Ebetaxel

Ebetaxel

paclitaxel

Manufacturer:

Sandoz

Distributor:

Zuellig
/
Firma Vai Hong
Full Prescribing Info
Contents
Paclitaxel.
Description
1 ml contains 6 mg of paclitaxel.
Excipients/Inactive Ingredients: Macrogol glycerol ricinoleate, water-free ethanol.
Action
Pharmacotherapeutic Group: Cytotoxic agent. ATC Code: L01C D01.
Pharmacology: Pharmacodynamics: Paclitaxel is a new anti-microtubular agent which promotes the formation of microtubules from tubulin dimers and stabilises the microtubules by preventing depolymerisation. This stability leads to a suppression of the normal dynamic reorganisation of the microtubule network that is essential for the vital cell functions in interphase and mitosis. Paclitaxel additionally induces the formation of abnormal rows or bundles of microtubules throughout the entire cell cycle and multiple star-like microtubule structures during mitosis.
The safety and efficacy of paclitaxel for first-line chemotherapy of ovarian cancer was evaluated in two large randomised controlled trials (versus 750 mg/m2 of cyclophosphamide and 75 mg/m2 of cisplatin). In the cross-group trial (B-MS CA 139-209) more than 650 patients with primary stage IIb-c, III or IV ovarian cancer received a maximum of 9 therapy courses with paclitaxel (175 mg/m2 over 3 hours), followed by cisplatin (75 mg/m2), or placebo. The second important trial (GOG 111/B-MS CA 139-022) comprised more than 400 patients with untreated stage III/IV ovarian cancer and residual tumours >1 cm after laparotomy, or peripheral metastases. They received a maximum of 6 therapy cycles with either paclitaxel (135 mg/m2 over 24 hours), followed by cisplatin (75 mg/m2) or a placebo. Although the two different dosages of paclitaxel were not directly compared with each other, in both trials the response rate of patients receiving paclitaxel-plus-cisplatin was significantly higher and progression-free survival and overall survival significantly prolonged in comparison to standard therapy.
In patients with advanced ovarian cancer receiving paclitaxel as a three-hour infusion, followed by cisplatin, the incidence of neurotoxicity and arthralgia/myalgia was increased, but the incidence of myelosuppression reduced, when compared to patients treated with cyclophosphamide-plus-cisplatin.
The efficacy and safety of paclitaxel in combination with Herceptin for first-line therapy of metastatic breast cancer were evaluated in a planned sub-group analysis of trial HO648g (patients with metastatic breast cancer previously receiving supportive treatment with anthracyclines). Efficacy of Herceptin in combination with paclitaxel in patients not previously undergoing supportive treatment with anthracyclines was not evaluated. The combination of trastuzumab (loading dose of 4 mg/kg, followed by 2 mg/kg weekly) and paclitaxel (175 mg/m2) as a three-hour infusion every 3 weeks was compared with single-use paclitaxel (175 mg/m2) as a three-hour infusion every 3 weeks in 188 patients with metastatic breast cancer overexpressing HER-2 (2+ or 3+; immunohistochemical measurement) and previously receiving anthracycline therapy. Paclitaxel was administered every 3 weeks for at least 6 therapy courses, trastuzumab was applied weekly until progression of the disease. The study demonstrated a significant benefit of paclitaxel-plus-trastuzumab compared to single-agent paclitaxel in terms of progression-free survival (6.9 vs. 3.0 months), response rate (41% vs. 17%) and duration of response (10.5 vs. 4.5 months).
Cardiac function impairment was found to be the most important toxic reaction in patients receiving paclitaxel-plus-trastuzumab (see Adverse Reactions).
