SUTENT 12.5 mg hard capsules

SUTENT 25 mg hard capsules

SUTENT 37.5 mg hard capsules

SUTENT 50 mg hard capsules

12.5 mg hard capsules

Each capsule contains sunitinib malate, equivalent to 12.5 mg of sunitinib.

25 mg hard capsules

Each capsule contains sunitinib malate, equivalent to 25 mg of sunitinib.

37.5 mg hard capsules

Each capsule contains sunitinib malate, equivalent to 37.5 mg of sunitinib.

50 mg hard capsules

Each capsule contains sunitinib malate, equivalent to 50 mg of sunitinib.

For the full list of excipients, see section 6.1.

Hard capsule.

SUTENT 12.5 mg hard capsules

Gelatin capsules with orange cap and orange body, printed with white ink “Pfizer” on the cap, “STN 12.5 mg” on the body, and containing yellow to orange granules.

SUTENT 25 mg hard capsules

Gelatin capsules with caramel cap and orange body, printed with white ink “Pfizer” on the cap, “STN 25 mg” on the body, and containing yellow to orange granules.

SUTENT 37.5 mg hard capsules

Gelatin capsules with yellow cap and yellow body, printed with black ink “Pfizer” on the cap, “STN 37.5 mg” on the body, and containing yellow to orange granules.

SUTENT 50 mg hard capsules

Gelatin capsules with caramel cap and caramel body, printed with white ink “Pfizer” on the cap, “STN 50 mg” on the body, and containing yellow to orange granules.

 

Gastrointestinal stromal tumour (GIST)

SUTENT is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) in adults after failure of imatinib treatment due to resistance or intolerance.

Metastatic renal cell carcinoma (MRCC)

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

Pancreatic neuroendocrine tumours (pNET)

SUTENT is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours (pNET) with disease progression in adults.

Therapy with sunitinib should be initiated by a physician experienced in the administration of anti-cancer agents.

Posology

For GIST and MRCC, the recommended dose of SUTENT 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.

For pNET, the recommended dose of SUTENT is 37.5 mg taken orally once daily without a scheduled rest period.

Dose adjustments

Safety and tolerability

For GIST and MRCC, dose modifications in 12.5 mg steps may be applied based on individual safety and tolerability. Daily dose should not exceed 75 mg nor be decreased below 25 mg.

For pNET, dose modification in 12.5 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.

CYP3A4 inhibitors/inducers

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 in 12.5 mg steps (up to 87.5 mg per day for GIST and MRCC or 62.5 mg per day for pNET) based on careful monitoring of tolerability.

Co-administration of sunitinib with potent CYP3A4 inhibitors, such as ketoconazole, should be avoided (see sections 4.4 and 4.5). 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.

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 SUTENT in patients below 18 years of age have not been established.

Currently available limited data are described in sections 4.8, 5.1, and 5.2 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. Sunitinib has not been studied in subjects with severe (Child-Pugh class C) hepatic impairment and therefore its use in patients with severe hepatic impairment cannot be recommended (see section 5.2).

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. Subsequent dose adjustments should be based on individual safety and tolerability (see section 5.2).

Method of administration

SUTENT 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.

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 sunitinib plasma concentration (see sections 4.2 and 4.5).

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

Skin and tissue disorders

Skin discolouration, possibly due to the active substance colour (yellow), is a very common adverse reaction occurring in approximately 30% of patients. Patients should be advised that depigmentation of the hair or skin may also occur during treatment with sunitinib. Other possible dermatologic effects may include dryness, thickness or cracking of the skin, blisters, or occasional 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) and cases suggestive of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (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 treatment should be discontinued. If the diagnosis of SJS or TEN is confirmed, treatment must not be re-started. In some cases of suspected EM, patients tolerated the reintroduction of sunitinib therapy at a lower dose after resolution of the reaction; some of these patients also received concomitant treatment with corticosteroids or antihistamines.

Haemorrhage and tumour bleeding

Haemorrhagic events, some of which were fatal, reported through post-marketing experience have included gastro-intestinal, respiratory, urinary tract and brain haemorrhages.

