pah-ZOE-puh-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

• Advanced renal cell carcinoma.
• Advanced soft tissue sarcoma in patients who have previously received chemotherapy.

• Acts as a tyrosine kinase inhibitor of several vascular endothelial growth factor receptors, platelet-derived growth factor receptor, fibroblast growth factor receptor, cytokine receptor, interleukin-2 receptor inducible T-cell kinase, leukocyte-specific protein tyrosine kinase, and transmembrane glycoprotein receptor tyrosine kinase. Overall effect is decreased angiogenesis in tumors.

• Decreased growth and spread of renal cell carcinoma.
• Improvement in progression-free survival

Absorption: Well absorbed following oral administration; crushing tablet and ingesting food ↑ absorption.

Distribution: Unknown.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme and to a lesser extent by the CYP1A2 and CYP2C8 isoenzymes; primarily eliminated in the feces, with <4% excreted by the kidneys.

Half-life: 30.9 hr.

(plasma concentrations)

Contraindicated in:

• Severe hepatic impairment
• History of hemoptysis or cerebral or GI bleeding in preceding 6 mo
• Risk/history of arterial thrombotic events, including MI, angina, or ischemic stroke within preceding 6 mo
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Congenital prolonged QTc interval or concurrent medications/diseases that prolong the QTc interval (may ↑ risk of torsades de pointes)
• Electrolyte abnormalities (correct prior to use; may ↑ risk of potentially serious arrhythmia)
• Patients at risk for GI perforation/fistula
• Surgery (interruption of therapy recommended)
• Hypertension (control before therapy is initiated)
• Hypothyroidism (may worsen condition)
• Moderate hepatic impairment (dose ↓ recommended)
• Patients of East Asian descent (↑ risk of neutropenia, thrombocytopenia, and palmar-plantar erythrodysesthesia)
• Rapidly growing tumors, high tumor burden, renal impairment, or dehydration (↑ risk of tumor lysis syndrome)
• Patients with genetically reduced UGT1A1 activity (presence of UGT1A1*28/*28 allele) (↑ risk of hyperbilirubinemia)
• Patients positive for HLA-B*5701 allele (↑ risk of hepatotoxicity)
• Women of reproductive potential and men with female partners of reproductive potential
• Pedi: Safety and effectiveness not established in children
• Geri: ↑risk of hepatotoxicity in older adults.

CV: bradycardia, hypertension, chest pain, DEEP VEIN THROMBOSIS (DVT), HF, MI, QT interval prolongation.

Derm: hair color changes (depigmentation), alopecia, facial edema, impaired wound healing, palmar-plantar erythrodysesthesia (hand-foot syndrome), rash, skin depigmentation.

Endo: hypothyroidism.

GI: abdominal pain, anorexia, diarrhea, nausea, vomiting, ↓ weight, dyspepsia, GI PERFORATION/FISTULA, HEPATOTOXICITY, PANCREATITIS.

GU: ↓fertility, HEMOLYTIC UREMIC SYNDROME, proteinuria.

Hemat: BLEEDING, neutropenia, thrombocytopenia, THROMBOTIC THROMBOCYTOPENIC PURPURA.

MS: arthralgia, muscle spasms.

Neuro: fatigue, weakness, dysgeusia, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), STROKE.

Resp: INTERSTITIAL LUNG DISEASE (ILD), PULMONARY EMBOLISM (PE).
Misc: TUMOR LYSIS SYNDROME.

Drug-Drug:

• Strong CYP3A4 inhibitors, including ketoconazole, ritonavir, and clarithromycin, may ↑ levels and risk of toxicity; avoid concurrent use; if concurrent use unavoidable, ↓ pazopanib dose.
• Strong CYP3A4 inducers, including rifampin, may ↓ levels and effectiveness; avoid concurrent use.
• May ↑ levels and risk of toxicity of CYP3A4 substrates, CYP2D6 substrates, or CYP2C8 substrates that have narrow therapeutic windows; concurrent use is not recommended.
• ↑risk of hepatotoxicity with simvastatin.
• Proton pump inhibitors and H₂ receptor antagonists may ↓ levels; avoid concurrent use; use short-acting antacid instead.
• Antacids may ↓ levels; separate doses by several hrs.
• QT interval prolonging drugs may ↑ risk of QT interval prolongation; avoid concurrent use.

Drug-Food:

• Grapefruit juice may ↑ levels; avoid concurrent use.

• PO (Adults): 800 mg once daily until disease progression or unacceptable toxicity; Concurrent use of strong CYP3A4 inhibitors: 400 mg once daily until disease progression or unacceptable toxicity.

(Generic available)

• Tablets: 200 mg;

