Sunitinib

Registered South African indications:

• Gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance
• Treatment-naïve advanced and/or metastatic renal cell carcinoma
• Metastatic renal cell carcinoma (MRCC) after failure of cytokine-based therapy (interferon α, interleukin-2)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Pre-existing moderate to severe proteinuria
• Diabetes
• Renal impairment or risk factors thereof
  - Older age
  - Diabetes mellitus
  - Cardiac failure
  - Hypertension
  - Sepsis
  - Dehydration/hypovolaemia
  - Rhabdomyolysis
• Severe hepatic impairment
• Lung cancer
• Hypertension
• Cardiovascular risk factors or history thereof
• Cardiac events within the last 12 months
  - Myocardial infarction
  - Severe/unstable angina
  - Coronary/peripheral artery bypass graft
  - Symptomatic congestive heart failure
  - Cerebrovascular accident
  - Transient ischaemic attack
  - Pulmonary embolism
• History of coronary disease
• History of QT prolongation
• Pre-existing cardiac disease
• Bradycardia
• Electrolyte disturbances
• Arterial thromboembolic events risk fators
  - Underlying malignant disease
  - ≥ 65 years
  - Hypertension
  - Diabetes mellitus
  - Prior thromboembolic disease
• History of aneurysm
• Pre-existing hypothyroidism or hyperthyroidism
• Major surgical interventions/ existing wounds
• Patients under wound care therapy
• Invasive dental procedures
• Tumour lysis syndrome risk factors
  - High tumour burden
  - Pre-existing chronic renal insufficiency
  - Oliguria
  - Hypotension
  - Acidic urine
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Used for the treatment of

Gastrointestinal stromal tumour (GIST)
- After failure of imatinib mesylate treatment due to resistance or intolerance
- Unresectable and/or metastatic malignant GIST after failure of imatinib treatment due to resistance or intolerance

Renal cell carcinoma (RCC)
- Advanced and/or metastatic
- After failure of cytokine-based therapy (interferon α, interleukin-2)

Pancreatic neuroendocrine tumours (pNET)
- Unresectable or metastatic, well-differentiated pNET with disease progression

Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Caution; positive evidence of risk
• There are no studies in pregnant women using sunitinib. Studies in animals have shown reproductive toxicity including foetal malformations
• Sunitinib should not be used during pregnancy or in women not using effective contraception unless the potential benefit justifies the potential risk to the foetus
• Women of childbearing potential should be advised to use effective contraception and avoid becoming pregnant while receiving treatment with sunitinib
• If sunitinib is used during pregnancy or if the patient becomes pregnant while on treatment with sunitinib, the patient should be apprised of the potential hazard to the foetus

Breastfeeding

• Caution; not recommended
• Sunitinib and/or its metabolites are excreted in rat milk. It is not known whether sunitinib or its primary active metabolite is excreted in human milk. Because active substances are commonly excreted in human milk and because of the potential for serious adverse reactions in breastfeeding infants, women should not breastfeed while taking sunitinib

Fertility

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

Renal Impairment

• Caution; no dose adjustment recommended
  No initial dose adjustment required; subsequent dose adjustments may be needed based on individual safety and tolerability

Hepatic Impairment

• Mild to moderate (Child-Pugh Class A & B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; no information available

Elderly            

• No dose adjustment recommended

Porphyria

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Peripheral neuropathy
• Paraesthesia
• Hypoaesthesia
• Hyperaesthesia
• Cerebral haemorrhage
• Cerebral infarction
• Cerebrovascular accident
• Ischaemic stroke
• Transient ischaemic attack
• Posterior reversible encephalopathy syndrome
• Insomnia
• Depression
• Fatigue
• Seizures

Cardiovascular Disorders

• Cardiac failure
• Hypertension
• Deep vein thrombosis
• Hot flush
• Flushing
• Tumour haemorrhage
• Myocardial ischaemia
  - Acute coronary syndrome
  - Angina pectoris
  - Angina unstable
  - Coronary artery occlusion
• Decreased/abnormal ejection fraction
• Congestive cardiac failure
• Myocardial infarction
  - Acute myocardial infarction
  - Silent myocardial infarction
• Cardiomyopathy
• Pericardial effusion
• QT prolongation
• Left ventricular failure
• Torsade de Pointes
• Aneurysms and artery dissections
• Chest pain