For the treatment of advanced non-small-cell lung cancer, a therapy regimen consisting of 175 mg/m² of paclitaxel, followed by 80 mg/m² of cisplatin, was evaluated in two phase III trials (367 patients received paclitaxel). Both were randomised studies, one drawing a comparison to 100 mg/m² of cisplatin, the other to 100 mg/m² of teniposide, followed by 80 mg/m² of cisplatin (367 patients in the control group). Both studies exhibited similar results. With regard to mortality as the primary end point, no significant difference between the paclitaxel arm and the control arm was detected (median survival was 8.1 and 9.5 months in the paclitaxel group and 8.6 and 9.9 months in the control group). Likewise, there was no significant difference in progression-free survival. A significant benefit in clinical response was observed. Data on paclitaxel therapy conclude that the quality of life as regards loss of appetite is improved and show a clear disadvantage of paclitaxel with respect to the occurrence of peripheral neuropathy (p >0.008).
Pharmacokinetics: Intravenous administration of paclitaxel demonstrates a biphasic plasma clearance.
The pharmacokinetic data were derived after three-hour and 24-hour infusions of 135 mg/m2 and 175 mg/m2.
A mean terminal elimination half-life of 3-52.7 hours has been registered. The mean non-compartment-dependent values for overall body clearance range from 11.6 o 24 l/h/m2. Overall clearance of the drug from the body seems to decrease with higher paclitaxel concentrations in the plasma.
The steady-state volume of distribution of paclitaxel ranges from 198 to 688 l/h/m2, indicating extensive extravascular and/or tissue binding.
Increasing dose levels in a three-hour infusion exhibit non-linear pharmacokinetics. Increasing dosage by 30% from 135 mg/m2 to 175 mg/m2 results in an increase in Cmax and AUC0 values by 75% and 81%, respectively.
Intraindividual variability after systemic administration is minimal. No evidence of a cumulative effect of paclitaxel in several treatment courses has been found.
In vitro studies investigating the binding kinetics of paclitaxel to human plasma proteins have shown extensive plasma binding ranging from 89% to 98%. Cimetidine, ranitidine, dexamethasone or diphenhydramine had no impact on the protein binding capacity of paclitaxel.
The elimination pathways of paclitaxel in humans are currently not fully known.
The mean values for cumulative urinary recovery of unchanged paclitaxel range from 1.3 to 12.6% of the administered dose, indicating pronounced non-renal clearance. Paclitaxel is assumed to be primarily metabolised in the liver and excreted in the bile. Paclitaxel seems to be metabolised mainly through cytochrome P450 enzymes. After administration of radioactively marked paclitaxel, mean recovery of the radioactive substance in the faeces is 26% as 6α-hydroxy paclitaxel, 2% as 3'-p-hydroxy paclitaxel and 6% as 6α,3'-p-dihydroxy paclitaxel. The formation of these hydroxylated metabolites is catalysed by the iso-enzymes CYP2C8, -3A4 (-2C8 and -3A4). There are no current data on elimination after three-hour infusion of paclitaxel in patients with hepatic and renal infusion impairment. The pharmacokinetic parameters of a patient undergoing haemodyalysis who received 135 mg/m2 of paclitaxel as a three-hour infusion were similar to the values exhibited in non-dialysis patients.
If paclitaxel is to be combined with other therapeutic agents, please consult the prescribing information (SPC) for cisplatin- or trastuzumab-containing medicinal products to learn more about the use of these agents.
Toxicology: Preclinical safety data: Studies on the carcinogenic potential of paclitaxel have not been performed. Due to its pharmacodynamic reaction mechanism, however, paclitaxel is regarded as potentially carcinogenic and genotoxic.
Both in vitro and in vivo studies demonstrate that paclitaxel has a mutagenic effect on mammalian cells.
Indications/Uses
Ovarian cancer: Paclitaxel is indicated: as first-line chemotherapy for the treatment of ovarian cancer in patients with advanced ovarian cancer or residual tumours (>1 cm) after preceding laparotomy, in combination with cisplatin; for second-line chemotherapy of metastatic ovarian cancer in patients who have failed conventional therapeutic treatment with platinum-containing agents.
Breast cancer: Paclitaxel is indicated for initial treatment of advanced or metastatic breast cancer in combination with trastuzumab in patients overexpressing HER-2 at 3+ level (immunohistochemical evidence) for whom anthracycline therapy is not indicated (see Pharmacology: Pharmacodynamics under Actions and Precautions).
