SUNITINIB ACCORD 50mg capsules medication leaflet

Sunitinib Accord 12.5 mg hard capsules

Sunitinib Accord 25 mg hard capsules

Sunitinib Accord 37.5 mg hard capsules

Sunitinib Accord 50 mg hard capsules

Sunitinib Accord 12.5 mg hard c apsules

Each hard capsule contains 12.5 mg of sunitinib.

Sunitinib Accord 25 mg hard c apsules

Each hard capsule contains 25 mg of sunitinib.

Sunitinib Accord 37.5 mg hard c apsules

Each hard capsule contains 37.5 mg of sunitinib.

Sunitinib Accord 50 mg hard c apsules

Each hard capsule contains 50 mg of sunitinib.

For the full list of excipients, see section 6.1.

Hard capsule (capsule)

Sunitinib Accord 12.5 mg hard capsules

Gelatin capsules of size 4 (approximate length 14.3 mm) with orange cap and orange body, printedwith white ink “12.5 mg” on the body, and containing yellow to orange granules.

Sunitinib Accord 25 mg hard capsules

Gelatin capsules of size 3 (approximate length 15.9 mm) with caramel cap and orange body, printedwith white ink “25 mg” on the body, and containing yellow to orange granules.

Sunitinib Accord 37.5 mg hard capsules

Gelatin capsules of size 2 (approximate length 18.0 mm) with yellow cap and yellow body, printedwith black ink “37.5 mg” on the body, and containing yellow to orange granules.

Sunitinib Accord 50 mg hard capsules

Gelatin capsule of size 1 (approximate length 19.4 mm) with caramel cap and caramel body, printedwith white ink “50 mg” on the body, and containing yellow to orange granules.

Gastrointestinal stromal tumour (GIST)

Sunitinib Accord is indicated for the treatment of unresectable and/or metastatic malignantgastrointestinal stromal tumour (GIST) in adults after failure of imatinib treatment due to resistance orintolerance.

Metastatic renal cell carcinoma (MRCC)

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

Pancreatic neuroendocrine tumours (pNET)

Sunitinib Accord is indicated for the treatment of unresectable or metastatic, well-differentiatedpancreatic neuroendocrine tumours (pNET) with disease progression in adults.

Therapy with Sunitinib Accord should be initiated by a physician experienced in the administration ofanticancer agents.

For GIST and MRCC, the recommended dose of Sunitinib Accord is 50 mg taken orally once daily,for 4 consecutive weeks, followed by a 2-week rest period (Schedule 4/2) to comprise a completecycle of 6 weeks.

For pNET, the recommended dose of Sunitinib Accord is 37.5 mg taken orally once daily without ascheduled rest period.

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

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 in12.5 mg steps (up to 87.5 mg per day for GIST and MRCC or 62.5 mg per day for pNET) based oncareful monitoring of tolerability.

Co-administration of sunitinib with potent CYP3A4 inhibitors, such as ketoconazole, should beavoided (see sections 4.4 and 4.5). If this is not possible, the dose of sunitinib may need to be reducedto a minimum of 37.5 mg daily for GIST and MRCC or 25 mg daily for pNET, based on carefulmonitoring of tolerability.

Selection of an alternative concomitant medicinal product with no or minimal potential to induce orinhibit CYP3A4 should be considered.

The safety and efficacy of Sunitinib 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 aposology can be made.

Approximately one-third of the patients in clinical studies who received sunitinib were 65 years of ageor over. No significant differences in safety or efficacy were observed between younger and olderpatients.

No starting dose adjustment is recommended when administering sunitinib to patients with mild ormoderate (Child-Pugh class A and B) hepatic impairment. Sunitinib has not been studied in subjectswith severe (Child-Pugh class C) hepatic impairment and therefore its use in patients with severehepatic impairment cannot be recommended (see section 5.2).

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

Sunitinib Accord 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 theusual prescribed dose on the following day.

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

Co-administration with potent CYP3A4 inducers should be avoided because it may decrease sunitinibplasma concentration (see sections 4.2 and 4.5).

Co-administration with potent CYP3A4 inhibitors should be avoided because it may increase theplasma concentration of sunitinib (see sections 4.2 and 4.5).

Patients should be advised that depigmentation of the hair or skin may occur during treatment withsunitinib. 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 intreatment discontinuation. Cases of pyoderma gangrenosum, generally reversible after discontinuationof sunitinib, have been reported. Severe cutaneous reactions have been reported, including cases oferythema multiforme (EM), cases suggestive of Stevens-Johnson syndrome (SJS) and toxic epidermalnecrolysis (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 treatmentshould 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 lowerdose after resolution of the reaction; some of these patients also received concomitant treatment withcorticosteroids or antihistamines (see section 4.8).

Haemorrhagic events, some of which were fatal, reported in clinical studies with sunitinib and duringpos-tmarketing surveillance have included gastrointestinal, respiratory, urinary tract, and brainhaemorrhages (see section 4.8).

Routine assessment of bleeding events should include complete blood counts and physicalexamination.

Epistaxis was the most common haemorrhagic adverse reaction, having been reported forapproximately half of the patients with solid tumours who experienced haemorrhagic events. Some ofthe epistaxis events were severe, but very rarely fatal.

Events of tumour haemorrhage, sometimes associated with tumour necrosis, have been reported; someof these haemorrhagic events were fatal.

Tumour haemorrhage may occur suddenly, and in the case of pulmonary tumours, may present assevere and life-threatening haemoptysis or pulmonary haemorrhage. Cases of pulmonaryhaemorrhage, some with a fatal outcome, have been observed in clinical studies and have beenreported in postmarketing experience in patients treated with sunitinib for MRCC, GIST, and lungcancer. sunitinib is not approved for use in patients with lung cancer.

Patients receiving concomitant treatment with anticoagulants (e.g., warfarin, acenocoumarole) may beperiodically monitored by complete blood counts (platelets), coagulation factors (PT/INR), andphysical examination.

Diarrhoea, nausea/vomiting, abdominal pain, dyspepsia, and stomatitis/oral pain were the mostcommonly reported gastrointestinal adverse reactions; oesophagitis events have been also reported(see section 4.8).

Supportive care for gastrointestinal adverse reactions requiring treatment may include medicinalproducts with antiemetic, antidiarrhoeal, or antacid properties.

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation werereported in patients with intra-abdominal malignancies treated with sunitinib.

Hypertension has been reported in association with sunitinib, including severe hypertension(> 200 mmHg systolic or 110 mmHg diastolic). Patients should be screened for hypertension andcontrolled as appropriate. Temporary suspension is recommended in patients with severe hypertensionthat is not controlled with medical management. Treatment may be resumed once hypertension isappropriately controlled (see section 4.8).

Decreased absolute neutrophil counts and decreased platelet counts were reported in association withsunitinib (see section 4.8). The above events were not cumulative, were typically reversible, andgenerally did not result in treatment discontinuation. None of these events in the Phase 3 studies werefatal, but rare fatal haematological events, including haemorrhage associated with thrombocytopeniaand 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 patientsreceiving treatment with sunitinib (see section 4.8).

