Overview
11 DESCRIPTION Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N- tert -butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. 12.
Indications
- 1 INDICATIONS AND USAGE Docetaxel Injection is a microtubule inhibitor indicated for: • Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC ( 1.1 ) • Non-small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC ( 1.
Common Doses
- 60 mg
- 100 mg
- 75 mg
- 50 mg
Dosage
2 DOSAGE AND ADMINISTRATION For all indications, toxicities may warrant dosage adjustments [ see Dosage and Administration (2.7) ]. Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over 1 hour every 3 weeks. PVC equipment is not recommended. Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial. • BC locally advanced or metastatic: 60 mg/m 2 to 100 mg/m 2 single agent ( 2.
Black Box Warning
WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION Treatment-related mortality associated with docetaxel is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive docetaxel as a single agent at a dose of 100 mg/m 2 [ see Warnings and Precautions (5.1) ] . Avoid the use of Docetaxel Injection in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.
Contraindications
- 4 CONTRAINDICATIONS Docetaxel Injection is contraindicated in patients with: • neutrophil counts of
Side Effects
- 6 ADVERSE REACTIONS The most serious adverse reactions from docetaxel are: • Toxic Deaths [ see Boxed Warning , Warnings and Precautions (5.1) ] • Hepatic Impairment [ see Boxed Warning , Warnings and Precautions (5.2) ] • Hematologic Effects [ see Boxed Warning , Warnings and Precautions (5.3) ] • Enterocolitis and Neutropenic Colitis [ see Warnings and Precautions (5.4) ] • Hypersensitivity Reactions [ see Boxed Warning , Warnings and Precautions (5.5) ] • Fluid Retention [ see Boxed Warning , Warnings and Precautions (5.6) ] • Second Primary Malignancies [ see Warnings and Precautions (5.
Interactions
- 7 DRUG INTERACTIONS Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel.