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

All patients must be pre-medicated with corticosteroids, antihistamines, and H₂antagonists prior to the treatment with Paclitaxel Ebetaxel 6 mg/ml concentrate for solution for infusion, e.g.:

^* 8-20 mg for KS patients
^** or an equivalent antihistamine e.g. chlorpheniramine

Paclitaxel Ebetaxel 6 mg/ml concentrate for solution for infusion should be administered through an “in-line” microporous membrane , pore size 0.22 µm (see 6.6)

First-line chemotherapy of ovarian carcinoma: Although other dosage regimens are under investigation, a combination regimen of paclitaxel and cisplatin is recommended. According to duration of infusion, two doses of paclitaxel are recommended: paclitaxel 175 mg/m² administered intravenously over 3 hours, followed by cisplatin at a dose of 75 mg/m² every three weeks or paclitaxel 135 mg/m², in a 24-hour infusion, followed by cisplatin 75 mg/m², with a 3 week interval between courses (see 5.1).

Second-line chemotherapy of ovarian carcinoma: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours, with a 3 week interval between courses.

Adjuvant chemotherapy in breast carcinoma: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours every 3 weeks for four courses, following AC therapy.

First-line chemotherapy of breast carcinoma: When used in combination with doxorubicin (50 mg/m²), paclitaxel 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 (see 4.5 and 5.1). When used in combination with trastuzumab, the recommended dose of paclitaxel is 175 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses (see 5.1). Paclitaxel infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated (for detailed trastuzumab posology see the Summary of Product Characteristics of Herceptin).

Second-line chemotherapy of breast carcinoma: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours, with a 3-week interval between courses.

Treatment of advanced NSCLC: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours, followed by cisplatin 80 mg/m², with a 3 week interval between courses.

Treatment of AIDS-related KS: The recommended dose of paclitaxel is 100 mg/m² administered as a 3-hour intravenous infusion every two weeks.

Subsequent doses of paclitaxel should be administered according to individual patient tolerance.

Paclitaxel should not be readministered until the neutrophil count is ≥1,500/mm³ (≥1,000/mm³ for KS patients) and the platelet count is ≥100,000/mm³ (≥75,000/mm³ for KS patients). Patients who experience severe neutropenia (neutrophil count <500/mm³ for ≥7 days) or severe peripheral neuropathy should receive a dose reduction of 20% for subsequent courses (25% for KS patients) (see 4.4).

Patients with hepatic impairment: Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see 4.4 and 5.2). 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.

There is no known antidote for paclitaxel overdosage. In case of overdose, the patient should be closely monitored. Treatment should be directed at the primary anticipated toxicities, which consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

Overdoses in paediatric patients may be associated with acute ethanol toxicity.

Vial before opening: 3 years.

After opening before dilution: Chemical and physical in-use stability has been demonstrated for 28 days at 25°C following multiple needle entries and product withdrawal. From a microbiological point of view, once opened the product may be stored for a maximum of 28 days at 25°C. Other in-use storage times and conditions are the responsibility of the user.

After dilution: Chemical and physical stability after dilution is documented for 48 hours at 25°C and at 2-8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Vial before opening: Store in the original container to protect from light.

For storage of the diluted medicinal product see section 6.3.

Type 1 glass vials (with butyl rubber stopper) containing 5ml, 16.7ml, 25ml, 50ml or 100ml of solution.

The 1, 5 or 10 vials are packaged with or without protective plastic overwrap (ONCO-SAFE) in a carton.

Not all pack sizes may be marketed.

Handling

As with all antineoplastic agents, caution should be exercised when handling paclitaxel.

Pregnant women or women of childbearing potential must be warned to avoid handling cytotoxic agents. Dilution should be carried out under aseptic conditions by trained personnel in a designated area. Adequate protective gloves should be worn. Contact with skin and mucous membranes should be avoided. In case of contact with skin, the skin should be washed with soap and water. Following topical exposure, tingling, burning and redness have been observed. In case of contact with the mucous membranes, these should be flushed thoroughly with water. Upon inhalation, dyspnoea, chest pain, burning throat and nausea have been reported.

If unopened vials are refrigerated, a precipitate may form that redissolves with little or no agitation upon reaching room temperature. Product quality is not affected. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded.

Following multiple needle entries and product withdrawals, the vials maintain microbial, chemical and physical stability for up to 28 days at 25°C. Other in-use storage times and conditions are the responsibility of the user.

Preparation for IV administration

Prior to infusion, paclitaxel must be diluted using aseptic techniques in 0.9% Sodium Chloride Injection, or 5% Dextrose Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection to a final concentration of 0.3 to 1.2 mg/ml.

Chemical and physical in-use stability of the solution prepared for infusion has been demonstrated at 5°C and at 25°C for 48 hours when diluted in 5% Dextrose solution, and for 48 hours when diluted in 0.9% Sodium Chloride Injection. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions. After dilution the solution is for single use only.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle, and is not removed by filtration. Paclitaxel should be administered through an in-line filter with a microporous membrane 0.22 µm. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line filter.

There have been rare reports of precipitation during paclitaxel infusions, usually towards the end of a 24 hour infusion period. Although the cause of this precipitation has not been elucidated, it is probably linked to the supersaturation of the diluted solution. To reduce the precipitation risk, paclitaxel should be used as soon as possible after dilution, and excessive agitation, vibration or shaking should be avoided. The infusion sets should be flushed thoroughly before use. During infusion, the appearance of the solution should be regularly inspected and the infusion should be stopped if precipitation is present.

To minimise patient exposure to DEHP, which may be leached from plasticised PVC infusion bags, sets, or other medical instruments, diluted Paclitaxel solutions should be stored in bottles without PVC (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Use of filter devices which incorporate short inlet and/or outlet plasticised PVC tubing has not resulted in significant leaching of DEHP.

Disposal

All items used for preparation, administration or otherwise coming into contact with paclitaxel should undergo disposal according to local guidelines for the handling of cytotoxic compounds.