Paclitaxel given as a single agent is indicated for the treatment of metastatic breast cancer in patients where standardised anthracycline therapy has either failed or is not suitable.
Advanced non-small-cell lung cancer: Paclitaxel in combination with cisplatin is indicated for the treatment of non-small cell lung cancer in patients for whom a potentially curative surgical treatment and/or radiation therapy is not suitable.
Only insufficient data on the efficiency of paclitaxel for this indication are available; a summary of relevant trials is contained in Pharmacology: Pharmacodynamics under Actions.
Dosage/Direction for Use
All patients must receive pre-medication treatment with corticosteroids, antihistaminic agents and H2-antagonists prior to paclitaxel therapy: See Table 1.

Click on icon to see table/diagram/image

Paclitaxel should be administered using a microporous filter with a pore size of 0.22μm (in-line filter)-(see Cautions for Usage: Instructions for Use).
For strictly intravenous infusion after dilution.
First-line chemotherapy of ovarian cancer: Although other dosage regimens are currently being evaluated, a combination therapy with paclitaxel and cisplatin is recommended for first-line treatment of ovarian cancer. Depending on the duration of infusion, two dosage regimens of paclitaxel are recommended: Intravenous administration of 175mg/m² of body surface area (BSA) over 3 hours, followed by 75mg/m² of cisplatin every 3 weeks, or 135mg/m² of paclitaxel as an infusion over 24 hours, followed by 75mg/m² of cisplatin. A therapy-free interval of three weeks is recommended between therapy courses (see Pharmacology: Pharmacodynamics under Actions).
Second-line chemotherapy of ovarian cancer: The recommended dosage is 175 mg/m2 of body surface area, administered as a three-hour infusion, with an interval of three weeks between therapy courses.
First-line chemotherapy of breast cancer: When used in combination with doxorubicin (50 mg/m2), paclitaxel 6 mg/ml should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m2 administered intravenously over a period of 3 hours, with a 3-week interval between courses.
In combination with trastuzumab the recommended dosage of paclitaxel is 175mg/m² BSA, administered intravenously over 3 hours, with an interval of 3 weeks between therapy courses (see Pharmacology: Pharmacodynamics under Actions). Paclitaxel infusion may be initiated the day after the first dose of trastuzumab, or immediately after a follow-up dose of trastuzumab if the previous trastuzumab dose was well tolerated (for details on the use of trastuzumab see the SPC for Herceptin).
Second-line chemotherapy of breast cancer: The recommended dosage of paclitaxel is 175 mg/m2 BSA, administered over 3 hours, with an interval of 3 weeks between therapy courses.
Treatment of advanced non-small-cell lung cancer: The recommended dosage of paclitaxel is 175 mg/m2 BSA, administered over 3 hours, followed by 80 mg/m2 of cisplatin, with an interval of 3 weeks between therapy courses.
Subsequent dosing of paclitaxel depends on individual patient tolerance levels.
Treatment with paclitaxel should only be continued after blood counts with at least 1,500/mm3 of neutrophils and at least 100,000/mm3 of platelets have been achieved. If patients develop severe neutropenia (with neutrophils < 500/mm3 for 7 days or longer) or severe peripheral neuropathy, dosage should be reduced by 20% in subsequent courses (see Precautions).
Patients with hepatic impairment: inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see Pharmacology: Pharmacokinetics under Actions and Precautions). Patients with severe hepatic impairment should not be treated with paclitaxel.
Paediatric use: Paclitaxel is not recommended for use in children below 18 years due to lack of data on safety and efficacy.
Overdosage
There is no specific antidote to remedy a paclitaxel overdose. In case of overdose, the patient should be closely monitored. Initial symptoms of paclitaxel overdosage may be bone marrow depression, peripheral neuropathy and mucositis.
Contraindications
Paclitaxel is contraindicated in patients who have shown severe hypersensitivity reactions to either paclitaxel or any of the excipients of the medicinal product, in particular macrogol glycerol ricinoleate (see Precautions).
Paclitaxel is contraindicated during pregnancy and lactation (see Use in Pregnancy and Lactation) and must not be given to patients with an initial blood count of <1500/mm³ for neutrophils.
