Active ingredients: Paclitaxel
TAXOL 6 mg / ml concentrate for solution for infusion
Why is Taxol used? What is it for?
Paclitaxel belongs to a group of anticancer medicines called taxanes. These agents inhibit the growth of cancer cells.
TAXOL is indicated for the treatment of:
Ovarian cancer:
- as first-line therapy (after initial surgery in combination with cisplatin, a platinum-containing medicine).
- after standard treatments with platinum-based medicines that have not been effective.
Breast cancer:
- as first-line therapy in advanced disease or disease that has spread to other parts of the body (metastatic disease). TAXOL is combined with both anthracyclines (eg doxorubicin) and a medicine called trastuzumab (in patients for whom anthracycline is not indicated and whose cancer cells have a protein called HER 2 on the surface, see the package leaflet for trastuzumab. ).
- after initial surgery, as an additional treatment, after treatment with anthracyclines and cyclophosphamide (AC).
- as second-line therapy in patients who have not responded to standard anthracycline treatments or for those for whom such treatment should not be used.
Advanced non-small cell lung cancer:
in combination with cisplatin, when surgery and / or radiation therapy are not suitable.
AIDS-related Kaposi's sarcoma:
- when another treatment (eg liposomal anthracyclines) was attempted but did not work.
Contraindications When Taxol should not be used
Do not use TAXOL
- if you are allergic (hypersensitive) to paclitaxel or any of the other ingredients of this medicine (listed in section 6), especially polyoxyethylated castor oil.
- if your white blood cell count is too low. Your doctor will ask for blood tests.
- if you are breastfeeding.
- if you have a severe and uncontrolled infection and Taxol is used to treat Kaposi's sarcoma.
If in any of these situations, please tell your doctor before starting treatment with TAXOL. The use of TAXOL is not recommended in children (under 18 years of age).
Precautions for use What you need to know before taking Taxol
Talk to your doctor before using TAXOL.
To minimize allergic reactions, you will be given other medicines before you are given TAXOL.
If you experience severe allergic reactions (e.g. difficulty in breathing, shortness of breath, chest tightness, drop in blood pressure, dizziness, dizziness, skin reactions such as rash or swelling).
If you have a fever, shaking chills, sore throat or mouth ulcers (signs of myelosuppression).
If you have numbness or weakness in the arms and legs (signs of peripheral neuropathy); a reduction in the dose of TAXOL may be necessary.
If you have severe liver problems; in this case the use of TAXOL is not recommended.
If you have abnormalities in cardiac conduction.
If you have severe or persistent diarrhea, with fever and stomach pain, during or shortly after treatment with TAXOL. The colon can be inflamed (pseudomembranous colitis). if you have received previous chest radiation (as this may increase the risk of lung inflammation).
If you have red or inflamed mouth (signs of mucositis) and are being treated for Kaposi's sarcoma.
You may need a lower dose.
If in any of these situations, tell your doctor immediately.
TAXOL must always be administered into a vein. Administration of TAXOL into the arteries can cause inflammation and can result in pain, swelling, redness and warmth.
Interactions Which drugs or foods can modify the effect of Taxol
Tell your doctor if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.
This is because TAXOL or other medicines may not work as expected or you may be more prone to side effects.
Interaction means that different medicines can affect each other.
Talk to your doctor when taking paclitaxel at the same time as taking any of the following:
- medicines to treat infections (i.e. antibiotics such as erythromycin, rifampicin, etc .; ask your doctor, nurse or pharmacist if you are unsure whether the drug you are taking is an antibiotic)
- medicines used to help stabilize your mood, sometimes called antidepressants (e.g. fluoxetine)
- medicines used to treat seizures (epilepsy) (e.g. carbamazepine, phenytoin)
- medicines used to help you lower blood fat levels (e.g. gemfibrozil)
- medicines used for heartburn or stomach ulcers (e.g. cimetidine)
- medicines used to treat HIV and AIDS (e.g., ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, nevirapine)
- a medicine called clopidogrel used to prevent blood clots
- a medicine called rifampicin, an antibiotic used for tuberculosis. An increase in the dose of TAXOL may be necessary
- vaccines: tell your doctor if you have recently been vaccinated or are planning to have a vaccination. The use of TAXOL together with some vaccines can cause serious complications
- cisplatin (anticancer): TAXOL should be administered before cisplatin. Kidney function may need more frequent monitoring
- doxorubicin (anticancer): TAXOL should be administered 24 hours after doxorubicin, to avoid high circulating levels of doxorubicin.
Warnings It is important to know that:
Pregnancy and breastfeeding
Tell your doctor if you are pregnant or think you are pregnant before receiving treatment with TAXOL. If there is a possibility that you may become pregnant, use an effective and safe contraceptive during treatment. TAXOL should not be used during pregnancy unless strictly necessary.
Female and male patients of childbearing potential, and / or their partners should use contraceptives for at least six months after treatment with paclitaxel. Male patients should inquire about sperm cryopreservation prior to paclitaxel treatment due to possible infertility.
If you are breastfeeding, please tell your doctor. Stop breastfeeding if you are using TAXOL. Do not resume breastfeeding without your doctor's permission.
Driving and using machines
This medicine contains alcohol. For this reason it may be unwise to drive vehicles immediately after a course of treatment. In any case, you should not drive if you are dizzy or if you feel insecure.
Important information about some of the ingredients of TAXOL
TAXOL contains castor oil (50% polyoxyethylated castor oil) which can cause severe allergic reactions. If you are allergic to castor oil, talk to your doctor before taking TAXOL.
TAXOL contains alcohol (about 50% ethanol) - each milliliter of TAXOL contains 0.396 g of alcohol. A 300 mg / 50 ml dose of TAXOL contains 20 g of alcohol, equivalent to 450 ml of beer or 175 ml of wine.
Dosage and method of use How to use Taxol: Dosage
- To minimize allergic reactions, you will be given other medicines before TAXOL. These medicines can be either tablets or intravenous infusions or both.
- You will receive TAXOL drip into a vein (for intravenous infusion), through an in-line filter. TAXOL will be given to you by a healthcare professional. He or she will prepare the infusion solution before it is given to you. The dose you will receive will also depend on the results of your blood tests. Depending on the type and severity of the cancer, you will receive TAXOL alone or in combination with another anticancer agent.
- TAXOL should always be administered into a vein over a period of 3 to 24 hours. It is usually given every 2 to 3 weeks, unless otherwise advised by your doctor. Your doctor will advise you on the number of TAXOL cycles you will need to take.
If you have any further questions on the use of this product, ask your doctor.
Overdose What to do if you have taken too much Taxol
There is no antidote for TAXOL overdose. You will receive treatment for your symptoms.
Side Effects What are the side effects of Taxol
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Tell your doctor right away if you notice any signs of allergic reactions. These can include one or more of the following:
- hot flashes,
- skin reactions,
- itch,
- chest tightness,
- shortness of breath or difficulty in breathing,
- swelling.
These can all be signs of serious side effects.
Tell your doctor immediately:
If you have fever, shaking chills, sore throat or mouth ulcers (signs of myelosuppression).
