SUNITINIB ZENTIVA

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. neutropoenia, thrombocytopoenia, 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 Neutropoenia Thrombocytopoenia Anaemia Leukopoenia Lymphopoenia Pancytopoenia Thrombotic microangiopathyh,* Immune system disorders Hypersensitivity Angioedema Endocrine disorders Hypothyroidism Hyperthyroidism Thyroiditis Metabolism and nutrition disorders Decreased appetitei Dehydration Hypoglycaemia Tumour lysis syndrome* Psychiatric disorders Insomnia Depression Nervous system disorders Dizziness Headache Taste disturbancej Neuropathy peripheral Paraesthesia Hypoaesthesia Hyperaesthesia Cerebral haemorrhage* Cerebrovascular accident* Transient ischaemic attack Posterior reversible encephalopathy syndrome* Hyperammo- naemic encephalopathy Eye disorders Periorbital oedema Eyelid oedema Lacrimation increased Cardiac disorders Myocardial ischemiak,* Ejection fraction decreasedl Cardiac failure congestive Myocardial infarctionm,* Cardiac failure* Cardiomyopathy* Pericardial effusion Electrocardiogram QT prolonged Left ventricular failure* Torsade de pointes Vascular disorders Hypertension Deep vein thrombosis Hot flush Tumour haemorrhage* Aneurysms and artery dissections* Flushing Respiratory, thoracic and mediastinal disorders Dyspnoea Epistaxis Cough Pulmonary embolism* Pleural effusion* Haemoptysis Dyspnoea exertional Oropharyngeal painn Nasal congestion Nasal dryness Pulmonary haemorrhage* Respiratory failure* Gastrointestinal disorders Stomatitiso Abdominal painp Vomiting Diarrhoea Dyspepsia Nausea Constipation Gastro- oesophageal reflux disease Dysphagia Gastrointestinal haemorrhage* Oesophagitis* Abdominal distension Abdominal discomfort Rectal haemorrhage Gingival bleeding Mouth ulceration Proctalgia Cheilitis Haemorrhoids Glossodynia Oral pain Dry mouth Flatulence Oral discomfort Eructation Gastrointestinal perforationq,* Pancreatitis Anal fistula Colitisr Hepatobiliary disorders Hepatic failure* Cholecystitiss,* Hepatic function abnormal Hepatitis Skin and subcutaneous tissue disorders Skin discolourationt Palmar-plantar erythrodysaesthesia syndrome Rashu Hair colour changes Dry skin Skin exfoliation Skin reactionv Eczema Blister Erythema Alopecia Acne Pruritus Skin hyperpigmentation Skin lesion Hyperkeratosis Dermatitis Erythema multiforme* Stevens-Johnson syndrome* Pyoderma gangrenosum Toxic epidermal necrolysis* Nail disorderw Musculoskeletal and connective tissue disorders Pain in extremity Arthralgia Back pain Musculoskeletal pain Muscle spasms Myalgia Muscular weakness Osteonecrosis of the jaw Fistula* Rhabdomyolysis* Myopathy Renal and urinary disorders Renal failure* Renal failure acute* Chromaturia Proteinuria Haemorrhage urinary tract Nephrotic syndrome General disorders and administration site conditions Mucosal inflammation Fatiguex Oedemay Pyrexia Chest pain Pain Influenza like illness Chills Impaired healing Investigations Weight decreased White blood cell count decreased Lipase increased Platelet count decreased Haemoglobin decreased Amylase increasedz Aspartate aminotransferase increased Alanine aminotransferase increased Blood creatinine increased Blood pressure increased Blood uric acid increased Blood creatine phosphokinase increased Blood thyroid stimulating hormone increased * Including fatal events.

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

Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), cases suggestive of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some of which were fatal. 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 post-marketing experience in patients treated with sunitinib for MRCC, GIST and lung cancer. Sunitinib is not approved for use in patients with lung cancer.

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