Cardiovascular events, including heart failure, cardiomyopathy, left ventricular ejection fractiondecline to below the lower limit of normal, myocarditis, myocardial ischaemia and myocardialinfarction, some of which were fatal, have been reported in patients treated with sunitinib. These datasuggest that sunitinib increases the risk of cardiomyopathy. No specific additional risk factors forsunitinib-induced cardiomyopathy apart from the drug-specific effect have been identified in thetreated 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 asmyocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft,symptomatic congestive heart failure (CHF), cerebrovascular accident or transient ischaemic attack, orpulmonary embolism were excluded from all sunitinib clinical studies. It is unknown whether patientswith these concomitant conditions may be at a higher risk of developing sunitinib-related leftventricular dysfunction.

Physicians are advised to weigh this risk against the potential benefits of sunitinib. Patients should becarefully monitored for clinical signs and symptoms of CHF while receiving sunitinib especiallypatients with cardiac risk factors and/or history of coronary artery disease. Baseline and periodicevaluations of LVEF should also be considered while the patient is receiving sunitinib. In patientswithout 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. Theadministration of sunitinib should be interrupted and/or the dose reduced in patients without clinicalevidence 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 patientswith relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Concomitantadministration of sunitinib with potent CYP3A4 inhibitors should be limited because of the possibleincrease in sunitinib plasma concentrations (see sections 4.2, 4.5 and 4.8).

Treatment-related venous thromboembolic events were reported in patients who received sunitinibincluding deep venous thrombosis and pulmonary embolism (see section 4.8). Cases of pulmonaryembolism with fatal outcome have been observed in postmarketing surveillance.

Cases of arterial thromboembolic events (ATE), sometimes fatal, have been reported in patientstreated with sunitinib. The most frequent events included cerebrovascular accident, transient ischaemicattack, and cerebral infarction. Risk factors associated with ATE, in addition to the underlyingmalignant disease and age  65 years, included hypertension, diabetes mellitus, and priorthromboembolic disease.

The use of vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or withouthypertension may promote the formation of aneurysms and/or artery dissections. Before initiatingsunitinib therapy, this risk should be carefully considered in patients with risk factors such ashypertension or history of aneurysm.

The diagnosis of TMA, including thrombotic thrombocytopaenic purpura (TTP) and haemolyticuraemic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, should be consideredin the occurrence of haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurologicalmanifestation, renal impairment, and fever. Sunitinib therapy should be discontinued in patients whodevelop TMA and prompt treatment is required. Reversal of the effects of TMA has been observedafter treatment discontinuation (see section 4.8).

Baseline laboratory measurement of thyroid function is recommended in all patients. Patients withpre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practiceprior to the start of sunitinib treatment. During sunitinib treatment, routine monitoring of thyroidfunction should be performed every 3 months. In addition, patients should be observed closely forsigns and symptoms of thyroid dysfunction during treatment, and patients who develop any signsand/or symptoms suggestive of thyroid dysfunction should have laboratory testing of thyroid functionperformed as clinically indicated. Patients who develop thyroid dysfunction should be treated as perstandard medical practice.

Hypothyroidism has been observed to occur early as well as late during treatment with sunitinib (seesection 4.8).

Increases in serum lipase and amylase activities were observed in patients with various solid tumourswho received sunitinib. Increases in lipase activities were transient and were generally notaccompanied by signs or symptoms of pancreatitis in subjects with various solid tumours (see section4.8).

Cases of serious pancreatic events, some with fatal outcome, have been reported. If symptoms ofpancreatitis are present, patients should have sunitinib discontinued and be provided with appropriatesupportive care.

Hepatotoxicity has been observed in patients treated with sunitinib. Cases of hepatic failure, some witha fatal outcome, were observed in < 1% of solid tumour patients treated with sunitinib. Monitor liverfunction tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) beforeinitiation of treatment, during each cycle of treatment, and as clinically indicated. If signs or symptomsof hepatic failure are present, sunitinib should be discontinued and appropriate supportive care shouldbe provided (see section 4.8).

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, inaddition 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 notbeen systematically evaluated.

Cases of proteinuria and rare cases of nephrotic syndrome have been reported. Baseline urinalysis isrecommended, and patients should be monitored for the development or worsening of proteinuria.

Discontinue sunitinib in patients with nephrotic syndrome.

If fistula formation occurs, sunitinib treatment should be interrupted. Limited information is availableon 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 patientsundergoing major surgical procedures. There is limited clinical experience regarding the timing ofreinitiation of therapy following major surgical intervention. Therefore, the decision to resumesunitinib therapy following a major surgical intervention should be based upon clinical judgment ofrecovery from surgery.

Cases of ONJ have been reported in patients treated with sunitinib . The majority of cases werereported in patients who had received prior or concomitant treatment with intravenousbisphosphonates, for which ONJ is an identified risk. Caution should therefore be exercised whensunitinib and intravenous bisphosphonates are used either simultaneously or sequentially.

Invasive dental procedures are also an identified risk factor. Prior to treatment with sunitinib , a dentalexamination and appropriate preventive dentistry should be considered. In patients who havepreviously received or are receiving intravenous bisphosphonates, invasive dental procedures shouldbe avoided if possible (see section 4.8).

If angioedema due to hypersensitivity occurs, sunitinib treatment should be interrupted and standardmedical care provided (see section 4.8).

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

Patients with seizures and signs/symptoms consistent with posterior reversible leukoencephalopathysyndrome (RPLS), such as hypertension, headache, decreased alertness, altered mental functioningand visual loss, including cortical blindness, should be controlled with medical management includingcontrol 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).

Cases of TLS, some fatal, have been rarely observed in clinical studies and have been reported inpostmarketing surveillance in patients treated with sunitinib. Risk factors for TLS include high tumourburden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension, and acidic urine.

These patients should be monitored closely and treated as clinically indicated, and prophylactichydration should be considered.

Serious infections, with or without neutropenia, including some with a fatal outcome, have beenreported. Uncommon cases of necrotising fasciitis, including of the perineum, sometimes fatal, havebeen reported (see section 4.8).

Sunitinib therapy should be discontinued in patients who develop necrotising fasciitis, and appropriatetreatment should be promptly initiated.

Decreases in blood glucose, in some cases clinically symptomatic and requiring hospitalisation due toloss of consciousness, have been reported during sunitinib treatment. In case of symptomatichypoglycaemia, sunitinib should be temporarily interrupted. Blood glucose levels in diabetic patientsshould be checked regularly in order to assess if antidiabetic medicinal product’s doses needs to beadjusted to minimise the risk of hypoglycaemia (see section 4.8).

Hyperammonaemic encephalopathy

Hyperammonaemic encephalopathy has been observed with sunitinib (see section 4.8). In patients whodevelop unexplained lethargy or changes in mental status, ammonia level should be measured andappropriate clinical management should be initiated.

This medicinal product contains less than 1 mmol (23 mg) sodium (croscarmellose sodium) per onecapsule, that is to say essentially “sodium-free“.

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 + primarymetabolite] maximum concentration (Cmax) and area under the curve (AUC0-) values of 49% and51%, 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 alternateconcomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered.

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 (seesection 4.2).

