su-NI-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

• Gastrointestinal stromal tumor that has progressed on or has intolerance to imatinib.
• Advanced renal cell carcinoma.
• Adjuvant treatment of patients at high risk of recurrent renal cell carcinoma following nephrectomy.
• Advanced pancreatic neuroendocrine tumors.

• Inhibits multiple receptor tyrosine kinases, which are enzymes implicated in tumor growth, abnormal vascular growth, and tumor metastases.

• Decreased tumor spread.

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: Sunitinib: 95%; primary active metabolite: 90%.

Metabolism/Excretion: Metabolized by the liver via the CYP3A4 isoenzyme to its primary active metabolite. This metabolite is further metabolized by CYP3A4. Excretion is primarily fecal.

Half-life: Sunitinib: 40–60 hr; primary active metabolite: 80–110 hr.

(plasma concentrations)

Contraindicated in:

• Hypersensitivity
• New York Heart Association class II-IV HF
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Renal impairment
• Hepatic impairment
• Concurrent use of bisphosphonates or a history of dental disease (may ↑ risk of osteonecrosis of the jaw [ONJ])
• History of myocardial ischemia or MI
• Left ventricular ejection fraction <50% and >20% below baseline with no signs/symptoms of HF (need to interrupt therapy or ↓ dose)
• Diabetes (↑ risk of hypoglycemia)
• History of QT interval prolongation, use of antiarrhythmics, cardiac disease, bradycardia, or electrolyte disturbances
• Women of reproductive potential and men with female partners of reproductive potential
• Pedi: Safety and effectiveness not established in children.

CV: hypertension, DEEP VEIN THROMBOSIS, HF, MI, peripheral edema, QT interval prolongation, TORSADES DE POINTES.

Derm: alopecia, ERYTHEMA MULTIFORME, hair color change, hand-foot syndrome, impaired wound healing, NECROTIZING FASCIITIS, rash, skin discoloration, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS.

EENT: epistaxis.

Endo: hypoglycemia, hypothyroidism, adrenal insufficiency, hyperthyroidism.

F and E: dehydration, hypophosphatemia.

GI: diarrhea, dyspepsia, hepatotoxicity, nausea, stomatitis, vomiting, ↑ lipase/amylase, ↑ liver enzymes, anorexia, cholecystitis, constipation, esophagitis, GI PERFORATION, oral pain.

GU: hemolytic uremic syndrome, ↓ fertility, nephrotic syndrome, proteinuria, renal failure.

Hemat: anemia, hemorrhage, lymphopenia, neutropenia, thrombocytopenia, thrombotic thrombocytopenic purpura.

Metab: hyperuricemia.

MS: arthralgia, back pain, limb pain, myalgia, osteonecrosis (primarily ONJ).

Neuro: fatigue, dizziness, dysgeusia, headache, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES).

Resp: PULMONARY EMBOLISM.
Misc: fever, TUMOR LYSIS SYNDROME.

Drug-Drug:

• Strong CYP3A4 inhibitors, including ketoconazole, may ↑ levels and the risk of toxicity; avoid concurrent use, if possible. If concurrent use necessary, ↓ sunitinib dose.
• Strong CYP3A4 inducers, including rifampin, may ↓ levels and effectiveness; avoid concurrent use, if possible. If concurrent use necessary, ↑ sunitinib dose.
• Concurrent use with alendronate, ibandronate, pamidronate, risedronate, or zoledronic acid may ↑ risk of jaw osteonecrosis
• ↑risk of microangiopathic hemolytic anemia when used with bevacizumab; concurrent use not recommended.
• Concurrent use of other QT-interval prolonging medications may ↑ risk of torsades de pointes.

Drug-Natural Products:

• St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

• Grapefruit juice may ↑ levels and the risk of toxicity; avoid concurrent use.

Gastrointestinal Stromal Tumor and Renal Cell Carcinoma

• PO (Adults): 50 mg once daily for 4 wk, followed by 2 wk off; continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitors: 37.5 mg once daily for 4 wk, followed by 2 wk off; continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inducers: 87.5 mg once daily for 4 wk, followed by 2 wk off; continue until disease progression or unacceptable toxicity.

Adjuvant Treatment of Renal Cell Carcinoma

• PO (Adults): 50 mg once daily for 4 wk, followed by 2 wk off for a total of nine 6-wk cycles. Concurrent use of strong CYP3A4 inhibitors: 37.5 mg once daily for 4 wk, followed by 2 wk off for a total of nine 6-wk cycles. Concurrent use of strong CYP3A4 inducers: 87.5 mg once daily for 4 wk, followed by 2 wk off for a total of nine 6-wk cycles.

Pancreatic Neuroendocrine Tumor

• PO (Adults): 37.5 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitors: 25 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inducers: 62.5 mg once daily until disease progression or unacceptable toxicity.

