pazopanib

Action

Specifically targets growth factor receptors associated with angiogenesis and tumor-cell proliferation; also exhibits inhibition of vascular endothelial growth factor receptors, platelet-derived growth factor receptors, fibroblast growth factor receptors, stem cell factor receptor (c-Kit), inter-leukin-2 receptor inducible T-cell kinase, leukocyte-specific protein tyro-sine kinase, and transmembrane glycoprotein receptor tyrosine kinase

Availability

Tablets: 200 mg

Indications and dosages

➣ Advanced renal cell carcinoma (RCC); advanced soft-tissue sarcoma (STS) in patients who have received prior chemotherapy

Adults: 800 mg P.O. daily. In RCC, initial dosage reduction should be 400 mg, and additional dosage decrease or increase should be in 200-mg steps based on individual tolerability. In STS, a decrease or increase should be in 200-mg steps based on individual tolerability.

Dosage adjustment

• Moderate hepatic impairment

• Strong CYP3A4 inducers/inhibitors

Contraindications

None

Precautions

Use cautiously in:

• severe hepatic impairment with total bilirubin greater than three times the upper limit of normal (ULN)

• mild to moderate hepatic impairment, proteinuria

• hypothyroidism, hypertension, cardiac disease, patients at risk for developing QT-interval prolongation

• signs and symptoms of serious infection

• patients at increased risk for myocardial infarction (MI), angina, ischemic stroke, transient ischemic attack, and GI perforation or fistula

• hemoptysis; cerebral or clinically significant GI hemorrhage in past 6 months (avoid use)

• patients undergoing surgical procedures

• concurrent use of other cancer therapies (not indicated)

• concurrent use of antiarrhythmics and other drugs that may prolong QT interval

• concurrent use of strong CYP3A4 inducers or inhibitors (avoid use)

• concurrent use of CYP substrates (use not recommended)

• concurrent use of simvastatin

• elderly patients

• pregnant or breastfeeding patients

• children (safety and efficacy not established).

Administration

• Administer without food at least 1 hour before or 2 hours after a meal. Don't give with grapefruit or grapefruit juice. Don't crush tablets.

• Perform baseline ECG and LVEF evaluation, and maintain electrolytes within normal range during therapy.

See Perform baseline urinalysis and discontinue drug for Grade 4 proteinuria.

• Ensure patient's blood pressure is well controlled before starting drug.

See Before starting treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

See Don't administer to patient who has had MI, angina, ischemic stroke, transient ischemic attack, hemoptysis, or clinically significant GI hemorrhage in previous 6 months.

See Be aware that serious infections, including some with fatal outcome, have been reported. Institute appropriate anti-infective therapy promptly and consider drug interruption or discontinuation for serious infections.

See Temporarily interrupt therapy in patients undergoing surgical procedures for at least 7 days before surgery. Discontinue drug in patients who develop wound dehiscence.

See Be aware that drug isn't indicated for use in combination with other cancer agents, because of possible increased toxicity and mortality (pulmonary hemorrhage, GI hemorrhage, and sudden death).

Adverse reactions

CNS: fatigue, asthenia, headache

CV: hypertension, decreased ejection

fraction, congestive heart failure (CHF), QT-interval prolongation, torsades de pointes

GI: nausea, vomiting, diarrhea, anorexia, dyspepsia, GI perforation and fistula

GU: proteinuria

Hematologic: leukopenia, neutropenia, thrombocytopenia, lymphocytopenia, arterial and venous thrombotic events, hemorrhagic events

Hepatic: abnormal liver function test values, hepatotoxicity

Metabolic: altered electrolyte levels, hypothyroidism

Musculoskeletal: musculoskeletal pain

Respiratory: dyspnea

Skin: alopecia, rash, skin depigmentation, impaired wound healing, palmar-plantar erythrodysesthesia

Other: hair color changes, chest pain, dysgeusia, facial edema, weight loss, decreased appetite, infection, tumor pain, reversible posterior leukoencephalopathy syndrome

Interactions

Drug-drug. CYP3A4 substrates (such as dextromethorphan, midazolam, paclitaxel): inhibited metabolism of these drugs

Simvastatin: increased risk of ALT elevations

Strong CYP3A4 inducers (such as rifampin): decreased pazopanib concentration

Strong CYP3A4 inhibitors (such as clarithromycin, ketoconazole, ritonavir): increased pazopanib concentration

Drug-diagnostic tests. ALT, AST, total

bilirubin: increased levels

Glucose: increased or decreased level Hemoglobin, magnesium, neutrophils, phosphorus, platelets, sodium: decreased levels

Drug-food. Any food: increased pazopanib systemic exposure

Grapefruit juice: inhibited CYP3A4 activity and increased pazopanib plasma concentration

Patient monitoring

• Monitor CBC with differential closely.

See Periodically monitor urinalysis during treatment, with follow-up measurement of 24-hour urine protein as clinically indicated. Interrupt therapy and reduce dosage for 24-hour urine protein of 3 g or more; discontinue drug for repeat episodes despite dosage reductions.

See Monitor serum liver function tests at least once every 4 weeks for at least first 4 months of treatment or as clinically indicated; continue periodic monitoring thereafter. If ALT levels of more than three times ULN occur concurrently with bilirubin levels of more than two times ULN, permanently discontinue drug.

See Closely monitor patient for QT-interval prolongation and signs or symptoms of CHF; periodically monitor ECG and maintain electrolyte levels within normal range.

• Periodically evaluate left ventricular ejection fraction in patients at risk for cardiac dysfunction, including patients who have received previous anthracycline exposure.

• Monitor patients for hypertension; treat as needed. If hypertension persists despite therapy, reduce dosage or discontinue drug as appropriate.

See Closely monitor patient for signs and symptoms of reversible posterior leukoencephalopathy syndrome (RPLS) (headache, seizure, lethargy, confusion, blindness, other visual and neurologic disturbances, and possibly mild to severe hypertension). Discontinue drug if RPLS develops.

See Closely monitor patient for signs and symptoms of infection, hemorrhage, thrombotic events, and GI perforation or fistula.

• Be aware that proactive thyroid function monitoring is recommended.

• Monitor patient for impaired wound healing after surgery.

• Closely watch for ALT elevations in patients also taking simvastatin.

Patient teaching

• Tell patient to take drug without food at least 1 hour before or 2 hours after a meal, not to crush tablets, and to avoid grapefruit and grapefruit juice.

See Instruct patient to immediately report unusual tiredness; dizziness; numbness or weakness on one side of the body; trouble talking; shortness of breath; irregular heartbeats; high blood pressure; chest pain; bleeding; itching; yellowing of skin or eyes; dark urine; right upper abdominal pain, discomfort, or distention; wounds that don't heal; or red, painful hands and feet.

• Teach patient how to manage diarrhea and to notify prescriber if moderate to severe diarrhea occurs.

• Tell patient that drug may cause depigmentation of the hair or skin.

• Instruct patient to tell prescriber about all drugs he's taking, because some drugs have potential for serious drug interactions and shouldn't be taken with pazopanib.

• Advise female patient of childbearing age to avoid pregnancy during therapy.

• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of drug for her treatment.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and food mentioned above.