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SUNItinib

Pronunciation

(su NIT e nib)

Index Terms

  • SU011248
  • SU11248
  • Sunitinib Malate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Sutent: 12.5 mg, 25 mg, 37.5 mg, 50 mg

Brand Names: U.S.

  • Sutent

Pharmacologic Category

  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor
  • Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Exhibits antitumor and antiangiogenic properties by inhibiting multiple receptor tyrosine kinases, including platelet-derived growth factors (PDGFRα and PDGFRβ), vascular endothelial growth factors (VEGFR1, VEGFR2, and VEGFR3), FMS-like tyrosine kinase-3 (FLT3), colony-stimulating factor type 1 (CSF-1R), and glial cell-line-derived neurotrophic factor receptor (RET).

Distribution

Vd/F: 2230 L

Metabolism

Hepatic; primarily metabolized by CYP3A4 to the N-desethyl metabolite SU12662 (active)

Excretion

Feces (61%); urine (16%)

Time to Peak

6 to 12 hours

Half-Life Elimination

Terminal: Sunitinib: 40 to 60 hours; SU12662: 80 to 110 hours

Protein Binding

Sunitinib: 95%; SU12662: 90%

Special Populations: Renal Function Impairment

Systemic exposure was 47% lower in subjects with ESRD on hemodialysis compared with patients with normal renal function.

Use: Labeled Indications

Gastrointestinal stromal tumor: Treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib

Pancreatic neuroendocrine tumors, advanced: Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease

Renal cell carcinoma, advanced: Treatment of advanced renal cell carcinoma

Use: Unlabeled

Treatment of advanced thyroid cancer; treatment of non-GIST soft tissue sarcomas

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: Hypersensitivity to sunitinib or any component of the formulation; pregnancy

Dosing: Adult

Note: Dosage modifications should be done in increments or decrements of 12.5 mg; individualize based on safety and tolerability.

Gastrointestinal stromal tumor (GIST): Oral: 50 mg once daily for 4 weeks of a 6-week treatment cycle (4 weeks on, 2 weeks off)

GIST off-label dosing: Oral: 37.5 mg once daily, continuous daily dosing (George, 2009, EJC)

Pancreatic neuroendocrine tumors, advanced (PNET): Oral: 37.5 mg once daily, continuous daily dosing (maximum daily dose used in clinical trials: 50 mg)

Renal cell cancer, advanced (RCC): Oral: 50 mg once daily for 4 weeks of a 6-week treatment cycle (4 weeks on, 2 weeks off)

Soft tissue sarcoma, non-GIST (off-label use): Oral: 37.5 mg once daily, continuous daily dosing (George, 2009, JCO)

Thyroid cancer, refractory (off-label use): Oral: 50 mg once daily for 4 weeks of a 6-week treatment cycle (4 weeks on, 2 weeks off) (Cohen, 2008; Ravaud, 2008)

Dosage adjustment with concurrent CYP3A4 inhibitor: Avoid concomitant administration with strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, protease inhibitors, telithromycin, voriconazole); if concomitant administration with a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction to a minimum of 37.5 mg/day (GIST, RCC) or 25 mg/day (PNET).

Dosage adjustment with concurrent CYP3A4 inducer: Avoid concomitant administration with strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St John’s wort); if concomitant administration with a strong CYP3A4 inducer cannot be avoided, consider a dosage increase (with careful monitoring for toxicity) to a maximum of 87.5 mg/day (GIST, RCC) or 62.5 mg/day (PNET).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild, moderate, or severe impairment: No initial adjustment required; subsequent adjustments may be needed based on safety and tolerance.

ESRD on hemodialysis: No initial adjustment required; subsequent dosage increases (up to twofold) may be required due to reduced (47%) exposure

Dosing: Hepatic Impairment

Pre-existing hepatic impairment: No adjustment is necessary with mild-to-moderate (Child-Pugh class A or B) hepatic impairment; not studied in patients with severe (Child-Pugh class C) hepatic impairment. Studies excluded patients with ALT or AST >2.5 x ULN, or if due to liver metastases, ALT or AST >5 x ULN.

