Active ingredients: Docetaxel
TAXOTERE 20 mg / 0.5 ml concentrate and solvent for solution for infusion
Taxotere package inserts are available for packs:- TAXOTERE 20 mg / 0.5 ml concentrate and solvent for solution for infusion
- TAXOTERE 80 mg / 2 ml concentrate and solvent for solution for infusion
- TAXOTERE 20 mg / 1 ml concentrate for solution for infusion
- TAXOTERE 80 mg / 4 ml concentrate for solution for infusion
- TAXOTERE 160 mg / 8 ml concentrate for solution for infusion
Why is Taxotere used? What is it for?
The name of this drug is TAXOTERE. The name of the active ingredient is docetaxel.
Docetaxel is a substance derived from the needle-like leaves of the yew plant and belongs to the group of anti-cancer called taxanes.
TAXOTERE has been prescribed by your doctor for the treatment of breast cancer, particular forms of lung cancer (non-small cell lung cancer), prostate cancer, gastric cancer, or head and neck cancer:
- For the treatment of advanced breast cancer, TAXOTERE can be administered alone or in combination with doxorubicin, or trastuzumab, or capecitabine.
- For the treatment of early breast cancer with or without lymph node involvement, TAXOTERE can be administered in combination with doxorubicin and cyclophosphamide.
- For the treatment of lung cancer, TAXOTERE can be administered alone or in combination with cisplatin.
- for the treatment of prostate cancer, TAXOTERE is given in combination with prednisone or prednisolone.
- for the treatment of metastatic gastric cancer, TAXOTERE is administered in combination with cisplatin and 5-fluorouracil.
- for the treatment of head and neck cancer, TAXOTERE is given in combination with cisplatin and 5-fluorouracil.
Contraindications When Taxotere should not be used
You must not take TAXOTERE
- if you are allergic (hypersensitive) to docetaxel or any of the other ingredients of Taxotere;
- if your white blood cell count is too low;
- if you have severe liver problems;
Precautions for use What you need to know before taking Taxotere
Before each treatment with TAXOTERE it is necessary to carry out the blood tests necessary to establish whether there are enough blood cells and if the liver is active enough. In the case of alterations in the white blood cells, fever or infections may also occur.
Tell your doctor, hospital pharmacist or nurse if you have vision problems. If you have any vision problems, especially blurred vision, you should immediately have your eyes and vision checked.
If you develop acute lung problems or if your existing symptoms get worse (fever, shortness of breath or cough), tell your doctor, hospital pharmacist or nurse immediately. Your doctor may stop treatment immediately.
You will be asked to take a preventive treatment with oral corticosteroids such as dexamethasone one day before the administration of TAXOTERE and to continue for one or two days thereafter in order to reduce some side effects that may arise following an infusion of TAXOTERE, in particular allergic reactions and fluid retention (swelling of the hands, feet, legs, or weight gain).
During treatment, you may need medicines to maintain your blood cell count.
Interactions Which drugs or foods can modify the effect of Taxotere
Tell your doctor or hospital pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is because TAXOTERE or other medicines may not work as expected and you may be more prone to side effects.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
Ask your doctor for advice before taking any medicine.
TAXOTERE should NOT be administered if you are pregnant unless clearly indicated by your doctor.
You must not become pregnant while being treated with this drug and must use adequate contraceptive measures during therapy because TAXOTERE may be dangerous for the baby. If you become pregnant during treatment, please inform your doctor immediately. You should not breastfeed while taking TAXOTERE.
If you are a man being treated with TAXOTERE it is advised not to procreate during and up to 6 months after treatment and to inquire about sperm storage prior to treatment as docetaxel may impair male fertility.
Driving and using machines:
No studies on the effects on the ability to drive and use machines have been performed.
Dosage and method of use How to use Taxotere: Dosage
TAXOTERE will be given to you by a healthcare professional.
Usual dosage:
The dosage will depend on your weight and general health condition. Your doctor will calculate your body surface area in square meters (m2) and determine the dose you will need to receive.
Method and route of administration:
TAXOTERE will be given to you by intravenous infusion (intravenous use). The infusion will last approximately 1 hour and will take place in the hospital.
Frequency of administration:
The infusion will normally be given to you once every 3 weeks.
Your doctor may vary the dose and frequency of administration in relation to your blood tests, your general condition and your response to TAXOTERE. In particular, tell your doctor if you have diarrhea, sore mouth, numbness, tingling, fever, and show the results of your blood tests. This information will allow him to decide whether a dose reduction is necessary. If you have any further questions on the use of this medicine, consult your doctor or hospital pharmacist.
Side Effects What are the side effects of Taxotere
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Your doctor will discuss this with you and explain the potential risks and benefits of the treatment.
The most commonly reported adverse reactions of TAXOTERE alone are: decreased number of red or white blood cells, hair loss, nausea, vomiting, inflammation in the mouth, diarrhea and fatigue
If TAXOTERE is given to you in combination with other chemotherapeutic agents, the severity of side effects may be increased.
The following allergic reactions may occur during the infusion in the hospital (may affect more than 1 in 10 people):
- flushing, skin reactions, itching
- chest tightness, difficulty in breathing
- fever or chills
- back pain
- low pressure
More severe reactions may occur.
Your condition will be carefully monitored by the hospital staff during treatment. Tell hospital staff immediately if you notice any of these effects.
The side effects listed below may occur in the time between two TAXOTERE infusions, and the frequency may vary depending on the combination medications you are taking:
Very common (may affect more than 1 in 10 people):
- infections, decreased number of red blood cells (anemia) or white blood cells (the latter are important in fighting infection) and platelets
- fever: in this case you must inform your doctor immediately
- allergic reactions as described above
- loss of appetite (anorexia)
- insomnia
- feeling of numbness or tingling or pain in the joints or muscles
- headache
- altered sense of taste
- inflammation of the eye or increased tearing of the eye
- swelling caused by insufficient lymphatic drainage
- difficulty in breathing
- loss of mucus from the nose; inflammation of the throat and nose; cough
- nosebleeds
- inflammation in the mouth
- stomach upset including nausea, vomiting and diarrhea, constipation
- abdominal pain
- indigestion
- hair loss (hair growth returns to normal in most cases)
- redness and swelling of the palms of the hands or soles of the feet, which can cause peeling of the skin (this can also happen on the arms, face or body)
- change in the color of the nails, which can peel off
- muscle aches; back pain or bone pain
- changes or absence of the menstrual period
- swelling of the hands, feet, legs
- tiredness or flu symptoms
- weight gain or loss
Common (may affect up to 1 in 10 people):
- oral candidiasis
- dehydration
- dizziness
- impaired hearing
- decrease in blood pressure; irregular or rapid heartbeat
- heart failure
- esophagitis
- dry mouth
- difficulty or pain in swallowing
- hemorrhage
- increased liver enzymes (hence the need for regular blood tests)
Uncommon (may affect up to 1 in 100 people):
- fainting
- at the injection site skin reactions, phlebitis (inflammation of the veins) or swelling
- inflammation of the colon, small intestine; intestinal perforation.
- formation of blood clots
Frequency not known:
- interstitial lung disease (lung inflammation which can cause cough and difficulty in breathing. Lung inflammation can also develop when docetaxel treatment is given concomitantly with radiotherapy)
- pneumonia (lung infections)
- pulmonary fibrosis (scarring and thickening in the lungs causing shortness of breath)
- blurred vision due to swelling of the retina inside the eye (cystoid macular edema)
- decrease in sodium in the blood.
Reporting of side effects
If you get any side effects, talk to your doctor, hospital pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V *. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton, blister and vial.
Do not store above 25 ° C or below 2 ° C.
Keep the medicine in the original package to protect it from direct light
The prediluted solution must be used immediately after preparation, even if the chemical-physical stability of said solution has been demonstrated for a period of 8 hours if stored between + 2 ° C and + 8 ° C or at room temperature (below 25 C ).
The solution should be used within 4 hours if stored at room temperature (below 25 ° C).
What does the vial of TAXOTERE concentrate contain:
The active ingredient is docetaxel (as a trihydrate). Each ml of docetaxel solution contains 40 mg of docetaxel (anhydrous). One vial contains 20 mg / 0.5 ml of docetaxel. The other ingredients are polysorbate 80 and citric acid.
What the solvent vial contains:
13% (w / w) 95% ethanol in water for injections.
Description of what TAXOTERE looks like and contents of the pack:
TAXOTERE 20 mg / 0.5 ml concentrate for solution for infusion is a clear, viscous, yellow to yellow-brown solution.
Each pack contains
- a single-dose vial of concentrate and,
- a single-dose vial of solvent
The following information is intended for healthcare professionals only.
PREPARATION GUIDE FOR TAXOTERE 20 mg / 0.5 ml CONCENTRATE FOR SOLUTION FOR INFUSION AND RELATIVE SOLVENT FOR TAXOTERE
It is important that you read the entire content of this guide before preparing both TAXOTERE prediluted solution and TAXOTERE solution for infusion.
1. FORMULATION
TAXOTERE 20 mg / 0.5 ml concentrate for solution for infusion is a clear, viscous yellow to yellow-brown solution containing 40 mg / ml docetaxel (anhydrous) in polysorbate 80 and citric acid. The TAXOTERE solvent is a 13% (w / w) solution of 95% ethanol in water for injections.
2. PRESENTATION
TAXOTERE is supplied in single-dose vials.
