness of breath.

High blood pressure.

Extreme tiredness, loss of strength.

Swelling caused by fluid under the skin and around the eye, deep allergic rash.

Mouth pain/irritation, mouth sores/inflammation/dryness, taste disturbances, upset stomach,

nausea, vomiting, diarrhoea, constipation, abdominal pain/swelling, loss/decrease of appetite.

Decreased activity of thyroid gland (hypothyroidism).

Dizziness.

Headache.

Nose bleeding.

Back pain, joint pain.

Pain in arms and legs.

Yellow skin/skin discoloration, excess pigmentation of the skin, hair colour change, rash on the

palms of the hands and soles of the feet, rash, dryness of the skin.

Cough.

Fever.

Difficulty in falling asleep.

Common: may affect up to 1 in 10 people

Blood clots in the blood vessels.

Deficiency of blood supply to the heart muscle, due to obstruction or constriction of the

coronary arteries.

Chest pain.

Decreased in the amount of blood pumped by the heart.

Fluid retention including around the lungs.

Infections.

Complication of severe infection (infection is present in the bloodstream) that can lead to tissue

damage, organ failure, and death.

Decreased blood sugar level (see section 2)..

Loss of protein in the urine sometime resulting in swelling.

Influenza-like syndrome.

Abnormal blood tests including pancreatic and liver enzymes.

High level of uric acid in the blood.

Haemorrhoids, pain in the rectum, gingival bleeding, difficulty in swallowing or inability to

swallow.

Burning or painful sensation in the tongue, inflammation of the digestive tract lining, excessive

gas in the stomach or intestine.

Weight loss.

Musculoskeletal pain (pain in muscles and bones), muscular weakness, muscular fatigue, muscle

pain, muscle spasms.

Nasal dryness, congested nose.

Excessive tear flow.

Abnormal sensation of the skin, itching, flaking and inflammation of the skin, blisters, acne, nail

discolouration, hair loss.

Abnormal sensations in extremities.

Abnormally decreased/increased sensitivity, particularly to touch.

Acid heartburn.

Dehydration.

Hot flushes.

Abnormally coloured urine.

Depression.

Chills.

Uncommon: may affect up to 1 in 100 people

Life-threatening infection of the soft tissue including the ano-genital region (see section 2).

Stroke.

Heart attack caused by an interrupted or decreased blood supply to the heart.

Changes in the electrical activity or abnormal rhythm of the heart.

Fluid around the heart (pericardial effusion).

Liver failure.

Pain in the stomach (abdomen) caused by inflammation of the pancreas.

Tumour destruction leading to hole in the intestine (perforation).

Inflammation (swelling and redness) of the gallbladder with or without associated gallstones.

Abnormal tube like passage from one normal body cavity to another body cavity or the skin.

Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of

heaviness in the jaw, or loosening of a tooth. These could be signs and symptoms of bone

damage in the jaw (osteonecrosis), see section 2.

Overproduction of thyroid hormones which increases the amount of energy the body uses at rest.

Problems with wound healing after surgery.

Increased blood level of enzyme (creatine phosphokinase) from muscle.

Excessive reaction to an allergen including hay fever, skin rash, itchy skin, hives, swelling of

body parts, and trouble breathing.

Inflammation of the colon (colitis, colitis ischaemic).

Rare: may affect up to 1 in 1,000 people

Severe reaction of the skin and/or mucous membranes (Stevens-Johnson syndrome, toxic

epidermal necrolysis, erythema multiforme).

Tumour lysis syndrome (TLS) – TLS consists of a group of metabolic complications that can

occur during treatment of cancer. These complications are caused by the break-down products of

dying cancer cells and may include the following: nausea, shortness of breath, irregular

heartbeat, muscular cramps, seizure, clouding of urine and tiredness associated with abnormal

laboratory test results (high potassium, uric acid and phosphorous levels and low calcium levels

in the blood) that can lead to changes in kidney function and acute renal failure.

Abnormal muscle breakdown which can lead to kidney problems (rhabdomyolysis).

Abnormal changes in the brain that can cause a collection of symptoms including headache,

confusion, seizures, and vision loss (reversible posterior leukoencephalopathy syndrome).

Painful skin ulceration (pyoderma gangrenosum).

Inflammation of the liver (hepatitis).

Inflammation of the thyroid gland.

Damage to the smallest blood vessels known as thrombotic microangiopathy (TMA).

Not known (frequency cannot be estimated from available data):

An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall

(aneurysms and artery dissections).

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible

side effects not listed in this

leaflet. You can also report side effects directly via the national reporting system listed in Appendix

V. By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Sutent

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on carton, bottle and blister foil

after “EXP”. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Sutent contains

Sutent 12.5 mg hard capsules

The active substance is sunitinib. Each capsule contains sunitinib malate equivalent to 12.5 mg

sunitinib. The other ingredients are:

Capsule content:

mannitol (E421), croscarmellose sodium, povidone (K-25), and magnesium

stearate.

Capsule shell:

gelatin, red iron oxide (E172), and titanium dioxide (E171).

Printing ink:

shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide

(E171).

Sutent 25 mg hard capsules

The active substance is sunitinib. Each capsule contains sunitinib malate equivalent to 25 mg.

The other ingredients are:

Capsule content:

mannitol, croscarmellose sodium, povidone (K-25), and magnesium stearate.

Capsule shell:

gelatin, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide

(E172), black iron oxide (E172).

Printing ink:

shellac, propylene glycol, sodium hydroxide, povidone, and titanium dioxide

(E171).

Sutent 37.5 mg hard capsules

The active substance is sunitinib. Each capsule contains sunitinib malate equivalent to 37.5 mg.

The other ingredients are:

Capsule content:

mannitol, croscarmellose sodium, povidone (K-25), and magnesium stearate.

Capsule shell:

gelatin, titanium dioxide (E171), yellow iron oxide (E172).

Printing ink:

shellac, propylene glycol, potassium hydroxide, black iron oxide (E172).

Sutent 50 mg hard capsules

The active substance is sunitinib. Each capsule contains sunitinib malate equivalent to 50 mg.

The other ingredients are:

Capsule content:

mannitol, croscarmellose sodium, povidone (K-25), and magnesium stearate.

Capsule shell:

gelatin, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide

(E172), and black iron oxide (E172).

Printing ink:

shellac, propylene glycol, sodium hydroxide, povidone, and titanium dioxide

(E171).

What Sutent looks like and contents of the pack

Sutent 12.5 mg is supplied as hard gelatin capsules with orange cap and orange body, printed with

white ink “Pfizer” on the cap, “STN 12.5 mg” on the body, containing yellow to orange granules.

Sutent 25 mg is supplied as hard gelatin capsules with caramel cap and orange body, printed with

white ink “Pfizer” on the cap, “STN 25 mg” on the body, containing yellow to orange granules.

Sutent 37.5 mg is supplied as hard gelatin capsules with yellow cap and yellow body, printed with

black ink “Pfizer” on the cap, “STN 37.5 mg” on the body, containing yellow to orange granules.

Sutent 50 mg is supplied as hard gelatin capsules with caramel cap and caramel body, printed with

white ink “Pfizer” on the cap, “STN 50 mg” on the body, containing yellow to orange granules.

It is available in plastic bottles of 30 capsules and in perforated unit dose blisters containing

28 x 1 capsules.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Pfizer Europe MA EEIG

Boulevard de la Plaine 17

1050 Bruxelles

Belgium

Manufacturer

Pfizer Italia S.r.l.

Via del Commercio – Zona Industriale

63100 Marino del Tronto (Ascoli Piceno)

Italy

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

Belgique / België /Belgien

Pfizer S.A. / N.V.

Tél/Tel: +32 (0)2 554 62 11

Lietuva

Pfizer Luxembourg SARL filialas Lietuvoje

Tel. + 370 52 51 4000

България

Пфайзер Люксембург САРЛ, Клон България

Тел.: +359 2 970 4333

Luxembourg/Luxemburg

Pfizer S.A.

Tél/Tel: +32 (0)2 554 62 11

Česká republika

Pfizer PFE, spol. s r.o.

Tel.: +420 283 004 111

Magyarország

Pfizer Kft.

Tel.: +36-1-488-37-00

Danmark

Pfizer ApS

Tlf: +45 44 20 11 00

Malta

Vivian Corporation Ltd.

Tel: +356 21344610

Deutschland

Pfizer Pharma GmbH

Tel: +49 (0)30 550055 51000

Nederland

Pfizer BV

Tel: +31 (0)10 406 43 01

Eesti

Pfizer Luxembourg SARL Eesti filiaal

Tel.: +372 666 7500

Norge

Pfizer Norge AS

Tlf: +47 67 52 61 00

Ελλάδα

Pfizer Ελλάς A.E.

λ: +30 210 6785 800

Österreich

Pfizer Corporation Austria Ges.m.b.H.

Tel: +43 (0)1 521 15-0

España

Pfizer, S.L.

Tél: +34 91 490 99 00

Polska

Pfizer Polska Sp. z o.o.

Tel.:+48 22 335 61 00

France

Pfizer

Tél: +33 (0)1 58 07 34 40

Portugal

Pfizer Biofarmacêutica, Sociedade Unipessoal Lda

Tel: +351 21 423 5500

Hrvatska

Pfizer Croatia d.o.o.

Tel: + 385 1 3908 777

România

Pfizer Romania S.R.L.

Tel: +40 (0) 21 207 28 00

Ireland

Pfizer Healthcare Ireland

Tel: 1800 633 363 (toll free)

+44 (0)1304 616161

Slovenija

Pfizer Luxembourg SARL

Pfizer, podružnica za svetovanje s področja

farmacevtske dejavnosti, Ljubljana

Tel.: + 386 (0)1 52 11 400

Ísland

Icepharma hf.

Sími: +354 540 8000

Slovenská republika

Pfizer Luxembourg SARL, organizačná zložka

Tel.: + 421 2 3355 5500

Italia

Pfizer S.r.l.

Tel: +39 06 33 18 21

Suomi/Finland

Pfizer Oy

Puh./Tel: +358 (0)9 43 00 40

Kύπρος

Pfizer Ελλάς A.E. (Cyprus Branch)

Tηλ.:+ 357 22 817690

Sverige

Pfizer Innovations AB

Tel: +46 (0)8 550 520 00

Latvija

Pfizer Luxembourg SARL filiāle Latvijā

Tel.: + 371 670 35 775

United Kingdom

Pfizer Limited

Tel: +44 (0) 1304 616161

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicine Agency

website: http://www.ema.europa.eu.

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Sutent 12.5 mg hard capsules

Sutent 25 mg hard capsules

Sutent 37.5 mg hard capsules

Sutent 50 mg hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

12.5 mg hard capsules

Each capsule contains sunitinib malate, equivalent to 12.5 mg of sunitinib.

25 mg hard capsules

Each capsule contains sunitinib malate, equivalent to 25 mg of sunitinib.

37.5 mg hard capsules

Each capsule contains sunitinib malate, equivalent to 37.5 mg of sunitinib.

50 mg hard capsules

Each capsule contains sunitinib malate, equivalent to 50 mg of sunitinib.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule.

Sutent 12.5 mg hard capsules

Gelatin capsules with orange cap and orange body, printed with white ink “Pfizer” on the cap,

“STN 12.5 mg” on the body, and containing yellow to orange granules.

Sutent 25 mg hard capsules

Gelatin capsules with caramel cap and orange body, printed with white ink “Pfizer” on the cap,

“STN 25 mg” on the body, and containing yellow to orange granules.

Sutent 37.5 mg hard capsules

Gelatin capsules with yellow cap and yellow body, printed with black ink “Pfizer” on the cap,

“STN 37.5 mg” on the body, and containing yellow to orange granules.

Sutent 50 mg hard capsules

Gelatin capsule with caramel cap and caramel body, printed with white ink “Pfizer” on the cap,

“STN 50 mg” on the body, and containing yellow to orange granules.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Gastrointestinal stromal tumour (GIST)

Sutent is indicated for the treatment of unresectable and/or metastatic malignant

gastrointestinal

stromal tumour (GIST) in adults after failure of imatinib treatment due to resistance or intolerance.