Hepatotoxicity during treatment: Hepatic adverse events ≥ grade 3 or 4: Withhold treatment; discontinue if hepatotoxicity does not resolve. Do not reinitiate in patients with severe changes in liver function tests or other signs/symptoms of liver failure.

Dosing: Adjustment for Toxicity

Dosage modifications should be done in increments or decrements of 12.5 mg; individualize based on safety and tolerability.

Cardiac toxicity:

Ejection fraction <50% and >20% below baseline without evidence of CHF: Interrupt treatment and/or reduce dose.

LV dysfunction with CHF clinical manifestations: Discontinue treatment.

Dermatologic toxicity:

Signs/symptoms of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), including progressive skin rash, often with blisters or mucosal lesions: Discontinue sunitinib; do not restart treatment if SJS or TEN are suspected.

Necrotizing fasciitis: Discontinue sunitinib.

Hypertension, severe: Temporarily interrupt treatment until hypertension is controlled.

Nephrotic syndrome: Discontinue treatment.

Pancreatitis: Discontinue treatment.

Proteinuria:

Urine protein ≥3 g/24 hours: Interrupt treatment and reduce the dose.

Persistent urine protein ≥3 g/24 hours despite dose reductions: Discontinue treatment.

Reversible posterior leukoencephalopathy (RPLS): Temporarily withhold treatment; after resolution, may resume with discretion.

Thrombotic microangiopathy: Discontinue treatment.

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). When manipulating capsules, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH, 2014).

A 10 mg/mL sunitinib oral suspension may be made with capsules and a 1:1 mixture of Ora-Sweet and Ora-Plus. Empty the contents of three 50 mg sunitinib capsules into a mortar; add small portions of vehicle and mix to a uniform paste. Mix while adding vehicle in incremental proportions to 15 mL. Transfer to amber plastic bottle and label "shake well". This suspension maintains an average concentration of 96% to 106% (of the original concentration) at room temperature or refrigerated for up to 60 days in plastic amber prescription bottles.

Navid F, Christensen R, Minkin P, et al, “Stability of Sunitinib in Oral Suspension,” Ann Pharmacother, 2008, 42(7):962-6.18577759

Administration

May be administered with or without food. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Avoid contact with broken or leaking capsules; if contact occurs, wash immediately with soap and water. If it is necessary to manipulate the capsules (eg, to prepare an oral suspension), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH, 2014).

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of SUNItinib. Applicable Isavuconazonium considerations are addressed in separate monographs. Exceptions: Isavuconazonium Sulfate. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bevacizumab: SUNItinib may enhance the adverse/toxic effect of Bevacizumab. Specifically, the risk for a specific form of anemia, microangiopathic hemolytic anemia (MAHA), may be increased. Bevacizumab may enhance the hypertensive effect of SUNItinib. Avoid combination

Bisphosphonate Derivatives: Systemic Angiogenesis Inhibitors may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing sunitinib dose and monitor clinical response and toxicity closely. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of SUNItinib. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of SUNItinib. Management: Advise patients to avoid consuming grapefruit and grapefruit juice during sunitinib treatment. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NiCARdipine: May increase the serum concentration of SUNItinib. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of SUNItinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Temsirolimus: May enhance the adverse/toxic effect of SUNItinib. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Hypertension (27% to 34%, GIST: 8% to 15%; grade 3: 10% to 13%, GIST: 4%), decreased left ventricular ejection fraction (RCC: 16% to 27%, grade 3: 3% to 7%; GIST: 11%, grade 3: 1%), peripheral edema (RCC: 24%), chest pain (RCC: 13%), severe hypertension (4% to 10%; >200 mmHg systolic or 110 mmHg diastolic)

Central nervous system: Fatigue (RCC: 62%, pNET: 33%), glossalgia (pNET: ≤48%; RCC: 11%), mouth pain (pNET: ≤48%; RCC: 6% to 14%), headache (18% to 23%), insomnia (15% to 18%), chills (RCC: 14%), depression (RCC: 11%), dizziness (RCC: 11%)

Dermatologic: Skin discoloration (≤25% to 30%; yellow color), hair discoloration (20% to 29%; GIST: 7%), palmar-plantar erythrodysesthesia (23% to 29%, GIST: 14%; grades 3/4: 4% to 8%), xeroderma (15% to 23%), skin rash (14% to 18%; RCC: 29%), alopecia (5% to 14%), erythema (RCC: 12%), pruritus (RCC: 12%)

