DOXORUBICIN

Treatment with Doxorubicin 2 mg/ml should be started by or after consultation with a doctor with extensive experience from cytostatic treatment. 9% intravenous infusion or Dextrose 5% intravenous infusion) over 2-15 minutes. This technique minimizes the risk of thrombophlebitis or perivenous extravasation which can lead to severe cellulitis and vesication.

Intravenous administration:

The dosage of doxorubicin depends on dosage regimen, general status and previous treatment of the patient. v. as a single dose or in divided doses on 2-3 consecutive days administered with 21 day’s intervals. The lower dose should be given to patients with bone marrow depression.

When Doxorubicin 2 mg/ml is administered in combination with other cytostatics, the dosage should be reduced to 30-60 mg/m². 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.

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; 450 mg/m² should not be exceeded in cases of previous radiation of mediastinum, previous or concomitant treatment with potentially cardiotoxic agents.

In cases of decreased liver function, the dosage should be reduced according to the following table: Serum bilirubin Recommended dose 20-50 micro mole/L 50% normal dose > 50 micro mole/L 25% normal dose In cases of renal insufficiency with a GFR less than 10 ml/min, 75% of the calculated dose should be administered.

Dosage in children may need to be reduced, please refer to treatment protocols and the specialist literature. 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 solution should remain in the bladder for 1-2 hours. During this period the patient should be turned 90o 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. 4). Control of the left ventricular function Analysis of LVEF using ultrasound or heart scintigraphy should be performed in order to optimise the heart condition of the patient.

4). 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. Intravesical instillation is contraindicated in invasive bladder tumours.

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.

Bone-marrow 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. g. g. sinus tachycardia, tachyarythmia, ventricular tachycardia, bradycardia, bundle branch block) Blood and lymphatic system disorders: Bone-marrow suppression Gastrointestinal disorders: Nausea, vomiting, mucositis, anorexia, diarrhoea Renal and urinary disorders: Local reactions (chemical cystitis) might occur at intravesical treatment Skin and subcutaneous tissue disorders: Alopecia Uncommon (≥ 1/1,000 to <1/100) Gastrointestinal disorders: In combination with cytarabine ulceration and necrosis of the colon, in particular the caecum, have been reported.

Rare (≥1/10,000 to <1/1,000) Eye disorders:

Conjunctivitis Skin and subcutaneous tissue disorders: Urticaria, exanthema, local erythematous reactions along the vein which was used for the injection, hyperpigmentation of skin and nails, onycholysis General disorders and administration site conditions: Anaphylactic reactions, shivering, fever, dizziness Blood and lymphatic system disorders: Maximal bone-marrow suppression occurs after 10-14 days, but the white and red blood cell counts (blood values) are often normalised after 21 days.

Dose reduction or increase of the dose interval should be considered if the blood values are not normalised. Haematological monitoring should be undertaken regularly in both haematological and non-haematological conditions. Secondary acute myeloid leukaemia (AML), with or without a pre-leukaemic phase, has in rare cases been reported in patients simultaneously treated with doxorubicin and antineoplastic drugs, which damage the DNA.

These cases might have a short latency period, 1-3 years.

Cardiac disorders:

Cardiotoxicity may be manifested in tachycardia including supraventricular tachycardia and ECG changes. Cardiomyopathy can develop even long after discontinuation of the treatment, and is of serious nature. It is often characterised by a decrease in LVEF, a decrease in amplitude of the QRS wave, rapid onset of cardiac dilatation, which often does not respond to treatment with medicinal products with inotropic effect.

Acute transient ECG changes that occur directly in connection with, or a few hours after the administration, are in most cases reversible and are usually of no clinical significance.

Gastrointestinal disorders:

Nausea and vomiting often occur during the first 24 hours after the administration. Mucositis (stomatitis and oesophagitis) may occur 5-10 days after administration, and is more frequent and serious when a therapy, which involves treatment during three consecutive days, is applied.