Special Precautions
Paclitaxel should only be administered by specially trained physicians with experience in the use of tumour therapy. Adequate emergency equipment must be kept ready as severe hypersensitivity reactions may occur.
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Patients must undergo prior treatment with corticosteroids, antihistaminic agents and H2 antagonists (see Dosage & Administration).
In combination therapy with cisplatin, paclitaxel must be given initially (see Interactions).
Severe anaphylactic reactions characterised by dyspnoea and hypotension requiring treatment, angioedema and generalised urticaria may occur in less than 1% of patients receiving paclitaxel despite pre-medication treatment. These reactions may be a result of histamine release. In case of severe hypersensitivity reactions, paclitaxel infusion must be discontinued immediately and a symptomatic therapy be initiated. Repeated treatment courses with paclitaxel are contraindicated in these patients.
Myelosuppression (primarily neutropenia) is a dose-limiting reaction. Frequent monitoring of haematological parameters is indicated. Treatment should only be continued after blood counts have adequately recovered and demonstrate neutrophils of at least 1,500/mm³ and platelets of at least 100,000/mm³.
Severe impulse conduction disorders in the heart have been rarely reported after administration of paclitaxel as a single agent. If severe disorders of impulse conduction during paclitaxel therapy occur, adequate treatment should be initiated and careful regular monitoring of the cardiac function must be performed throughout subsequent paclitaxel therapy courses.
Hypotension, hypertension and bradycardia have been observed during paclitaxel therapy; patients were generally asymptomatic and did not require treatment.
Frequent monitoring of vital parameters, especially in the first hour of paclitaxel infusion, is recommended. Severe cardiovascular side effects were more frequently observed in patients with non-small-cell lung cancer than in patients with breast or ovarian cancer.
If paclitaxel is concurrently used with doxorubicin or trastuzumab for initial treatment of metastatic breast cancer, careful monitoring of the cardiac function must be performed.
Patients for whom this combination therapy is recommended should undergo initial examination of the heart including a case history, clinical examination, ECG, echocardiography and/or MUGA scan. Cardiac function should be further monitored during treatment (e.g. every three months). Monitoring may help to identify patients who develop cardiac dysfunction and treating physicians should carefully assess the cumulative dose (mg/m2) of anthracycline administered when making decisions regarding frequency of ventricular function assessment. When testing indicates deterioration in cardiac function, even asymptomatic, treating physicians should carefully assess the clinical benefits of further therapy against the potential for producing cardiac damage, including potentially irreversible damage. If further treatment is administered, monitoring of cardiac function should be more frequent (e.g. every 1-2 cycles). For further information see SPC for Trastuzumab or Doxorubicin.
Peripheral neuropathy commonly occurs during treatment with paclitaxel, but severe symptoms rarely develop. In case of severe peripheral neuropathies a dose reduction by 20% in subsequent treatment courses is recommended.
In patients with non-small-cell lung cancer or ovarian cancer receiving first-line therapy, administration of paclitaxel as a three-hour infusion in combination with cisplatin, neurotoxicity was more common than in patients who were either treated with paclitaxel alone or cyclophosphamide followed by cisplatin.
Patients with hepatic impairment may be at increased risk of toxicity, particularly Grade 3-4 myelosuppression. There is no evidence that toxicity of paclitaxel is increased when given as a 3-hour infusion to patients with mildly abnormal liver function. When paclitaxel is given as a longer infusion, increased myelosuppression may be seen in patients with mild to moderate hepatic impairments. Patients should be monitored closely for the development of profound myelosuppression. Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments. No data are available for patients with severe baseline cholestasis. Patients with severe hepatic impairment must not be treated with paclitaxel.
Since paclitaxel contains ethanol (401.66 mg/ml), attention must be paid to a potential impact on the central nervous system or other effects.
Intraarterial application of paclitaxel must be strictly avoided as in animal studies this mode of application has caused severe tissue reactions.
Pseudomembranous colitis has been rarely reported; in some of the cases patients did not receive concomitant therapy with antibiotics. This should be kept in mind in the differential diagnosis of severe or persistent diarrhoea which occurs during or shortly after paclitaxel therapy.