Endocrine & metabolic: Increased uric acid (RCC: 46%), decreased serum calcium (34% to 42%), decreased serum albumin (pNET: 41%, RCC: 28%), decreased serum phosphate (31% to 36%), increased serum glucose (RCC: 23%), decreased serum potassium (12% to 21%), decreased serum sodium (RCC: 20%), decreased serum magnesium (pNET: 19%), increased serum potassium (16% to 18%), hypothyroidism (4% to 7%; RCC: 16%), increased serum calcium (RCC: 13%), increased serum sodium (10% to 13%)

Gastrointestinal: Diarrhea (59% to 66%; GIST: 40%), nausea (RCC: 58%; pNET: 45%), increased serum lipase (17% to 25%; RCC: 56%; grades 3/4: 5% to 18%), anorexia (RCC: 48%; GIST: 33%), mucositis (47% to 48%, GIST: 29%; includes aphthous stomatitis, dry mucous membranes, gingival pain, gingivitis, glossitis, oral discomfort, oral mucosal ulcer, stomatitis, tongue ulceration), dysgeusia (21%; RCC: 47%), vomiting (34% to 39%), abdominal pain (30% to 39%), increased serum amylase (17% to 20%; RCC: 35%; grades 3/4: 4% to 6%), dyspepsia (RCC: 34%; pNET: 15%), constipation (20% to 23%), weight loss (16%), flatulence (RCC: 14%), xerostomia (RCC: 13%), gastroesophageal reflux disease (RCC: 12%)

Hematologic & oncologic: Decreased hemoglobin (RCC: 79%, pNET: 65%, GIST: 26%; grades 3/4: ≤8%), leukocyte disorder (decreased leukocytes; RCC: 78%; grades 3/4: 8%), decreased neutrophils (71% to 77%, GIST: 53%; grades 3/4: 10% to 17%), abnormal absolute lymphocyte count (decreased; RCC: 68%, pNET: 56%, GIST: 38%; grades 3/4: RCC: 18%, pNET: 7%), decreased platelet count (60% to 68%, GIST: 38%, GIST and RCC: grades 3/4: 5% to 9%), hemorrhage (18% to 22%; RCC: 37%; RCC and GIST, grades 3/4: 3% to 4%; includes hematemesis, hematochezia, hematoma, hemoptysis, melena, metrorrhagia)

Hepatic: Increased serum AST (pNET: 72%, RCC: 56%, GIST: ≤39%; grades 3/4: ≤2% to 5%), increased serum ALT (pNET: 61%; RCC: 51%; GIST: ≤39%; grades 3/4: ≤2% to 4%), increased serum alkaline phosphatase (RCC: 46%; GIST: 24%; grades 3/4: 2% to 4%), increased serum bilirubin (16% to 20%; pNET: 37%; RCC and GIST, grades 3/4: 1%), increased indirect serum bilirubin (RCC and GIST: 10% to 13%; grades 3/4: ≤1%)

Neuromuscular & skeletal: Increased creatine phosphokinase (RCC: 49%), limb pain (RCC: 40%; GIST: ≤14%), weakness (22% to 34%), arthralgia (RCC: 30%; pNET: 15%), back pain (RCC: 28%), myalgia (GIST: ≤14%)

Renal: Increased serum creatinine (RCC: 70%; GIST: 12%)

Respiratory: Cough (RCC: 27%), dyspnea (RCC: 26%), epistaxis (pNET: 20%), nasopharyngitis (RCC: 14%), oropharyngeal pain (RCC: 14%), upper respiratory tract infection (RCC: 11%)

Miscellaneous: Fever (RCC: 22%)

1% to 10%:

Cardiovascular: Deep vein thrombosis (≤3%), pulmonary embolism (≤3%)

Endocrine & metabolic: Hypoglycemia (2%; pNET: 10%)

Gastrointestinal: Hemorrhoids (RCC: 10%), pancreatitis (1%)

Respiratory: Flu-like symptoms (RCC: 5%)

