Download Docetaxel

Docetaxel
OH
OH HO
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O
OH
O
H
O
O
OO
O
O
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CH3
(CH3)3 NH C
Trade Names
Taxotere
Classification
Taxane, anti-microtubule agent
Category
Chemotherapy drug
Drug Manufacturer
Sanofi-Aventis
Mechanism of Action
Semisynthetic taxane. Derived from the needles of the European yew
tree.
High-affinity binding to microtubules enhances tubulin polymerization.
Normal dynamic process of microtubule network is inhibited, leading
to inhibition of mitosis and cell division.
Cell cycle–specific agent with activity in the mitotic (M) phase.
Mechanism of Resistance
Alterations in tubulin with decreased affinity for drug.
Multidrug-resistant (MDR-1) phenotype with increased expression
of P170 glycoprotein. Results in enhanced drug efflux with
decreased intracellular accumulation of drug. Cross-resistant to other
natural products, including vinca alkaloids, anthracyclines, taxanes,
and VP-16.
Absorption
Not administered orally.
Distribution
Distributes widely to all body tissues. Extensive binding (_90%) to
plasma and cellular proteins.
Metabolism
Extensively metabolized by the hepatic P450 microsomal system. About
75% of drug is excreted via fecal elimination. Less than 10% is eliminated
as the parent compound with the majority being eliminated as metabolites.
Renal clearance is relatively minor with less than 10% of drug clearance via
the kidneys. Plasma elimination is tri-exponential with a terminal half-life
of 11 hours.
Indications
Breast cancer—Locally advanced or metastatic breast cancer after failure
of prior chemotherapy. FDA-approved.
Breast cancer—FDA-approved in combination with doxorubicin and
cyclophosphamide for adjuvant treatment of patients with nodepositive
breast cancer.
Non–small cell lung cancer—Locally advanced or metastatic disease
after failure of prior platinum-based chemotherapy. FDA-approved.
Non–small cell lung cancer—FDA-approved in combination with
cisplatin for treatment of patients with locally advanced or metastatic
disease who have not previously received chemotherapy.
Prostate cancer—FDA-approved in combination with prednisone
for androgen-independent (hormone-refractory) metastatic prostate
cancer.
Gastric cancer—FDA-approved in combination with cisplatin and
5-fluorouracil for advanced gastric cancer, including adenocarcinoma
of the gastroesophageal junction, in patients who have not received
prior chemotherapy.
Head and neck cancer—FDA-approved for use in combination with
cisplatin and 5-fluorouracil for induction treatment of patients with
inoperable, locally advanced disease.
Small cell lung cancer.
Refractory ovarian cancer—Advanced platinum.
Bladder cancer.
Dosage Range
Metastatic breast cancer: 60, 75, and 100 mg/m 2 IV every 3 weeks or
35–40 mg/m 2 IV weekly for 3 weeks with 1 week of rest.
Breast cancer: 75 mg/m 2 IV every 3 weeks in combination with
cyclophosphamide and doxorubicin for adjuvant therapy.
Non–small cell lung cancer: 75 mg/m 2 IV every 3 weeks or
35–40 mg/m 2 IV weekly for 3 weeks with 1 week rest after platinumbased
chemotherapy.
Non–small cell lung cancer: 75 mg/m 2 IV every 3 weeks in combination
with cisplatin in patients who have not received prior chemotherapy.
Metastatic prostate cancer: 75 mg/m 2 IV every 3 weeks in combination
with prednisone.
Advanced gastric cancer: 75 mg/m 2 IV every 3 weeks in combination
with cisplatin and 5-FU.
Head and neck cancer: 75 mg/m 2 IV every 3 weeks in combination with
cisplatin and 5-FU for induction therapy of locally advanced disease.
Drug Interaction 1
Radiation therapy—Docetaxel acts as a radiosensitizing agent.
Drug Interaction 2
Inhibitors and/or activators of the liver cytochrome P450 CYP3A4 enzyme
system—Concurrent use with drugs such as cyclosporine, ketoconazole, and
erythromycin may affect docetaxel metabolism and its subsequent antitumor
and toxic effects.
Special Considerations
Use with caution in patients with abnormal liver function. Patients
with abnormal liver function are at significantly higher risk for
toxicity, including treatment-related mortality.
Closely monitor CBCs, and docetaxel therapy should not be given to
patients with neutrophil counts of _1,500 cells/mm 3 .
Patients should receive steroid premedication to reduce the incidence
and severity of fluid retention and hypersensitivity reactions. Give
dexamethasone 8 mg PO bid for 3 days beginning 1 day before drug
administration.
Closely monitor patients for allergic and/or hypersensitivity reactions.
Usually occur with the first and second treatments. Emergency equipment,
including Ambu bag, EKG machine, fluids, pressors, and other
drugs for resuscitation, must be at bedside before initiation of treatment.
Contraindicated in patients with known hypersensitivity reactions to
docetaxel and/or polysorbate 80.
Use only glass, polypropylene bottles, or polypropylene or polyolefin
plastic bags for drug infusion. Administer only through polyethylenelined
administration sets.
Monitor patient’s weight, measure daily input and output, and evaluate
for peripheral edema.
Pregnancy category D. Breast-feeding should be avoided.
Toxicity 1
Myelosuppression. Neutropenia is dose-limiting with nadir at days 7–10
and recovery by day 14. Thrombocytopenia and anemia are also observed.
Toxicity 2
Hypersensitivity reactions with generalized skin rash, erythema, hypotension,
dyspnea, and/or bronchospasm. Usually occur within the first
2–3 minutes of an infusion and almost always within the first 10 minutes.
Most frequently observed with first or second treatments. Usually prevented
by premedication with steroid; overall incidence decreased to less than 3%.
When it occurs during drug infusion, treat with hydrocortisone IV, diphenhydramine
50 mg IV, and/or cimetidine 300 mg IV.
Toxicity 3
Fluid retention syndrome. Presents as weight gain, peripheral and/or
generalized edema, pleural effusion, and ascites. Incidence increases with
total doses _400 mg/m 2 . Occurs in about 50% of patients.
Toxicity 4
Maculopapular skin rash and dry, itchy skin. Most commonly affect forearms
and hands. Brown discoloration of fingernails may occur. Observed in
up to 50% of patients usually within 1 week after therapy.
Toxicity 5
Alopecia occurs in up to 80% of patients.
Toxicity 6
Mucositis and/or diarrhea seen in 40% of patients. Mild to moderate
nausea and vomiting, usually of brief duration.
Toxicity 7
Peripheral neuropathy is less commonly observed with docetaxel than
with paclitaxel.
Toxicity 8
Generalized fatigue and asthenia are common, occurring in 60%–70% of
patients. Arthralgias and myalgias also observed.
Toxicity 9
Reversible elevations in serum transaminases, alkaline phosphatase, and
bilirubin.
Toxicity 10
Vesicant. Phlebitis and/or swelling can be seen at the injection site.