If you have numbness or weakness in the arms and legs (signs of peripheral neuropathy).
If you develop severe or persistent diarrhea, with fever and stomach pain.
Very common side effects (may affect more than 1 in 10 people):
- Minor allergic reactions such as flushing, rash, itching
- Infections: mainly upper respiratory tract infections, urinary tract infections
- Shortness of breath
- Sore throat or mouth ulcers, sore and red mouth, diarrhea, feeling or being sick (nausea, vomiting)
- Hair loss (most cases of hair loss occurred less than a month after starting paclitaxel treatment. When this happens, hair loss is evident [more than 50%] in most of patients).
- Pain in the muscles, cramps, pain in the joints
- Fever, shaking chills, headache, dizziness, tiredness, paleness, bruising more easily
- Numbness, tingling or weakness in the arms and legs (all symptoms of peripheral neuropathy)
- Tests can show: decreased number of platelets, number of white or red blood cells, low blood pressure
Common side effects (may affect up to 1 in 10 people):
- Mild and transient nail and skin changes, injection site reactions (localized swelling, pain, and skin redness)
- Investigations can show: slow heart rate, severe increase in liver enzymes (alkaline phosphatase and AST - SGOT)
Uncommon side effects (may affect up to 1 in 100 people):
- Shock due to infections (known as "septic shock")
- Palpitations, heart disease (AV block), increased heart rate, heart attack, respiratory distress
- Fatigue, sweating, fainting (syncope), significant allergic reactions, inflammation of the veins caused by a thrombus (thrombophlebitis), swelling of the face, lips, mouth, tongue or throat
- Back pain, chest pain, pain in hands and feet, chills, abdominal (belly) pain
- Investigations can show: severe elevation of bilirubin (jaundice), high blood pressure, clot
Rare side effects (may affect up to 1 in 1,000 people)
- Decrease in white blood cells with fever and increased risk of infection (febrile neutropenia)
- Nerve involvement with a sense of weakness in the muscles of the arms and legs (motor neuropathy)
- Shortness of breath, pulmonary embolism, pulmonary fibrosis, interstitial pneumonia, dyspnoea, pleural effusion
- Bowel obstruction, intestinal perforation, inflammation of the colon (ischemic colitis), inflammation of the pancreas (pancreatitis)
- Itching, rash, skin redness (erythema)
- Infection of the blood (sepsis), peritonitis
- Pyrexia, dehydration, asthenia, edema, malaise
- Serious and life-threatening hypersensitivity reactions (anaphylactic reactions)
- Investigations can show: increased blood creatinine indicating renal dysfunction
Very rare side effects (may affect up to 1 in 10,000 people):
- Accelerated and irregular heart rhythm (atrial fibrillation, supraventricular tachycardia)
- Sudden change in blood cell formation (acute myeloid leukemia, myelodysplastic syndrome)
- Optic nerve disorder and / or visual disturbances (scintillating scotome)
- Loss or reduction of hearing (ototoxicity), ringing in the ears (tinnitus), dizziness
- Cough
- Clot in a vein in the abdomen and intestine (mesenteric thrombosis), inflammation of the colon sometimes with severe and persistent diarrhea (pseudomembranous colitis, neutropenic colitis), edema (ascites), oesophagitis, constipation
- Severe hypersensitivity reactions including fever, redness of the skin, pain in the joints and / or inflammation of the eye (Stevens-Johnson syndrome), localized peeling of the skin (epidermal necrolysis), redness with red and irregular (exudative) spots (erythema multiforme) ), inflammation of the skin with blisters and peeling (exfoliative dermatitis), hives, nail loss (patients on therapy should protect hands and feet with sunscreen)
- Loss of appetite (anorexia)
- Serious and life-threatening hypersensitivity reactions with shock (anaphylactic shock)
- Disturbed liver function (hepatic necrosis, hepatic encephalopathy (both have reported fatal cases))
- Confusional state
- Not known (frequency cannot be estimated from the available data) Disseminated intravascular coagulation or "DIC" has been reported. This is a serious condition that makes people easily susceptible to bleeding, blood clots, or both.
- Hardening / thickening of the skin (Scleroderma)
- Metabolic complications after chemotherapy (tumor lysis syndrome)
- Eye disorders, such as thickening and swelling of the macula (macular edema), flashes of light (photopsia) and patches, specks, dots and "cobwebs" floating in its field of vision (flying flies)
- Inflammation of the veins (phlebitis)
- Autoimmune disease with multiple symptoms such as red, scaly patches on the skin, joint pain or fatigue (systemic lupus erythematosus)
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. 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 and vial. The expiry date refers to the last day of that month.
Before diluting TAXOL:
Store below 25 ° C.
Store in the original package to protect the medicine from light. Freezing does not adversely affect closed vials.
From a microbiological point of view, once opened the product can be stored for a maximum of 28 days at 25 ° C. Other storage periods and conditions are the responsibility of the user.
After diluting TAXOL:
From a microbiological point of view, the diluted product should be used immediately. If not used immediately, store in a refrigerator (2 ° C - 8 ° C) for no more than 24 hours, unless dilution has been done under validated and controlled aseptic conditions. For more details on stability after dilution, see the section for healthcare professionals.
Other information
What TAXOL contains
The active ingredient is paclitaxel.
Each ml concentrate contains 6 mg of paclitaxel.
Each vial contains 5 - 16.7 - 25 or 50 ml (corresponding to 30, 100, 150 or 300 mg of paclitaxel respectively).
The other ingredients are ethanol (alcohol) and polyoxyethylated castor oil.
Description of what TAXOL looks like and contents of the pack
TAXOL 6 mg / ml concentrate for solution for infusion is a clear, colorless to slightly viscous yellow solution, contained in vials of 5 ml, 16.7 ml, 25 ml and 50 ml of concentrate for dilution.
The vials are individually packed in a carton, boxes containing 10 cartons are also available.
Not all pack sizes may be marketed.
The following information is intended for healthcare professionals only
Preparation of Infusion Solutions:
- Containers and infusion sets used with TAXOL must be DEHP free. This will reduce the risk of patient exposure to the plasticizer DEHP [di- (2-ethylhexyl) phthalate], which can be released from PVC containers or infusion sets. The use of filter devices (eg IVEX-2 ) incorporating short PVC inlet and / or outlet devices did not show significant divestments of DEHP.
- As with all antineoplastic agents TAXOL must be handled with care. Always wear suitable protective gloves when handling vials containing paclitaxel. The dilution of paclitaxel must be done under aseptic conditions by trained personnel in a specific area. In case of contact with the skin, wash the area with soap and water. In case of contact with mucous membranes, wash with plenty of water.
- Do not use the Chemo-Dispensing Pin device or similar piercing devices which may cause the stopper to fall inside the vial, resulting in a loss of sterility.
Step 1: Dilute the concentrate
Before administration, TAXOL must be diluted with one of the following:
- 0.9% Sodium Chloride
- 5% Dextrose
- 5% Dextrose and 0.9% Sodium Chloride Injection Solution
- 5% Dextrose in Ringer's solution for injection
The concentration of the final paclitaxel solution should be between 0.3 mg / ml and 1.2 mg / ml. DEHP-free containers and infusion devices should be used.
