Taceedo 20: Each Single Dose Vial (0.5 mL) contains: Docetaxel (as Trihydrate) 20 mg.
Taceedo 80: Each Single Dose Vial (2 mL) contains: Docetaxel (as Trihydrate) 80 mg.
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.
Docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5 (-20 epoxy-1, 2α, 4,7β, 10β, 13α-hexahydroxytax-I1-en-9-one 4-acetale 2-benzoate, trihydrate.
Docetaxel is a white to almost white powder with an empirical formula of C43H53NO14·3H2O and a molecular weight of 861.9.
Solvent: Solvent for Docetaxel injection is a clear colorless solution. It is supplied as an aqueous solution for preparing a premix solution of docetaxel injection and this premix solution is intended for further dilution with either 0.9% sodium chloride injection USP or 5% dextrose injection USP.
Pharmacology: Pharmacodynamics: 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 most spindle poisons currently in clinical use.
Pharmacokinetics: The pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20-115 mg/m2. 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 3 compartment pharmacokinetic model, with half-lives for the α, β and phase of 4 minutes, 36 minutes and 11.1 hours, respectively. This 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.
Mean values for total body clearance and steady-state volume of distribution were 21 L/hr/m2 and 113 L, respectively.
Docetaxel was eliminated in both the urine and faeces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within seven days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as one major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.
Based on in vitro studies, isoenzymes of the cytochrome P4503A (CYP3A) subfamily appear to be involved in docetaxel metabolism.
The pharmacokinetics of docetaxel was not influenced by age or gender and docetaxel total body clearance was not modified by pre-treatment with dexamethasone. In patients with clinical chemistry data suggestive of mild to moderate liver function impairment [SGOT and/or SGPT >15 times the upper limit of normal (ULN) concomitant with alkaline phosphatase >2.5 times ULN], total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC).
In vitro studies showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin and lipoproteins.
Breast Cancer: Docetaxel (Taceedo) is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy and in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.
Non-Small Cell Lung Cancer: Docetaxel (Taceedo) as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.
Docetaxel (Taceedo) in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.
Prostate Cancer: Taceedo in combination with prednisolone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.
Gastric Adenocarcinoma: Docetaxel (Taceedo) in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.
Head and Neck Cancer: Docetaxel (Taceedo) in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Premedication Regimen: All patients should be premedicated with oral corticosteroids eg, dexamethasone 16 mg per day (eg, 8 mg BID) for 5 days starting 1 day prior to docetaxel administration in order to reduce the incidence and severity of hypersensitivity reactions.
Breast Cancer: For treatment of patients with locally advanced or metastatic carcinoma of the breast after progression during anthracycline-based therapy for metastatic disease or relapse during anthracycline-based adjuvant therapy, the recommended dose is 60-100 mg/m2 intravenously over 1 hour every 3 weeks.
NSCLC: For treatment of patients with advanced or metastatic non-small cell lung cancer alter the failure of prior platinum containing therapy, the recommended dose of docetaxel is 75-100 mg/m2 IV over 1 hour every 3 weeks.
Prostate Cancer: For hormone-refractory metastatic prostate cancer, the recommended dose is 75 mg/m2 every 3 weeks as a 1 hour IV infusion. Prednisone 5 mg orally twice daily is administered continuously.
Gastric Adenocarcinoma: Recommended Dose: 75 mg/m2 as a 1 hr IV infusion, followed by cisplatin 75 mg/m2 as a 1 to 3 hour IV infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous IV infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every 3 weeks.
Head and Neck Cancer: Induction chemotherapy followed by radiotherapy: For the induction treatment of locally advanced inoperable SCCHN, the recommended dose is 75 mg/m2 as a 1-hour IV infusion followed by cisplatin 75 mg/m2 IV over 1 hour, on day 1, followed by fluorouracil as a continuous IV infusion at 750 mg/m2/day for 5 days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.
Induction chemotherapy followed by chemoradiotherapy: For the induction treatment of patients with locally advanced (unresectable, low-surgical cure organ preservation) SCCHN, the recommended dose is 75 mg/m2 as a 1-hour IV infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3-hour infusion, followed by fluorouracil 1000 mg/m2 /day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.
Dosage Adjustments During Treatment: Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy should have the dosage adjusted from 100 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and do not experience febrile neutropenia, neutrophils <500/mm3 for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy may tolerate higher doses.
There is no known antidote for docetaxel overdosage. In case of overdosage, the patient should be kept in to specialized units where vital functions can be closely monitored.
Anticipated complications of overdosage include: Bone marrow suppression, peripheral neurotoxicity and mucositis.
There are two reports of overdose, one patient received 150 mg/m2 ad the other received 200 mg/m2 as one hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia and recovered without incident.
Patients who have a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80. Docetaxel should not be used in patients with neutrophil counts of <1,500 cells/mm3.
Docetaxel for injection concentrate should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
General: Responding patients may not experience an improvement in performance status or therapy and may experience worsening. The relationship between changes in performance status, response to therapy and treatment-related side effects has not been established.
Hematologic Effects: In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving docetaxel. Patients should not be retreated with subsequent cycles of docetaxel, until neutrophils recover to a level of >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.
A 25% reduction in the dose of docetaxel is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia or grade 4 infections in a docetaxel cycle.
