sunitinib (Sutent)

Dosing and uses of Sutent (sunitinib)

• Adult
• Pediatric

 

Adult dosage forms and strengths

capsule

• 12.5mg
• 25mg
• 50mg

 

GI Stromal Tumor, Metastatic Renal Cell Carcinoma

50 mg PO qDay for 4 weeks, THEN 2 weeks drug-free, repeat cycle

Dose modification GI stromal tumor (GIST) or metastic renal cell carcinoma (MRCC)

• Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability
• Concurrent CYP3A4 Inhibitors: Consider dose reduction to 37.5 mg qDay
• Concurrent CYP3A4 Inducers: Consider dose increase not to exceed 87.5 mg qDay (in 12.5 mg increments)
• Ideally, selection of an alternate concomitant medication with no or minimal enzyme inhibition/induction is recommended

 

Pancreatic Neuroendocrine Tumors

Indicated for progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease

Standard dose: 37.5 mg PO qDay continuously without a scheduled off-treatment period

Dose modification Pancreatic Neuroendocrine Tumors (PNET)

• Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability
• Coadministration with potent CYP4503A4 inhibitors: Consider dose reduction to 25 mg PO qDay
• Coadministration with CYP4503A4 inducers: Consider dose increase not to exceed 62.5 mg PO qDay
• Ideally, selection of an alternate concomitant medication with no or minimal enzyme inhibition/induction is recommended

 

Renal Impairment

No dose adjustment necessary

 

Hepatic Impairment

Mild to moderate impairment: Dose adjustment not necessary for initial dose; monitor subsequent doses

Severe impairment: Not studied

 

Monitoring

CBC, blood chemistries

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Sutent (sunitinib) adverse (side) effects

>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

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

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

 

Warnings

Black box warnings

Hepatotoxicity has been observed in clinical trials (7/2281) and post-marketing experience (0.3%)

Hepatotoxicity may be severe and deaths have been reported

Monitor liver function tests (ALT, AST, bilirubin) before treatment initiation, during each treatment cycle, and as clinically indicated

Interrupted for Grade 3 or 4 drug-related hepatic related adverse events and discontinued if there is no resolution

Do not restart if subsequently experience severe changes in liver function tests or other signs and symptoms of liver failure emerge

Safety in patients with ALT or AST >2.5 x ULN or, if due to liver metastases, >5 x ULN has not been established

Use and handle product with caution

 

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

Avoid concurrent St John's Wort and other metabolic inducers

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

Prolonged QT intervals and Torsade de Pointes reported; 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 and assess if anti-diabetic drug dose modifications 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

Cardiovascular risks

• Myocardial ischemia, myocardial infarction, cardiac failure including death, and left ventricular ejection fraction declines to below the lower limit of normal have occurred
• Increased risk for heart failure and highgrade heart failure
• 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 and lactation

Pregnancy category: d

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

Bosutinib 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

 

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.

 

Pharmacology of Sutent (sunitinib)

Mechanism of action

Multikinase inhibitor (including VEGF & 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%)