If the use of paclitaxel is combined with radiation therapy on the lungs, irrespective of the order of treatment, it may contribute to the development of interstitial pneumonitis.
Effects on the ability to drive and use machines: Paclitaxel has not been shown to impair the ability to drive and use machines. However, it should be taken into consideration that paclitaxel contains ethanol (see Excipients/Inactive Ingredients under Description and Precautions.).
Use In Pregnancy & Lactation
Paclitaxel has demonstrated an embryotoxic and foetotoxic effect in rabbits and has been shown to reduce fertility in rats.
Data on the use of paclitaxel in pregnant women are not available. As with any other cytotoxic agents, the use of paclitaxel during pregnancy may result in a potential hazard to the foetus and is therefore contraindicated during pregnancy.
Women of childbearing potential receiving paclitaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur. Female and male patients of fertile age, and/or their partners should use contraceptions for at least 6 months after treatment with paclitaxel. Male patients should seek advice regarding cryoconservation of sperm prior to treatment with paclitaxel because of the possibility of infertility.
It is not known whether paclitaxel is secreted into human milk.
Paclitaxel is contraindicated during breast-feeding. Breast-feeding should be discontinued before treatment with paclitaxel.
Adverse Reactions
Unless indicated otherwise, the frequency and severity of adverse effects were generally similar in patients receiving paclitaxel for the treatment of ovarian cancer, breast cancer or non-small-cell lung cancer (NSCLC). No association has been established between the age of the patients and any occurring adverse effects. A significant hypersensitivity reaction with possible fatal outcome (defined as hypotension requiring therapy, angiooedema, respiratory distress requiring bronchodilator therapy, or generalised urticaria) occurred in two (<1%) patients. Thirty-four per cent of patients (17% of all courses) experienced minor hypersensitivity reactions. These minor reactions, mainly flushing and rash, did not require therapeutic intervention nor did they prevent continuation of paclitaxel therapy.
The most frequent significant adverse event was bone marrow suppression. Severe neutropenia (< 500 cells/mm³) occurred in 28% of patients, but was not associated with febrile episodes. Only 1% of patients experienced severe neutropenia for ≥7 days. Thrombocytopenia was reported in 11% of patients. Three per cent of patients had a platelet count nadir <50,000/mm³ at least once while on study. Anaemia was observed in 64% of patients, but was severe (Hb <5 mmol/l) in only 6% of patients. Incidence and severity of anaemia is related to baseline haemoglobin status.
Neurotoxicity, mainly peripheral neuropathy, appeared to be more frequent and severe with a 175 mg/m2 3-hour infusion (85% neurotoxicity, 15% severe) than with a 135 mg/m2 24-hour infusion (25% peripheral neuropathy, 3% severe) when paclitaxel was combined with cisplatin. In NSCLC patients and in ovarian cancer patients treated with paclitaxel over 3 hours followed by cisplatin, there is an apparent increase in the incidence of severe neurotoxicity. Peripheral neuropathy can occur following the first course and can worsen with increasing exposure to paclitaxel. Peripheral neuropathy was the cause of paclitaxel discontinuation in a few cases. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy.
Arthralgia or myalgia affected 60% of patients and was severe in 13% of patients.
Injection site reactions during intravenous administration may lead to localised oedema, pain, erythema, and induration; on occasion, extravasation can result in cellulitis. Skin sloughing and/or peeling has been reported, sometimes related to extravasation. Skin discoloration may also occur. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e. "recall", has been reported rarely. A specific treatment for extravasation reactions is unknown at this time. In some cases, the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.
The table as follows lists adverse reactions associated with the administration of single agent paclitaxel administered as a three hour infusion in the metastatic setting (812 patients treated in clinical studies) and as reported in the postmarketing surveillance* of paclitaxel.
The frequency of adverse reactions listed as follows is defined using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Click on icon to see table/diagram/image

Breast cancer patients who received paclitaxel in the adjuvant setting following AC experienced more neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anaemia, infection, fever, nausea/vomiting and diarrhoea than patients who received AC alone. However, the frequency of these events was consistent with the use of single agent paclitaxel, as reported previously.
