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SUNItinib

Medically reviewed by Drugs.com. Last updated on Jun 26, 2020.

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

Sunitinib 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 primary active metabolite, SU12662.

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

Although sunitinib is not eliminated through hemodialysis, sunitinib systemic exposure was 47% lower in patients with end-stage renal disease on hemodialysis compared to patients with normal renal function.

Use: Labeled Indications

GI stromal tumor: Treatment of gastrointestinal stromal tumor (GIST) in adults after disease progression on or intolerance to imatinib.

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

Renal cell carcinoma: Adjuvant treatment of adults at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy; treatment of advanced RCC in adults.

Off Label Uses

Soft tissue sarcoma (non-GI stromal tumor)

Data from an open-label, multicenter, phase 2 study support the use of sunitinib for the treatment of non-GIST soft tissue sarcoma [George 2009b].

Thyroid cancer

Data from 2 phase 2 studies support the use of sunitinib for the treatment of thyroid cancer [Cohen 2008], [Ravaud 2017].

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: Withhold sunitinib treatment for at least 3 weeks prior to elective surgery; do not administer sunitinib for at least 2 weeks after major surgery and until adequate wound healing. If possible, withhold sunitinib for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures.

Gastrointestinal stromal tumor (GIST): Oral: 50 mg once daily for 4 weeks of a 6-week treatment cycle (4 weeks on, 2 weeks off) until disease progression or unacceptable toxicity (Demetri 2006).

GIST off-label dosing: Oral: 37.5 mg once daily, continuous daily dosing until disease progression or unacceptable toxicity (George 2009a).

Pancreatic neuroendocrine tumors, advanced: Oral: 37.5 mg once daily, continuous daily dosing until disease progression or unacceptable toxicity (Raymond 2011); the maximum daily dose used in clinical trials was 50 mg.

Renal cell carcinoma, adjuvant treatment: Oral: 50 mg once daily for 4 weeks of a 6-week treatment cycle (4 weeks on, 2 weeks off) for 9 cycles (Ravaud 2016); the minimum daily dose used in clinical trials was 37.5 mg.

Renal cell carcinoma, advanced: Oral: 50 mg once daily for 4 weeks of a 6-week treatment cycle (4 weeks on, 2 weeks off) until disease progression or unacceptable toxicity (Motzer 2006a; Motzer 2006b; Motzer 2009).

Renal cell carcinoma (advanced) (off-label dosing) (may improve tolerability): Oral: 50 mg once daily for 2 weeks of a 3-week treatment cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity (Bracarda 2015).

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

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) until disease progression or unacceptable toxicity (Cohen 2008; Ravaud 2017).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

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

Cardiotoxicity:

Ejection fraction <50% but >20% below baseline or below the lower limit of normal (if baseline ejection fraction is not available) without evidence of congestive heart failure: Interrupt treatment and/or reduce dose.

Clinical manifestations of heart failure: Discontinue sunitinib.

Dermatologic toxicity:

Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: Permanently discontinue sunitinib.

Necrotizing fasciitis: Discontinue sunitinib.

Hypertension: Temporarily interrupt sunitinib until hypertension is controlled. Initiate and/or adjust antihypertensive therapy as appropriate.

Osteonecrosis of the jaw: Withhold sunitinib until complete resolution.

Reversible posterior leukoencephalopathy: Withhold sunitinib until resolution; the safety of resuming sunitinib in patients with reversible posterior leukoencephalopathy is unknown.

Thrombotic microangiopathy: Discontinue sunitinib.

Extemporaneously Prepared

A sunitinib 10 mg/mL oral suspension may be prepared with capsules and a 1:1 mixture of Ora-Sweet and Ora-Plus. Empty the contents of 3 sunitinib 50 mg 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):962-966. doi:10.1345/aph.1K65418577759

A sunitinib 10 mg/mL oral suspension may also be prepared by mixing the contents of 3 sunitinib 50 mg capsules with 15 mL of a 1:1 mixture of an Ora-Sweet/Ora-Plus solution to yield a final concentration of 10 mg/mL. Shake well.

