EPIRUBICIN HYDROCHLORIDE Solution for injection or infusion Ref.[8072] Active ingredients: Epirubicin

Epirubicin is for intravenous or intravesical use only.

The safety and efficacy of epirubicin in children has not been established

Intravenous administration

It is advisable to administer epirubicin via the tubing of a free-running intravenous saline infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation (see section 4.4). In case of extravasation, administration should be stopped immediately.

Conventional dose

When epirubicin is used as a single agent, the recommended dosage in adults is 60-90 mg/m² body area. Epirubicin should be injected intravenously over 3-5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient’s haematomedullary status.

If signs of toxicity, including severe neutropenia/neutropenic fever and thrombocytopenia occur (which could persist at day 21), dose modification or postponement of the subsequent dose may be required.

High dose

Epirubicin as a single agent for the high dose treatment of lung cancer should be administered according to the following regimens:

• Small cell lung cancer (previously untreated): 120 mg/m² day 1, every 3 weeks.

For high dose treatment, epirubicin may be given as an intravenous bolus over 3-5 minutes or as an infusion of up to 30 minutes duration.

Breast Cancer

In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of epirubicin ranging from 100 mg/m² (as a single dose on day 1) to 120 mg/m² (in two divided doses on days 1 and 8) every 3-4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen (in accordance with local guidelines) are recommended.

Lower doses (60-75 mg/m² for conventional treatment and 105-120 mg/m² for high dose treatment) are recommended for patients whose bone marrow function has been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone marrow infiltration. The total dose per cycle may be divided over 2-3 successive days.

The following doses of epirubicin are commonly used in monotherapy and combination chemotherapy for various tumours, as shown:

^a Doses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals

Combination therapy

If epirubicin is used in combination with other cytotoxic products, the dose should be reduced accordingly. Commonly used doses are shown in the table above. In establishing the maximal cumulative doses of Epirubicin (usually: 720 – 1000 mg/m²), any concomitant therapy with potentially cardiotoxic drugs should be taken into account.

Impaired liver function

The major route of elimination of epirubicin is the hepatobiliary system. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

* AST-aspartate aminotransferase

Impaired renal function

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route. Lower starting doses should be considered in patients with severe renal impairment (serum creatinine >450µmol/l).

Intravesical administration

Epirubicin can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be given intravesically for the treatment of invasive tumours that have penetrated the bladder wall, systemic therapy or surgery is more appropriate in these situations (see section 4.3). Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water).

If local toxicity is observed: A dose reduction to 30 mg/50 ml is advised.

Carcinoma-in-situ: Up to 80 mg/50 ml (depending on individual tolerability of the patient)

For prophylaxis: 4 weekly administrations of 50 mg/50 ml followed by 11 monthly instillations at the same dose.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

The solution should be retained intravesically for 1-2 hour. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void urine at the end of the instillation time.

Acute overdosage with epirubicin hydrochloride will result in severe myelosuppression (mainly leucopoenia and thrombocytopenia), gastrointestinal toxic effects (mainlymucosal inflammation) and acute cardiac complications. Latent cardiac failure has been observed with anthracyclines several months to years after completion of treatment (see section 4.4). Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment

Symptomatic. Epirubicin cannot be removed by dialysis.

Shelf life of the product as package for sale: 2 year.

Shelf life after first opening the container: The vials are for single use only and any unused portion must be discarded after use. From a microbiological point of view, the product should be used immediately after the first penetration of the rubber stopper. If not used immediately, in use storage times and conditions are the responsibility of the user.

Shelf life after dilution of the solution for injection: Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted, under aseptic conditions, in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. 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 not normally be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C-8°C). Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage after dilution, see section 6.3.

5 and 10 ml vials: Type I tubular glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white seal.

25 ml vial: Type I tubular glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white/royal blue seal.

50 ml vial: Type I clear moulded glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off royal blue seal.

100 ml vial: Type I clear moulded glass vial with 20 mm chlorobutyl RTS rubber stopper and aluminium flip-off white/royal blue seal.

Pack size: 1 vial.

Not all pack sizes may be marketed.

Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. For information on the stability of the infusion solutions, please refer to section 6.3.

The solution for injection or infusion contains no preservative and any unused portion of the vial should be discarded immediately in accordance with local requirements.

Guidelines for the safe handling and disposal of antineoplastic agents:

1. If an infusion solution is to be prepared, this should be performed by trained personnel under aseptic conditions.
2. Preparation of an infusion solution should be performed in a designated aseptic area.
3. Adequate protective disposable gloves, goggles, gown and mask should be worn.
4. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or 0.9% sodium chloride solution. Then seek medical evaluation by a physician.
5. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Always wash hands after removing gloves.
6. Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as detailed below.
7. Pregnant staff should not handle the cytotoxic preparation.
8. Adequate care and precautions should be taken in the disposal of items (syringes, needles etc) used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste material should be disposed of in accordance with local requirements.