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Powder 10 mg: a red, caked and powdery mass of 10 mg doxorubicin HCl contained in a 10 mL clear glass vial. The vials are closed with a grey rubber stopper and a black snap-cap.
Powder 50 mg: a red, caked and powdery mass of 50 mg doxorubicin HCl contained in a 50 mL clear glass vial. The vials are closed with a grey rubber stopper and a green snap-cap.
Doxorubicin is an anti-neoplastic antibiotic which may act by forming a stable complex with DNA and interfering with the synthesis of nucleic acids. It is a cell-cycle non-specific agent but is most active against cells in S phase. It also has actions on cell membranes, and immunosuppressant properties. It is an effective anti-neoplastic against a wide range of tumours. Doxorubicin is used, often in association with other anti-neoplastic agents, in the treatment of acute leukaemias, lymphomas, sarcomas, neuroblastomas, Wilms' tumour, and malignant neoplasms of the bladder, breast, lung, ovary, and thyroid. It has also been used in other tumours including those of the cervix, endometrium, stomach and testis.
Following intravenous injection, doxorubicin is rapidly cleared from the blood, and distributed into tissues including lungs, liver, heart, spleen and kidneys. It undergoes rapid metabolism in the liver to metabolites including the active metabolite doxorubicinol (adriamycinol). Biliary excretion represents the major route of elimination, 40 to 50% of the administered dose being recovered in the bile or faeces in 7 days, of which about half is as unchanged doxorubicin. Patients with impaired hepatic function have prolonged and elevated plasma concentrations of both the drug and its metabolites. Only about 5% of a dose is excreted in urine within 5 days. It does not cross the blood-brain barrier but may cross the placenta.
Doxorubicin is intended for the treatment of disseminated neoplastic conditions, such as acute leukaemia, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, lymphomas of both Hodgkin and non-Hodgkin type, small cell lung cancer and gastric carcinoma and bladder carcinoma.
Reconstituted doxorubicin solution is for intravenous administration only.
The most commonly used dosage schedule is 60-75 mg/m² as a single intravenous injection administered at 21 day intervals. Lower doses may be required in patients with inadequate marrow reserves. An alternative dosage schedule of 20 mg/m² weekly has been reported to produce a lower incidence of congestive heart failure.
Doxorubicin dosage should be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL - give half normal dose; bilirubin > 3.0 mg/dL - give quarter normal dose.
Doxorubicin 10 mg and 50 mg vials should be reconstituted with 5 mL and 25 mL, respectively, of sodium chloride solution (0.9%). When water for injection is used for reconstitution, it is recommended to dilute the solution with ample amounts of sodium chloride solution (0.9%), to obtain an approximately isotonic solution. The reconstituted solution should be used within 8 hours (see Pharmaceutical Precautions).
Doxorubicin therapy should not be started in the following cases:
Initial treatment with doxorubicin requires close observation of the patient and extensive laboratory monitoring. It is recommended, therefore, that patients be hospitalised at least during the first phase of the treatment.
Special attention must be given to the cardiac toxicity exhibited by doxorubicin. Although uncommon, acute left ventricular failure has occurred, particularly in patients who have received total dosage of the medicine exceeding the currently recommended limit of 550mg/m². The limit appears to be lower in patients who received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. The total dose of doxorubicin administered to the individual patient should also take into account a previous or concomitant therapy with related compounds such as daunorubicin.
Congestive heart failure and/or cardiomyopathy may be encountered several weeks after discontinuation of doxorubicin therapy. Cardiac failure is often not favourably affected by presently known medical or physical therapy for cardiac support. Early clinical diagnosis of doxorubicin-induced heart failure appears to be essential for successful treatment with digitalis, diuretics, low salt diet and bed rest. Severe cardiac toxicity may occur precipitously without antecedent ECG changes. A baseline ECG and ECGs performed prior to each dose or course after 300 mg/m² cumulative dose has been given is suggested. Transient ECG changes consisting of T-wave flattening, S-T depression and arrhythmias lasting up to two weeks after a dose or course of doxorubicin are presently not considered indications for suspension of doxorubicin therapy. Doxorubicin cardiomyopathy has been reported to be associated with a persistent reduction in the voltage of the QRS wave, a prolongation of the systolic time interval and a reduction of the ejection fraction as determined by echocardiography or radionuclide angiography. None of these tests have yet been confirmed to consistently identify those individual patients that are approaching their maximally tolerated cumulative dose of doxorubicin. If test results indicate change in cardiac function associated with doxorubicin the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage. Acute life-threatening arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.