This suspension maintains a concentration of >96% of initial concentration when stored for 60 days at room temperature. Shake well.

The contents of the capsules (up to 750 mg) may also be mixed with 75 mL apple juice to yield a 10 mg/mL suspension. Administer within 2 hours after preparation. Suspension maintains >98% of initial concentration for 2 hours at room temperature or under fluorescent light.

Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31(2):164-192. doi:10.1592/phco.31.2.16421275495

Administration

Oral: May be administered with or without food.

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

CYP3A4 Inducers (Strong): May decrease the serum concentration of SUNItinib. Management: Avoid when possible. If combined, increase sunitinib dose to a max of 87.5 mg daily when treating GIST or RCC. Increase sunitinib dose to a max of 62.5 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of SUNItinib. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of SUNItinib. Management: Avoid when possible. If combined, decrease sunitinib dose to a minimum of 37.5 mg daily when treating GIST or RCC. Decrease sunitinib dose to a minimum of 25 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

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

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Itraconazole: May increase the serum concentration of SUNItinib. Management: Avoid when possible. If combined, decrease sunitinib dose to a minimum of 37.5 mg daily when treating GIST or RCC. Decrease sunitinib dose to a minimum of 25 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

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

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

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

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

Saquinavir: May increase the serum concentration of SUNItinib. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Monitor therapy

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Increased serum creatine kinase (49%), hypertension (15% to 39%), peripheral edema (≤24%), decreased left ventricular ejection fraction (11% to 16%), chest pain (13%)

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

Dermatologic: Palmar-plantar erythrodysesthesia (14% to 50%), skin discoloration (18% to 30%; yellow color), skin rash (14% to 29%), hair discoloration (7% to 29%), xeroderma (14% to 23%), alopecia (5% to 14%), erythema of skin (12%), pruritus (12%)

Endocrine & metabolic: Increased uric acid (46%), decreased serum calcium (34% to 42%), decreased serum albumin (28% to 41%), decreased serum phosphate (31% to 36%), hypothyroidism (≤24%), increased thyroid stimulating hormone level (≤24%), decreased serum potassium (12% to 21%), decreased serum sodium (20%), decreased serum magnesium (19%), weight loss (16%), increased serum calcium (13%), increased serum sodium (10% to 13%)

Gastrointestinal: Diarrhea (40% to 66%), stomatitis (29% to 61%; grades 3/4: 3% to 6%; grade 4: <1%), nausea (34% to 58%), increased serum lipase (17% to 56%), anorexia (≤48%), dysgeusia (21% to 47%), abdominal pain (25% to 39%), vomiting (19% to 39%), increased serum amylase (17% to 35%), dyspepsia (15% to 34%), constipation (12% to 23%), decreased appetite (≤19%), flatulence (14%), xerostomia (13%), gastroesophageal reflux disease (12%), glossalgia (11%)

Hematologic & oncologic: Decreased hemoglobin (26% to 79%; grades 3/4: 3% to 8%; grade 4: 2%), lymphocytopenia (38% to 68%; grades 3/4: 3% to 18%, grade 4: 2%), hemorrhage (22% to 37%; grades 3/4: ≤4%), neutropenia (grades 3/4: 13%)

Hepatic: Increased serum aspartate aminotransferase (≤72%), increased serum alanine aminotransferase (≤61%), increased serum alkaline phosphatase (24% to 46%), increased serum bilirubin (16% to 37%), increased indirect serum bilirubin (10% to 13%)

Local: Localized edema (18%)

Neuromuscular & skeletal: Asthenia (≤57%), limb pain (≤40%), arthralgia (11% to 30%), back pain (28%), myalgia (≤14%)

Renal: Increased serum creatinine (12% to 70%)

Respiratory: Cough (27%), dyspnea (26%), epistaxis (21%), nasopharyngitis (14%), oropharyngeal pain (14%), upper respiratory tract infection (11%)

Miscellaneous: Fever (12% to 22%)

1% to 10%:

Cardiovascular: Edema (≤10%), venous thromboembolism (4%), cardiac failure (3%)

