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Sunitinib Malate

Pronunciation: SOO-NI-ti-nib MAL-ate
Class: Tyrosine kinase inhibitor

Trade Names

Sutent
- Capsules, oral 12.5 mg
- Capsules, oral 25 mg
- Capsules, oral 50 mg

Pharmacology

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

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Pharmacokinetics

Absorption

T max between 6 and 12 h. Food does not affect bioavailability. 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 the active metabolite range from 62.9 to 101 ng/mL.

Distribution

Plasma protein binding is 95%. Protein binding of primary metabolite is 90%. Vd is 2,230 L.

Metabolism

Sunitinib and its active metabolite are metabolized in the liver by CYP3A4.

Elimination

Elimination in the feces (61%) and renal (16%). Oral Cl ranged from 34 to 62 L/h. Terminal half-life of sunitinib and the primary metabolite are 40 to 60 h and 80 to 110 h, respectively.

Special Populations

Renal Function Impairment

Systemic exposure was similar in subjects with severe renal impairment compared with subjects with healthy renal function, but was 47% lower in subjects with ESRD on hemodialysis.

Hepatic Function Impairment

Systemic exposures after a single dose of sunitinib were similar in subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment compared with subjects with healthy hepatic function. Sunitinib was not studied in patients with severe (Child-Pugh class C) hepatic impairment.

Elderly

No clinically relevant effect.

Children

Pharmacokinetics have not been evaluated.

Gender

No clinically relevant effect.

Race

No clinically relevant effect.

Body weight

No clinically relevant effect.

Indications and Usage

Treatment of GI stromal tumor after disease progression on or intolerance to imatinib; treatment of advanced renal cell carcinoma; treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.

Contraindications

None well documented.

Dosage and Administration

GI Stromal Tumor
Adults

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

Pancreatic Neuroendocrine Tumor
Adults

PO 37.5 mg (max, 50 mg) once daily continuously without a scheduled off-treatment period.

Renal Cell Carcinoma
Adults

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

Dose modification

Increase or decrease in 12.5 mg increments based on individual safety and tolerability. For ejection fraction decrease of 20% to 50% from baseline without signs of heart failure or for severe hypertension (more than 200/100 mm Hg), reduce dose or temporarily interrupt therapy; when symptoms resolve, resume therapy at reduced doses. For grade 3 or 4 hepatic adverse reactions, interrupt dose; discontinue therapy if there is no resolution. Do not restart if patients subsequently experience changes in LFTs or have other signs and symptoms of liver failure. For thrombotic microangiopathy or reversible posterior leukoencephalopathy syndrome, temporarily suspend therapy; following resolution, therapy may be resumed. For CHF, nephrotic syndrome, pancreatitis, and/or hepatic failure, discontinue therapy.

Concomitant therapy

Reduce dosage to minimum of 37.5 mg (GI stromal tumor and renal cell carcinoma) or 25 mg (pancreatic neuroendocrine tumor) once daily if coadministered with a strong CYP3A4 inhibitor. Increase dosage to max of 87.5 mg (GI stromal tumor and renal cell carcinoma) or 62.5 mg (pancreatic neuroendocrine tumor) daily if coadministered with CYP3A4 inducer.

General Advice

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

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Bevacizumab

Concurrent use of sunitinib and bevacizumab may result in unexpected severe toxicity. Coadministration is not recommended.

CYP3A4 inducers (eg, carbamazepine, dexamethasone, modafinil, nevirapine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort)

May reduce sunitinib levels, decreasing the therapeutic effect. Consider a dosage increase for sunitinib to a max of sunitinib 87.5 mg daily if sunitinib must be coadministered with a CYP3A4 inducer. Monitor for toxicity. St. John's wort may decrease sunitinib plasma concentrations unpredictably. Coadministration is not recommended.

CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

May elevate sunitinib levels, increasing the pharmacologic effects and risk of adverse reactions, including ventricular arrhythmias (eg, torsades de pointes). Consider a dose decrease for sunitinib to a minimum of sunitinib 37.5 mg daily if sunitinib must be coadministered with a strong CYP3A4 inhibitor.

Drugs that prolong the QT interval (eg, antiarrhythmic agents [eg, amiodarone, bretylium, disopyramide, dofetilide, procainamide, quinidine, sotalol], arsenic trioxide, chloroquine, chlorpromazine, cisapride, dolasetron, doxepin, droperidol, gatifloxacin, halofantrine, haloperidol, iloperidone, levomethadyl, lithium, maprotiline, mefloquine, mesoridazine, methadone, moxifloxacin, paliperidone, pentamidine, pimozide, probucol, romidepsin, sparfloxacin, tacrolimus, thioridazine, toremifene, tyrosine kinase inhibitors [eg, dasatinib, lapatinib, pazopanib], vandetanib, ziprasidone)

Prolongation of the QT interval with possible development of cardiac arrhythmias, including torsades de pointes, should be considered when sunitinib is coadministered with these agents. Caution is advised when two agents that are suspected to prolong the QT interval are used concomitantly. If concurrent use is not contraindicated in the respective product information, patients should be monitored for QT prolongation, especially when adding sunitinib to a stable regimen of another QT prolonging agent, or vice versa.

Grapefruit juice

May elevate sunitinib levels, increasing the pharmacologic and adverse effects. Patients taking sunitinib should avoid grapefruit products, including grapefruit juice.

Temsirolimus

Concurrent use of sunitinib and temsirolimus may result in unexpected toxicity. Use with caution and closely monitor the patient for toxicity.