Effect of Breast Cancer Resistance Protein (BCRP) inhibitors

Limited clinical data are available on the interaction between sunitinib and BCRP inhibitors and thepossibility of an interaction between sunitinib and other BCRP inhibitors cannot be excluded (seesection 5.2).

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]

Cmax and AUC0- 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 medicinalproduct, with no or minimal potential to induce CYP3A4 should be considered. If this is not possible,the dose of sunitinib may need to be increased in 12.5 mg increments (up to 87.5 mg per day for GISTand MRCC or 62.5 mg per day for pNET), based on careful monitoring of tolerability (seesection 4.2).

Women of childbearing/Contraception

Women of childbearing potential should be advised to use effective contraception and avoid becomingpregnant while receiving treatment with sunitinib.

There are no studies in pregnant women using sunitinib. Studies in animals have shown reproductivetoxicity including foetal malformations (see section 5.3). sunitinib should not be used duringpregnancy or in women not using effective contraception, unless the potential benefit justifies thepotential risk to the foetus. If sunitinib is used during pregnancy or if the patient becomes pregnantwhile on treatment with sunitinib, the patient should be apprised of the potential hazard to the foetus.

Sunitinib and/or its metabolites are excreted in rat milk. It is not known whether sunitinib or itsprimary active metabolite is excreted in human milk. Because active substances are commonlyexcreted in human milk and because of the potential for serious adverse reactions in breast-feedinginfants, women should not breast-feed while taking sunitinib.

Based on nonclinical findings, male and female fertility may be compromised by treatment withsunitinib (see section 5.3).

Sunitinib has minor influence on the ability to drive and use machines. Patients should be advised thatthey may experience dizziness during treatment with sunitinib.

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 reactionsof any grade (experienced by patients in RCC, GIST, and pNET registrational trials) includeddecreased appetite, taste disturbance, hypertension, fatigue, gastrointestinal disorders (i.e. diarrhoea,nausea, stomatitis, dyspepsia, and vomiting), skin discolouration, and palmar-plantarerythrodysaesthesia 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 consideredpossibly related to sunitinib included multi-system organ failure, disseminated intravascularcoagulation, peritoneal haemorrhage, adrenal insufficiency, pneumothorax, shock, and sudden death.

Adverse reactions that were reported in GIST, MRCC, and pNET patients in a pooled dataset of7,115 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 eachfrequency 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 (1/1,000to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated fromthe available data).

Table 1. Adverse reactions reported in clinical studies

System organ class Very common Common Uncommon Rare Not known

Infections and Viral infections* Necrotisinginfestations Respiratory fasciitis*infectionsb,* Bacterial infectionsg

Abscessc,*

Fungal infectionsd

Skin infectionse

Sepsisf,*

Blood and Neutropoenia Lymphopoenia Pancytopenia Thromboticlymphatic system Thrombocytopoenia microangiopathyh,*disorders Anaemia

Leukopoenia

Immune system Hypersensitivity Angioedemadisorders

Endocrine Hypothyroidism Hyperthyroidism Thyroiditisdisorders

Metabolism and Decreased appetite1 Dehydration Tumour lysisnutrition disorders Hypoglycaemia syndrome*

Psychiatric Insomnia Depressiondisorders

System organ class Very common Common Uncommon Rare Not known

Nervous system Dizziness Neuropathy peripheral Cerebral Posterior reversible Hyperammondisorders Headache Paraesthesia haemorrhage* encephalopathy aemic

Taste disturbancej Hypoaesthesia Cerebrovascular syndrome* encephalopat

Hyperaesthesia accident* hy

Transient ischaemicattack

Eye disorders Periorbital oedema

Eyelid oedema

Lacrimation increased

Cardiac disorders Myocardial Cardiac failure Left ventricularischemiak,* congestive failure*

Ejection fraction Myocardial Torsade de pointesdecreased1 infarctionm,*

Cardiac failure*

Cardiomyopathy*

Pericardial effusion

Electrocardiogram

QT prolonged

Vascular disorders Hypertension Deep vein thrombosis Tumour Aneurysms

Hot flush haemorrhage* and artery

Flushing dissections*

Respiratory, Dyspnoea Pulmonary embolism* Pulmonarythoracic and Epistaxis Pleural effusion* haemorrhage*mediastinal Cough Haemoptysis Respiratory failure*disorders Dyspnoea exertional

Oropharyngeal painn

Nasal congestion

Nasal dryness

Gastrointestinal Stomatitiso Gastro-oesophageal Gastrointestinaldisorders Abdominal painp reflux disease perforationq,*

Vomiting Dysphagia Pancreatitis

Diarrhoea Gastrointestinal Anal fistula

Dyspepsia haemorrhage* Colitisr

Nausea Oesophagitis*

Constipation Abdominal distension

Abdominal discomfort

Rectal haemorrhage

Gingival bleeding

Mouth ulceration

Proctalgia

Cheilitis

Haemorrhoids

Glossodynia

Oral pain

Dry mouth

Flatulence

Oral discomfort

Eructation

Hepatobiliary Hepatic failure* Hepatitisdisorders Cholecystitiss,*

Hepatic functionabnormal

Skin and Skin discolourationt Skin exfoliation Erythemasubcutaneous Palmar-plantar Skin reactionv multiforme*tissue disorders erythrodysaesthesia Eczema Stevens-Johnsonsyndrome Blister syndrome*

Rashu Erythema Pyoderma

Hair colour changes Alopecia gangrenosum

Dry skin Acne Toxic epidermal

Pruritus necrolysis*

Skinhyperpigmentation

Skin lesion

Hyperkeratosis

Dermatitis

Nail disorderw

System organ class Very common Common Uncommon Rare Not known

Musculoskeletal Pain in extremity Musculoskeletal pain Osteonecrosis of the Rhabdomyolysis*and connective Arthralgia Muscle spasms jaw Myopathytissue disorders Back pain Myalgia Fistula*

Muscular weakness

Renal and urinary Renal failure* Haemorrhage Nephrotic syndromedisorders Renal failure acute* urinary tract

Chromaturia

Proteinuria

General disorders Mucosal inflammation Chest pain Impaired healingand administration Fatiguex Painsite conditions Oedemay Influenza like illness

Pyrexia Chills

Investigations Weight decreased Blood creatine

White blood cell count phosphokinasedecreased increased

Lipase increased Blood thyroid

Platelet count stimulatingdecreased hormone increased

Haemoglobindecreased

Amylase increasedz

Aspartateaminotransferaseincreased

Alanineaminotransferaseincreased

Blood creatinineincreased

Blood pressureincreased

Blood uric acidincreased

* Including fatal events.