Each pack contains one vial of TAXOTERE (20 mg / 0.5 ml) and one vial of the corresponding solvent for TAXOTERE in blister packs.
TAXOTERE vials must be stored between + 2 ° C and + 25 ° C protected from light.
TAXOTERE must not be used after the expiry date which is stated on the carton, blister and vial.
2.1 TAXOTERE 20 mg / 0.5 ml vials:
- The vial of TAXOTERE 20 mg / 0.5 ml, has a capacity of 7 ml, is made of clear glass with a removable green cap.
- The vial of TAXOTERE 20 mg / 0.5 ml contains a solution of docetaxel in polysorbate 80 at a concentration of 40 mg / ml.
- Each vial of TAXOTERE 20 mg / 0.5 ml contains 0.5 ml of docetaxel solution of 40 mg / ml in polysorbate 80 (filling volume: 24.4 mg / 0.61 ml). This overdose was established during the development of TAXOTERE to compensate for the loss of liquid during preparation of the prediluted solution (see section 4) due to foaming, adhesion to the vial walls and 'dead space'. This overdose ensures that after dilution with the entire contents of the solvent vial enclosed with TAXOTERE, the minimum extractable volume of prediluted solution is 2 ml, containing 10 mg / ml of docetaxel, which corresponds to the content declared on the label of 20 mg / 0, 5 ml per vial.
2.2 Solvent for TAXOTERE 20 mg / 0.5 ml vials:
- The solvent for TAXOTERE 20 mg / 0.5 ml is contained in a clear glass vial of 7 ml with a clear flip-off cap.
- The solvent for TAXOTERE 20 mg / 0.5 ml consists of a 13% (w / w) solution of 95% ethanol in water for injections.
- Each vial of solvent for TAXOTERE 20 mg / 0.5 ml contains 1.98 ml of solution. This volume was calculated based on the actual volume of the TAXOTERE 20 mg / 0.5 ml vials. Adding the entire contents of the solvent vial to that of TAXOTERE 20 mg / 0.5 ml ensures that a prediluted 10 mg / ml solution of docetaxel is obtained.
3. RECOMMENDATIONS FOR SAFE HANDLING
TAXOTERE is an antineoplastic drug and, as with other potentially toxic products, caution should be exercised in handling and preparing solutions. The use of gloves is recommended.
If TAXOTERE in concentrated, pre-diluted form or solution for infusion should come into contact with the skin, wash immediately and thoroughly with soap and water. If TAXOTERE in concentrated, pre-diluted form or in solution for infusion should come into contact with mucous membranes, wash immediately and thoroughly with water.
4. PREPARATION FOR INTRAVENOUS ADMINISTRATION
4.1 Preparation of the prediluted solution of TAXOTERE (10 mg docetaxel / ml)
4.1.1 If the vials are stored in a refrigerator, leave the required number of boxes of TAXOTERE at room temperature (below 25 ° C) for 5 minutes.
4.1.2 Using a graduated syringe with a needle, aseptically withdraw the entire contents of the vial of solvent for TAXOTERE by partially inverting the vial.
4.1.3 Inject the entire contents of the syringe into the corresponding vial of TAXOTERE
4.1.4 Remove the syringe and needle and mix the solution manually by inverting repeatedly for 45 seconds. Do not shake.
4.1.5 Let the vial of prediluted solution stand for 5 minutes at room temperature (below 25 ° C) and then check that the solution is clear and homogeneous (foaming is normal even after 5 minutes due to the polysorbate content 80 in the wording).
The prediluted solution contains 10 mg / ml of docetaxel and must be used immediately after preparation, even if the chemical-physical stability of this solution has been demonstrated for a period of 8 hours if stored between + 2 ° C and + 8 C or ambient temperature (below 25 C).
4.2 Preparation of the solution for infusion
4.2.1 Multiple vials of prediluted solution may be required to obtain the required patient dose. Based on the required patient dose in mg, aseptically withdraw the corresponding volume of prediluted solution containing 10 mg / ml docetaxel from an appropriate number of vials using a graduated syringe with needle. For example, for a dose of 140 mg of docetaxel, 14 ml of docetaxel prediluted solution should be withdrawn.
4.2.2 Inject the required volume of prediluted solution into a 250 ml bag or bottle containing 5% glucose solution or 9 mg / ml sodium chloride (0.9%) solution for infusion. If a docetaxel dose greater than 200 mg is required, use a larger volume of solution for infusion so that the docetaxel concentration does not exceed 0.74 mg / ml.
4.2.3 Manually mix the bag or bottle with a twisting motion.
4.2.4 The TAXOTERE solution for infusion should be used within 4 hours and should be administered as a 1 hour infusion, aseptically, at room temperature (below 25 C) and in normal light conditions. Document made available by AIFA on 05/27/2015 243
4.2.5 As with all products for parenteral use, the prediluted solution and the infusion solution of TAXOTERE must be visually examined before use, solutions containing precipitates must be discarded.
5. METHOD OF ELIMINATION
All devices that have been used to dilute or administer TAXOTERE should be treated in accordance with standard procedures. Do not throw any medicines down the drain. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TAXOTERE 20 MG / 0.5 ML
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each single-dose vial of TAXOTERE 20 mg / 0.5 ml concentrate containing docetaxel in the form of trihydrate, corresponding to 20 mg of docetaxel (anhydrous). The viscous solution contains 40 mg / ml docetaxel (anhydrous).
Excipient: Each single-dose vial of solvent contains 13% (w / w) 95% ethanol in water for injections.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate and solvent for solution for infusion.
The concentrate is a clear, viscous, yellow to yellow-brown solution.
The solvent is a colorless solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Breast cancer:
TAXOTERE in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with:
- operable lymph node positive breast cancer;
- operable node negative breast cancer.
In patients with operable node-negative breast cancer, adjuvant treatment should be limited to patients who are candidates for chemotherapy according to international criteria for the primary treatment of early stage breast cancer. (see section 5.1).
TAXOTERE in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not received prior cytotoxic therapy for this disease.
TAXOTERE as monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy must have included an anthracycline or alkylating agent.
TAXOTERE in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer with HER2 overexpression and who have not previously received chemotherapy for metastatic disease.
TAXOTERE in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy.
Previous chemotherapy must have included an anthracycline. Non-small cell lung cancer TAXOTERE is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.
TAXOTERE 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 received prior chemotherapy for this condition.
Prostate cancer:
TAXOTERE in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer.
Gastric adenocarcinoma:
TAXOTERE in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including gastroesophageal junction adenocarcinoma, who have not previously received chemotherapy for their metastatic disease.
Head and neck cancer:
TAXOTERE 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.
04.2 Posology and method of administration
The use of docetaxel should be limited to wards specialized in the administration of cytotoxic therapies and its administration should be under the supervision of a physician specialized in the use of anticancer chemotherapy (see section 6.6).
Recommended dose:
For breast cancer, non-small cell lung cancer, gastric adenocarcinoma and head and neck cancer, premedication with an oral corticosteroid such as dexamethasone 16 mg / day (eg 8 mg BID) for 3 days starting 1 day prior to docetaxel administration (see section 4.4) G-CSF prophylaxis can be used to reduce the risk of haematological toxicity.
For prostate cancer, given the concomitant use of prednisone or prednisolone, the recommended premedication is oral dexamethasone 8 mg 12 hours, 3 hours and 1 hour prior to the docetaxel infusion (see section 4.4).
Docetaxel is given as a one-hour infusion every three weeks.
Breast cancer:
For adjuvant therapy of operable node positive and node negative breast cancer, the recommended docetaxel dose is 75 mg / m2 administered 1-hour after doxorubicin 50 mg / m2 and cyclophosphamide 500 mg / m2 every 3-weeks for 6-cycles. (TAC regimen) (see also Dose adjustment during treatment).
For the treatment of patients with locally advanced or metastatic breast cancer the recommended dose of docetaxel monotherapy is 100 mg / m2. In first-line treatment, docetaxel 75 mg / m2 is administered in combination with doxorubicin (50 mg / m2).
In combination with trastuzumab the recommended dose of docetaxel is 100 mg / m2 every 3 weeks, with trastuzumab administered weekly. In the pivotal study, the initial docetaxel infusion was started the day after the first trastuzumab administration. Subsequent docetaxel doses were administered immediately following the trastuzumab infusion if the previous trastuzumab dose was well tolerated. For trastuzumab dose and administration see the summary of product characteristics for trastuzumab.
In combination with capecitabine the recommended dosage of docetaxel is 75 mg / m2 every three weeks, in combination with capecitabine at a dose of 1250 mg / m2 twice daily (within 30 minutes after a meal) for 2 weeks followed by an interval of 1 week. For calculation of capecitabine dose by body surface area, see the summary of product characteristics of capecitabine.
Non-small cell lung cancer:
In patients who have never received chemotherapy for non-small cell lung cancer, the recommended dose is docetaxel 75 mg / m2 followed immediately by cisplatin 75 mg / m2 over 30-60 minutes. For treatment after failure of previous platinum-containing chemotherapy the recommended dose is 75 mg / m2 as monotherapy.
Prostate cancer:
The recommended dose of docetaxel is 75 mg / m2. Prednisone or prednisolone 5 mg orally twice daily is administered for the duration of treatment (see section 5.1).
Gastric adenocarcinoma:
The recommended dose of docetaxel is 75 mg / m2 as a 1 hour infusion, followed by cisplatin 75 mg / m2, as a 1- 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg. / m2 per day administered as a continuous 24-hour infusion for 5 days, starting from the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients should receive premedication with antiemetics and adequate hydration for administration. of cisplatin.
