Sutent

1.

NAME OF THE MEDICINAL PRODUCT

SUTENT 12.5 mg hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule.

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.

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 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).

4.2 Posology and method of administration

Therapy with sunitinib should be initiated by a physician experienced in the administration of anti-

cancer agents.

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.

2

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 SUTENT 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 SUTENT 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 SUTENT 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 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.

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 sunitinib in patients below 18 years of age have not been established.

No data are available.

There is no relevant use of Sutent in children from birth to less than 6 years in the indication of

unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) after failure of

imatinib mesilate treatment due to resistance or intolerance. There is no relevant use of Sutent in the

paediatric population in the indications treatment of advanced/metastatic renal cell carcinoma and

treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours with

disease progression.

Use of SUTENT in the paediatric population is not recommended.

Elderly patients (≥ 65 years old)

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 effectiveness were observed between younger and

older patients.

Hepatic insufficiency

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 sever (Child-Pugh class C) hepatic impairment (see section 5.2).

Renal insufficiency

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

impairment (mild-severe) or with end-stage renal disease (ESRD) on hemodialysis. 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.

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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 s disorders

Skin discolouration, possibly due to the active substance colour (yellow), is a common adverse

reaction occurring in approximately 30% of patients. Patients should be advised that depigmentation

of the hair or skin may also occur during treatment with sunitinib. Other possible dermatologic effects

may include dryness, thickness or cracking of the skin, blisters or occasional rash on the palms of the

hands and soles of the feet.

Mouth pain/irritation was reported in approximately 14% of patients. The above events were not

cumulative, were typically reversible and generally did not result in treatment discontinuation.

Haemorrhage and tumour bleeding

Haemorrhagic events, some of which were fatal, reported through post-marketing experience have

included gastro-intestinal, respiratory, tumour, urinary tract and brain haemorrhages. In clinical trials,

treatment-related tumour haemorrhage occurred in approximately 2% of patients with GIST. These

events may occur suddenly, and in the case of pulmonary tumours, may present as severe and life-

threatening haemoptysis or pulmonary haemorrhage. Fatal pulmonary haemorrhage occurred in 2

patients (~ 1.8%) receiving sunitinib on a phase 2 clinical trial of patients with metastatic non-small

cell lung cancer (NSCLC). Both patients had squamous cell histology. SUTENT is not approved for

use in patients with NSCLC.

Bleeding events occurred in 18% of patients receiving sunitinib in a phase 3 GIST Study compared to

17% of patients receiving placebo. In patients receiving sunitinib for treatment-naïve MRCC, 39%

had bleeding events compared to 11% of patients receiving IFN-α. Eleven (3.1%) patients on sunitinib

versus 1 (0.3%) of patients on IFN-α experienced Grade 3 or greater treatment-related bleeding

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

Bleeding events, excluding epistaxis, occurred in 19% of patients receiving sunitinib in the phase 3

pNET study compared to 4% of patients receiving placebo. Routine assessment of this event 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.

Gastrointestinal disorders

Nausea, diarrhoea, stomatitis, dyspepsia and vomiting were the most commonly reported

gastrointestinal adverse reactions (see section 4.8).

Supportive care for gastrointestinal adverse reactions requiring treatment may include medicinal

products with anti-emetic or anti-diarrhoeal properties.

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation have

occurred rarely in patients with intra-abdominal malignancies treated with sunitinib. Treatment-

related fatal gastrointestinal bleeding occurred in 0.5% of patients receiving placebo in the GIST

phase 3 study.

Hypertension

Treatment-related hypertension was reported in approximately 16% of patients with solid tumours .

The dose of sunitinib was reduced or its administration temporarily suspended in approximately 2.7%

of the patients who experienced hypertension. In none of these patients sunitinib was permanently

discontinued. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 4.7% of

patients with solid tumours. Treatment-related hypertension was reported in approximately 30% of

patients receiving sunitinib for treatment-naïve MRCC, compared to 6% of patients receiving IFN-α.

Severe hypertension occurred in 12% of treatment-naïve patients on sunitinib and 6% of patients on

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IFN-α. Treatment-related hypertension was reported in 23% of patients receiving sunitinib in a phase

3 pNET study, compared to 4% of patients receiving placebo. Severe hypertension occurred in 10% of

pNET patients on sunitinib and 3% of patients on placebo. 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 .

Haematological disorders

Decreased absolute neutrophil counts of grade 3 and 4 severity 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 severity 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. 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 through post-marketing experience.

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

receiving treatment with sunitinib.

Cardiac disorders

Cardiovascular events, including heart failure, cardiomyopathy, and myocardial disorders, some of

which were fatal, have been reported through post-marketing experience. 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.

In clinical trials, decreases in LVEF of ≥ 20% and below the lower limit of normal occurred 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% patients on

sunitinib and 15% of patients on IFN-α had an LVEF value below the lower limit of normal. Two

patients (<1%) who received sunitinib were diagnosed with congestive heart failure (CHF).

In GIST patients treatment-related ‘cardiac failure’, ‘cardiac failure congestive’ or ‘left ventricular

failure’ were reported in 0.7% 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 occurred

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-α

arm and 0% patients on the sunitinib arm experienced fatal cardiac events. In the phase 3 pNET study,

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

if any, between receptor tyrosine kinase (RTK) inhibition and cardiac function remains unclear.

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 CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism

were excluded from sunitinib clinical studies. It is unknown whether patients with these concomitant

conditions may be at a higher risk of developing drug-related left ventricular dysfunction.

Close monitoring for clinical signs and symptoms of CHF should be performed, especially in patients

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

Physicians are advised to weigh this risk against the potential benefits of sunitinib. These patients

should be carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib.

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.

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QT interval prolongation

Data from non-clinical ( in vitro and 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 occurred in 0.5%, and changes from baseline in excess

of 60 msec occurred in 1.1% of the 450 solid tumour patients; both of these parameters are recognized

as potentially significant changes. At approximately twice therapeutic concentrations, sunitinib has

been shown to prolong the QTcF Interval (Frederica’s Correction).

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% 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 post-

dose (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 ITT populations were observed to

develop QTc interval prolongation considered as “severe” (i.e. equal to or greater than Grade 3 by

CTCAE version 3.0).

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

change from baseline was 9.6 msec (90% CI 15.1msec). 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).