The following terms have been combined:a Nasopharyngitis and oral herpes.b Bronchitis, lower respiratory tract infection, pneumonia, and respiratory tract infection.c Abscess, abscess limb, anal abscess, gingival abscess, liver abscess, pancreatic abscess, perineal abscess, perirectalabscess, rectal abscess, subcutaneous abscess, and tooth abscess.d Oesophageal candidiasis and oral candidiasis.e Cellulitis and skin infection.f Sepsis and sepsis shock.g Abdominal abscess, abdominal sepsis, diverticulitis, and osteomyelitis.h Thrombotic microangiopathy, thrombotic thrombocytopenic purpura, and haemolytic uraemic syndrome.i Decreased appetite and anorexiaj Dysgeusia, ageusia, and taste disturbance.k Acute coronary syndrome, angina pectoris, angina unstable, coronary artery occlusion, and myocardial ischaemia.l Ejection fraction decreased/abnormal.m Acute myocardial infarction, myocardial infarction, and silent myocardial infarction.n Oropharyngeal and pharyngolaryngeal pain.o Stomatitis and aphtous stomatitis.p Abdominal pain, abdominal pain lower, and abdominal pain upper.q Gastrointestinal perforation and intestinal perforation.r Colitis and colitis ischaemic.s Cholecystitis and acalculous cholecystitis.t Yellow skin, skin discolouration, and pigmentation disorder.u Dermatitis psoriasiform, exfoliative rash, rash, rash erythematous, rash follicular, rash generalised, rash macular, rashmaculo-papular, rash papular, and rash pruritic.v Skin reaction and skin disorder.w Nail disorder and discolouration.x Fatigue and asthenia.y Face oedema, oedema, and oedema peripheral.z Amylase and amylase increased.

Cases of serious infection (with or without neutropenia), including cases with fatal outcome, havebeen reported. Cases of necrotising fasciitis, including of the perineum, sometimes fatal, have beenreported (see also section 4.4).

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 MRCCstudy, 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% ofpatients 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% hadbleeding events vs 11% of patients receiving interferon- (IFN-α). Seventeen (4.5%) patients onsunitinib versus 5 (1.7%) patients on IFN-α experienced Grade 3 or greater bleeding events. Ofpatients receiving sunitinib for cytokine-refractory MRCC, 26% experienced bleeding. Bleedingevents, excluding epistaxis, were reported in 21.7% of patients receiving sunitinib in the Phase 3pNET study compared to 9.85% of patients receiving placebo (see section 4.4)

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

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

Hypothyroidism was reported as an adverse reaction in 7 patients (4%) receiving sunitinib across the2 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 evidenceof treatment-emergent hypothyroidism. Acquired hypothyroidism was noted in 6.2% of GIST patientson sunitinib versus 1% on placebo. In the Phase 3 pNET study hypothyroidism was reported in6 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; sunitinib isnot approved for use in breast cancer. In 1 study, hypothyroidism was reported in 15 (13.6%) patientson 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 nosunitinib-treated patients and 1 (1.0%) patient receiving standard of care. In the other studyhypothyroidism was reported in a total of 31 (13%) patients on sunitinib and 2 (0.8%) patients oncapecitabine. Blood TSH increase was reported in 12 (5.0%) patients on sunitinib and no patients oncapecitabine. Hyperthyroidism was reported in 4 (1.7%) patients on sunitinib and no patients oncapecitabine. Blood TSH decrease was reported in 3 (1.3%) patients on sunitinib and no patients oncapecitabine. T4 increase was reported in 2 (0.8%) patients on sunitinib and 1 (0.4%) patient oncapecitabine. T3 increase was reported in 1 (0.8%) patient on sunitinib and no patients oncapecitabine. All thyroid-related events reported were Grade 1-2 (see section 4.4).

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 notconsidered related to study treatment (see section 4.4).

In clinical studies of sunitinib and from post-marketing surveillance, there have been few reports(< 1%), some fatal, of subjects presenting with seizures and radiological evidence of RPLS. Seizureshave been observed in patients with or without radiological evidence of brain metastases (see section4.4).

In clinicalstudies, decreases in left ventricular ejection fraction (LVEF) of  20% and below the lowerlimit of normal were reported in approximately 2% of sunitinib-treated GIST patients, 4% ofcytokine-refractory MRCC patients, and 2% of placebo-treated GIST patients. These LVEF declinesdo not appear to have been progressive and often improved as treatment continued. In thetreatment-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 werediagnosed with CHF.

In GIST patients ‘cardiac failure’, ‘cardiac failure congestive’, or ‘left ventricular failure’ werereported in 1.2% of patients treated with sunitinib and 1% of patients treated with placebo. In thepivotal Phase 3 GIST study (N = 312), treatment-related fatal cardiac reactions were reported in 1% ofpatients on each arm of the study (i.e. sunitinib and placebo arms). In a Phase 2 study incytokine-refractory MRCC patients, 0.9% of patients experienced treatment-related fatal myocardialinfarction 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 pNETstudy, 1 (1%) patient who received sunitinib had treatment-related fatal cardiac failure.

Hypertension was a very common adverse reaction reported in clinicalstudies. The dose of sunitinibwas reduced or its administration temporarily suspended in approximately 2.7% of the patients whoexperienced hypertension. Sunitinib was not permanently discontinued in any of these patients. Severehypertension (> 200 mmHg systolic or 110 mmHg diastolic) was reported in 4.7% of patients withsolid tumours. Hypertension was reported in approximately 33.9% of patients receiving sunitinib fortreatment-naïve MRCC compared to 3.6% of patients receiving IFN-. Severe hypertension wasreported in 12% of treatment-naïve patients on sunitinib and < 1% of patients on IFN-. Hypertensionwas reported in 26.5% of patients receiving sunitinib in a Phase 3 pNET study, compared to 4.9% ofpatients receiving placebo. Severe hypertension was reported in 10% of pNET patients on sunitiniband 3% of patients on placebo.

Treatment-related venous thromboembolic events were reported in approximately 1.0% of patientswith solid tumours who received sunitinib on clinicalstudies, including GIST and RCC.

Seven patients (3%) on sunitinib and none on placebo in a Phase 3 GIST study experienced venousthromboembolic events; 5 of the 7 were Grade 3 deep venous thrombosis (DVT) and 2 were Grade 1or 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 ofthese patients had pulmonary embolisms; 1 was Grade 2 and 8 were Grade 4. Eight of these patientshad DVT; 1 with Grade 1, 2 with Grade 2, 4 with Grade 3, and 1 with Grade 4. One patient withpulmonary embolism in the cytokine-refractory MRCC study experienced dose interruption.

In treatment-naïve MRCC patients receiving IFN-, 6 (2%) venous thromboembolic events werereported; 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. Caseswith fatal outcome have been observed in the postmarketing surveillance.

Cases of pulmonary embolism were observed in approximately 3.1% of patients with GIST and inapproximately 1.2% of patients with MRCC, who received sunitinib in Phase 3 studies. No pulmonaryembolism was reported for patients with pNET who received sunitinib in the Phase 3 study. Rare caseswith fatal outcome have been observed in the post-marketing surveillance.

Patients who presented with pulmonary embolism within the previous 12 months were excluded fromsunitinib 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 withpNET.

Approximately 22.2% of patients with solid tumours, including GIST and MRCC, who receivedsunitinib in clinical studies experienced pulmonary events.

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 Phase3 study.

Hepatic dysfunction has been reported and may include Liver Function Test abnormalities, hepatitis,or liver failure (see section 4.4).

Cases of pyoderma gangrenosum, generally reversible after discontinuation of sunitinib, have beenreported (see also section 4.4).

