Sunitinib

Sunitinib is an oral, small-molecule inhibitor of multiple receptor tyrosine kinases (RTKs) that are implicated in tumour growth, neoangiogenesis and metastatic progression of cancer.

Mechanism of Action

• Targets: sunitinib was identified as an inhibitor of the platelet-derived growth factor receptors PDGFR-α and PDGFR-β, the VEGF receptors VEGFR1, VEGFR2 and VEGFR3, the stem cell factor receptor KIT, FLT3, the colony-stimulating factor receptor CSF-1R and the glial cell-line derived neurotrophic factor receptor RET. DrugBank notes that more than 80 kinases were screened.
• Evidence: inhibition of these receptors was shown in biochemical and cellular assays and in cell-proliferation assays.
• Active metabolite: the primary metabolite (desethyl sunitinib) has a potency similar to sunitinib in biochemical and cellular assays.

Pharmacokinetics

• Absorption: peak concentrations (Cmax) are generally reached 6 to 12 hours after an oral dose, and food does not change bioavailability. Between 25 and 100 mg, AUC and Cmax rise in proportion to dose. With daily dosing sunitinib accumulates 3- to 4-fold and its primary active metabolite 7- to 10-fold, and steady state is reached within 10 to 14 days. The primary active metabolite makes up 23% to 37% of total exposure.
• Distribution: in vitro, 95% of sunitinib and 90% of its primary metabolite bind to plasma proteins. The apparent volume of distribution is large, 2,230 L, indicating distribution into tissues.
• Metabolism: mainly by CYP3A4, which produces the primary active metabolite; the same enzyme then metabolises that metabolite further. In vitro, sunitinib is a substrate of the efflux transporter BCRP; a small study with the BCRP inhibitor gefitinib showed no clinically relevant effect on sunitinib exposure.
• Elimination: mainly in faeces (61% of the dose), with 16% eliminated by the kidneys as unchanged drug and metabolites. Total oral clearance is 34–62 L/h. Half-lives are about 40–60 hours for sunitinib and 80–110 hours for the primary metabolite.
• Special populations: single-dose exposure was similar in mild or moderate hepatic impairment (Child-Pugh A and B); severe impairment (Child-Pugh C) was not studied. Exposure was similar in severe renal impairment; in end-stage renal disease on haemodialysis, total exposure was 47% lower for sunitinib and 31% lower for its metabolite. No starting dose change is needed for weight or performance status. Women may have about 30% lower apparent clearance than men, which does not call for a different starting dose.

• Gastrointestinal stromal tumour (GIST): unresectable and/or metastatic malignant GIST in adults after failure of imatinib treatment due to resistance or intolerance.
• Metastatic renal cell carcinoma (MRCC): advanced or metastatic renal cell carcinoma in adults.
• Pancreatic neuroendocrine tumours (pNET): unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours with disease progression in adults.

• Hypersensitivity to sunitinib or to any of the excipients.

The most serious reactions, some fatal, are renal failure, heart failure, pulmonary embolism, gastrointestinal perforation and haemorrhages (respiratory tract, gastrointestinal, tumour, urinary tract and brain). The most common reactions of any grade are decreased appetite, taste disturbance, hypertension, fatigue, gastrointestinal disorders (diarrhoea, nausea, stomatitis, dyspepsia, vomiting), skin discolouration and palmar-plantar erythrodysaesthesia syndrome; these may diminish as treatment continues. Hypothyroidism may develop, and neutropenia, thrombocytopenia and anaemia are among the most common reactions. The SmPC table is based on a pooled dataset of 7,115 patients with GIST, MRCC and pNET and also includes post-marketing reactions identified in clinical studies.

Very common (≥1/10): neutropenia, thrombocytopenia, anaemia, leucopenia, hypothyroidism, decreased appetite, insomnia, dizziness, headache, taste disturbance, hypertension, dyspnoea, epistaxis, cough, stomatitis, abdominal pain, vomiting, diarrhoea, dyspepsia, nausea, constipation, skin discolouration, palmar-plantar erythrodysaesthesia syndrome, rash, hair colour change, dry skin, pain in extremity, arthralgia, back pain, mucosal inflammation, fatigue, oedema, pyrexia.