After dilution, the solutions may exhibit turbidity, attributable to the vehicle formulation, and are not removable by filtration. No significant decrease in concentration was noted following simulated administration of the solution through the intravenous cannula equipped with an in-line filter.
Step 2: Administration of the infusion
Premedicate all patients with corticosteroids, antihistamines and H2 antagonists prior to administration.
Do not re-administer TAXOL until the neutrophil count is ≥ 1,500 / mm3 (≥ 1,000 / mm3 for patients with Kaposi's sarcoma) and the platelet count is ≥ 100,000 / mm3 (≥ 75,000 / mm3 for patients with Kaposi).
Avoid precipitation of the infusion solution:
- Use as soon as possible after dilution
- Avoid excessive shaking, vibration or agitation
- Infusion sets must be thoroughly cleaned before use.
- Regularly check the appearance of the solution and stop the infusion if there are precipitates.
Chemical-physical stability of the solution has been demonstrated at 5 ° C and 25 ° C for 7 days when diluted with 5% dextrose solution for injection, and for 14 days when diluted with 0.9% sodium chloride solution. From a microbiological point of view, the diluted product should be used immediately or stored at 2 ° C-8 ° C for up to 24 hours.
TAXOL should be administered via an appropriate in-line filter with a micro-pore membrane having a diameter of ≤ 0.2 micrometers. DEHP-free containers and infusion sets should be used. The use of filters incorporating short PVC inlet and outlet devices have not shown significant releases of DEHP.
Step 3: Disposal
The disposal of any unused or waste material must be in accordance with the regulations relating to the handling of cytotoxic drugs.
Dose:
The recommended doses for the intravenous infusion of TAXOL are as follows:
Do not re-administer TAXOL until the neutrophil count is ≥ 1,500 / mm3 (≥ 1,000 / mm3 for patients with Kaposi's sarcoma) and the platelet count is ≥ 100,000 / mm3 (≥ 75,000 / mm3 for patients with Kaposi's sarcoma).
Patients with severe neutropenia (neutrophil count <500 / mm3 for one or more weeks) or severe peripheral neuropathy should receive a 20% reduced dose for subsequent courses (25% for patients with Kaposi's sarcoma) (see Summary of Characteristics of Product).
There are insufficient data to recommend dose modifications in patients with mild to moderate hepatic dysfunction. Patients with severe hepatic dysfunction should not be treated with TAXOL (see Summary of Product Characteristics).
The use of TAXOL is not recommended in children under 18 years of age due to poor data on safety and efficacy.
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
TAXOL 6 MG / ML
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains 6 mg / ml of paclitaxel (6 mg per 1 ml of concentrate for solution for infusion).
One 5 ml vial contains 30 mg of paclitaxel.
One 16.7 ml vial contains 100 mg of paclitaxel.
One 25 ml vial contains 150 mg of paclitaxel.
One 50 ml vial contains 300 mg of paclitaxel.
Excipients: 396 mg / ml anhydrous ethanol and castor oil.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear, colorless to pale yellow viscous solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Ovarian cancer: In first-line chemotherapy of ovarian cancer TAXOL is indicated for the treatment of patients with advanced ovarian cancer or with residual cancer (> 1 cm) after initial laparatomy, in combination with cisplatin.
In second-line chemotherapy of ovarian cancer TAXOL is indicated for the treatment of metastatic ovarian cancer when standard therapy, containing platinum derivatives, has not proved effective.
Breast cancer: In adjuvant therapy, Taxol is indicated for the treatment of patients with node-positive breast cancer after anthracycline and cyclophosphamide (AC) therapy. Adjuvant treatment with TAXOL should be considered as an alternative to continuing AC therapy.
TAXOL is indicated for the initial treatment of locally advanced or metastatic breast cancer in combination with both an anthracycline in patients for whom anthracycline therapy is suitable and with trastuzumab in patients with HER-2 level 3+ overexpression. "immunohistochemical examination, and for which treatment with an anthracycline is not possible" (see sections 4.4 and 5.1).
As monotherapy, TAXOL is indicated for the treatment of metastatic breast cancer when standard therapy, containing anthracycline derivatives, is not considered possible or has not been found to be effective.
Advanced non-small cell lung cancer : TAXOL, in combination with cisplatin, is indicated for the treatment of non-small cell lung cancer (NSCLC) in patients who cannot undergo radical surgery and / or radiation therapy.
AIDS-related Kaposi's sarcoma: Taxol is indicated for the treatment of patients with advanced AIDS-related Kaposi's sarcoma (KS) who have failed prior liposomal anthracycline therapy.
There are limited efficacy data to support this indication, a summary of the relevant studies is presented in section 5.1.
04.2 Posology and method of administration
TAXOL should be administered under the supervision of a qualified oncologist in facilities specialized in the administration of cytotoxic agents (see section 6.6).
Prior to administration of TAXOL, all patients should be premedicated with corticosteroids, antihistamines and H2 antagonists, for example:
* 8-20 mg for patients with Kaposi's sarcoma
** or an equivalent antihistamine, eg: chlorpheniramine
For instructions on dilution of the product before administration, see section 6.6. TAXOL should be administered intravenously through an in-line filter with a micropores membrane having a diameter of ≤ 0.22 μm (see section 6.6).
First-line chemotherapy of ovarian cancer: Although other dosing regimens are being investigated, a combination regimen consisting of TAXOL and cisplatin is recommended. Based on the duration of the infusion, two doses of TAXOL are recommended: TAXOL at a dose of 175 mg / m2, administered intravenously over 3 hours, followed by cisplatin at a dose of 75 mg / m2, every three weeks or TAXOL 135 mg. / m2, administered as a 24-hour infusion, followed by cisplatin at a dose of 75 mg / m2, with an interval of three weeks between one administration of this combination and the next (see section 5.1).
Second-line chemotherapy of ovarian cancer: the recommended dose of TAXOL is 175 mg / m2, administered over 3 hours, with an interval of 3 weeks between one administration and the next.
Adjuvant chemotherapy in breast cancer: The recommended dose of TAXOL is 175 mg / m2 administered over 3 hours every 3 weeks for four cycles after AC therapy.
First-line chemotherapy of breast cancer: when used in combination with doxorubicin (50 mg / m2), TAXOL should be administered 24 hours after doxorubicin. The recommended dose of TAXOL is 220 mg / m2 administered intravenously over a 3 hour period, with a 3 week interval between courses (see sections 4.5 and 5.1).
When used in combination with trastuzumab, the recommended dose of TAXOL is 175 mg / m2, administered intravenously over a 3 hour period, with a 3 week interval between courses (see section 5.1).The infusion of TAXOL can be started the day after the first dose of trastuzumab or immediately after the following if the previous dose of trastuzumab is well tolerated (for the detailed posology of trastuzumab see the Summary of Product Characteristics of the medicinal product Herceptin).
Second-line chemotherapy of breast cancer: The recommended dose of TAXOL is 175 mg / m2, administered over a 3 hour period, with a 3 week interval between courses.