G-CSF prophylaxis should be used to mitigate the risk of haematological toxicities (see also Dose adjustment during treatment).
Head and neck cancer:
Patients should receive premedication antiemetics and adequate hydration (before and after administration of cisplatin). G-CSF prophylaxis can be done in such a way as to mitigate the risk of haematological toxicities. All docetaxel-treated patients of the studies TAX 323 and TAX 324 received antibiotic prophylaxis.
Induction chemotherapy followed by radiotherapy (TAX 323):
For the induction treatment of patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg / m2 as a 1 hour infusion followed by 75 mg / m2 cisplatin for over 1 hour, on day 1, followed by 5-fluorouracil 750 mg / m2 per day administered as a continuous 24 hour infusion for 5 days. This dosing schedule is administered every 3 weeks for 4 cycles. Following chemotherapy, patients must receive radiotherapy.
Induction chemotherapy followed by chemoradiotherapy (TAX 324):
For the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) (technically inoperable, with a low probability of surgical success, and with a view to organ preservation) the recommended dose of docetaxel is 75 mg / m2 as a 1 hour infusion on day 1, followed by cisplatin 100 mg / m2 administered as an infusion lasting 30 minutes to three hours, followed by 5-fluorouracil 1000 mg / m2 daily, administered in continuous infusion of 1 - 4 days. This dosing schedule is given every three weeks for three cycles. After chemotherapy, patients should receive chemo-radiotherapy.
For dose modifications of 5-fluorouracil and cisplatin, see the specific Summary of Product Characteristics. Dosage adjustment during treatment:
General
Docetaxel should be administered when the neutrophil count is 3 1500 cells / mm3.
In patients who have experienced febrile neutropenia, neutrophil severe peripheral neuropathy during docetaxel therapy, the docetaxel dose should be reduced from 100 mg / m2 to 75 mg / m2 and / or from 75 to 60 mg / m2. If, at 60 mg / m2, the patient continues to experience these reactions, the treatment should be discontinued.
Adjuvant therapy for breast cancer:
Primary G-CSF prophylaxis should be considered for patients receiving adjuvant therapy with docetaxel, doxorubicin and cyclophosphamide (TAC) for breast cancer. In patients presenting with febrile neutropenia and / or neutropenic infection the docetaxel dose should be reduced to 60 mg / m2 in all subsequent courses (see sections 4.4 and 4.8). In patients experiencing Grade 3 or 4 stomatitis the dose should be reduced to 60 mg / m2
In association with cisplatin:
For patients initially treated with docetaxel 75 mg / m2 in combination with cisplatin and whose platelet count nadir in the previous course of therapy was
In combination with capecitabine:
For capecitabine dose adjustment, see the Summary of Product Characteristics for capecitabine.
In patients who develop the first appearance of Grade 2 toxicity that persists at the time of subsequent docetaxel / capecitabine administration, treatment should be postponed until resolution to Grade 0-1, and then resumed at 100% of the starting dose.
In patients who develop the second occurrence of Grade 2 toxicity, or the first occurrence of Grade 3 toxicity at any point in the course of therapy, treatment should be postponed until resolution to Grade 0-1, and then resumed with docetaxel 55 mg / m2.
For any subsequent occurrence of toxicity or for any Grade 4 toxicity, discontinue docetaxel therapy.
For trastuzumab dose modifications, see the Summary of Product Characteristics for trastuzumab.
In association with cisplatin and 5-fluorouracil:
If an episode of febrile neutropenia, prolonged neutropenia or infection neutropenia occurs despite the use of G-CSF, the docetaxel dose should be reduced from 75 to 60 mg / m2. If further episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg / m2. For Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg / m2. Patients should not be re-treated with further courses of docetaxel until neutrophils return to a level> 1,500 cells / mm3 and platelets return to a level> 100,000 cells / mm3. Discontinue treatment if these toxicities persist (see section 4.4). Recommended dose modifications due to toxicity in patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (5-FU):
For dose modifications of cisplatin and 5-fluorouracil, see the specific Summary of Product Characteristics.
In the pivotal SCCHN study in patients who experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infection), the use of GCSF was suggested to provide prophylactic coverage (eg, days 6-15) in all subsequent cycles.
Special populations:
Patients with hepatic insufficiency:
Based on pharmacokinetic data with docetaxel at 100 mg / m2 given as single treatment, in patients with elevations in transaminases (ALT and / or AST) greater than 1.5 times the upper limit of normal and alkaline phosphatase greater than 2.5 times the upper limit of normal, the recommended docetaxel dose is 75 mg / m2 (see sections 4.4 and 5.2). For patients with serum bilirubin above the upper limit of normal and / or ALT and AST> 3.5 times the upper limit of normal associated with alkaline phosphatase greater than 6 times the upper limit of normal, no dose reduction can be recommended and docetaxel will not it must be administered except in cases where it is strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical study excluded patients with ALT and / or AST> 1.5 times the upper limit of normal associated with an alkaline phosphatase value. > 2.5 times the upper limit of normal and at a bilirubin value> 1 times the upper limit of normal; for these patients, no dose reduction can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated with docetaxel in combination in the other indications.
Pediatric population:
The safety and efficacy of TAXOTERE in nasopharyngeal cancer in children aged 1 month to less than 18 years have not been established.
There are no data on the use of TAXOTERE in the pediatric population in the indications of breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer and head and neck cancer, excluding less differentiated type II and III nasopharyngeal cancer. .
Senior citizens.
Based on population pharmacokinetics, there are no special instructions for use in the elderly.
In combination with capecitabine for patients aged 60 years and older, a reduction of the starting dose to 75% is recommended (see the Summary of Product Characteristics for capecitabine).
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Docetaxel should not be used in patients with an initial neutrophil count
Docetaxel should not be used in patients with severe hepatic impairment due to lack of available data (see sections 4.2 and 4.4).
Contraindications for other drugs also apply when used in combination with docetaxel.
04.4 Special warnings and appropriate precautions for use
Unless contraindicated, premedication with oral corticosteroids, such as dexamethasone 16 mg daily (e.g. 8 mg BID) for 3 days, starting the day before docetaxel administration, for 3 days starting the day before docetaxel administration for breast and non-small cell lung cancers, may reduce the "incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. For prostate cancer, premedication is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour prior to the docetaxel infusion (see paragraph 4.2).
Hematology:
Neutropenia is the most frequent of the adverse reactions observed with docetaxel. Neutrophil nadirs appeared after 7 days (median value) but in heavily pretreated patients this interval may be shortened. A complete blood count should be checked frequently in all patients receiving docetaxel. Patients should not be re-treated with docetaxel until the neutrophil value returns to 3 1,500 cells / mm3 (see section 4.2).
In the case of severe neutropenia (
In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infection occurred with a lower incidence when patients received prophylactic G-CSF. Patients treated with TCF should receive G-CSF as prophylaxis to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia, or neutropenic infection). Patients receiving TCF should be monitored very closely (see sections 4.2 and 4.8).
In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC regimen), febrile neutropenia and / or neutropenic infection occurred with a "lower incidence when patients received primary G-CSF prophylaxis. Primary G-CSF prophylaxis. CSF should be considered in patients receiving adjuvant CT therapy for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving CT scan should be monitored closely (see sections 4.2 and 4.8 ).
Hypersensitivity reactions:
Patients should be closely monitored for the possible occurrence of hypersensitivity reactions, especially during the first and second infusion. Hypersensitivity reactions may occur within minutes of starting the docetaxel infusion therefore means should be available to treat hypotension and bronchospasm. If hypersensitivity reactions with minor symptoms such as flushing or localized skin reactions occur, it is not necessary to discontinue therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalized rash / erythema require immediate discontinuation of the docetaxel infusion and appropriate treatment. Patients experiencing severe hypersensitivity reactions should no longer take docetaxel.
Skin reactions:
Localized skin erythema in the extremities (palm of the hand and sole of the foot) with edema followed by desquamation have been observed. Severe symptoms such as rash followed by peeling leading to temporary or permanent discontinuation of docetaxel treatment have been reported (see section 4.2).
Fluid retention:
Patients with severe fluid retention, such as pleural, pericardial and ascites effusions, should be monitored closely.
Patients with hepatic dysfunction:
In patients treated with docetaxel at 100 mg / m2 administered alone who have serum transaminase levels (ALT and / or AST) greater than 1.5 times the upper limit of normal concomitantly with serum alkaline phosphatase levels greater than 2.5 times the upper limit of normal, c "is a higher risk of developing serious adverse reactions such as toxic death including gastrointestinal sepsis and haemorrhage which may be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Therefore, in patients with liver function tests high, the recommended docetaxel dose is 75 mg / m2 and liver function tests should be performed before starting treatment and before each cycle (see section 4.2).
In patients who have serum bilirubin values greater than the upper limit of normal and / or ALT and AST values greater than 3.5 times the upper limit of normal with alkaline phosphatase higher than 6 times the upper limit of normal, a dose reduction cannot be recommended. and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical study excluded patients with ALT and / or AST> 1.5 times the upper limit of normal associated with an alkaline phosphatase value. > 2.5 times the upper limit of normal and at a bilirubin value> 1 times the upper limit of normal; for these patients, no dose reduction can be recommended and docetaxel should not be used unless strictly indicated. No data are available on patients with hepatic impairment treated with docetaxel in combination in the other indications.
