VOTRIENT- pazopanib hydrochloride tablet, film coated
GlaxoSmithKline LLC
WARNING: HEPATOTOXICITY
Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [see Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
VOTRIENT� is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.
Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)]. The dose of VOTRIENT should not exceed 800 mg.
Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3)].
If a dose is missed, it should not be taken if it is less than 12 hours until the next dose.
3 DOSAGE FORMS AND STRENGTHS
200-mg tablets of VOTRIENT - modified capsule-shaped, gray, film-coated with GS JT debossed on one side. Each tablet contains 216.7 mg of pazopanib hydrochloride equivalent to 200 mg of pazopanib.
DESCRIPTION
VOTRIENT (pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C21 H23 N7 O2 S�HCl and a molecular weight of 473.99.
Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.
Tablets of VOTRIENT are for oral administration. Each 200-mg tablet of VOTRIENT contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base.
The inactive ingredients of VOTRIENT are: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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), leukocyte-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. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.