Cases of myopathy and/or rhabdomyolysis, some with acute renal failure, have been reported. Patientswith signs or symptoms of muscle toxicity should be managed as per standard medical practice (seesection 4.4).

Cases of fistula formation, sometimes associated with tumour necrosis and regression, in some caseswith fatal outcomes, have been reported (see section 4.4).

Cases of ONJ have been reported in patients treated with sunitinib, most of which occurred in patientswho had identified risk factors for ONJ, in particular, exposure to intravenous bisphosphonates and/ora history of dental disease requiring invasive dental procedures (see also section 4.4).

Data from non clinical (in vitro and in vivo) studies, at doses higher than the recommended humandose, indicated that sunitinib has the potential to inhibit the cardiac action potential repolarisationprocess (e.g., prolongation of QT interval).

Increases in the QTc interval to over 500 msec were reported in 0.5%, and changes from baseline inexcess of 60 msec were reported in 1.1% of the 450 solid tumour patients; both of these parameters arerecognised 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 advancedmalignancies. 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] upperlimit > 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. Nopatients had a QTc interval > 500 msec. Although an effect on QTcF interval was observed on Day 3at 24 hours postdose (i.e., at therapeutic plasma concentration expected after the recommended startingdose of 50 mg) with the within-day baseline correction method, the clinical significance of this findingis unclear.

Using comprehensive serial ECG assessments at times corresponding to either therapeutic or greaterthan therapeutic exposures, none of the patients in the evaluable or intent-to-treat (ITT) populationswere observed to develop QTc interval prolongation considered as “severe” (i.e. equal to or greaterthan Grade 3 by Common Terminology Criteria for Adverse Events [CTCAE] version 3.0).

At therapeutic plasma concentrations, the maximum QTcF interval (Frederica’s correction) meanchange from baseline was 9 msec (90% CI: 15.1 msec). At approximately twice therapeuticconcentrations, 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 greaterthan Grade 2 (CTCAE version 3.0) (see section 4.4).

The long-term safety of sunitinib in patients with MRCC was analysed across 9 completed clinicalstudies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settingsin 5,739 patients, of whom 807 (14%) were treated for ≥ 2 years up to 6 years. In the 807 patients whoreceived long-term sunitinib treatment, most treatment-related adverse events (TRAEs) occurredinitially in the first 6 months-1 year and then were stable or decreased in frequency over time, with theexception of hypothyroidism, which gradually increased over time, with new cases occurring over the6 year period. Prolonged treatment with sunitinib did not appear to be associated with new types of

TRAEs.

The safety profile of sunitinib has been derived from a Phase 1 dose-escalation study, a Phase 2open-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 of30 paediatric patients (aged 3 years to 17 years) and 5 young adult patients (aged 18 to 21 years), withrefractory solid tumours, the majority of whom had a primary diagnosis of brain tumour. All studyparticipants experienced adverse drug reactions; most of these were severe (toxicity grade ≥ 3) andincluded 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 behigher in paediatric patients with previous exposure to cardiac irradiation or anthracycline comparedto those paediatric patients without previous exposure. In these paediatric patients without previousexposure to anthracyclines or cardiac irradiation, the maximum tolerated dose (MTD) has beenidentified (see section 5.1).

A phase 2 open-label study was conducted in 29 patients comprised of 27 paediatric patients (aged3 years to 16 years) and 2 young adult patients (aged 18 years to 19 years) withrecurrent/progressive/refractory high grade glioma (HGG) or ependymoma. There were no Grade 5adverse reactions in either group. The most common (≥10%) treatment-related adverse events wereneutrophil 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) withadvanced unresectable GIST. The most frequent adverse drug reactions were diarrhoea, nausea, WBCcount decreased, neutropenia, and headache in 3 (50.0%) patients each, primarily Grade 1 or 2 inseverity. 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 4neutropenia in 1 patient). There were no serious adverse events (SAEs) or Grade 5 adverse drugreactions reported in this study. In both the clinical study and the publications, the safety profile wasconsistent with the known safety profile in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for overdose with Sunitinib and treatment of overdose should consist ofgeneral supportive measures. If indicated, elimination of unabsorbed active substance may be achievedby emesis or gastric lavage. Cases of overdose have been reported; some cases were associated withadverse reactions consistent with the known safety profile of sunitinib.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors; ATC code: L01EX01

Sunitinib inhibits multiple RTKs that are implicated in tumour growth, neoangiogenesis, andmetastatic progression of cancer. Sunitinib was identified as an inhibitor of platelet-derived growthfactor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1,

VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colonystimulating 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 andcellular assays.

The clinical safety and efficacy of sunitinib has been studied in the treatment of patients with GISTwho were resistant to imatinib (i.e., those who experienced disease progression during or followingtreatment with imatinib) or intolerant to imatinib (i.e., those who experienced significant toxicityduring 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, onprogression-free survival (PFS) and objective response rates (ORR) for treatment-naïve andcytokine-refractory MRCC respectively, and on PFS for pNET.

An initial open-label, dose-escalation study was conducted in patients with GIST after failure ofimatinib (median maximum daily dose 800 mg) due to resistance or intolerance. Ninety-seven patientswere enrolled at various doses and schedules; 55 patients received 50 mg at the recommendedtreatment 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 patientswith GIST who were intolerant to, or had experienced disease progression during or followingtreatment with imatinib (median maximum daily dose 800 mg). In this study, 312 patients wererandomised (2:1) to receive either 50 mg sunitinib or placebo, orally once daily on Schedule 4/2 untildisease progression or withdrawal from the study for another reason (207 patients received sunitiniband 105 patients received placebo). The primary efficacy endpoint of the study was TTP, defined asthe time from randomisation to first documentation of objective tumour progression. At the time of theprespecified interim analysis, the median TTP on sunitinib was 28.9 weeks (95% CI: 21.3, 34.1) asassessed by the investigator and 27.3 weeks (95% CI: 16.0, 32.1) as assessed by the independentreview 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 bythe 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 inthe 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 wereoffered open-label sunitinib treatment.

A total of 255 patients received sunitinib in the open-label treatment phase of the study, including99 patients who were initially treated with placebo.

The analyses of primary and secondary endpoints in the open-label phase of the study reaffirmed theresults obtained at the time of the interim analysis, as shown in Table 2:

Table 2. GIST summary of efficacy endpoints (ITT population)

Double-blind treatmenta

Median (95% CI) Hazard ratio Placebo

Endpoint cross-overgroup

Sunitinib Placebo (95% CI) p-value treatmentb

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)c

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 (%)d

Interim 6.8 (3.7, 11.1) 0 (-) NA 0.006 -

Final 6.6 (3.8, 10.5) 0 (-) NA 0.004 10.1 (5.0, 17.8)

OS (weeks)e

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.a Results of double-blind treatment are from the ITT population and using central radiologist measurement, asappropriate.b Efficacy results for the 99 subjects who crossed over from placebo to sunitinib after unblinding. Baselinewas 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 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 includedthose patients randomised to placebo who subsequently received open-label sunitinib treatment.