Treatment of advanced non-small cell lung cancer: the recommended dose of TAXOL is 175 mg / m2, administered over 3 hours, followed by the administration of cisplatin at a dose of 80 mg / m2, with an interval of 3 weeks between one therapeutic cycle and the next.
Treatment of AIDS-related Kaposi's Sarcoma: The recommended dose of TAXOL is 100 mg / m2, administered as a 3 hour intravenous infusion every two weeks.
Subsequent doses of TAXOL should be administered taking into account the individual tolerability of the medicinal product.
It is advisable not to re-administer TAXOL until the neutrophil count reaches or exceeds the value of 1,500 / mm3 (≥ 1,000 / mm3 for patients with Kaposi's sarcoma) and the platelet count reaches a value of ≥ 100,000 / mm3 (≥ 75,000 / mm3 for patients with Kaposi's sarcoma). In case of severe neutropenia (neutrophils less than 500 / mm3 for 7 or more days) or severe peripheral neuropathy, the dose, in subsequent courses of therapy, should be reduced by 20% (25% for patients with Kaposi's sarcoma) (see section 4.4).
Patients with hepatic dysfunction: There are no adequate data available to recommend dosage adjustments in patients with mild to moderate hepatic dysfunction (see sections 4.4 and 5.2). Patients with severe hepatic dysfunction should not be treated with paclitaxel.
Pediatric Use: The use of TAXOL is not recommended in children under 18 years as no data on safety and efficacy are available.
04.3 Contraindications
Hypersensitivity to paclitaxel or to any of the excipients, especially polyoxyethylated castor oil (see section 4.4).
TAXOL should not be used in patients with an initial neutrophil count of 3 (3 for patients with Kaposi's sarcoma).
TAXOL is contraindicated during lactation (see section 4.6).
In Kaposi's sarcoma, TAXOL is also contraindicated in patients with concomitant, severe and uncontrolled infections.
04.4 Special warnings and appropriate precautions for use
TAXOL should be administered under the supervision of a physician with experience in the use of anticancer chemotherapy. Due to the possible occurrence of severe hypersensitivity reactions to the drug, adequate supportive care equipment should be available.
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Patients should be pretreated with corticosteroids, antihistamines and H2 antagonists (see section 4.2).
TAXOL should be administered prior to cisplatin when used in combination (see section 4.5).
Following treatment with TAXOL, preceded by adequate premedication, significant hypersensitivity reactions, characterized by dyspnoea and hypotension requiring treatment, angioedema and generalized urticaria manifested in histamine. In case of severe hypersensitivity reactions, TAXOL should be discontinued immediately, symptomatic therapy instituted and the medicine not re-administered.
Myelosuppression (mainly neutropenia) is dose limiting toxicity. Frequent monitoring of haematological parameters should be instituted and treatment should not be resumed until the neutrophil value returns ≥ 1,500 / mm3 (≥ 1,000 / mm3 for patients with Kaposi's sarcoma) and that of platelets ≥ 100,000 / mm3 (≥ 75,000 / mm3 for patients with Kaposi's sarcoma). In the Kaposi sarcoma clinical trial, most patients received granulocyte growth factor (G-CSF).
Patients with liver dysfunction may be at increased risk of toxicity, especially grade 3-4 myelosuppression. The toxicity of TAXOL has not been shown to increase when administered over three hours in patients with mildly impaired liver function. When TAXOL is given as a slower infusion, increased myelosuppression may be noted in patients with moderate to severe hepatic dysfunction. Patients should be closely monitored for the development of severe myelosuppression (see section 4.2). There are no adequate data available to recommend dose adjustments in patients with mild to moderate hepatic dysfunction (see section 5.2). No data are available in patients with severe cholestasis at initiation of therapy. Patients with severe hepatic dysfunction should not be treated with paclitaxel.
Serious abnormalities in cardiac conduction have been reported rarely with TAXOL alone. If they occur during the administration of TAXOL, appropriate therapy should be instituted and continuous cardiac monitoring performed during subsequent cycles. Hypotension, hypertension and bradycardia have been observed during treatment with TAXOL; patients are usually asymptomatic and in generally do not require treatment. Frequent monitoring of vital signs is recommended, particularly during the first hour of TAXOL infusion. Serious cardiovascular events were observed more frequently in patients with non-small cell lung cancer than in patients with cancer In the clinical study of AIDS-related Kaposi's sarcoma, a single case of paclitaxel-related heart failure was observed.
When TAXOL is used in combination with doxorubicin or trastuzumab for the initial treatment of metastatic breast cancer, cardiac function should be closely monitored. Patients who are candidates for treatment with TAXOL in these combinations should undergo a basic cardiac evaluation, including a "medical history, physical examination, ECG, echocardiogram and / or angio cardioscintigraphy (MUGA scan). Cardiac function should be further monitored during the Treatment (eg every three months) Monitoring can help identify patients who develop cardiac dysfunction and treating physicians should carefully evaluate the cumulative dose (mg / m2) of anthracycline administered when making decisions about the rate of ventricular function. When evidence indicates deterioration in heart function, even asymptomatic, treating physicians should carefully weigh the clinical benefits of further therapy against the possibility of producing heart damage, including potentially irreversible damage. heart function should be more frequent (e.g. every 1-2 cycles). For more details see the Summary of Product Characteristics of the medicinal product Herceptin or doxorubicin.
Although the peripheral neuropathy is a frequent occurrence, the development of severe symptoms is rare. In severe cases, a 20% (25% in patients with Kaposi's sarcoma) dose reduction is recommended for all subsequent treatments with TAXOL. In patients with non-small cell lung cancer and in patients with ovarian cancer on first-line treatment, administration of TAXOL infused over three hours in combination with cisplatin resulted in a higher incidence of severe neurotoxicity compared to both TAXOL alone and cyclophosphamide followed by cisplatin.
In animal studies conducted to evaluate local tolerability, severe tissue reactions were observed following intra-arterial administration; for this reason, particular care must be taken in avoiding the administration of TAXOL by this route.
Treatment with TAXOL in combination with radiation therapy of the lung, regardless of their sequence of use, can contribute to the development of interstitial pneumonia.
Since TAXOL contains ethanol (396 mg / ml), it is necessary to evaluate its potential effects on the central nervous system and other possible effects.
Cases of pseudomembranous colitis , including cases in patients who were not concurrently on antibiotic therapy. This reaction should be taken into account in the differential diagnosis of cases of severe or persistent diarrhea occurring during or shortly after treatment with paclitaxel.
In patients with Kaposi's sarcoma, the severe mucositis it is rare. If severe reactions occur, the paclitaxel dosage should be reduced by 25%.
04.5 Interactions with other medicinal products and other forms of interaction
It is recommended to administer TAXOL first of cisplatin in first-line chemotherapy of ovarian cancer, since, in this case, the tolerability profile of TAXOL is comparable to that typical of use alone. When TAXOL was administered after cisplatin, more pronounced than normal myelosuppression and an approximately 20% decrease in paclitaxel clearance were observed in treated patients. Patients treated with TAXOL and cisplatin may be at greater risk of kidney damage than those treated with cisplatin alone in gynecological carcinomas.
