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, arterial (including aortic) aneurysms, dissections, and rupture

Reversible posterior leukoencephalopathy syndrome

Impaired wound healing

Contraindications

None

Cautions

Fatal liver failure has been observed (see Black Box Warnings)

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

Hyperthyroidism, some followed by hypothyroidism, have been reported; monitor thyroid function at baseline, periodically during treatment and as clinically indicated; initiate and/or adjust therapies for thyroid dysfunction as appropriate

Impaired wound healing reported; withhold therapy for at least 3 weeks prior to elective surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing; safety of resumption of therapy after resolution of wound healing complications has not been established

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

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

Cases of tumor lysis syndrome (TLS) reported in patients 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 postmarketing experience; not approved for use in combination with bevacizumab

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

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

Osteonecrosis

• Osteonecrosis of the jaw reported; concomitant exposure to other risk factors, such as bisphosphonates or dental disease/invasive dental procedures, may increase risk of ONJ
• Perform oral examination prior to initiation of therapy and periodically during therapy; advise patients regarding good oral hygiene practices
• Withhold treatment for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible; withhold treatment for development of ONJ until complete resolution

Reversible posterior leukoencephalopathy syndrome (RPLS)

• RPLS some of which were fatal reported
• Patients can present with hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness
• Magnetic resonance imaging is necessary to confirm diagnosis; withhold therapy until resolution;
• Safety of reinitiating therapy in patients with RPLS unknown

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 for signs and symptoms of congestive heart failure

Drug interaction overview

• Coadministration with strong CYP3A4 inhibitors

  • Use an alternative with no or minimal CYP3A4 activity
  • Strong CYP3A4 inhibitors may increase sunitinib concentrations

• Coadministration with strong CYP3A4 inducers

  • Use an alternative with no or minimal CYP3A4 activity
  • Coadministration with CYP3A4 inducers may decrease sunitinib concentrations

• Coadministration with QT-prolonging drugs

  • Treatment is associated with QTc interval prolongation; monitor QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval

Pregnancy

Based on animal reproduction studies and its mechanism of action, fetal harm may occur when administered to pregnant females

No data available in pregnant women to inform a drug-associated risk

Verify pregnancy status of females of reproductive potential before initiating treatment

Animal data

• 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 combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the recommended daily doses of 50 mg, respectively
• Advise females of reproductive potential of the potential risk to a fetus

Contraception

• Females of reproductive potential: Use effective contraceptive during treatment and for at least 4 weeks after final dose
• Males with female partners of reproductive potential: Use effective contraceptive during treatment and for 7 weeks after final dose

Infertility

• Based on findings in animals, male and female fertility may be impaired

Lactation

There is no information regarding the presence of sunitinib and its metabolites in human milk

Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12-fold higher than in plasma

Advise females not to breastfeed during treatment and for at least 4 weeks after final 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

Absorption

Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10-14

Peak plasma time: 6-12 hr

Distribution

Vd: 2,230 L

Protein bound

• Sunitinib: 95%
• Active metabolite: 90%

Metabolism

Primarily metabolized by CYP3A4 to its primary active metabolite, which is further metabolized by CYP3A4

Elimination

Clearance: 34-62 L/hr

Half-life

• Single-oral dose: ~40-60 hr
• Active metabolite: 80-110 hr

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)