<1% (Limited to important or life-threatening): Acute renal failure, adrenocortical insufficiency, arterial thrombosis (includes cerebral infarction, cerebrovascular accident, transient ischemic attack), cardiac failure, cardiomyopathy, cerebral hemorrhage, cholecystitis (particularly acalculous), erythema multiforme, esophagitis, fistula (sometimes associated with tumor necrosis and/or regression), fulminant necrotizing fasciitis (including of the perineum), gastrointestinal hemorrhage, gastrointestinal perforation, hemolytic uremic syndrome, hepatic failure, hepatotoxicity, hypersensitivity (includes angioedema), hyperthyroidism, ischemic heart disease, myocardial infarction, nephrotic syndrome, neutropenic infection, osteonecrosis of the jaw, preeclampsia (proteinuria and reversible hypertension) (Gallucci 2013; Patel 2008), prolonged Q-T interval on ECG (dose dependent), proteinuria, pulmonary hemorrhage, pyoderma gangrenosum (including positive dechallenges), renal insufficiency, respiratory tract hemorrhage, respiratory tract infection (may be serious), reversible posterior leukoencephalopathy syndrome, rhabdomyolysis (with/without acute renal failure), seizure, sepsis, skin infection (may be serious), Stevens-Johnson syndrome, thrombotic thrombocytopenic purpura, thyroiditis (Feldt 2012), torsades de pointes, toxic epidermal necrolysis, tumor hemorrhage, tumor lysis syndrome, urinary tract hemorrhage, urinary tract infection (may be serious), ventricular arrhythmia, wound healing impairment

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Hepatotoxicity has been observed in clinical trials and postmarketing experience. Hepatotoxicity may be severe, and deaths have been reported.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal toxicity: Has been reported; monitor for adrenal insufficiency in patients with stress such as trauma, severe infection, or who are undergoing surgery.

• Bleeding: Hemorrhagic events have been reported including epistaxis, rectal, gingival, upper GI, wound bleeding, urinary tract, genital, brain, tumor-related, and hemoptysis/pulmonary hemorrhage; may be serious and/or fatal.

• Cardiovascular events: Cardiovascular events (some fatal), including heart failure, cardiomyopathy, myocardial ischemia and myocardial infarction (MI) have been reported. Use with caution in patients at risk for cardiovascular events. May cause a decrease in left ventricular ejection fraction (LVEF), including some grade 3 reductions. Obtain LVEF evaluation prior to treatment. Discontinue with clinical signs and symptoms of heart failure. Interrupt therapy and/or decrease dose with LVEF <50% and >20% reduction from baseline in patients without clinical heart failure signs/symptoms. Patients with cardiac events (MI, bypass grafts, symptomatic heart failure, cerebrovascular accident, transient ischemic attack, and pulmonary embolism) within the previous 12 months were excluded from clinical trials and it is not known if the risk for left ventricular dysfunction is increased in patient with these conditions; assess risks versus benefits; monitor for clinical signs/symptoms of heart failure, in addition to baseline, also obtain periodic LVEF evaluation.

• Dermatologic toxicities: Severe cutaneous reactions, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported (some fatal); if signs/symptoms of EM, SJS, or TEN (progressive skin rash, often with blisters or mucosal lesions) are present, discontinue sunitinib. Do not restart treatment if SJS or TEN are suspected. Necrotizing fasciitis (with fatalities) has been reported, including perineum necrotizing fasciitis and fasciitis secondary to fistula formation. Discontinue sunitinib in patients who develop necrotizing fasciitis. Sunitinib may cause skin and/or hair depigmentation or discoloration.

• GI complications: Serious and fatal GI complications, including GI perforation, have occurred (rarely). Pancreatitis has been observed in RCC patients; discontinue sunitinib if symptoms are present.