Since the elimination of doxorubicin and its active metabolites may be reduced when paclitaxel and doxorubicin are given at short notice, TAXOL in the initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin (see section 5.2).
The metabolism of paclitaxel is catalysed, in part, by the cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Clinical studies have shown that CYP2C8-mediated metabolism of paclitaxel to 6a-hydroxypaclitaxel is the major metabolic pathway in humans. Co-administration of ketoconazole, a known potent inhibitor of CYP3A4, does not inhibit the elimination of paclitaxel in patients; therefore the two medicinal products can be administered together without the need for dosage adjustments. Further data on the potential drug interactions between paclitaxel and other CYP3A4 substrates / inhibitors are limited. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicinal products capable of inhibiting (e.g. erythromycin, fluoxetine, gemfibrozil) or inducing (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) both CYP2C8 than 3A4.
Paclitaxel clearance is not affected by pretreatment with cimetidine.
Studies in Kaposi's sarcoma patients taking numerous concomitant therapies suggest that the systemic clearance of paclitaxel was significantly reduced in the presence of nelfinavir and ritonavir, but not with indinavir. There is insufficient information on interactions with other protease inhibitors. Consequently, paclitaxel should be administered with caution to patients receiving protease inhibitors as concomitant therapy.
04.6 Pregnancy and breastfeeding
There is no adequate information on the use of paclitaxel in pregnancy. Paclitaxel has been shown to be embryotoxic and foetotoxic in rabbits, and to reduce fertility in rats.
Like other cytotoxic agents, paclitaxel can cause fetal harm when administered to pregnant women, and therefore should not be used during pregnancy unless absolutely necessary. Women of childbearing potential should be advised not to become pregnant while on paclitaxel therapy and to notify the treating physician immediately if this occurs. Women and men of childbearing potential, and / or their partners should use a contraceptive for at least 6 months after paclitaxel treatment Male patients should inquire about sperm cryopreservation prior to paclitaxel treatment due to possible infertility.
Paclitaxel is contraindicated during lactation (see section 4.3). It is not known whether paclitaxel is excreted in human milk. It is recommended that lactation be discontinued during therapy.
04.7 Effects on ability to drive and use machines
TAXOL has not been shown to interfere with the ability to drive and use machines. However, the fact that TAXOL contains alcohol should be taken into account (see sections 4.4 and 6.1).
04.8 Undesirable effects
Unless otherwise specified, the following refers to a comprehensive safety database of 812 solid tumor patients treated with Taxol monotherapy in clinical trials. As the KS population is very specific, a special chapter based on a clinical trial with 107 patients is presented at the end of this section.
Unless otherwise reported, the frequency and severity of adverse events are generally similar in patients receiving TAXOL for the treatment of ovarian, breast or non-small cell lung cancer. None of the toxicities observed were clearly influenced by age.
A significant hypersensitivity reaction with possible fatal outcome (defined as hypotension requiring treatment, angioedema, respiratory distress syndromes requiring bronchodilator therapy, or generalized urticaria) occurred in 2 patients (
The most frequent significant side effect was the myelosuppression. Severe neutropenia, not associated with febrile episodes, occurred in 28% of patients. Only 1% of patients showed severe neutropenia for 7 or more days.
Thrombocytopenia was reported in 11% of patients. 3% of patients experienced a platelet count nadir 3 at least once during the study. Anemia was observed in 64% of patients but was considered severe (Hb hemoglobin.
When TAXOL was given in combination with cisplatin la neurotoxicity, mainly peripheral neuropathy, appeared more frequent and more severe at the dose of 175 mg / m2 infused over 3 hours (85% neurotoxicity, 15% severe) than with the 24 hour infusion of 135 mg / m2 (25% peripheral neuropathy, 3% severe) . In patients with non-small cell lung cancer and in patients with ovarian cancer treated with TAXOL as a three-hour infusion followed by cisplatin, there is an evident increase in the incidence of severe neurotoxicity. Peripheral neuropathy may occur after the first course of therapy and may worsen by increasing exposure to TAXOL. Peripheral neuropathy required the discontinuation of TAXOL in some cases.
Sensory symptoms generally improved or resolved several months after stopping TAXOL.
Pre-existing neuropathies, caused by previous therapies, are not a contraindication to therapy with TAXOL.
Arthralgia or myalgia they occurred in 60% of patients and were severe in 13% of cases.
Reactions at the infusion site during intravenous administration they can lead to localized edema, pain, erythema and induration; sometimes, the medicine leaking from the vessel can cause cellulite. Eschar formation and / or skin peeling, sometimes related to drug leakage from the vessel, have been reported. In addition, skin depigmentation can occur. Rarely, recurrence of skin reactions at the site of a previous extravasation has been reported following administration of TAXOL at a different site. A specific treatment for reactions due to drug extravasation is not yet known.
In some cases, the onset of the injection site reaction occurred during a prolonged infusion or with a delay of one week to 10 days.
The table below lists adverse reactions associated with administration of Taxol as a three-hour infusion as monotherapy, in the treatment of metastatic disease (in 812 patients in clinical trials) and as reported in the post-marketing surveillance * of Taxol.
The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100,
* as reported in the post-marketing surveillance.
Breast cancer patients who received TAXOL in adjuvant therapy after AC treatment experienced greater sensorineural toxicity, hypersensitivity reactions, arthralgia / myalgia, anemia, infection, fever, nausea / vomiting and diarrhea compared to patients treated with AC alone. However, the frequency of these events was consistent with the use of TAXOL alone, as reported above.
Combination treatment
The following refers to the two main clinical trials for the first-line treatment of ovarian cancer (TAXOL + cisplatin: over 1,050 patients); two Phase III clinical trials in first-line treatment of metastic breast cancer: one looked at the combination with doxorubicin (TAXOL + doxorubicin: 267 patients), another looked at the combination with trastuzumab (at a scheduled analysis of a subgroup TAXOL + trastuzumab: 188 patients) and two phase III clinical trials for the treatment of advanced non-small cell lung cancer (TAXOL + cisplatin: over 360 patients) (see section 5.1)
Given as a three-hour infusion schedule for the first-line treatment of ovarian cancer, neurotoxicity, arthralgia / myalgia and hypersensitivity were encountered more frequently and with features of greater severity in patients treated with TAXOL followed by cisplatin than in those treated with cyclophosphamide. followed by cisplatin. Myelosuppression appeared less frequent and less severe with TAXOL infused over three hours followed by cisplatin than with cyclophosphamide followed by cisplatin.
When TAXOL (220 mg / m2) was administered as a 3-hour infusion, 24 hours after doxorubicin (50 mg / m2) in first-line chemotherapy of metastatic breast cancer, they were reported more frequently and with greater severity: neutropenia , anemia, peripheral neuropathy, arthralgia / myalgia, asthenia, fever and diarrhea, compared with standard FAC therapy (5-FU 500 mg / m2, doxorubicin 50 mg / m2, cyclophosphamide 500 mg / m2). During treatment with TAXOL (220 mg / m2) / doxorubicin (50 mg / m2), nausea and vomiting were reported with less frequency and severity than with standard FAC therapy. The use of corticosteroids may have contributed to the lower frequency and severity of nausea and vomiting in the TAXOL / doxorubicin arm.