Patients with impaired renal function:
There are no data available in patients with severe renal impairment receiving docetaxel therapy.
Nervous system:
The occurrence of severe peripheral neurotoxicity requires dose reduction (see section 4.2).
Cardiac toxicity:
Heart failure has been observed in patients treated with docetaxel in combination with trastuzumab, particularly after chemotherapy containing anthracyclines (doxorubicin or epirubicin).
This was found to be moderate to severe and has been associated with death (see section 4.8).
When patients are candidates for docetaxel in combination contrastuzumab they should undergo a baseline cardiac evaluation. Cardiac function should be further monitored during treatment (e.g. every three months) to identify patients who may develop cardiac abnormalities. See the summary of product characteristics for trastuzumab for more details.
Other:
Contraceptive measures should be used during treatment for both men and women and for men for at least six months after its discontinuation (see section 4.6).
Additional precautions for adjuvant treatment of breast cancer
Complicated neutropenia:
For patients presenting with complicated neutropenia (prolonged neutropenia, febrile neutropenia or infection), G-CSF therapy and dose reduction should be considered (see section 4.2).
Gastrointestinal adverse events:
Symptoms such as abdominal pain and malaise, fever, diarrhea with or without neutropenia, could be early manifestations of severe gastrointestinal toxicity and should be evaluated and treated immediately.
Congestive heart failure:
Patients should be followed up for symptoms that may lead to congestive heart failure during therapy and the follow-up period.
Leukemia:
In patients treated with docetaxel, doxorubicin and cyclophosphamide (TAC) the risk of delayed myelodysplasia or myeloid leukemia requires haematological follow-up.
Patients with 4 or more positive lymph nodes:
The benefit-risk balance of CT therapy in patients with 4 or more positive lymph nodes is not fully established with the interim analysis (see section 5.1).
Senior citizens:
Limited data are available in patients over 70 years of age treated with docetaxel in combination with doxorubicin and cyclophosphamide.
In a prostate cancer study of 333 patients treated with docetaxel every three weeks, 209 were 65 years of age or older and 68 patients over 75 years of age. In patients treated with docetaxel every three weeks, the incidence of changes drug-related nail plates, in patients 65 years of age or older, were more than 10% higher than in younger patients. The incidence of drug-related fever, diarrhea, anorexia and peripheral edema in patients 75 years of age and older was more than 10% higher than in patients below 65 years of age.
Among the 300 patients (221 in the phase III study and 79 in the phase II study) treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were 65 or older and 4 were 75 or older. The incidence of serious adverse events was higher in elderly compared to younger patients. The incidence of adverse events was higher in elderly than in young patients. The incidence of the following adverse events (all grades): lethargy, stomatitis, and neutropenic infection occurred with a frequency of> 10% in patients 65 years or older compared to younger patients. Elderly patients treated with TCF should be monitored very carefully.
04.5 Interactions with other medicinal products and other forms of interaction
In vitro studies have shown that the metabolism of docetaxel can be modified by the concomitant administration of compounds which induce or inhibit cytochrome P450-3A or which are metabolised by it (and can therefore competitively inhibit the enzyme), such as cyclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin Therefore, caution should be exercised when treating patients concomitantly with such medicinal products due to the potential risk of important interactions.
Docetaxel is highly protein bound (> 95%). Although the possible in vivo interaction between docetaxel and concomitant therapies has not been specifically investigated, the in vitro interactions between closely protein-bound drugs such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole and sodium valproate have not shown any influence on the binding of docetaxel to proteins. Furthermore, dexamethasone does not change the protein binding of docetaxel. Docetaxel does not affect the binding of digitoxin. The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide did not interfere during their co-administration. Limited data from a single uncontrolled study appear to indicate an interaction between docetaxel and carboplatin. When used in combination with docetaxel, the clearance of carboplatin was approximately 50% higher than previously reported values for use alone.
The pharmacokinetics of docetaxel in the presence of prednisone were studied in patients with metastatic prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone causes induction of CYP3A4. No statistically significant effect of prednisone on docetaxel pharmacokinetics was observed.
Docetaxel should be administered with caution to patients who are concomitantly taking a potent CYP3A4 inhibitor (eg protease inhibitors such as ritonavir, azole antifungals such as ketoconazole or itraconazole). A drug interaction study conducted in patients taking ketoconazole and docetaxel showed that docetaxel clearance is reduced by half due to ketoconazole, possibly because docetaxel metabolism involves CYP3A4 as the predominant metabolic pathway. Impaired tolerance to docetaxel may occur, even at low doses.
04.6 Pregnancy and lactation
There is no information on the use of docetaxel in pregnant women. In studies in rats and rabbits, docetaxel is embryotoxic and foetotoxic and reduces fertility in rats. As with other cytotoxic medicinal products, docetaxel can cause fetal harm when administered to pregnant women For this reason docetaxel should not be administered to pregnant women unless clearly indicated.
Women of childbearing age / contraception:
Women of childbearing potential being treated with docetaxel should be advised to avoid the risk of pregnancy and to notify their physician immediately if this occurs.
An effective method of contraception should be used during treatment.
In non-clinical studies, docetaxel has genotoxic effects and may impair male fertility (see section 5.3). Therefore, men being treated with docetaxel are recommended not to procreate during and up to 6 months after treatment and to inquire about sperm storage prior to treatment.
Feeding time:
Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk. Consequently, given the potential for adverse reactions in the infant, breastfeeding should be discontinued during docetaxel treatment.
04.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive or use machines have been performed.
04.8 Undesirable effects
Adverse reactions considered possibly or probably related to docetaxel administration were obtained in:
1312 and 121 patients who received docetaxel 100 mg / m2 and 75 mg / m2 as monotherapy, respectively.
258 patients who received docetaxel in combination with doxorubicin.
406 patients who received docetaxel in combination with cisplatin.
92 patients treated with docetaxel in combination with trastuzumab.
255 patients who received docetaxel in combination with capecitabine.
332 patients who received docetaxel in combination with prednisone or prednisolone (clinically relevant treatment related undesirable effects are presented).
1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received docetaxel in combination with doxorubicin and cyclophosphamide (clinically relevant treatment related undesirable effects are presented).
300 gastric adenocarcinoma patients (221 in the phase III study and 79 in the phase II study) treated with docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment-related undesirable effects occurred).
174 patients with head and neck cancer treated with docetaxel in combination with cisplatin and 5-fluorouracil (clinically important side effects related to treatment have occurred).
These reactions have been described using the NCI Common Toxicity Criteria (grade 3 = G3; grade 3- -4 = G3 / 4; grade 4 = G4) and the terms COSTART and MedDRA. Frequencies are defined as:
very common (≥ 1/10); common (≥ 1/100 to
Within each frequency class, undesirable effects are reported in descending order of severity.
The most frequently reported adverse reactions during use of docetaxel alone are: neutropenia (reversible and non-cumulative; mean day to nadir was day 7 and mean duration of severe neutropenia (anemia, alopecia, nausea, vomiting, stomatitis, diarrhea and asthenia The severity of docetaxel adverse events may be increased when docetaxel is administered in combination with other chemotherapeutic agents.
For combination with trastuzumab, adverse events (all grades) were reported as a percentage of 10%. There was an increased incidence of serious adverse events (40% vs 31%) and grade 4 adverse events (34% vs 23%) in the trastuzumab combination group versus docetaxel monotherapy. For combination with capecitabine, the most frequent treatment-related undesirable effects (≥ 5%) observed in a phase III clinical study in breast cancer patients after failure of anthracycline therapy are reported (see summary of product characteristics. of capecitabine).
The following adverse reactions have been frequently observed with docetaxel:
Immune system disorders:
Hypersensitivity reactions usually occurred within minutes of starting the docetaxel infusion and were generally mild to moderate in severity. The most frequently reported symptoms were hot flashes, rash with or without itching, chest tightness, back pain, dyspnoea, and fever or chills. Severe reactions were characterized by hypotension and / or bronchospasm or generalized rash / erythema (see section 4.4)
Nervous system disorders:
Development of severe peripheral neurotoxicity requires dose reduction (see sections 4.2 and 4.4).
Mild to moderate sensorineural signs are characterized by paraesthesia, dysesthesia or pain including burning. Neuromotor events are characterized mainly by weakness.
Skin and subcutaneous tissue disorders:
Reversible skin reactions have been observed and are generally considered to be mild to moderate in severity. Reactions were characterized by rash, including localized eruptions mainly in the feet and hands (including severe hand-foot syndrome), but also in the arms, face or chest, frequently associated with pruritus. Eruptions generally occurred within one week of the docetaxel infusion. Less frequently, severe symptoms such as eruptions followed by desquamation have been reported which rarely required temporary or permanent discontinuation of treatment (see sections 4.2 and 4.4). Serious symptoms have been reported. nail changes characterized by hypopigmentation or hyperpigmentation, sometimes pain and onycholysis.
General disorders and administration site conditions:
Infusion site reactions were generally mild and were characterized by hyperpigmentation, inflammation, redness and dryness of the skin, phlebitis or extravasation, "increased permeability" of the vein.
Fluid retention which includes cases of peripheral edema and less frequently cases of pleural, pericardial effusions, ascites and weight gain. Peripheral edema usually occurs starting in the lower extremities and may become generalized with weight gain of 3 kg or more. Fluid retention is cumulative in incidence and intensity (see section 4.4).
