Presentation and Status in Health Basket
Solution for Injection
50 mg / 25 ml
Solution for Injection
200 mg / 100 ml
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.
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/m².
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 minimizes 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.
Intravenous administration: 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).
Monotherapy: 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.
Combination therapy: 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.
Maximal cumulative dose: 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/m² body surface area and the cardiac function of these patients should be monitored.
Special population groups:
Immunosuppressed patients: The dose should be reduced in the case of immunosuppression, an alternative dosage is 15-20 mg/m² body surface per week.
Patients with impaired hepatic function: In the case of decreased liver function, the dosage should be reduced according to the following:
Serum bilirubin 20-50 μmol/L; Recommended dose: ½ normal dose.
Serum bilirubin> 50-85 μmol/L; Recommended dose: ¼ normal dose
Serum bilirubin> 85 μmol/L; Recommended dose: Stop treatment.
Patients with impaired renal function: In patients with renal insufficiency (GFR less than 10 ml/min), only 75% of the planned dose should be administered.
Patients with risk of cardiac impairment: 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.
Patients with limited bone marrow reserve not related to bone marrow involvement of the disease: The dosages may be reduced in patients with a history of treatment with myelosuppressive agents. Their bone marrow reserve may be insufficient.
Elderly: The dosages may be reduced in elderly patients.
Paediatric population: 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.
To produce regression in disseminated neoplastic conditions such as: acute lymphoblastic leukaemia, acute myeloblastic leukaemia, Wilms’ tumour neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, lymphomas of both Hodgkin’s and non-Hodgkin’s types, bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types, and gastric carcinoma.
Hypersensitivity to doxorubicin, other anthracyclines or anthracenediones or to any of the excipients.
Contraindications for intravenous administration:
– marked persisting myelosuppression and/or severe stomatitis induced by previous cytotoxic treatment and/or radiation (including patients with a high risk of haemorrhage)
– acute systemic infection
– severe impaired liver function
– severe arrhythmia, impaired heart function, acute myocardial infarction, previous myocardial infarction, acute inflammatory heart disease
– previous treatment with anthracyclines with maximal cumulative doses
Contraindications for intravesical administration:
– invasive tumours that have penetrated the bladder (beyond T1)
– urinary tract infections
– inflammation of the bladder
– problems with catheterization
Doxorubicin 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.
A careful control of possible clinical complications should be performed, particularly in elderly patients, in patients with a history of heart disease, or with bone-marrow suppression, or patients who previously have been treated with anthracyclines, or treated with radiation in the mediastinum.
Before or during treatment with doxorubicin the following monitoring examinations are recommended (how often these examinations are done will depend on the general condition of the patient, the dose and the concomitant medication being taken):
– radiographs of the lungs and chest and ECG
– regular monitoring of heart function (LVEF by e.g., ECG, UCG and MUGA scan)
– inspection of the oral cavity and pharynx for mucosal changes
– blood tests: haematocrit, platelets, differential white cell count, SGPT, SGOT, LDH, bilirubin, uric acid.
Doxorubicin should not be administered by the intramuscular, subcutaneous, oral or intrathecal route.
The patient should be informed that the urine might be reddish after administration.
Nausea, vomiting and mucositis are often extremely severe and should be treated appropriately.
See prescribing information for full details.
Treatment with doxorubicin often causes undesirable effects, and some of these effects are serious enough to entail careful monitoring of the patient. The frequency and kind of undesirable effects are influenced by the speed of administration and the dosage. Bonemarrow suppression is an acute dose limiting adverse effect, but is mostly transient. Clinical consequences of doxorubicin bone marrow/haematological toxicity may be fever, infections, sepsis/septicaemia, septic shock, haemorrhages, tissue hypoxia or death. Nausea and vomiting as well as alopecia are seen in almost all patients.
Intravesical administration may cause the following adverse reactions: hematuria, vesical and urethral irritation, stranguria and pollakisuria. These reactions are usually of moderate severity and of short duration.
Intravesical administration of doxorubicin may sometimes cause hemorrhagic cystitis; this may cause a decrease in bladder capacity.
Extravasation can lead to severe cellulitis, vesication, thrombophlebitis, lymphangitis and local tissue necrosis which may require surgical measures (including skin grafts).
See prescribing information for full details.
Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines, or other potentially cardiotoxic drugs (e.g. 5-fluorouracil, cyclophosphamide or paclitaxel) or with products affecting cardiac function (like calcium antagonists). When doxorubicin is used together with the above mentioned agents, cardiac function must be followed carefully.
