Taxotere (Docetaxel)

TAXOTERE®

Rhône-Poulenc Rorer

Docetaxel

Antineoplastic

Caution: Docetaxel concentrate for injection should be administered under the supervision of a physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Docetaxel therapy should not be given to patients with neutrophil counts of less than 1 500 cells/mm

Severe hypersensitivity reactions resulting in immediate discontinuations occurred in 0.4% (5 of 1 260) of patients. Docetaxel must not be given to patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80.

Action and Clinical

Docetaxel is an antineoplastic agent which acts by disrupting the microtubular network in cells that is essential for vital mitotic and interphase cellular functions. Docetaxel promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. Docetaxel binds to free tubulin thereby decreasing the critical intracellular concentration of tubulin. The promoted polymerization of microtubules leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, resulting in the inhibition of mitosis in cells. The binding of docetaxel to microtubules does not alter the number of protofilaments in the bound microtubules; in that, it differs from other spindle poisons.:

Docetaxel was found to be cytotoxic in vitro against various murine and human tumor cell lines, and against freshly excised human tumor cells in clonogenic assays.

In addition, docetaxel was found to be active on a number of cell lines overexpressing the p-glycoprotein which is encoded by the multidrug resistant gene.

At doses of 70 to 115 mg/m

A population pharmacokinetic analysis has been performed in patients receiving docetaxel. Pharmacokinetic parameters estimated by the model were very close to those estimated from Phase I studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient. In a small number of patients with clinical chemistry data suggestive of mild to moderate liver function impairment (ALT, AST ³ 1.5 times the upper limit of normal associated with alkaline phosphatase ³ 2.5 times the upper limit of normal), total clearance was lowered by 27% on average (see Dosage).

Based on in vitro studies, isoenzymes of the cytochrome P450-3A subfamily appear to be involved in docetaxel metabolism.

Docetaxel is more than 95% protein bound. Dexamethasone does not affect the protein binding of docetaxel.

Indications And Clinical Uses :

Breast Cancer: Treatment of patients with locally advanced or metastatic breast carcinoma after failure of a previous chemotherapy regimen.

Non-Small Cell Lung Cancer: Treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy.

Ovarian Cancer: Treatment of metastatic carcinoma of the ovary after failure of first-line or subsequent chemotherapy.

Contraindications:

Docetaxel should not be used in patients with neutrophil counts of Docetaxel is contraindicated in patients with severe liver impairment.

Warnings in Clinical States: Hematologic Effects: Neutropenia is the most frequently reported adverse event. Neutrophil nadirs occurred at a median of 8 days. Frequent monitoring of blood counts should be conducted during docetaxel treatment. Patients should not be retreated with docetaxel until neutrophils recover to a level ³ 1 500 cells/mm

Hypersensitivity Reactions: Severe hypersensitivity reactions characterized by hypotension, bronchospasm and generalized rash/erythema have occurred. These reactions resulted in immediate discontinuation in approximately 0.4% (5 of 1 260) of patients. Severe symptoms resolve after discontinuation of the infusion and administration of appropriate therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with docetaxel.

Pregnancy: Docetaxel may cause fetal harm when administered to a pregnant woman. There are no studies in pregnant women. No evidence of teratogenic effect was found when docetaxel was administered at 1.8 or 1.2 mg/m

Children: The safety and effectiveness of docetaxel in children have not been established.

Precautions:

Hematology: Docetaxel therapy should not be administered until the neutrophil count is over 1 500 cells/mmSupplied 3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent blood cell counts be performed on all patients receiving docetaxel (see Warnings). Patients should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level of >1 500 cells/mmSupplied 3. In cases of severe neutropenia (<500 cells/mmSupplied 3) for 7 days or more during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy is recommended (see Dosage).

Hypersensitivity Reactions: Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of docetaxel. If minor reactions such as flushing or localized skin reactions occur, therapy with docetaxel does not have to be discontinued. However, severe reactions, such as hypotension requiring treatment, bronchospasm, or generalized rash/erythema require immediate discontinuation of docetaxel and aggressive therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with docetaxel. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of docetaxel (see Dosage).

Cutaneous: Localized erythema of the extremities (palm of the hands and soles of the feet) with edema, followed by desquamation has been observed. In case of severe skin toxicity during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy is recommended (see Dosage).

Fluid Retention: Severe fluid retention has been reported following docetaxel therapy. Therefore, patients should be premedicated with oral corticosteroids prior to each docetaxel administration to reduce the incidence and severity of fluid retention (see Dosage). Patients with pre-existing effusion should be closely monitored from the first dose for the possible exacerbation of the effusions.

Patients with Liver Impairment: In patients treated with docetaxel at 100 mg/m

Neurologic: The development of severe peripheral neurotoxicity is infrequent and requires a reduction in dose (see Dosage). If symptoms persist, treatment should be discontinued.

Carcinogenicity, Mutagenicity, Impairment of Fertility: The carcinogenic potential of docetaxel has not been studied. Docetaxel has been shown to be mutagenic in the in vitro chromosome aberration test in CHO-K 1 cells and in the in vivo micronucleus test in the mouse. However, it did not induce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent with the pharmacological activity of docetaxel.

