Skin and Tissues: Skin discoloration, possibly due to the active substance color (yellow) was a very common adverse reaction reported in clinical trials. 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 previously mentioned events were not cumulative, were typically reversible and generally did not result in treatment discontinuation.
Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM) and cases suggestive of Stevens-Johnson syndrome (SJS), some of which were fatal. If signs or symptoms of SJS 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 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.
Hemorrhagic Events: Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included gastrointestinal (GI), respiratory, tumor, urinary tract and brain hemorrhages. In clinical trials, tumor hemorrhage occurred in approximately 2% of subjects with GIST. These events may occur suddenly, and in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, 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 advanced RCC, GIST and metastatic non-small cell lung cancer (NSCLC). Sunitinib is not approved for use in patients with NSCLC.
Treatment-emergent bleeding events occurred in 18% of subjects receiving sunitinib in the double-blind treatment phase of GIST Study compared to 17% of subjects receiving placebo. In subjects receiving sunitinib for treatment-naïve advanced RCC, 39% of patients had bleeding events compared with 11% of subjects receiving interferon-α (IFN-α). Seventeen (4.5%) subjects on sunitinib versus 5 (1.7%) of subjects on IFN-α experienced Grade 3 or greater bleeding events. Of subjects receiving sunitinib for cytokine-refractory advanced RCC, 26% experienced bleeding. Bleeding events, excluding epistaxis, occurred in 21.7% of subjects receiving sunitinib in the phase 3 pNET study compared to 9.85% of subjects receiving placebo. Routine assessment of these events should include complete blood counts and physical examination.
Gastrointestinal Tract: Serious, sometimes fatal GI complications including GI perforation, have occurred in subjects with intra-abdominal malignancies treated with sunitinib.
Gastrointestinal Events: Nausea, diarrhea, stomatitis, dyspepsia, and vomiting were the most commonly reported treatment-related GI events. Supportive care for GI adverse events requiring treatment may include anti-emetic or anti-diarrheal medication.
Pancreatitis: Pancreatitis has been reported in clinical trials of sunitinib. Increases in serum lipase and amylase were observed in subjects with various solid tumors who received sunitinib. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with various solid tumors. If symptoms of pancreatitis are present, patients should have sunitinib discontinued and be provided with appropriate supportive care.
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. Sunitinib should be interrupted for Grade 3 or 4 hepatic-related adverse events and discontinued if there is no resolution.
Hematological: Decreased absolute neutrophil counts and decreased platelet counts were reported in clinical trials. Such events were not cumulative, were typically reversible and generally did not result in treatment discontinuation. In addition, some cases of fatal hemorrhage associated with thrombocytopenia were reported through post-marketing experience.
Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with sunitinib.
Cardiovascular: Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia and myocardial infarction, some of which were fatal, have been reported through post-marketing experience. 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 ≥20% and below the lower limit of normal (LLN) occurred in approximately 2% of sunitinib-treated GIST subjects, 4% of cytokine-refractory advanced RCC subjects and 2% of placebo-treated subjects. These LVEF declines do not appear to have been progressive and often improved as treatment continued.
In the treatment-naïve advanced RCC study, 27% and 15% of subjects on sunitinib and IFN-α, respectively, had an LVEF value below the LLN. Two (<1%) subjects who received sunitinib were diagnosed with congestive heart failure (CHF).
Cardiac failure, cardiac failure congestive, or left ventricular failure were reported in 0.8% of subjects with solid tumors* and 1% of subjects treated with placebo. In the phase 3 pNET study, 1 (1.2%) subject who received sunitinib had treatment-related fatal cardiac failure.
Subjects who presented with cardiac events, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism within 12 months prior to sunitinib administration, were excluded from sunitinib clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib. Baseline and periodic evaluations of LVEF should also be considered while the patient is receiving sunitinib. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.
In the presence of clinical manifestations of CHF, discontinuation of sunitinib is recommended. The dose of sunitinib should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.
