Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most serious adverse reactions associated with sunitinib, some fatal, are renal failure, heart failure, pulmonary embolism, gastrointestinal perforation, and haemorrhages (e.g., respiratory tract, gastrointestinal, tumour, urinary tract, and brain haemorrhages). The most common adverse reactions of any grade (experienced by patients in RCC, GIST, and pNET registrational trials) included decreased appetite, taste disturbance, hypertension, fatigue, gastrointestinal disorders (i.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. Haematological disorders (e.g., neutropenia, thrombocytopenia, and anaemia) are amongst the most common adverse drug reactions.

Fatal events other than those listed in section 4.4 above or in section 4.8 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                             Viral infectionsa        Necrotising infestations                               Respiratory              fasciitis* infectionsb,*            Bacterial infectionsg
Abscessc,*
Fungal infectionsd
Urinary tract infection
Skin infectionse
Sepsisf,*
Blood and             Neutropoenia         Lymphopoenia             Pancytopenia            Thrombotic lymphatic system      Thrombocytopoenia                                                     microangiopathy disorders             Anaemia                                                               h,* 
Leukopoenia
Immune system                                                       Hypersensitivity        Angioedema disorders
Endocrine             Hypothyroidism                                Hyperthyroidism         Thyroiditis disorders
Metabolism and        Decreased appetitei Dehydration                                       Tumour lysis nutrition disorders                       Hypoglycaemia                                     syndrome* Psychiatric           Insomnia            Depression disorders
Nervous system        Dizziness            Neuropathy               Cerebral                Posterior      Hyperammonaemic disorders             Headache             peripheral               haemorrhage*            reversible     encephalopathy Taste disturbancej   Paraesthesia             Cerebrovascular         encephalopathy Hypoaesthesia            accident*               syndrome*
Hyperaesthesia           Transient ischaemic attack
Eye disorders                              Periorbital oedema
Eyelid oedema
Lacrimation increased


System organ class Very common          Common                   Uncommon           Rare               Not known 
Cardiac disorders                       Myocardial           Cardiac failure        Left ventricular ischemiak,*          congestive             failure*
Ejection fraction    Myocardial             Torsade de decreasedl           infarctionm,*          pointes
Cardiac failure*
Cardiomyopathy*
Pericardial effusion
Electrocardiogram
QT prolonged
Vascular disorders Hypertension         Deep vein thrombosis Tumour                                    Aneurysms and Hot flush            haemorrhage*                              artery dissections* Flushing
Respiratory,       Dyspnoea             Pulmonary            Pulmonary thoracic and       Epistaxis            embolism*            haemorrhage* * mediastinal        Cough                Pleural effusion     Respiratory failure* disorders                               Haemoptysis
Dyspnoea exertional
Oropharyngeal painn
Nasal congestion
Nasal dryness
Gastrointestinal   Stomatitiso          Gastro-oesophageal Gastrointestinal disorders          Abdominal painp      reflux disease       perforationq,* Vomiting             Dysphagia            Pancreatitis
Diarrhoea            Gastrointestinal     Anal fistula
Dyspepsia            haemorrhage*         Colitisr
Nausea               Oesophagitis*
Constipation         Abdominal distension
Abdominal discomfort
Rectal haemorrhage
Gingival bleeding
Mouth ulceration
Proctalgia
Cheilitis
Haemorrhoids
Glossodynia
Oral pain
Dry mouth
Flatulence
Oral discomfort
Eructation
Hepatobiliary                                                Hepatic failure*       Hepatitis disorders                                                    Cholecystitiss,* Hepatic function abnormal
Skin and           Skin discolourationt Skin exfoliation                            Erythema subcutaneous       Palmar-plantar       Skin reactionv                              multiforme* tissue disorders   erythrodysaesthesia Eczema                                       Stevens-Johnson syndrome             Blister                                     syndrome* Rashu                Erythema                                    Pyoderma Hair colour changes Alopecia                                     gangrenosum Dry skin             Acne                                        Toxic epidermal Pruritus                                    necrolysis*
Skin hyperpigmentation
Skin lesion
Hyperkeratosis
Dermatitis
Nail disorderw
Musculoskeletal    Pain in extremity    Musculoskeletal pain Osteonecrosis of the   Rhabdomyolysis and connective     Arthralgia           Muscle spasms        jaw                    *  tissue disorders   Back pain            Myalgia              Fistula*               Myopathy Muscular weakness
Renal and urinary                       Renal failure*       Haemorrhage            Nephrotic disorders                               Renal failure acute* urinary tract          syndrome Chromaturia
Proteinuria
System organ class Very common             Common                   Uncommon              Rare            Not known 
General disorders Mucosal                  Chest pain             Impaired healing and administration inflammation            Pain site conditions    Fatiguex                Influenza like illness
Oedemay                 Chills
Pyrexia
Investigations                             Weight decreased         Blood creatine White blood cell         phosphokinase count decreased          increased
Lipase increased         Blood thyroid
Platelet count           stimulating hormone decreased                increased
Haemoglobin decreased
Amylase increasedz
Aspartate aminotransferase increased
Alanine aminotransferase increased
Blood creatinine increased
Blood pressure increased
Blood uric acid 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 haemolytic uraemic syndrome.
i    Decreased appetite and anorexia j    Dysgeusia, ageusia, and taste disturbance.
k    Acute coronary syndrome, angina pectoris, angina unstable, coronary artery occlusion, and myocardial ischaemia.
l    Ejection fraction decreased/abnormal.
m    Acute myocardial infarction, myocardial infarction, and silent myocardial infarction.
n    Oropharyngeal and pharyngolaryngeal pain.
o    Stomatitis and aphtous stomatitis.
p    Abdominal pain, abdominal pain lower, and abdominal pain upper.
q    Gastrointestinal perforation and intestinal perforation.
r    Colitis and colitis ischaemic.
s    Cholecystitis and acalculous cholecystitis.
t    Yellow skin, skin discolouration, and pigmentation disorder.
u    Dermatitis psoriasiform, exfoliative rash, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, and rash pruritic.
v    Skin reaction and skin disorder.
w    Nail disorder and discolouration.
x    Fatigue and asthenia.
y    Face oedema, oedema, and oedema peripheral.
z    Amylase and amylase increased.

