Advanced renal cell carcinoma. Advanced soft tissue sarcoma who have received prior chemotherapy. Limitation of Use: The efficacy of it for the treatment of patients with adipocytic soft tissue sarcoma or gastrointestinal stromal tu mors has not been demonstrated
Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR 2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, Pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors.
Absorption: Pazopanib is absorbed orally with median time to achieve peak concentrations of 2 to 4 hours after the dose. Daily dosing at 800 mg results in geometric mean AUC and C max of 1,037 mcg/mL and 58.1 mcg/mL (equivalent to 132 µM), respectively. There was no consistent increase in AUC or C max at Pazopanib doses above 800 mg.
Distribution: Binding of Pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10 to 100 mcg/mL. In vitro, studies suggest that Pazopanib is a substrate for P-gp and BCRP.
Metabolism: In vitro studies demonstrated that Pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.
Elimination: Pazopanib has a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via feces with renal elimination accounting for less than 4% of the administered dose.
800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). ? Baseline moderate hepatic impairment ? 200 mg orally once daily. Not recommended in patients with severe hepatic impairment
Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of Pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of Pazopanib.
CYP3A4 Inhibitors: Coadministration of Pazopanib with strong inhibitors of CYP3A4 (e.g., Ketoconazole, Ritonavir, Clarithromycin) increases Pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of Pazopanib to 400 mg. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of Pazopanib.
CYP3A4 Inducers: CYP3A4 inducers, such as Rifampin, may decrease plasma Pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. Pazopanib should not be used if chronic use of strong CYP3A4 inducers cannot be avoided.
Drugs that Inhibit Transporters: In vitro studies suggested that Pazopanib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of Pazopanib may be influenced by products that affect P-gp and BCRP. Concomitant treatment with strong inhibitors of P-gp or BCRP should be avoided due to risk of increased exposure to Pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit P-gp or BCRP should be considered.
Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that Pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19. Concomitant use of Pazopanib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.
Effect of Concomitant Use of Pazopanib and Simvastatin: Concomitant use of Pazopanib and Simvastatin increases the incidence of ALT elevations. Across monotherapy trials with Pazopanib, ALT greater than 3 x ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of Simvastatin. If a patient receiving concomitant Simvastatin develops ALT elevations, follow dosing guidelines for Pazopanib or consider alternatives to Pazopanib. Alternatively, consider discontinuing Simvastatin. Insufficient data are available to assess the risk of concomitant administration of alternative statins and Pazopanib.
Fatigue, diarrhea, nausea, decreased weight, hypertension, decrea sed appetite, hair color changes, vomiting, tu mor pain, dysgeusia, hea dache, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea.
It can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, it is expected to result in adverse reproductive effects. In preclinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of it in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking it
Pazopanib doses up to 2000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2000 mg daily and 1000 mg daily, respectively. Treatment of overdose with Pazopanib should consist of general supportive measures. There is no specific antidote for overdosage of Pazopanib. Hemodialysis is not expected to enhance the elimination of Pazopanib because Pazopanib is not significantly renally excreted and is highly bound to plasma proteins.
Store below 30° C in a cool and dry place, away from sunlight. Keep out of reach of children.
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