Daxotel

Docetaxel.

Each mL contains Docetaxel anhydrous 20 mg.
Excipients/Inactive Ingredients: Polysorbate 80 (Purified), dehydrated alcohol, anhydrous citric acid.

Pharmacology: Pharmacodynamics: Docetaxel is an antineoplastic agent acting at the microtubules. Docetaxel enhances polymerization of the tubulin into stable microtubules and inhibits their depolymerization. This induces the formation of stable microtubule bundles leading to cell death.
Pharmacokinetics: The pharmacokinetic studies on Docetaxel reveal that there is no schedule dependence of Docetaxel disposition. The area under the curve (AUC) was dose proportional following doses of 70 mg/m² to 115 mg/m² with infusion times of 1 to 2 hours. At the highest clinical doses level examined in the 1-h infusion schedule every 3 weeks, docetaxel disposition was triphasic, with a terminal half-life of 11 to 18 h and a plasma clearance of 16 to 21 l/h/m². The half lives for α, β and γ phases were 4 min, 36 min and 11.1 hours respectively while systemic clearance was 21 l/h/m².
The major route of elimination of Docetaxel and its metabolites is fecal through which about 80% of the drug is excreted. About 5% excretion takes place from urine. Only a minor fraction of administered drug is excreted as the parent drug. Docetaxel metabolism involves the isoenzymes of the cytochrome P450-3A subfamily and more than 95% of Docetaxel is bound to plasma proteins.
Toxicology: Preclinical safety data: Carcinogenicity studies with Docetaxel have not been performed.
Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60^th to 1/15^th the recommended human dose on a mg/m² basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.
Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50^th the recommended human dose on a mg/m² basis), but decreased testicular weights were reported. This correlates with findings of a 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 intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3^rd and 1/15^th the recommended human dose on a mg/m² basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels

Breast cancer: DAXOTEL (Docetaxel) as monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.
DAXOTEL (Docetaxel) in combination with Doxorubicin and Cyclophosphamide is indicated for the adjuvant treatment of patients with operable node- positive breast cancer.
DAXOTEL (Docetaxel) in combination with Doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not received prior chemotherapy.
DAXOTEL (Docetaxel) in combination with Capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.
DAXOTEL (Docetaxel) in combination with Trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress HER 2 and who previously have not received prior chemotherapy for metastatic disease.
Non-small cell lung cancer: DAXOTEL (Docetaxel) is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.
DAXOTEL (Docetaxel) in combination with Cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not previously received chemotherapy for this condition.
Gastric adenocarcinoma: DAXOTEL (Docetaxel) in combination with Cisplatin and 5-fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarinoma of the gastro esophageal junction, who have not received prior chemotherapy for advanced disease.
Head and neck cancer: DAXOTEL (Docetaxel) in combination with Cisplatin and 5-fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck.
Prostate cancer: DAXOTEL (Docetaxel) in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer.