The use of trastuzumab in combination with anthracyclines (such as doxorubicin) is associated with a high cardiotoxic risk.
If possible, physicians should avoid anthracycline-based therapy for up to 24 weeks after stopping trastuzumab. If anthracyclines are used, the patient’s cardiac function should be monitored carefully. Concurrent use of anthracyclines and trastuzumab should be restricted to a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with trastuzumab treatment, although the risk is lower than with concurrent use of trastuzumab and anthracyclines.
(Pre-) treatment with drugs affecting the function of the bone marrow (e.g. cytostatic agents, sulfonamides, chloramphenicol, phenytoin, amidopyrine derivates, antiretroviral drugs) might lead to severe hematopoetic disturbances. The dosage of doxorubicin has to be changed if necessary. The toxic effects of a doxorubicin therapy may be increased in a combination with other cytostatics (e.g. cytarabine, cisplatin, cyclophosphamide).
Doxorubicin hepatotoxicity may be enhanced by other hepatotoxic treatment modalities (e.g. 6-mercaptopurine).
Doxorubicin hydrochloride used in combination with ciclosporin might require doseadjustment. At concomitant administration of ciclosporin, the clearance of doxorubicin is reduced by approximate 50%. The doxorubicin AUC is increased by 55% and AUC of doxorubicinol by 350%. With this combination a 40% dose reduction of doxorubicin is suggested. Ciclosporin inhibits, similar to verapamil, both CYP3A4 and P-glycoprotein, which might explain the interaction and resulting increase in adverse effects.
Cytochrome P-450 inhibitors (e.g. cimetidine) also reduce the plasma clearance and increase the AUC of doxorubicin, possibly by similar mechanisms as suggested for ciclosporin, and may thus lead to an increase in adverse effects. Conversely, cytochrome P-450 inducers (e.g. phenobarbital and rifampicin) decrease doxorubicin plasma levels and may thus lead to a decrease in efficacy.
Doxorubicin is a potent, radiosensitizing agent (“radiosensitizer”), and recall phenomena induced by it may be life-threatening. Any preceding, concomitant or subsequent radiation therapy may increase the cardiotoxicity or hepatotoxicity of doxorubicin. This applies also to concomitant therapies with cardiotoxic or hepatotoxic drugs. If a doxorubicin therapy follows a treatment with cyclophosphamide, this may not only increase cardiotoxicity, but also aggravate haemorrhagic cystitis.
If paclitaxel is given before doxorubicin, this may result in an elevated plasma concentration of doxorubicin and/or its metabolites. There are data suggesting that this effect is lower if the anthracycline is given before paclitaxel.
Doxorubicin therapy may lead to increased serum uric acid; therefore dose adjustment of uric acid lowering agents may be necessary.
Doxorubicin may reduce oral bioavailability of digoxin.
The absorption of antiepileptic drugs (e.g. carbamazepine, phenytoin, valproate) is decreased after concomitant use of Doxorubicin hydrochloride.
During treatment with Doxorubicin hydrochloride patients should not be actively vaccinated and also avoid contact with recently polio vaccinated persons.
Doxorubicin binds to heparin and 5-fluorouracil. Precipitations and loss of action of both substances are therefore possible.
Pregnancy and Lactation
Pregnancy: Doxorubicin should not be given during pregnancy. In general cytostatics should only be administered during pregnancy on strict indication, and the benefit to the mother weighed against possible hazards to the foetus. In animal studies, doxorubicin has shown embryo-, feto- and teratogenic effects.
Men and women should use effective contraception during and up to 6 months after treatment.
Women should not become pregnant during and up to 6 month after treatment.
Lactation: Doxorubicin has been reported to be excreted in human breast milk. A risk to the suckling child cannot be excluded. Since the use of doxorubicin during breast-feeding is contraindicated, breast-feeding should be discontinued during treatment with doxorubicin.
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.
Extravasation: 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, débridement 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.
Incompatibilities: Doxorubicin must not be mixed with heparin, as this will result in precipitation. Until detailed compatibility information about miscibility is available, doxorubicin should not be mixed with other medicinal products than those mentioned under section 6.6 at the attached doctor’s leaflet.
Incompatibilities with the following products have been reported: Aminophyllin, cephalotin, dexamethasone, fluorouracil, hydrocortisone.
Shelf life: Vial before opening: The expiry date of the product is indicated on the packaging materials.
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.
Storage: Store in a refrigerator (2-8°C). Do not freeze.