When TAXOL was administered as a 3-hour infusion in combination with trastuzumab for the first-line treatment of patients with metastatic breast cancer, the following events (regardless of their correlation with TAXOL or trastuzumab) were reported more frequently than with TAXOL alone: heart failure (8% vs 1%), infections (46% vs 27%), chills (42% vs 4%), fever (47% vs 23%), cough (42% vs 22%), rash (39% vs 18%), arthralgia (37% vs 21%), tachycardia (12% vs 4%), diarrhea (45% vs 30%), hypertonia (11% vs 3%), epistaxis (18% vs 4 %), acne (11% vs 3%), herpes simplex (12% vs 3%), accidental injury (13% vs 3%), insomnia (25% vs 13%), rhinitis (22% vs 5%), sinusitis (21% vs 7%) and injection site reaction (7% vs 1%). In some cases the differences in frequency may be due to the increase in the number and duration of treatments with the combination TAXOL / trastuzumab towards TAXOL in monotherapy. Serious events have been reported with similar rates in patients treated with TAXOL / trastuzumab and TAXOL alone.
When doxorubicin was given in combination with TAXOL in metastatic breast cancer, abnormality in cardiac contraction (≥ 20% reduction in left ventricular ejection fraction) were observed in 15% of patients versus 10% with standard FAC treatment. Congestive heart failure it was observed in less than 1% in both the TAXOL / doxorubicin and standard FAC arms.
Administration of trastuzumab in combination with TAXOL in patients previously treated with anthracyclines resulted in an increase in the frequency and severity of cardiac dysfunction compared to patients treated with TAXOL monotherapy (NYHA Class I / II 10% vs. 0%; NYHA Class III / IV 2% vs. 1%) and has rarely been associated with death (see Summary of Product Characteristics for trastuzumab)
In all but these rare cases, the patients responded to appropriate medical treatment.
Radiation pneumonia has been reported in patients undergoing concomitant radiotherapy.
AIDS-related Kaposi's sarcoma
Based on a clinical study including 107 patients, except for haematological and hepatic side effects (see below), the frequency and severity of side effects are generally similar for both patients treated for KS and patients treated with paclitaxel in monotherapy for other solid tumors.
Alterations of the blood and lymphatic system: myelosuppression was the most important dose-limiting toxicity.
Neutropenia is the most important haematological toxicity. During the first course of treatment, severe neutropenia occurred in 20% of patients.
During the entire treatment period, severe neutropenia was observed in 39% of patients. The duration of neutropenia was greater than 7 days in 41% and lasted 30-35 days in 8% of patients. In all followed patients, it resolved within 35 days. The incidence of Grade 4 neutropenia lasting 7 days or more was 22%.
Paclitaxel-related neutropenic fever was reported in 14% of patients and 1.3% of treatment cycles. There were 3 (2.8%) septic episodes during administration of paclitaxel, related to the drug, which were found to be fatal.
Thrombocytopenia was observed in 50% of patients and was severe in 9% of cases.
A decrease in platelet count 3 occurred in only 14% of cases, at least once during treatment. Paclitaxel-related bleeding episodes were reported in less than 3% of patients but the bleeding episodes were localized.
Anemia (Hb red blood cells was needed in 21% of patients.
Hepato-biliary disorders: Among patients (> 50% treated with protease inhibitors) with normal liver function at baseline, there was an increase in bilirubin, alkaline phosphatase and AST (SGOT), respectively, in 28%, 43% and 44%. For each of these parameters, the increases were severe in 1% of cases.
04.9 Overdose
There is no known antidote for TAXOL overdose. In the event of an overdose, the patient should be carefully monitored. Treatment should target the main expected toxicities, i.e. myelosuppression, peripheral neurotoxicity and mucositis. Overdose in pediatric patients may be associated with acute ethanol toxicity.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents (taxanes).
ATC code: L01C D01.
Paclitaxel is an antimicrotubular agent that promotes the aggregation of microtubules from tubulin dimers and stabilizes the microtubules preventing their depolymerization. This stabilization causes the inhibition of the normal dynamic reorganization of the microtubule structure, essential for the vital interphase and for the cellular mitotic functions Furthermore, paclitaxel induces the formation of abnormal aggregations or bundles of microtubules during the cell cycle and of multiple astrospheres of microtubules during mitosis.
Ovarian cancer
In first-line chemotherapy of ovarian cancer, the efficacy and safety of TAXOL were evaluated in two major, randomized, controlled clinical trials (vs cyclophosphamide 750 mg / m2 / cisplatin 75 mg / m2). In the Intergroup Study (B- MS CA139-209), more than 650 patients with stage IIb-c, III or IV primary ovarian cancer received a maximum of nine courses of treatment with TAXOL (175 mg / m2 over 3 hours) followed by cisplatin (75 mg / m2) or control. The second major study (GOG-111 / B-MS CA139-022) evaluated a maximum of 6 courses with TAXOL (135 mg / m2 in 24 hours) followed by cisplatin (75 mg / m2) or control , on more than 400 patients with stage III / IV primary ovarian cancer with residual disease> 1 cm after staging laparatomy, or with distant metastases. Although the two different posologies of TAXOL were not directly compared, in both studies patients treated with TAXOL in combination with cisplatin have mos found a significantly higher response rate, a longer time to progression and a longer survival time compared to standard therapy. "Increased neurotoxicity, arthralgia / myalgia, but less myelosuppression, compared to patients treated with cyclophosphamide / cisplatin, was observed in patients with advanced ovarian cancer treated with the three-hour infusion regimen of TAXOL / cisplatin.
Breast cancer
In the adjuvant treatment of breast cancer, 3,121 patients with node-positive breast cancer were treated with either adjuvant therapy with TAXOL or no chemotherapy after 4 courses of doxorubicin and cyclophosphamide (CALGB 9344, B-MS CA 139-223). The median of the follow up it has been 69 months. Generally, patients treated with TAXOL showed a significant 18% reduction in the risk of disease relapse compared to patients treated with AC alone (p = 0.0014) and a significant 19% reduction in the risk of death (p = 0 , 0044) compared to patients treated only with AC. Retrospective analyzes show benefit in all patient subgroups. In patients with tumors with hormone negative / unknown receptors, the reduction in the risk of disease relapse was 28% (95% CI: 0.59-0.86). In the subgroup of patients with hormone receptor positive tumors, the reduction in the risk of disease relapse was 9% (95% CI: 0.78-1.07). However, the study design did not evaluate the effect of continuing AC therapy beyond 4 cycles. It cannot be excluded, based on this study alone, that the observed effects may be partly due to the difference in the duration of chemotherapy between the two arms (AC 4 cycles; AC + TAXOL 8 cycles) Therefore, adjuvant treatment with TAXOL should be considered as an alternative to continuing AC therapy.