Metastatic renal cell carcinoma (MRCC)

Sutent is indicated for the treatment of advanced/metastatic renal cell carcinoma (MRCC) in adults.

Pancreatic neuroendocrine tumours (pNET)

Sutent is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic

neuroendocrine tumours (pNET)

with disease progression in adults.

4.2

Posology and method of administration

Therapy with Sutent should be initiated by a physician experienced in the administration of anticancer

agents.

Posology

For GIST and MRCC, the recommended dose of Sutent is 50 mg taken orally once daily, for

4 consecutive weeks, followed by a 2-week rest period (Schedule 4/2) to comprise a complete cycle of

6 weeks.

For pNET, the recommended dose of Sutent is 37.5 mg taken orally once daily without a scheduled

rest period.

Dose adjustments

Safety and tolerability

For GIST and MRCC, dose modifications in 12.5 mg steps may be applied based on individual safety

and tolerability. Daily dose should not exceed 75 mg nor be decreased below 25 mg.

For pNET, dose modification in 12.5 mg steps may be applied based on individual safety and

tolerability. The maximum dose administered in the Phase 3 pNET study was 50 mg daily.

Dose interruptions may be required based on individual safety and tolerability.

CYP3A4 inhibitors/inducers

Co-administration of sunitinib with potent CYP3A4 inducers, such as rifampicin, should be avoided

(see sections 4.4 and 4.5). If this is not possible, the dose of sunitinib may need to be increased in

12.5 mg steps (up to 87.5 mg per day for GIST and MRCC or 62.5 mg per day for pNET) based on

careful monitoring of tolerability.

Co-administration of sunitinib with potent CYP3A4 inhibitors, such as ketoconazole, should be

avoided (see sections 4.4 and 4.5). If this is not possible, the dose of sunitinib may need to be reduced

to a minimum of 37.5 mg daily for GIST and MRCC or 25 mg daily for pNET, based on careful

monitoring of tolerability.

Selection of an alternative concomitant medicinal product with no or minimal potential to induce or

inhibit CYP3A4 should be considered.

Special populations

Paediatric population

The safety and efficacy of Sutent in patients below 18 years of age have not been established.

Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a

posology can be made.

Elderly

Approximately one-third of the patients in clinical studies who received sunitinib were 65 years of age

or over. No significant differences in safety or efficacy were observed between younger and older

patients.

Hepatic impairment

No starting dose adjustment is recommended when administering sunitinib to patients with mild or

moderate (Child-Pugh class A and B) hepatic impairment. Sunitinib has not been studied in subjects

with severe (Child-Pugh class C) hepatic impairment and therefore its use in patients with severe

hepatic impairment cannot be recommended (see section 5.2).

Renal impairment

No starting dose adjustment is required when administering sunitinib to patients with renal impairment

(mild-severe) or with end-stage renal disease (ESRD) on haemodialysis. Subsequent dose adjustments

should be based on individual safety and tolerability (see section 5.2).

Method of administration

Sutent is for oral administration. It may be taken with or without food.

If a dose is missed, the patient should not be given an additional dose. The patient should take the

usual prescribed dose on the following day.

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

Co-administration with potent CYP3A4 inducers should be avoided because it may decrease sunitinib

plasma concentration (see sections 4.2 and 4.5).

Co-administration with potent CYP3A4 inhibitors should be avoided because it may increase the

plasma concentration of sunitinib (see sections 4.2 and 4.5).

Skin and tissue disorders

Patients should be advised that depigmentation of the hair or skin may occur during treatment with

sunitinib. Other possible dermatological effects may include dryness, thickness or cracking of the skin,

blisters, or rash on the palms of the hands and soles of the feet.

The above reactions were not cumulative, were typically reversible, and generally did not result in

treatment discontinuation. Cases of pyoderma gangrenosum, generally reversible after discontinuation

of sunitinib, have been reported. Severe cutaneous reactions have been reported, including cases of

erythema multiforme (EM), cases suggestive of Stevens-Johnson syndrome (SJS) and toxic epidermal

necrolysis (TEN), some of which were fatal. If signs or symptoms of SJS, TEN, or EM

(e.g., progressive skin rash often with blisters or mucosal lesions) are present, sunitinib treatment

should be discontinued. If the diagnosis of SJS or TEN is confirmed, treatment must not be restarted.

In some cases of suspected EM, patients tolerated the reintroduction of sunitinib therapy at a lower

dose after resolution of the reaction; some of these patients also received concomitant treatment with

corticosteroids or antihistamines (see section 4.8).

Haemorrhage and tumour bleeding

Haemorrhagic events, some of which were fatal, reported in clinical studies with sunitinib and during

postmarketing surveillance have included gastrointestinal, respiratory, urinary tract, and brain

haemorrhages (see section 4.8).

Routine assessment of bleeding events should include complete blood counts and physical

examination.

Epistaxis was the most common haemorrhagic adverse reaction, having been reported for

approximately half of the patients with solid tumours who experienced haemorrhagic events. Some of

the epistaxis events were severe, but very rarely fatal.

Events of tumour haemorrhage, sometimes associated with tumour necrosis, have been reported; some

of these haemorrhagic events were fatal.

Tumour haemorrhage may occur suddenly, and in the case of pulmonary tumours, may present as

severe and life-threatening haemoptysis or pulmonary haemorrhage. Cases of pulmonary

haemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported

in postmarketing experience in patients treated with sunitinib for MRCC, GIST, and lung cancer.

Sutent is not approved for use in patients with lung cancer.

Patients receiving concomitant treatment with anticoagulants (e.g., warfarin, acenocoumarole)

may be

periodically monitored by complete blood counts (platelets), coagulation factors (PT/INR), and

physical examination.

Gastrointestinal disorders

Diarrhoea, nausea/vomiting, abdominal pain, dyspepsia, and stomatitis/oral pain were the most

commonly reported gastrointestinal adverse reactions; oesophagitis events have been also reported

(see section 4.8).

Supportive care for gastrointestinal adverse reactions requiring treatment

may include medicinal

products with antiemetic, antidiarrhoeal, or antacid properties.

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation were

reported in patients with intra-abdominal malignancies treated with sunitinib.

Hypertension

Hypertension has been reported in association with sunitinib, including severe hypertension

(> 200 mmHg systolic or 110 mmHg diastolic). Patients should be screened for hypertension and

controlled as appropriate

.

Temporary suspension is recommended in patients with severe hypertension

that is not controlled with medical management. Treatment may be resumed once hypertension is

appropriately controlled (see section 4.8)

.

Haematological disorders

Decreased absolute neutrophil counts and decreased platelet counts were reported in association with

sunitinib (see section 4.8). The above events were not cumulative, were typically reversible, and

generally did not result in treatment discontinuation. None of these events in the Phase 3 studies were

fatal, but rare fatal haematological events, including haemorrhage associated with thrombocytopenia

and neutropenic infections, have been reported during postmarketing surveillance.

Anaemia has been observed to occur early as well as late during treatment with sunitinib.

Complete blood counts should be performed at the beginning of each treatment cycle for patients

receiving treatment with sunitinib (see section 4.8).

Cardiac disorders

Cardiovascular events, including heart failure, cardiomyopathy, left ventricular ejection fraction

decline to below the lower limit of normal, myocarditis, myocardial ischaemia and myocardial

infarction, some of which were fatal, have been reported in patients treated with sunitinib. These data

suggest that sunitinib increases the risk of cardiomyopathy. No specific additional risk factors for

sunitinib-induced cardiomyopathy apart from the drug-specific effect have been identified in the

treated patients. Use sunitinib with caution in patients who are at risk for, or who have a history of,

these events (see section 4.8).

Patients who presented with cardiac events within 12 months prior to sunitinib administration, such as

myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft,

symptomatic congestive heart failure (CHF), cerebrovascular accident or transient ischaemic attack, or

pulmonary embolism were excluded from all sunitinib clinical studies. It is unknown whether patients

with these concomitant conditions may be at a higher risk of developing sunitinib-related left

ventricular dysfunction.

Physicians are advised to weigh this risk against the potential benefits of sunitinib. Patients should be

carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib especially

patients with cardiac risk factors and/or history of coronary artery disease. Baseline and periodic

evaluations of LVEF should also be considered while the patient is receiving sunitinib. In patients

without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

In the presence of clinical manifestations of CHF, discontinuation of sunitinib is recommended. The

administration of sunitinib should be interrupted and/or the dose reduced in patients without

clinical

evidence of CHF but with an ejection fraction < 50% and > 20% below baseline.

QT interval prolongation

Prolongation of QT interval and Torsade de pointes have been observed in sunitinib-exposed patients.

QT interval prolongation may lead to an increased risk of ventricular arrhythmias including

Torsade de pointes.

Sunitinib should be used with caution in patients with a known history of QT interval prolongation,

patients who are taking antiarrhythmics or medicinal products that can prolong QT interval, or patients

with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Concomitant

administration of sunitinib with potent CYP3A4 inhibitors should be limited because of the possible

increase in sunitinib plasma concentrations (see sections 4.2, 4.5 and 4.8).

Venous thromboembolic events

Treatment-related venous thromboembolic events were reported in patients

who received sunitinib

including deep venous thrombosis and pulmonary embolism (see section 4.8). Cases of pulmonary

embolism with fatal outcome have been observed in postmarketing surveillance.

Arterial thromboembolic events

Cases of arterial thromboembolic events (ATE), sometimes fatal, have been reported in patients

treated with sunitinib. The most frequent events included cerebrovascular accident, transient ischaemic

attack, and cerebral infarction. Risk factors associated with ATE, in addition to the underlying

malignant disease and age

65 years, included hypertension, diabetes mellitus, and prior

thromboembolic disease.

Aneurysms and artery dissections

The use of vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or without

hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating

sunitinib, this risk should be carefully considered in patients with risk factors such as hypertension or

history of aneurysm.

Thrombotic microangiopathy (TMA)

The diagnosis of TMA, including thrombotic thrombocytopaenic purpura (TTP) and haemolytic

uraemic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, should be considered

in the occurrence of haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological

manifestation, renal impairment, and fever. Sunitinib therapy should be discontinued in patients who

develop TMA and prompt treatment is required. Reversal of the effects of TMA has been observed

after treatment discontinuation (see section 4.8).

Thyroid dysfunction

Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with

pre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practice

prior to the start of sunitinib treatment. During sunitinib treatment, routine monitoring of thyroid

function should be performed every 3 months. In addition, patients should be observed closely for

signs and symptoms of thyroid dysfunction during treatment, and patients who develop any signs

and/or symptoms suggestive of thyroid dysfunction should have laboratory testing of thyroid function

performed as clinically indicated. Patients who develop thyroid dysfunction should be treated as per

standard medical practice.

Hypothyroidism has been observed to occur early as well as late during treatment with sunitinib (see

section 4.8).

Pancreatitis

Increases in serum lipase and amylase activities were observed in patients with various solid tumours

who received sunitinib. Increases in lipase activities were transient and were generally not

accompanied by signs or symptoms of pancreatitis in subjects with various solid tumours (see section

4.8).

Cases of serious pancreatic events, some with fatal outcome, have been reported. If symptoms of

pancreatitis are present, patients should have sunitinib discontinued and be provided with appropriate

supportive care.

Hepatotoxicity

Hepatotoxicity has been observed in patients treated with sunitinib. Cases of hepatic failure, some with

a fatal outcome, were observed in < 1% of solid tumour patients treated with sunitinib. Monitor liver

function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) before

initiation of treatment, during each cycle of treatment, and as clinically indicated. If signs or symptoms

of hepatic failure are present, sunitinib should be discontinued and appropriate supportive care should

be provided (see section 4.8).

Renal function

Cases of renal impairment, renal failure and/or acute renal failure, in some cases with fatal outcome,

have been reported (see section 4.8).