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, it is recommended that women be advised not to breast-feed during docetaxel therapy.

Drug Interactions :

There have been no formal clinical studies to evaluate the drug interactions of docetaxel with other medications. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds which induce, inhibit or are metabolized by (and thus may inhibit the enzyme competitively) cytochrome P450-3A such as cyclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with these drugs as concomitant therapy since there is a potential for a significant interaction.

Adverse Reactions:

There were 2 045 patients with normal liver function tests (LFTs) at baseline who received an initial planned dose of 100 mg/m

Hematologic: Neutropenia was the most frequent adverse reaction associated with docetaxel; it was reversible and not cumulative. The median time to nadir was 8 days, while the median duration of severe neutropenia (Fever was associated with neutropenia (Thrombocytopenia).
Anemia (<11 g/dL) was observed in 90% of the patients and was severe (<8 g/dL) in 9% of the cases.

Hypersensitivity Reactions: Hypersensitivity reactions occurred in 21% of the patients generally within a few minutes following the start of the infusion of docetaxel and were usually mild to moderate. The most frequent minor manifestations were flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills.

Severe reactions characterized by hypotension, bronchospasm, or generalized rash/erythema have occurred within a few minutes following the initiation of infusion of docetaxel. Severe symptoms were observed in 4% of the patients; however, 1.2% (25 of 2 045) had immediate discontinuation of treatment. All hypersensitivity reactions resolved after discontinuation of the infusion and appropriate therapy.

Fluid Retention: Fluid retention has been reported in 52% of the patients (receiving premedication) which includes edema, and less frequently, pleural effusion, ascites, pericardial effusion, and weight gain. Fluid retention usually begins at the lower extremities and may become generalized with a weight gain of 3 kg or more.

The incidence of fluid retention in patients without premedication was 81.6%; of these 22.4% were severe. In patients premedicated up to 4 to 5 days with oral corticosteroids, the incidence of fluid retention was 52%; of these 6% were severe. Table  below describes the effect on fluid retention with corticosteroid premedication (see Dosage for treatment regimen).

Fluid retention has not been accompanied by acute episodes of dehydration, oliguria or hypotension, and was slowly reversible after docetaxel treatment was stopped.

Cutaneous: Cutaneous reactions have been observed in 48% of the patients treated with docetaxel. These reactions were characterized by a rash, including localized eruptions mainly on feet and hands, but also on arms, face or thorax. They were occasionally associated with pruritus. Eruptions generally occurred within 1 week following the docetaxel infusion, resolved before the next infusion, and were not disabling.

Severe symptoms such as eruptions followed by desquamation occurred less frequently (5%). These reactions rarely lead to interruption or discontinuation of docetaxel treatment.

Severe nail disorders occurred in 2% of the patients. These reactions were characterized by hypo- or hyperpigmentation, and infrequently onycholysis and pain.

Neurologic: Neurosensory symptoms characterized by paresthesia, dysthenia or pain (including burning sensation) were reported in 49% of all patients. Severe reactions were observed in less than 4% of the patients.

Neuromotor events were reported in 14% of patients. These reactions were severe in 4% of patients.

Gastrointestinal: Nausea (39%), diarrhea (39%), and vomiting (22%), were observed in patients treated with docetaxel. These reactions were generally mild to moderate. Severe gastrointestinal reactions generally occurred in less than 5% of the cases reported. Rare occurrences of gastrointestinal perforation have been reported.

Cardiovascular: Hypotension occurred in 3% of the patients and required therapy in 0.5% of the patients. Dysrhythmia occurred in 2% of the patients and was severe in 0.4% of the patients. Clinically meaningful events occurred in less than 2% of patients. These events included: heart failure (0.3%), tachycardia (1.4%) and hypertension (1.6%).

Infusion Site Reactions: Infusion site reactions occurred in 6% of the patients treated with docetaxel and were generally mild. These reactions included skin sensitivities such as hyperpigmentation, inflammation, local erythema, dryness of the skin, or swelling of the vein. Phlebitis or extravasation were observed less frequently.

Hepatic: Increases ALT, AST, bilirubin, and alkaline phosphatase which were greater than 2.5 times the upper limit of normal were observed in less than 2% of patients.

Other: Alopecia was observed in 76% of patients. Asthenia was reported by 62% of patients and was considered severe in 13% of these patients. Stomatitis was reported by 42% of patients. Arthralgias (9%) and myalgias (19%) were reported by patients but were generally considered to be mild to moderate.

Symptoms And Treatment Of Overdose :

OverdoseThere is no known antidote for docetaxel overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored and supportive treatment administered as necessary. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis.

There were 2 reports of overdose. One patient received 150 mg/m

Dosage & Administration: Recommended Dosage: The recommended dosage of docetaxel is 100 mg/m

Premedication Regimen: In order to reduce the incidence and severity of fluid retention, all patients should be pretreated with oral corticosteroids. The recommended premedication should consist only of oral corticosteroids, such as dexamethasone 16 mg/day (e.g., 8 mg b.i.d.), for 3 days starting 1 day prior to each docetaxel administration. Antihistamines have not been shown to be useful in controlling fluid retention.