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

de pointes. Torsade de pointes has been observed in <0.1% of sunitinib-exposed patients. Sunitinib

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

who are taking antiarrhythmics, 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 section 4.2

and 4.5).

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 MRCC.

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

thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT) and two were

Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of

DVT.

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

patients (2%) on the two cytokine-refractory MRCC studies had treatment-related venous

thromboembolic events reported. Nine of these patients had pulmonary embolisms, one was Grade 2

and eight were Grade 4. Eight of these patients had DVT, one with Grade 1, two with Grade 2, four

with Grade 3 and one with Grade 4.

In treatment-naïve MRCC patients receiving IFN-α, six (2%) venous thromboembolic events

occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary

embolisms, all with Grade 4.

No treatment-related venous thromboembolic events were reported for patients receiving sunitinib,

and one Grade 2 DVT was reported for a patient receiving placebo in the phase 3 pNET study.

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

with fatal outcome have been observed in post-marketing setting (see respiratory events and section

4.8).

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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.

Respiratory events

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, treatment-related pulmonary

events (i.e. dyspnoea, pleural effusion, pulmonary embolism or pulmonary oedema) were reported in

approximately 5% of patients with GIST, in approximately 14% of patients with MRCC and in 7.2%

of patients with pNET.

Approximately 8% of patients with solid tumours, including GIST and MRCC, who received sunitinib

in clinical trials experienced treatment-related pulmonary events.

Cases of pulmonary embolism were observed in approximately 1.3% of patients with GIST and in

approximately 0.8% of patients with MRCC, who received sunitinib in phase 3 studies (see section

4.4 - Venous thromboembolic events). No treatment-related 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 post-marketing setting (see section 4.8).

Thyroid dysfunction

Baseline laboratory measurement of thyroid function is recommended and patients with

hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the

start of sunitinib treatment. All patients should be observed closely for signs and symptoms of thyroid

dysfunction on sunitinib treatment. Patients with signs and/or symptoms suggestive of thyroid

dysfunction should have laboratory monitoring of thyroid function performed and be treated as per

standard medical practice.

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

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

cytokine-refractory MRCC studies; in nine patients (2%) on sunitinib and one patient (<1%) in the

IFN-α arm in the treatment-naïve MRCC study. Additionally, 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. Treatment-emergent acquired

hypothyroidism was noted in 8 GIST patients (4%) on sunitinib versus 1 (1%) on placebo. In the

phase 3 pNET study treatment-related hypothyroidism was reported in 5 patients (6%) receiving

sunitinib and in one patient (1%) on placebo.

Rare cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials

and through post-marketing experience.

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.

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

MRCC.

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.

No treatment-related pancreatitis was reported in the phase 3 pNET study.

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 tumor patients treated with sunitinib. Monitor

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

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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.

Renal function

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

have been reported.

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

addition to underlying renal cell carcinoma, older age, diabetes mellitus, underlying renal

insufficiency, cardiac failure, hypertension, sepsis, dehydration/hypovolemia, 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.

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 occurred in

patients who had received prior or concomitant treatment with i.v. bisphosphonates, for which ONJ is

an identified risk. Caution should therefore be exercised when SUTENT and i.v. 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 i.v. 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.

Nervous system disorders

Taste disturbance

Dysgeusia was reported in approximately 28% of patients receiving sunitinib in clinical trials.

Seizures

In clinical studies of sunitinib and from post-marketing experience, seizures have been observed in

subjects with or without radiological evidence of brain metastases. In addition, there have been few

reports (<1%) of subjects presenting with seizures and radiological evidence of reversible posterior

leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with

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.

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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

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] C max and AUC 0-∞ 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).

Medicinal products that may decrease sunitinib plasma concentrations

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] C max and

AUC 0-∞ 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).

Anticoagulants

Haemorrhage has been observed rarely in patients treated with sunitinib (see section 4.4 and 4.8).

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no studies in pregnant women using SUTENT. 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.

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

becoming pregnant while receiving treatment with SUTENT .

Breastfeeding

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 nursing infants,

women should not breast-feed while taking SUTENT .

Fertility

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

SUTENT (see section 5.3).

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4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Patients

should be advised that they may experience dizziness during treatment with SUTENT.

4.8 Undesirable effects

The most important serious adverse reactions associated with SUTENT in patients with solid tumours

were pulmonary embolism (1%), thrombocytopoenia (1%), tumour haemorrhage (0.9%), febrile

neutropoenia (0.4%) and hypertension (0.4%). The most common adverse reactions (experienced by

at least 20% of the patients) of any grade included: fatigue; gastrointestinal disorders, such as

diarrhoea, nausea, stomatitis, dyspepsia and vomiting; skin discolouration; dysgeusia and anorexia.

Fatigue, hypertension and neutropoenia were the most common Grade 3 adverse reactions and

increased lipase was the most frequent Grade 4 adverse reaction in patients with solid tumours.

Hepatitis and hepatic failure occurred in <1% of patients and prolonged QT interval in < 0.1% (see

section 4.4).

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, rhabdomyolysis, cerebrovascular accident, dehydration, adrenal

insufficiency, renal failure, respiratory failure, pleural effusion, pneumothorax, shock, and sudden

death.

Adverse reactions that were reported in >2% of GIST and MRCC patients and in >5% of pNET

patients in the phase 3 study are listed below, by system organ class, frequency and grade of severity

(NCI-CTCAE). 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 GIST studies with SUTENT

System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Blood and

lymphatic

system disorders

Very common Anaemia 86 (19.5%) 24 (5.5%) 3 (0.7%)

Very common Neutropoenia 81 (18.4%) 39 (8.9%) 5 (1.1%)

Very common Thrombocytopoenia 67 (15.2%) 19 (4.3%) 6 (1.4%)

Common

Leukopoenia

26 (5.9%)

9 (2.0%)

1 (0.2%)

Common

Lymphopoenia

10 (2.3%)

3 (0.7%)

1 (0.2%)

Endocrine

disorders

Very common Hypothyroidism

59 (13.4%) 5 (1.1%)

1 (0.2%)

Metabolism and

nutrition

disorders

Very common Decreased appetite a 117 (26.6%) 8 (1.8%)

0 (0.0%)