Risk factors associated with renal impairment/failure in patients receiving sunitinib included, in

addition to underlying RCC, older age, diabetes mellitus, underlying renal impairment, cardiac failure,

hypertension, sepsis, dehydration/hypovolaemia, and rhabdomyolysis.

The safety of continued sunitinib treatment in patients with moderate to severe proteinuria has not

been systematically evaluated.

Cases of proteinuria and rare cases of nephrotic syndrome have been reported. Baseline urinalysis is

recommended, and patients should be monitored for the development or worsening of proteinuria.

Discontinue sunitinib in patients with nephrotic syndrome.

Fistula

If fistula formation occurs, sunitinib treatment should be interrupted. Limited information is available

on the continued use of sunitinib in patients with fistulae (see section 4.8).

Impaired wound healing

Cases of impaired wound healing have been reported during sunitinib therapy.

No formal clinical studies of the effect of sunitinib on wound healing have been conducted.

Temporary interruption of sunitinib therapy is recommended for precautionary reasons in patients

undergoing major surgical procedures. There is limited clinical experience regarding the timing of

reinitiation of therapy following major surgical intervention. Therefore, the decision to resume

sunitinib therapy following a major surgical intervention should be based upon clinical judgment of

recovery from surgery.

Osteonecrosis of the jaw (ONJ)

Cases of ONJ have been reported in patients treated with Sutent. The majority of cases were reported

in patients who had received prior or concomitant treatment with intravenous bisphosphonates, for

which ONJ is an identified risk. Caution should therefore be exercised when Sutent and intravenous

bisphosphonates are used either simultaneously or sequentially.

Invasive dental procedures are also an identified risk factor. Prior to treatment with Sutent, a dental

examination and appropriate preventive dentistry should be considered. In patients who have

previously received or are receiving intravenous bisphosphonates, invasive dental procedures should

be avoided if possible (see section 4.8).

Hypersensitivity/angioedema

If angioedema due to hypersensitivity occurs, sunitinib treatment should be interrupted and standard

medical care provided (see section 4.8).

Seizures

In clinical studies of sunitinib and from postmarketing surveillance, seizures have been reported.

Patients with seizures and signs/symptoms consistent with posterior reversible leukoencephalopathy

syndrome (RPLS), such as hypertension, headache, decreased alertness, altered mental functioning

and visual loss, including cortical blindness, should be controlled with medical management including

control of hypertension. Temporary suspension of sunitinib is recommended; following resolution,

treatment may be resumed at the discretion of the treating physician (see section 4.8).

Tumour lysis syndrome (TLS)

Cases of TLS, some fatal, have been rarely observed in clinical trials and have been reported in

postmarketing surveillance in patients treated with sunitinib. Risk factors for TLS include high tumour

burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension, and acidic urine.

These patients should be monitored closely and treated as clinically indicated, and prophylactic

hydration should be considered.

Infections

Serious infections, with or without neutropenia, including some with a fatal outcome, have been

reported. Uncommon cases of necrotising fasciitis, including of the perineum, sometimes fatal, have

been reported (see section 4.8).

Sunitinib therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate

treatment should be promptly initiated.

Hypoglycaemia

Decreases in blood glucose, in some cases clinically symptomatic and requiring hospitalisation due to

loss of consciousness, have been reported during sunitinib treatment. In case of symptomatic

hypoglycaemia, sunitinib should be temporarily interrupted. Blood glucose levels in diabetic patients

should be checked regularly in order to assess if antidiabetic medicinal product’s dosage needs to be

adjusted to minimise the risk of hypoglycaemia (see section 4.8).

4.5

Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Medicinal products that may increase sunitinib plasma concentrations

Effect of CYP3A4 inhibitors

In healthy volunteers, concomitant administration of a single dose of sunitinib with the potent

CYP3A4 inhibitor ketoconazole resulted in an increase of the combined [sunitinib + primary

metabolite] maximum concentration (C

) and area under the curve (AUC

) values of 49% and

51%, respectively.

Administration of sunitinib with potent CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin,

clarithromycin, grapefruit juice) may increase sunitinib concentrations.

Combination with CYP3A4 inhibitors should therefore be avoided, or the selection of an alternate

concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered.

If this is not possible, the dose of Sutent may need to be

reduced to a minimum of 37.5 mg daily for

GIST and MRCC or 25 mg daily for pNET, based on careful monitoring of tolerability (see

section 4.2).

Effect of Breast Cancer Resistance Protein (BCRP) inhibitors

Limited clinical data are available on the interaction between sunitinib and BCRP inhibitors and the

possibility of an interaction between sunitinib and other BCRP inhibitors cannot be excluded (see

section 5.2).

Medicinal products that may decrease sunitinib plasma concentrations

Effect of CYP3A4 inducers

In healthy volunteers, concomitant administration of a single dose of sunitinib with the

CYP3A4 inducer rifampicin resulted in a reduction of the combined [sunitinib + primary metabolite]

and AUC

values of 23% and 46%, respectively.

Administration of sunitinib with potent CYP3A4 inducers (e.g., dexamethasone, phenytoin,

carbamazepine, rifampicin, phenobarbital or herbal preparations containing St. John’s

Wort

/Hypericum perforatum

) may decrease sunitinib concentrations. Combination with

CYP3A4 inducers should therefore be avoided, or selection of an alternate concomitant medicinal

product, with no or minimal potential to induce CYP3A4 should be considered. If this is not possible,

the dose of Sutent may need to be increased in 12.5 mg increments (up to 87.5 mg per day for GIST

and MRCC or 62.5 mg per day for pNET), based on careful monitoring of tolerability (see

section 4.2).

4.6

Fertility, pregnancy and lactation

Contraception in males and females

Women of childbearing potential should be advised to use effective contraception and avoid becoming

pregnant while receiving treatment with Sutent.

Pregnancy

There are no studies in pregnant women using sunitinib. Studies in animals have shown reproductive

toxicity including foetal malformations (see section 5.3). Sutent should not be used during pregnancy

or in women not using effective contraception, unless the potential benefit justifies the potential risk to

the foetus. If Sutent is used during pregnancy or if the patient becomes pregnant while on treatment

with Sutent, the patient should be apprised of the potential hazard to the foetus.

Breast-feeding

Sunitinib and/or its metabolites are excreted in rat milk. It is not known whether sunitinib or its

primary active metabolite is excreted in human milk. Because active substances are commonly

excreted in human milk and because of the potential for serious adverse reactions in breast-feeding

infants, women should

not breast-feed while taking Sutent

.

Fertility

Based on nonclinical findings, male and female fertility may be compromised by treatment with

sunitinib (see section 5.3).

4.7

Effects on ability to drive and use machines

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

they may experience dizziness during treatment with sunitinib.

4.8

Undesirable effects

Summary of the safety profile

The most serious adverse reactions associated with sunitinib, some fatal, are renal failure, heart failure,

pulmonary embolism, gastrointestinal perforation, and haemorrhages (e.g., respiratory tract,

gastrointestinal, tumour, urinary tract, and brain haemorrhages). The most common adverse reactions

of any grade (experienced by patients in RCC, GIST, and pNET registrational trials) included

decreased appetite, taste disturbance, hypertension, fatigue, gastrointestinal disorders (i.e. diarrhoea,

nausea, stomatitis, dyspepsia, and vomiting), skin discolouration, and palmar-plantar

erythrodysaesthesia syndrome. These symptoms may diminish as treatment continues.

Hypothyroidism may develop during treatment. Haematological disorders (e.g., neutropenia,

thrombocytopenia, and anaemia) are amongst the most common adverse drug reactions.

Fatal events other than those listed in section 4.4 above or in section 4.8 below that were considered

possibly related to sunitinib included multi-system organ failure, disseminated intravascular

coagulation, peritoneal haemorrhage, adrenal insufficiency, pneumothorax, shock, and sudden death.

Tabulated list of adverse reactions

Adverse reactions that were reported in GIST, MRCC, and pNET patients in a pooled dataset of

7,115 patients are listed below, by system organ class, frequency and grade of severity (NCI-CTCAE).

Post-marketing adverse reactions identified in clinical studies are also included. Within each

frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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), very rare (<1/10,000), not known (cannot be estimated from

the available data).

Table 1.

Adverse reactions reported in clinical trials

System organ class

Very common

Common

Uncommon

Rare

Not known

Infections and

infestations

Viral infections

Respiratory

infections

Abscess

Fungal infections

Urinary tract infection

Skin infections

Sepsis

Necrotising

fasciitis*

Bacterial infections

Blood and

lymphatic system

disorders

Neutropoenia

Thrombocytopoenia

Anaemia

Leukopoenia

Lymphopoenia

Pancytopenia

Thrombotic

microangiopathy

Immune system

disorders

Hypersensitivity

Angioedema

Endocrine

disorders

Hypothyroidism

Hyperthyroidism

Thyroiditis

Metabolism and

nutrition disorders

Decreased appetite

Dehydration

Hypoglycaemia

Tumour lysis

syndrome*

Psychiatric

disorders

Insomnia

Depression

Nervous system

disorders

Dizziness

Headache

Taste disturbance

Neuropathy peripheral

Paraesthesia

Hypoaesthesia

Hyperaesthesia

Cerebral

haemorrhage

Cerebrovascular

accident

Transient ischaemic

attack

Posterior reversible

encephalopathy

syndrome

Eye disorders

Periorbital oedema

Eyelid oedema

Lacrimation increased

System organ class

Very common

Common

Uncommon

Rare

Not known

Cardiac disorders

Myocardial

ischemia

Ejection fraction

decreased

Cardiac failure

congestive

Myocardial

infarction

Cardiac failure

Cardiomyopathy

Pericardial effusion

Electrocardiogram

QT prolonged

Left ventricular

failure

Torsade de pointes

Vascular disorders

Hypertension

Deep vein thrombosis

Hot flush

Flushing

Tumour

haemorrhage

Aneurysms

and artery

dissections

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea

Epistaxis

Cough

Pulmonary embolism

Pleural effusion

Haemoptysis

Dyspnoea exertional

Oropharyngeal pain

Nasal congestion

Nasal dryness

Pulmonary

haemorrhage

Respiratory failure

Gastrointestinal

disorders

Stomatitis

Abdominal pain

Vomiting

Diarrhoea

Dyspepsia

Nausea

Constipation

Gastro-oesophageal

reflux disease

Dysphagia

Gastrointestinal

haemorrhage

Oesophagitis

Abdominal distension

Abdominal discomfort

Rectal haemorrhage

Gingival bleeding

Mouth ulceration

Proctalgia

Cheilitis

Haemorrhoids

Glossodynia

Oral pain

Dry mouth

Flatulence

Oral discomfort

Eructation

Gastrointestinal

perforation

Pancreatitis

Anal fistula

Colitis

Hepatobiliary

disorders

Hepatic failure

Cholecystitis

Hepatic function

abnormal

Hepatitis

Skin and

subcutaneous

tissue disorders

Skin discolouration

Palmar-plantar

erythrodysaesthesia

syndrome

Rash

Hair colour changes

Dry skin

Skin exfoliation

Skin reaction

Eczema

Blister

Erythema

Alopecia

Acne

Pruritus

Skin

hyperpigmentation

Skin lesion

Hyperkeratosis

Dermatitis

Nail disorder

Erythema

multiforme

Stevens-Johnson

syndrome

Pyoderma

gangrenosum

Toxic epidermal

necrolysis

Musculoskeletal

and connective

tissue disorders

Pain in extremity

Arthralgia

Back pain

Musculoskeletal pain

Muscle spasms

Myalgia

Muscular weakness

Osteonecrosis of the

Fistula

Rhabdomyolysis

Myopathy

Renal and urinary

disorders

Renal failure

Renal failure acute

Chromaturia

Proteinuria

Haemorrhage

urinary tract

Nephrotic syndrome

System organ class

Very common

Common

Uncommon

Rare

Not known

General disorders

and administration

site conditions

Mucosal inflammation

Fatigue

Oedema

Pyrexia

Chest pain

Pain

Influenza like illness

Chills

Impaired healing

Investigations

Weight decreased

White blood cell count

decreased

Lipase increased

Platelet count

decreased

Haemoglobin

decreased

Amylase increased

Aspartate

aminotransferase

increased

Alanine

aminotransferase

increased

Blood creatinine

increased

Blood pressure

increased

Blood uric acid

increased

Blood creatine

phosphokinase

increased

Blood thyroid

stimulating

hormone increased

Including fatal events.