Adverse Reactions

Cardiovascular

Hypertension (34%); decreased left ventricular ejection fraction (LVEF) (27%); venous thromboembolic events [eg, deep venous thrombosis, pulmonary embolism] (3%); CHF; thrombotic microangiopathy (postmarketing).

CNS

Fatigue (62%); asthenia (34%); headache (23%); dysgeusia (21%); insomnia (18%); depression, dizziness (11%).

Dermatologic

Skin discoloration (30%); hair color changes, hand-foot syndrome, rash (29%); dry skin (23%); alopecia (14%); erythema, pruritus (12%).

EENT

Epistaxis (21%); nasopharyngitis, oropharyngeal pain (14%).

GI

Diarrhea (66%); nausea (58%); anorexia (48%); altered taste, mucositis/stomatitis (47%); abdominal pain, vomiting (39%); dyspepsia (34%); constipation (23%); flatulence, oral pain (14%); dry mouth (13%); GERD/gastroesophageal reflux esophagitis (12%); glossodynia (11%); hemorrhoids (10%); pancreatitis (1%); liver failure (postmarketing).

Hematologic-Lymphatic

Bleeding (37%); fatal hemorrhage associated with thrombocytopenia (postmarketing).

Lab Tests

Hemoglobin (79%); leukocytes (78%); neutrophils (77%); AST increased (72%); increased glucose (71%); creatinine (70%); lymphocytes, platelets (68%); alkaline phosphatase increased (63%); ALT increased (61%); lipase (56%); creatine kinase (49%); uric acid (46%); calcium decreased (42%); albumin decreased (41%); total bilirubin increased (37%); phosphorus decreased (36%); amylase (35%); sodium decreased (29%); decreased glucose (22%); decreased potassium (21%); decreased magnesium (19%); increased potassium (18%); calcium increased, sodium increased, indirect bilirubin (13%).

Metabolic-Nutritional

Peripheral edema (24%); hypothyroidism, weight decreased (16%).

Musculoskeletal

Pain in extremity/limb discomfort (40%); arthralgia (30%); back pain (28%); limb pain/myalgia (14%); myopathy and/or rhabdomyolysis with or without acute renal failure, in some cases with fatal outcome (postmarketing).

Renal

Nephrotic syndrome, proteinuria, renal impairment and/or failure (in some cases with fatal outcome) (postmarketing).

Respiratory

Cough (27%); dyspnea (26%); upper respiratory tract infection (11%).

Miscellaneous

Fever (22%); chills (14%); chest pain (13%); influenza-like illness (5%); hypersensitivity reactions (including angioedema), fistula formation sometimes associated with tumor necrosis and/or regression (in some cases with fatal outcome), serious infection (with or without neutropenia, in some cases with fatal outcome) (postmarketing).

Precautions

Warnings

Hepatotoxicity has been observed and may be severe. Deaths have been reported.


Monitor

Monitor LFTs (AST, ALT, and bilirubin) before initiation of therapy, during each cycle of treatment, and as clinically indicated. Perform CBC with platelet count and serum chemistries, including phosphate and urinalysis, at the beginning of each treatment cycle. Monitor for clinical signs and symptoms of CHF. Consider baseline and periodic evaluations of LVEF in patients with cardiac risk factors. Also consider baseline ejection fraction in patients without cardiac risk factors. Consider periodic monitoring with on-treatment ECGs and electrolytes. Monitor patients for hypertension and for the development of proteinuria. Observe all patients for signs and symptoms of thyroid dysfunction, and monitor thyroid function in patients with symptoms suggestive of hypothyroidism. Monitor patients who experience stress (eg, severe infection, surgery, trauma) for adrenal insufficiency.


Pregnancy

Category D . Because angiogenesis is a critical component of embryonic and fetal development, expect inhibition of angiogenesis following administration to result in adverse effects on pregnancy.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Renal Function

Exposure is lower in patients with ESRD on hemodialysis; subsequent doses may require a dosage increase.

Adrenal toxicity

Adrenal toxicity has been noted in animals. Abnormal adrenal function tests have been reported in patients during treatment.

CV effects

CV events, including decline in LVEF, heart failure, hypertension, myocardial disorders, and cardiomyopathy, some of which were fatal, have been reported. Sunitinib has also been shown to prolong the QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias, including torsades de pointes. Use with caution in patients who have a history of QT interval prolongation, are taking antiarrhythmics, or have relevant preexisting cardiac disease, bradycardia, or electrolyte disturbances.

Fertility

May impair fertility.

GI effects

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

Hemorrhagic events

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

Thyroid dysfunction

Treatment-emergent acquired hypothyroidism has been reported. Cases of hyperthyroidism, some followed by hypothyroidism, have been reported.

Wound healing

Cases of impaired wound healing have been reported. Temporary interruption of therapy is recommended in patients undergoing major surgical procedures.

Overdosage

Symptoms

Adverse reactions were consistent with the known safety profile of sunitinib or did not occur at all.

Patient Information

  • Advise patient or caregiver to read the Medication Guide carefully before starting therapy, and to read and check for new information each time the medication is refilled.
  • Advise patient that the dose may be increased (when certain other medications are used concurrently) or reduced, or the medication temporarily withheld if bothersome adverse 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 of 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, 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 consume grapefruit products, including grapefruit juice, or take St. John's wort while taking sunitinib.

Copyright © 2009 Wolters Kluwer Health.

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