• Hand-foot skin reaction: Hand-foot skin reaction (HFSR) observed with tyrosine kinase inhibitors (TKIs) is distinct from hand-foot syndrome (palmar-plantar erythrodysesthesia) associated with traditional chemotherapy agents; HFSR due to TKIs is localized with defined hyperkeratotic lesions; symptoms include burning, dysesthesia, paresthesia, or tingling on the palms/soles, and generally occur within the first 2 to 4 weeks of treatment; pressure and flexor areas may develop blisters (callus-like), dry/cracked skin, edema, erythema, desquamation, or hyperkeratosis (Appleby, 2011). The following treatments may be used in addition to the recommended dosage modifications (Lacouture, 2008). Prior to treatment initiation, a pedicure is recommended to remove hyperkeratotic areas/calluses, which may predispose to HFSR; avoid vigorous exercise/activities that may stress hands or feet. During therapy, patients should reduce exposure to hot water (may exacerbate hand-foot symptoms); avoid constrictive footwear and excessive skin friction. Patients may also wear thick cotton gloves or socks and should wear shoes with padded insoles. Grade 1 HFSR may be relieved with moisturizing creams, cotton gloves and socks (at night) and/or keratolytic creams such as urea (20% to 40%) or salicylic acid (6%). Apply topical steroid (eg, clobetasol ointment) twice daily to erythematous areas of grade 2 HFSR; topical anesthetics (eg, lidocaine 2%) and then systemic analgesics (if appropriate) may be used for pain control. Resolution of acute erythema may result in keratotic areas which may be softened with keratolytic agents.

• Hepatotoxicity: [US Boxed Warning]: Hepatotoxicity, which may be severe and/or fatal, has been observed in clinical trials and in postmarketing surveillance. Signs of liver failure include jaundice, elevated transaminases, and/or hyperbilirubinemia, in conjunction with encephalopathy, coagulopathy and/or renal failure. Monitor liver function tests at baseline, with each treatment cycle and if clinically indicated. Withhold treatment for grade 3 or 4 hepatotoxicity; discontinue if hepatotoxicity does not resolve. Do not reinitiate in patients with severe changes in liver function tests or other signs/symptoms of liver failure. Sunitinib has not been studied in patients with ALT or AST >2.5 times ULN (or >5 times ULN if due to liver metastases).

• Hypertension: May cause hypertension; monitor and control with antihypertensives if needed; interrupt therapy until hypertension is controlled for severe hypertension. Use caution and closely monitor in patients with underlying or poorly controlled hypertension.

• Hypoglycemia: Symptomatic hypoglycemia has been associated with sunitinib; may result in loss of consciousness or require hospitalization. Hypoglycemia occurred infrequently in patients with renal cell cancer and gastrointestinal stromal tumors (GIST); however, the incidence is higher (~10%) in patients with pancreatic neuroendocrine tumors (PNET); preexisting glucose homeostasis abnormalities were not always present in hypoglycemic patients with PNET. Blood glucose decreases may be worse in patients with diabetes. Monitor blood glucose levels regularly during and following discontinuation of treatment. Dose modifications of antidiabetic medications may be necessary to minimize the risk of hypoglycemia.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported with sunitinib. Concurrent bisphosphonate use or dental disease may increase the risk for ONJ. According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy. Antiangiogenic agents, when given concomitantly with antiresorptive agents, are associated with an increased risk of ONJ. Other risk factors for MRONJ include dentoalveolar surgery (eg, tooth extraction, dental implants), preexisting inflammatory dental disease, and concomitant corticosteroid use. Consider a dental examination and preventive dentistry prior to initiation of sunitinib (and during therapy); if possible, avoid invasive dental procedures in patients with current or prior bisphosphonate use. The AAOMS suggests that if medically permissible, initiation of antiangiogenic agents for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiangiogenesis therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once antiangiogenic therapy for oncologic disease is initiated, procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]).

• Proteinuria/nephrotic syndrome: Proteinuria and nephrotic syndrome have been reported; some cases have led to renal failure and fatal outcomes. Monitor for new onset or worsening proteinuria with baseline and periodic urinalysis and follow up with 24-hour urine protein if clinically indicated. If urine protein is ≥3 g/24 hours, interrupt treatment and reduce the dose. Discontinue treatment in patients with nephrotic syndrome or persistent urine protein ≥3 g/24 hours despite dose reductions. The safety of continuing treatment with sunitinib in patients with moderate to severe proteinuria has not been evaluated.