In a second large clinical trial in the adjuvant treatment of node-positive breast cancer with a similar design, 3060 patients were randomized to receive or not 4 courses of TAXOL at a higher dose of 225 mg / m2 after 4 courses of AC ( NSABP B-28, B-MS CA 139-270). At a median of 64 months of follow-up, patients treated with TAXOL showed a significant reduction of 17% in the risk of disease relapse compared to patients who received AC therapy alone (p = 0.006); TAXOL treatment was associated with a 7% reduction in the risk of death (95% CI: 0.78-1.12). All subgroup analyzes favored the TAXOL arm. In this study, patients with hormone receptor positive tumors showed a 23% reduction in the risk of disease relapse (95% CI: 0.6-0.92); in the subgroup of patients with hormone receptor negative cancer, the reduction in the risk of disease relapse was 10% (95% CI: 0.7-1.11).
In the first-line treatment of metastatic breast cancer, the efficacy and safety of TAXOL were evaluated in two pilot phase III, open-label, randomized, controlled clinical trials.
• In the first study (B-MS CA 139-278), the bolus combination of doxorubicin (50 mg / m2) followed after 24 hours by TAXOL (220 mg / m2 as a 3 hour infusion) (AT), was compared versus standard FAC treatment (5-FU 500 mg / m2, doxorubicin 50 mg / m2, cyclophosphamide 500 mg / m2), both administered every 3 weeks for eight cycles. In this randomized study, 267 patients with metastatic breast cancer were enrolled who, in the adjuvant treatment, had not received prior chemotherapy or had only received chemotherapy that did not contain anthracycline. The results showed a significant difference in time to progression for patients treated with AT versus those treated with FAC (8.2 vs 6.2 months; p = 0.029). Median survival was in favor of TAXOL / doxorubicin versus FAC (23.0 vs 18.3 months; p = 0.004). In the AT and FAC arm, 44% and 48% respectively received follow-up chemotherapy which included 7% and 50% taxanes, respectively. The overall response rate was also significantly higher in the AT arm than in the FAC arm (68% vs 55%). Complete responses were observed in 19% of patients in the TAXOL / doxorubicin arm versus 8% of patients in the FAC arm. All efficacy results were subsequently confirmed by a review independent in blind.
• In the second pilot study the efficacy and safety of TAXOL in combination with Herceptin were evaluated in a subgroup analysis (patients with metastatic breast cancer who received an "adjuvant anthracycline)" of the HO648g study. of Herceptin in combination with paclitaxel in patients who had not received adjuvant anthracyclines has not been verified. The combination of trastuzumab (4 mg / kg loading dose followed by 2 mg / kg every week) and TAXOL (175 mg / m2) as an infusion over three hours every three weeks was compared with TAXOL alone (175 mg / m2) m2) infused for three hours every three weeks in 188 patients with breast cancer with HER2 overexpression (2+ or 3+ measured by the immunohistochemical method) previously treated with anthracyclines. TAXOL was given every three weeks for at least 6 cycles while trastuzumab was given weekly until disease progression. The study showed a significant benefit for the TAXOL / trastuzumab combination in terms of time to progression (6.9 versus 3.0 months), response rate (41% versus 17%) and duration of response (10, 5 versus 4.5 months) compared to TAXOL alone. The most significant toxicity observed with the TAXOL / trastuzumab combination was cardiac dysfunction (see section 4.8).
Advanced non-small cell lung cancer
In the treatment of advanced non-small cell lung cancer, the combination of TAXOL 175 mg / m2 followed by 80 mg / m2 of cisplatin was evaluated in two phase III studies (367 patients treated with TAXOL). Both studies were randomized, one comparison with 100 mg / m2 of cisplatin, the other with 100 mg / m2 of teniposide, followed by 80 mg / m2 of cisplatin as a control regimen (367 patients in the comparator arm). The results of each study were similar. Preliminary mortality results did not show a significant difference between the TAXOL-containing regimen and the comparator regimen (median survival 8.1 and 9.5 months with the TAXOL-containing regimens, 8.6 and 9.9 months with the comparator regimens ).Similarly, there was no significant difference between treatments for progression-free survival. A significant benefit in terms of clinical response rate was demonstrated. The quality of life results suggest a benefit for TAXOL-containing regimens in terms of loss of appetite, and provide clear evidence of inferiority of TAXOL-containing regimens in terms of of peripheral neuropathy (p
AIDS-related Kaposi's sarcoma
In the treatment of AIDS-related Kaposi's sarcoma, the efficacy and safety of paclitaxel were investigated in a non-comparative study in patients with advanced KS previously treated with systemic chemotherapy.
The primary end point was best tumor response. Of the 107 patients, 63 were considered resistant to liposomal anthracyclines. This subgroup is considered to constitute the effective "core" population.
The overall response rate (complete / partial response) after 15 treatment cycles was 57% (CI 44-70%) in patients resistant to liposomal anthracyclines. More than 50% of the responses were obtained after the first 3 cycles.
In patients resistant to liposomal anthracyclines, the response rate in patients who had never received a protease inhibitor (55.6%) and in those who had received one at least 2 months prior to paclitaxel treatment (60.9%) , was comparable. Median time to progression in the core population was 468 days (95% CI 257 -NE).
Median survival could not be detected, but the lowest 95% band was 617 days in core patients.
05.2 Pharmacokinetic properties
Following intravenous infusion, paclitaxel exhibits a biphasic decrease in plasma concentrations.
Paclitaxel pharmacokinetics were determined after 3 and 24 hour infusions with doses of 135 mg / m2 and 175 mg / m2. The mean terminal half-life is considered to be in the range 3.0-52.7 hours and the mean values of total body clearance, according to a non-compartmental model, were in the range 11.6-24.0 l / h / m2. Total body clearance appears to decrease with higher paclitaxel plasma concentrations. The mean volume of distribution at steady state was in the range 198-688 L / m2 demonstrating extensive extravascular distribution and / or tissue binding. With the 3-hour infusion, progressively higher doses resulted in a non-linear pharmacokinetic profile. For the 30% dose increase, ie from 135 mg / m2 to 175 mg / m2, the Cmax and AUC0 values increased by 75% and 81%, respectively.
Following an intravenous dose of 100 mg / m2 given as a 3-hour infusion to 19 KS patients, the mean Cmax was 1,530 ng / ml (range 761-2,860 ng / ml) and the mean AUC was 5,619 ng • h / ml (range 2,609-9,428 ng • h / ml). Clearance was 20.6 L / h / m2 (range 11-38) and the volume of distribution was 291 L / m2 (range 121-638). The mean terminal elimination half-life was 23.7 hours (range 12-33).
Individual variability in systemic absorption of paclitaxel was minimal and there was no evidence of its accumulation following subsequent treatment courses.
Education in vitro protein binding to human serum indicates that 89-98% of the medicinal product is protein bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the protein binding of paclitaxel.
The distribution of paclitaxel in humans has not been fully understood. The mean cumulative urinary excretion values of unchanged drug ranged from 1.3% to 12.6% of the administered dose, demonstrating extensive non-renal clearance. hepatic metabolism and biliary clearance can be considered the main mechanisms influencing the elimination of paclitaxel.