Psychiatric

disorders

Common

Insomnia

14 (3.2%)

0 (0.0%)

Nervous system

disorders

Very common Taste disturbance b

105 (23.9%) 1 (0.2%)

0 (0.0%)

Very common Headache

76 (17.3%) 5 (1.1%)

0 (0.0%)

Common

Paraesthesia

27 (6.1%)

1 (0.2%)

0 (0.0%)

Common

Dizziness

18 (4.1%)

1 (0.2%)

0 (0.0%)

Common

Neuropathy peripheral 11 (2.5%)

0 (0.0%)

Common

Hypoaesthesia

10 (2.3%)

0 (0.0%)

Vascular

disorders

Very common Hypertension

101 (23.0%) 43 (9.8%) 0 (0.0%)

Respiratory,

Common

Epistaxis

28 (6.4%)

1 (0.2%)

0 (0.0%)

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System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

thoracic and

mediastinal

disorders

Common

Dyspnoea

16 (3.6%)

2 (0.5%)

0 (0.0%)

Renal and

urinary

disorders

Common

Chromaturia

18 (4.1%)

0 (0.0%)

Gastrointestinal

disorders

Very common Diarrhoea

187 (42.5%) 24 (5.5%) 0 (0.0%)

Very common Nausea

161 (36.6%) 15 (3.4%) 0 (0.0%)

Very common Vomiting

98 (22.2%) 7 (1.6%)

0 (0.0%)

Very common Stomatitis

90 (20.5%) 7 (1.6%)

0 (0.0%)

Very common Dyspepsia

80 (18.2%) 4 (0.9%)

0 (0.0%)

Very common Abdominal pain C /

distension

77 (17.5%) 15 (3.4%)

2 (0.5%)

Very common Flatulence

46 (10.5%) 0 (0.0%)

0 (0.0%)

Very common Oral pain

44 (10.0%) 2 (0.5%)

0 (0.0%)

Common

Constipation

37 (8.4%)

2 (0.5%)

0 (0.0%)

Common

Glossodynia

37 (8.4%)

0 (0.0%)

Common

Dry mouth

31 (7.0%)

0 (0.0%)

Common

Gastro-oesophageal

reflux disease

12 (2.7%)

1 (0.2%)

0 (0.0%)

Common

Mouth ulceration

11 (2.5%)

0 (0.0%)

Common

Oral discomfort

11 (2.5%)

0 (0.0%)

Skin and

subcutaneous

tissue disorders

Very common Yellow skin/

Skin discolouration

146 (33.2%) 0 (0.0%)

0 (0.0%)

Very common Palmar-plantar

erythrodysaesthesia

syndrome

106 (24.1%) 27 (6.1%) 0 (0.0%)

Very common Hair colour changes 67 (15.2%) 0 (0.0%)

0 (0.0%)

Very common Rash

64 (14.5%) 3 (0.7%)

0 (0.0%)

Common

Dry skin

41 (9.3%)

0 (0.0%)

Common

Alopecia

33 (7.5%)

0 (0.0%)

Common

Dermatitis

29 (6.6%)

1 (0.2%)

0 (0.0%)

Common

Periorbital oedema

20 (4.5%)

0 (0.0%)

Common

Skin Reaction

20 (4.5%)

3 (0.7%)

0 (0.0%)

Common

Erythema

18 (4.1%)

0 (0.0%)

Common

Eczema

16 (3.6%)

1 (0.2%)

0 (0.0%)

Common

Pruritus

16 (3.6%)

0 (0.0%)

Common

Skin

hyperpigmentation

15 (3.4%)

0 (0.0%)

Common

Skin exfoliation

12 (2.7%)

0 (0.0%)

Common

Blister

10 (2.3%)

1 (0.2%)

0 (0.0%)

Common

Skin lesion

10 (2.3%)

1 (0.2%)

0 (0.0%)

Musculoskeletal

and connective

tissue disorders

Very Common Pain in extremity/limb 54 (12.3%) 5 (1.1%)

0 (0.0%)

Common

Arthralgia

39 (8.9%)

3 (0.7%)

0 (0.0%)

Common

Myalgia

29 (6.6%)

0 (0.0%)

Common

Muscle spasm

21 (4.8%)

1 (0.2%)

0 (0.0%)

Common

Back pain

11 (2.5%)

2 (0.5%)

0 (0.0%)

Common

Muscular weakness

10 (2.3%)

1 (0.2%)

0 (0.0%)

General

disorders and

administration

site conditions

Very common Fatigue/Asthenia 287 (65.2%) 64 (14.5%) 5 (1.1%)

Very common Mucosal inflammation 70 (15.9%) 6 (1.4%)

1 (0.2%)

Very common Oedema d

59 (13.4%) 1 (0.2%)

0 (0.0%)

Common

Pyrexia

26 (5.9%)

2 (0.5%)

0 (0.0%)

11

System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Investigations

Common

Lipase increase

35 (8.0%)

12 (2.7%) 7 (1.6%)

Common

White blood cell

count decreased e

33 (7.5%)

15 (3.4%)

0 (0.0%)

Common

Ejection fraction

decreased

27 (6.1%)

5 (1.2%)

0 (0.0%)

Common

Haemoglobin

decreased

27 (6.1%)

6 (1.4%)

0 (0.0%)

Common

Platelet count

decrease

25 (5.7%)

4 (0.9%)

1 (0.2%)

Common

Weight decreased

23 (5.2%)

1 (0.2%)

0 (0.0%)

Common

Blood creatinine

phosphokinase

increased

22 (5.0%)

1 (0.2%)

Common

Amylase increased

21 (4.8%)

8 (1.8%)

0 (0.0%)

Common

Aspartate

aminotransferase

increased

18 (4.1%)

2 (0.5%)

1 (0.2%)

Common

Alanine

aminotransferase

increased

12 (2.7%)

1 (0.2%)

0 (0.0%)

Any adverse event

414 (94.1%) 204

(46.4%)

53 (12.0%)

The following terms have been combined:

a Anorexia and decreased appetite

b Dysgeusia, ageusia and taste disturbance

c Abdominal pain and abdominal pain upper

d Oedema, oedema peripheral and oedema face

e White blood cell count decreased, neutrophil count decreased, and leukocyte count decreased

