DOXORUBICIN Concentrate for solution for infusion Ref.[7916] Active ingredients: Doxorubicin

Doxorubicin Injection should be administered only under the supervision of a qualified physician with extensive experience in cytotoxic treatment. Also, patients must be carefully and frequently monitored during the treatment (see section 4.4).

Due to the risk of often lethal cardiomyopathy, the risks and benefits of the individual patient should be weighted before each application.

Doxorubicin is administered intravenously and intravesically and must not be administered orally, subcutaneously, intramuscularly or intrathecally. Doxorubicin can be administered intravenously as bolus within minutes, as short infusion for up to an hour or as continuous infusion for up to 96 hours.

The solution is given via the tubing of a freely running intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection within 2 to 15 minutes. This technique minimises the risk of thrombophlebitis or perivenous extravasation, which can lead to severe local cellulites, vesication and tissue necrosis. A direct intravenous injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration.

Intravenous administration

The dosage of doxorubicin depends on dosage regimen, general status and previous treatment of the patient. Dose schedule of doxorubicin hydrochloride administration could vary according to indication (solid tumors or acute leukemia) and according to its use in the specific treatment regimen (as single agent or in combination with other cytotoxic agents or as a part of multidisciplinary procedures that include combination of chemotherapy, surgical procedure and radiotherapy and hormonal treatment).

Monotherapy

Dosage is usually calculated on the basis of body surface area (mg/m²). On this basis, a dose of 60-75 mg/m² body surface area is recommended every three weeks when doxorubicin is used as a single agent.

Combination regimen

When doxorubicin hydrochloride is administered in combination with other antitumour agents with overlapping toxicity, such as high-dose i.v. cyclophosphamide or related anthracycline compounds such as daunorubicin, idarubicin and/or epirubicin, the dosage of doxorubicin should be reduced to 30-60 mg/m² every 3–4 weeks.

In patients, who cannot receive the full dose (eg. in case of immunosuppression, old age), an alternative dosage is 15-20 mg/m² body surface per week.

Intravesical administration

Doxorubicin may be used by intravesical instillation for the treatment of superficial bladder carcinoma or in prophylaxis of tumor recurrence after transurethral resection (T.U.R) in patients with high risk of recurrence. The recommended doxorubicin hydrochloride dose for local intravesical treatment of superficial bladder tumors is instillation of 30-50 mg in 25-50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. The optimal concentration is about 1 mg/ml. Generally the solution should be retained intravesically for 1 to 2 hours. During this period the patient should be turned 90° every 15 minutes. The patient should not drink fluids for 12 hours prior to the treatment to avoid undesired dilution with urine (this should reduce the production of urine to about 50 ml/h). The instillation may be repeated with an interval of 1 week to 1 month, dependent on whether the treatment is therapeutic or prophylactic.

Patients with impaired hepatic function

Since doxorubicin hydrochloride is mainly excreted via liver and bile, the elimination of the medicinal product may be decreased in patients with hepatic function impairment or bile flow obstruction and this could result in severe secondary effects.

General dose adjustment recommendations in patients with hepatic function impairment are based on serum bilirubin concentration:

Doxorubicin is contraindicated in patients with severe liver function disorder (see section 4.3).

Patients with impaired renal function

In patients with renal insufficiency (GFR < 10 ml/min), only 75% of the planned dose should be given.

In order to avoid cardiomyopathy, it is recommended that the cumulative total lifetime dose of Doxorubicin (including related drugs such as daunorubicin) should not exceed 450-550mg/m² body surface area. If a patient with concomitant heart disease receives mediastinal and/or heart irradiation, prior treatment with alkylating agents, and high-risk patients (with arterial hypertension since > 5 years, with prior coronary, valvular or myocardial heart damage, age over 70 years) with a maximum total dose of 400 mg/m² body surface area should not be exceeded and the cardiac function of these patients should be monitored (see section 4.4).

Dose in children

Dosage in children may need to be reduced, please refer to treatment protocols and the specialist literature.

Obese patients

A reduced starting dose or prolonged dose interval might need to be considered in obese patients (see section 4.4).

Single doses of 250 mg and 500 mg of doxorubicin have proved fatal.

