Hentaxel

Docetaxel has a molecular formula of C₄₃H₅₃NO₁₄.

Pharmacology: Docetaxel is an antineoplastic agent belonging to paclitaxel family. It acts by disrupting the microtubular network in cells. Such action is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin thereby resulting in the formation of stable microtubules and subsequently into microtubule bundles without normal function. This leads to the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a characteristic not found in most spindle poisons currently in clinical use.
Pharmacokinetics: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-115 mg/m² in phase I studies. The area under the curve (AUC) was dose proportional following doses of 70-115 mg/m² with infusion times of 1-2 hrs. Docetaxel's pharmacokinetic profile is consistent with a 3-compartment pharmacokinetic model, with half-lives for the α, β and γ phases of 4 min, 36 min and 666 min, respectively. The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part to a relatively slow efflux of docetaxel from the peripheral compartment. IV infusion of docetaxel at a dose of 100 mg/m² within 1 hr, mean peak concentration is 3.7 mcg/mL and AUC is 4.6 mcg/mL·hr. Mean values for total body clearance and steady-state volume of distribution were 21 L/hr/m² and 113 L, respectively. Docetaxel and its metabolites are eliminated in the urine and feces, 75 and 6%, respectively. Only little amount is excreted in original drug. In vitro studies showed that docetaxel is about 94-97% protein bound. Dexamethasone does not affect the protein binding of docetaxel. In vitro studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme and its metabolism is inhibited by CYP3A4 inhibitors.
Toxicology: Docetaxel for injection has been shown to be clastogenic in the in vitro chromosome aberration test in CHO-K₁ cells and in the in vivo micronucleus test in the mouse, but it did not induce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assays.
Teratogenicity: Docetaxel for injection produces no impairment of fertility in rats when administered at the dose of 0.3 mg/kg (about 1/50 the recommended human dose on a mg/m² basis), but decreased testicular weights were reported. This correlates with the finding of 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3 and 1/15 the recommended dose on a mg/m² basis). An increased frequency of dosing in rats produced similar effects at lower dose levels.
Docetaxel for injection can cause fetal harm when administered to pregnant women. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on an mg/m² basis), administered during the period of organogenesis, have shown that docetaxel for injection is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight and fetal ossification delay). Previously mentioned dosages may cause maternal toxicity.

Treatment of patients with advanced or metastatic breast cancers after failure of prior chemotherapy including anticancer agents of anthracene ring and patients with advanced or metastatic non-small cell lung cancer after administration of cisplatin-based therapy.

Docetaxel is for IV infusion. All patients should be premedicated with oral corticosteroids eg, dexamethasone 16 mg/day for 3 days starting 1 day prior to docetaxel administration in order to prevent allergic reaction and fluid retention.
Withdraw corresponding diluent of docetaxel into appropriate solution before use. Shake gently and mix well. Allow the vial to stand at room temperature for 5 min. Check whether the solution is clear. Then according to dosage, withdraw mixed solution to a syringe and inject into an infusion bag or bottle of 5% dextrose solution or 0.9% sodium chloride solutions. Shake gently and mix well to produce a final concentration not more than 0.9 mg/mL. The recommended dose for docetaxel is 75 mg/m² administered over 1 hr every 3 weeks.

In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. There is no known antidote for docetaxel for injection overdosage. Anticipated complications of overdosage include: Bone marrow suppression, peripheral neurotoxicity and mucositis.

Patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80.
Patients with leukocyte counts of <1500 cells/mm³ and patients with severe liver function impairment.

