CAPRELSA- vandetanib tablet
AstraZeneca Pharmaceuticals LP
WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH
CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA [see Warnings and Precautions (5.1, 5.15)].
1. INDICATIONS AND USAGE
CAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.
Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.
2. DOSAGE AND ADMINISTRATION
The recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable toxicity occurs.
CAPRELSA may be taken with or without food.
Do not take a missed dose within 12 hours of the next dose.
Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immediately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow.
The dispersion can also be administered through nasogastric or gastrostomy tubes.
DOSAGE FORMS & STRENGTHS
CAPRELSA 100-mg tablets are white, round, biconvex, film-coated, and intagliated with 'Z 100′ on one side and plain on the reverse side.
CAPRELSA 300-mg tablets are white, oval, biconvex, film-coated, and intagliated with 'Z 300′ on one side and plain on the reverse side.
DESCRIPTION
Vandetanib has the chemical name N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl) methoxy]quinazolin-4-amine.
The structural and molecular formulas are:
Chemical Structure
(click image for full-size original)
C22 H24 BrFN4 O2
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).
CAPRELSA tablets for daily oral administration are available in two dosage strengths containing either 100 mg or 300 mg of vandetanib. The tablet cores contain the following inactive ingredients: 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.
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
In vitro studies have shown that vandetanib inhibits the tyrosine kinase activity of the EGFR and VEGFR families, RET, BRK, TIE2, and members of the EPH receptor and Src kinase families. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. In addition, the N-desmethyl metabolite of the drug, representing 7 to 17.1% of vandetanib exposure, has similar inhibitory activity to the parent compound for VEGF receptors (KDR and Flt-1) and EGFR.
In vitro , vandetanib inhibited 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.