Endocrine & metabolic: Hypoglycemia (2% to 10%), hyperglycemia (grades 3/4: 2%), hyperkalemia (grades 3/4: 2%)

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

Hematologic & oncologic: Thrombocytopenia (grades 3/4: 5%), leukopenia (grades 3/4: 3%)

Respiratory: Flu-like symptoms (5%)

Frequency not defined:

Gastrointestinal: Aphthous stomatitis, dry mucous membranes, gingival pain, gingivitis, glossitis, hematemesis, hematochezia, melena, oral discomfort, oral mucosal ulcer, tongue ulcer

Genitourinary: Abnormal uterine bleeding

Hematologic & oncologic: Hematoma

Respiratory: Hemoptysis

<1%, postmarketing, and/or case reports: Acute renal failure, angioedema, arterial thrombosis, cardiac failure, cardiomyopathy, cerebral hemorrhage, cerebral infarction, cerebrovascular accident, cholecystitis (particularly acalculous), erythema multiforme, esophagitis, fistula (sometimes associated with tumor necrosis and/or regression), necrotizing fasciitis (including of the perineum), gastrointestinal hemorrhage, gastrointestinal perforation, hemolytic-uremic syndrome, hepatic failure, hepatotoxicity, hypersensitivity reaction, hyperthyroidism, ischemic heart disease, myocardial infarction, myopathy, nephrotic syndrome, neutropenic infection, osteonecrosis of the jaw, pleural effusion, preeclampsia (like syndrome with proteinuria and reversible hypertension) (Gallucci 2013; Patel 2008), prolonged QT interval on ECG, proteinuria, pulmonary embolism, pulmonary hemorrhage, pyoderma gangrenosum (including positive dechallenges), renal insufficiency, respiratory tract hemorrhage, respiratory tract infection, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, seizure, sepsis, septic shock, serious infection, skin infection, Stevens-Johnson syndrome, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, thyroiditis (Feldt 2012), torsades de pointes, toxic epidermal necrolysis, transient ischemic attacks, tumor hemorrhage, tumor lysis syndrome, urinary tract hemorrhage, urinary tract infection, ventricular arrhythmia, wound healing impairment

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Hepatotoxicity may be severe, and in some cases, fatal. Monitor hepatic function and interrupt, dose reduce, or discontinue sunitinib as recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular events: Cardiovascular events (some fatal), including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction (MI) have been reported. A majority of patients with heart failure recovered. Grade 2 ejection fraction decrease has been observed. Consider left ventricular ejection fraction (LVEF) evaluation at baseline and periodically as indicated; monitor for clinical signs/symptoms of heart failure during sunitinib treatment. Discontinue with clinical manifestations of heart failure. In patients without clinical signs/symptoms of heart failure, interrupt therapy and/or decrease dose with LVEF <50% but >20% below baseline or below the lower limit of normal (if baseline ejection fraction is not available). Patients with cardiac events (MI [including severe/unstable angina], bypass graft, symptomatic heart failure, cerebrovascular accident, transient ischemic attack, and pulmonary embolism) within the previous 12 months were excluded from clinical trials, and patients with prior anthracycline use or cardiac radiation were also excluded from some clinical trials; it is not known if the risk for left ventricular dysfunction is increased in patients with these conditions.

• Dermatologic toxicities: Severe cutaneous adverse reactions, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported (some fatal). Permanently discontinue sunitinib for EM, SJS, or TEN. Necrotizing fasciitis (with fatalities) has been reported with sunitinib, 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) in patients with intra-abdominal malignancies treated with sunitinib. Pancreatitis has been observed (rarely) with sunitinib.

• Hand-foot skin reaction: Hand-foot skin reaction (HFSR) observed with tyrosine kinase inhibitors (TKIs), including sunitinib, and 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.