The use of Docetaxel should be confined to specialized unit in the administration of cytotoxic agents/chemotherapy and it should only be administered under the supervision of a qualified physician in the use of anticancer chemotherapy.
Recommended dose: For breast, non-small cell lung, gastric and head and neck cancers, premeditation consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to Docetaxel administration, unless contraindicated, can be used (see Precautions).
Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities.
For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended premeditation regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the Docetaxel infusion. Docetaxel is administered as a one-hour infusion every three weeks.
Breast cancer: For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose of Docetaxel is 100 mg/m² once every 3 weeks in monotherapy. In first-line treatment, Docetaxel 75 mg/m² once every 3 weeks is given in combination therapy with Doxorubicin 50 mg/m².
In the adjuvant treatment of operable node-positive breast cancer, the recommended dose of Docetaxel is 75 mg/m² administered 1-hour after Doxorubicin 50 mg/m² and Cyclophosphamide 500 mg/m² every 3 weeks for 6 cycles.
In combination with Capecitabine the recommended dose of Docetaxel is 75 mg/m² every three weeks, combined with Capecitabine at 1,250 mg/m² twice daily (within 30 minutes after a meal) for 2 weeks followed by 1-week rest period. For Capecitabine dose calculation according to body surface area, see Capecitabine summary of product characteristics.
In combination with Trastuzumab the recommended dose of Docetaxel is 100 mg/m² every three weeks, with Trastuzumab administered weekly. In the pivotal trial the initial Docetaxel infusion was started the day following the first dose of Trastuzumab. The subsequent Docetaxel doses were administered immediately after completion of the Trastuzumab infusion, the preceding dose of Trastuzumab was well tolerated. For Trastuzumab dose and administration, see summary of product characteristics.
Non-small cell lung cancer: The recommended dose is 75 mg/m² as monotherapy administered IV over 1 hour every 3 weeks. In chemotherapy naive patients treated for non-small cell lung cancer, the recommended dose regimen is Docetaxel 75 mg/m² over 1 hour immediately followed by Cisplatin 75 mg/m² over 30-60 minutes every 3 weeks or Carboplatin (AUC 6 mg/ml-min) for treatment after failure of prior platinum-based chemotherapy.
Gastric adenocarcinoma: The recommended dose of Docetaxel is 75 mg/m² as 1 hour infusion, followed by cisplatin 75 mg/m² as a 1 to 3 hour infusion (both on day 1 only) followed by 5-fluorouracil 750 mg/m² per day given as a 24 hour continuous infusion for 5 days, starting at the end of the Cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premeditation with antiemetic and appropriate hydration for cisplatin administration.
Prophylactic G-CSF should be used to alleviate the risk of hematological toxicities.
Head and neck cancer: Patients must receive antiemetic and appropriate hydration (prior to and after cisplatin administration).
Prophylactic G-CSF may be used to alleviate the risk of hematological toxicities.
The recommended dose of Docetaxel is 75 mg/m² as a 1 hour infusion followed by Cisplatin 75 mg/m² over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750 mg/m² per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy or the recommended dose of Docetaxel is 75 mg/m² as a 1 hour intravenous infusion on day 1 followed by Cisplatin 100 mg/m² administered as a 30-minute to 3 hour infusion, followed by 5-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. Cisplatin and 5-fluorouracil dose can be adjusted, see the corresponding summary of product characteristic.
Prostate cancer: The recommended dose of Docetaxel is 75 mg/m² once every 3 weeks with Prednisone or prednisolone 5 mg orally twice daily is administered continuously.
Administration Precautions: If Docetaxel Injection concentrate, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection concentrate, initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water. Contact of the Docetaxel Injection concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final Docetaxel Injection concentrate dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
PREPARATION AND ADMINISTRATION: Do not use the two-vial formulation (Injection Concentrate and diluent) with the one-vial formulation.
One-vial Docetaxel Injection Concentrate (Injection Concentrate).
Docetaxel Injection Concentrate (20 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution.
1. Aseptically withdraw the required amount of Docetaxel Injection concentrate (20 mg docetaxel/ml) with a calibrated syringe and inject 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 mg/mL to 0.74 mg/mL.
If a dose greater than 200 mg of Docetaxel Injection concentrate is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL Docetaxel Injection concentrate is not exceeded.
2. Thoroughly mix the infusion by gentle manual rotation.
3. As with all parenteral products, Docetaxel Injection concentrate should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Docetaxel Injection concentrate dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded.
The Docetaxel Injection concentrate dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.

There is no known antidote for docetaxel overdose. The known complications of overdose include neutropenia, cutaneous reactions and sensory neuropathy. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

Docetaxel Injection concentrate is contraindicated in patients who have a history of severe hypersensitivity reactions to Docetaxel or to other drugs formulated with polysorbate 80.
Docetaxel Injection concentrate should not be used in patients with neutrophil counts of <1500 cells/mm³.

Docetaxel should be administered under supervision of a physician experienced in the use of cancer chemotherapeutic agents. Since significant hypersensitivity reactions may occur, appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. During the infusion, it is recommended that vital functions should be closely monitored.
In order to reduce fluid retention all the patients should be premedicated with oral corticosteroids like Dexamethasone 16 mg per day for 4-5 days beginning 1 day prior to Docetaxel administration.
Patient should be treated with Docetaxel only when baseline neutrophil count is > 1500/mm³. Frequent monitoring of complete blood count should be performed regularly during Docetaxel therapy. The subsequent dose of docetaxel should be reduced in case of Grade IV neutropenia (neutrophil Count < 500/mm³) lasting for 7 days or more.
Hypersensitivity reactions (HSR) may occur within a few minutes following the initiation of the infusion of Docetaxel. Minor HSR may manifest as mild flushing or localized skin reactions however, interruption of therapy is not required in such cases. Severe HSRs such as hypotension or bronchospasm or generalized rashes require immediate cessation of infusion and aggressive symptomatic therapy. Patients who have developed severe HSRs should not be rechallenged with Docetaxel.
Peripheral neuropathy may be observed in a few patients during Docetaxel therapy. Subsequent dose reductions is suggested in case of peripheral neuropathy.
Safety of Docetaxel has not been established in children; hence, a cautious use is suggested utilizing risk vs. benefit ratio.
Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Docetaxel. There is a higher risk of developing severe adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage which can be fetal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia.
Skin reactions such as localized skin erythema of the extremities (palm of the hand and sole of the feet) with oedema followed by desquamation have been reported with Docetaxel therapy. This type of toxicity can lead to interruption or discontinuation of therapy.
Effects on Ability to Drive and Use Machines: No studies of the effects on the ability to drive and use machines have been performed. The amount of alcohol in this medicinal product may impair the patients ability to drive or use machines.

