sunitinib (Rx)

>10%

Dyspepsia (MRCC 46%)

Altered taste (MRCC 43%; GIST 21%)

Fatigue (GIST 42%; MRCC 74%)

Diarrhea (GIST 40%; MRCC 55%)

Rash (MRCC 38%; GIST 14%)

Vomiting (MRCC 37%; GIST 24%)

Constipation (MRCC 34%; GIST 20%)

Skin discoloration (MRCC 33%; GIST 30%)

Abdominal pain (GIST 33%; MRCC 20%)

Nausea (GIST 31%; MRCC 54%)

Anorexia (MRCC 31%; GIST 33%)

Mucositis/stomatitis (GIST 29%; MRCC 53%)

Dyspnea (MRCC 28%; GIST 10%)

HTN (MRCC 28%; GIST 15%)

Arthralgia (MRCC 28%; GIST 12%)

Bleeding (MRCC 26%; GIST 18%)

Headache (MRCC 25%; GIST 13%)

Asthenia (GIST 22%)

Lymphopenia (MRCC 21%)

Fever (GIST 18%; MRCC 15%),

Limb pain (MRCC 18%)

Back pain (MRCC 17%; GIST 11%)

Myalgia (MRCC 17%; GIST 14%)

Cough (MRCC 17%; GIST 8%)

Dry skin (17%)

Hair color changes (17%)

Neutropenia (MRCC 13%; GIST 11%)

Alopecia (MRCC 12%)

Hand-foot syndrome (MRCC 12%; GIST 14%)

Dehydration (MRCC 11%)

1-10%

Venous thrombotic events

Hemorrhoids

Pancreatitis

Flu-like syndrome

<1%

Hepatotoxicity

Acute renal failure

Adrenal dysfunction

Postmarketing Reports

Blood and lymphatic system disorders: Thrombotic microangiopathy; hemorrhage associated with thrombocytopenia (hold dose, following resolution, treatment may be resumed at the discretion of the treating physician)

Immune system disorders: Hypersensitivity reactions, including angioedema Infections and infestations: Serious infection (with or without neutropenia); necrotizing fasciitis, including of the perineum; most commonly observed infections include respiratory, urinary tract, skin infections, and sepsis

Metabolism and nutrition disorders: Tumor lysis syndrome

Musculoskeletal and connective tissue disorders: Fistula formation, sometimes associated with tumor necrosis and/or regression; osteonecrosis of the jaw, and myopathy and/or rhabdomyolysis with or without acute renal failure

Renal and urinary disorders: Renal impairment and/or failure; proteinuria; rare cases of nephrotic syndrome (discontinue treatment)

Respiratory disorders: Pulmonary embolism; pulmonary hemorrhage, pleural effusion

Skin and subcutaneous tissue disorders: Pyoderma gangrenosum, including positive dechallenges

Vascular disorders: Arterial thromboembolic events, most frequent events included CVA, TIA, cerebral infarction

Contraindications

Hypersensitivity

Renal impairment

Cautions

Hepatotoxicity, including liver failure, observed; monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated; interrupt therapy for Grade 3 or 4 drug-related hepatic adverse events and discontinue if no resolution; do not restart if patient subsequently experiences severe changes in liver function tests or have other signs and symptoms of liver failure (see Black Box Warning)

Hemorrhagic events including tumor-related hemorrhage reported; perform serial complete blood counts and physical examinations

Adrenal hemorrhage observed in animal studies; monitor adrenal function in case of stress such as surgery, trauma or severe infection

Monitor urine protein; interrupt treatment for 24-hr urine protein ≥3 g; discontinue for repeat episodes of protein ≥3 g despite dose reductions or nephrotic syndrome

Hypothyroidism reported; measure baseline thyroid function in patients with hypothyroidism or hyperthyroidism and treat per standard medical practice prior to initiating therapy

Impaired wound healing reported; temporary interruption of therapy recommended if undergoing major surgical procedures

