Source: Health Products Regulatory Authority (IE) Revision Year: 2011 Publisher: Teva Pharma B.V. Computerweg 10 3542 DR Utrecht Netherlands
Doxorubicin is frequently used in combination chemotherapy regimens with other cytotoxic drugs.
Doxorubicin hydrochloride should be administered only under the supervision of a qualified physician experienced in cytotoxic therapy. Also, patients must be carefully and frequently monitored during the treatment.
Due to the risk of an often lethal cardiomyopathy, the risks and benefits to the individual patient should be assessed before each application.
Prior to start of the treatment it is recommended to measure the liver function by using conventional tests such as AST, ALT, ALP and bilirubin, as well as measuring renal function (see section 4.4).
Analysis of LVEF using ultrasound or heart scintigraphy should be performed in order to assess the heart condition of the patient. This control should be made prior to the start of the treatment and after each accumulated dose of approximately 100 mg/m (see section 4.4).
Intravenous (i.v.) administration of doxorubicin must be given with great care and it is advisable to give the drug via the tubing of a freely running i.v. saline or 5% glucose within 3-5 minutes. This method minimises the risk of thrombosis development and perivenous extravasation that result in severe cellulitis, vesication and tissue necrosis. Doxorubicin can be administered intravenously as a bolus within minutes, as a short infusion for up to an hour, or as continuous infusion for up to 96 hours. 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.
Doxorubicin should not be administered by the intramuscular, subcutaneous, oral or intrathecal route.
The dose is usually calculated based on body surface area (mg/m²). The dosage schedule of doxorubicin administration may vary according to indication (solid tumours or acute leukaemia) and according to its use in the specific treatment regimen (as a 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).
The recommended dose is 60-75 mg/m² body surface i.v. as a single dose or in divided doses on 2-3 consecutive days administered intravenously at 21 day intervals. Dosage schedule and dosages may be adjusted according to the protocol. For exact information on posology, refer to current protocols.
When Doxorubicin hydrochloride is administered in combination with other cytostatics, the dosage should be reduced to 30-60 mg/m² every 3 to 4 weeks.
The maximum total dose of 450-550 mg/m² body surface area should not be exceeded (including use with related drugs such as daunorubicin).
Patients with concomitant heart disease receiving mediastinal and/or heart irradiation, patients treated previously with alkylating agents, and high-risk patients (i.e. patients with arterial hypertension for a period exceeding 5 years; with prior coronary, valvular or myocardial heart damage; or aged over 70 years) should not exceed a maximum total dose of 400 mg/m body surface area and the cardiac function of these patients should be monitored (see section 4.4).
The dose should be reduced in the case of immunosuppression, an alternative dosage is 15-20 mg/m body surface per week.
In the case of decreased liver function, the dosage should be reduced according to the following table:
| Serum bilirubin | Recommended dose |
|---|---|
| 20-50 μmol/L | 1/2 normal dose |
| > 50-85 nmol/L | 1/4 normal dose |
| > 85 μmol/L | Stop treatment |
In patients with renal insufficiency (GFR less than 10 ml/min), only 75% of the planned dose should be administered.
Patients with an increased risk of cardiac toxicity should be considered for treatment with a 24 hours continuous infusion of single dose, rather than injection. In this way, cardiac toxicity may be less frequent, without a reduction in therapeutic efficacy. In these patients, the ejection fraction should be measured before each course.
The dosages may be reduced in patients with a history of treatment with myelosuppressive agents. Their bone marrow reserve may be insufficient.
The dosages may be reduced in elderly patients.
In view of the substantial risk of doxorubicin induced cardiotoxicity during childhood certain maximum cumulative dosages that depend on the youth of patients should be applied. In children (under 12 years of age) the maximal cumulative dose is usually considered 300 mg/m2 , whereas in adolescents (over 12 years of age) the maximal cumulative dose is set to 450 mg/m2 . For infants the maximal cumulative dosages are still indecisive, but even lower tolerability is assumed.
Dosage for children should be reduced, since they have an increased risk for cardiac toxicity, especially late. Myelotoxicity should be anticipated, with nadirs at 10 to 14 days after start of treatment. Please refer to current treatment protocols and the specialist literature.
Note: Posology of S-liposomal Doxorubicin and (conventional) doxorubicin are different. The two formulations cannot be used interchangeably.