A phase 3, randomised, multi-centre, international study evaluating the efficacy and safety of sunitinibcompared with IFN- in treatment-naïve MRCC patients was conducted. Seven hundred and fiftypatients were randomised 1:1 to the treatment arms; they received treatment with either sunitinib inrepeated 6-week cycles, consisting of 4 weeks of 50 mg daily oral administration followed by 2 weeksof rest (Schedule 4/2), or IFN-α, administered as a subcutaneous injection of 3 million units (MU) thefirst week, 6 MU the second week, and 9 MU the third week and thereafter, on 3 nonconsecutive dayseach week.

The median duration of treatment was 11.1 months (range: 0.4-46.1) for sunitinib treatment and4.1 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. Dosereductions occurred in 194 patients (52%) on sunitinib and 98 patients (27%) on IFN-α. Patients weretreated 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 with22.0 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 theprimary endpoint had been met. At the final analysis, the ORR as determined by the investigator’sassessment 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 was114.6 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 unstratifiedlog-rank).

The overall PFS and OS, observed in the ITT population, as determined by the core radiologylaboratory assessment, are summarised in Table 3.

Table 3. Treatment-naïve mRCC summary of efficacy endpoints (ITT population)

Sunitinib IFN-

Summary of progression-free survival (N = 375) (N = 375)

Subject did not progress or die [n (%)] 161 (42.9) 176 (46.9)

Subject observed to have progressed or died 214 (57.1) 199 (53.1)[n (%)]

PFS (weeks)

Quartile (95% CI)25% 22.7 (18.0, 34.0) 10.0 (7.3, 10.3)50% 48.3 (46.4, 58.3) 22.1 (17.1, 24.0)75% 84.3 (72.9, 95.1) 58.1 (45.6, 82.1)

Unstratified analysis

Hazard ratio (sunitinib versus IFN-) 0.526895% CI for hazard ratio (0.4316, 0.6430)p-valuea < 0.0001

Sunitinib IFN-

Summary of progression-free survival (N = 375) (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)25% 56.6 (48.7, 68.4) 41.7 (32.6, 51.6)50% 114.6 (100.1, 142.9) 94.9 (77.7, 117.0)75% NA (NA, NA) NA (NA, NA)

Unstratified analysis

Hazard ratio (sunitinib versus IFN-) 0.820995% CI for hazard ratio (0.6730, 1.0013)p-valuea 0.0510

Abbreviations: CI=confidence interval; INF-α=interferon-alfa; ITT=intent-to-treat; N=number of patients; NA=notapplicable; OS=overall survival; PFS=progression-free survival.a From a 2-sided log-rank test.

A phase 2 study of sunitinib was conducted in patients who were refractory to prior cytokine therapywith 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 of6 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 was37.7 weeks (95% CI: 24.0, 46.4).

A confirmatory, open-label, single-arm, multi-centre study evaluating the efficacy and safety ofsunitinib was conducted in patients with MRCC who were refractory to prior cytokine therapy. Onehundred 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 ofresponse (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 beenreached.

A supportive phase 2, open-label, multi-centre study evaluated the efficacy and safety of single-agentsunitinib 50 mg daily on Schedule 4/2 in patients with unresectable pNET. In a pancreatic islet celltumour 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 ofsingle-agent sunitinib was conducted in patients with unresectable pNET.

Patients were required to have documented progression, based on RECIST, within the prior 12 monthsand were randomised (1:1) to receive either 37.5 mg sunitinib once daily without a scheduled restperiod (N = 86) or placebo (N = 85).

The primary objective was to compare PFS in patients receiving sunitinib versus patients receivingplacebo. Other endpoints included OS, ORR, PROs, and safety.

Demographics were comparable between the sunitinib and placebo groups. Additionally, 49% ofsunitinib patients had nonfunctioning tumours versus 52% of placebo patients and 92% of patients inboth 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 placebopatients. In addition, 24% of sunitinib patients had received somatostatin analogues compared with22% of placebo patients.

A clinically significant advantage in investigator-assessed PFS for sunitinib over placebo wasobserved. The median PFS was 11.4 months for the sunitinib arm compared to 5.5 months for theplacebo arm [hazard ratio: 0.418 (95% CI: 0.263, 0.662), p-value=0.0001]; similar results wereobserved when derived tumour response assessments based upon application of RECIST toinvestigator 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 armand 24 in the placebo arm had received no prior systemic treatment; among these patients, the hazardratio for PFS was 0.365 (95% CI: 0.156, 0.857), p=0.0156. Similarly, among 57 patients in thesunitinib arm (including 28 with 1 prior systemic therapy and 29 with 2 or more prior systemictherapies) and 61 patients in the placebo arm (including 25 with 1 prior systemic therapy and 36 with 2or 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-reportedtumour measurements and where all subjects censored for reasons other than study termination weretreated as PFS events. This analysis provided a conservative estimate of the treatment effect ofsunitinib 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 therecommendation of an independent drug monitoring committee and the primary endpoint was basedupon 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 Placebo Hazard p-value

Sunitinib(N = 86) (N = 85) Ratio(95% CI)

Progression-free survival [median, 11.4 5.5 0.418 0.0001amonths (95% CI)] by Investigator (7.4, 19.8) (3.6, 7.4) (0.263, 0.662)

Assessment

Progression-free survival 12.6 5.4 0.401 0.000066a[median, months (95% CI)] (7.4, 16.9) (3.5, 6.0) (0.252, 0.640)by derived tumour responseassessment based uponapplication of RECIST toinvestigator tumourassessments

Progression-free survival 12.6 5.8 0.315 0.000015a[median, months (95% CI)] (11.1, 20.6) (3.8, 7.2) (0.181, 0.546)by blinded independentcentral review of tumourassessments

Overall survival [5 years 38.6 29.1 0.730 0.0940afollow-up] (25.6, 56.4) (16.4, 36.8) (0.504,[median, months (95% CI)] 1.057)

Objective response rate 9.3 0 NA 0.0066b[%, (95% CI)] (3.2, 15.4)

Abbreviations: CI=confidence interval; N=number of patients; NA=not applicable; pNET=pancreaticneuroendocrine tumours; RECIST=response evaluation criteria in solid tumours.a 2-sided unstratified log-rank testb Fisher’s Exact test

Figure 1. Kaplan-Meier plot of PFS in the pNET Phase 3 study100 Sunitinib (N=86)

SUTENT (N=86)

Median 11.4 months

Placebo (N=85)

Median 5.5 months

Hazard Ratio = 0.4210 95% CI (0.26 - 0.66)p = 0.00010 3 6 9 12 15 18 21

Time (Months)

Number of subjects at risk

SUTENT 86 52 34 20 15 4 2

Sunitinib

Placebo 85 42 20 9 2 2 2

Placebo

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

OS data were not mature at the time of the study closure [20.6 months (95% CI: 20.6, NR) for thesunitinib arm compared to NR (95% CI: 15.5, NR) for the placebo arm, hazard ratio:

Progression Free Survival Probability (%)0.409 (95% CI: 0.187, 0.894), p-value=0.0204]. There were 9 deaths in the sunitinib arm and21 deaths in the placebo arm.

