EBETAXEL Concentrate for solution for infusion Ref.[50343] Active ingredients: Paclitaxel

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Since significant hypersensitivity reactions may occur, appropriate supportive 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 must be pretreated with corticosteroids, antihistamines and H2 antagonists (see 4.2).

Paclitaxel should be given before cisplatin when used in combination (see 4.5).

Significant hypersensitivity reactions characterised by dyspnoea and hypotension requiring treatment, angioedema and generalised urticaria have occurred in <1% of patients receiving paclitaxel after adequate premedication. These reactions are probably histamine-mediated. In the case of severe hypersensitivity reactions, paclitaxel infusion should be discontinued immediately, symptomatic therapy should be initiated and the patient should not be rechallenged with the drug.

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until neutrophils recover to ≥1,500/mm³ (≥1,000/mm³ for KS patients) and platelets recover to ≥100,000/mm³ (≥75,000/mm³ for KS patients). In the KS clinical study, the majority of patients were receiving granulocyte colony stimulating factor (G-CSF).

Severe cardiac conduction abnormalities have been reported rarely with single agent paclitaxel. If patients develop significant conduction abnormalities (e.g. atrioventricular conduction block, ventricular tachycardia) during paclitaxel administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel. Hypotension, hypertension, and bradycardia have been observed during paclitaxel administration; patients are usually asymptomatic and generally do not require treatment. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Severe cardiovascular events were observed more frequently in patients with NSCLC than breast or ovarian carcinoma. A single case of heart failure related to paclitaxel was seen in the AIDS-KS clinical study.

When paclitaxel is used in combination with doxorubucin or trastuzumab for initial treatment of metastatic breast cancer, attention should be placed on the monitoring of cardiac function. When patients are candidates for treatment with paclitaxel in these combinations, they should undergo baseline cardiac assessment including history, physical examination, ECG, echocardiogram, 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 more details see Summary of Product Characteristics of Herceptinor doxorubicin.

Although the occurrence of peripheral neuropathy is frequent, the development of severe symptoms is rare. In severe cases, a dose reduction of 20% (25% for KS patients) for all subsequent courses of paclitaxel is recommended. In NSCLC patients and in ovarian cancer patients treated in the first-line setting, the administration of paclitaxel as a three hour infusion in combination with cisplatin, resulted in a greater incidence of severe neurotoxicity than both single agent paclitaxel and cyclophosphamide followed by cisplatin.

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III-IV myelosuppression. There is no evidence that the 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 moderate to severe hepatic impairment. Patients should be monitored closely for the development of profound myelosuppression (see 4.2). Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see 5.2). No data are available for patients with severe baseline cholestasis. Patients with severe hepatic impairment should not be treated with paclitaxel.

Since paclitaxel contains ethanol (401.7 mg/ml), consideration should be given to possible CNS and other effects.

Special care should be taken to avoid intra-arterial application of paclitaxel, since in animal studies testing for local tolerance severe tissue reactions were observed after intra-arterial application.

Pseudomembranous colitis has been rarely reported including cases in patients who have not been concomitantly treated with antibiotics. This reaction should be considered in the differential diagnosis of cases of severe or persistent diarrhoea occurring during or shortly after treatment with paclitaxel.

Paclitaxel in combination with radiation of the lung, irrespective of their chronological order, may contribute to the development of interstitial pneumonitis.

In KS patients, severe mucositis is rare. If severe reactions occur, the paclitaxel dose should be reduced by 25%.

As Paclitaxel Ebetaxel 6 mg/ml concentrate for solution for infusion contains polyethoxyl castor oil (macrogolglycerol ricinoleate) it may cause severe allergic reactions.

Paclitaxel clearance is not affected by cimetidine premedication.

The recommended regimen of paclitaxel administration for the first-line chemotherapy of ovarian carcinoma is for paclitaxel to be given before cisplatin. When paclitaxel is given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single-agent use. When paclitaxel was given after cisplatin, patients showed a more profound myelosuppression and an approximately 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 (see 5.2).