Common (≥1/100 to <1/10): viral infections (for example nasopharyngitis and oral herpes), respiratory infections (for example bronchitis, lower respiratory tract infection and pneumonia), abscesses, fungal infections, urinary tract infection, skin infections, sepsis, lymphopenia, dehydration, hypoglycaemia, depression, peripheral neuropathy, paraesthesia, hypoaesthesia, hyperaesthesia, periorbital and eyelid oedema, increased lacrimation, myocardial ischaemia, decreased ejection fraction, deep vein thrombosis, hot flush, flushing, pulmonary embolism, pleural effusion, haemoptysis, exertional dyspnoea, oropharyngeal pain, nasal congestion, nasal dryness, gastro-oesophageal reflux disease, dysphagia, gastrointestinal haemorrhage, oesophagitis, abdominal distension or discomfort, rectal haemorrhage, gingival bleeding, mouth ulceration, proctalgia, cheilitis, haemorrhoids, glossodynia, oral pain or discomfort, dry mouth, flatulence, eructation, skin exfoliation, skin reaction, eczema, blisters, erythema, alopecia, acne, pruritus, skin hyperpigmentation, skin lesion, hyperkeratosis, dermatitis, nail disorder, musculoskeletal pain, muscle spasms, myalgia, muscular weakness, renal failure, acute renal failure, chromaturia, proteinuria, chest pain, pain, influenza-like illness, chills, and laboratory changes (weight decrease, decreased white blood cell and platelet counts, decreased haemoglobin, raised lipase, amylase, AST, ALT, blood creatinine, blood pressure and uric acid).

Uncommon (≥1/1,000 to <1/100): necrotising fasciitis, bacterial infections, pancytopenia, hypersensitivity, hyperthyroidism, cerebral haemorrhage, cerebrovascular accident, transient ischaemic attack, congestive heart failure, myocardial infarction, cardiac failure, cardiomyopathy, pericardial effusion, QT prolongation, tumour haemorrhage, pulmonary haemorrhage, respiratory failure, gastrointestinal perforation, pancreatitis, anal fistula, colitis, hepatic failure, cholecystitis, abnormal liver function, osteonecrosis of the jaw, fistula, urinary tract haemorrhage, impaired wound healing, raised creatine phosphokinase, raised thyroid-stimulating hormone.

Rare (≥1/10,000 to <1/1,000): thrombotic microangiopathy, angioedema, thyroiditis, tumour lysis syndrome, reversible posterior leukoencephalopathy syndrome, left ventricular failure, torsade de pointes, hepatitis, erythema multiforme, Stevens-Johnson syndrome, pyoderma gangrenosum, toxic epidermal necrolysis, rhabdomyolysis, myopathy, nephrotic syndrome.

Not known: hyperammonaemic encephalopathy, aneurysms and artery dissections.

Several of these reactions have had fatal outcomes, among them respiratory infections, abscesses, sepsis, necrotising fasciitis, pulmonary embolism, haemorrhages (cerebral, gastrointestinal, pulmonary, tumour), myocardial infarction, heart failure, gastrointestinal perforation, hepatic and renal failure, tumour lysis syndrome and severe skin reactions. Other fatal events considered possibly related to sunitinib were multi-system organ failure, disseminated intravascular coagulation, peritoneal haemorrhage, adrenal insufficiency, pneumothorax, shock and sudden death.

Sunitinib is metabolised mainly by CYP3A4, so strong modulators of this enzyme change its exposure. Interaction studies have only been done in adults.

• Potent CYP3A4 inhibitors (for example ketoconazole, ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice): ketoconazole raised the combined sunitinib and metabolite Cmax by 49% and AUC by 51%. Avoid the combination or choose another medicine; if that is not possible, reduce the sunitinib dose (see Administration and Dosage).
• Potent CYP3A4 inducers (for example rifampicin, dexamethasone, phenytoin, carbamazepine, phenobarbital, St John’s wort): rifampicin lowered the combined Cmax by 23% and AUC by 46%. Avoid the combination; if that is not possible, the sunitinib dose may need to be increased with careful monitoring.
• BCRP inhibitors: clinical data are limited and an interaction cannot be excluded.
• Anticoagulants (warfarin, acenocoumarol): periodic blood counts (platelets), PT/INR and physical examination.
• QT-prolonging medicines and anti-arrhythmics: use sunitinib with caution.
• Intravenous bisphosphonates: use with caution, as osteonecrosis of the jaw has been reported, mostly in patients who had received these.
• Antidiabetic medicines: because sunitinib can lower blood glucose, glucose should be checked regularly in diabetic patients to see whether doses need adjusting.
• Food: sunitinib can be taken with or without food. Grapefruit products and St John’s wort should be avoided (DrugBank).