TAXOTERE 100 mg / m2 as monotherapy
Disorders of the blood and lymphatic system
Rare: bleeding episodes associated with grade 3/4 thrombocytopenia.
Nervous system disorders
Reversibility data are available in 35.3% of patients who developed neurotoxicity after treatment with docetaxel 100 mg / m2 monotherapy. The events were spontaneously reversible within 3 months.
Skin and subcutaneous tissue disorders
Very rare: one case of non-reversible alopecia at the end of the study. 73% of the skin reactions were reversible within 21 days.
General disorders and administration site conditions
The mean cumulative dose at treatment discontinuation was more than 1,000 mg / m2 and the median time to reversibility of fluid retention was 16.4 weeks (range 0 to 42 weeks). The onset of moderate to severe retention (mean cumulative dose: 818.9 mg / m2) is delayed in patients who received premedication compared to patients without premedication (mean cumulative dose: 489.7 mg / m2); however, in some patients, it has been reported during the first courses of therapy.
TAXOTERE 75 mg / m2 as monotherapy
TAXOTERE 75 mg / m2 in combination with doxorubicin
TAXOTERE 75 mg / m2 in combination with cisplatin
TAXOTERE 100 mg / m2 in combination with trastuzumab
Cardiac pathologies
Symptomatic heart failure was reported in 2.2% of patients who received docetaxel in combination with trastuzumab, compared with 0% of patients who received docetaxel alone. In the docetaxel and trastuzumab group, 64% of patients had previously received anthracyclines as adjuvant therapy compared with 55% of patients treated with docetaxel alone.
Disorders of the blood and lymphatic system
Very common: Haematological toxicity was increased in patients treated with trastuzumab and docetaxel compared to those treated with docetaxel alone (grade 3/4 neutropenia 32% vs 22%, according to NCI-CTC criteria). Note that this is likely an underestimation as docetaxel alone at a dose of 100 mg / m2 is known to lead to neutropenia in 97% of patients, grade 4 in 76%, based on nadir of neutrophil count. The incidence of febrile neutropenia / neutropenic sepsis was also increased in patients treated with Herceptin and docetaxel (23% versus 17% of patients treated with docetaxel alone).
TAXOTERE 75 mg / m2 in combination with capecitabine
TAXOTERE 75 mg / m2 in combination with prednisone or prednisolone
Adjuvant therapy with TAXOTERE 75 mg / m2 in combination with doxorubicin and cyclophosphamide in patients with node positive (TAX 316) and node negative (GEICAM 9805) breast cancer - cumulative data:
Nervous system disorders
During follow-up, 12 of the 83 patients who had experienced peripheral sensory neuropathy at the end of chemotherapy still had symptoms of peripheral sensory neuropathy.
Cardiac pathologies
Congestive heart failure (CHF) was reported in 18 of 1276 patients during the follow-up period. In the node-positive study (TAX316) one patient in each treatment group died from heart failure.
Skin and subcutaneous tissue disorders
During follow-up, 25 of the 736 patients who experienced alopecia at the end of chemotherapy still had alopecia.
Diseases of the reproductive system and breast
During follow-up, 140 of the 251 patients who experienced amenorrhea at the end of chemotherapy still had symptoms of amenorrhea.
General disorders and administration site conditions
During follow-up, 18 of 112 patients who experienced peripheral edema at the end of chemotherapy in study TAX 316 still had symptoms of peripheral edema, while 4 of the 5 patients who experienced lymphoedema at the end of chemotherapy in GEICAM 9805 still had symptoms of peripheral edema. symptoms of lymphoedema.
Acute Leukemia / Myelodysplastic Syndrome.
At a mean follow-up of 77 months, acute leukemia occurred in 1 of 532 (0.2%) patients who received docetaxel, doxorubicin and cyclophosphamide in GEICAM 9805. No cases were reported in patients who received fluorouracil. , doxorubicin and cyclophosphamide. No cases of myelodysplastic syndrome were diagnosed in any of the treatment groups. The table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection were reduced in patients who received primary G-CSF prophylaxis after it became mandatory in the TAC arm - GEICAM study.
Neutropenic complications in patients who received CT with or without primary G-CSF prophylaxis (GEICAM 9805)
TAXOTERE 75 mg / m2 in combination with cisplatin and 5-fluorouracil for gastric adenocarcinoma
Disorders of the blood and lymphatic system
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients, respectively, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of courses). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of patients who received G-CSF as prophylaxis, in 15.6% and 12.9% of patients without prophylaxis with G-CSF (see section 4.2).
TAXOTERE 75 mg / m2 in combination with cisplatin and 5-fluorouracil for head and neck cancers
Induction chemotherapy followed by radiotherapy (TAX 323)
Induction chemotherapy followed by chemo radiotherapy (TAX324)
Post-marketing experience:
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Very rare cases of acute myeloid leukemia and myelodysplastic syndrome have been reported when docetaxel is used in combination with other chemotherapeutic and / or radiotherapeutic agents.
Disorders of the blood and lymphatic system
Bone marrow suppression and other haematological adverse reactions have been reported. Disseminated intravascular coagulation has been reported often in association with sepsis or multi-organ failure.
Disorders of the immune system
A few cases of anaphylactic shock, some fatal, have been reported.
Nervous system disorders
Rare cases of convulsions or temporary loss of consciousness have been observed following administration of docetaxel. These reactions sometimes appear during the infusion.
Eye disorders
Very rare cases of transient visual changes (flashes, flashes of light, scotoma) and in association with hypersensitivity reactions have typically occurred during the infusion of the medicinal product. These have been reversible after discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis have been reported rarely, such as cases of tear duct obstruction as a result of excessive tearing.
Ear and labyrinth disorders
Rare cases of ototoxicity, hearing impairment and / or hearing loss have been reported.
Cardiac pathologies
Rare cases of myocardial infarction have been reported.
Vascular pathologies
Venous thromboembolic events have been reported rarely.
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome, interstitial pneumonia and pulmonary fibrosis have been reported rarely. Rare cases of radiation-induced pneumonia have been reported in patients also undergoing radiation therapy.
Gastrointestinal disorders
Rare episodes of dehydration have been reported as a consequence of gastrointestinal disturbances, gastrointestinal perforation, ischemic colitis, colitis and neutropenic enterocolitis. Rare cases of ileal and intestinal obstruction have been reported.
Hepatobiliary disorders
Very rare cases of hepatitis, sometimes fatal, have been reported mainly in patients with pre-existing liver disease.
Skin and subcutaneous tissue disorders
Cases of lupus erythematosus skin and bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. In some cases, other concomitant factors may have contributed to the development of these effects. Schleroderma-like manifestations usually preceded by peripheral lymphoedema have been reported during treatment with docetaxel.
General disorders and administration site conditions
Radiation recall phenomena have rarely been reported.
Fluid retention was not associated with acute episodes of oliguria or hypotension. Dehydration and pulmonary edema have rarely been reported.
04.9 Overdose
Some cases of overdose have been reported. There is no known antidote for docetaxel overdose. In the event of an overdose, the patient should be kept in a specialized unit and vital functions monitored closely. In the event of an overdose, an exacerbation of adverse events can be expected. The main complications to be expected in overdose are bone marrow suppression, peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as possible after evidence of overdose. Other appropriate symptomatic measures should be taken as needed.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: taxanes, ATC code: L01CD 02
Preclinical data:
Docetaxel is an antineoplastic drug which acts by promoting the aggregation of tubulin into stable microtubules and inhibits their breakdown, thus leading to a significant decrease in free tubulin. The binding of docetaxel to microtubules does not alter the number of protofilaments. Docetaxel in vitro it breaks up the cellular microtubular system which is essential for vital cell functions such as mitosis and interphase.
The docetaxel in vitro it is cytotoxic towards various mouse and human tumor lines and human tumors recently removed in the clonogenic tests carried out. Docetaxel achieves high and long-lasting intra-cellular concentrations. Furthermore, docetaxel is active on some of the cell lines (but not all) that express an excess of p-glycoprotein, encoded by the multidrug resistance gene. In vivo, docetaxel experimentally has a broad spectrum of action against advanced murine tumors and grafted human tumors, regardless of the dosage regimen.
Clinical data:
Breast cancer
TAXOTERE in combination with doxorubicin and cyclophosphamide: adjuvant treatment.
Patients with operable node positive breast cancer (TAX 316)
Data from an open-label, randomized multicenter study support the use of docetaxel as an adjuvant treatment in patients with operable node positive breast cancer and KPS 3 80% aged 18 to 70 years. Following stratification by number of positive lymph nodes (1-3, more than 4), 1491 patients were randomized to receive docetaxel 75 mg / m2 administered 1 hour after doxorubicin 50 mg / m2 and cyclophosphamide 500 mg / m2 (TAC group) or doxorubicin 50 mg / m2 followed from fluorouracil 500 mg / m2 and cyclophosphamide 500 mg / m2 (FAC group). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1 hour infusion, all other medicinal products were administered as intravenous bolus on day 1. G-CSF was administered as secondary prophylaxis to patients with complicated neutropenia (febrile neutropenia, prolonged neutropenia or infection).
Patients in the TAC group received antibiotic prophylaxis with ciprofloxacin 500 mg orally or equivalent antibiotics twice daily for 10 days starting on day 5 of each cycle. In both groups, after the last course of chemotherapy, patients positive for estrogen and / or progestogen receptors received tamoxifen 20 mg / day for 5 years. Adjuvant radiation therapy was prescribed according to the guidelines valid in each participating center and it was administered to 69% of patients who received TAC and to 72% of patients who received FAC.