Respiratory Disorders

• Dyspnoea
• Epistaxis
• Cough
• Pulmonary embolism
• Pleural effusion
• Haemoptysis
• Exertional dyspnoea 
• Oropharyngeal pain
• Pharyngolaryngeal pain
• Nasal congestion
• Nasal dryness
• Pulmonary haemorrhage
• Respiratory failure
• Respiratory infections
  - Bronchitis
  - Lower respiratory tract infection
  - Pneumonia
  - Respiratory tract infection
• Pneumothorax

Gastrointestinal Disorders

• Stomatitis
• Aphtous stomatitis
• Abdominal pain
  - Lower abdominal pain
  - Upper abdominal pain
• Diarrhoea
• Dyspepsia
• Nausea and vomiting
• Constipation
• Gastro-oesophageal reflux disease
• Dysphagia
• Gastrointestinal haemorrhage
• Oesophagitis
• Abdominal distension
• Abdominal discomfort
• Rectal haemorrhage
• Gingival bleeding
• Mouth ulceration
• Proctalgia
• Cheilitis
• Haemorrhoids
• Glossodynia
• Oral pain
• Dry mouth
• Flatulence
• Oral discomfort
• Eructation
• Gastrointestinal perforation
  -  Intestinal perforation
• Pancreatitis
• Anal fistula
• Colitis
• Ischaemic colitis

Hepatobiliary Disorders

• Hepatic failure
• Cholecystitis
• Acalculous cholecystitis
• Abnormal hepatic function
• Hepatitis
• Increased amylase
• Increased aspartate aminotransferase
• Increased alanine aminotransferase

Genitourinary Disorders

• Renal failure
• Acute renal failure
• Chromaturia
• Proteinuria
• Urinary tract haemorrhage
• Nephrotic syndrome
• Urinary tract infection
• Increased blood creatinine
• Increased blood uric acid

Endocrine and Metabolic Disorders

• Hypothyroidism
• Hyperthyroidism
• Thyroiditis
• Decreased appetite
• Anorexia
• Dehydration
• Hypoglycaemia
• Tumour lysis syndrome
• Increased lipase
• Decreased weight
• Increased blood thyroid stimulating hormone
• Adrenal insufficiency

Musculoskeletal Disorders

• Pain in extremity
• Arthralgia
• Back pain
• Musculoskeletal pain
• Muscle spasms
• Myalgia
• Muscular weakness
• Osteonecrosis of the jaw
• Fistula
• Rhabdomyolysis
• Myopathy
• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Skin discolouration
  - Yellow skin
  - Pigmentation disorder
• Palmar-plantar erythrodysaesthesia syndrome
• Rash
  - Dermatitis psoriasiform
  - Exfoliative rash
  - Erythematous rash
  - Follicular rash
  - Generalised rash
  - Macular rash
  - Maculo-papular rash
  - Papular rash
  - Pruritic rash
• Hair colour changes
• Dry skin
• Skin exfoliation
• Skin reaction
  - Skin disorder
• Eczema
• Blister
• Erythema
• Alopecia
• Acne
• Pruritus
• Skin hyperpigmentation
• Skin lesion
• Hyperkeratosis
• Dermatitis
• Nail disorder/ discoluration
• Erythema multiforme
• Stevens-Johnson syndrome
• Pyoderma gangrenosum
• Toxic epidermal necrolysis
• Oedema
  - Face oedema
  - Peripheral oedema
• Mucosal inflammation
• Skin infections
  - Cellulitis
  - Skin infection
• Necrotising fasciitis
• Peritoneal haemorrhage

Immune, Blood and Lymphatic System Disorders

• Neutropoenia
• Thrombocytopaenia
• Anaemia
• Leukopaenia
• Lymphopenia
• Pancytopenia
• Thrombotic microangiopathy
  - Thrombotic thrombocytopenic purpura
  - Haemolytic uraemic syndrome
• Hypersensitivity
• Angioedema
• Fever
• Influenza like illness
• Chills
• Impaired healing
• Viral infections
  - Nasopharyngitis
  - Oral herpes
• Fungal infections
  - Oesophageal candidiasis
  - Oral candidiasis
• Sepsis/sepsis shock
• Bacterial infections
  - Abdominal abscess
  - Abdominal sepsis
  - Diverticulitis
  - Osteomyelitis
• Decreased white blood cell count
• Decreased platelet count
• Decreased haemoglobin
• Disseminated intravascular coagulation
• Shock
• Abscess
  - Abscess limb
  - Anal abscess
  - Gingival abscess
  - Liver abscess
  - Pancreatic abscess
  - Perineal abscess
  - Perirectal abscess
  - Rectal abscess
  - Subcutaneous abscess
  - Tooth abscess