• Hemorrhage: Hemorrhagic events (some fatal) have been reported with sunitinib. Events (including grades 3 and 4 toxicity) have included GI tract, respiratory tract, tumor, urinary tract, and brain hemorrhages. Epistaxis was the most common hemorrhagic event, while GI hemorrhage was the most common ≥ grade 3 event. Tumor-related hemorrhage has been reported and may occur suddenly. Pulmonary tumor hemorrhage may present as severe or life-threatening hemoptysis or pulmonary hemorrhage; cases of pulmonary hemorrhage with some fatalities have been reported. Monitor for signs/symptoms of bleeding/hemorrhage and obtain CBC and physical exam as clinically necessary.

• Hepatotoxicity: [US Boxed Warning]: Hepatotoxicity may be severe and sometimes fatal. Monitor hepatic function and interrupt, dose reduce, or discontinue sunitinib as recommended. Liver failure included jaundice, elevated transaminases, and/or hyperbilirubinemia, in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor LFTs at baseline, during each treatment cycle, and as clinically indicated. Withhold treatment until resolution for grade 3 or 4 hepatotoxicity; discontinue if hepatotoxicity does not resolve or in patients with subsequent severe changes in LFTs 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 and liver metastases).

• Hypertension: Sunitinib may cause hypertension, including grade 3 and 4 hypertension. Monitor BP at baseline and routinely during sunitinib treatment; if indicated, initiate appropriate antihypertensive treatment to reduce the risk for cardiotoxicity (ASCO [Armenian 2017]). Initiate and/or adjust antihypertensive therapy as appropriate. Withhold sunitinib until hypertension is controlled.

• 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 (RCC) 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 patients who experienced hypoglycemia. Blood glucose decreases may be worse in patients with diabetes. Monitor blood glucose levels at baseline, regularly during treatment, as clinically indicted, and following sunitinib discontinuation. 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/invasive dental procedures 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. A dental examination and preventive dentistry should be performed prior to initiation of sunitinib (and during therapy); if possible, avoid invasive dental procedures in patients with current or prior bisphosphonate use (particularly IV 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]). Advise patients of good oral hygiene practices. If possible, withhold sunitinib for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. If ONJ develops, withhold sunitinib until complete resolution.

• 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 per 24 hours, interrupt treatment and reduce the dose. Discontinue sunitinib in patients with nephrotic syndrome or persistent urine protein ≥3 g per 24 hours despite dose reductions. The safety of continuing treatment with sunitinib in patients with moderate to severe proteinuria has not been evaluated.

• QT prolongation: Sunitinib may cause dose-dependent QT interval prolongation, which may increase the risk for ventricular arrhythmias, including torsade de pointes (which has been observed rarely). Monitor patients who are at higher risk of developing QT interval prolongation, including those with a history of QTc prolongation, patients taking antiarrhythmics, or who have preexisting (relevant) cardiac disease, bradycardia, or electrolyte imbalance. Consider periodic monitoring of ECGs and electrolytes (eg, magnesium, potassium) during sunitinib treatment. Monitor QT interval (with ECGs) more frequently when sunitinib is administered concomitantly with strong CYP3A4 inhibitors or medications known to prolong QT interval. Consider dose reductions.

• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported rarely (some cases were fatal). RPLS may present with altered mental status, decreased alertness, headache, hypertension, and/or visual loss (including blindness). MRI is necessary to confirm RPLS. Withhold treatment until resolution; the safety of resuming sunitinib in patients with RPLS is unknown.

• Thyroid disorders: Hyperthyroidism, sometimes followed by hypothyroidism, has been reported with sunitinib. Monitor thyroid function at baseline, periodically during treatment, and as clinically indicated. Also monitor for signs/symptoms of thyroid dysfunction (hyperthyroidism, hypothyroidism, and thyroiditis) closely during treatment. Patients not receiving thyroid hormone replacement therapy at sunitinib initiation should be monitored (thyroid-stimulating hormone [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). Initiate and/or modify therapies for thyroid dysfunction as appropriate.

• 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 sunitinib if thrombotic microangiopathy develops; thrombotic microangiopathy effects may be reversible after sunitinib discontinuation.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS), including fatalities, has been reported, predominantly in patients with RCC or GIST. The risk for TLS is higher in patients with a high tumor burden prior to treatment; monitor closely and manage as appropriate.