Combination treatment: The following discussion refers to two major trials for the first-line chemotherapy of ovarian carcinoma (paclitaxel + cisplatin: over 1050 patients); two phase III trials in the first line treatment of metastatic breast cancer: one investigating the combination with doxorubicin (paclitaxel + doxorubicin: 267 patients), another one investigating the combination with trastuzumab (planned subgroup analysis paclitaxel + trastuzumab: 188 patients) and two phase III trials for the treatment of advanced NSCLC (paclitaxel + cisplatin: over 360 patients) (see Pharmacology: Pharmacodynamics under Actions).
When administered as a three hour infusion for the first-line chemotherapy of ovarian cancer, neurotoxicity, arthralgia/myalgia, and hypersensitivity were reported as more frequent and severe by patients treated with paclitaxel followed by cisplatin than patients treated with cyclophosphamide followed by cisplatin.
Myelosuppression appeared to be less frequent and severe with paclitaxel as a three hour infusion followed by cisplatin compared with cyclophosphamide followed by cisplatin.
For the first line chemotherapy of metastatic breast cancer, neutropenia, anaemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhoea were reported more frequently and with greater severity when paclitaxel (220 mg/m²) was administered as a 3-hour infusion 24 hours following doxorubicin (50 mg/m²) when compared to standard FAC therapy (5-FU 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²). Nausea and vomiting appeared to be less frequent and severe with the paclitaxel (220 mg/m²)/doxorubicin (50 mg/m²) regimen as compared to the standard FAC regimen. The use of corticosteroids may have contributed to the lower frequency and severity of nausea and vomiting in the paclitaxel/doxorubicin arm.
When paclitaxel 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 relationship to paclitaxel or trastuzumab) were reported more frequently than with single agent paclitaxel: heart failure (8% vs. 1%), infection (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%), diarrhoea (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%). Some of these frequency differences may be due to the increased number and duration of treatments with paclitaxel/trastuzumab combination vs. single agent paclitaxel. Severe events were reported at similar rates for paclitaxel/trastuzumab and single agent paclitaxel. When doxorubicin was administered in combination with paclitaxel in metastatic breast cancer, cardiac contraction abnormalities (≥20% reduction of left ventricular ejection fraction) were observed in 15% of patients vs. 10% with standard FAC regimen. Congestive heart failure was observed in <1% in both paclitaxel/doxorubicin and standard FAC arms. Administration of trastuzumab in combination with paclitaxel in patients previously treated with anthracyclines resulted in an increased frequency and severity of cardiac dysfunction in comparison with patients treated with paclitaxel single agent (NYHA Class I/II 10% vs. 0%; NYHA Class III/IV 2% vs. 1%) and rarely has been associated with death (see trastuzumab Summary of Product Characteristics). In all but these rare cases, patients responded to appropriate medical treatment.
Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.
Drug Interactions
Treatment with cimetidine has no influence on paclitaxel clearance.
In the first-line therapy of ovarian cancer, the recommended treatment regimen is to give paclitaxel before cisplatin. If paclitaxel is administered prior to cisplatin, the safety profile is similar to the use of paclitaxel as a single agent. Administration of paclitaxel after cisplatin has led to an increase in myelotoxicity and a 20% decrease in paclitaxel clearance. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers.
Since the elimination of doxorubicin and its active metabolites can be reduced when paclitaxel and doxorubicin are given closer in time, paclitaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin.
The metabolisation of paclitaxel is catalysed by the cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see Pharmacology: Pharmacokinetics under Actions). Clinical trials have shown that CYP2C8-mediated metabolisation to 6α-hydroxy paclitaxel is the main step in the human metabolism. Concomitant use of ketokonazole, which is known as a strong inhibitor of CYP3A4, does not inhibit the elimination of paclitaxel in patient. Therefore no further dose adjustment is necessary in the combination therapy of paclitaxel and ketoknoazole. Since additional data on paclitaxel and other CYP3A4 substrates/inhibitors are limited, special care must be exercised when using paclitaxel in combination with known substrates or inhibitors of CYP3A4.