The following terms have been combined:

Nasopharyngitis and oral herpes.

Bronchitis, lower respiratory tract infection, pneumonia, and respiratory tract infection.

Abscess, abscess limb, anal abscess, gingival abscess, liver abscess, pancreatic abscess, perineal abscess, perirectal

abscess, rectal abscess, subcutaneous abscess, and tooth abscess.

Oesophageal candidiasis and oral candidiasis.

Cellulitis and skin infection.

Sepsis and sepsis shock.

Abdominal abscess, abdominal sepsis, diverticulitis, and osteomyelitis.

Thrombotic microangiopathy, thrombotic thrombocytopenic purpura, and haemolytic uraemic syndrome.

Decreased appetite and anorexia

Dysgeusia, ageusia, and taste disturbance.

Acute coronary syndrome, angina pectoris, angina unstable, coronary artery occlusion, and myocardial ischaemia.

Ejection fraction decreased/abnormal.

Acute myocardial infarction, myocardial infarction, and silent myocardial infarction.

Oropharyngeal and pharyngolaryngeal pain.

Stomatitis and aphtous stomatitis.

Abdominal pain, abdominal pain lower, and abdominal pain upper.

Gastrointestinal perforation and intestinal perforation.

Colitis and colitis ischaemic.

Cholecystitis and acalculous cholecystitis.

Yellow skin, skin discolouration, and pigmentation disorder.

Dermatitis psoriasiform, exfoliative rash, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash

maculo-papular, rash papular, and rash pruritic.

Skin reaction and skin disorder.

Nail disorder and discolouration.

Fatigue and asthenia.

Face oedema, oedema, and oedema peripheral.

Amylase and amylase increased.

Description of selected adverse reactions

Infections and infestations

Cases of serious infection (with or without neutropenia), including cases with fatal outcome, have

been reported. Cases of necrotising fasciitis, including of the perineum, sometimes fatal, have been

reported (see also section 4.4).

Blood and lymphatic system disorders

Decreased absolute neutrophil counts of Grade 3 and 4 severities, respectively, were reported in 10%

and 1.7% of patients on the Phase 3 GIST study, in 16% and 1.6% of patients on the Phase 3 MRCC

study, and in 13% and 2.4% of patients on the Phase 3 pNET study. Decreased platelet counts of

Grade 3 and 4 severities, respectively, were reported in 3.7% and 0.4% of patients on the Phase 3

GIST study, in 8.2% and 1.1% of patients on the Phase 3 MRCC study, and in 3.7% and 1.2% of

patients on the Phase 3 pNET study (see section 4.4).

Bleeding events were reported in 18% of patients receiving sunitinib in a Phase 3 GIST study vs 17%

of patients receiving placebo. In patients receiving sunitinib for treatment-naïve MRCC, 39% had

bleeding events vs 11% of patients receiving interferon-

(IFN-α). Seventeen (4.5%) patients on

sunitinib versus 5 (1.7%) patients on IFN-α experienced Grade 3 or greater bleeding events. Of

patients receiving sunitinib for cytokine-refractory MRCC, 26% experienced bleeding. Bleeding

events, excluding epistaxis, were reported in 21.7% of patients receiving sunitinib in the Phase 3

pNET study compared to 9.85% of patients receiving placebo (see section 4.4)

In clinical trials, tumour haemorrhage was reported in approximately 2% of patients with GIST.

Immune system disorders

Hypersensitivity reactions, including angioedema, have been reported (see section 4.4).

Endocrine disorders

Hypothyroidism was reported as an adverse reaction in 7 patients (4%) receiving sunitinib across the

2 cytokine-refractory MRCC studies; in 61 patients (16%) on sunitinib and 3 patients (< 1%) in the

IFN-

arm in the treatment-naïve MRCC study.

Additionally, thyroid-stimulating hormone (TSH) elevations were reported in 4 cytokine-refractory

MRCC patients (2%). Overall, 7% of the MRCC population had either clinical or laboratory evidence

of treatment-emergent hypothyroidism. Acquired hypothyroidism was noted in 6.2% of GIST patients

on sunitinib versus 1% on placebo. In the Phase 3 pNET study hypothyroidism was reported in

6 patients (7.2%) receiving sunitinib and in 1 patient (1.2%) on placebo.

Thyroid function was monitored prospectively in 2 studies in patients with breast cancer; Sutent is not

approved for use in breast cancer. In 1 study, hypothyroidism was reported in 15 (13.6%) patients on

sunitinib and 3 (2.9%) patients on standard of care. Blood TSH increase was reported in 1 (0.9%)

patient on sunitinib and no patients on standard of care. Hyperthyroidism was reported in no

sunitinib-treated patients and 1 (1.0%) patient receiving standard of care. In the other study

hypothyroidism was reported in a total of 31 (13%) patients on sunitinib and 2 (0.8%) patients on

capecitabine. Blood TSH increase was reported in 12 (5.0%) patients on sunitinib and no patients on

capecitabine. Hyperthyroidism was reported in 4 (1.7%) patients on sunitinib and no patients on

capecitabine. Blood TSH decrease was reported in 3 (1.3%) patients on sunitinib and no patients on

capecitabine. T4 increase was reported in 2 (0.8%) patients on sunitinib and 1 (0.4%) patient on

capecitabine. T3 increase was reported in 1 (0.8%) patient on sunitinib and no patients on

capecitabine. All thyroid-related events reported were Grade 1-2 (see section 4.4).

Metabolism and nutrition disorders

A higher incidence rate of hypoglycaemia events was reported in patients with pNET in comparison to

MRCC and GIST. Nevertheless, most of these adverse events observed in clinical studies were not

considered related to study treatment (see section 4.4).

Nervous system disorders

In clinical studies of sunitinib and from postmarketing surveillance, there have been few reports

(< 1%), some fatal, of subjects presenting with seizures and radiological evidence of RPLS. Seizures

have been observed in patients with or without radiological evidence of brain metastases (see section

4.4).

Cardiac disorders

In clinical trials, decreases in left ventricular ejection fraction (LVEF) of

20% and below the lower

limit of normal were reported in approximately 2% of sunitinib-treated GIST patients, 4% of

cytokine-refractory MRCC patients, and 2% of placebo-treated GIST patients. These LVEF declines

do not appear to have been progressive and often improved as treatment continued. In the

treatment-naïve MRCC study, 27% of patients on sunitinib and 15% of patients on IFN-

had an

LVEF value below the lower limit of normal. Two patients (< 1%) who received sunitinib were

diagnosed with CHF.

In GIST patients ‘cardiac failure’, ‘cardiac failure congestive’, or ‘left ventricular failure’ were

reported in 1.2% of patients treated with sunitinib and 1% of patients treated with placebo. In the

pivotal Phase 3 GIST study (N = 312), treatment-related fatal cardiac reactions were reported in 1% of

patients on each arm of the study (i.e. sunitinib and placebo arms). In a Phase 2 study in

cytokine-refractory MRCC patients, 0.9% of patients experienced treatment-related fatal myocardial

infarction and in the Phase 3 study in treatment-naïve MRCC patients, 0.6% of patients on the IFN-

arm and 0% of patients on the sunitinib arm experienced fatal cardiac events. In the Phase 3 pNET

study, 1 (1%) patient who received sunitinib had treatment-related fatal cardiac failure.

Vascular disorders

Hypertension

Hypertension was a very common adverse reaction reported in clinical trials. The dose

of sunitinib

was reduced or its administration temporarily suspended in approximately 2.7% of the patients who

experienced hypertension. Sunitinib was not permanently discontinued in any of these patients. Severe

hypertension (> 200 mmHg systolic or 110 mmHg diastolic) was reported in 4.7% of patients with

solid tumours. Hypertension was reported in approximately 33.9% of patients receiving sunitinib for

treatment-naïve MRCC compared to 3.6% of patients receiving IFN-

. Severe hypertension was

reported in 12% of treatment-naïve patients on sunitinib and < 1% of patients on IFN-

. Hypertension

was reported in 26.5% of patients receiving sunitinib in a Phase 3 pNET study, compared to 4.9% of

patients receiving placebo. Severe hypertension was reported in 10% of pNET patients on sunitinib

and 3% of patients on placebo.

Venous thromboembolic events

Treatment-related venous thromboembolic events were reported in approximately 1.0% of patients

with solid tumours who received sunitinib on clinical trials, including GIST and RCC.

Seven patients (3%) on sunitinib and none on placebo in a Phase 3 GIST study experienced venous

thromboembolic events; 5 of the 7 were Grade 3 deep venous thrombosis (DVT) and 2 were Grade 1

or 2. Four of these 7 GIST patients discontinued treatment following first observation of DVT.

Thirteen patients (3%) receiving sunitinib in the Phase 3 treatment-naïve MRCC study and 4 patients

(2%) on the 2 cytokine-refractory MRCC studies had venous thromboembolic events reported. Nine of

these patients had pulmonary embolisms; 1 was Grade 2 and 8 were Grade 4. Eight of these patients

had DVT; 1 with Grade 1, 2 with Grade 2, 4 with Grade 3, and 1 with Grade 4. One patient with

pulmonary embolism in the cytokine-refractory MRCC study experienced dose interruption.

In treatment-naïve MRCC patients receiving IFN-

, 6 (2%) venous thromboembolic events were

reported; 1 patient (< 1%) experienced a Grade 3 DVT and 5 patients (1%) had pulmonary embolisms,

all with Grade 4.

Venous thromboembolic events were reported for 1 (1.2%) patient in the sunitinib arm and 5 (6.1%)

patients in the placebo arm in the Phase 3 pNET study. Two of these patients on placebo had DVT,

1 with Grade 2 and 1 with Grade 3.

No cases with fatal outcome were reported in GIST, MRCC, and pNET registrational studies. Cases

with fatal outcome have been observed in the postmarketing surveillance.

Cases of pulmonary embolism were observed in approximately 3.1% of patients with GIST and in

approximately 1.2% of patients with MRCC, who received sunitinib in Phase 3 studies. No pulmonary

embolism was reported for patients with pNET who received sunitinib in the Phase 3 study. Rare cases

with fatal outcome have been observed in the postmarketing surveillance.

Patients who presented with pulmonary embolism within the previous 12 months were excluded from

sunitinib clinical studies.

In patients who received sunitinib in Phase 3 registrational studies, pulmonary events (i.e. dyspnoea,

pleural effusion, pulmonary embolism, or pulmonary oedema) were reported in approximately 17.8%

of patients with GIST, in approximately 26.7% of patients with MRCC and in 12% of patients with

pNET.

Approximately 22.2% of patients with solid tumours, including GIST and MRCC, who received

sunitinib in clinical trials experienced pulmonary events.

Gastrointestinal disorders

Pancreatitis has been observed uncommonly (< 1%) in patients receiving sunitinib for GIST or

MRCC. No treatment-related pancreatitis was reported in the Phase 3 pNET study (see section 4.4).

Fatal gastrointestinal bleeding was reported in 0.98% of patients receiving placebo in the GIST Phase

3 study.

Hepatobiliary disorders

Hepatic dysfunction has been reported and may include Liver Function Test abnormalities, hepatitis,

or liver failure (see section 4.4).

Skin and subcutaneous tissue disorders

Cases of pyoderma gangrenosum, generally reversible after discontinuation of sunitinib, have been

reported (see also section 4.4).