• Wound healing complications: Impaired wound healing has been reported with sunitinib. Withhold sunitinib treatment for at least 3 weeks prior to elective surgery; do not administer sunitinib for at least 2 weeks after major surgery and until adequate wound healing. The safety of resuming sunitinib treatment after resolution of wound healing complications has not been established.

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 metastatic RCC (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 populations:

• Elderly: Patients ≥65 years of age who received adjuvant sunitinib therapy for RCC experienced a higher incidence of grade 3 or 4 adverse reactions (compared to younger patients).

Other warnings/precautions:

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

Monitoring Parameters

LFTs (baseline, during each cycle, and as clinically indicated), serum chemistries including magnesium, phosphate, calcium, and potassium (prior to each treatment cycle), blood glucose levels (baseline, regularly during treatment, as clinically indicated, and following sunitinib discontinuation), urinalysis for proteinuria (baseline and periodic; follow up with 24-hour urine protein if clinically indicated); BP at baseline and routinely during sunitinib treatment; obtain dental exam prior to treatment initiation; consider periodic monitoring of ECGs and electrolytes (eg, magnesium, potassium) during sunitinib treatment. CBC and physical exam as clinically necessary for hemorrhage. Consider left ventricular ejection fraction evaluation at baseline and periodically as indicated. Evaluate pregnancy status prior to treatment in females of reproductive potential. Monitor for symptoms of hypothyroidism, hyperthyroidism, or thyroiditis. Monitor for signs/symptoms of bleeding/hemorrhage, heart failure, hypoglycemia, severe cutaneous adverse reactions, hand-foot skin reaction, GI complications (eg, perforation), reversible posterior leukoencephalopathy syndrome, thrombotic microangiopathy, tumor lysis syndrome, and/or wound healing complications. Monitor adherence.

Thyroid function testing: Monitor thyroid function at baseline, periodically during treatment, and as clinically indicated. Patients not receiving thyroid hormone replacement therapy at sunitinib initiation should be monitored (thyroid-stimulating hormone [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).

Reproductive Considerations

Evaluate pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment and for at least 4 weeks after the last sunitinib dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 7 weeks after the last sunitinib dose.

Pregnancy Considerations

Based on data from animal reproduction studies and its mechanism of action, in utero exposure to sunitinib may cause fetal harm. Because sunitinib inhibits angiogenesis, a critical component of fetal development, adverse effects on pregnancy would be expected.

Patient Education

What is this drug used for?

• It is used to treat cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling tired or weak

• Constipation, diarrhea, stomach pain, upset stomach, throwing up, or feeling less hungry

• Weight loss

• Skin or hair that is lighter in color

• Hair loss

• Dry skin

• Itching

• Trouble sleeping

• Change in taste

• Mouth irritation or sores

• Back, muscle, or joint pain

• Nose or throat irritation

• Dry mouth

• Gas

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, feeling tired, not hungry, upset stomach, stomach pain, light-colored stools, throwing up, or yellow skin

• Low blood sugar like dizziness, headache, feeling tired, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating

• Bleeding like throwing up or coughing up blood; vomit that looks like coffee grounds; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a cause or that get bigger; or bleeding you cannot stop

• Kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain

• Thyroid problems like change in weight; feeling nervous, excitable, restless, or weak; hair thinning; depression; neck swelling; not able to focus; trouble with heat or cold; menstrual changes; shakiness; or sweating

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up

• Jaw pain

• Redness or irritation of palms or soles of feet

• Low mood (depression)

• Dizziness or passing out

• Flu-like signs

• Headache

• Heart problems like a heartbeat that does not feel normal, chest pain or pressure, shortness of breath, a big weight gain, or swelling in the arms or legs

• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome like bruising or bleeding; loss of strength and energy; dark urine or yellow skin; pale skin; change in 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

• Tumor lysis syndrome like fast or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, diarrhea, or not able to eat; or feel sluggish

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or very bad headache

• Necrotizing fasciitis like warm skin with red or purple areas of swelling that spread quickly; ulcers, blisters, black spots on the skin; or any other skin changes

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.