Therapy should be started by a physician experienced in the use of anticancer agents. Sutent is taken by mouth, with or without food.

Recommended Dose

• GIST and metastatic renal cell carcinoma: 50 mg once daily for 4 consecutive weeks, followed by a 2-week rest period (Schedule 4/2), making a complete 6-week cycle.
• Pancreatic neuroendocrine tumours: 37.5 mg once daily without a scheduled rest period.

Dose Adjustments

• Safety and tolerability, GIST and MRCC: adjust in 12.5 mg steps. The daily dose should not exceed 75 mg or fall below 25 mg.
• Safety and tolerability, pNET: adjust in 12.5 mg steps. The maximum dose given in the phase 3 pNET study was 50 mg daily.
• Interruptions: dose interruptions may be needed according to individual safety and tolerability.
• Potent CYP3A4 inducers (such as rifampicin): avoid. If that is not possible, the dose may need to be raised in 12.5 mg steps, up to 87.5 mg a day for GIST and MRCC or 62.5 mg a day for pNET, with careful monitoring of tolerability.
• Potent CYP3A4 inhibitors (such as ketoconazole): avoid. If that is not possible, the dose may need to be lowered to a minimum of 37.5 mg daily for GIST and MRCC or 25 mg daily for pNET. Choosing a co-medication with no or minimal CYP3A4 effect should be considered.

Special Populations

• Elderly: about one-third of patients in the studies were 65 or older; no significant differences in safety or efficacy were seen.
• Hepatic impairment: no starting dose adjustment in mild or moderate (Child-Pugh A and B) impairment. Sunitinib has not been studied in severe (Child-Pugh C) impairment, and its use there cannot be recommended.
• Renal impairment: no starting dose adjustment in mild to severe impairment or in end-stage renal disease on haemodialysis; later adjustments follow individual safety and tolerability.
• Children and adolescents: safety and efficacy below 18 years have not been established. Available data are described in the SmPC, but no dose recommendation can be made.

Missed Dose

If a dose is missed, no extra dose is given. The patient takes the usual prescribed dose the next day.

Haemorrhage and Tumour Bleeding

Haemorrhages, some fatal, have involved the gastrointestinal tract, airways, urinary tract and brain; epistaxis was the most common. Tumour haemorrhage, sometimes with tumour necrosis, can occur suddenly. In lung tumours it can present as severe, life-threatening haemoptysis or pulmonary haemorrhage (sunitinib is not approved for lung cancer). Routine assessment includes complete blood counts and physical examination.

Gastrointestinal Disorders

Diarrhoea, nausea and vomiting, abdominal pain, dyspepsia and stomatitis or oral pain are the most common; oesophagitis has also been reported. Supportive care may include antiemetic, antidiarrhoeal or antacid medicines. Serious, sometimes fatal gastrointestinal complications, including perforation, were reported in patients with intra-abdominal malignancies.

Heart and Circulation

• Cardiac events: heart failure, cardiomyopathy, a fall in left ventricular ejection fraction, myocarditis, myocardial ischaemia and myocardial infarction, some fatal, have been reported. Use with caution in patients at risk or with such a history. Patients with cardiac events in the 12 months before starting were excluded from all studies. Monitor for signs of heart failure, and consider baseline and periodic ejection fraction checks. Discontinue sunitinib in clinical heart failure; interrupt and/or reduce the dose if the ejection fraction is below 50% and more than 20% below baseline without clinical heart failure.
• QT prolongation: QT prolongation and torsade de pointes have been seen. Use with caution in patients with a history of QT prolongation, on anti-arrhythmics or QT-prolonging medicines, or with relevant cardiac disease, bradycardia or electrolyte disturbances. Limit co-administration with potent CYP3A4 inhibitors.
• Hypertension: severe hypertension has been reported. Patients should be screened and blood pressure controlled. Temporary suspension is recommended for severe hypertension not controlled by medical management, and treatment can resume once it is controlled.
• Thromboembolism: venous events (deep vein thrombosis, pulmonary embolism, some fatal) and arterial events (most often stroke, transient ischaemic attack and cerebral infarction, sometimes fatal) have been reported. Risk factors for arterial events include hypertension, diabetes mellitus, prior thromboembolic disease and older age.
• Aneurysms and artery dissections: VEGF pathway inhibitors may promote them, with or without hypertension. Consider this risk before starting in patients with hypertension or a history of aneurysm.
• Thrombotic microangiopathy: consider it with haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological signs, renal impairment and fever. Stop sunitinib and treat promptly.