Upon disease progression, patients were unblinded and placebo patients were offered access toopen-label sunitinib in a separate extension study. As a result of the early study closure, remainingpatients were unblinded and offered access to open-label sunitinib in an extension study. A total of 59out of 85 patients (69.4%) from the placebo arm crossed over to open-label sunitinib following diseaseprogression or unblinding at study closure. OS observed after 5 years of follow-up in the extensionstudy 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 the5 functioning domains (physical, role, cognitive, emotional, and social) were maintained for patientson 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 safetyof 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-linecohort) 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).

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 of30 paediatric patients (aged 3 years to 17 years) and 5 young adult patients (aged: 18 years to21 years), with refractory solid tumours, the majority of whom were enrolled with a primary diagnosisof brain tumour. Dose-limiting cardiotoxicity was observed in the first part of the study which wastherefore 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 withprior anticancer therapy but without risk factors for cardiac toxicity, sunitinib was generally tolerableand clinically manageable at the dose of 15 mg/m2 daily (MTD) on Schedule 4/2. None of the subjectsachieved complete response or partial response. Stable disease was observed in 6 patients (17%). Onepatient with GIST was enrolled at the 15 mg/m2 dose level with no evidence of benefit. The observedadverse 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 (aged3 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 OSwas 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 neutrophilcount decreased (6 patients [20.7%]) and haemorrhage intracranial (3 patients [10.3%]) (seesection 4.8).

Evidence from a phase 1/2 study of oral sunitinib conducted in 6 paediatric patients with GIST aged13 years to 16 years who received sunitinib on Schedule 4/2, at doses ranging between 15 mg/m2 dailyand 30 mg/m2 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, eitherafter 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 progressionwas observed in 3 out of 6 patients each (1 patient received neo adjuvant and 1 patient receivedadjuvant imatinib, respectively). In the same study, 4 out of 6 patients (66.7%) experienced Grade 3-4treatment-related adverse events (Grade 3 hypophosphataemia, neutropenia, and thrombocytopenia in1 patient each and a Grade 4 neutropenia in 1 patient). In addition, the publications reported thefollowing Grade 3 adverse drug reactions experienced by 5 patients: fatigue (2), gastrointestinaladverse drug reactions (including diarrhoea) (2), haematologic adverse drug reactions (includinganaemia) (2), cholecystitis (1), hyperthyroidism (1), and mucositis (1).

A population pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analysis wasconducted with the scope to extrapolate the PK and key safety and efficacy endpoints of sunitinib inpaediatric patients with GIST (aged: 6 years to 17 years). This analysis was based on data collectedfrom adults with GIST or solid tumours and from paediatric patients with solid tumours. Based on themodelling analyses, the younger age and lower body size did not appear to affect negatively the safetyand efficacy responses to sunitinib plasma exposures. Sunitinib benefit/risk did not appear to benegatively 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 sunitinib in all subsets of thepaediatric population for the treatment of kidney or renal pelvis carcinoma (excludingnephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullarycarcinoma, and rhabdoid tumour of the kidney) (see section 4.2).

The EMA has waived the obligation to submit the results of the studies with sunitinib in all subsets ofthe paediatric population for the treatment of gastroenteropancreatic neuroendocrine tumours(excluding neuroblastoma, neuroganglioblastoma, and phaeochromocytoma) (see section 4.2).

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

Cmax increase proportionally with dose. With repeated daily administration, sunitinib accumulates 3- to4-fold and its primary active metabolite accumulates 7- to 10-fold. Steady-state concentrations ofsunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combinedplasma concentrations of sunitinib and its active metabolite are 62.9-101 ng/ml, which are targetconcentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro and result intumour stasis/growth reduction in vivo. The primary active metabolite comprises 23% to 37% of thetotal exposure. No significant changes in the PK of sunitinib or the primary active metabolite areobserved with repeated daily administration or with repeated cycles in the dosing schedules tested.

After oral administration of sunitinib, Cmax are generally observed from 6 to 12 hours time tomaximum concentration (tmax) postadministration.

Food has no effect on the bioavailability of sunitinib.

In vitro, binding of sunitinib and its primary active metabolite to human plasma protein was 95% and90%, respectively, with no apparent concentration dependence. The apparent volume of distribution(Vd) 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) indicatedthat sunitinib and its primary active metabolite are unlikely to induce metabolism, to any clinicallyrelevant extent, of other actives substances that may be metabolised by these enzymes.

Sunitinib is metabolised primarily by CYP3A4, the CYP isoform which produces its primary activemetabolite, desethyl sunitinib, which is then further metabolised by the same isoenzyme.

Co-administration of sunitinib with potent CYP3A4 inducers or inhibitors should be avoided becausethe plasma levels of sunitinib may be altered (see sections 4.4 and 4.5).

Excretion is primarily via faeces (61%), with renal elimination of unchanged active substance andmetabolites accounting for 16% of the administered dose. Sunitinib and its primary active metabolitewere the major compounds identified in plasma, urine, and faeces, representing 91.5%, 86.4%, and73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine andfaeces, but generally were not found in plasma. Total oral clearance (CL/F) was 34-62 L/h. Followingoral administration in healthy volunteers, the elimination half-lives of sunitinib and its primary activedesethyl 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 theco-administration of gefitinib, a BCRP inhibitor, did not result in a clinically relevant effect on the

Cmax and AUC for sunitinib or total drug (sunitinib + metabolite) (see section 4.5). This study was amulti-centre, open-label, Phase 1/2 study examining the safety/tolerability, the maximum tolerateddose, 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 asecondary study objective. Changes in sunitinib PK parameters were of no clinical significance anddid not indicate any drug-drug interactions; however, considering the relatively low number ofsubjects (i.e. N=7+4) and the moderate-large interpatient variability in the pharmacokineticparameters, caution needs to be taken when interpreting the PK drug-drug interaction findings fromthis study.

Sunitinib and its primary metabolite are mainly metabolised by the liver. Systemic exposures after asingle 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. Sunitinib was not studied insubjects 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 ofnormal) or > 5.0 x ULN if due to liver metastasis.

Population PK analyses indicated that sunitinib apparent clearance (CL/F) was not affected bycreatinine clearance (CLcr) within the range evaluated (42-347 ml/min). Systemic exposures after asingle 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 itsprimary metabolite were not eliminated through haemodialysis in subjects with ESRD, the totalsystemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared tosubjects with normal renal function.

Population PK analyses of demographic data indicate that no starting dose adjustments are necessaryfor weight or Eastern Cooperative Oncology Group (ECOG) performance status.

Available data indicate that females could have about 30% lower apparent clearance (CL/F) ofsunitinib than males: this difference, however, does not necessitate starting dose adjustments.

Experience on the use of sunitinib in paediatric patients is limited (see section 4.2). Population PKanalyses of a pooled dataset from adult patients with GIST and solid tumours and paediatric patientswith solid tumours were completed. Stepwise covariate modelling analyses were performed toevaluate the effect of age and body size (total body weight or body surface area) as well as othercovariates on important PK parameters for sunitinib and its active metabolite. Among age andbodysize 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, bodysurface area was a significant covariate on the apparent clearance of the active metabolite (the lowerthe body surface area, the lower the apparent clearance).