• Monitor BP frequently during therapy; may cause hypertension. BP should be well controlled prior to initiating therapy.If Grade 2 or 3 hypertension occurs,↓ dose and start or adjust antihypertensive therapy. Permanently discontinue pazopanib if hypertension remains Grade 3 despite recommended intervention. If Grade 4 hypertension or hypertensive crisis occurs, permanently discontinue pazopanib. Baseline and periodic evaluation of left ventricular ejection fraction is recommended in patients at risk of cardiac dysfunction. If left ventricular systolic dysfunction is symptomatic or Grade 3, hold pazopanib until improved to Grade <3. Resume therapy based on medical judgment. If left ventricular systolic dysfunction is Grade 4, permanently discontinue pazopanib.
• Monitor ECG and electrolytes at baseline and as indicated during therapy. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to starting and during therapy. Monitor patients who are at risk of developing QTc interval prolongation (history of QT interval prolongation, taking antiarrhythmics or other medications that may prolong the QT interval, relevant pre-existing cardiac disease).
• Monitor for signs and symptoms of GI perforation and fistula (abdominal pain and bloating, hematemesis, black tarry stools, GI bleeding) during therapy. If Grade 2 or 3 GI fistula occurs, hold pazopanib and resume based on medical judgment. If Grade 4 fistula occurs, permanently discontinue pazopanib.
• Monitor for signs and symptoms of bleeding. If Grade 2 symptoms occur, hold pazopanib until improvement to Grade 1. Resume at ↓ dose. If Grade 2 symptoms recur after dose interruption and ↓ or Grade 3 or 4 symptoms occur, permanently discontinue pazopanib.
• Monitor for signs and symptoms of arterial thromboembolic events (MI, stroke). If symptoms occur, permanently discontinue pazopanib.
• Monitor for signs and symptoms of venous thromboembolic events (DVT, PE). If Grade 3 symptoms occur, hold pazopanib and resume at same dose if managed with appropriate therapy for 1 wk. If Grade 4 symptoms occur, permanently discontinue pazopanib.
• Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue pazopanib in patients who develop ILD or pneumonitis.
• Monitor for signs and symptoms of PRES (headache, seizure, lethargy, confusion, blindness, mild hypertension). If signs of PRES occur,confirm diagnosis by MRI and discontinue pazopanib permanently.

• Verify negative pregnancy status prior to starting therapy.
• Monitor liver function before initiation; at wk 3, 5, 7, and 9; and then at 3 mo and 4 mo if symptoms occur. Monitor periodically after 4 mo. If isolated ALT ↑ between 3 and 8 times the upper limit of normal (ULN), therapy may continue with weekly monitoring of liver function until ALT returns to Grade 1 or baseline. If isolated ALT ↑ >8 times ULN, stop therapy until ALT returns to Grade 1 or baseline. If benefit outweighs risk, may reintroduce at ↓ dose of 400 mg/day with weekly serum liver tests for 8 wk. Following reintroduction, if ALT ↑ >3 times ULN recurs, permanently discontinue pazopanib. If ALT ↑ occurs concurrently with ↑ serum bilirubin >2 times ULN, discontinue pazopanib permanently. Monitor liver function tests until return to baseline. Patients with only mild indirect hyperbilirubinemia (Gilbert's syndrome) and ↑ ALT >3 times ULN should be managed as per recommendations for ↑ ALT.
  • Monitor thyroid function at baseline and during therapy as clinically indicated. Manage hypothyroidism as appropriate.
  • Obtain baseline and periodic urinalysis; perform 24-hr urine protein as clinically indicated. If 24-hr urine protein 3 g, hold pazopanib until improvement to Grade 1. Resume at a ↓ dose. If 24-hr urine protein 3 g does not improve or recurs despite dose ↓ or if nephrotic syndrome is confirmed, permanently discontinue pazopanib. May cause proteinuria. Discontinue therapy if Grade 4 proteinuria develops.
  • May cause leukopenia, neutropenia, thrombocytopenia, and lymphocytopenia.
  • May cause ↑ AST and ↓ serum phosphorous, sodium, and magnesium. May cause ↑ or ↓ serum glucose.

• Do not confuse pazopanib with ponatinib.
• May impair wound healing. Hold pazopanib 1 wk prior to elective surgery. Do not administer for 2 wk following major surgery and until adequate wound healing.
• Recommended Dose Reductions: For renal carcinoma, 1st reduction: 400 mg once daily; 2nd reduction: 200 mg once daily. For soft tissue sarcoma, 1st reduction: 600 mg once daily; 2nd reduction: 400 mg once daily.
• PO: Administer 1 hr before or 2 hr after a meal. DNC: Swallow tablets whole; do not crush tablets.

• Instruct patient to take on an empty stomach as directed. Take missed doses as soon as remembered; if <12 hr before next dose, omit dose. Advise patient to read the Medication Guide prior to taking pazopanib and with each Rx refill; new information may be available.
• Advise patient to avoid drinking grapefruit juice or eating grapefruit during therapy; may ↑ pazopanib absorption.
• Advise patient to notify health care professional immediately if signs and symptoms of liver problems (yellowing of skin or whites of eyes, dark urine, tiredness, right upper abdominal pain); HF, heart attack or stroke (chest pain or pressure; pain in arms, back, neck, or jaw; shortness of breath; numbness or weakness on one side of body; trouble talking; headache; dizziness); blood clots (sudden shortness of breath; leg pain; or coolness, pallor, swelling of extremities); bleeding problems (easy bleeding, bruising, wounds that do not heal); GI perforation or fistula; PRES (headaches, seizures, lack of energy, confusion, high BP, loss of speech, blindness or changes in vision, problems thinking); ILD (persistent cough, shortness of breath); tumor lysis syndrome (irregular heartbeat, seizures, confusion, muscle cramps or spasms, ↓ urine output); or severe infections occur.
• Inform patient that diarrhea frequently occurs. Instruct patient on ways to manage diarrhea and to notify health care professional if moderate to severe diarrhea occurs.
• Inform patient that loss of color of skin or hair may occur during therapy.
• 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.
• Advise patient to notify health care professional of any impending surgery. Pazopanib must be stopped for 7 days prior to surgery due to the effects on healing and held for 2 wk after major surgery or until adequate healing.
• Advise females of reproductive potential and male patients with partners of reproductive potential to use effective contraception during therapy and for 2 wk after discontinuing therapy and to notify health care professional immediately if pregnancy is suspected. Advise patient to avoid breastfeeding during therapy and for 2 wk after final dose. Inform patient that pazopanib may impair fertility for both men and women during therapy.

• Decreased growth and spread of renal cell carcinoma.
• Improvement in spread of sarcoma.

Votrient