Table 2 - Adverse reactions reported in cytokine-refractory and treatment-naïve MRCC studies

with SUTENT

System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Blood and

lymphatic

system disorders

Very common Neutropoenia 89 (16.4%) 46 (8.5%) 5 (0.9%)

Very common Thrombocytopoenia 86 (15.8%) 37 (6.8%) 5 (0.9%)

Very common Anaemia

68 (12.5%) 21 (3.9%) 4 (0.7%)

Very Common Leukopoenia

55 (10.1%) 20 (3.7%) 0 (0%)

Common

Lymphopenia

21 (3.9%)

12 (2.2%)

1 (0.2%)

Endocrine

disorders

Very common Hypothyroidism

69 (12.7%) 7 (1.3%)

0 (0%)

Metabolism and

nutrition

disorders

Very Common Decreased appetite a 205 (37.7%) 9 (1.7%)

0 (0%)

Common

Dehydration

33 (6.1%)

7 (1.3%)

1 (0.2%)

Psychiatric

disorders

Common

Insomnia

22 (4.0%)

0 (0%)

Common

Depression

15 (2.8%)

1 (0.2%)

0 (0%)

Nervous system

disorders

Very common Taste disturbance b

251 (46.1%) 1 (0.2%)

0 (0%)

Very common Headache

82 (15.1%) 3 (0.6%)

0 (0%)

Common

Dizziness

38 (7.0%)

2 (0.4%)

0 (0%)

Common

Neuropathy

peripheral

35 (6.4%)

2 (0.4%)

0 (0%)

12

System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Common

Paraesthesia

35 (6.4%)

0 (0%)

Common

Hypoaesthesia

20 (3.7%)

0 (0%)

Common

Hyperaesthesia

18 (3.3%)

0 (0%)

Eye disorders

Common

Lacrimation

increased

39 (7.2%)

0 (0%)

Common

Eyelid oedema

12 (2.2%)

0 (0%)

Vascular

disorders

Very common Hypertension

149 (27.4%) 56 (10.3%) 0 (0%)

Common

Flushing

17 (3.1%)

0 (0%)

Common

Hot flush

12 (2.2%)

0 (0%)

Respiratory,

thoracic and

mediastinal

disorders

Very common Epistaxis

87 (16.0%) 3 (0.6%)

0 (0%)

Common

Dyspnoea

45 (8.3%)

6 (1.1%)

0 (0%)

Common

Pharyngolaryngeal

pain

26 (4.8%)

2 (0.4%)

0 (0%)

Common

Cough

23 (4.2%)

0 (0%)

Common

Dysphonia

16 (2.9%)

0 (0%)

Common

Nasal dryness

14 (2.6%)

0 (0%)

Common

Pleural effusion

12 (2.2%)

3 (0.6%)

0 (0%)

Common

Nasal congestion

12 (2.2%)

0 (0%)

Common

Dyspnoea exertional 11 (2.0%)

0 (0%)

Gastrointestinal

disorders

Very common Diarrhoea

326 (59.9%) 39 (7.2%) 0 (0%)

Very common Nausea

290 (53.3%) 19 (3.5%) 0 (0%)

Very common Stomatitis/aphthous

stomatitis

192 (35.3%) 14 (2.6%) 0 (0%)

Very common Dyspepsia

189 (34.7%) 8 (1.5%)

0 (0%)

Very common Vomiting

180 (33.1%) 17 (3.1%) 0 (0%)

Very common Abdominal pain c /

distension

99 (18.2%) 9 (1.7%)

0 (0%)

Very common Constipation

83 (15.3%) 1 (0.2%)

0 (0%)

Very common Glossodynia

63 (11.6%) 0 (0%)

0 (0%)

Very common Oral pain

62 (11.4%) 2 (0.4%)

0 (0%)

Very common Flatulence

60 (11.0%) 0 (0%)

0 (0%)

Very common Dry mouth

56 (10.3%) 0 (0%)

0 (0%)

Common

Gastroesophageal

reflux disease

50 (9.2%)

2 (0.4%)

0 (0%)

Common

Dysphagia

20 (3.7%)

2 (0.4%)

1 (0.2%)

Common

Cheilitis

19 (3.5%)

1 (0.2%)

0 (0%)

Common

Gingival bleeding

18 (3.3%)

0 (0%)

Common

Haemorrhoids

18 (3.3%)

0 (0%)

Common

Proctalgia

17 (3.1%)

1 (0.2%)

0 (0%)

Common

Mouth ulceration

16 (2.9%)

0 (0%)

1 (0.2%)

Common

Rectal haemorrhage

13 (2.4%)

0 (0%)

Common

Stomach discomfort

12 (2.2%)

0 (0%)

Common

Eructation

11 (2.0%)

0 (0%)

Skin and

subcutaneous

tissue disorders

Very common Yellow

discolouration/

Skin discolouration/

Pigmentation

disorder

153 (28.1%) 1 (0.2%)

0 (0%)

Very common Palmar-plantar

erythrodysaesthesia

syndrome

139 (25.6%) 44 (8.1%) 0 (0%)

13

System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Very common Rash

122 (22.4%) 3 (0.6 %)

1 (0.2%)

Very common Dry skin

108 (19.9%) 1 (0.2%)

0 (0%)

Very common Hair colour changes 103 (18.9%) 0 (0%)

0 (0%)

Very common Alopecia

64 (11.8%) 0 (0%)

0 (0%)

Very Common Erythema

58 (10.7%) 2 (0.4%)

0 (0%)

Common

Skin exfoliation

47 (8.6%)

4 (0.7%)

0 (0%)

Common

Skin reaction/skin

disorder

42 (7.7%)

6 (1.1%)

0 (0%)

Common

Pruritus

40 (7.4%)

1 (0.2%)

0 (0%)

Common

Periorbital oedema

31 (5.7%)

1 (0.2%)

0 (0%)

Common

Skin lesion

27 (5.0%)

1 (0.2%)

0 (0%)

Common

Dermatitis

26 (4.8%)

4 (0.7%)

0 (0%)

Common

Nail disorder/

discolouration

25 (4.6%)

0 (0%)

Common

Blister

23 (4.2%)

1 (0.2%)

0 (0%)

Common

Hyperkeratosis

22 (4.0%)

4 (0.7%)

0 (0%)

Common

Acne

19 (3.5%)