Hypersensitivity Reactions: Hypersensitivity reactions may occur within a few mins following initiation of docetaxel infusion, if minor reactions eg, flushing or localized skin reactions occur, interruption of therapy is not required. More severe reactions, however, require immediate discontinuation of docetaxel and aggressive therapy. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion docetaxel.
Cutaneous: Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended.
Fluid Retention: Severe fluid retention has been reported following docetaxel therapy. Patients should be premedicated with oral corticosteroids prior to each docetaxel administration to reduce the incidence and severity of fluid retention. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions. The media cumulative dose to onset of moderate or severe fluid retention was 705 mg/m2 in patients receiving premedication. Patients developing peripheral edema may be treated with standard measures, eg, salt restriction, oral diuretics.
Neurologic: Severe neurosensory symptoms (paresthesia, dysesthesia, pain) were observed among with anthracycline-resistant breast cancer. When these occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued. Peripheral motor neuropathy, mainly manifested as distal extremity weakness, occurred in 13.4% (7.1% severe) of the 127 anthracycline-resistant breast cancer patients with normal LFTs.
Asthenia: Severe asthenia has been reported in 11.1% of the patients but has led to treatment discontinuation in only 2.6% of the patients. Severe asthenia was reported in 23% patients with anthracycline-resistant breast cancer and 5.5% of the 786 cycles received. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.
Pediatric use: The safety and effectiveness of docetaxel in pediatric patients have not been established.
Pregnancy: Docetaxel can cause fetal harm when administered to pregnant women.
Nursing Mothers: It is not known whether docetaxel is excreted in human milk and because of the potential for serious adverse reactions in nursing infants from docetaxel, mothers should discontinue nursing prior to taking docetaxel.
Bone marrow suppression is the major dose-limiting toxicity of docetaxel.
Neutropenia is reversible and not cumulative. The median day to nadir was 8 days, while the median duration of severe neutropenia (<500 cell/mm3
) was 7 days. Among patients with normal liver function treated with docetaxel, severe neutropenia occurred in 76% and lasted for more than 7 days in 4.3% of cycles. Anemia was reported in 89.5% with severe cases being reported in 8.4% of the patients).
Hypersensitivity reactions requiring discontinuation of the docetaxel infusion were reported in patients who did not receive premedication. Severe hypersensitivity reactions characterized by hypotension and/or bronchospasm, or generalized rash/erythemas have been observed in only 0.9% of patients with normal liver function receiving the recommended premedication regimen and none of these patients had to discontinue therapy.
Minor events, including flushing, rash with or without pruritus, chest lightness, back pain, dyspnea, drug fever or chills have been reported and resolved after discontinuing the infusion and appropriate therapy.
Events such as edema and weight gain and, less frequently, pleural effusion, pericardial effusion or ascites have been described.
Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face or thorax, usually associated with pruritus, have been observed.
Neurosensory symptoms characterized by paresthesia, dysesthesia or pain (including burning sensation) have been reported in patients receiving docetaxel.
Gastrointestinal reactions (nausea, and/or vomiting, and/or diarrhea were generally mild to moderate and severe reactions occurred in 8.2% of the patients. Stomatitis was reported in 42.3% of patients receiving docetaxel. Severe reactions were observed in 5.3% of patients.
Hypertension occurred in 3.6% of the patients; 3.4% required treatment.
Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely.
Infusion Site Reactions:
Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein.
There have been no formal clinical studies to evaluate the drug interactions of docetaxel with other medications. Docetaxel may be notified by the concomitant administration of compounds that induce, inhibit or are metabolized by cytochrome P450 3A4, such as cyclosporine, terfenadine, ketoconazole, erythromycin, and troleandomycin. Caution should be exercised with these drugs when treating patients receiving docetaxel as there is a potential for a significant interaction.
Handling: Docetaxel is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised when handling and preparing docetaxel solutions. The use of gloves is recommended. If docetaxel concentrate, premix solution or infusion come into contact with skin or mucosa immediately and thoroughly wash with soap and water.
Reconstitution: Reconstitute docetaxel injection after bringing it to room temperature using the solvent. Use 1.5 mL solvent pack for 20 mg, 6 mL solvent pack for 80 mg and 9 mL solvent pack for 120 mg. Rotate the vial gently and allow the premix to stand for 5 minutes. The solution should be clear and homogenous. Use docetaxel premix for further dilution.
Preparation of the Infusion Solution: Transfer the content of the solvent to the concentrate vial, shake and dilute with 0.9% sodium chloride or 5% dextrose to a final concentration of 0.3-0.9 mg/mL. Docetaxel infusion solution should be administered IV as a 1-hr infusion under ambient room temperature and lighting condition.
Store at a temperature not exceeding 2°C to 8°C. Protect from light.
L01CD02 - docetaxel ; Belongs to the class of plant alkaloids and other natural products, taxanes. Used in the treatment of cancer.
Taceedo 20: Soln for IV infusion (conc) (vial + 1.5-mL vial solvent) 20 mg/0.5 mL x 5 mL x 1's.
Taceedo 80: Soln for IV infusion (conc) (vial + 6-mL vial solvent) 80 mg/2 mL x 10 mL x 1's.