Sunitinib Malate

Trade Names:
Sutent
- Capsules 12.5 mg
- Capsules 25 mg
- Capsules 50 mg

Pharmacology

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Sunitinib inhibits multiple receptor tyrosine kinases, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer.

Pharmacokinetics

Absorption

T _max between 6 and 12 h. Food does not affect bioavailability.

Distribution

Plasma protein binding is 95%. Protein binding of primary metabolite is 90%. Vd is 2,230 L. C _max and AUC increase proportionally with the dose in the range of 25 to 100 mg.

Metabolism

Sunitinib and its active metabolite are metabolized by CYP3A4.

Elimination

Elimination in feces 61% and renal 16%. Oral Cl ranged from 34 to 62 L/h. Terminal t _½ of sunitinib and the primary metabolite are 40 to 60 h and 80 to 110 h, respectively. With repeat daily dosing, sunitinib accumulates 3- to 4-fold, and the primary active metabolite accumulates 7- to 10-fold. Steady-state concentrations of the primary drug and primary metabolite are achieved within 10 to 14 days. The combined plasma levels of sunitinib plus active metabolite range from 62.9 to 101 ng/mL.

Special Populations

No studies conducted.

No studies conducted.

No clinically relevant effect.

No clinically relevant effect.

Indications and Usage

Treatment of GI stromal tumor after disease progression on, or intolerance to, imatinib mesylate; treatment of advanced renal cell carcinoma.

Contraindications

Standard considerations.

Dosage and Administration

PO 50 mg once daily on a schedule of 4 wk on treatment followed by 2 wk off treatment.

PO 50 mg once daily on a schedule of 4 wk on treatment followed by 2 wk off treatment.

Increase or decrease in 12.5 mg increments based on individual safety and tolerability. Reduce dose to minimum of 37.5 mg once daily if coadministered with strong CYP3A4 inhibitor. Increase dose to max of 87.5 mg if coadministered with CYP3A4 inducer.

General Advice

• Administer without regard to meals. Administer with food if GI upset occurs.

Storage/Stability

Store capsules at controlled room temperature (59° to 86°F).

Drug Interactions

May reduce sunitinib levels, decreasing the therapeutic effect.

May elevate sunitinib levels, increasing the pharmacologic and adverse effects.

May elevate sunitinib levels, increasing the pharmacologic and adverse effects.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (15%).

Hypertension (28%); peripheral edema (17%).

CNS

Fatigue (42%); headache (13%).

Fatigue (74%); headache (25%); dizziness (16%); peripheral neuropathy (10%).

Dermatologic

Skin discoloration (30%); hand-foot syndrome, rash (14%); hair color changes (7%); alopecia (5%).

Rash (38%); skin discoloration (33%); dry skin, hair color changes (17%); alopecia, hand-food syndrome (12%); skin blistering (7%).

EENT

Periorbital edema (7%); increased lacrimation (6%).

GI

Diarrhea (40%); abdominal pain, anorexia (33%) nausea (31%); mucositis/stomatitis (29%); vomiting (24%); altered taste (21%); constipation (20%); oral pain (6%).

Diarrhea (55%); nausea (54%); mucositis/stomatitis (53%); dyspepsia (46%); altered taste (43%); vomiting (37%); constipation (34%); anorexia (31%); abdominal pain (20%); glossodynia (15%); flatulence (14%); appetite disturbance (9%).

Hematologic-Lymphatic

Bleeding (18%); venous thromboembolic events (3%).

Bleeding (26%); venous thromboembolic events (2%).

Lab Tests

Abnormalities of the following: AST/ALT, alkaline phosphatase, total bilirubin, amylase, lipase, creatinine, and uric acid (at least 10%); anemia, decreased left ventricular ejection fraction, hypernatremia, hypokalemia, lymphopenia, neutropenia, thrombocytopenia (at least 10%); hypophosphatemia (9%); hyponatremia, hyperkalemia (6%); acquired hypothyroidism (4%).

Lymphopenia (20%); increased lipase (16%); neutropenia (12%); hyperuricemia, hypophosphatemia (10%); leukopenia (7%); anemia, increased amylase (5%); thrombocytopenia (3%).

Metabolic-Nutritional

Asthenia (22%).

Dehydration (11%).

Musculoskeletal

Limb pain/myalgia (14%); arthralgia (12%); back pain (11%).

Arthralgia (28%); limb pain (18%); back pain, myalgia (17%).

Respiratory

Dyspnea (10%); cough (8%).

Dyspnea (28%); cough (17%).

Miscellaneous

Fever (18%).

Fever (15%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Adrenal function

Adrenal toxicity has been noted in animals. Abnormal adrenal function tests have been reported in patients during treatment. Monitor patients who experience stress (eg, severe infection, surgery, trauma) for adrenal insufficiency.

GI effects

Serious, sometimes fatal GI complications including GI perforation, have occurred rarely in patients with intra-abdominal malignancies treated with sunitinib.

Hemorrhagic events

Have been reported during treatment. Epistaxis was most commonly reported but rectal, gingival, upper GI, genital, and wound bleeding have been documented. Tumor-related hemorrhage has been observed.

Hypertension

May develop during treatment. Treat as needed with standard antihypertensive agents. Temporarily suspend therapy in cases of severe hypertension until hypertension has been controlled.

Left ventricular dysfunction

May occur or worsen during treatment. Interrupt therapy or reduce dose of sunitinib in patients without clinical evidence of heart failure who have an ejection fraction greater than 20% but less than 50% below baseline. Discontinue therapy if clinical manifestations of heart failure develop.

Pancreatitis

Has occurred rarely. Discontinue therapy and provide supportive care if patient develops symptoms of pancreatitis.

Overdosage

Symptoms

No overdose reported in clinical studies.

Patient Information

• Advise patient or caregiver to read patient information leaflet carefully before starting therapy, and to read and check for new information each time the medication is refilled.
• Advise patient that usual dose is 50 mg taken once daily for 4 wk followed by 2 wk off medication. Advise patient that the dose may be increased (when certain other medications are used concurrently), reduced, or the medication temporarily withheld, if bothersome side effects develop or when certain other medications are used concurrently.
• Advise patient to take each dose without regard to meals but to take with food if stomach upset occurs.
• Instruct patient not to change the dose or stop taking unless advised by health care provider.
• Advise patient that sunitinib can cause high BP and to check BP periodically during treatment. Advise patient that BP medications may be needed to control elevated BP.
• Instruct patient to immediately notify health care provider if any of the following occur: bleeding or unusual bruising; blistering, pain, redness, or swelling of palms or hands or soles of feet; chills, fever, sore throat, or other symptoms of infection; mouth sores; rapid weight gain or swelling in ankles and/or feet; rash or itching; unexplained shortness of breath.
• Advise patient or caregiver that GI disorders (eg, diarrhea, indigestion, mouth sores, nausea, vomiting) occur commonly and to report intolerable GI symptoms to health care provider. Advise patient that additional therapy (eg, antidiarrheal, antiemetic) may be needed.
• Advise patient that a yellowish skin discoloration may occur because of the color of drug.
• Advise patient that skin changes (eg, dryness, thickening, cracking, blistering, or rash on palms of hands or soles of feet), and loss of skin or hair pigment may occur during treatment.
• Caution women of childbearing potential to avoid becoming pregnant during treatment.
• Instruct patient not to take St. John's wort while taking sunitinib.

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