Pregnancy: Category D.
Docetaxel can cause fetal harm when administered to pregnant women. Studies in rats and rabbits at doses of 0.3 and 0.03 mg/kg/day or greater, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m² basis), administered during the period of organogenesis, have shown that Docetaxel is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity.
There are no adequate and well-controlled studies in pregnant women using Docetaxel. If Docetaxel 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. Women of childbearing potential should be advised to avoid becoming pregnant during therapy.
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, have the mother discontinue nursing prior to using this drug.

The most common adverse reactions across all Docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.
The following side effects have been reported from several clinical trials on Docetaxel.
Bone Marrow Suppression: Usually mild but in some cases severe neutropenia (neutrophils <500 cell/mm³) has been reported. This is non-cumulative and reversible. Neutropenic fevers and anaemia have also been reported. Severe thrombocytopenia has been reported in few patients.
Hypersensitivity Reactions: Mild hypersensitivity reactions such as flushing, tightness in the chest, rashes, pruritis, mild dyspnoea, or chills may occur.
Severe hypersensitivity reactions: In the form of hypotension (fall in B.P. by more than 20mm Hg) and bronchospasm may occur. This may require discontinuation of therapy and aggressive symptomatic treatment.
Fluid retention: Gain of body weight by more than 3 kg has been reported after 4 or more cycles or after a cumulative dose of > 400 mg/m² as a result of fluid retention. Fluid retention in the form of oedema, pleural effusion, ascites, and increased capillary permeability has been reported. Discontinuation of Docetaxel treatment causes slow reversal of this fluid retention.
Premedication with oral corticosteroids has been observed to reduce the fluid retention.
Skin Reaction: Skin reactions have been observed in the form of rash, localized eruptions mainly on feet, hands, arms, face and chest and are often associated with itching. Usually these reactions occur within a week of docetaxel infusion and recover before the next infusion. Rarely severe symptoms such as desquamation may occur. Nails have also been reported to exhibit symptoms of toxicity as hyperpigmentation, pain and onycholysis.
Gastrointestinal effects such as nausea, vomiting, or diarrhoea may occur.
Neurotoxicity has been reported during the clinical trials conducted abroad.
Cardiovascular events of clinical meaning occurred rarely.
Other undesirable effects have included alopecia, asthenia, mucositis, arthralgias, toxic deaths.

In vitro studies have shown that the metabolism of docetaxel may be modified by concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4, such as cyclosporine, ketoconazole, erythromycin and troleandomycin. Exercise caution with these drugs when treating patients receiving docetaxel, as there is a potential for a significant interaction. Based on in vitro findings, it is likely that CYP3A4 inhibitors and/or substrates may lead to substantial increases in docetaxel blood concentrations.

Special Precautions for Disposal and Other Handling: Standard procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines have been issued but there is no general agreement that all the procedures are necessary or appropriate.
However, the following general procedure may be adopted.
Docetaxel is potential toxic compound and caution should be exercised while handling it and preparing Docetaxel solution.
Use of protective gloves and clothing is recommended and only an expert should reconstitute the agent.
In the event of the docetaxel concentrate, premix solution or infusion solution coming in direct contact with the skin, the skin should be washed immediately with soap and water. If they come into the direct contact with eye or sensitive mucous membranes they should be washed immediately and thoroughly with water. Adequate precautions and care should be taken while disposing off the items used to reconstitute the solution, especially concern on working area and environmental contamination.

Store below 30°C. Protect from light.
Shelf life: 24 months.

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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