Intravesical administration:
Doxorubicin hydrochloride can be given by intravesical instillation for treatment of superficial cancer of the bladder and to prevent relapse after transurethral resection (T.U.R). The recommended dose for intravesical treatment of superficial cancer of the bladder is 30-50 mg in 25-50 ml of physiological saline per instillation. The optimal concentration is about 1 mg/ml. The solution should remain in the bladder for 1-2 hours. During this period the patient should be turned 90° every 15 minutes. To avoid undesired dilution with urine the patient should be informed not to drink anything for a period of 12 hours before the instillation (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.
No specific antidote for doxorubicin is known.
An acute intoxication can become manifest within 24 hours as, e.g., heart failure with chest pain, angina pectoris and myocardial infarction. A cardiologist has to be consulted in such cases. Other signs of overdose are severe myelosuppression, which usually occurs 10 to 14 days after the beginning of therapy, and severe inflammation of the mucous membranes. Pronounced myelosuppression has to be treated in a hospital. According to the circumstances, the treatment can include the substitution of the lacking components and antibiotic therapy. Referring the patient to a germ-free room may be necessary. If signs of intoxication occur, the administration of doxorubicin should be discontinued at once. The signs of chronic intoxication are in particular the above-mentioned signs of cardiotoxicity. If heart failure occurs, a cardiologist has to be consulted.
A haemodialytic therapy is probably useless in intoxications with doxorubicin because doxorubicin has a very large volume of distribution and only 5% of a dose is eliminated by the kidneys.
Perivenous misinjection results in local necrosis and thrombophlebitis. A burning sensation in the region of the infusion needle is indicative of perivenous administration.
If extravasation occurs, the infusion or injection has to be stopped at once; the needle should be left in place for a short time and then be removed after short aspiration.
In case of extravasation start intravenous infusion of dexrazoxane, no later than 6 hours after extravasation (see the SmPC of dexrazoxane for dosing and further information). In case dexrazoxane is contraindicated, it is recommended to apply 99% dimethylsulfoxide (DMSO) locally to an area twice the size of the area concerned (4 drops to 10 cm² of skin surface area) and to repeat this three times a day for a period of no less than 14 days. If necessary, debridement should be considered. Because of the antagonistic mechanism, the area should be cooled after the application of DMSO (vasoconstriction vs. vasodilatation), e.g., to reduce pain.
Do not use DMSO in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation.
Other measures have been treated controversially in the literature and have no definite value.
Vial before opening: 24 months.
After first opening: Use immediately after first opening.
After dilution: Chemical and physical in-use stability after dilution to a concentration of 0.5 mg/ml in 9 mg/ml (0.9%) sodium chloride solution for infusion or in 50 mg/ml (5%) glucose solution for infusion has been demonstrated for 7 days when stored protected from light at room temperature (15-25°C) and at 2-8°C.
After dilution to the concentration of 0.05 mg/ml, the diluted solution should be used immediately.
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 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Store in a refrigerator (2-8°C).
Do not freeze.
For storage conditions of the diluted medicinal product, see section 6.3.
Doxorubicin Teva 2 mg/ml concentrate for solution for infusion is supplied in vials of 5 ml (10 mg), 10 ml (20 mg), 25 ml (50 mg) or 100 ml (200 mg) containing a red-orange, clear, sterile solution.
Primary packaging material: Vials with a nominal volume of 5, 10,25 or 100 ml, colourless glass type I (Ph.Eur.), with a chlorobutyl rubber stopper with an inert fluoropolymer (PTFE) coating on the inner side and with an aluminium seal covered with a coloured polypropylene disc.
Trade package quantities: Boxes with one vial of 5, 10,25 or 100 ml.
Not all pack sizes may be marketed.
Doxorubicin can also be administered as intravenous infusion diluted in the concentration range of 0.05 mg/ml to 0.5 mg/ml in 9 mg/ml (0.9%) sodium chloride solution for infusion or in 50 mg/ml (5%) glucose solution for infusion using non-PVC infusion bags.
Personnel should be trained in good technique for handling cytotoxic drugs. Pregnant staff should be excluded from working with this drug. Personnel handling this, and all cytotoxic drugs, should wear protective clothing: goggles, gowns and disposable gloves and masks.
If Doxorubicin comes in contact with skin or mucous membranes, the exposed area should be thoroughly washed with soap and water. If the substance gets into the eyes, rinse with water or sterile physiological saline, whereupon an eye specialist should be consulted.
After use, bottles and injection materials, including gloves, should be destroyed according to the rules for cytostatics. Any unused product or waste material should be disposed of in accordance with local requirements.
Inactivation of spilled or leaked drug can be obtained with 1% sodium hypochlorite solution or most simply with phosphate buffer (pH>8) until solution is destained. All cleaning materials should be disposed of as indicated previously.
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