Geriatrics: Based on the population pharmacokinetics, there are no special instructions for the use in the elderly.

Dosage Adjustments: Patients with Neutropenia, Cutaneous Reactions or Peripheral Neuropathy: Like many other chemotherapeutic agents, careful monitoring of neutrophil counts are an essential part of docetaxel therapy. Docetaxel should not be administered until the neutrophil count is at least 1 500 cells/mm

Patients with Hepatic Impairment: Based on pharmacokinetic data, in patients who have both elevations of transaminase values (ALT and/or AST) greater than 1.5 times the upper limit of the normal (ULN) and increases in alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel is 75 mg/m

Administration Precautions: Docetaxel must be administered i.v. It is extremely important that the i.v. needle or catheter be properly positioned before any docetaxel is injected. Leakage into surrounding tissue during i.v. administration of docetaxel may cause considerable irritation, local tissue necrosis and/or thrombophlebitis. If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should be introduced into another vein.

Stability and Storage Recommendations: Stability: Unopened vials of docetaxel are stable until the expiration date indicated on the package when stored under refrigeration at 2 to 8°C and protected from bright light. Freezing does not adversely affect the product.

Storage: Store the unopened vials under refrigeration, 2 to 8°C. Retain in the original package to protect from bright light.

Taxotere premix solution (10 mg docetaxel/mL) and fully prepared Taxotere infusion solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used a soon as possible after preparation. However, they are stable for 8 hours at room temperature, 15 to 25°C or under refrigeration, 2 to 8°C.

Reconstitution of Solutions: Preparation and Administration Precautions: Taxotere Concentrate for Injection requires dilution prior to administration. Please follow the preparation instructions provided below.

A. Preparation of the Premix Solution: 1. Remove the appropriate number of vials of Taxotere Concentrate for Injection and diluent from the refrigerator. Allow the vials to stand at room temperature for approximately 5 minutes.

2. Aseptically withdraw the entire contents of the diluent vial into a syringe and transfer it to the vial of Taxotere Concentrate for Injection.

3. Gently rotate each premix solution vial for approximately 15 seconds to assure full mixture of the concentrate and diluent.

4. The Taxotere premix solution (10 mg docetaxel/mL) should be clear; however, there may be some foam on top of the solution due to the polysorbate 80. Allow the premix solution to stand for a few minutes to allow any foam to dissipate. It is not required that all foam dissipate prior to continuing the preparation process.

B. Preparation of the Infusion Solution: 1. Aseptically withdraw the required amount of Taxotere premix with a calibrated syringe and inject the required volume of premix solution into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.9 mg/mL. If a dose greater than 200 mg of Taxotere is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL Taxotere is not exceeded.

2. Thoroughly mix the infusion by manual rotation.

3. As with all parenteral products, Taxotere should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Taxotere for Injection premix solution or infusion solution is not clear or appears to have precipitation, the solution should be discarded.

Taxotere infusion solution should be aseptically administered i.v. as a 1-hour infusion under ambient room temperature and lighting conditions.

Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solution for infusion is not recommended. In order to minimize patient exposure to plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, Taxotere infusion solution should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Special Instructions: 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. Please refer to Handling and Disposal section.

If docetaxel concentrate, premix solution or infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If docetaxel concentrate, premix solution, or infusion solution should come into contact with mucosa, immediately and thoroughly wash with water.

Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Availability And Storage: 20 mg/0.5 mL: Single-dose vial of sterile, pyrogen-free, nonaqueous, clear yellow to brownish-yellow viscous solution contains: docetaxel (anhydrous) 20 mg in 0.5 mL polysorbate 80 (Fill: docetaxel 23.6 mg in 0.59 mL polysorbate 80) with an accompanying sterile, nonpyrogenic diluent vial containing 1.83 mL of ethanol 13% in water for injection. This overfill ensures that there is a minimal extractable premix volume of 2 mL containing 10 mg/mL docetaxel which corresponds to the labelled amount of 20 mg/vial. Nonmedicinal ingredients: ethyl alcohol, polysorbate 80 and water for injection. Both items are in blister pack in 1 carton.

80 mg/2 mL: Single-dose vial of sterile, pyrogen-free, nonaqueous, clear yellow to brownish-yellow viscous solution contains: docetaxel (anhydrous) 80 mg in 2 mL polysorbate 80 (Fill: docetaxel 94.4 mg in 2.36 mL polysorbate 80) with an accompanying sterile, nonpyrogenic diluent vial containing 7.33 mL of ethanol 13% in water for injection. This overfill ensures that there is a minimal extractable premix volume of 8 mL containing 10 mg/mL docetaxel which corresponds to the labelled amount of 80 mg/vial. Nonmedicinal ingredients: ethyl alcohol, polysorbate 80 and water for injection. Both items are in blister pack in 1 carton.

TAXOTERE® Rhône-Poulenc Rorer Docetaxel Antineoplastic

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