Description of selected adverse reactions

Infections and infestations
Cases of serious infection (with or without neutropenia), including cases with fatal outcome, have been reported. Cases of necrotising fasciitis, including of the perineum, sometimes fatal, have been reported (see also section 4.4).


Blood and lymphatic system disorders
Decreased absolute neutrophil counts of Grade 3 and 4 severities, 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 severities, 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 (see section 4.4).

Bleeding events were reported in 18% of patients receiving sunitinib in a Phase 3 GIST study vs 17% of patients receiving placebo. In patients receiving sunitinib for treatment-naïve MRCC, 39% had bleeding events vs 11% of patients receiving interferon- (IFN-α). Seventeen (4.5%) patients on sunitinib versus 5 (1.7%) 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, were reported in 21.7% of patients receiving sunitinib in the Phase 3 pNET study compared to 9.85% of patients receiving placebo (see section 4.4) 
In clinical trials, tumour haemorrhage was reported in approximately 2% of patients with GIST.

Immune system disorders
Hypersensitivity reactions, including angioedema, have been reported (see section 4.4).
Endocrine disorders
Hypothyroidism was reported as an adverse reaction in 7 patients (4%) receiving sunitinib across the 2 cytokine-refractory MRCC studies; in 61 patients (16%) on sunitinib and 3 patients (< 1%) in the
IFN- arm in the treatment-naïve MRCC study.

Additionally, thyroid-stimulating hormone (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 1 patient (1.2%) on placebo.