Docetaxel for injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Because severe hypersensitivity reactions may occur, relevant first aid facilities should be available. Main function index should be closely monitored during infusion.
In patients with abnormal hepatic function, patients on high-dose docetaxel and patients with non-small cell lung cancer previously treated with platinum-based chemotherapy, administered docetaxel at a dose of 100 mg/m², the incidence of death associated with treatment is increased.
All patients should be premedicated with oral corticosteroids eg, dexamethasone 16 mg/day for 4-5 days starting 1 day prior to docetaxel administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.
Neutropenia is the most common adverse reaction. Frequent monitoring of leukocyte counts is essential during docetaxel therapy. Docetaxel should not be administered to patients until neutrophils return to be >1500 cells/mm³. If severe neutropenia (<500 cells/mm³ and duration of ≥7 days) occurs during docetaxel therapy, dosage decrease is recommended for the next cycle. If the problem recurs, dosing maybe tapered or therapy discontinued.
Hypersensitivity reactions may occur within a few minutes following initiation of a docetaxel infusion. If minor reactions eg, flushing or localized skin reactions occur, cessation of therapy may not be necessary. If severe reactions are observed, ie, blood pressure decreases by >20 mmHg, bronchospasm or eruption/erythema, immediate discontinuation of docetaxel may be required. Patients with a history of severe hypersensitivity reactions should not be rechallenged with docetaxel for injection.
During docetaxel therapy, peripheral neurotoxicity may occur. If it is severe, dosage decrease is recommended for next administration.
If observed cutaneous reactions include localized erythema of the extremities, edema and desquamation, therapy may be interrupted or discontinued.
Patients with liver function impairment: If serum transaminase (ALT and/or AST) is >1.5 times the upper limit of normal (ULN) concomitant with alkaline phosphatase >2.5 times ULN, there is a high-risk for severe adverse reactions, eg, toxicity, death, including lethal pyemia, GIT bleeding and febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Liver function tests should be conducted at baseline and before each chemotherapy cycle.
Use in pregnancy: There are no adequate and well-controlled studies in pregnant women using docetaxel for injection. If docetaxel for injection is used during pregnancy, or if the patient becomes pregnant while receiving Hentaxel, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with docetaxel.
Use in lactation: It is not known whether docetaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from docetaxel for injection, mothers should discontinue nursing prior to taking the drug.
Use in children: The safety and effectiveness of docetaxel in pediatric patients have not been established.

Use in pregnancy: There are no adequate and well-controlled studies in pregnant women using docetaxel for injection. If docetaxel for injection is used during pregnancy, or if the patient becomes pregnant while receiving Hentaxel, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with docetaxel.
Use in lactation: It is not known whether docetaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from docetaxel for injection, mothers should discontinue nursing prior to taking the drug.

Marrow Suppression: Neutropenia is the most common adverse reaction and generally severe (<500 cells/mm³). It is reversible and not accumulative.
Hypersensitivity Reactions: Severe hypersensitivity reactions characterized by hypotension and/or bronchospasm occurred in some cases that require discontinuation of treatment. After discontinuing the infusion and appropriate therapy, the patients recovered. Some cases may develop mild allergic reactions eg, flushing, erythema with or without pruritus, chest stuffiness, back pain, dyspnea, drug fever or chills.
Cutaneous reactions are often characterized by erythema on extremities but mainly on the hands and feet. Localized eruptions on the face and chest, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after docetaxel infusion, recovered before the next infusion. Severe symptoms eg, eruption followed by desquamation seldom occurred. Severe nail disorders were characterized by hypo- or hyperpigmentation and occasionally by onycholysis and pain.
Fluid retention includes edema and very seldom cases reported pleural effusion, ascites, pericardial effusion, capillary permeability increase and body weight gain. After 4-cycle of treatment or cumulative dose of 100 mg/m² , fluid retention occurred in lower extremity and probably develop to hyposarca, with body weight gain of ≥3 kg. After discontinuing docetaxel treatment, fluid retention disappeared gradually. Patients should be premedicated with corticosteroids before docetaxel administration to reduce the incidence of fluid retention.
GI symptoms include nausea, vomiting and diarrhea.
Neurotoxicity was reported in clinical trials.
Cardiovascular adverse reactions including hypotension, sinus tachycardia, cardio palmus, pulmonary edema and hypertension may occur.
Other adverse reactions include alopecia, asthenia, catarrh, arthritis, myalgia, hypotension and injection site reaction.
In patients with normal liver function tests at baseline, bilirubin values increased during therapy. The relation of which with the drug has not been adequately established.

In vitro drug interaction studies revealed that CYP3A4 inhibitors may affect the metabolism of docetaxel, so it should be cautiously co-administered with this kind of agents, eg ketoconazole, erythromycin, troleandomycin and nifedipine.

Store between 2-8°C.

Cytotoxic Chemotherapy

L01CD02 - docetaxel ; Belongs to the class of taxanes from plant alkaloids and other natural products. Used in the treatment of cancer.

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