SUNITINIB

Therapy with sunitinib should be initiated by a physician experienced in the administration of anticancer agents. Posology For GIST and MRCC, the recommended dose of Sunitinib 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.

5 mg taken orally once daily without a scheduled rest period. 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. 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. 5). 5 mg per day for pNET) based on careful monitoring of tolerability. 5). 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.

2 but no recommendation on a posology can be made. Elderly Approximately one-third of the patients in clinical studies who received sunitinib were 65 years of age or over. No significant differences in safety or efficacy were observed between younger and older patients.

Hepatic impairment No starting dose adjustment is recommended when administering sunitinib to patients with mild or moderate (Child- Pugh Class A and B) hepatic impairment. 2). Renal impairment No starting dose adjustment is required when administering sunitinib to patients with renal impairment (mild-severe) or with end-stage renal disease (ESRD) on haemodialysis.

2). Method of administration Sunitinib 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.

g. respiratory tract, gastrointestinal, tumour, urinary tract, and brain haemorrhages). e. diarrhoea, nausea, stomatitis, dyspepsia and vomiting), skin discolouration, and palmar-plantar erythrodysaesthesia syndrome. These symptoms may diminish as treatment continues.

Hypothyroidism may develop during treatment. g. neutropenia, thrombocytopenia, and anaemia) are amongst the most common adverse drug reactions. 8 below that were considered possibly related to sunitinib included multi-system organ failure, disseminated intravascular coagulation, peritoneal haemorrhage, adrenal insufficiency, pneumothorax, shock, and sudden death.

Tabulated list of adverse reactions Adverse reactions that were reported in GIST, MRCC and pNET patients in a pooled dataset of 7,115 patients are listed below, by system organ class, frequency and grade of severity (NCI-CTCAE). Post-marketing adverse reactions identified in clinical studies are also included.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1 - Adverse reactions reported in clinical trials System organ class Very common Common Uncommon Rare Not known Infections and infestations Viral infectionsa Respiratory infectionsb,* Abscessc,* Fungal infectionsd Urinary tract infection Skin infectionse Sepsisf,* Necrotising fasciitis* Bacterial infectionsg Blood and lymphatic system disorders Neutropoeni a Thrombocyt Lymphopoen ia Pancytopenia Thrombotic microangiop athyh,* opoenia Anaemia Leukopoenia Immune system disorders Hypersensitivi ty Angioedema Endocrine disorders Hypothyroidi sm Hyperthyroidi sm Thyroiditis Metabolism and nutrition disorders Decreased appetitei Dehydration Hypoglycae mia Tumour lysis syndrome* Psychiatric disorders Insomnia Depression Nervous system disorders Dizziness Headache Taste disturbancej Neuropathy peripheral Paraesthesia Hypoaesthes ia Hyperaesthe sia Cerebral haemorrhage* Cerebrovascul ar accident* Transient ischaemic attack Posterior reversible encephalopat hy syndrome* Hyperammon aemic encephalopath y Eye disorders Periorbital oedema Eyelid oedema Lacrimation increased Cardiac disorders Myocardial ischemiak,* Ejection fraction decreasedl Cardiac failure congestive Myocardial infarctionm,* Cardiac failure* Cardiomyopat hy* Pericardial effusion Electrocardio gram Left ventricular failure* Torsade de pointes QT prolonged Vascular disorders Hypertension Deep vein thrombosis Hot flush Flushing Tumour haemorrhage* Aneurysms and artery dissections* Respiratory, thoracic and mediastinal disorders Dyspnoea Epistaxis Cough Pulmonary embolism* Pleural effusion* Haemoptysis Dyspnoea exertional Oropharynge al painn Nasal congestion Nasal dryness Pulmonary haemorrhage* Respiratory failure* Gastrointesti nal disorders Stomatitiso Abdominal painp Vomiting Diarrhoea Dyspepsia Nausea Constipation Gastro- oesophageal reflux disease Dysphagia Gastrointesti nal haemorrhage * Oesophagitis * Abdominal distension Abdominal discomfort Rectal haemorrhage Gingival bleeding Mouth ulceration Proctalgia Cheilitis Haemorrhoid s Glossodynia Oral pain Dry mouth Flatulence Oral discomfort Eructation Gastrointestin al perforationq,* Pancreatitis Anal fistula Colitisr Ischaemic colitisr Hepatobiliar y disorders Hepatic failure* Cholecystitiss, * Hepatic function abnormal Hepatitis Skin and subcutaneou s tissue disorders Skin discolouratio nt Palmar- plantar erythrodysae sthesia syndrome Rashu Hair colour changes Dry skin Skin exfoliation Skin reactionv Eczema Blister Erythema Alopecia Acne Pruritus Skin hyperpigment ation Skin lesion Hyperker atosis Dermatiti s Nail disorderw Erythema multiforme* Stevens- Johnson syndrome* Pyod erma gang renos um Toxic epidermal necrolysis* Musculoske letal and connective tissue disorders Pain in extremity Arthralgia Back pain Musculoskel etal pain Muscle spasms Myalgia Muscular weakness Osteonecro sis of the jaw Fistula* Rhabdomyol ysis* Myopathy Renal and urinary disorders Renal failure* Renal failure acute* Haemorr hage urinary tract Nephrotic syndrome Chromaturia Proteinuria General disorders and administrati on site conditions Mucosal inflammation Fatiguex Oedemay Pyrexia Chest pain Pain Influenza like illness Chills Impaired healing Investigation s Weight decreased White blood cell count decreased Lipase increased Platelet count decreased Haemoglobi n decreased Amylase increasedz Aspartate aminotransfe rase increased Alanine aminotransfe rase increased Blood creatinine increased Blood pressure increased Blood uric acid Blood creatine phosphokinase increased Blood thyroid stimulat ing hormone increased increased * 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, perirectal abscess, 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 […]

5). 5). Skin and tissue disorders Patients should be advised that depigmentation of the hair or skin may occur during treatment with sunitinib. Other possible dermatological effects may include dryness, thickness or cracking of the skin, blisters, or rash on the palms of the hands and soles of the feet.

The above reactions were not cumulative, were typically reversible and generally did not result in treatment discontinuation. Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), cases suggestive of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some of which were fatal.

g. progressive skin rash often with blisters or mucosal lesions) are present, sunitinib treatment should be discontinued. If the diagnosis of SJS or TEN is confirmed, treatment must not be restarted. 8). 8). Routine assessment of bleeding events should include complete blood counts and physical examination.

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

Events of tumour haemorrhage, sometimes associated with tumour necrosis, have been reported; some of these haemorrhagic events were fatal. Tumour haemorrhage may occur suddenly, and in the case of pulmonary tumours, may present as severe and life-threatening haemoptysis or pulmonary haemorrhage.

Cases of pulmonary haemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported in postmarketing experience in patients treated with sunitinib for MRCC, GIST and lung cancer. Sunitinib is not approved for use in patients with lung cancer.

g. warfarin, acenocoumarole) may be periodically monitored by complete blood counts (platelets), coagulation factors (PT/INR) and physical examination. 8). Supportive care for gastrointestinal adverse reactions requiring treatment may include medicinal products with antiemetic, antidiarrhoeal or antacid properties.

1.