An interim analysis was conducted at a median follow-up of 55 months. Disease-free survival was significantly increased in the TAC group compared to the FAC group.
The 5-year relapse incidence was reduced in patients who received TAC compared to those who received FAC (25% vs 32% respectively) ie an absolute risk reduction of 7% (p = 0.001). Overall survival at 5 years it was also significantly increased with TAC compared to FAC (87% vs 81% respectively) ie an absolute 6% reduction in the risk of death (p = 0.008). The subgroups of patients treated with TAC in accordance with the main prognostic factors defined a priori were analyzed:
* hazard ratio less than 1 indicates that TAC is associated with disease-free survival and overall survival superior to FAC
At the interim analysis, the therapeutic advantage of TAC in patients with 4 or more lymph nodes (37% of the population) was not demonstrated. The therapeutic advantage of TAC appears to be less evident than that observed in patients with 1-3 positive lymph nodes. The risk / benefit ratio, therefore, in patients with 4 or more positive lymph nodes was not fully defined at this stage of analysis.
Patients with operable node-negative breast cancer candidates for chemotherapy (GEICAM 9805):
Data from a multicenter, open, randomized study support the use of TAXOTERE for adjuvant therapy in patients with operable node-negative breast cancer who are candidates for chemotherapy. 1060 patients were randomized to receive TAXOTERE 75 mg / m2 administered 1 hour after doxorubicin. 50 mg / m2 and cyclophosphamide 500 mg / m2 (539 patients in the TAC arm), or doxorubicin 50 mg / m2 followed by fluorouracil 500 mg / m2 and cyclophosphamide 500 mg / m2 (521 patients in the FAC arm) as adjuvant therapy in cancer of the operable breast negative lymph node with high risk of relapse according to the 1998 St. Gallen criteria (tumor size> 2 cm and / or ER and PR negative and / or high histological / nuclear grade (grade 2 to 3) and / or age
The median duration of follow-up was 77 months. A statistically significant increase in disease-free survival was demonstrated for the TAC arm compared to the FAC arm. Patients treated with TAC had a 32% reduction in the risk of relapse compared to those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93), p = 0.01). Overall survival (OS) was also longer in the TAC arm with a 24% reduction in the risk of death for patients treated with TAC compared to FAC (hazard ratio = 0.76, 95% CI (0.46-1 , 26, p = 0.29) However, the distribution of overall survival was not significantly different between the two groups.
Subgroups of patients treated with TAC were analyzed divided according to prospectively defined major prognostic factors (see table below):
Subgroup Analysis - Study of Adjuvant Therapy in Patients with Node-Negative Breast Cancer (Intent-to-Treat Analysis)
* a hazard ratio (TAC / FAC) of less than 1 indicates that TAC is associated with a longer disease-free survival than FAC.
Exploratory subgroup analyzes for disease-free survival in patients meeting the 2009 St. Gallen criteria for chemotherapy - (ITT population) were performed and are presented in the table below:
TAC = docetaxel, doxorubicin and cyclophosphamide
FAC = 5-fluorouracil, doxorubicin and cyclophosphamide
CI = confidence interval; ER = estrogen receptor
PR = progesterone receptor
a ER / PR-negative or Grade 3 or tumor size> 5 cm
The hazard ratio was estimated with the Cox proportional hazard model using the therapy group as a factor.
TAXOTERE as the only treatment
Two phase III randomized comparative studies with docetaxel at recommended doses and a regimen of 100 mg / m2 every 3 weeks were conducted in patients with metastatic breast cancer, of which 326 after failure of alkylating treatment and 392 after failure. of a treatment with anthracyclines.
In patients in whom treatment with alkylating agents was found to be ineffective, docetaxel was compared with doxorubicin (75 mg / m2 every 3 weeks). Docetaxel increased the response rate (52% versus 37%, p = 0.01) and decreased the response time (12 weeks versus 23 weeks, p = 0.007), without changing the survival time (15 months for docetaxel versus 14 months for doxorubicin, p = 0.38) or time to progression (27 weeks for docetaxel versus 23 weeks for doxorubicin, p = 0.54). Three docetaxel-treated patients (2%) had to discontinue treatment due to fluid retention, while 15 doxorubicin-treated patients (9%) had to discontinue due to cardiac toxicity (three deaths from congestive heart failure) .
In patients whose anthracycline treatment was ineffective, docetaxel was compared with the combination of mitomycin C and vinblastine (12 mg / m2 every 6 weeks and 6 mg / m2 every 3 weeks). Docetaxel increased the response rate (33% vs 12%, p
The tolerability profile of docetaxel during these two phase III studies was in line with the tolerability profile found in the phase II studies (see section 4.8).
A randomized, open-label, multicentre Phase III study comparing docetaxel monotherapy with paclitaxel was conducted in the treatment of advanced breast cancer in patients in whom prior therapy already included an "anthracycline. A total of 449 patients were randomized to receive either docetaxel monotherapy 100 mg / m2 as a 1 hour infusion or paclitaxel 175 mg / m2 as a 3 hour infusion, the two treatments being administered every 3 weeks.
Docetaxel prolonged median time to progression (24.6 weeks vs 15.6 weeks; p
TAXOTERE in combination with doxorubicin
A randomized phase III study was conducted in 429 patients with non-pretreated metastatic cancer comparing doxorubicin (50 mg / m2) in combination with docetaxel (75 mg / m2) (AT arm) to doxorubicin (60 mg / m2). in combination with cyclophosphamide (600 mg / m2) (AC arm). Both regimens were administered on day 1 every three weeks.
Time to progression (TTP) was significantly increased in the AT arm compared to that of the AC arm, p = 0.0138. The median TTP was 37.3 weeks (95% CI: 33.4 - 42.1) in the AT arm and 31.9 weeks (95% CI: 27.4 - 36.0) in the AC arm.
The observed response rate was significantly higher in the AT arm than in the AC arm, p = 0.009. This rate was 59.3% (95% CI: 52.8 - 65.9) in the AT arm compared to 46.5% (95% CI: 39.8 - 53.2) in the AC arm.
In this study, the AT arm had a higher incidence than the AC arm of severe neutropenia (90% vs 68.6%), febrile neutropenia (33.3% vs 10%), infections (8% vs 2.4%), diarrhea (7.5% vs 1.4%), asthenia (8.5% vs 2.4%), and pain (2.8% vs 0%). On the other hand, the AC arm showed a higher incidence of severe anemia than the AT arm (15.8% versus 8.5%) and a higher incidence of cardiac toxicity: congestive heart failure (3.8% versus 2, 8%), absolute decrease in LVEF 3 20% (13.1% vs 6.1%), absolute decrease in LVEF ≥ 30% (6.2% vs 1.1%). Toxic death occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1 due to septic shock and 3 due to congestive heart failure).
In both arms the quality of life, measured with the EORTC questionnaire, was comparable and stable during treatment and follow up.
TAXOTERE in combination with trastuzumab
Docetaxel in combination with trastuzumab has been evaluated in the treatment of patients with metastatic breast cancer overexpressing HER2 and who have not received prior chemotherapy for metastatic disease.186 patients were randomized to receive docetaxel (100 mg / m2) with or without trastuzumab; 60% of patients previously received adjuvant chemotherapy with anthracyclines. Docetaxel with trastuzumab was effective in patients who had or had not previously received adjuvant anthracycline therapy. The most commonly used test to determine HER2 positivity in this pivotal study was immunohistochemistry (IHC). Fluorescence in situ assay (FISH) was used for a smaller number of patients. In this study 87% of patients had disease that was IHC 3+ and 95% of enrolled patients had IHC 3+ disease and / or FISH positive. Efficacy results are summarized in the table below:
TTP = time to progression; "ne" indicates that it cannot be estimated or has not yet been
reached up.
1 Intent-to-treat population
2 Estimated median survival
TAXOTERE in combination with capecitabine
Data from a multicentre, randomized, controlled phase III clinical trial support the use of docetaxel in combination with capecitabine for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy that included an anthracycline. . In this study, 255 patients were randomized to treatment with docetaxel (75 mg / m2 as a 1 hour intravenous infusion every 3 weeks) and capecitabine (1250 mg / m2 twice daily for 2 weeks followed by a 1-week rest period. ). 256 patients were randomized to treatment with docetaxel alone (100 mg / m2 as a 1 hour intravenous infusion every 3 weeks). Survival was superior in the docetaxel + capecitabine combination arm (p = 0.0126). Median survival was 442 days (docetaxel + capecitabine) compared with 352 days (docetaxel alone). The overall objective response rate in the entire randomized population (investigator assessment) was 41.6% (docetaxel + capecitabine) versus 29.7% (docetaxel alone); p = 0.0058. Time to disease progression was superior in the docetaxel + capecitabine combination arm (p
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III clinical study, in pre-treated patients, time to progression (12.3 weeks vs 7 weeks) and survival were significantly increased with docetaxel at 75 mg / m2 compared to Best Supportive Treatment (MTS).
The 1-year survival rate was significantly higher with docetaxel (40%) than with MTS (16%).
Less morphine was used in patients treated with docetaxel at 75 mg / m2 (p non-morphine analgesics (p
In evaluable patients, the overall response rate was 6.8%, and the mean duration of response was 26.1 weeks.