(Generic available)

• Capsules: 12.5 mg; 25 mg; 37.5 mg; 50 mg;

• Monitor for signs of HF (dyspnea, edema, jugular venous distention) during therapy. Assess LVEF at baseline and periodically during therapy in patients with cardiac events in the previous 12 mo and a baseline ejection fraction in patients without cardiovascular risk factors. If asymptomatic cardiomyopathy (LVEF >20% but <50% below baseline or below lower limit of normal if baseline was not obtained) occurs, hold sunitinib until resolution to Grade 0 or 1 or baseline. Resume at a reduced dose. If clinically manifested HF occurs, discontinue sunitinib permanently.
• Monitor for hypertension and treat with standard antihypertensive therapy. If Grade 3 hypertension occurs, hold sunitinib until resolution to Grade 0 or 1 or baseline. Resume at a reduced dose. If Grade 4 hypertension occurs, permanently discontinue therapy.
• Monitor for signs and symptoms of bleeding (epistaxis, GI bleeding) during therapy. If Grade 3 or 4 hemorrhage occurs, hold sunitinib until resolution to Grade 0 to 1 or baseline. Either resume at reduced dose or discontinue depending on the severity and persistence of adverse reaction.
• Perform an oral examination before starting and periodically during therapy. Monitor for signs and symptoms of ONJ (tooth or jaw pain, swelling of the jaw) during therapy. Patients taking bisphosphonates, who have dental disease, or undergo invasive dental procedures, are at increased risk. Hold sunitinib for at least 3 wk before scheduled dental surgery or invasive dental procedures, if possible. Hold therapy for development of ONJ until complete resolution occurs.
• Monitor ECG and electrolytes periodically during therapy; may cause QT interval prolongation and torsades de pointes.
• Monitor for rash. If progressive skin rash with blisters or mucosal lesions or necrotizing fasciitis occurs, discontinue and do not restart sunitinib.
• Monitor for signs and symptoms of PRES (hypertension, headache, decreased alertness, altered mental functioning, visual loss, including cortical blindness) during therapy. An MRI is necessary to confirm diagnosis. Discontinue sunitinib in patients developing PRES.

• Monitor CBC with platelet count and serum chemistries including phosphate at the beginning of each treatment cycle. May cause neutropenia, lymphopenia, anemia, and thrombocytopenia. May cause ↑ serum creatinine, hypokalemia, and hyperuricemia.
  • Monitor ALT, AST, and bilirubin before starting therapy, during each cycle of treatment, and as clinically indicated. If Grade 3 hepatotoxicity occurs, hold sunitinib until resolution to Grade 0 or 1 or baseline. Resume therapy at reduced dose. If Grade 3 hepatotoxicity recurs or Grade 4 hepatotoxicity occurs, permanently discontinue sunitinib. May cause ↑ AST, ALT, alkaline phosphatase, total and indirect bilirubin, amylase, and lipase.
  • Monitor thyroid function at baseline and in patients with symptoms of hypothyroidism or hyperthyroidism. May be treated with standard medical practice.
  • Monitor urinalysis for urine protein at baseline and periodically during therapy. Follow up with 24-hr urine protein as clinically indicated. If 3 grams proteinuria in 24 hr in the absence of nephrotic syndrome occurs, hold sunitinib until resolution to Grade 0 or 1 or baseline. Resume therapy at reduced dose. If nephrotic syndrome or recurrent proteinuria of 3 grams per 24 hr despite dose reductions occurs, permanently discontinue sunitinib.
  • Monitor blood glucose levels periodically during and after therapy. Assess if antidiabetic drug dose needs to be adjusted to minimize the risk of hypoglycemia.

• Do not confuse sunitinib with sorafenib.
• Recommended Dose Modifications: For patients with gastrointestinal stromal tumor and advanced renal cell carcinoma: First dose reduction, 37.5 once daily. Second dose reduction, 25 mg once daily. For patients with adjuvant renal cell carcinoma: First dose reduction, 37.5 mg once daily. For patients with pancreatic neuroendocrine tumor: First dose reduction, 25 mg once daily.
• PO: Administer once daily with or without food.

• Instruct patient to take sunitinib as directed. Take missed doses as soon as remembered if within 12 hr of missed dose. If >12 hr since missed dose, omit dose and take next dose at regular time. Do not take more than 1 dose at a time. Tell your health care professional about the missed dose.
• Advise patient to avoid grapefruit juice and grapefruit products during therapy.
• Instruct patient to notify health care professional promptly if signs and symptoms of liver failure (itching, yellow eyes or skin, dark urine, pain or discomfort in the right upper stomach area), rash, bleeding (painful, swollen abdomen, black, sticky stools, bloody urine, vomiting blood, headache, coughing up blood, change in your mental status), ONJ (tooth or jaw pain, jaw swelling) or tumor lysis syndrome (nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness) occur.
• Advise patient that GI disorders (diarrhea, nausea, stomatitis, dyspepsia, vomiting) are common and may require antiemetic and antidiarrheal medications.
• Inform patient that sunitinib may cause discoloration (yellow) of skin and depigmentation of hair or skin.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
• Advise patient to notify health care professionals of therapy. Therapy must be stopped for at least 3 wk before scheduled dental surgery, invasive dental procedures, or elective surgeries and then held for at least 2 wk after major surgery until adequate wound healing.
• Advise patient to notify health care professional if bleeding or swelling occur.
• May cause fetal harm. Advise females of reproductive potential to use effective contraception during and after therapy and to avoid breastfeeding during and for 4 wk after last dose. Advise males with female partners of reproductive potential to use effective contraception during and for 7 wk after last dose. May impair male and female fertility.

• Decrease in tumor spread.

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