Bleeding events occurred in 18% of patients receiving sunitinib in a phase 3 GIST Study compared to 17% of patients receiving placebo. In patients receiving sunitinib for treatment-naïve MRCC, 39% had bleeding events compared to 11% of patients receiving IFN-α. Seventeen (4.5%) patients on sunitinib versus 5 (1.7%) of patients on IFN-α experienced Grade 3 or greater bleeding events. Of patients receiving sunitinib for cytokine-refractory MRCC, 26% experienced bleeding. Bleeding events, excluding epistaxis, occurred in 21.7% of patients receiving sunitinib in the phase 3 pNET study compared to 9.85% of patients receiving placebo. Routine assessment of this event 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.

In clinical trials, tumour haemorrhage occurred in approximately 2% of patients with GIST. These events 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. SUTENT is not approved for use in patients with lung cancer.

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

Gastrointestinal disorders

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

Supportive care for gastrointestinal adverse reactions requiring treatment may include medicinal products with anti-emetic, anti-diarrhoeal or antacid properties.

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation have occurred in patients with intra-abdominal malignancies treated with sunitinib. Fatal gastrointestinal bleeding occurred in 0.98% of patients receiving placebo in the GIST phase 3 study.

Hypertension

Hypertension was a very common adverse reaction reported in clinical trials. The dose of sunitinib was reduced or its administration temporarily suspended in approximately 2.7% of the patients who experienced hypertension. In none of these patients sunitinib was permanently discontinued. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 4.7% of patients with solid tumours. Hypertension was reported in approximately 33.9% of patients receiving sunitinib for treatment-naive MRCC compared to 3.6% of patients receiving IFN-α. Severe hypertension occurred in 12% of treatment-naive patients on sunitinib and <1% of patients on IFN-α. Hypertension was reported in 26.5% of patients receiving sunitinib in a Phase 3 pNET study, compared to 4.9% of patients receiving placebo. Severe hypertension occurred in 10% of pNET patients on sunitinib and 3% of patients on placebo. Patients should be screened for hypertension and controlled as appropriate. Temporary suspension is recommended in patients with severe hypertension that is not controlled with medical management. Treatment may be resumed once hypertension is appropriately controlled.

Haematological disorders

Decreased absolute neutrophil counts of Grade 3 and 4 severity 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 MRCC study, and in 13% and 2.4% of patients on the phase 3 pNET study. Decreased platelet counts of Grade 3 and 4 severity 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% of patients on the phase 3 pNET study. The above events were not cumulative, were typically reversible and generally did not result in treatment discontinuation. None of these events in the phase 3 studies were fatal, but rare fatal haematological events, including haemorrhage associated with thrombocytopenia and neutropenic infections, have been reported through post-marketing experience.

Anaemia has been observed to occur early as well as late during treatment with sunitinib; Grade 3 and 4 cases have been reported.

Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with sunitinib.

Cardiac disorders

Cardiovascular events, including heart failure, cardiomyopathy, and myocardial ischemia and myocardial infarction, some of which were fatal, have been reported in patients treated with sunitinib. These data suggest that sunitinib increases the risk of cardiomyopathy. No specific additional risk factors for sunitinib-induced cardiomyopathy apart from the drug-specific effect have been identified in the treated patients. Use sunitinib with caution in patients who are at risk for, or who have a history of, these events.

In clinical trials, decreases in left ventricular ejection fraction (LVEF) of ³20% and below the lower limit of normal occurred in approximately 2% of sunitinib-treated GIST patients, 4% of cytokine-refractory MRCC patients, and 2% of placebo-treated GIST patients. These LVEF declines do not appear to have been progressive and often improved as treatment continued. In the treatment-naïve MRCC study, 27% patients on sunitinib and 15% of patients on IFN-α had an LVEF value below the lower limit of normal. Two patients (<1%) who received sunitinib were diagnosed with congestive heart failure (CHF).