Paclitaxel appears to be mainly metabolised by cytochrome P450 enzymes. After administration of radiolabelled paclitaxel, an average of 26%, 2% and 6% of the radioactivity is eliminated in the faeces as 6a-hydroxypaclitaxel, 3 "-p-hydroxypaclitaxel and 6a-3" -p-dihydroxyaclitaxel, respectively. The formation of these hydroxylated metabolites is catalysed by CYP2C8, CYP3A4, and by both CYP2C8 and CYP3A4, respectively. The effect of impaired renal or hepatic function on the elimination of paclitaxel after a 3-hour infusion has not been studied. The pharmacokinetic parameters obtained from a patient undergoing hemodialysis and who received a dose of TAXOL of 135 mg / m2, by means of a 3-hour infusion, they were within the expected range for patients not on dialysis.
In clinical studies where TAXOL and doxorubicin were administered concomitantly, the distribution and elimination of doxorubicin and its metabolites was prolonged. Total plasma exposure to doxorubicin was 30% higher when paclitaxel was administered immediately after doxorubicin compared to when there was a 24 hour interval between administrations.
For the use of TAXOL in combination with other therapies, please consult the Summary of Product Characteristics of the medicinal products of cisplatin, doxorubicin or trastuzumab for information on their use.
05.3 Preclinical safety data
The carcinogenic potential of TAXOL has not been studied. However, based on its mechanism of action, TAXOL appears to be a potential carcinogenic and genotoxic agent. TAXOL was found to be mutagenic in both mammalian cell systems in vitro that in vivo. Paclitaxel has been shown to be embryotoxic and foetotoxic in rabbits, and to reduce fertility in rats.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Anhydrous ethanol.
Chromatographically purified polyoxyethylated castor oil.
06.2 Incompatibility
Polyoxyethylated castor oil can cause release of DEHP, [di- (2-ethylhexyl) phthalate], from plastic containers containing polyvinyl chloride (PVC) at levels that increase with time and concentration. Consequently, the preparation, storage and administration of TAXOL, once diluted, must be done using PVC-free devices.
This medicinal product must not be mixed with other products except those mentioned in section 6.6
06.3 Period of validity
Before opening the vial:
2 years.
After opening and before dilution:
Chemical and physical stability studies have shown that the ready-made product is stable for 28 days at 25 ° C after repeated needle insertions and product withdrawal.
From a microbiological point of view, once opened, the product can be stored for no more than 28 days at 25 ° C. Other conditions and different storage periods are the responsibility of the user.
After dilution:
Chemical and physical stability studies have shown that the ready-to-infusion solution is stable at 5 ° C and 25 ° C for 7 days when diluted with 5% dextrose solution for injection, and for 14 days when diluted with 5% dextrose solution for injection. 0.9% sodium chloride.
From a microbiological point of view, the product should be used immediately. If not used immediately, other conditions and storage periods for the ready for infusion product are the responsibility of the user and would normally not be longer than 24 hours at 2 - 8 ° C, unless dilution has been carried out under controlled and validated aseptic conditions.
06.4 Special precautions for storage
Store below 25 ° C.
Store in the original package to protect the medicine from light.
Freezing does not adversely affect closed vials.
For storage conditions of the diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Different pack sizes are available in vials (type I glass) with stopper (butyl rubber) individually packed in a cardboard box:
one 5 ml vial containing 30 mg of paclitaxel
one 16.7 ml vial containing 100 mg of paclitaxel
one 25 ml vial containing 150 mg of paclitaxel
one 50 ml vial containing 300 mg of paclitaxel
Boxes containing 10 cartons are also available.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Handling :
Like all antineoplastic agents, TAXOL must be handled with care. The dilution of the medicinal product must be carried out under aseptic conditions in a specific area by trained personnel. Protective gloves must be used and all precautions taken to avoid contact with skin and mucous membranes. In case of contact with the skin, wash the area with water and soap Tingling, burning and redness have been observed following skin exposure. In case of contact with mucous membranes, wash with plenty of water. Dyspnoea, chest pain, burning throat and nausea have been reported following inhalation.
Closed vials, if refrigerated, may give rise to a precipitate which, after being brought back to room temperature, redissolves with light or no shaking. The quality of the product does not undergo alterations. If the solution remains cloudy and an insoluble precipitate is observed, the vial should be discarded.
Following repeated needle insertions and product withdrawals, the vials maintain microbiological, chemical and physical stability for up to 28 days at 25 ° C. Other conditions and different storage periods are the responsibility of the user.
The Chemo-Dispensing Pin device or similar piercing devices which could cause the stopper to fall inside the vial, with consequent loss of sterility of the product, should not be used.
Preparation of intravenous administration :
Prior to infusion, TAXOL must be diluted under aseptic conditions to a concentration of 0.3 - 1.2 mg / ml with 0.9% sodium chloride solution for injection, or 5% dextrose solution for injection, or 5% dextrose solution for injection and 0.9% sodium chloride, or 5% dextrose in Ringer's solution for injection.
Chemical and physical stability studies have shown that the ready-to-infusion solution is stable at 5 ° C and 25 ° C for 7 days when diluted with 5% dextrose solution for injection, and for 14 days when diluted with 5% dextrose solution for injection. 0.9% sodium chloride.
From a microbiological point of view, the product should be used immediately. If not used immediately, other conditions and storage periods for the ready-to-infuse product are the responsibility of the user and would normally not be longer than 24 hours at 2 - 8 ° C, unless dilution has been carried out under controlled and validated aseptic conditions. After dilution the solution is for single use only.
After dilution, the solutions may show turbidity, attributable to the vehicle of the formulation, which is not removed by filtration. It is therefore advisable to administer TAXOL through an in-line filter with a micro-pore membrane having a diameter of ≤ 0.22 mcm.
The simulated administration of the drug solution, using an intravenous infusion cannula equipped with an in-line filter, did not show a significant decrease in potency.
Precipitation has been reported rarely during administration of TAXOL, usually at the end of the 24 hour infusion period. Although the cause of this precipitation has not been clarified, it is probably due to the oversaturation of the diluted solution. To reduce the risk of precipitation, TAXOL must be used immediately after dilution, avoiding excessive shaking, agitation or vibration. Infusion sets should be thoroughly cleaned before use. During the infusion, constantly check the appearance of the solution, and immediately stop it in case of precipitation.
To minimize patient exposure to DEHP which can be released from PVC-containing materials (plastic bags and infusion sets or other medical-surgical aids), diluted solutions of TAXOL should be stored in non-PVC vials (glass, polypropylene ) or in plastic bags (polypropylene or polyolefin) and administered through polyethylene devices.
Filters (eg IVEX-2) incorporating short PVC inlet and outlet devices did not show significant sales of DEHP.
Disposal :
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Bristol-Myers Squibb S.r.l. Via Virgilio Maroso, 50 - Rome
08.0 MARKETING AUTHORIZATION NUMBER
5 ml vial containing 30 mg of paclitaxel: 028848012 / M.
16.7 ml vial containing 100 mg of paclitaxel: 028848024 / M
25 ml vial containing 150 mg of paclitaxel: 028848048 / M
50 ml vial containing 300 mg of paclitaxel: 028848036 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
September 2008
10.0 DATE OF REVISION OF THE TEXT
March 2013
