帕唑帕尼Votrient (Pazopanib)

[Function and indications]
Pazopanib Votrient is a tyrosine kinase inhibitor (TKI) suitable for the treatment of patients with advanced renal cell carcinoma and patients with advanced soft tissue sarcoma who have received chemotherapy.

[Model and specifications]
Tablets, 200 mg/tablet.

[Usage and dosage]
General patients: once a day, 4 tablets each time, i.e. 800 mg, on an empty stomach (1 hour before meals, or 2 hours after meals);
Patients with moderate liver operation at baseline: once a day, one tablet of 200 mg each time;
Patients with severe liver damage: Pazopanib Votrient is not recommended.

【Clinical studies】
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)- and -, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, pazopanib inhibits ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-receptors. In vivo, pazopanib inhibits VEGF-induced VEGFR-2 phosphorylation in mouse lung, angiogenesis in a mouse model, and the growth of some human tumors in mouse xenografts.
Increased blood pressure has been observed and is related to the steady-state trough concentration of plasma pazopanib.
The QT prolongation potential of pazopanib was evaluated as part of the uncontrolled period. In an open-label, dose-escalation study in patients with advanced cancer, 63 patients received pazopanib at doses ranging from 50 to 2,000 mg daily. Serial ECGs were collected on Day 1 and single predose ECGs were collected on Days 8, 15, and 22 to evaluate the effect of pazopanib on the QTc interval. Two of the 63 patients had a QTcF (Fridericia-corrected QT) >500 msec and three patients had an increase in QTcF from baseline >60 msec. [see Warnings and Precautions (5.2).]
Absorption: Pazopanib is absorbed orally, with median times to peak concentrations of 2 to 4 hours after dosing. Daily dosing of 800 mg resulted in geometric mean AUC and Cmax of 1,037 hr g/mL and 58.1 g/mL (equivalent to 132 M), respectively. There was no consistent increase in AUC or Cmax at pazopanib doses above 800 mg.
Administration of a single dose of pazopanib 400 mg crushed tablet increased AUC(0-72) by 46% and Cmax by approximately 2-fold and shortened tmax by approximately 2 hours compared to administration of the whole tablet. These results suggest that the bioavailability and rate of oral absorption of pazopanib are increased following administration of the crushed tablet relative to administration of the whole tablet. Therefore, due to this potential for increased exposure, VOTRIENT tablets should not be crushed.
Systemic exposure of pazopanib is increased when administered with food. Administration of pazopanib with a high-fat or low-fat meal resulted in an approximately 2-fold increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal [see Dosage and Administration (2.1)].
Distribution: Pazopanib is bound to human plasma proteins in vivo by greater than 99% in a concentration-free range of 10 to 100 μg/mL. In vitro studies suggest that pazopanib is a substrate for P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP).
Metabolism: In vitro studies have demonstrated that pazopanib is metabolized by CYP3A4 with minor contributions from CYP1A2 and CYP2C8.
Elimination: The mean half-life of pazopanib is 30.9 hours after administration of the recommended dose of 800 mg. It is eliminated primarily through the feces, with renal elimination accounting for <4% of the administered dose.

[Precautions]

1) Increased serum transaminase levels and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Liver chemistry should be measured regularly before and during treatment.

2) QT interval prolongation and torsades de pointes have been observed. Use with caution in patients at higher risk for QT interval prolongation. Consider monitoring ECGs and electrolytes.

3) Fatal hemorrhagic events have been reported. VOTRIENT has not been studied in patients with a history of hemoptysis, cerebral, or clinically significant gastrointestinal bleeding within the past 6 months and should not be used in these patients.

4) Arterial thrombotic events and possible fatalities have been observed. Use with caution in patients at increased risk for these events.
5) Gastrointestinal perforation or fistula has occurred. Fatal perforation has occurred. Use with caution in patients with increased risk of gastrointestinal perforation or fistula.
6) Hypertension has been observed. Blood pressure should be adequately controlled when starting VOTRIENT. Monitor and treat hypertension as needed.
7) It is recommended to interrupt VOTRIENT treatment in patients undergoing surgery.
8) Hypothyroidism may occur. It is recommended to monitor thyroid function.
9) Proteinuria: Monitor urine protein. Discontinue the drug for grade 4 proteinuria.
10) When VOTRIENT is given to pregnant women, it may harm the fetus. Women of pregnancy potential should be advised of the potential harm to the fetus and to avoid pregnancy when taking it.

[Adverse Reactions and Contraindications]
Uncommon adverse reactions: hepatotoxic reactions, abdominal pain, dizziness, bloody stools, increased blood pressure, etc.

[Contraindications]
This product is contraindicated in patients with severe liver damage.
It is contraindicated in those who are allergic to this product and its ingredients.

[Pregnant women use]
Doctors should advise pregnant women that this product has potential harm to the fetus. If you need to take this product, you can consider advising patients to use contraception.

[Children use]
Clinical studies on this product for children have not yet been established.

[Storage]
Store at room temperature away from light.

[Manufacturer]
GlaxoSmithKline Pharmaceuticals, USA.