Musculoskeletal and connective tissue disorders

Cases of myopathy and/or rhabdomyolysis, some with acute renal failure, have been reported. Patients

with signs or symptoms of muscle toxicity should be managed as per standard medical practice (see

section 4.4).

Cases of fistula formation, sometimes associated with tumour necrosis and regression, in some cases

with fatal outcomes, have been reported (see section 4.4).

Cases of ONJ have been reported in patients treated with Sutent, most of which occurred in patients

who had identified risk factors for ONJ, in particular, exposure to intravenous bisphosphonates and/or

a history of dental disease requiring invasive dental procedures (see also section 4.4).

Investigations

Data from non clinical (

in vitro

in vivo

) studies, at doses higher than the recommended human

dose, indicated that sunitinib has the potential to inhibit the cardiac action potential repolarisation

process (e.g., prolongation of QT interval).

Increases in the QTc interval to over 500 msec were reported in 0.5%, and changes from baseline in

excess of 60 msec were reported in 1.1% of the 450 solid tumour patients; both of these parameters are

recognised as potentially significant changes. At approximately twice therapeutic concentrations,

sunitinib has been shown to prolong the QTcF interval (Fridericia corrected QT interval).

QTc interval prolongation was investigated in a trial in 24 patients, ages 20-87 years, with advanced

malignancies. The results of this study demonstrated that sunitinib had an effect on QTc interval

(defined as a mean placebo-adjusted change of > 10 msec with a 90% confidence interval [CI] upper

limit > 15 msec) at therapeutic concentration (Day 3) using the within-day baseline correction method,

and at greater than therapeutic concentration (Day 9) using both baseline correction methods. No

patients had a QTc interval > 500 msec.

Although an effect on QTcF interval was observed on Day 3

at 24 hours postdose (i.e., at therapeutic plasma concentration expected after the recommended starting

dose of 50 mg) with the within-day baseline correction method, the clinical significance of this finding

is unclear.

Using comprehensive serial ECG assessments at times corresponding to either therapeutic or greater

than therapeutic exposures, none of the patients in the evaluable or intent-to-treat (ITT) populations

were observed to develop QTc interval prolongation considered as “severe” (i.e. equal to or greater

than Grade 3 by Common Terminology Criteria for Adverse Events [CTCAE] version 3.0).

At therapeutic plasma concentrations, the maximum QTcF interval (Frederica’s correction) mean

change from baseline was 9 msec (90% CI: 15.1 msec). At approximately twice therapeutic

concentrations, the maximum QTcF interval change from baseline was 15.4 msec (90%

CI: 22.4 msec). Moxifloxacin (400 mg) used as a positive control showed a 5.6 msec maximum mean

QTcF interval change from baseline. No subjects experienced an effect on the QTc interval greater

than Grade 2 (CTCAE version 3.0) (see section 4.4).

Long-term safety in MRCC

The long-term safety of sunitinib in patients with MRCC was analysed across 9 completed clinical

studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings

in 5,739 patients, of whom 807 (14%) were treated for ≥ 2 years up to 6 years. In the 807 patients who

received long-term sunitinib treatment, most treatment-related adverse events (TRAEs) occurred

initially in the first 6 months–1 year and then were stable or decreased in frequency over time, with the

exception of hypothyroidism, which gradually increased over time, with new cases occurring over the

6 year period. Prolonged treatment with sunitinib did not appear to be associated with new types of

TRAEs.

Paediatric population

The safety profile of sunitinib has been derived from a Phase 1 dose-escalation study, a Phase 2

open-label study, a Phase 1/2 single-arm study and from publications as described below.

A Phase 1 dose-escalation study of oral sunitinib was conducted in 35 patients comprised of

30 paediatric patients (aged 3 years to 17 years) and 5 young adult patients (aged 18 to 21 years), with

refractory solid tumours, the majority of whom had a primary diagnosis of brain tumour. All study

participants experienced adverse drug reactions; most of these were severe (toxicity grade ≥ 3) and

included cardiac toxicity. The most common adverse drug reactions were gastrointestinal (GI) toxicity,

neutropenia, fatigue, and ALT elevation. The risk of cardiac adverse drug reactions appeared to be

higher in paediatric patients with previous exposure to cardiac irradiation or anthracycline compared

to those paediatric patients without previous exposure. In these paediatric patients without previous

exposure to anthracyclines or cardiac irradiation, the maximum tolerated dose (MTD) has been

identified (see section 5.1).

A phase 2 open-label study was conducted in 29 patients comprised of 27 paediatric patients (aged

3 years to 16 years) and 2 young adult patients (aged 18 years to 19 years) with

recurrent/progressive/refractory high grade glioma (HGG) or ependymoma. There were no Grade 5

adverse reactions in either group. The most common (≥10%) treatment-related adverse events were

neutrophil count decreased (6 [20.7%] patients) and haemorrhage intracranial (3[10.3%] patients).

A Phase 1/2 single-arm, study was conducted in 6 paediatric patients (aged 13 years to 16 years) with

advanced unresectable GIST. The most frequent adverse drug reactions were diarrhoea, nausea, WBC

count decreased, neutropenia, and headache in 3 (50.0%) patients each, primarily Grade 1 or 2 in

severity. Four out of 6 patients (66.7%) experienced Grade 3-4 treatment-related adverse events

(Grade 3 hypophosphataemia, neutropenia, and thrombocytopenia in 1 patient each and a Grade 4

neutropenia in 1 patient). There were no serious adverse events (SAEs) or Grade 5 adverse drug

reactions reported in this study. In both the clinical study and the publications, the safety profile was

consistent with the known safety profile in adults.

Reporting of suspected adverse reactions

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

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

professionals are asked to report any suspected adverse reactions via the national reporting

system listed in Appendix V.

4.9

Overdose

There is no specific antidote for overdose with Sutent and treatment of overdose should consist of

general supportive measures. If indicated, elimination of unabsorbed active substance may be achieved

by emesis or gastric lavage. Cases of overdose have been reported; some cases were associated with

adverse reactions consistent with the known safety profile of sunitinib.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors; ATC code: L01XE04

Mechanism of action

Sunitinib inhibits multiple RTKs that are implicated in tumour growth, neoangiogenesis, and

metastatic progression of cancer. Sunitinib was identified as an inhibitor of platelet-derived growth

factor receptors (PDGFRα and PDGFRβ), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), stem

cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor

(CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). The primary metabolite

exhibits similar potency compared to sunitinib in biochemical and cellular assays.

Clinical efficacy and safety

The clinical safety and efficacy of sunitinib has been studied in the treatment of patients with GIST

who were resistant

to imatinib (i.e., those who experienced disease progression

during or following

treatment with imatinib) or intolerant

to imatinib (i.e., those who experienced significant toxicity

during treatment with imatinib that precluded further treatment), the treatment of patients with MRCC,

and the treatment of patients with unresectable pNET.

Efficacy is based on time-to-tumour progression (TTP) and an increase in survival in GIST, on

progression-free survival (PFS) and objective response rates (ORR) for treatment-naïve and

cytokine-refractory MRCC respectively, and on PFS for pNET.

Gastrointestinal stromal tumours

An initial open-label, dose-escalation study was conducted in patients with GIST after failure of

imatinib (median maximum daily dose 800 mg) due to resistance or intolerance. Ninety-seven patients

were enrolled at various doses and schedules; 55 patients received 50 mg at the recommended

treatment Schedule 4 weeks on /2 weeks off (“Schedule 4/2”).

In this study, the median TTP was 34.0 weeks (95% CI: 22.0, 46.0).

A Phase 3, randomised, double-blind, placebo-controlled study of sunitinib was conducted in patients

with GIST who were intolerant to, or had experienced disease progression during or following

treatment with imatinib (median maximum daily dose 800 mg). In this study, 312 patients were

randomised (2:1) to receive either 50 mg sunitinib or placebo, orally once daily on Schedule 4/2 until

disease progression or withdrawal from the study for another reason (207 patients received sunitinib

and 105 patients received placebo). The primary efficacy endpoint of the study was TTP, defined as

the time from randomisation to first documentation of objective tumour progression. At the time of the

prespecified interim analysis, the median TTP on sunitinib was 28.9 weeks (95% CI: 21.3, 34.1) as

assessed by the investigator and 27.3 weeks (95% CI: 16.0, 32.1) as assessed by the independent

review and was statistically significantly longer than the TTP on placebo of 5.1 weeks

(95% CI: 4.4, 10.1) as assessed by the investigator and 6.4 weeks (95% CI: 4.4, 10.0) as assessed by

the independent review. The difference in overall survival (OS) was statistically in favour of sunitinib

[hazard ratio (HR): 0.491; (95% CI: 0.290, 0.831)]; the risk of death was 2 times higher in patients in

the placebo arm compared to the sunitinib arm.

After the interim analysis of efficacy and safety, at the recommendation of the independent Data and

Safety Monitoring Board (DSMB), the study was unblinded and patients on the placebo arm were

offered open-label sunitinib treatment.

A total of 255 patients received sunitinib in the open-label treatment phase of the study, including

99 patients who were initially treated with placebo.

The analyses of primary and secondary endpoints in the open-label phase of the study reaffirmed the

results obtained at the time of the interim analysis, as shown in Table 2:

Table 2.

GIST summary of efficacy endpoints (ITT population)

Double-blind treatment

Median (95% CI)

Hazard ratio

Placebo

cross-over

group

treatment

b

Endpoint

Sutent

Placebo

(95% CI)

p-value

Primary

TTP (weeks)

Interim

27.3 (16.0, 32.1)

6.4 (4.4, 10.0)

0.329 (0.233, 0.466) < 0.001

Final

26.6 (16.0, 32.1)

6.4 (4.4, 10.0)

0.339 (0.244, 0.472) < 0.001

10.4 (4.3,

22.0)

Secondary

PFS (weeks)

Interim

24.1 (11.1, 28.3)

6.0 (4.4, 9.9)

0.333 (0.238, 0.467) < 0.001

Final

22.9 (10.9, 28.0)

6.0 (4.4, 9.7)

0.347 (0.253, 0.475) < 0.001

ORR (%)

Interim

6.8 (3.7, 11.1)

0 (-)

0.006

Final

6.6 (3.8, 10.5)

0 (-)

0.004

10.1 (5.0,

17.8)

OS (weeks)

Interim

0.491 (0.290, 0.831)

0.007

Final

72.7 (61.3, 83.0) 64.9 (45.7, 96.0)

0.876 (0.679, 1.129)

0.306

Abbreviations: CI=confidence interval; ITT=intent-to-treat; NA=not applicable; ORR=objective response

rate; OS=overall survival; PFS=progression-free survival; TTP=time-to-tumour progression.

Results of double-blind treatment are from the ITT population and using central radiologist

measurement, as appropriate.

Efficacy results for the 99 subjects who crossed over from placebo to Sutent after unblinding. Baseline

was reset at cross-over and efficacy analyses were based on investigators assessment.

The interim PFS numbers have been updated based on a recalculation of the original data.

Results for ORR are given as percent of subjects with confirmed response with the 95% CI.

Median not achieved because the data were not yet mature.

Median OS in the ITT population was 72.7 weeks and 64.9 weeks (HR: 0.876; 95% CI: 0.679, 1.129;

p=0.306), in the sunitinib and placebo arms, respectively. In this analysis, the placebo arm included

those patients randomised to placebo who subsequently received open-label sunitinib treatment.

Treatment-naïve metastatic renal cell carcinoma

A Phase 3, randomised, multi-centre, international study evaluating the efficacy and safety of sunitinib

compared with IFN-

in treatment-naïve MRCC patients was conducted. Seven hundred and fifty

patients were randomised 1:1 to the treatment arms; they received treatment with either sunitinib in

repeated 6-week cycles, consisting of 4 weeks of 50 mg daily oral administration followed by 2 weeks

of rest (Schedule 4/2), or IFN-α, administered as a subcutaneous injection of 3 million units (MU) the

first week, 6 MU the second week, and 9 MU the third week and thereafter, on 3 nonconsecutive days

each week.