0 (0%)

Musculoskeletal

and connective

tissue disorders

Very common Pain in extremity

96 (17.6%) 6 (1.1%)

0 (0%)

Common

Arthralgia

51 (9.4%)

1 (0.2%)

0 (0%)

Common

Myalgia

49 (9.0%)

2 (0.4%)

0 (0%)

Common

Muscle Spasm

26 (4.8%)

0 (0%)

Common

Back pain

17 (3.1%)

2 (0.4%)

0 (0%)

Common

Musculoskeletal pain 11 (2.0%)

2 (0.4%)

0 (0%)

Renal and

urinary

disorders

Common

Chromaturia

17 (3.1%)

0 (0%)

General

disorders and

administration

site conditions

Very common Fatigue/asthenia

373 (68.6%) 93 (17.1%) 1 (0.2%)

Very common Mucosal

inflammation

134 (24.6%) 8 (1.5%)

0 (0%)

Very common Oedema d

83 (15.3%) 4 (0.7%)

0 (0%)

Common

Pyrexia

37 (6.8%)

3 (0.6%)

0 (0%)

Common

Chills

34 (6.3%)

2 (0.4%)

0 (0%)

Common

Pain

21 (3.9%)

0 (0%)

Common

Chest pain

13 (2.4%)

2 (0.4%)

0 (0%)

Common

Influenza like illness 11 (2.0%)

0 (0%)

Investigations

Very common Ejection fraction

decreased/abnormal

86 (15. 8%) 16 (2.9%)

0 (0%)

Very common Weight decreased

58 (10.7%) 1 (0.2%)

0 (0%)

Common

Platelet count

decreased

41 (7.5%)

15 (2.8%) 2 (0.4%)

Common

White blood cell

count decreased e

37 (6.8%)

16 (2.9%)

0 (0%)

Common

Lipase increased

36 (6.6%)

19 (3.5%)

11 (2.0%)

Common

Haemoglobin

decreased

25 (4.6%)

8 (1.5%)

0 (0%)

Common

Blood amylase

increased

19 (3.5%)

11 (2.0%)

2 (0.4%)

Common

Blood creatine

phosphokinase

increased

19 (3.5%)

7 (1.3%)

2 (0.4%)

14

System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Common

Aspartate

aminotransferase

increased

18 (3.3%)

7 (1.3%)

0 (0%)

Common

Blood creatinine

increased

17 (3.1%)

3 (0.6%)

0 (0%)

Common

Blood pressure

increased

15 (2.8%)

2 (0.4%)

0 (0%)

Common

Alanine

aminotransferase

increased

14 (2.6%)

7 (1.3%)

2 (0.4%)

Any adverse event

524 (96.3%) 297

(54.6%)

59 (10.8%)

The following terms have been combined:

a Anorexia and decreased appetite

b Dysgeusia, ageusia and taste disturbance

c Abdominal pain and abdominal pain upper

d Oedema, oedema peripheral and oedema face

e White blood cell count decreased, neutrophil count decreased, and leukocyte count decreased

Table 3 - Adverse reactions reported in the phase 3 pNET study with SUTENT

System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Blood and

lymphatic

system disorders

Very common Neutropoenia

24 (28.9%) 6 (7.2%)

4 (4.8%)

Very common Thrombocytopoenia 14 (16.9%) 2 (2.4%)

1 (1.2%)

Common

Leukopoenia

8 (9.6%)

4 (4.8%)

1 (1.2%)

Endocrine

disorders

Common

Hypothyroidism

5 (6.0%)

0 (0.0%)

Metabolism and

nutrition

disorders

Very common Anorexia

17 (20.5%) 2 (2.4%)

0 (0.0%)

Common

Decrease appetite

5 (6.0%)

0 (0.0%)

Psychiatric

disorders

Common

Insomnia

7 (8.4%)

0 (0.0%)

Nervous system

disorders

Very common Dysgeusia

16 (19.3%)

0 (0.0%)

Very common Headeache

10 (12.0%)

0 (0.0%)

Common

Dizziness

5 (6.0%)

1 (1.2%)

0 (0.0%)

Eye disorders

Common

Eyelid oedema

5 (6.0%)

1 (1.2%)

0 (0.0%)

Vascular

disorders

Very common Hypertension

19 (22.9%) 8 (9.6%)

0 (0.0%)

Respiratory,

thoracic and

mediastinal

disorders

Very common Epistaxis

16 (19.3%) 1 (1.2%)

0 (0.0%)

Common

Dyspnoea

6 (7.2%)

1 (1.2%)

0 (0.0%)

Gastrointestinal

disorders

Very common Diarrhoea

44 (53.0%)

4 (4.8%)

0 (0.0%)

Very common Nausea

32 (38.6%)

1 (1.2%)

0 (0.0%)

Very common Vomiting

21 (25.3%)

0 (0.0%)

Very common Stomatitis

18 (21.7%)

3 (3.6%)

0 (0.0%)

Very common Abdominal pain

12 (14.5%)

1 (1.2%)

0 (0.0%)

Very common Dyspepsia

12 (14.5%)

0 (0.0%)

Common

Constipation

8 (9.6%)

0 (0.0%)

Common

Dry mouth

7 (8.4%)

0 (0.0%)

15

System Organ

Class

Frequency

Adverse reactions

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Common

Abdominal pain

upper

6 (7.2%)

1 (1.2%)

0 (0.0%)

Common

Aphtous stomatitis

5 (6.0%)

0 (0.0%)

Common

Flatulence

5 (6.0%)

0 (0.0%)

Common

Gingival bleeding

5 (6.0%)

0 (0.0%)

Skin and

subcutaneous

tissue disorders

Very common Hair colour changes

24 (28.9%)

1 (1.2%)

0 (0.0%)

Very common Palmar-plantar

erythrodysaesthesia

syndrome

19 (22.9%) 5 (6.0%)

0 (0.0%)

Very common Rash

13 (15.7%)

0 (0.0%)

Very common Dry skin

11 (13.3%)

0 (0.0%)

Common

Nail disorder

8 (9.6%)

0 (0.0%)

Common

Erythema

7 (8.4%)

0 (0.0%)

Common

Yellow Skin

6 (7.2%)

0 (0.0%)

Common

Alopecia

5 (6.0%)

0 (0.0%)

Musculoskeletal

and connective

tissue disorders

Common

Pain in extremity

7 (8.4%)

0 (0.0%)

Common

Arthralgia

6 (7.2%)

0 (0.0%)

General

disorders and

administration

site conditions

Very common Fatigue/ Asthenia

46 (55.4%) 5 (6.0%)

1 (1.2%)

Very common Mucosal

Inflammation

13 (15.7%) 1 (1.2%)

0 (0.0%)

Investigations

Very common Weight decreased

11 (13.3%) 1 (1.2%)

0 (0.0%)

Any adverse event

81 (97.6%) 29 (34.9%) 7 (8.4%)

Table 4 - Adverse reactions reported through post-marketing experience

The following adverse reactions have been identified during post-approval use of SUTENT. This

includes spontaneous case reports as well as serious adverse events from ongoing studies, the

expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved

indications.