The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and 3A4 (see 5.2). Clinical studies have demonstrated that CYP2C8-mediated metabolism of paclitaxel, to 6-hydroxypaclitaxel, is the major metabolic pathway in humans. Concurrent administration of ketoconazole, a known potent inhibitor of CYP3A4, does not inhibit the elimination of paclitaxel in patients; thus, both medicinal products may be administered together without dosage adjustment. Further data on the potential of drug interactions between paclitaxel and other CYP3A4 substrates/inhibitors are limited. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. erythromycin, fluoxetine, gemfibrozil) or induce (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) either CYP2C8 or 3A4.

Studies in KS patients, who were taking multiple concomitant medications, suggest that the systemic clearance of paclitaxel was significantly lower in the presence of nelfinavir and ritonavir, but not with indinavir. Insufficient information is available on interactions with other protease inhibitors. Consequently, paclitaxel should be administered with caution in patients receiving protease inhibitors as concomitant therapy.

There is no adequate data from the use of paclitaxel in pregnant women. Paclitaxel has been shown to be both embryotoxic and foetotoxic in rabbits, and to reduce fertility in rats. As with other cytotoxic medicinal products, paclitaxel may cause foetal harm when administered to pregnant women. Therefore, paclitaxel should not be used during pregnancy unless clearly necessary. 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.

Paclitaxel is contraindicated during lactation (see section 4.3 Contraindications). It is not known whether paclitaxel is excreted in human milk. Breastfeeding should be discontinued for the duration of therapy.

Paclitaxel has not been demonstrated to interfere with the ability to drive and use machines. However, it should be noted that paclitaxel does contain alcohol (see 4.4 and 6.1).

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent paclitaxel in clinical studies. As the KS population is very specific, a special chapter based on a clinical study with 107 patients, is presented at the end of this section.

The frequency and severity of undesirable effects, unless otherwise mentioned, are generally similar between patients receiving paclitaxel for the treatment of ovarian carcinoma, breast carcinoma, or NSCLC. None of the observed toxicities were clearly influenced by age.

The most frequent significant undesirable effect 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 percent 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.

A significant hypersensitivity reaction with possible fatal outcome (defined as hypotension requiring therapy, angioedema, respiratory distress requiring bronchodilator therapy, or generalised urticaria) occurred in two (<1%) of patients. Thirty-four percent 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.

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 below lists undesirable effects regardless of severity 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 undesirable effects listed below 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).; not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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 above.

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 5.1).

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.

AIDS-related Kaposi’s sarcoma: Except for haematologic and hepatic undesirable effects (see below), the frequency and severity of undesirable effects are generally similar between KS patients and patients treated with paclitaxel monotherapy for other solid tumours, based on a clinical study including 107 patients.

Blood and the lymphatic system disorders: bone marrow suppression was the major dose-limiting toxicity.

Neutropenia is the most important haematological toxicity. During the first course of treatment, severe neutropenia (<500 cells/mm³) occurred in 20% of patients. During the entire treatment period, severe neutropenia was observed in 39% of patients. Neutropenia was present for >7 days in 41% and for 30-35 days in 8% of patients. It resolved within 35 days in all patients who were followed. The incidence of Grade 4 neutropenia lasting 7 days was 22%.

Neutropenic fever related to paclitaxel was reported in 14% of patients and in 1.3% of treatment cycles. There were 3 septic episodes (2.8%) during paclitaxel administration related to the medicinal product that proved fatal.

Thrombocytopenia was observed in 50% of patients, and was severe (<50,000 cells/mm³) in 9%. Only 14% experienced a drop in their platelet count <75,000 cells/mm³, at least once while on treatment. Bleeding episodes related to paclitaxel were reported in <3% of patients, but the haemorrhagic episodes were localised.

Anaemia (Hb <11 g/dL) was observed in 61% of patients and was severe (Hb <8 g/dL) in 10%. Red cell transfusions were required in 21% of patients.

Hepato-biliary disorders: Among patients (>50% on protease inhibitors) with normal baseline liver function, 28%, 43% and 44% had elevations in bilirubin, alkaline phosphatase and AST (SGOT), respectively. For each of these parameters, the increases were severe in 1% of cases.

The polyethoxylated castor oil may result in DEHP [di(2-ethylhexyl)phthalate] leaching from plasticised polyvinylchloride (PVC) containers at levels which increase with time and concentration. Consequently, the preparation, storage and administration of diluted Paclitaxel should be carried out using non-PVC-containing equipment.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.