Thyroid function was monitored prospectively in 2 studies in patients with breast cancer; Sutent is not approved for use in breast cancer. In 1 study, hypothyroidism was reported in 15 (13.6%) patients on sunitinib and 3 (2.9%) patients on standard of care. Blood TSH increase was reported in 1 (0.9%) patient on sunitinib and no patients on standard of care. Hyperthyroidism was reported in no sunitinib-treated patients and 1 (1.0%) patient receiving standard of care. In the other study hypothyroidism was reported in a total of 31 (13%) patients on sunitinib and 2 (0.8%) patients on capecitabine. Blood TSH increase was reported in 12 (5.0%) patients on sunitinib and no patients on capecitabine. Hyperthyroidism was reported in 4 (1.7%) patients on sunitinib and no patients on capecitabine. Blood TSH decrease was reported in 3 (1.3%) patients on sunitinib and no patients on capecitabine. T4 increase was reported in 2 (0.8%) patients on sunitinib and 1 (0.4%) patient on capecitabine. T3 increase was reported in 1 (0.8%) patient on sunitinib and no patients on capecitabine. All thyroid-related events reported were Grade 1-2 (see section 4.4).

Metabolism and nutrition disorders
A higher incidence rate of hypoglycaemia events was reported in patients with pNET in comparison to MRCC and GIST. Nevertheless, most of these adverse events observed in clinical studies were not considered related to study treatment (see section 4.4).

Nervous system disorders
In clinical studies of sunitinib and from postmarketing surveillance, there have been few reports (< 1%), some fatal, of subjects presenting with seizures and radiological evidence of RPLS. Seizures have been observed in patients with or without radiological evidence of brain metastases (see section 4.4).


Cardiac disorders
In clinical trials, decreases in left ventricular ejection fraction (LVEF) of  20% and below the lower limit of normal were reported 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% of patients on sunitinib and 15% of patients on IFN- had an LVEF value below the lower limit of normal. Two patients (< 1%) who received sunitinib were diagnosed with 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 were reported 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- arm and 0% of patients on the sunitinib arm experienced fatal cardiac events. In the Phase 3 pNET study, 1 (1%) patient who received sunitinib had treatment-related fatal cardiac failure.

Vascular disorders
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. Sunitinib was not permanently discontinued in any of these patients. Severe hypertension (> 200 mmHg systolic or 110 mmHg diastolic) was reported in 4.7% of patients with solid tumours. Hypertension was reported in approximately 33.9% of patients receiving sunitinib for treatment-naïve MRCC compared to 3.6% of patients receiving IFN-. Severe hypertension was reported in 12% of treatment-naïve patients on sunitinib and < 1% of patients on IFN-. 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 was reported in 10% of pNET patients on sunitinib and 3% of patients on placebo.

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 RCC.

Seven patients (3%) on sunitinib and none on placebo in a Phase 3 GIST study experienced venous thromboembolic events; 5 of the 7 were Grade 3 deep venous thrombosis (DVT) and 2 were Grade 1 or 2. Four of these 7 GIST patients discontinued treatment following first observation of DVT.

Thirteen patients (3%) receiving sunitinib in the Phase 3 treatment-naïve MRCC study and 4 patients (2%) on the 2 cytokine-refractory MRCC studies had venous thromboembolic events reported. Nine of these patients had pulmonary embolisms; 1 was Grade 2 and 8 were Grade 4. Eight of these patients had DVT; 1 with Grade 1, 2 with Grade 2, 4 with Grade 3, and 1 with Grade 4. One patient with pulmonary embolism in the cytokine-refractory MRCC study experienced dose interruption.

In treatment-naïve MRCC patients receiving IFN-, 6 (2%) venous thromboembolic events were reported; 1 patient (< 1%) experienced a Grade 3 DVT and 5 patients (1%) had pulmonary embolisms, all with Grade 4.

Venous thromboembolic events were reported for 1 (1.2%) patient in the sunitinib arm and 5 (6.1%) patients in the placebo arm in the Phase 3 pNET study. Two of these patients on placebo had DVT, 1 with Grade 2 and 1 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 the postmarketing surveillance.


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. 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 the postmarketing surveillance.

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.

Gastrointestinal disorders
Pancreatitis has been observed uncommonly (< 1%) in patients receiving sunitinib for GIST or MRCC. No treatment-related pancreatitis was reported in the Phase 3 pNET study (see section 4.4).

Fatal gastrointestinal bleeding was reported in 0.98% of patients receiving placebo in the GIST Phase 3 study.

Hepatobiliary disorders
Hepatic dysfunction has been reported and may include Liver Function Test abnormalities, hepatitis, or liver failure (see section 4.4).