• QTc prolongation: QTc prolongation and torsade de pointes have been observed (dose dependent); use caution in patients with a history of QTc prolongation, with medications known to increase sunitinib levels or prolong the QT interval, or patients with preexisting (relevant) cardiac disease, bradycardia, or electrolyte imbalance. A baseline and periodic 12-lead ECG should be obtained; correct electrolyte abnormalities prior to treatment and monitor and correct potassium, calcium, and magnesium levels during therapy.

• Reversible posterior leukoencephalopathy syndrome (RPLS): Has been reported (rarely, some fatal). Symptoms of RPLS include confusion, headache, hypertension, lethargy, seizure, blindness and/or other vision, or neurologic disturbances; interrupt treatment and begin management of hypertension.

• Thyroid disorders: Thyroid dysfunction (eg, hypothyroidism, hyperthyroidism, and thyroiditis) may occur; the risk for hypothyroidism appears to increase with therapy duration. Hyperthyroidism, sometimes followed by hypothyroidism, has also been reported. Monitor thyroid function at baseline. Patients not receiving thyroid hormone replacement therapy at sunitinib initiation should be monitored (TSH) every 4 weeks for 4 months and then every 2 to 3 months; those patients already receiving levothyroxine prior to initiating sunitinib should have TSH monitored every 4 weeks until levels and levothyroxine dose are stable, then monitor every 2 months (Hamnvik 2011).

• Thrombotic microangiopathy: Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome), sometimes leading to renal failure or fatality, has been reported with sunitinib, both as monotherapy and in combination with bevacizumab. Discontinue if thrombotic microangiopathy develops; effects may be reversible after discontinuation.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS), including fatalities, has been reported, predominantly in patients with RCC or GIST. Risk for TLS is higher in patients with a high tumor burden prior to treatment; monitor closely. Correct clinically significant dehydration and treat high uric acid levels prior to initiation of treatment.

• Wound healing complications: Impaired wound healing has been reported with sunitinib; temporarily withhold treatment for patients undergoing major surgical procedures. The optimal time to resume treatment after a procedure has not been determined.

Disease-related concerns:

• Renal insufficiency: An increased incidence of fatigue, thyroid dysfunction and treatment-induced hypertension was reported in patients with renal insufficiency (CrCl ≤60 mL/minute) who received sunitinib for the treatment of renal cell cancer (Gupta 2011).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Administration: Dosing schedules vary by indication; some treatment regimens are continuous daily dosing; other treatment schedules are daily dosing for 4 weeks of a 6-week cycle (4 weeks on, 2 weeks off).

Monitoring Parameters

LVEF, baseline (and periodic with cardiac risk factors), ECG (12-lead; baseline and periodic), blood pressure; adrenal function CBC with differential and platelets (prior to each treatment cycle), liver function tests (baseline, with each cycle and if clinically indicated), serum chemistries including magnesium, phosphate, and potassium (prior to each treatment cycle), blood glucose levels (regularly during and following discontinuation of treatment), urinalysis (for proteinuria development or worsening); consider dental exam prior to treatment initiation; symptoms of hypothyroidism, hyperthyroidism, or thyroiditis; signs/symptoms of hypoglycemia

Thyroid function testing (Hamnvik, 2011):

Preexisting levothyroxine therapy: Obtain baseline TSH levels, then monitor every 4 weeks until levels and levothyroxine dose are stable, then monitor every 2 months

Without preexisting thyroid hormone replacement: TSH at baseline, then every 4 weeks for 4 months, then every 2-3 months

Pregnancy Risk Factor

D

Pregnancy Considerations

Animal reproduction studies have demonstrated teratogenicity, embryotoxicity, and fetal loss. Because sunitinib inhibits angiogenesis, a critical component of fetal development, adverse effects on pregnancy would be expected. Women of childbearing potential should be advised to avoid pregnancy if receiving sunitinib.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, nausea, vomiting, lack of appetite, headache, constipation, diarrhea, skin or hair discoloration, hair loss, dry skin, itching, insomnia, change in taste, dry mouth, flatulence, muscle pain, or joint pain. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, jaw pain, redness or irritation of palms or soles of feet, signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding; feeling very tired or weak; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; vision changes; change in strength on one side is greater than the other, trouble speaking or thinking, or change in balance; or fever), signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), signs of posterior reversible encephalopathy syndrome (illogical thinking, not alert, vision changes, seizures, or severe headache), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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