TAXOTERE in combination with platinum-derivatives in patients never treated with chemotherapy
In a phase III study, 1218 patients with inoperable stage IIIB or IV non-small cell lung cancer, with Karnofsky Performance Status of 70% and above, who had not received prior chemotherapy for this condition, were randomized to docetaxel (T ) 75 mg / m2 as a one-hour infusion followed immediately by cisplatin (TCis) 75 mg / m2 over 30-60 minutes every three weeks, docetaxel 75 mg / m2 as a one-hour infusion in combination with carboplatin (AUC 6 mg /ml.min) over 30-60 minutes every three weeks, or vinorelbine (VCis) 25 mg / m2 administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg / m2 administered on the first day of cycle repeated every 4 weeks.
Survival, mean time to progression and response rate data for two study arms are presented in the table below.
*: Corrected for multiple comparisons and adjusted for stratification factors (disease stage and treatment region), based on the evaluable patient population.
Secondary endpoints included change in pain, global quality of life assessment by EuroQoL-5D, Lung Cancer Symptom Scale (LCSS), and change in Karnofsky performance status. The results of these objectives confirmed the results of the primary objectives.
For the docetaxel / carboplatin combination, it was not possible to demonstrate either equivalence or non-inferiority of efficacy with respect to the reference treatment: the VCis combination.
Prostate cancer
The tolerability and efficacy of docetaxel in combination with prednisone or prednisolone in patients with hormone-refractory metastatic prostate cancer were evaluated in a phase III multicentre randomized study. A total of 1006 patients with KPS 60 were randomized to the following therapeutic groups:
Docetaxel 75 mg / m2 every 3 weeks for 10 cycles.
Docetaxel 30 mg / m2 administered weekly for the first 5 weeks of a 6-week cycle for a total of 5 cycles.
Mitoxantrone 12 mg / m2 every 3 weeks for 10 cycles.
All three regimens were administered in combination with prednisone or prednisolone 5 mg twice daily, continuously.
Patients who received docetaxel every three weeks demonstrated significantly longer overall survival than patients treated with mitoxantrone. The increase in survival observed in the docetaxel-treated group every week was not statistically significant compared to the mitoxantrone-treated control group. The efficacy parameters obtained in the docetaxel-treated groups compared to the control group are summarized in the following table:
† Stratified log rank test
* Limit for statistical significance = 0.0175
** PSA: Prostate-Specific Antigen
As docetaxel every week had a slightly better tolerability profile than docetaxel every 3 weeks, it is possible that some patients may benefit from weekly docetaxel therapy.
There was no statistically significant difference in Overall Quality of Life between the treatment groups.
Gastric adenocarcinoma
An open-label, randomized, multicenter study was conducted to evaluate the safety and efficacy of docetaxel in the treatment of patients with metastatic gastric adenocarcinoma, including gastroesophageal junction adenocarcinoma, who had not previously received chemotherapy for their metastatic disease. A total of 445 patients with KPS> 70 were treated with docetaxel (T) (75 mg / m2 on day 1) in combination with cisplatin (C) (75 mg / m2 on day 1) and 5-fluorouracil (F) ( 750 mg / m2 per day for 5 days) or with cisplatin (100 mg / m2 on day 1) and 5-fluorouracil (1000 mg / m2 per day for 5 days). The duration of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The mean number of cycles administered per patient was 6 (with a range of 1-16) for the TCF arm and 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was the primary end point. The reduction in risk of progression was 32.1% and was associated with a significantly longer TTP (p = 0.0004) for the TCF arm. Overall survival was also significantly longer (p = 0.0201) for the TCF arm with a risk reduction of mortality of 22.7%. The efficacy results are summarized in the following table:
Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma
* Unstratified logrank test
Subgroup analyzes for age, gender, and race consistently favored the TCF arm over the CF arm.
An updated survival analysis conducted with a mean follow-up time of 41.6 months no longer showed a statistically significant difference, albeit always in favor of the TCF regimen and highlighted that the benefit of TCF over CF is evident. between 18 and 30 months of follow-up.
Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favor of the TCF arm. Patients treated with TCF had a 5% longer time to deterioration in health status on the QLQ-C30 questionnaire (p = 0.0121) and a longer time to definitive worsening of Karnofsky performance status (p = 0, 0088) compared to patients treated with CF.
Head and neck cancer
Induction chemotherapy followed by radiotherapy (TAX 323)
The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) were evaluated in an open-label, multicentre phase III randomized study (TAX323). In this study, 358- patients with locally advanced inoperable SCCHN with WHO performance status 0 - 1 were randomized from one to two arms. Patients who received docetaxel (T) 75 mg / m2 followed by cisplatin (P) 75 mg / m2 followed by 5- fluorouracil (F) 750 mg / m2 per day as a continuous infusion for 5-days. This dosing regimen is administered every three weeks for 4 cycles, a mimic response (> 25% tumor shrinkage measured bidimensionally) was observed after 2 cycles. At the end of chemotherapy, with a minimum interval of 4 weeks and a maximum of seven weeks, patients for whom the disease does not progress receive radiotherapy (RT), in accordance with institutional guidelines, for 7 weeks. and (TPF / RT). Patients in the comparator arm received cisplatin (P) 100 mg / m2 followed by 5-fluorouracil (F) 1000 mg / m2 daily for 5 days. This dosing regimen was administered every three weeks for 4 cycles if at least one response (≥ 25% reduction in measured two-dimensional tumor size) was observed after 2 cycles. At the conclusion of chemotherapy, with a minimum interval of 4 weeks and a maximum interval of 7 weeks, patients in whom the disease had not progressed received radiotherapy (RT) according to the guideline for 7 weeks (PF / RT) . Locoregional radiation therapy was applied to a conventional fraction (1.8 Gy-2.0 Gy once daily, 5 days per week for a total dose of 66 to 70 Gy), or to accelerated / hyperfractionated radiotherapy regimens ( twice a day, with a minimum interval of fractions of 6 hours, of 5 days a week). A total of 70 Gy was suggested for the accelerated regimens and 74 Gy for the hyperfractionated schemes. Surgical resection is allowed after chemotherapy, before or after radiotherapy. Patients in the TPF arm received oral ciprofloxacin 500 mg twice daily for 10 days starting on day 5 of each cycle, or equivalent, as prophylaxis. The primary end point in this study, progression free survival (PFS), was significantly longer in the TPF arm than in the PF arm, p = 0.0042 (median PFS: 11.4 vs 8.3 months, respectively) with median time of 33.7 months. Median survival was also significantly longer for the TPF arm compared to the PF (median OS: 18.6 vs 14.5 months, respectively) with a 28% reduction in mortality risk, p = 0.0128. The efficacy results are presented in the table below:
Efficacy of docetaxel in the induction treatment of patients with locally advanced inoperable SCCHN. (Intent-to-Treat Analysis).
Hazard ratio lower than 1 in favor of the docetaxel + cisplatin + 5-FU combination
* Cox model (adjustment for primary tumor site, staging on T and N and PS-WHO)
** Logrank test
*** Chi-square test
Parameters to define the quality of life.
Patients treated with TPF exhibit significantly decreased deterioration in their overall health compared to those treated with PF (p = 0.01, using EORTC QLQ-C30 scale).
Parameters to define the clinical benefits
The performance scale, for head and neck (PSS-HN), which aimed to measure speech comprehension, the possibility of eating in public and the normality of the diet, was found to be significantly in favor of the TPF arm compared to the PF arm. Median time to first deterioration in WHO performance condition was significantly longer in the TPF arm compared to the PF arm. The pain intensity scale shows improvement during treatment in both groups, indicating that pain management is adequate.
Induction chemotherapy followed by chemo-radiotherapy (TAX324)
The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced head and neck squamous cell carcinoma (SCCHN) was evaluated in a phase III, randomized, open-label, multicenter clinical trial (TAX 324). study, 501 patients with locally advanced SCCHN with WHO performance status 0 or 1 were randomized to one of the two arms. The study population also included technically inoperable patients, patients with a low probability of successful surgical resection, and patients who aimed at organ preservation. The evaluation of the safety and efficacy profile considered only the survival endpoints, while the success in organ preservation was not formally considered.
Docetaxel-treated patients received docetaxel (T) 75 mg / m2 as an intravenous infusion on day 1 followed by cisplatin (P) 100 mg / m2 administered as an intravenous infusion lasting 30 minutes to three hours, followed by continuous intravenous infusion of 5-fluorouracil (F) 1000 mg / m2 / day from day 1 to day 4. Cycles were repeated every three weeks for 3 cycles.
All patients who did not have disease progression were to receive chemo radiotherapy (CRT) as per protocol (TPF / CRT). Patients in the comparator arm received cisplatin (P) 100 mg / m2 administered as an infusion lasting from 30 minutes to three hours on day 1, followed by 5-fluorouracil (F) 1000 mg / m2 / day from day 1 to day. 5. Cycles were repeated every three weeks for 3 cycles. All patients who did not have disease progression were to receive protocol-compliant CRTs (PF / CRT).