Skin and subcutaneous tissue disorders
Cases of pyoderma gangrenosum, generally reversible after discontinuation of sunitinib, have been reported (see also section 4.4).

Musculoskeletal and connective tissue disorders
Cases of myopathy and/or rhabdomyolysis, some with acute renal failure, have been reported. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice (see section 4.4).

Cases of fistula formation, sometimes associated with tumour necrosis and regression, in some cases with fatal outcomes, have been reported (see section 4.4).

Cases of ONJ have been reported in patients treated with Sutent, most of which occurred in patients who had identified risk factors for ONJ, in particular, exposure to intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also section 4.4).

Investigations
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 were reported in 0.5%, and changes from baseline in excess of 60 msec were reported in 1.1% of the 450 solid tumour patients; both of these parameters are recognised as potentially significant changes. At approximately twice therapeutic concentrations, sunitinib has been shown to prolong the QTcF interval (Fridericia corrected QT interval).

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% confidence interval [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 postdose (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 evaluable or intent-to-treat (ITT) populations were observed to develop QTc interval prolongation considered as “severe” (i.e. equal to or greater than Grade 3 by Common Terminology Criteria for Adverse Events [CTCAE] version 3.0).

At therapeutic plasma concentrations, the maximum QTcF interval (Frederica’s correction) mean change from baseline was 9 msec (90% CI: 15.1 msec). 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) (see section 4.4).

Long-term safety in MRCC
The long-term safety of sunitinib in patients with MRCC was analysed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings in 5,739 patients, of whom 807 (14%) were treated for ≥ 2 years up to 6 years. In the 807 patients who received long-term sunitinib treatment, most treatment-related adverse events (TRAEs) occurred initially in the first 6 months–1 year and then were stable or decreased in frequency over time, with the exception of hypothyroidism, which gradually increased over time, with new cases occurring over the 6 year period. Prolonged treatment with sunitinib did not appear to be associated with new types of TRAEs.

Paediatric population
The safety profile of sunitinib has been derived from a Phase 1 dose-escalation study, a Phase 2 open-label study, a Phase 1/2 single-arm study and from publications as described below.

A Phase 1 dose-escalation study of oral sunitinib was conducted in 35 patients comprised of 30 paediatric patients (aged 3 years to 17 years) and 5 young adult patients (aged 18 to 21 years), with refractory solid tumours, the majority of whom had a primary diagnosis of brain tumour. All study participants experienced adverse drug reactions; most of these were severe (toxicity grade ≥ 3) and included cardiac toxicity. The most common adverse drug reactions were gastrointestinal (GI) toxicity, neutropenia, fatigue, and ALT elevation. The risk of cardiac adverse drug reactions appeared to be higher in paediatric patients with previous exposure to cardiac irradiation or anthracycline compared to those paediatric patients without previous exposure. In these paediatric patients without previous exposure to anthracyclines or cardiac irradiation, the maximum tolerated dose (MTD) has been identified (see section 5.1).

A phase 2 open-label study was conducted in 29 patients comprised of 27 paediatric patients (aged 3 years to 16 years) and 2 young adult patients (aged 18 years to 19 years) with recurrent/progressive/refractory high grade glioma (HGG) or ependymoma. There were no Grade 5 adverse reactions in either group. The most common (≥10%) treatment-related adverse events were neutrophil count decreased (6 [20.7%] patients) and haemorrhage intracranial (3[10.3%] patients).

A Phase 1/2 single-arm, study was conducted in 6 paediatric patients (aged 13 years to 16 years) with advanced unresectable GIST. The most frequent adverse drug reactions were diarrhoea, nausea, WBC count decreased, neutropenia, and headache in 3 (50.0%) patients each, primarily Grade 1 or 2 in severity. Four out of 6 patients (66.7%) experienced Grade 3-4 treatment-related adverse events (Grade 3 hypophosphataemia, neutropenia, and thrombocytopenia in 1 patient each and a Grade 4 neutropenia in 1 patient). There were no serious adverse events (SAEs) or Grade 5 adverse drug 
 reactions reported in this study. In both the clinical study and the publications, the safety profile was consistent with the known safety profile in adults.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/