The median duration of treatment was 11.1 months (range: 0.4-46.1) for sunitinib treatment and

4.1 months (range: 0.1-45.6) for IFN-α treatment. Treatment-related serious adverse events (TRSAEs)

were reported in 23.7% of patients receiving sunitinib and in 6.9% of patients receiving IFN-α.

However, the discontinuation rates due to adverse events were 20% for sunitinib and 23% for IFN-α.

Dose interruptions occurred in 202 patients (54%) on sunitinib and 141 patients (39%) on IFN-α. Dose

reductions occurred in 194 patients (52%) on sunitinib and 98 patients (27%) on IFN-α. Patients were

treated until disease progression or withdrawal from the study. The primary efficacy endpoint was

PFS. A planned interim analysis showed a statistically significant advantage for sunitinib over IFN-α,

in this study, the median PFS for the sunitinib-treated group was 47.3 weeks, compared with

22.0 weeks for the IFN-α-treated group; the HR was 0.415 (95% CI: 0.320, 0.539; p-value < 0.001).

Other endpoints included ORR, OS, and safety. Core radiology assessment was discontinued after the

primary endpoint had been met. At the final analysis, the ORR as determined by the investigator’s

assessment was 46% (95% CI: 41%, 51%) for the sunitinib arm and 12.0% (95% CI: 9%, 16%) for the

IFN-α arm (p<0.001).

Sunitinib treatment was associated with longer survival compared to IFN-α. The median OS was

114.6 weeks for the sunitinib arm (95% CI: 100.1, 142.9) and 94.9 weeks for the IFN-α arm

(95% CI: 77.7, 117.0) with a hazard ratio of 0.821 (95% CI: 0.673, 1.001; p=0.0510 by unstratified

log-rank).

The overall PFS and OS, observed in the ITT population, as determined by the core radiology

laboratory assessment, are summarised in Table 3.

Table 3.

Treatment-naïve mRCC summary of efficacy endpoints (ITT population)

Summary of progression-free survival

Sunitinib

(N = 375)

IFN-

(N = 375)

Subject did not progress or die [n (%)]

161 (42.9)

176 (46.9)

Subject observed to have progressed or died

[n (%)]

214 (57.1)

199 (53.1)

PFS (weeks)

Quartile (95% CI)

22.7 (18.0, 34.0)

10.0 (7.3, 10.3)

48.3 (46.4, 58.3)

22.1 (17.1, 24.0)

84.3 (72.9, 95.1)

58.1 (45.6, 82.1)

Unstratified analysis

Hazard ratio (sunitinib versus IFN-

0.5268

95% CI for hazard ratio

(0.4316, 0.6430)

p-value

< 0.0001

Summary of progression-free survival

Sunitinib

(N = 375)

IFN-

(N = 375)

Summary of overall survival

Subject not known to have died [n (%)]

185 (49.3)

175 (46.7)

Subject observed to have died [n (%)]

190 (50.7)

200 (53.3)

OS (weeks)

Quartile (95% CI)

56.6 (48.7, 68.4)

41.7 (32.6, 51.6)

114.6 (100.1, 142.9)

94.9 (77.7, 117.0)

NA (NA, NA)

NA (NA, NA)

Unstratified analysis

Hazard ratio (sunitinib versus IFN-

0.8209

95% CI for hazard ratio

(0.6730, 1.0013)

p-value

0.0510

Abbreviations: CI=confidence interval; INF-α=interferon-alfa; ITT=intent-to-treat; N=number of patients;

NA=not applicable; OS=overall survival; PFS=progression-free survival.

From a 2-sided log-rank test.

Cytokine-refractory metastatic renal cell carcinoma

A Phase 2 study of sunitinib was conducted in patients who were refractory to prior cytokine therapy

with interleukin-2 or IFN-

. Sixty-three patients received a starting dose of 50 mg sunitinib orally,

once daily for 4 consecutive weeks followed by a 2-week rest period, to comprise a complete cycle of

6 weeks (Schedule 4/2). The primary efficacy endpoint was ORR, based on Response Evaluation

Criteria in Solid Tumours (RECIST).

In this study the objective response rate was 36.5% (95% CI:

24.7%, 49.6%) and the median TTP was

37.7 weeks (95% CI: 24.0, 46.4).

A confirmatory

,

open-label

,

single-arm, multi-centre study evaluating the efficacy and safety of

sunitinib was conducted in patients with MRCC who were refractory to prior cytokine therapy

.

hundred and 6 patients received at least one 50 mg dose of sunitinib on Schedule 4/2

.

The primary efficacy endpoint of this study was ORR. Secondary endpoints included TTP, duration of

response (DR) and OS.

In this study the ORR was 35.8% (95% CI: 26.8% , 47.5 %). The median DR and OS had not yet been

reached.

Pancreatic neuroendocrine tumours

A supportive Phase 2, open-label, multi-centre study evaluated the efficacy and safety of single-agent

sunitinib 50 mg daily on Schedule 4/2 in patients with unresectable pNET. In a pancreatic islet cell

tumour cohort of 66 patients, the primary endpoint of response rate was 17%.

A pivotal Phase 3, multi-centre, international, randomised, double-blind, placebo-controlled study of

single-agent sunitinib was conducted in patients with unresectable pNET.

Patients were required to have documented progression, based on RECIST, within the prior 12 months

and were randomised (1:1) to receive either 37.5 mg sunitinib once daily without a scheduled rest

period (N = 86) or placebo (N = 85).

The primary objective was to compare PFS in patients receiving sunitinib versus patients receiving

placebo. Other endpoints included OS, ORR, PROs, and safety.

Demographics were comparable between the sunitinib and placebo groups. Additionally, 49% of

sunitinib patients had nonfunctioning tumours versus 52% of placebo patients and 92% of patients in

both arms had liver metastases.

Use of somatostatin analogues was allowed in the study.

A total of 66% of sunitinib patients received prior systemic therapy compared with 72% of placebo

patients. In addition, 24% of sunitinib patients had received somatostatin analogues compared with

22% of placebo patients.

A clinically significant advantage in investigator-assessed PFS for sunitinib over placebo was

observed. The median PFS was 11.4 months for the sunitinib arm compared to 5.5 months for the

placebo arm [hazard ratio: 0.418 (95% CI: 0.263, 0.662), p-value=0.0001]; similar results were

observed when derived tumour response assessments based upon application of RECIST to

investigator tumour measurements were used to determine disease progression, as shown in Table 4.

A hazard ratio favouring sunitinib was observed in all subgroups of baseline characteristics evaluated,

including an analysis by number of prior systemic therapies. A total of 29 patients in the sunitinib arm

and 24 in the placebo arm had received no prior systemic treatment; among these patients, the hazard

ratio for PFS was 0.365 (95% CI: 0.156, 0.857), p=0.0156. Similarly, among 57 patients in the

sunitinib arm (including 28 with 1 prior systemic therapy and 29 with 2 or more prior systemic

therapies) and 61 patients in the placebo arm (including 25 with 1 prior systemic therapy and 36 with 2

or more prior systemic therapies), the hazard ratio for PFS was 0.456 (95% CI: 0.264, 0.787),

p=0.0036.

A sensitivity analysis of PFS was conducted where progression was based upon investigator-reported

tumour measurements and where all subjects censored for reasons other than study termination were

treated as PFS events. This analysis provided a conservative estimate of the treatment effect of

sunitinib and supported the primary analysis, demonstrating a hazard ratio of 0.507 (95% CI: 0.350,

0.733), p=0.000193. The pivotal study in pancreatic NET was terminated prematurely at the

recommendation of an independent drug monitoring committee and the primary endpoint was based

upon investigator assessment, both of which may have affected the estimates of the treatment effect.

In order to rule out bias in the investigator-based assessment of PFS, a BICR of scans was performed;

this review supported the investigator assessment, as shown in Table 4.

Table 4 - pNET efficacy results from the Phase 3 study

Efficacy parameter

Sutent

(N = 86)

Placebo

(N = 85)

Hazard Ratio

(95% CI)

p-value

Progression-free survival

[median,

months (95% CI)] by Investigator

Assessment

11.4

(7.4, 19.8)

(3.6, 7.4)

0.418

(0.263, 0.662)

0.0001

Progression-free survival

[median,

months (95% CI)] by derived tumour

response assessment based upon

application of RECIST to

investigator tumour assessments

12.6

(7.4, 16.9)

(3.5, 6.0)

0.401

(0.252, 0.640)

0.000066

Progression-free survival

[median,

months (95% CI)] by blinded

independent central review of

tumour assessments

12.6

(11.1, 20.6)

(3.8, 7.2)

0.315

(0.181, 0.546)

0.000015

Overall survival [5 years follow-up]

[median, months (95% CI)]

38.6

(25.6, 56.4)

29.1

(16.4, 36.8)

0.730

(0.504, 1.057)

0.0940

Objective response rate

[%, (95% CI)]

(3.2, 15.4)

0.0066

Abbreviations: CI=confidence interval; N=number of patients; NA=not applicable; pNET=pancreatic

neuroendocrine tumours; RECIST=response evaluation criteria in solid tumours.

2-sided unstratified log-rank test

Fisher’s Exact test

Figure 1.

Kaplan-Meier plot of PFS in the pNET Phase 3 study

Time (Months)

Progression Free Survival Probability (%)

SUTENT (N=86)

Median 11.4 months

Placebo (N=85)

Median 5.5 months

Hazard Ratio = 0.42

95% CI (0.26 - 0.66)

p = 0.0001

SUTENT

Placebo

Number of subjects at risk

Abbreviations: CI=confidence interval; N=number of patients; PFS=progression-free survival; pNET=pancreatic

neuroendocrine tumours.

OS data were not mature at the time of the study closure [20.6 months (95% CI: 20.6, NR) for the

sunitinib arm compared to NR (95% CI: 15.5, NR) for the placebo arm, hazard ratio:

0.409 (95% CI: 0.187, 0.894), p-value=0.0204]. There were 9 deaths in the sunitinib arm and

21 deaths in the placebo arm.

Upon disease progression, patients were unblinded and placebo patients were offered access to

open-label sunitinib in a separate extension study. As a result of the early study closure, remaining

patients were unblinded and offered access to open-label sunitinib in an extension study. A total of 59

out of 85 patients (69.4%) from the placebo arm crossed over to open-label sunitinib following disease

progression or unblinding at study closure. OS observed after 5 years of follow-up in the extension

study showed a hazard ratio of 0.730 (95% CI: 0.504, 1.057).

Results from the European Organisation for Research and Treatment of Cancer Quality of Life

Questionnaire (EORTC QLQ-C30) showed that the overall global health-related quality of life and the

5 functioning domains (physical, role, cognitive, emotional, and social) were maintained for patients

on sunitinib treatment as compared to placebo with limited adverse symptomatic effects.

A Phase 4 multinational, multi-centre, single-arm, open-label study evaluating the efficacy and safety

of sunitinib was conducted in patients with progressive, advanced/metastatic, well-differentiated,

unresectable pNET.

One hundred six patients (61 patients in the treatment-naïve cohort and 45 patients in the later-line

cohort) received treatment with sunitinib orally at 37.5 mg once a day on a continuous daily dosing

(CDD) schedule.

The investigator-assessed median PFS was 13.2 months, both in the overall population (95% CI: 10.9,

16.7) and in the treatment-naïve cohort (95% CI: 7.4, 16.8).

Paediatric population

Experience on the use of sunitinib in paediatric patients is limited (see section 4.2).