Severe cutaneous reactions have been reported, including cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, some of which were fatal; necrotizing fasciitis, including fatal cases, also reported

Advise women of childbearing potential of potential hazard to fetus and to avoid becoming pregnant (see Pregnancy)

Prolonged QT intervals and Torsade de Pointes may occur in a dose-dependent manner; use caution in patients at higher risk for developing QT interval prolongation; consider monitoring with on-treatment ECG and electrolytes; hypertension may occur; monitor blood pressure and treat as needed

Cases of tumor lysis syndrome (TLS) reported in atients with RCC and GIST with high tumor burden; monitor closely and treat as necessary

Thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or fatal outcome reported in clinical trials and post-marketing experience

Hypoglycemia may occur; monitor blood glucose levels regularly during and after discontinuation treatment; assess if antidiabetic drugs dosage modifications are necessary

Osteonecrosis of the jaw reported; consider preventive dentistry prior to treatment; avoid, if possible, invasive dental procedures, particularly in patients receiving intravenous bisphosphonate therapy

Monitor patients for hypertension and treat as needed with standard antihypertensive therapy; in cases of severe hypertension, temporary suspend treatment until hypertension is controlled

Drug interactions overview

• See Dosage Modifications
• Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations
• Coadministration with CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) may decrease sunitinib concentrations

Cardiovascular risks

• Cardiovascular events (eg, heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction), some of which were fatal, have been reported
• Increased risk for heart failure and high grade heart failure; discontinue treatment if patient presents with signs or symptoms of congestive heart failure (CHF); interrupt and/or reduce dose in patients without clinical evidence of CHF who either have an ejection fraction (EF) of >20% but <50% below baseline or below the lower limit of normal if baseline EF is not obtained
• Cardiac dysfunction occurs 28 to 180 days after sunitinib initiation and most commonly after the third cycle
• Heart failure risk is associated with preexisting hypertension and coronary artery disease
• Monitor patients for signs and symptoms of congestive heart failure

Pregnancy

No available data established in pregnant women to inform a drug-associated risk In animal developmental and reproductive toxicology studies, oral administration of sunitinib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity (embryolethality, craniofacial and skeletal malformations) at 5.5 and 0.3 times the AUC in patients administered the recommended daily doses (RDD), respectively

Advise pregnant women or females of reproductive potential of the potential hazard to a fetus

Females of reproductive potential should have a pregnancy test before initiating treatment

Advise females of reproductive potential to use effective contraception during treatment and for at least 4 weeks after the last dose

Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 7 weeks after the last dose

Based on findings in animals, male and female fertility may be compromised by treatment

Lactation

Unknown if excreted in human milk; a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Parent drug and/or its metabolites were excreted in the milk of lactating rats; radioactivity was present in the plasma of suckling offspring 24-48 hr after lactating rats received a single oral dose of radioactive bosutinib

Because of the potential for serious adverse reactions in breastfed infants from sunitinib, advise a lactating woman not to breastfeed during treatment with sunitinib and for at least 4 weeks after the last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Multikinase inhibitor (including VEGF and PDGF receptor tyrosine kinases) some of which are implicated in tumor growth, angiogenesis, and metastasis

Pharmacokinetics

Bioavailability: Not affected by food

Peak plasma time: 6-12 hr

Half-life elimination: 40-60 hr

Vd: 2230 L

Protein bound: Sunitinib 95%; primary active metabolite: 90%

Metabolism: by CYP3A4 to a primary active metabolite which is further metabolized by CYP3A4

Excretion: Feces (61%); urine (16%)

Oral administration

Take with or without food

Do not drink grapefruit juice or eat grapefruit during your treatment

Missed dose

• Missed dose <12 hr: Take the missed dose right away
• Missed dose >12 hr: Take next dose at regular time
• Do not make up missed dose

Storage

Tablets: Store at room temperature at 68-77°F (20-25°C)