Acute overdosage of doxorubicin may lead to myelosuppression (particularly leucopenia and thrombocytopenia), generally 10-15 days following overdose, and acute cardiac alterations, which may occur within 24 hours. Treatment includes intravenous antibiotics, transfusion of granulocytes and thrombocytes and reverse barrier nursing and treatment of heart effects. Moving the patient to a sterile room and the use of a haemopoietic growth factor should be considered.

Acute overdose with doxorubicin will also result in gastrointestinal toxic effects (mainly mucositis). This generally appears early after drug administration, but most patients recover from this within three weeks.

Chronic overdosage, with a cumulative dose exceeding 550 mg/m² increases the risk for cardiomyopathy and may lead to heart failure.

Delayed cardiac failure may occur up to six months after the overdosage. Patients should be observed carefully and should signs of cardiac failure arise, be treated along conventional lines.

Shelf life

Unopened vials: 18 months.

Opened vials: The product should be used immediately after opening the vial.

Prepared infusion solutions:

Chemical and physical in-use stability has been demonstrated in 0.9% sodium chloride injection and 5% dextrose injection for up to 28 days at 2–8°C and for up to 7 days at 25°C when prepared in glass containers protected from light.

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°C to 8°C, unless dilution has taken place in controlled and validated aseptic condition.

Store in a refrigerator (2°C-8°C).

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

For storage conditions of the diluted medicinal product, see section 6.3.

For 5 ml: Concentrate for solution for infusion is filled in 5 ml Type – I clear tubular glass vial closed with chlorobutyl rubber stopper and aluminium flip off pink seal.

For 10 ml: Concentrate for solution for infusion is filled in 10 ml Type – I clear tubular glass vial closed with chlorobutyl rubber stopper and aluminium flip off pink seal.

For 25 ml: Concentrate for solution for infusion is filled in 30 ml Type – I clear molded glass vial closed with chlorobutyl rubber stopper and aluminium flip off pink seal.

For 50 ml: Concentrate for solution for infusion is filled in 50 ml Type-I clear molded glass vial closed with chlorobutyl rubber stopper and aluminium flip off pink seal.

For 100 ml: Concentrate for solution for infusion is filled in 100 ml Type – I clear molded glass vial closed with chlorobutyl rubber stopper and aluminium flip off pink seal.

Pack sizes:

1 × 5 ml vial
1 × 10 ml vial
1 × 25 ml vial
1 × 50 ml vial
1 × 100 ml vial

Not all pack sizes may be marketed.

Doxorubicin is a potent cytotoxic agent which should only be prescribed, prepared and administered by professionals who have been trained in the safe use of the preparation. The following guidelines should be followed when handling, preparing and disposing of doxorubicin.

Preparation:

1. Personnel should be trained in good technique for handling.
2. Pregnant staff should be excluded from working with this drug.
3. Personnel handling doxorubicin should wear protective clothing: goggles, gowns, disposable gloves and masks.
4. All items used for administration or cleaning, including gloves, should be placed in high risk waste disposal bags for high temperature (700°C) incineration.
5. All cleaning materials should be disposed of as indicated previously.
6. Always wash hands after removing gloves.

Contamination:

1. In case of contact with skin or mucous membrane, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not graze the skin by using a scrubbing brush. A bland cream may be used to treat transient stinging of skin.
2. In case of contact with eye(s), hold back the eyelid(s) and flush the affected eyes with copious amounts of water for at least 15 minutes or normal sodium chloride 9 mg/ml (0.9%) solution for injection. Then seek medical evaluation by a physician or eye specialist.
3. In the event of spillage or leakage treat with 1% sodium hypochlorite solution or most simply with phosphate buffer (pH>8) until solution is destained. Use a cloth/sponge kept in the designate area. Rinse twice with water. Put all cloths into a plastic bag and seal for incineration.

Administration:

Intravenous (IV) administration of Doxorubicin must be very careful and it is advisable to give the medicinal product via the tubing of a freely running intravenous sodium chloride 9 mg/ml (0.9%) or dextrose 50 mg/ml (5%) within 2 to 15 minutes. This method minimizes the risk of thrombosis development and perivenous extravasation that result in severe cellulitis, vesication and tissue necrosis, and also provides rinse of the vein after the administration.

Remnants of the medicinal product as well as all materials that have been used for dilution and administration must be destroyed according to hospital standard procedures applicable to cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.

Disposal:

Single use only. Any unused product or waste material should be disposed of in accordance with local requirements. Observe guidelines for handling cytotoxic drugs.