There is a high incidence of bone marrow depression, primarily of leucocytes, requiring careful haematologic monitoring. With the recommended dosage schedule, leukopenia is usually transient, reaching its nadir at 10-14 days after treatment with recovery usually occurring by the 21st day. White blood cell counts as low as 1000/mm³ are to be expected during treatment with appropriate doses of doxorubicin. Red blood cell and platelet levels should also be monitored since they may also be depressed. Haematologic toxicity may require dose reduction or suspension or delay of doxorubicin therapy. Persistent severe myelosuppression may result in superinfection or haemorrhage.
Toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment; therefore, prior to the individual dosing, evaluation of hepatic function is recommended using conventional clinical laboratory tests, such as SGOT, SGPT, alkaline phosphatase and bilirubin. (See Dosage and Administration).
Necrotizing colitis manifested by typhlitis (caecal inflammation), bloody stools and severe and sometimes fatal infections have been associated with a combination of doxorubicin given by i.v. daily for 3 days and cytarabine given by continuous infusion daily for 7 or more days.
On intravenous administration of doxorubicin extravasation may occur with or without an accompanying stinging or burning sensation and even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred the injection or infusion should be immediately terminated and restarted in another vein. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and plastic surgery consultation obtained. Early wide excision of the involved area should be considered.
Like other cytotoxic agents, doxorubicin may induce hyperuricaemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use supportive and pharmacologic measures as might be necessary to control this problem.
Doxorubicin imparts a red colouration to the urine 1-2 days after administration and patients should be advised to expect this during active therapy.
Doxorubicin is a potentially teratogenic and embryotoxic agent. Therefore, the benefits to the pregnant patient should be carefully weighed against the potential toxicity to foetus and embryo.
Doxorubicin is excreted into the milk in small amounts.
Usage during pregnancy and lactation should be avoided as much as possible.
Not applicable.
Dose limiting toxicities of therapy are myelosuppression and cardiotoxicity. Other adverse reactions reported are:
Reversible and complete alopecia occurs in most cases. Hyperpigmentation of nailbeds and dermal creases, primarily in children, and onycholysis have been reported in a few cases. Recall of skin reaction due to prior radiotherapy has occurred with doxorubicin administration.
Acute nausea and vomiting occurs frequently and may be severe. This may be alleviated by antiemetic therapy. Mucositis (stomatitis and oesophagitis) may occur 5-10 days after administration. The effect may be severe leading to ulceration and represents a site of origin for severe infections. The dose regimen consisting of administration of doxorubicin on three consecutive days results in the greater incidence and severity of mucositis. Ulceration and necrosis of the colon, especially the caecum, may occur leading to bleeding or severe infections which can be fatal. This reaction has been reported in patients with acute non-lymphocytic leukaemia treated with a 3-day course of doxorubicin combined with cytarabine. Anorexia and diarrhoea have been occasionally reported.
Phlebosclerosis has been reported especially when small veins are used or a single vein is used for repeated administration. Facial flushing may occur if the injection is given too rapidly.
Severe cellulitis, vesication and tissue necrosis will occur if doxorubicin is extravasated during administration. Erythematous streaking along the vein proximal to the site of the injection has been reported.
Fever, chills and urticaria have been reported occasionally. Anaphylaxis may occur. A case of apparent cross sensitivity to lincomycin has been reported.
Conjunctivitis and lacrimation occur rarely.
Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced cystitis and enhancement of 6-mercaptopurine hepatotoxicity have been reported. Radiation-induced toxicity to the myocardium, mucosae, skin and liver has been reported to be increased by the administration of doxorubicin.
Acute overdosage of doxorubicin enhances the toxic effects of mucositis, leukopenia and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.
Chronic overdosage with cumulative doses exceeding 550 mg/m² increases the risk of cardiomyopathy and resultant congestive heart failure. Treatment consists of vigorous management of congestive heart failure with digitalis preparations and diuretics. The use of peripheral vasodilators has been recommended.
Store at controlled room temperature 15 to 25°C. Protect from exposure to sunlight; retain in outer pack until time of use.
Due to the risk of microbial contamination, it is recommended that the reconstituted solution be used within 8 hours. Discard any unused solution.
Prescription Medicine
Doxorubicin hydrochloride powder for injection 10 mg and 50 mg vials are packed in hospital packs containing 10 vials.
Doxorubicin should not be mixed with 5-fluorouracil or heparin.
Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other agents.
Manufacturer:
PHARMACHEMIE B.V
PO Box 552
2003 RN Haarlem
The Netherlands
Distributor:
ASTA Medica Representative Office
c/- N Z M S Limited
PO Box 24-138, Royal Oak
Auckland
25 June 1999