PHARMORUBICIN Solution for injection or infusion Ref.[27631] Active ingredients: Epirubicin

Posology

Pharmorubicin is not active when given orally and should not be injected intramuscularly or intrathecally.

It is advisable to give the drug via the tubing of a freely-running IV saline infusion after checking that the needle is well placed in the vein. This method minimises the risk of drug extravasation and makes sure that the vein is flushed with saline after the administration of the drug. Extravasation of Pharmorubicin from the vein during injection may give rise to severe tissue lesions, even necrosis. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.

Conventional doses

When Pharmorubicin is used as a single agent, the recommended dosage in adults is 60-90 mg/m² body area; the drug should be injected I.V. over 3-5 minutes and, depending on the patient’s haematomedullary status, the dose should be repeated at 21-day intervals.

High doses

Pharmorubicin as a single agent for the treatment of lung cancer at high doses should be administered according to the following regimens:

Lung cancer:

• Small cell lung cancer (previously untreated): 120 mg/m² day 1, every 3 weeks.
• Non small cell lung cancer (squamous, large cell, and adenocarcinoma previously untreated): 135 mg/m² day 1 or 45 mg/m² days 1, 2, 3, every 3 weeks.

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, are recommended.

The drug should be given as an I.V. bolus over 3-5 minutes or as an infusion up to 30 minutes. Lower doses (60-75 mg/m² for conventional treatment and 105-120 mg/m² for high dose schedules) are recommended for patients whose bone marrow function has already 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.

When the drug is used in combination with other antitumour agents, the doses need to be adequately reduced. Since the major route of elimination of Pharmorubicin is the hepatobiliary system, the dosage should be reduced in patients with impaired liver function, in order to avoid an increase of overall toxicity. Moderate liver impairment (bilirubin: 1.4-3 mg/100 ml) requires a 50% reduction of dose, while severe impairment (bilirubin >3mg/100 ml) necessitates a dose reduction of 75%.

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of Pharmorubicin excreted by this route.

Intravesical administration

Pharmorubicin can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be used in this way for the treatment of invasive tumours which have penetrated the bladder wall where systemic therapy or surgery is more appropriate. Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours in order to prevent recurrences.

While many regimens have been used, the following may be helpful as a guide: for therapy, 8 x weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water). In the case of local toxicity (chemical cystitis), a dose reduction to 30 mg/50ml is advised. For carcinoma-in-situ, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg/50 ml. For prophylaxis, 4 x weekly administrations of 50 mg/50 ml, followed by 11 x monthly instillations at the same dosage, is the schedule most commonly used.

The solution should be retained intravesically for 1 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 at the end of the instillation time.

Acute overdosage with epirubicin will result in severe myelosuppression (mainly leucopoenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucosal 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.

a) Shelf life of the product as package for sale:

Glass vials: 3 years.

Polypropylene Cytosafe vials: 3 years.

b) Shelf life after first opening the container:

Pharmorubicin Solution for Injection does not contain a preservative or bacteriostatic agent. Vials are, therefore 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 first penetration of the rubber stopper. If not used immediately, in use storage times and conditions are the responsibility of the user.

Store at 2°C-8°C (in a refrigerator).

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

Storage of the solution for injection or infusion at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15-25°C). Solution for injection or infusion should be used within 24 hours after removal from refrigeration.

Colourless glass 5ml, 10ml, 25ml, or 100ml vial (type I), with Teflon-faced chlorobutyl rubber bung and aluminium cap with inset grey polypropylene disk.

Colourless polypropylene 5ml, 10ml, 25ml or 100ml vial with Teflon faced halobutyl-rubber stopper and aluminium cap with plastic flip-off top.

Intravenous administration. Epirubicin should be administered into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride). To minimize the risk of thrombosis or perivenous extravasation, the usual infusion times range between 3 and 20 minutes depending upon dosage and volume of the infusion solution. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration (see section 4.4).

Discard any unused solution.

Intravesical administration. Epirubicin should be instilled using a catheter and retained intravesically for 1 hour. During instillation, the patient should be rotated to ensure that the vesical mucosa of the pelvis receives the most extensive contact with the solution. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. The patient should be instructed to void at the end of the instillation.

Protective measures: The following protective recommendations are given due to the toxic nature of this substance:

Personnel should be trained in good technique for reconstitution and handling.

• Pregnant staff should be excluded from working with this drug.
• Personnel handling epirubicin should wear protective clothing: goggles, gowns and disposable gloves and masks.
• A designated area should be defined for reconstitution (preferably under a laminar flow system); the work surface should be protected by disposable, plastic-backed, absorbent paper.
• All items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high temperature incineration. 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 indicated previously.
• 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. In case of contact with the eye(s), hold back the eyelid of the affected eye(s) and flush with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.
• Always wash hands after removing gloves.