In GIST patients 'cardiac failure', 'cardiac failure congestive' or 'left ventricular failure' were reported in 1.2% of patients treated with sunitinib and 1% of patients treated with placebo. In the pivotal phase 3 GIST study (n = 312), treatment-related fatal cardiac reactions occurred in 1% of patients on each arm of the study (i.e. sunitinib and placebo arms). In a phase 2 study in cytokine-refractory MRCC patients, 0.9% of patients experienced treatment-related fatal myocardial infarction and in the phase 3 study in treatment-naïve MRCC patients, 0.6% of patients on the IFN-α arm and 0% patients on the sunitinib arm experienced fatal cardiac events. In the phase 3 pNET study, one (1%) patient who received sunitinib had treatment-related fatal cardiac failure. The relationship, if any, between receptor tyrosine kinase (RTK) inhibition and cardiac function remains unclear.

Patients who presented with cardiac events within 12 months prior to sunitinib administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from sunitinib clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing sunitinib-related left ventricular dysfunction.

Close monitoring for clinical signs and symptoms of CHF should be performed, especially in patients with cardiac risk factors and/or history of coronary artery disease.

Physicians are advised to weigh this risk against the potential benefits of sunitinib. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib. Baseline and periodic eva luations of LVEF should also be considered while the patient is receiving sunitinib. In patients without cardiac risk factors, a baseline eva luation of ejection fraction should be considered.

In the presence of clinical manifestations of CHF, discontinuation of sunitinib is recommended. The administration of sunitinib should be interrupted and/or the dose reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.

QT interval prolongation

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

Increases in the QTc interval to over 500 msec occurred in 0.5%, and changes from baseline in excess of 60 msec occurred in 1.1% of the 450 solid tumour patients; both of these parameters are recognized as potentially significant changes. At approximately twice therapeutic concentrations, sunitinib has been shown to prolong the QTcF Interval (Frederica's Correction).

QTc interval prolongation was investigated in a trial in 24 patients, ages 20 - 87 years, with advanced malignancies. 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% CI upper limit >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. No patients had a QTc interval >500 msec. Although an effect on QTcF interval was observed on Day 3 at 24 hours post-dose (i.e. at therapeutic plasma concentration expected after the recommended starting dose of 50 mg) with the within-day baseline correction method, the clinical significance of this finding is unclear.

Using comprehensive serial ECG assessments at times corresponding to either therapeutic or greater than therapeutic exposures, none of the patients in the eva luable or ITT populations were observed to develop QTc interval prolongation considered as “severe” (i.e. equal to or greater than Grade 3 by CTCAE version 3.0).

At therapeutic plasma concentrations, the maximum QTcF interval (Frederica's correction) mean change from baseline was 9.6 msec (90% CI: 15.1msec). At approximately twice therapeutic concentrations, 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 greater than Grade 2 (CTCAE version 3.0).

QT interval prolongation may lead to an increased risk of ventricular arrhythmias including Torsade de pointes. Torsade de pointes has been observed in <0.1% of sunitinib-exposed patients. 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 patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Concomitant administration of sunitinib with potent CYP3A4 inhibitors should be limited because of the possible increase in sunitinib plasma concentrations (see sections 4.2 and 4.5).

Venous thromboembolic events

Treatment-related venous thromboembolic events were reported in approximately 1.0% of patients with solid tumours who received sunitinib on clinical trials, including GIST and MRCC.

Seven patients (3%) on sunitinib and none on placebo in a phase 3 GIST study experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT) and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT.

Thirteen patients (3%) receiving sunitinib in the phase 3 treatment-naïve MRCC study and four patients (2%) on the two cytokine-refractory MRCC studies had venous thromboembolic events reported. Nine of these patients had pulmonary embolisms, one was Grade 2 and eight were Grade 4. Eight of these patients had DVT, one with Grade 1, two with Grade 2, four with Grade 3 and one with Grade 4. One patient with pulmonary embolism in the cytokine-refractory MRCC study experienced dose interruption.

In treatment-naïve MRCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolisms, all with Grade 4.