Ulceration and necrosis of the colon, in particular the caecum, resulting in bleeding and serious infections, sometimes fatal, have been reported in patients with acute non lymphocytic leukaemia, who, during three days, were treated with doxorubicin in combination with cytarabine.

Hyperpigmentation of oral mucosa also occurred.

Skin and subcutaneous tissue disorders:

Alopecia is dose-dependent and in most cases reversible. Photosensitization, “radiation recall reaction”. Extravasation can lead to severe cellulitis, vesication and local tissue necrosis which may require surgical measures (including skin grafts).

Other side effects:

Hyperuricaemia, bronchospasm, amenorrhoea, transient increase of liver enzymes.

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.

Control of blood values:

Before every treatment cycle total and differential leukocyte count, erythrocyte and thrombocyte counts should be performed. Bone-marrow suppression induced by Doxorubicin Hydrochloride 2 mg/ml, primarily affecting the leukocytes, requires a thorough haematological monitoring since severe myelosuppression may lead to superinfections and bleedings.

Severe leucopoenia may appear at doses recommended for treatment of solid tumours (a number of leukocytes of 1 000/mm3 or lower is expected during full dose treatment with Doxorubicin 2 mg/ml ). The leucopoenia is most pronounced 10 – 14 days after the treatment and leukocytes have in most cases returned to normal at day 21.

Control of heart function:

There is a known risk of development of anthracycline induced cumulative dose-dependent cardiomyopathy. Therefore a cumulative dose of (450-)550 mg/m2 should not be exceeded. At doses above this, the risk of development of heart failure considerably increases.

The heart function should therefore be assessed before start of the treatment and carefully monitored during the whole treatment. Electrocardiography before and after each treatment cycle is recommended. Changes in ECG such as depression or negative T-wave, decrease in the ST-segment or arrhythmias are usually signs of an acute but transient (reversible) toxic effect and are not considered indications for suspension of doxorubicin therapy.

However, a reduction in the amplitude of the QRS-wave and a prolongation of the systolic interval are considered more indicative of anthracycline-induced cardiac toxicity. The best sign to predict cardiomyopathy is a reduction in the left ventricular ejection fraction (LVEF), determined by ultrasound or heart scintigraphy.

LVEF-investigations should be performed before treatment and be repeated after each accumulated dose of about 100 mg/m2 , and at clinical signs of heart failure. As a rule, an absolute decrease with >10 % or a decrease below 50 %, in patients with normal initial LVEF-values, is a sign of an impairment of the heart function.

Continued treatment with doxorubicin must in these cases be carefully evaluated. The risk for cardiotoxicity may increase in patients previously on radiotherapy towards the mediastinal pericardium, in patients previously treated with other anthracyclines and/or anthracenediones, or in patients with a history of heart diseases.

v. cyclophosphamide, mediastinal irradiation or related anthracycline compounds such as daunorubicin.

Control of liver function:

Doxorubicin is mainly eliminated via the hepatobiliary system. The elimination of the drug can therefore be prolonged with subsequent general toxicity if the liver function is impaired or biliary secretion is obstructed. Before start and during treatment, control of the liver function with conventional tests such as AST, ALT, ALP and bilirubin is recommended.

2).

Control of serum uric acid:

During therapy serum uric acid may increase. In case of hyperuricemia antihyperuricemic therapy should be initiated. 2). 5). Doxorubicin amplifies the radiation toxicity to heart muscle, mucous membranes, skin and liver. A stinging or burning sensation at the site of administration may signify a small degree of extravasation.

If extravasation is suspected or occurs, the injection should be discontinued and restarted in a different blood vessel. Cooling the area for 24 hours can reduce the discomfort. The patient should be carefully monitored for several weeks.

Surgical measures might be necessary. The patient should be informed that the urine might be reddish after administration. 54 mg sodium per 1 ml of doxorubicin hydrochloride concentrate for solution for infusion. This should be taken into consideration by patients on a controlled sodium diet

6)..