Patients in both treatment arms received 7 days of CRT after induction chemotherapy with a minimum interval of 3 weeks and no longer than 8 weeks after the start of the last cycle (day 22 to day 56. During radiotherapy, carboplatin (AUC 1.5) was administered as a one-hour intravenous infusion for up to 7 doses. The radiation was administered with a high voltage instrument using daily fractionation (2Gy per day, 5 days per week for 7 weeks, for a total dose of 70-72 Gy). Surgery at the primary tumor site and / or neck could be considered at any time after completion of the CRT. All study patients in the docetaxel arm received antibiotic prophylaxis. The primary efficacy endpoint of this study, survival (OS) was significantly longer (log-rank test p = 0.0058) with the docetaxel-containing regimen compared to PF (median OS: 70.6 vs 30.1 months, respectively), with a 30% reduction in the risk of death from PF (hazard ratio (HP) = 0.70, 95% confidence interval (CI) = 0.54-0.90) at a median follow-up of 41.9 months The secondary endpoint, PFS, demonstrated a 29% reduction in the risk of progression or death and an improvement in median PFS of 22 months (35.5 months for TPF and 13.1 for PF).This was also statistically significant with an HR of 0.71, 95% CI 0.56-0.90; log-rank test p = 0.004. The efficacy results are presented in the following table:
Hazard ratio lower than 1 in favor of the docetaxel + cisplatin + 5-fluorouracil combination
* log rank test adjustment
** log rank test adjustment, no adjustment for multiple comparisons
*** Chi-square test, no adjustment for multiple comparisons
NA - not applicable
The European Medicines Agency has granted a waiver from the obligation to provide the results of studies with TAXOTERE in all subsets of patients of the pediatric population in breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer and head and neck cancer, excluding less differentiated type II and type III nasopharyngeal carcinoma (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
The pharmacokinetics of docetaxel were studied in cancer patients following administration of 20-115 mg / m2 in phase I studies. The kinetic profile of docetaxel is not dose-dependent and is consistent with a three-compartment pharmacokinetic model, with half-lives per phases a, b and b respectively of 4 min., 36 min. and 11.1 hours. The late phase is partly due to the relatively slow return of docetaxel from the peripheral compartment. After administration of 100 mg / m2 as a one-hour infusion, a mean peak plasma level of 3.7 mcg / ml was obtained, with a corresponding AUC of 4.6 h mcg / ml. Mean total clearance values and volume of distribution at steady state were 21 1 / h / m2 and 113 L. Interindividual changes in total clearance were approximately 50%. Docetaxel is more than 95% bound to plasma proteins.
A study with 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both urine and faeces by cytochrome P 450-mediated oxidation of the tertbutyl ester group; within seven days, approximately 6% and 75% of the administered radioactivity is excreted in the urine and faeces, respectively. Approximately 80% of the radioactivity found in faeces is excreted within the first 48 hours as one major metabolite and three inactive minor metabolites and very small amounts of the parent drug.
A population pharmacokinetic study was performed in 577 patients. The pharmacokinetic parameters calculated by the model were very close to those observed in the phase I studies. The pharmacokinetics of docetaxel were not modified by the age or gender of the patient. In a small number of patients (n = 23) with biochemical results. suggesting moderate hepatic dysfunction (ALAT, ASAT 3 1.5 times the upper limit of normal, associated with alkaline phosphatase 3 2.5 the upper limit of normal), total clearance decreased on average by 27% (see section 4.2). Docetaxel clearance is not affected in patients with mild or moderate fluid retention No data are available in patients with severe fluid retention.
When used in combination, docetaxel does not affect the clearance of doxorubicin and the plasma levels of doxorubicinol (a metabolite of doxorubicin). The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide are not affected by their co-administration.
A Phase I study evaluating the effects of capecitabine on the pharmacokinetics of docetaxel and vice versa demonstrated that there is no effect of capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC) and that there is no effect of docetaxel on the pharmacokinetics of a metabolite. relevant of capecitabine, 5 "-DFUR.
The clearance of docetaxel in combination therapy with cisplatin was similar to that observed during monotherapy. The pharmacokinetic profile of cisplatin administered shortly after the docetaxel infusion is similar to that seen with cisplatin alone.
The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of the individual medicinal products.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard premedication with dexamethasone was studied in 42 patients. No effect of prednisone on docetaxel pharmacokinetics was observed.
05.3 Preclinical safety data
The carcinogenic potential of docetaxel has not been studied.
Docetaxel was shown to be mutagenic in the test in vitro of chromosomal aberration in CHO-K1 cells e in vivo in the mouse micronucleus test. However docetaxel is not mutagenic in the Ames test or the CHO / HGPRT gene mutation test. These results are consistent with the pharmacological activity of docetaxel.
Undesirable effects on the male genital organs, observed in toxicity studies in rodents, suggest that docetaxel may impair male fertility.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Vial of concentrate:
polysorbate 80, citric acid.
Solvent vial:
95% ethanol, water for injections.
06.2 Incompatibility
The medicinal product must not be mixed with other products except those mentioned in section 6.6.
06.3 Period of validity
2 years.
Pre-mixed solution: the pre-diluted solution contains 10 mg / ml of docetaxel and must be used immediately after preparation, even if the chemical-physical stability of this solution has been demonstrated for a period of 8 hours if stored between + 2 ° C and +8 ° C or at room temperature (below 25 ° C).
Solution for infusion: The solution for infusion, stored at room temperature (below 25 ° C), should be used within 4 hours.
06.4 Special precautions for storage
Do not store above 25 ° C or below 2 ° C.
Store in the original package to keep it away from light.
For storage conditions of the diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Each blister contains:
one single-dose vial of concentrate and one single-dose vial of solvent.
Vial of TAXOTERE 20 mg / 0.5 ml concentrate for solution for infusion:
7 ml clear Type I glass vial with green flip off cap.
The vial contains a solution of docetaxel in 0.5 ml of polysorbate 80 and a concentration of 40 mg / ml (filling volume: 24.4 mg / 0.61 ml). This fill volume was established during the development of TAXOTERE to compensate for the loss of liquid during the preparation of the prediluted solution due to foaming, adhesion to the vial walls and 'dead space'. The overfill ensures that after the dilution with the entire contents of the solvent vial enclosed with TAXOTERE the minimum extractable volume of prediluted solution is 2 ml, containing 10 mg / ml of docetaxel which corresponds to the content declared on the label of 20 mg / 0.5 ml per vial.
Solvent vial:
Type I clear glass vial of 7 ml with colorless clear flip-off cap.
The vial of solvent contains 1.5 ml of 13% (w / w) solution of 95% ethanol in water for injections (filling volume: 1.98 ml). The addition of the entire contents of the solvent vial to that of TAXOTERE 20 mg / 0.5 ml, concentrate for solution for infusion ensures that a premixed solution is obtained with a concentration of 10 mg / ml of docetaxel.
06.6 Instructions for use and handling
TAXOTERE is an antineoplastic drug and, as with other potentially toxic products, caution should be exercised in handling and preparing solutions. The use of gloves is recommended. If TAXOTERE in concentrated, pre-diluted form or solution for infusion should come into contact with the skin, wash immediately and thoroughly with soap and water. If TAXOTERE in concentrated, pre-diluted form or solution for infusion should come into contact with mucous membranes, wash immediately and thoroughly with water.
Preparation for intravenous administration
a) Preparation of the ready-to-use solution of TAXOTERE (10 mg docetaxel / ml)
If the vials are stored in the refrigerator, leave the required number of boxes of TAXOTERE at room temperature (below 25 ° C) for 5 minutes.
Using a graduated syringe with needle, withdraw the entire contents of the vial of solvent for TAXOTERE by partially inverting the vial.
Inject the entire contents of the syringe into the corresponding vial of TAXOTERE.
Remove the syringe and needle and mix the solution manually by inverting repeatedly for 45 seconds. Do not shake.
Let the vial of prediluted solution stand for 5 minutes at room temperature (below 25 ° C) and then check that the solution is clear and homogeneous. (Foaming is normal even after 5 minutes due to the polysorbate 80 content in the formulation).
The prediluted solution contains 10 mg / ml of docetaxel and must be used immediately after preparation, even if the chemical-physical stability of this solution has been demonstrated for a period of 8 hours if stored between + 2 ° C and + 8 ° C or at room temperature (below 25 ° C).
b) Preparation of the solution for infusion
Multiple vials of prediluted solution may be required to obtain the required patient dose. Based on the dose needed for the patient expressed in mg, aseptically withdraw the corresponding volume of prediluted solution containing 10 mg / ml docetaxel from an appropriate number of prediluted solution vials using a graduated syringe with needle. For example, for a dose of 140 mg of docetaxel, 14 ml of docetaxel prediluted solution should be withdrawn. Inject the required volume of prediluted solution into a 250 ml bag or bottle containing 5% glucose solution or solution for infusion with 9 mg / ml sodium chloride (0.9%).
If a docetaxel dose greater than 200 mg is required, use a larger volume of the infusion solution so that the docetaxel concentration does not exceed 0.74 mg / ml. Manually mix the bag or bottle with a twisting motion.
The TAXOTERE solution for infusion should be used within 4 hours and should be administered as a 1 hour infusion, aseptically, at room temperature (below 25 ° C) and in normal light conditions.
As with all products for parenteral use, the prediluted solution and the perfusion solution of TAXOTERE must be visually examined before use, solutions containing precipitates must be discarded.
Unused product and waste derived from this medicine must be disposed of in accordance with local legal requirements.
07.0 MARKETING AUTHORIZATION HOLDER
Aventis Pharma S.A., 20 Avenue Raymond Aron, 92165 Antony Cedex, France
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/95/002/001
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: November 27, 1995
Date of last renewal: November 27, 2005.
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