A Phase 1 dose-escalation study of oral sunitinib was conducted in 35 patients comprised of

30 paediatric patients (aged 3 years to 17 years) and 5 young adult patients (aged: 18 years to

21 years), with refractory solid tumours, the majority of whom were enrolled with a primary diagnosis

of brain tumour. Dose-limiting cardiotoxicity was observed in the first part of the study which was

therefore amended to exclude patients with previous exposure to potentially cardiotoxic therapies

(including anthracyclines) or cardiac radiation. In the second part of the study, including patients with

prior anticancer therapy but without risk factors for cardiac toxicity, sunitinib was generally tolerable

and clinically manageable at the dose of 15 mg/m

daily (MTD) on Schedule 4/2. None of the subjects

achieved complete response or partial response. Stable disease was observed in 6 patients (17%). One

patient with GIST was enrolled at the 15 mg/m

dose level with no evidence of benefit. The observed

adverse drug reactions were similar overall to those seen in adults (see section 4.8).

A Phase 2 open-label study was conducted in 29 patients comprised of 27 paediatric patients (aged

3 years to 16 years) and 2 young adult patients (aged 18 years to 19 years) with HGG or ependymoma.

The study was closed at the time of planned interim analysis due to the lack of disease control. Median

PFS was 2.3 months in the HGG group and 2.7 months in the ependymoma group. Median overall OS

was 5.1 months in the HGG group and 12.3 months in the ependymoma group. The most common

(≥10%) reported treatment-related adverse events in patients in both groups combined were neutrophil

count decreased (6 patients [20.7%]) and haemorrhage intracranial (3 patients [10.3%]) (see

section 4.8).

Evidence from a Phase 1/2 study of oral sunitinib conducted in 6 paediatric patients with GIST aged

13 years to 16 years who received sunitinib on Schedule 4/2, at doses ranging between 15 mg/m

daily

and 30 mg/m

daily, and available published data (20 paediatric or young adult patients with GIST)

indicated that sunitinib treatment resulted in disease stabilization in 18 of 26 (69.2%) patients, either

after imatinib failure or intolerance (16 patients with stable disease out of 21), or de novo/after surgery

(2 patients with stable disease out of 5). In the Phase 1/2 study, stable disease and disease progression

was observed in 3 out of 6 patients each (1 patient received neo adjuvant and 1 patient received

adjuvant imatinib, respectively). In the same study, 4 out of 6 patients (66.7%) experienced Grade 3-4

treatment-related adverse events (Grade 3 hypophosphataemia, neutropenia, and thrombocytopenia in

1 patient each and a Grade 4 neutropenia in 1 patient). In addition, the publications reported the

following Grade 3 adverse drug reactions experienced by 5 patients: fatigue (2), gastrointestinal

adverse drug reactions (including diarrhoea) (2), haematologic adverse drug reactions (including

anaemia) (2), cholecystitis (1), hyperthyroidism (1), and mucositis (1).

A population pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analysis was

conducted with the scope to extrapolate the PK and key safety and efficacy endpoints of sunitinib in

paediatric patients with GIST (aged: 6 years to 17 years). This analysis was based on data collected

from adults with GIST or solid tumours and from paediatric patients with solid tumours. Based on the

modelling analyses, the younger age and lower body size did not appear to affect negatively the safety

and efficacy responses to sunitinib plasma exposures. Sunitinib benefit/risk did not appear to be

negatively affected by younger age or lower body size, and was mainly driven by its plasma exposure.

The EMA has waived the obligation to submit the results of studies with Sutent in all subsets of the

paediatric population for the treatment of kidney or renal pelvis carcinoma (excluding

nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary

carcinoma, and rhabdoid tumour of the kidney) (see section 4.2).

The EMA has waived the obligation to submit the results of the studies with Sutent in all subsets of

the paediatric population for the treatment of gastroenteropancreatic neuroendocrine tumours

(excluding neuroblastoma, neuroganglioblastoma, and phaeochromocytoma) (see section 4.2).

5.2

Pharmacokinetic properties

The PK of sunitinib were evaluated in 135 healthy volunteers and 266 patients with solid tumours. The

PK were similar in all solid tumours populations tested and in healthy volunteers.

In the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and

increase proportionally with dose. With repeated daily administration, sunitinib accumulates 3- to

4-fold and its primary active metabolite accumulates 7- to 10-fold. Steady-state concentrations of

sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined

plasma concentrations of sunitinib and its active metabolite are 62.9-101 ng/ml, which are target

concentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro and result in

tumour stasis/growth reduction in vivo. The primary active metabolite comprises 23% to 37% of the

total exposure. No significant changes in the PK of sunitinib or the primary active metabolite are

observed with repeated daily administration or with repeated cycles in the dosing schedules tested.

Absorption

After oral administration of sunitinib, C

are generally observed from 6 to 12 hours time to

maximum concentration (t

) postadministration.

Food has no effect on the bioavailability of sunitinib

.

Distribution

In vitro

, binding of sunitinib and its primary active metabolite to human plasma protein was 95% and

90%, respectively, with no apparent concentration dependence. The apparent volume of distribution

) for sunitinib was large, 2230 L, indicating distribution into the tissues.

Metabolic interactions

The calculated

in

vitro

Ki values for all cytochrome P450 (CYP) isoforms tested (CYP1A2, CYP2A6,

CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11) indicated

that sunitinib and its primary active metabolite are unlikely to induce metabolism, to any clinically

relevant extent, of other actives substances that may be metabolised by these enzymes.

Biotransformation

Sunitinib is metabolised primarily by CYP3A4, the CYP isoform which produces its primary active

metabolite, desethyl sunitinib, which is then further metabolised by the same isoenzyme.

Co-administration of sunitinib with potent CYP3A4 inducers or inhibitors should be avoided because

the plasma levels of sunitinib may be altered (see sections 4.4 and 4.5).

Elimination

Excretion is primarily via faeces (61%), with renal elimination of unchanged active substance and

metabolites accounting for 16% of the administered dose. Sunitinib and its primary active metabolite

were the major compounds identified in plasma, urine, and faeces, representing 91.5%, 86.4%, and

73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and

faeces, but generally were not found in plasma. Total oral clearance (CL/F) was 34-62 L/h. Following

oral administration in healthy volunteers, the elimination half-lives of sunitinib and its primary active

desethyl metabolite are approximately 40-60 hours and 80-110 hours, respectively.

Co-administration with medicinal products that are BCRP inhibitors

In vitro

, sunitinib is a substrate of the efflux transporter BCRP. In study A6181038 the

co-administration of gefitinib, a BCRP inhibitor, did not result in a clinically relevant effect on the

and AUC for sunitinib or total drug (sunitinib + metabolite) (see section 4.5).

This study was a

multi-centre, open-label, Phase 1/2 study examining the safety/tolerability, the maximum tolerated

dose, and the antitumour activity of sunitinib in combination with gefitinib in subjects with MRCC.

The PK of gefitinib (250 mg daily) and sunitinib (37.5 mg [Cohort 1, n=4] or 50 mg [Cohort 2, n=7]

daily on a 4-weeks on followed by 2 weeks-off schedule) when co-administered was evaluated as a

secondary study objective.

Changes in sunitinib PK parameters were of no clinical significance and

did not indicate any drug-drug interactions; however, considering the relatively low number of

subjects (i.e. N=7+4) and the moderate-large interpatient variability in the pharmacokinetic

parameters, caution needs to be taken when interpreting the PK drug-drug interaction findings from

this study.

Special populations

Hepatic impairment

Sunitinib and its primary metabolite are mainly metabolised by the liver. Systemic exposures after a

single dose of sunitinib were similar in subjects with mild or moderate (Child-Pugh Class A and B)

hepatic impairment compared to subjects with normal hepatic function. Sutent was not studied in

subjects with severe (Child-Pugh Class C) hepatic impairment.

Studies in cancer patients have excluded patients with ALT or AST > 2.5 x ULN (upper limit of

normal) or > 5.0 x ULN if due to liver metastasis.

Renal impairment

Population PK analyses indicated that sunitinib apparent clearance (CL/F) was not affected by

creatinine clearance (CLcr) within the range evaluated (42-347 ml/min). Systemic exposures after a

single dose of sunitinib were similar in subjects with severe renal impairment (CLcr < 30 ml/min)

compared to subjects with normal renal function (CLcr > 80 ml/min). Although sunitinib and its

primary metabolite were not eliminated through haemodialysis in subjects with ESRD, the total

systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to

subjects with normal renal function.

Weight, performance status

Population PK analyses of demographic data indicate that no starting dose adjustments are necessary

for weight or Eastern Cooperative Oncology Group (ECOG) performance status.

Gender

Available data indicate that females could have about 30% lower apparent clearance (CL/F) of

sunitinib than males: this difference, however, does not necessitate starting dose adjustments.

Paediatric population

Experience on the use of sunitinib in paediatric patients is limited (see section 4.2). Population PK

analyses of a pooled dataset from adult patients with GIST and solid tumours and paediatric patients

with solid tumours were completed. Stepwise covariate modelling analyses were performed to

evaluate the effect of age and body size (total body weight or body surface area) as well as other

covariates on important PK parameters for sunitinib and its active metabolite. Among age and

bodysize related covariates tested, age was a significant covariate on apparent clearance of sunitinib

(the younger the age of the paediatric patient, the lower the apparent clearance). Similarly, body

surface area was a significant covariate on the apparent clearance of the active metabolite (the lower

the body surface area, the lower the apparent clearance).

Furthermore, based on an integrated population PK analysis of pooled data from the 3 paediatric

studies (2 paediatric solid tumour studies and 1 paediatric GIST study; ages: 6 years to 11 years and

12 years to 17 years), baseline body surface area (BSA) was a significant covariate on apparent

clearance of sunitinib and its active metabolite. Based on this analysis, a dose of approximately

20 mg/m

daily in paediatric patients, with BSA values between 1.10 and 1.87 m

, is expected to

provide plasma exposures to sunitinib and its active metabolite comparable (between 75 and 125% of

the AUC) to those in adults with GIST administered sunitinib 50 mg daily on Schedule 4/2 (AUC

1233 ng.hr/mL). In paediatric studies, the starting dose of sunitinib was 15 mg/m

(based on the MTD

identified in the Phase 1 dose-escalation study, see section 5.1), which in paediatric patients with GIST

increased to 22.5 mg/m

and subsequently to 30 mg/m

(not to exceed the total dose of 50 mg/day)

based on individual patient safety/tolerability. Furthermore, according to the published literatures in

paediatric patients with GIST, the calculated starting dose ranged from 16.6 mg/m

to 36 mg/m

increased to doses as high as 40.4 mg/m

(not exceeding the total dose of 50 mg/day).

5.3

Preclinical safety data

In rat and monkey repeated-dose toxicity studies up to 9-months duration, the primary target organ

effects were identified in the gastrointestinal tract (emesis and diarrhoea in monkeys); adrenal gland

(cortical congestion and/or haemorrhage in rats and monkeys, with necrosis followed by fibrosis in

rats); haemolymphopoietic system (bone morrow hypocellularity and lymphoid depletion of thymus,

spleen, and lymph node); exocrine pancreas (acinar cell degranulation with single cell necrosis);

salivary gland (acinar hypertrophy); bone joint (growth plate thickening); uterus (atrophy); and ovaries

(decreased follicular development). All findings occurred at clinically relevant sunitinib plasma

exposure levels. Additional effects observed in other studies included: QTc interval prolongation,

LVEF reduction and testicular tubular atrophy, increased mesangial cells in kidney, haemorrhage in

gastrointestinal tract and oral mucosa, and hypertrophy of anterior pituitary cells. Changes in the

uterus (endometrial atrophy) and bone growth plate (physeal thickening or dysplasia of cartilage) are

thought to be related to the pharmacological action of sunitinib. Most of these findings were reversible

after 2 to 6 weeks without treatment.

Genotoxicity

The genotoxic potential of sunitinib was assessed

in vitro

in vivo

. Sunitinib was not mutagenic in

bacteria using metabolic activation provided by rat liver. Sunitinib did not induce structural

chromosome aberrations in human peripheral blood lymphocyte cells

in vitro.

Polyploidy (numerical

chromosome aberrations) was observed in human peripheral blood lymphocytes

in vitro

, both in the

presence and absence of metabolic activation. Sunitinib was not clastogenic in rat bone marrow

in vivo.