Caution For Usage
Instructions for Use: Handling: As with other cytotoxic agents, utmost caution should be exercised when handling paclitaxel.
Dilution of paclitaxel should take place in a designated area under aseptic conditions and be carried out by specially trained medical staff. The use of protective gloves is recommended. Contact with skin or mucous membranes must be strictly avoided. If skin contact occurs, immediate washing with water and soap is required. Upon direct contact a tingling and burning feeling and redness of the skin have been observed.
In case of contamination of the eyes, immediate rinsing with water and medical assistance are needed.
Pregnant women should be excluded from the handling of paclitaxel. Dyspnoea, thoracic pain, throat burning and nausea were reported after inhalation.
Guidelines for the handling and disposal of cytotoxic agents must be observed.
Caution should be exercised when handling paclitaxel. Contact with skin should be avoided.
The use of chemo-dispensing pins or any other pointed devices is not recommended as they may cause the stopper to collapse, sacrificing sterility of the paclitaxel solution.
Preparation of an intravenous infusion: Prior to infusion, Ebetaxel must be diluted under aseptic conditions in 0.9% sodium chloride injection or 5% glucose injection or 5% glucose and 0.9% sodium chloride solution up to a final concentration of 0.3 to 1.2 mg/ml. Chemical and physical stability of the reconstituted solution has been demonstrated for up to 48 hours (including preparation and application) at room temperature (approx. 25°C) and exposure to light. Diluted solutions should not be stored in the refrigerator.
Streaks may appear in the solution after dilution, which result from the solvent and cannot be eliminated through filtration. Infusion of Ebetaxel must take place using a filter (in-line filter) with a microporous membrane and a pore size of <0.22 µm. In a trial with a respective infusion system using an in-line filter no significant efficiency loss was detected.
In rare cases the formation of precipitates, mostly towards the end of a 24-hour infusion of Ebetaxl, was observed. These precipitates may be an indication of oversaturation of the diluted solution. Ebetexel should be used immediately after reconstitution to reduce the risk of precipitates. Excessive handling, vibrations or shaking should be avoided. Infusion sets should be carefully flushed prior to use. The solution should be closely inspected for any signs of precipitates throughout the infusion; if precipitates are observed, the infusion should be discontinued.
To minimise patient exposure to DEHP, which may be leached from PVC infusion bags, sets or other medicinal instruments, Ebetaxel preparations should only be stored in non-PVC-containing bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined infusion sets. The use of filtering devices with short PVC inlet or outlet tubing does not lead to a significant release of DEHP.
Incompatibilities: Ebetaxel as well as reconstituted paclitaxel solutions must not get in contact with containers or medical devices made of or containing PVC as the excipient macrogol glycerol ricinoleate may cause leaching of the plasticizer di-(2-ethoxyhexyl) phthalate (DEHP).
The leached amount is time- and concentration-dependent. This applies to the manufacturing and storage as well as to the administration of paclitaxel solutions. Paclitaxel should be administered by using polyethylene-lined infusion sets.
The use of filtering devices with short PVC-coated inlet or outlet tubing has not resulted in significant leaching of DEHP.
Storage
Do not store above 25°C. Keep container in the outer carton.
Freezing may result in precipitates, which redissolve at room temperature (25°C). If haziness of the solution persists or the precipitates do not dissolve, the vial must be discarded. Freezing does not impair the stability of the medicinal product.
The reconstituted solution for infusion need not be protected from light for the time of infusion.
Do not store diluted solutions in the refrigerator to avoid precipitation.
Shelf life: 3 years. Use within 28 days after opening.
The reconstituted solution for infusion can be stored for up to 48 hours if used in combination with an in-line filter.
ATC Classification
L01CD01 - paclitaxel ; Belongs to the class of plant alkaloids and other natural products, taxanes. Used in the treatment of cancer.
Presentation/Packing
Conc for soln for infusion (vial; clear, colourless to pale yellowish solution) 6 mg/mL x 1's.
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