Infections and infestations a

Non known Infections (with or without neutropoenia)

Blood and lymphatic system disorder b

Not known Thrombotic microangiopathy

Immune system disorders c

Not known Angioedema, hypersensitivity reaction

Endocrine disorderse d

Not known

Hyperthyroidism

Cardiac disorders

Uncommon Cardiac failure, cardiac failure congestive, left ventricular failure

Rare Prolonged QT interval, Torsade de pointes

Not known Cardiomyopathy, Pericardial effusion

Gastrointestinal disorders

Uncommon Pancreatitis

Rare Gastrointestinal perforation

Hepatobiliary disorders e

Uncommon Hepatic failure

Not known Hepatitis

Musculoskeletal and connective tissue disorders f

Not known

Myopathy and/or rhabdomyolysis

Not known

Fistula formation

16

Not Known Impaired wound healing

Not Known Osteonecrosis of the jaw

Renal and urinary disorders g

Not known Renal failure, Renal failure acute, Proteinuria, Nephrotic syndrome

Pulmonary disorders h

Not known

Pleural effusion

Not known

Pulmonary embolism and respiratory failure

Investigations

Common Elevated thyroid stimulating hormone (TSH)

a Infection and infestations : Cases of serious infection (with or without neutropoenia), including

pneumonia have been reported. Few cases had a fatal outcome.

b Blood and lymphatic system disorders: Rare cases of thrombotic microangiopathy have been

reported. Temporary suspension of SUTENT is recommended; following resolution, treatment may

be resumed at the discretion of the treating physician.

c Immune system disorders: Hypersensitivity reactions, including angioedema, have been reported.

d Endocrine Disorders: Rare cases of hyperthyroidism, some followed by hypothyroidism, have been

reported in clinical trials and through post-marketing experience (See also section 4.4).

e Hepatobiliary disorders : Hepatic dysfunction has been reported and may include LFT abnormalities,

hepatitis or liver failure (See also section 4.4).

f Musculoskeletal and connective tissue disorders : Rare 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.

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

with fatal outcomes, have been reported.

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

Cases of osteonecrosis of the jaw (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 i.v.

bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also

section 4.4).

g Renal and urinary disorders:

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

have been reported.

Cases of proteinuria and rare cases of nephrotic syndrome have been reported. The safety of

continued SUTENT treatment in patients with moderate to severe proteinuria has not been

systematically evaluated. Discontinue SUTENT in patients with nephrotic syndrome (see also section

4.4).

h Pulmonary disorders: Cases of pulmonary embolism, in some cases with fatal outcome, have been

reported.

4.9 Overdose

There is no specific antidote for overdose with sunitinib 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. A few cases of overdose have been reported; these cases were

associated with adverse reactions consistent with the known safety profile of sunitinib, or without

adverse reactions.

17

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Protein kinase inhibitors; ATC code: L01XE04

Mechanism of action

Sunitinib inhibits multiple receptor tyrosine kinases (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), vascular endothelial growth factor

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 and an increase in survival in GIST, on progression

free survival and objective response rates for treatment-naïve and cytokine-refractory MRCC

respectively, and on progression free survival for pNET.

Gastrointestinal stromal tumours (GIST)

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 Time to Tumour Progression (TTP) was 34.0 weeks (95% CI = 22.0 – 46.0

weeks).

A phase 3, randomized, double-blind, placebo-controlled study of SUTENT 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

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

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

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

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

the pre-specified interim analysis, the median TTP on SUTENT was 28.9 weeks (95% CI = 21.3-34.1

weeks) as assessed by the Investigator and 27.3 weeks (95% CI = 16.0-32.1 weeks) 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 weeks) as assessed by the Investigator and 6.4 weeks (95% CI = 4.4-10.0 weeks)

as assessed by the Independent Review. The difference in overall survival was statistically in favour

of SUTENT [hazard ratio: 0.491 (95%C.I. 0.290- 0.831)]; the risk of death was 2 times higher in

patients in the placebo arm compared to the SUTENT arm.

After the interim analysis of efficacy and safety, at recommendation of the Independent DSMB, the

study was unblinded and patients on the placebo arm were offered open-label SUTENT treatment.

A total of 255 patients received SUTENT 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 the table below:

18

Table 5 - Summary of Efficacy Endpoints (ITT population)

Double-Blind Treatment a

Median (95% CI)

Hazard Ratio

Placebo

Cross-Over

Group

Endpoint

SUTENT

Placebo

(95% CI)

p

Treatment b

Primary: TTP

(weeks)

Interim

27.3 (16.0 to

32.1)

6.4 (4.4 to 10.0)

0.329 (0.233 to

0.466)

<0.001

-

Final

26.6 (16.0 to

32.1)

6.4 (4.4 to 10.0 )

0.339 (0.244 to

0.472)

<0.001

10.4 (4.3 to

22.0)

PFS (weeks) c

Interim

24.1 (11.1 to

28.3)

6.0 (4.4 to 9.9)

0.333 (0.238 to

0.467)

<0.001

-

Final

22.9 (10.9 to

28.0)

6.0 (4.4 to 9.7)

0.347 (0.253 to

0.475)

<0.001

-

ORR (%) d

Interim

6.8 (3.7 to 11.1)

0 (-)

NA

0.006

-

Final

6.6 (3.8 to 10.5)

0 (-)

NA

0.004

10.1 (5.0 to

17.8)

OS (weeks) e

Interim

-

0.491 (0.290 to

0.831)

0.007

-

Final

72.7 (61.3 to

83.0)

64.9 (45.7 to

96.0)

0.876 (0.679 to

1.129)

0.306

-

a Results of double-blind treatment are from the ITT population and using central radiologist measurement, as

appropriate.

b 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

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

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

e Median not achieved because the data were not yet mature.