Blood Disorders

Decreases in neutrophil and platelet counts occurred; they were not cumulative and typically reversible. Rare fatal events, including haemorrhage with thrombocytopenia and neutropenic infections, have been reported after marketing. Anaemia can occur early or late. Complete blood counts should be done at the start of each treatment cycle.

Skin Reactions

Depigmentation of hair or skin, dryness, thickening or cracking of the skin, blisters, and rash on the palms and soles can occur; these were not cumulative and typically reversible. Pyoderma gangrenosum has been reported. Severe skin reactions, including erythema multiforme and cases suggestive of Stevens-Johnson syndrome and toxic epidermal necrolysis, some fatal, require stopping sunitinib. If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, treatment must not be restarted.

Thyroid, Pancreas, Liver and Kidney

• Thyroid: measure thyroid function at baseline in all patients and treat existing thyroid disease before starting. During treatment, check thyroid function every 3 months and test if symptoms suggest dysfunction. Hypothyroidism can develop early or late.
• Pancreas: lipase and amylase rises are usually transient and symptom-free. Serious pancreatic events, some fatal, have been reported; stop sunitinib if pancreatitis symptoms occur.
• Liver: hepatotoxicity occurs, and hepatic failure, some fatal, was seen in below 1% of solid tumour patients. Check ALT, AST and bilirubin before treatment, during each cycle and as clinically indicated. Stop sunitinib if signs of hepatic failure appear.
• Kidney: renal impairment, renal failure and acute renal failure, some fatal, have been reported. Risk factors include underlying renal cell carcinoma, older age, diabetes mellitus, underlying renal impairment, heart failure, hypertension, sepsis, dehydration or hypovolaemia and rhabdomyolysis. A baseline urinalysis is recommended and proteinuria should be monitored. Discontinue sunitinib in nephrotic syndrome.

Other Precautions

• Fistula: interrupt treatment if a fistula forms.
• Wound healing: impaired healing has been reported. As a precaution, interrupt sunitinib around major surgery and restart on clinical judgement of recovery.
• Osteonecrosis of the jaw: reported mostly in patients who had received or were receiving intravenous bisphosphonates; invasive dental procedures are also a risk factor. Consider a dental examination and preventive dentistry before treatment, and avoid invasive dental procedures where possible in patients on intravenous bisphosphonates.
• Hypersensitivity and angioedema: interrupt treatment and give standard medical care.
• Seizures and posterior reversible leukoencephalopathy: seizures have been reported. Patients with seizures and signs such as hypertension, headache, reduced alertness, altered mental function or visual loss (including cortical blindness) need medical management, including blood pressure control, and temporary suspension of sunitinib.
• Tumour lysis syndrome: rarely observed, some fatal. Risk factors are high tumour burden, chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. Monitor closely and consider prophylactic hydration.
• Infections: serious infections, with or without neutropenia, some fatal, have been reported. Necrotising fasciitis, including of the perineum, is uncommon and sometimes fatal; stop sunitinib and treat promptly.
• Hypoglycaemia: blood glucose can fall, sometimes with loss of consciousness and hospitalisation. Interrupt sunitinib in symptomatic hypoglycaemia and check glucose regularly in diabetic patients.
• Hyperammonaemic encephalopathy: measure ammonia in patients with unexplained lethargy or changes in mental status.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception and avoid becoming pregnant during treatment.
• Pregnancy: there are no studies in pregnant women. Animal studies showed reproductive toxicity including foetal malformations. Sunitinib should not be used in pregnancy or in women not using effective contraception unless the potential benefit justifies the potential risk to the foetus. A patient who becomes pregnant during treatment should be told of the potential hazard to the foetus.
• Breastfeeding: sunitinib and/or its metabolites pass into rat milk; it is not known whether they pass into human milk. Women should not breastfeed during treatment.
• Fertility: nonclinical findings suggest male and female fertility may be compromised.

Sodium

Each capsule contains less than 1 mmol (23 mg) of sodium, so the medicine is essentially sodium-free.

Effect on Driving

Sutent has a minor influence on the ability to drive and use machines. Patients may feel dizzy during treatment.

Sutent capsules need no special storage conditions. They are supplied in HDPE bottles with a polypropylene closure containing 30 hard capsules, and in transparent perforated unit-dose blisters containing 28 × 1 hard capsules; not all pack sizes may be marketed.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B); therapy is started by a physician experienced in the use of anticancer agents. Sunitinib capsules are taken at home, so they are supplied to the patient or to the treating clinic on prescription.