Sutent Adverse Reactions

Adverse drug reaction (ADR) frequencies presented represent the frequencies of the events that occurred in sunitinib-treated subjects regardless of causality assessment.
The most important serious adverse reactions associated with sunitinib treatment of patients with solid tumors* were pulmonary embolism, thrombocytopenia, tumor hemorrhage, febrile neutropenia, and hypertension (see Precautions).
The most common ADRs of any grade included: fatigue; gastrointestinal disorders, such as diarrhea, nausea, stomatitis, dyspepsia and vomiting; skin discoloration; rash; palmar plantar erythrodysesthesia; dry skin; hair color changes; mucosal inflammation; asthenia; dysgeusia; anorexia and hypertension. Fatigue, hypertension and neutropenia were the most common ADRs of Grade 3 maximum severity and increased lipase was the most frequently occurring ADRs of Grade 4 maximum severity in subjects with solid tumors.
Epistaxis was the most frequent hemorrhagic ADR, having been reported for approximately half of the subjects with solid tumors* who experienced hemorrhagic events (see Precautions).
In clinical studies of sunitinib, seizures have been observed in subjects with radiological evidence of brain metastases. In addition, there have been reports (<1%), some fatal, of subjects presenting with seizures and radiological evidence of RPLS (see Precautions).
* From initial clinical trials including primarily patients with GIST and cytokine-refractory MRCC.
Table 7 presents the ADRs that were reported in GIST patients who received sunitinib. (See Table 7.)

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Table 8 presents the ADRs that were reported in cytokine-refractory MRCC patients who received sunitinib. (See Table 8.)

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Table 9 presents the ADRs that were reported in patients with pNET who received sunitinib. (See Table 9.)

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Table 10 presents the ADRs that were reported in patients with treatment-naive MRCC who received sunitinib or interferon-α (IFN-α). (See Table 10.)

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Table 11 presents the ADRs that were reported in patients with RCC who received adjuvant therapy with sunitinib. (See Table 11.)

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Post-marketing experience: The ADRs that have been identified during post-marketing use of sunitinib from any source (clinical trials, spontaneous reports and other sources) are listed as follows (see Precautions). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Infections and infestations: Cases of serious infection (with or without neutropenia), in some cases with fatal outcome, have been reported. The infections observed most commonly with sunitinib treatment are infections typically seen in cancer patients, e.g., respiratory infections (e.g., pneumonia, bronchitis), urinary tract infections, skin infections (e.g., cellulitis), sepsis/septic shock, and abscess (e.g., oral, genital, anorectal, skin, limb, visceral). Infections may be bacterial, or fungal. Rare cases of necrotizing fasciitis, including of the perineum, sometimes fatal, have been reported (see Precautions).
Investigations: TSH, and blood uric acid increase have been reported.
Blood and lymphatic system disorders: Cases of thrombotic microangiopathy, in some cases with fatal outcome, have been reported. Temporary suspension of sunitinib is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.
Immune system disorders: Hypersensitivity reactions, including angioedema, have been reported.
Endocrine disorders: Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience (see Precautions). Cases of thyroiditis have been reported.
Metabolism and nutrition disorders: Cases of TLS, some fatal, have been reported in patients treated with sunitinib.
Decreases in blood glucose, in some cases clinically symptomatic, have been reported during sunitinib treatment.
Nervous system disorders: Taste disturbance, including ageusia, has been reported.
Cardiac disorders: Cardiac failure, cardiac failure congestive, prolonged QT interval, and Torsade de pointes. Cardiomyopathy, myocardial ischaemia, left ventricular failure, and myocardial infarction, in some cases with fatal outcome, have been reported.
Vascular disorders: Arterial thromboembolic events (ATE): 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.
Venous thromboembolic events (VTE): In the double-blind treatment phase of GIST study, 7 patients (3%) on sunitinib and none on placebo experienced VTE; 5 of the 7 were Grade 3 deep vein 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 for treatment-naive MRCC and 4 (2%) patients in the 2 cytokine-refractory MRCC studies had VTE reported. Nine of these patients had pulmonary embolism: 1 was Grade 2 and 8 were Grade 4. Eight 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 subjects receiving IFN-α, 6 (2%) VTE occurred; 1 (<1%) patient experienced a Grade 3 DVT and 5 (1%) patients had pulmonary embolism, all Grade 4. In the adjuvant treatment of RCC study, pulmonary embolism was reported in 2.0% of patients receiving sunitinib and 0.7% of patients receiving placebo. DVT was reported in 0.3% of patients receiving sunitinib and placebo.
Pulmonary embolism was reported in approximately 2.2% of patients with solid tumors* who received sunitinib. None of these events resulted in a patient discontinuing treatment with sunitinib; however, a dose reduction or temporary delay in treatment occurred in a few cases. There were no further occurrences of pulmonary embolism in these patients after treatment was resumed.
*From initial clinical trials including primarily patients with GIST and cytokine-refractory MRCC.
Hemorrhagic events: Cases of pulmonary, gastrointestinal, tumor, urinary tract, and brain hemorrhage, some fatal, have been reported in patients treated with sunitinib.
Hepatobiliary disorders: Hepatic failure and cholecystitis, particularly acalculous cholecystitis.
Respiratory, thoracic and mediastinal disorders: Pulmonary embolism, in some cases with fatal outcome, has been reported. Cases of Pleural effusion have been reported.
Gastrointestinal disorders: Pancreatitis, gastrointestinal perforation, and esophagitis.
Skin and subcutaneous tissue disorders: Cases of pyoderma gangrenosum, erythema multiforme and Stevens-Johnson syndrome have been reported.
Musculoskeletal and connective tissue disorders: Rare cases of myopathy and/or rhabdomyolysis with or without acute renal failure, in some cases with fatal outcome, have been reported. Most of these patients had pre-existing risk factors and/or were receiving concomitant medications known to be associated with these adverse reactions. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.
Cases of fistula formation, sometimes associated with tumor necrosis and/or regression, in some cases with fatal outcome, have been reported.
Cases of ONJ have been reported in patients treated with sunitinib, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to IV bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also Precautions).
Renal and urinary disorders: Cases of renal impairment and/or failure, in some cases with fatal outcome, have been reported. Cases of proteinuria and nephrotic syndrome have been reported (see Precautions).
Long-term safety in RCC: The long-term safety of sunitinib in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory and cytokine-refractory treatment settings. The analysis included 5739 patients, of whom 807 (14%) were treated for ≥2 years up to 6 years. Prolonged treatment with sunitinib was not associated with new types or increased severity of treatment-related adverse events and except for hypothyroidism, toxicity was not cumulative.