Venous thromboembolic events were reported for 1 (1.2%) subject in the sunitinib arm and 5 (6.1%) subjects in the placebo arm in the phase 3 pNET study. Two of these subjects on placebo had DVT, one with Grade 2 and one with Grade 3.

No cases with fatal outcome were reported in GIST, MRCC and pNET registrational studies. Cases with fatal outcome have been observed in post-marketing setting (see respiratory events and section 4.8).

Arterial thromboembolic events

Cases of arterial thromboembolic events (ATE), sometimes fatal, have been reported in patients treated with sunitinib. The most frequent events included cerebrovascular accident, transient ischaemic attack, and cerebral infarction. Risk factors associated with ATE, in addition to the underlying malignant disease and age ≥65 years, included hypertension, diabetes mellitus, and prior thromboembolic disease.

Thrombotic Microangiopathy (TMA)

TMA, including thrombotic thrombocytopaenic purpura (TTP) and haemolytic uremic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, has been reported in clinical trials and in post-marketing experience of sunitinib as monotherapy and in combination with bevacizumab. The diagnosis of TMA should be considered in the occurrence of haemolytic anaemia, thrombocytopaenia, fatigue, fluctuating neurologic 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 (see section 4.8).

Respiratory events

Patients who presented with pulmonary embolism within the previous 12 months were excluded from sunitinib 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 with pNET.

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

Cases of pulmonary embolism were observed in approximately 3.1% of patients with GIST and in approximately 1.2% of patients with MRCC, who received sunitinib in phase 3 studies (see section 4.4 - Venous thromboembolic events). No pulmonary embolism was reported for patients with pNET who received sunitinib in the phase 3 study. Rare cases with fatal outcome have been observed in post-marketing setting (see section 4.8).

Thyroid dysfunction

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

Hypothyroidism has been observed to occur early as well as late during treatment with sunitinib.

Hypothyroidism was reported as an adverse reaction in 7 patients (4%) receiving sunitinib across the two cytokine-refractory MRCC studies; in 61 patients (16%) on sunitinib and three patients (<1%) in the IFN-α arm in the treatment-naïve MRCC study.

Additionally, TSH elevations were reported in 4 cytokine-refractory MRCC patients (2%). Overall, 7% of the MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism. Acquired hypothyroidism was noted in 6.2% of GIST patients on sunitinib versus 1% on placebo. In the phase 3 pNET study hypothyroidism was reported in 6 patients (7.2%) receiving sunitinib and in one patient (1.2%) on placebo.

Thyroid function was monitored prospectively in two studies in patients with breast cancer; SUTENT is not approved for use in breast cancer. In one study, hypothyroidism was reported in 15 (13.6%) subjects on sunitinib and 3 (2.9%) subjects on standard of care. Blood TSH increase was reported in 1 (0.9%) subject on sunitinib and no subjects on standard of care. Hyperthyroidism was reported in no sunitinib-treated subjects and 1 (1.0%) subject receiving standard of care. In the other study hypothyroidism was reported in a total of 31 (13%) sunitinib subjects and 2 (0.8%) capecitabine subjects. Blood TSH increase was reported in 12 (5.0%) sunitinib subjects and no capecitabine subjects. Hyperthyroidism was reported in 4 (1.7%) sunitinib subjects and no capecitabine subjects. Blood TSH decrease was reported in 3 (1.3%) sunitinib subjects and no capecitabine subjects. T4 increase was reported in 2 (0.8%) sunitinib subjects and 1 (0.4%) capecitabine subject. T3 increase was reported in 1 (0.8%) sunitinib subject and no capecitabine subjects. All thyroid-related events reported were Grade 1-2.

Cases of hyperthyroidism, some followed by hypothyroidism, and cases of thyroiditis have been uncommonly reported in clinical trials and through post-marketing experience.

Pancreatitis

Increases in serum lipase and amylase activities were observed in patients with various solid tumours who received sunitinib. Increases in lipase activities were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with various solid tumours.

Pancreatitis has been observed uncommonly (<1%) in patients receiving sunitinib for GIST or MRCC.