Furthermore, based on an integrated population PK analysis of pooled data from the 3 paediatricstudies (2 paediatric solid tumour studies and 1 paediatric GIST study; ages: 6 years to 11 years and12 years to 17 years), baseline body surface area (BSA) was a significant covariate on apparentclearance of sunitinib and its active metabolite. Based on this analysis, a dose of approximately20 mg/m2 daily in paediatric patients, with BSA values between 1.10 and 1.87 m2, is expected toprovide plasma exposures to sunitinib and its active metabolite comparable (between 75 and 125% ofthe AUC) to those in adults with GIST administered sunitinib 50 mg daily on Schedule 4/2 (AUC1233 ng.hr/mL). In paediatric studies, the starting dose of sunitinib was 15 mg/m2 (based on the MTDidentified in the Phase 1 dose-escalation study, see section 5.1), which in paediatric patients with GISTincreased to 22.5 mg/m2 and subsequently to 30 mg/m2 (not to exceed the total dose of 50 mg/day)based on individual patient safety/tolerability. Furthermore, according to the published literatures inpaediatric patients with GIST, the calculated starting dose ranged from 16.6 mg/m2 to 36 mg/m2,increased to doses as high as 40.4 mg/m2 (not exceeding the total dose of 50 mg/day).

In rat and monkey repeated-dose toxicity studies up to 9-months duration, the primary target organeffects 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 inrats); 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 plasmaexposure levels. Additional effects observed in other studies included: QTc interval prolongation,

LVEF reduction and testicular tubular atrophy, increased mesangial cells in kidney, haemorrhage ingastrointestinal tract and oral mucosa, and hypertrophy of anterior pituitary cells. Changes in theuterus (endometrial atrophy) and bone growth plate (physeal thickening or dysplasia of cartilage) arethought to be related to the pharmacological action of sunitinib. Most of these findings were reversibleafter 2 to 6 weeks without treatment.

The genotoxic potential of sunitinib was assessed in vitro and in vivo. Sunitinib was not mutagenic inbacteria using metabolic activation provided by rat liver. Sunitinib did not induce structuralchromosome aberrations in human peripheral blood lymphocyte cells in vitro. Polyploidy (numericalchromosome aberrations) was observed in human peripheral blood lymphocytes in vitro, both in thepresence and absence of metabolic activation. Sunitinib was not clastogenic in rat bone marrowin vivo. The major active metabolite was not evaluated for genotoxic potential.

In a 1-month, oral gavage dose-range finding study (0, 10, 25, 75, or 200 mg/kg/day) with continuousdaily dosing in rasH2 transgenic mice, carcinoma and hyperplasia of Brunner’s glands of theduodenum 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 dailydosing was conducted in rasH2 transgenic mice. Gastroduodenal carcinomas, an increased incidenceof background haemangiosarcomas, and/or gastric mucosal hyperplasia were observed at dosesof ≥ 25 mg/kg/day following 1- or 6-months duration (≥ 7.3 times the AUC in patients administeredthe recommended daily dose RDD).

In a 2-year rat carcinogenicity study (0, 0.33, 1, or 3 mg/kg/day), administration of sunitinib in 28-daycycles followed by 7-day dose-free periods resulted in increases in the incidence ofphaeochromocytomas and hyperplasia in the adrenal medulla of male rats given 3 mg/kg/dayfollowing > 1 year of dosing (≥ 7.8 times the AUC in patients administered the RDD). Brunner’sglands 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, whichoccurred at ≥ 0.9, 7.8, and 7.8 times the AUC in patients administered the RDD, respectively. Therelevance to humans of the neoplastic findings observed in the mouse (rasH2 transgenic) and ratcarcinogenicity studies with sunitinib treatment is unclear.

No effects on male or female fertility were observed in reproductive toxicity studies. However, inrepeated-dose toxicity studies performed in rats and monkeys, effects on female fertility wereobserved in the form of follicular atresia, degeneration of corpora lutea, endometrial changes in theuterus, 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 ofspermatozoa in epididymides, and colloid depletion in prostate and seminal vesicles at plasmaexposure 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 of28 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 numberof resorptions, increases in postimplantation loss and complete litter loss in 4 of 6 pregnant females atplasma exposure levels 3 times the systemic exposure in humans. Sunitinib treatment in rats duringorganogenesis resulted in developmental effects at  5 mg/kg/day consisting of increased incidence offoetal skeletal malformations, predominantly characterised as retarded ossification of thoracic/lumbarvertebrae and occurred at plasma exposure levels 5.5 times the systemic exposure in humans. Inrabbits, developmental effects consisted of increased incidence of cleft lip at plasma exposure levelsapproximately equal to that observed in clinic, and cleft lip and cleft palate at plasma exposure levels2.7 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 inpregnant 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 (estimateexposure ≥ 2.3 times the AUC in patients administered the RDD). Reduced offspring body weightswere observed during the preweaning and postweaning periods at 3 mg/kg/day. No developmenttoxicity was observed at 1 mg/kg/day (approximate exposure ≥ 0.9 times the AUC in patientsadministered the RDD).

Sunitinib Accord 12.5 mg hard c apsules

Cellulose, microcrystalline

Mannitol (E421)

Croscarmellose sodium

Povidone (E1201)

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Red Iron oxide (E172)

Printing ink white

Printing ink white

Shellac

Titanium dioxide (E171)

Sunitinib Accord 25 mg hard c apsules

Cellulose, microcrystalline

Mannitol (E421)

Croscarmellose sodium

Povidone (E1201)

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Black Iron oxide (E172)

Red Iron oxide (E172)

Yellow Iron oxide (E172)

Printing ink white

Printing ink white

Shellac

Titanium dioxide (E171)

Sunitinib Accord 37.5 mg hard c apsules

Cellulose, microcrystalline

Mannitol (E421)

Croscarmellose sodium

Povidone (E1201)

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Yellow Iron oxide (E172)

Printing ink black

Printing ink black

Shellac

Black iron oxide (E172)

Ammonium hydroxide

Sunitinib Accord 50 mg hard c apsules

Cellulose, microcrystalline

Mannitol (E421)

Croscarmellose sodium

Povidone (E1201)

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Black Iron oxide (E172)

Red Iron oxide (E172)

Yellow Iron oxide (E172)

Printing ink white

Printing ink white

Shellac

Titanium dioxide (E171)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Aluminium-OPA/Alu/PVC blisters in pack sizes of 28 hard capsules per carton.

Aluminium-OPA/Alu/PVC perforated unit dose blister in pack sizes of 28 x 1 hard capsules percarton.

High-density polyethylene (HDPE) bottle with a child resistant polypropylene closure containing 30hard capsules per carton.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll De Barcelona s/n,

Edifici Est, 6a Planta,

Barcelona, 08039,

Spain

Sunitinib Accord 12.5 mg hard capsules

EU/1/20/1511/001-003

Sunitinib Accord 25 mg hard capsules

EU/1/20/1511/004-006

Sunitinib Accord 37.5 mg hard capsules

EU/1/20/1511/007-009

Sunitinib Accord 50 mg hard capsules

EU/1/20/1511/010-012

Date of first authorisation: 11 February 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.