Median overall survival (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 SUTENT and placebo arms respectively. In this analysis, the

placebo arm included those patients randomized to placebo who subsequently received open-label

SUTENT treatment.

Treatment-naïve metastatic renal cell carcinoma (MRCC)

A phase 3, randomized, multi-centre international study evaluating the efficacy and safety of sunitinib

compared with IFN-α in treatment-naïve MRCC patients was conducted. Seven hundred and fifty

patients were randomized 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 non-consecutive

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

19

Secondary

was progression free survival (PFS). A planned interim analysis showed a statistically significant

advantage for SUTENT 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 hazard ratio was 0.415

(95% CI: 0.320-0.539, p-value <0.001). Other endpoints included objective response rate (ORR),

overall survival (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 investigators’ 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 weeks) and 94.9 weeks for the IFN-α arm

(95% CI: 77.7 - 117.0 weeks) 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 summarized in the table below:

Summary of Efficacy Endpoints (ITT population)

Summary of Progression-Free Survival

Sunitinib

(N=375)

IFN- α

(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)

25%

22.7 (18.0 to 34.0)

10.0 (7.3 to 10.3)

50%

48.3 (46.4 to 58.3)

22.1 (17.1 to 24.0)

75%

84.3 (72.9 to 95.1)

58.1 (45.6 to 82.1)

Unstratified Analysis

Hazard Ratio (sunitinib vs IFN-α)

0.5268

95% CI for Hazard Ratio

(0.4316 to 0.6430)

p-value a

<0.0001

a From a 2-sided log-rank test.

Summary of Overall Survival

Sunitinib

(N = 375)

IFN- α

(N = 375)

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)

25%

56.6 (48.7 to 68.4)

41.7 (32.6 to 51.6)

50%

114.6 (100.1 to 142.9)

94.9 (77.7 to 117.0)

75%

NA (NA to NA)

Unstratified Analysis

Hazard Ratio (sunitinib vs IFN-α)

0.8209

95% CI for Hazard Ratio

(0.6730 to 1.0013)

p-value a

0.0510

a From a 2-sided log-rank test.

NA: Not Available (Not Reached)

Cytokine-refractory metastatic renal cell carcinoma (MRCC)

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

with interleukin-2 or IFN-α. 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 objective response rate (ORR), based on

Response Evaluation Criteria in Solid Tumours (RECIST).

20

In this study the objective response rate was 36.5% (95% C.I. 24.7% - 49.6%) and the median time to

progression (TTP) was 37.7 weeks (95% C.I. 24.0 - 46.4 weeks).

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 . One

hundred and six patients received at least one 50 mg dose of sunitinib on schedule 4/2 .

The primary efficacy endpoint of this study was Objective Response Rate (ORR). Secondary

endpoints included TTP, duration of response (DR) and overall survival (OS).

In this study the ORR was 35.8% (95% C.I. 26.8% – 47.5 %). The median DR and OS had not yet

been reached.

Pancreatic neuroendocrine tumours (pNET)

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

SUTENT 50 mg daily on Schedule 4/2 [4 weeks on treatment, 2-week rest period] 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, randomized, 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 randomized (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 Progression-Free Survival (PFS) in patients receiving sunitinib

versus patients receiving placebo. Other endpoints included Overall Survival (OS), Objective

Response Rate (ORR), Patient-reported Outcomes (PRO) and safety.

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

sunitinib patients had non-functioning tumours versus 52% of placebo patients and 92% patients in

both arms had liver metastases.

Use of somatostatin analogs 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 analogs 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 6.

A hazard ratio favouring SUTENT 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) who had received prior systemic therapy, 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) and 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 blinded independent central

review of scans was performed and supported the investigator assessment, as shown in Table 6.

21

Table 6 - pNET Efficacy Results from the Phase 3 Study

Efficacy Parameter

SUTENT

(n=86)

Placebo

(n=85)

HR

(95% CI)

P-value

Progression-Free Survival [median,

months (95% CI)] by Investigator

Assessment

0.418

(0.263, 0.662)

11.4

(7.4, 19.8)

5.5

(3.6, 7.4)

0.0001 a

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)

5.4

(3.5, 6.0)

0.401

(0.252, 0.640)

0.000066 a

Progression-Free Survival [median,

months (95% CI)] by blinded

independent central review of tumour

assessments

12.6

(11.1, 20.6)

5.8

(3.8, 7.2)

0.315

(0.181, 0.546)

0.000015 a

Overall Survival

[median, months (95% CI)]

20.6

(20.6, NR)

NR

(15.5, NR)

0.409

(0.187, 0.894)

0.0204 a

Objective Response Rate

[%, (95% CI)]

9.3

(3.2, 15.4)

0

NA

0.0066 b

CI=Confidence interval, HR=Hazard ratio, NA=Not applicable, NR=Not reached

a 2-sided unstratified log-rank test

b Fisher’s Exact test

Figure 1 - Kaplan-Meier Curve of PFS in the pNET Phase 3 Study

100

SUTENT (N=86)

Median 11.4 months

90

80

Placebo (N=85)

Median 5.5 months

70

60

50

40

30

20

10

Hazard Ratio = 0.42

95% CI (0.26 - 0.66)

p = 0.0001

0

3

6

9

12

15

18

21

Time (Months)

Number of subjects at risk

SUTENT

86

52

34

20

15

4

2

Placebo

85

42

20

9

2

OS data were not mature at the time of the analysis. There were 9 deaths in the sunitinib arm and 21

deaths in the placebo arm. A statistically significant difference in ORR favouring sunitinib over

placebo was observed.

Upon disease progression, patients were unblinded and placebo patients could have been offered

access to open-label SUTENT in a separate extension study. As a result of the early study closure,

22

remaining patients were unblinded and offered access to open-label SUTENT in an extension study. A

total of 59 patients from the placebo arm received SUTENT in an extension study.

