Oncology Division
HENPLATIN (Oxaliplatin) HENTAXEL (Docetaxel) TPIAO (Thrombopoietin) ZEFEI (Gemcitabine) ZILONGJIN (Astragalus) HENSETRON (Tropisetron HCl)
Hematology Division
EPOSINO (Epoetin Alfa) FERROFER (Iron Sucrose) TPIAO (Thrombopoietin) WHITE-C (Filgrastim)
Nephrology Division
EPOSINO (Epoetin Alfa) FERROFER (Iron Sucrose)
GoodFellow Pharma Corporation

HENTAXEL (Docetaxel)

Solution for Injection 20 mg/0.5mL vial and 80mg/2mL vial
Formulation
Each 0.5 mL contains Docetaxel 20mg
Each 2 mL contains Docetaxel 80mg

Structural Formula
C43H53NO14



Indication
It is indicated for the treatment of patients with advanced or metastatic breast cancers after failure of prior chemotherapy including anticancer agents of anthracene ring. It is indicated for the treatment of patients with advanced or metastatic non-small cell lung cancer after administration of cisplatin-based therapy.

Dosage and Administration
Docetaxel is for intravenous infusion. All patients should be premedicated with oral corticosteroids such as dexamethasone 16 mg per 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 minutes. 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. The recommended dose for Docetaxel is 75mg/m2 administered in an hour every 3 weeks or 21 days.

Pharmacological Action
It 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.

Toxicology (Genetoxicity)
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.

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

Overdosage
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.

Shelf-Life
Product is stable for two years

Storage
Store between 2oC and 8oC

Caution
Foods, Drugs and Cosmetics Act prohibits dispensing without prescription.

Reproductive Toxicity
Docetaxel for injection produces no impairment of fertility in rats when administered at the dose of 0.3mg/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 5mg/kg in rats and 0.375mg/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). Above dosages may cause maternal toxicity. 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 this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with docetaxel.

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.

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 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-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. Intravenous infusion of docetaxel at dose of 100mg/m2 within 1 hour, mean peak concentration is 3.7µg/ml and AUC is 4.6µg/mlh. Mean values for total body clearance and steady state volume of distribution were 21 L/h/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% to 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.

Adverse Reactions
  1. Marrow suppression: neutropenia is the most common adverse reaction and generally severe (< 500 cells/mm3). It is reversible and not accumulative.
  2. 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, such as flushing, erythema with or without pruritus, chest stuffiness, back pain, dyspnea, drug fever or chills.
  3. 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, such as eruption followed by desquamation seldom occurred. Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis and pain.
  4. 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 100mg/m2, fluid retention occurred in lower extremity, and probably develop to hyposarca, with body weight gain of 3 kg or greater. After discontinuing docetaxel treatment, fluid retention disappeared gradually. Patients should be premedicated with corticosteroids before docetaxel administration to reduce the incidence of fluid retention.
  5. Gastrointestinal symptoms include nausea, vomiting and diarrhea.
  6. Neurotoxicity was reported in clinical trials.
  7. Cardiovascular adverse reactions including hypotension, sinus tachycardia, cardio palmus, pulmonary edema, and hypertension may occur.
  8. Other adverse reactions include alopecia, asthenia, catarrh, arthritis, myalgia, and hypotension and injection site reaction.
  9. 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.
Contraindications
  1. It is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80.
  2. It should not be used in patients with leukocyte counts of < 1500 cells/mm3.
  3. Patients with severe liver function impair.
Precautions
  • 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 such as dexamethasone 16 mg per day for 4 to 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 returns to be > 1500 cells/mm3. If severe neutropenia (< 500 cells/mm3 and duration of 7 days or above) 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 such as flushing or localized skin reactions occur, cessation of therapy may not be necessary. If severe reactions are observed, for example, blood pressure decreases by more than 20mmHg, bronchospasm or eryption/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 high risk for severe adverse reactions, such as toxicity death, including lethal pyemia, gastrointestinal tract bleeding, and febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Liver function tests should be conducted at baseline and before each chemotherapy cycle.


Manufactured By
Jiangsu-Hengrui Medicine Co., Ltd.
No. 145 East Renmin Road, Xinpu District,
Lianyungang, Jiangsu Province, China

Exclusively Imported By
Goodfellow Pharma Corporation
Unit 3009 Jollibee Plaza Bldg., Emerald Ave.,
Ortigas Center, Pasig City
Tel. Nos.: (632) 632-7031
Fax: (632) 635-3957
E-mail: good_fellow88@yahoo.com
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