The major active metabolite was not evaluated for genotoxic potential.

Carcinogenicity

In a 1-month, oral gavage dose-range finding study (0, 10, 25, 75, or 200 mg/kg/day) with continuous

daily dosing in rasH2 transgenic mice, carcinoma and hyperplasia of Brunner’s glands of the

duodenum were observed at the highest dose (200 mg/kg/day) tested.

A 6-month, oral gavage carcinogenicity study (0, 8, 25, 75 [reduced to 50] mg/kg/day), with daily

dosing was conducted in rasH2 transgenic mice. Gastroduodenal carcinomas, an increased incidence

of background haemangiosarcomas, and/or gastric mucosal hyperplasia were observed at doses

of ≥ 25 mg/kg/day following 1- or 6-months duration (≥ 7.3 times the AUC in patients administered

the recommended daily dose

In a 2-year rat carcinogenicity study (0, 0.33, 1, or 3 mg/kg/day), administration of sunitinib in 28-day

cycles followed by 7-day dose-free periods resulted in increases in the incidence of

phaeochromocytomas and hyperplasia in the adrenal medulla of male rats given 3 mg/kg/day

following > 1 year of dosing (≥ 7.8 times the AUC in patients administered the RDD). Brunner’s

glands carcinoma occurred in the duodenum at ≥ 1 mg/kg/day in females and at 3 mg/kg/day in males,

and mucous cell hyperplasia was evident in the glandular stomach at 3 mg/kg/day in males, which

occurred at ≥ 0.9, 7.8, and 7.8 times the AUC in patients administered the RDD, respectively. The

relevance to humans of the neoplastic findings observed in the mouse (rasH2 transgenic) and rat

carcinogenicity studies with sunitinib treatment is unclear.

Reproductive and developmental toxicity

No effects on male or female fertility were observed in reproductive toxicity studies. However, in

repeated-dose toxicity studies performed in rats and monkeys, effects on female fertility were

observed in the form of follicular atresia, degeneration of corpora lutea, endometrial changes in the

uterus, and decreased uterine and ovarian weights at clinically relevant systemic exposure levels.

Effects on male fertility in rat were observed in the form of tubular atrophy in the testes, reduction of

spermatozoa in epididymides, and colloid depletion in prostate and seminal vesicles at plasma

exposure levels 25 times the systemic exposure in humans.

In rats, embryo-foetal mortality was evident as significant reductions in the number of live foetuses,

increased numbers of resorptions, increased postimplantation loss, and total litter loss in 8 of

28 pregnant females at plasma exposure levels 5.5 times the systemic exposure in humans. In rabbits,

reductions in gravid uterine weights and number of live foetuses were due to increases in the number

of resorptions, increases in postimplantation loss and complete litter loss in 4 of 6 pregnant females at

plasma exposure levels 3 times the systemic exposure in humans. Sunitinib treatment in rats during

organogenesis resulted in developmental effects at

5 mg/kg/day consisting of increased incidence of

foetal skeletal malformations, predominantly characterised as retarded ossification of thoracic/lumbar

vertebrae and occurred at plasma exposure levels 5.5 times the systemic exposure in humans. In

rabbits, developmental effects consisted of increased incidence of cleft lip at plasma exposure levels

approximately equal to that observed in clinic, and cleft lip and cleft palate at plasma exposure levels

2.7 times the systemic exposure in humans.

Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre-and postnatal development study in

pregnant rats. Maternal body weight gains were reduced during gestation and lactation at

≥ 1 mg/kg/day but no maternal reproductive toxicity was observed up to 3 mg/kg/day (estimate

exposure ≥ 2.3 times the AUC in patients administered the RDD). Reduced offspring body weights

were observed during the preweaning and postweaning periods at 3 mg/kg/day. No development

toxicity was observed at 1 mg/kg/day (approximate exposure ≥ 0.9 times the AUC in patients

administered the RDD).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

12.5 mg hard capsules

Capsule content

Mannitol (E421)

Croscarmellose sodium

Povidone (K-25)

Magnesium stearate

Capsule shell

Gelatin

Red iron oxide (E172)

Titanium dioxide (E171)

Printing ink

Shellac

Propylene glycol

Sodium hydroxide

Povidone

Titanium dioxide (E171)

25 mg hard capsules

Capsule content

Mannitol (E421)

Croscarmellose sodium

Povidone (K-25)

Magnesium stearate

Capsule shell

Gelatin

Red iron oxide (E172)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Black iron oxide (E172)

Printing ink

Shellac

Propylene glycol

Sodium hydroxide

Povidone

Titanium dioxide (E171)

37.5 mg hard capsules

Capsule content

Mannitol (E421)

Croscarmellose sodium

Povidone (K-25)

Magnesium stearate

Capsule shell

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Printing ink

Shellac

Propylene glycol

Potassium hydroxide

Black iron oxide (E172)

50 mg hard capsules

Capsule content

Mannitol (E421)

Croscarmellose sodium

Povidone (K-25)

Magnesium stearate

Capsule shell

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Printing ink

Shellac

Propylene glycol

Sodium hydroxide

Povidone

Titanium dioxide (E171)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

High-density polyethylene (HDPE) bottle with a polypropylene closure containing 30 hard capsules.

Poly(chlorotrifluoroethylene)/PVC transparent perforated unit dose blister with aluminium foil coated

with heat seal lacquer containing 28 x 1 hard capsules.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MARKETING AUTHORISATION HOLDER

Pfizer Europe MA EEIG

Boulevard de la Plaine 17

1050 Bruxelles

Belgium

8.

MARKETING AUTHORISATION NUMBER(S)

Sutent 12.5 mg hard capsules

EU/1/06/347/001

EU/1/06/347/004

Sutent 25 mg hard capsules

EU/1/06/347/002

EU/1/06/347/005

Sutent 37.5 mg hard capsules

EU/1/06/347/007

EU/1/06/347/008

Sutent 50 mg hard capsules

EU/1/06/347/003

EU/1/06/347/006

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 July 2006

Date of latest renewal: 9 November 2016

10.

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu.

30 Churchill Place

Canary Wharf

London E14 5EU

United Kingdom

An agency of the European Union

Telephone

+44 (0)20 3660 6000

Facsimile

+44 (0)20 3660 5555

Send a question via our website

www.ema.europa.eu/contact

© European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged.

EMA/487080/2014

EMEA/H/C/000687

EPAR summary for the public

Sutent

sunitinib

This is a summary of the European public assessment report (EPAR) for Sutent. It explains how the

Committee for Medicinal Products for Human Use (CHMP) assessed the medicine to reach its opinion in

favour of granting a marketing authorisation and its recommendations on the conditions of use for

Sutent.

What is Sutent?

Sutent is a medicine that contains the active substance sunitinib. It is available as capsules (12.5 mg,

25 mg, 37.5 mg and 50 mg).

What is Sutent used for?

Sutent is used to treat adults with the following types of cancer:

gastrointestinal stromal tumour (GIST), a type of cancer of the stomach and bowel where there is

uncontrolled growth of cells in the supporting tissues of these organs. Sutent is used in patients

with GISTs that cannot be removed with surgery or have spread to other parts of the body. It is

used after treatment with imatinib (another cancer medicine) has failed;

metastatic renal cell carcinoma, a type of kidney cancer, that has spread to other parts of the

body;

pancreatic neuroendocrine tumours (tumours of the hormone-producing cells in the pancreas) that

have spread or cannot be removed with surgery. Sutent is used if the disease is getting worse and

the tumour cells are well-differentiated (similar to normal cells in the pancreas).

The medicine can only be obtained with a prescription.

Sutent

EMA/487080/2014

Page 2/3

How is Sutent used?

Treatment with Sutent should be started by doctors who have experience in administering cancer

medicines.

For GIST and metastatic renal cell carcinoma, Sutent is given in six-week cycles, at a dose of 50 mg

once a day for four weeks, followed by a two-week ‘rest period’. The dose can be adjusted according to

the patient’s response to the treatment, but should be kept within the range of 25 to 75 mg.

For pancreatic neuroendocrine tumours, Sutent is given at a dose of 37.5 mg once a day without a rest

period. This dose may also be adjusted.

How does Sutent work?

The active substance in Sutent, sunitinib, is a protein kinase inhibitor. This means that it blocks some

specific enzymes known as protein kinases. These enzymes can be found in some receptors at the

surface of cancer cells, where they are involved in the growth and spread of cancer cells and in the

blood vessels that supply the tumours, where they are involved in the development of new blood

vessels. By blocking these enzymes, Sutent can reduce the growth and spread of the cancer and cut

off the blood supply that keeps cancer cells growing.

How has Sutent been studied?

Sutent was compared with placebo (a dummy treatment) in 312 patients with GIST whose previous

treatment with imatinib had failed and in 171 patients with worsening pancreatic neuroendocrine

tumours that could not be removed with surgery. Sutent was also compared with another cancer

medicine, interferon alfa, in 750 patients with metastatic renal cell carcinoma whose cancer had not

been treated before.

The main measure of effectiveness in all of the studies was how long the patients lived without their

tumours getting worse.

What benefit has Sutent shown during the studies?

Sutent was more effective than placebo in treating GIST and pancreatic neuroendocrine tumours.

Patients with GIST taking Sutent lived for an average of 26.6 weeks without the disease getting worse,

compared with 6.4 weeks in the patients taking placebo. For pancreatic neuroendocrine tumours the

figures were 11.4 months in the Sutent group and 5.5 months in the placebo group.

In metastatic renal cell carcinoma, patients taking Sutent lived for an average of 47.3 weeks without

their disease worsening, compared with 22.0 weeks in the patients receiving interferon alfa.

What is the risk associated with Sutent?

The most common side effects with Sutent (seen in more than 1 in 10 patients) include fatigue

(tiredness), gastrointestinal disorders (such as diarrhoea, feeling sick, inflammation of the lining of the

mouth, indigestion and vomiting), respiratory (such as shortness of breath and cough) and skin

disorders (such as skin discoloration, dryness of the skin and rash), hair color changes, dysgeusia

(taste disturbances), epistaxis (nosebleeds), loss of appetite, hypertension (high blood pressure),

palmar-plantar erythrodysaesthesia syndrome (rash and numbness on the palms and soles),

hypothyroidism (an underactive thyroid gland), insomnia (difficulty falling and staying asleep),

dizziness, headache, arthralgia (joint pain), neutropenia (low levels of neutrophils, a type of white

Sutent

EMA/487080/2014

Page 3/3

blood cell), thrombocytopenia (low blood platelet counts), anaemia (low red blood cell counts), and

leucopenia (low white blood cell counts).

The most serious side effects reported with Sutent include heart and kidney failure, pulmonary

embolism (clot in a blood vessel supplying the lungs), gastrointestinal perforation (holes in the wall of

the gut), and internal haemorrhages (bleeding).

For the full list of all side effects and restrictions with Sutent, see the package leaflet.

Why has Sutent been approved?

The CHMP decided that Sutent’s benefits are greater than its risks and recommended that it be given

marketing authorisation.

Sutent was originally given ‘conditional approval’ because there was more evidence to come about the

medicine, in particular in the treatment of renal cell carcinoma. As the company has supplied the

additional information necessary, the authorisation has been switched from conditional to full approval.

What measures are being taken to ensure the safe and effective use of

Sutent?

A risk management plan has been developed to ensure that Sutent is used as safely as possible. Based

on this plan, safety information has been included in the summary of product characteristics and the

package leaflet for Sutent, including the appropriate precautions to be followed by healthcare

professionals and patients.

Other information about Sutent

The European Commission granted a conditional marketing authorisation valid throughout the

European Union for Sutent on 19 July 2006. This was switched to a full marketing authorisation on 11

January 2007.

The full EPAR for Sutent can be found on the Agency’s website

ema.europa.eu/Find medicine/Human

medicines/European Public Assessment Reports. For more information about treatment with Sutent,

read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

This summary was last updated in 08-2014.

Aðrar vörur

search_alerts

share_this_information