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

Questionnaire (EORTC QLQC-30) showed that the overall global health-related quality of life and the

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

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

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of the studies with

SUTENT in one or more subsets of the paediatric population in gastrointestinal stromal tumours

(GIST) (see section 4.2 for information on the paediatric use).

The European Medicines Agency has waived the obligation to submit the results of studies with

SUTENT in all subsets of the paediatric population for treatment of kidney and renal pelvis

carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic

nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for

information on paediatric use).

The European Medicines Agency has waived the obligation to submit the results of the studies with

SUTENT in all subsets of the paediatric population for treatment of gastroenteropancreatic

neuroendocrine tumours (excluding neuroblastoma, neuroganglioblastoma, phaeochromocytoma) (see

section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of sunitinib has been evaluated in 135 healthy volunteers and 266 patients with

solid tumours. The pharmacokinetics 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

Cmax 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 is 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 pharmacokinetics 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, maximum concentrations (C max ) are generally observed from 6

to 12 hours (t max ) post-administration.

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

(V d ) for sunitinib was large, 2230 l, indicating distribution into the tissues.

Metabolic interactions

The calculated in vitro Ki values for all cytochrome (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.

23

Biotransformation

Sunitinib is metabolised primarily by CYP3A4, the cytochrome P450 isoform which produces its

primary active metabolite, desethyl sunitinib, which is then further metabolized by the same

isoenzyme.

Co-administration of SUTENT 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.

Special populations

Hepatic impairment : Sunitinib and its primary metabolite are mainly metabolized 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, if due to liver metastasis, > 5.0 x ULN.

Renal impairment : Population pharmacokinetic analyses indicated that sunitinib apparent clearance

(CL/F) was not affected by creatinine clearance within the range evaluated (42 - 347 ml/min).

Systemic exposures after a single dose of SUTENT 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 hemodialysis 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 pharmacokinetic 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.

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, pituitary hypertrophy, and testicular tubular atrophy, increased mesangial cells in

kidney, haemorrhage in gastro-intestinal 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.

24

Genotoxicity

The g enotoxic potential of sunitinib was assessed in vitro and 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

The carcinogenic potential of sunitinib has been evaluated in rasH2 transgenic mice. Gastroduodenal

carcinomas, an increased incidence of background haemangiosarcomas, and/or gastric mucosal

hyperplasia have been observed at doses of ≥25 mg/kg/day following 1- or 6-months duration (≥7.3

times the AUC in patients administered the RDD). No proliferative changes were observed in rasH2

transgenic mice at 8 mg/kg/day (≥0.7 times the AUC in patients administered the RDD). The

relevance of the carcinogenicity findings observed in the rasH2 transgenic mouse to humans

following 1- and 6-months 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 18-fold higher than observed in clinic.

In rats, embryo-foetal mortality was evident as significant reductions in the number of live foetuses,

increased numbers of resorptions, increased post-implantation loss, and total litter loss in 8 of 28

pregnant females at plasma exposure levels 5.5-fold higher than observed in clinic. In rabbits,

reductions in gravid uterine weights and number of live foetuses were due to increases in the number

of resorptions, increases in post-implantation loss and complete litter loss in 4 of 6 pregnant females

at plasma exposure levels 3-fold higher than observed in clinic. Sunitinib treatment in rats during

organogenesis resulted in developmental effects at ≥ 5 mg/kg/day consisting of increased incidence of

foetal skeletal malformations, predominantly characterized as retarded ossification of thoracic/lumbar

vertebrae and occurred at plasma exposure levels 6-fold higher than is observed in clinic. 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-fold higher than observed in clinic.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content

Mannitol (E421)

Croscarmellose sodium

Povidone (K-25)

Magnesium stearate

Capsule Shell

Gelatin

Red Iron oxide (E172)

Titanium dioxide (E171)

Printing ink

Shellac

25

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.

Aclar/PVC transparent blister with aluminium foil coated with heat seal lacquer containing 28 (4 x 7)

hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Pfizer Ltd

Ramsgate Road

Sandwich, Kent CT13 9NJ

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/06/347/001

EU/1/06/347/004

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 July 2006

10. DATE OF REVISION OF THE TEXT

26

1.

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 blister packs of 28 capsules (4x7).

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich, Kent CT13 9NJ

United Kingdom

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

Luxembourg/Luxemburg

Pfizer S.A.

Tél/Tel: +32 (0)2 554 62 11

България

Пфайзер Люксембург САРЛ, Клон България

Тел.: +359 2 970 4333

Magyarország

Pfizer Kft.

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

Česká republika

Pfizer s.r.o.

Tel.: +420-283-004-111

Malta

V.J. Salomone Pharma Ltd.

Tel. +356 21220174

Danmark

Pfizer ApS

Tlf: +45 44 20 11 00

Nederland

Pfizer BV

Tel: +31 (0)10 406 43 01

137

Deutschland

Pfizer Pharma GmbH

Tel: +49 (0)30 550055 51000

Norge

Pfizer AS

Tlf: +47 67 52 61 00

Eesti

Pfizer Luxembourg SARL Eesti filiaal

Tel.: +372 6 405 328

Österreich

Pfizer Corporation Austria Ges.m.b.H.

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

Ελλάδα

Pfizer Hellas A.E.

Τηλ: +30 210 6785 800

Polska

Pfizer Polska Sp.z.o.o

Tel.:+48 22 335 61 00

España

Pfizer S.A.

Tél: +34 91 490 99 00

Portugal

Laboratórios Pfizer, Lda.

Tel: +351 21 423 5500

France

Pfizer

Tél: +33 (0)1 58 07 34 40

Rom â nia

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 Italia S.r.l.

Tel: +39 06 33 18 21

Suomi/Finland

Pfizer Oy

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

Kύπρος

Geo. Pavlides & Araouzos Ltd.

Tηλ.:+ 357 22 818087

Sverige

Pfizer AB

Tel: +46 (0)8 550-52000

Latvija

Pfizer Luxembourg SARL filiāle Latvijā

Tel.: + 371 670 35 775

United Kingdom

Pfizer Limited

Tel: +44 (0) 1304 616161

Lietuva

Pfizer Luxembourg SARL filialas Lietuvoje

Tel. + 370 52 51 4000

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

Detailed information on this medicine is available on the European Medicine Agency (EMA) website:

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

138

Source: European Medicines Agency

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