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

No treatment-related pancreatitis was reported in the phase 3 pNET study.

Hepatotoxicity

Hepatotoxicity has been observed in patients treated with sunitinib. Cases of hepatic failure, some with a fatal outcome, were observed in <1% of solid tumor patients treated with sunitinib. Monitor liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) before initiation of treatment, during each cycle of treatment, and as clinically indicated. If signs or symptoms of hepatic failure are present, sunitinib should be discontinued and appropriate supportive care should be provided.

Hepatobiliary disorders

Sunitinib treatment may be associated with cholecystitis, including acalculous cholecystitis and emphysematous cholecystitis. In clinical registrational studies the incidence of cholecystitis was 0.5%. Post-marketing cases of cholecystitis have been reported.

Renal function

Cases of renal impairment, renal failure and/or acute renal failure, in some cases with fatal outcome, have been reported.

Risk factors associated with renal impairment/failure in patients receiving sunitinib included, in addition to underlying renal cell carcinoma, older age, diabetes mellitus, underlying renal impairment, cardiac failure, hypertension, sepsis, dehydration/hypovolemia, and rhabdomyolysis.

The safety of continued sunitinib treatment in patients with moderate to severe proteinuria has not been systematically eva luated.

Cases of proteinuria and rare cases of nephrotic syndrome have been reported. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. Discontinue sunitinib in patients with nephrotic syndrome.

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 SUTENT. The majority of cases occurred 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 SUTENT and intravenous bisphosphonates are used either simultaneously or sequentially.

Invasive dental procedures are also an identified risk factor. Prior to treatment with SUTENT, 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 (see section 4.8).

Hypersensitivity/angioedema

If angioedema due to hypersensitivity occurs, sunitinib treatment should be interrupted and standard medical care provided.

Nervous system disorders

Dysgeusia was reported in approximately 28% of patients receiving sunitinib in clinical trials.

Seizures

In clinical studies of sunitinib and from post-marketing experience, seizures have been observed in subjects with or without radiological evidence of brain metastases. In addition, there have been few reports (<1%), some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning and visual loss, including cortical blindness, should be controlled with medical management including control of hypertension. Temporary suspension of sunitinib is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Tumour Lysis Syndrome (TLS)

Cases of TLS, some fatal, have been rarely observed in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib. Risk factors for TLS include high tumour burden, preexisting chronic renal insufficiency, oliguria, dehydration, hypotension, and acidic urine. These patients should be monitored closely and treated as clinically indicated, and prophylactic hydration should be considered.

Infections

Serious infections, with or without neutropenia, including some with a fatal outcome, have been reported. The infections observed most commonly with sunitinib treatment are infections typically seen in cancer patients, e.g. respiratory, urinary tract, skin infections and sepsis.

Rare cases of necrotising fasciitis, including of the perineum, sometimes fatal, have been reported. Sunitinib therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.

Hypoglycaemia

Decreases in blood glucose, in some cases clinically symptomatic and requiring hospitalization due to loss of consciousness, have been reported during sunitinib treatment. In case of symptomatic hypoglycemia, sunitinib should be temporarily interrupted. Blood glucose levels in diabetic patients should be checked regularly in order to assess if anti-diabetic medicinal product's dosage needs to be adjusted to minimize the risk of hypoglycaemia.

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 + primary metabolite] C_max and AUC_0-∞ values of 49% and 51%, 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 alternate concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered.

If this is not possible, the dose of SUTENT 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 (see section 4.2).

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] C_max and AUC_0-∞ 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 medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

If this is not possible, the dose of SUTENT may need to be increased in 12.5 mg increments (up to 87.5 mg per day for GIST and MRCC or 62.5 mg per day for pNET), based on careful monitoring of tolerability (see section 4.2).

Contraception in males and females

Women of childbearing potential should be advised to use effective contraception and avoid becoming pregnant while receiving treatment with SUTENT.

Pregnancy

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

Breast-feeding

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 breast-feeding infants, women should not breast-feed while taking SUTENT.

Fertility

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

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