se in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established. [see Dosage and Administration (2.5) and Warnings and Precautions (5.13)].
10. OVERDOSAGE
There is no specific treatment in the event of overdose with CAPRELSA and possible symptoms of overdose have not been established. Because of the 19-day half-life, adverse reactions may not resolve quickly. In phase 1 clinical trials, a limited number of patients were treated with daily doses of up to 600 mg and healthy volunteers with daily doses up to 1200 mg. An increase in the frequency and severity of some adverse reactions, like rash, diarrhea and hypertension, was observed at multiple doses at and above 300 mg in healthy volunteer studies and in patients. In adition the possibility of QTc prolongation and Torsades de pointes should be considered.
Adverse reactions associated with overdose are to be treated symptomatically; in particular, severe diarrhea must be managed appropriately. In the event of an overdose, further doses of CAPRELSA must be interrupted, and appropriate measures taken to assure that an adverse event has not occurred, i.e., ECG within 24 hours to determine QTc prolongation [see Dosage and Administration (2.1)].
11. DESCRIPTION
CAPRELSA tablets for daily oral administration are available in two dosage strengths, 100 mg and 300 mg, containing 100 mg and 300 mg of vandetanib, respectively. The tablet cores contain the following inactive ingredients: Tablet core: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet film-coat contains the following inactive ingredients: hypromellose 2910, macrogol 300, and titanium dioxide E171.
Vandetanib is chemically described as N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl) methoxy]quinazolin-4-amine.
The structural and molecular formulas are:
C22H24BrFN4O2
Vandetanib has a molecular weight of 475.36. Vandetanib exhibits pH-dependent solubility, with increased solubility at lower pH. Vandetanib is practically insoluble in water with a value of 0.008 mg/mL at 25°C (77°F ).
12. CLINICAL PHARMACOLOGY
12.1. Mechanism of Action
Vandetanib is a kinase inhibitor. In vitro studies have shown that vandetanib inhibits the activity of tyrosine kinases including members of the epidermal growth factor receptor (EGFR) family, vascular endothelial cell growth factor (VEGF) receptors, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the Src family of tyrosine kinases. Vandetanib inhibits endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. Vandetanib inhibits EGFR-dependent cell survival in vitro. In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells.
In vivo vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer.
In vitro studies have shown that vandetanib also inhibits the activity of other tyrosine kinases, including rearranged during transfection (RET) and VEGF receptor-3 (Flt-4) .
There is no evidence |