QT Interval Prolongation: At approximately twice the therapeutic concentrations, sunitinib has been shown to prolong the QTcF (Fridericia's correction) interval (see Pharmacology: Pharmacodynamics: Clinical studies under Actions). There were no patients with greater than Grade 2 Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) QT/QTc interval prolongation. QT interval prolongation may lead to an increased risk for 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 patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and the dose of sunitinib reduced (see Dosage & Administration and Interactions).
Hypertension: Hypertension was a very common adverse reaction reported in clinical trials in subjects with solid tumors, including primarily GIST and cytokine-refractory RCC†. Sunitinib dosing was reduced or temporarily delayed in approximately 2.7% of this patient population. None of these subjects were discontinued from treatment with sunitinib. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 4.7% of this patient population. Hypertension was reported in approximately 33.9% of subjects receiving sunitinib for treatment-naïve advanced RCC compared to 3.6% of subjects receiving IFN-α. Severe hypertension occurred in 12% of treatment-naïve subjects on sunitinib and <1% of patients on IFN-α. Hypertension was reported in 26.5% of subjects receiving sunitinib in a phase 3 pNET study, compared to 4.9% of subjects receiving placebo. Severe hypertension occurred in 10% of pNET subjects on sunitinib and 3% of subjects 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.
* From initial clinical trials including primarily patients with GIST and cytokine-refractory advanced RCC.
† From initial clinical trials including primarily patients with GIST and cytokine-refractory advanced RCC. 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.
Thyroid Dysfunction: Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of sunitinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on sunitinib treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.
Acquired hypothyroidism was noted in 6.2% of GIST subjects on sunitinib versus 1% on placebo. Hypothyroidism was reported as an adverse event in 16% of subjects on sunitinib in the treatment-naïve advanced RCC study and 3 subjects (<1%) in the IFN-α arm, and in 4% of subjects across the 2 cytokine-refractory advanced RCC studies. Additionally, thyroid stimulating hormone (TSH) elevations were reported in 2% of cytokine-refractory advanced RCC subjects. Overall, 7% of the cytokine-refractory advanced RCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism. In the phase 3 pNET study, hypothyroidism was reported in 6 (7.2%) subjects receiving sunitinib and in 1 (1.2%) subject on placebo.
Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.
Seizures: In clinical studies of sunitinib, seizures have been observed in subjects with radiological evidence of brain metastases. In addition, there have been rare (<1%) reports, 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.
Surgical Procedures: Cases of impaired wound healing have been reported during sunitinib therapy. 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): ONJ has been uncommonly observed in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib. The majority of cases occurred in patients who had received prior or concomitant treatment with intravenous (IV) bisphosphonates, for which ONJ is an identified risk. Caution should therefore be exercised when sunitinib and IV bisphosphonates are used either simultaneously or sequentially.
Invasive dental procedures are also an identified risk factor for ONJ. Prior to treatment with sunitinib, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with sunitinib, who have previously received or are receiving IV bisphosphonates, invasive dental procedures should be avoided, if possible.
Tumor 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. Patients generally at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as clinically indicated.
Necrotizing Fasciitis: Rare cases of necrotizing fasciitis, including of the perineum, sometimes fatal, have been reported. Sunitinib therapy should be discontinued in patients who develop necrotizing fasciitis, and appropriate treatment should be promptly initiated.
Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic 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. Discontinue sunitinib in patients developing TMA. Reversal of the effects of TMA has been observed after treatment discontinuation.
Proteinuria: Cases of proteinuria and nephrotic syndrome have been reported. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. The safety of continued sunitinib treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue sunitinib in patients with nephrotic syndrome.
Hypoglycemia: Decreases in blood glucose, in some cases clinically symptomatic, have been reported during sunitinib treatment. Blood glucose levels in diabetic patients should be checked regularly in order to assess if anti-diabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive or operate machinery have been performed. Patients should be advised that they may experience dizziness during treatment with sunitinib.