Sensory Disorders

• Taste disturbance
  - Dysgeusia
  - Ageusia
• Periorbital oedema
• Eyelid oedema
• Increased lacrimation 

Others

• Multi-system organ failure
• Sudden death
• Pain

• CYP3A4 inducers
• Rifampicin
• Dexamethasone
• Phenytoin
• Carbamazepine
• Phenobarbital
• St John's Wort (Hypericum perforatum)
• CYP3A4 inhibitors
• Ketoconazole
• Ritonavir
• Itraconazole
• Erythromycin
• Clarithromycin
• Grapefruit juice
• Antiarrhythmics
• QT-prolonging agents
• Bisphosphonates (IV)
• Breast cancer resistance protein inhibitors
• Vascular endothelial growth factor (VEGF) pathway inhibitors (See Special Prescribing Points)

• Full blood count with differential and platelets
• Physical examination
• Coagulation factors
• Thyroid function
• Blood pressure
• Hepatic function
• Electrolytes
• Pregnancy test
• Urinanalysis
• Blood glucose

None routine. Specific cases may require 

• ECG
• Dental examination
• Left ventricular ejection fraction evaluation

Tyrosine kinase inhibitors (TKI) and cerebrovascular adverse events safety concern

• TKI containing medicines may have different kinase inhibition profiles and/or off target binding profiles, with some TKIs approved for very similar indications and others approved for different indications
• Although many adverse events/side effects/toxicities could not be explained by a class related adverse event or a related off-target kinase inhibition effect, there is some evidence that the TKIs share to a variable degree, class related cerebrovascular adverse events
• The abovementioned cerebrovascular adverse events may occur in patients on treatment with TKI containing medicines with or without risk factors for these events and may occur at any time during treatment with TKIs
• Patients on treatment with TKI containing medicine should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events
• Treatment with TKI containing medicines should be discontinued, and alternative treatment options be considered in patients who develop these class related cerebrovascular adverse events

Special Precautions

Aneurysms and artery dissections

• The use of vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections
• Before initiating sunitinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm

Thrombotic microangiopathy (TMA)

• The diagnosis of TMA, including thrombotic thrombocytopaenic purpura (TTP) and haemolytic uraemic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, should be considered in the occurrence of haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological manifestation, renal impairment, and fever
• Sunitinib therapy should be discontinued in patients who develop TMA and prompt treatment is required. Reversal of the effects of TMA has been observed after treatment discontinuation

Fistula

• If fistula formation occurs, sunitinib treatment should be interrupted. Limited information is available on the continued use of sunitinib in patients with fistulae.

Impaired wound healing

• Cases of impaired wound healing have been reported during sunitinib therapy
• No formal clinical studies of the effect of sunitinib on wound healing have been conducted
• Temporary interruption of sunitinib therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sunitinib therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.

Osteonecrosis of the jaw (ONJ)

• Cases of ONJ have been reported in patients treated with sunitinib. The majority of cases were reported in patients who had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should, therefore, be exercised when sunitinib and intravenous bisphosphonates are used either simultaneously or sequentially
• Invasive dental procedures are also an identified risk factor. Prior to treatment with sunitinib, a dental examination and appropriate preventive dentistry should be considered. In patients who have previously received or are receiving intravenous bisphosphonates, invasive dental procedures should be avoided if possible

Sunitinib inhibits multiple receptor tyrosine kinases (RTKs) that are implicated in tumour growth, neoangiogenesis, and metastatic progression of cancer. Sunitinib is identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.

Capsule 12.5mg

• Sutent (Pfizer) originator

Capsule 25mg

• Sutent (Pfizer) originator

Capsule 50mg

• Sutent (Pfizer) originator