Daunorubicin

The dosage should be reduced in patients with impaired hepatic or renal function. A 25% reduction is recommended in patients with serum bilirubin concentrations of 1.2-3mg/100ml and a 50% reduction in cases with serum bilirubin or creatinine concentrations above 3 mg/100ml.

Daunorubicin hydrochloride is mainly metabolised in the liver and eliminated via the bile. Hepatic function should be monitored before starting treatment with daunorubicin hydrochloride in order to prevent complications. The dose should be reduced in case of impaired hepatic function since the toxic effects of the drug may be exacerbated in this population. This should be based on serum bilirubin levels.

An impaired renal function can also lead to increased toxicity. Renal function should therefore be monitored before initiating treatment.

Daunorubicin should be used with care in patients at risk of hyperuricaemia (e.g. in the presence of gout, urate and renal calculi), tumor cell infiltration of the bone marrow and in patients with inadequate bone marrow reserves due to previous cytotoxic drug or radiation therapy. The cumulative dose of daunorubicin should be limited to 400mg/m² when radiation therapy to the mediastinum has been previously administered. The dose of daunorubicin should not be repeated in the presence of bone marrow depression or buccal ulceration.

Rapid destruction of a large number of leukaemia cells may cause a rise in the blood uric acid or urea and so it is a wise precaution to check these concentrations three or four times a week during the first week of treatment. Fluids should be administered and allopurinol used in severe cases to prevent the development of hyperuricaemia.

Daunorubicin treatment may lead to hyperuricaemia as a consequence of tumour lysis syndrome.

Immunosuppressive effect of daunorubicin can be more pronounced when daunorubicin is concomitantly administered with other immunosuppressive agents.

The combination of daunorubicin hydrochloride with phenytoin (and by extrapolation fosphenytoin) can lead to risk of seizure since daunorubicin hydrochloride reduces the gastrointestinal absorption of phenytoin, or risk of increased toxicity or decreased efficacy of daunorubicin hydrochloride since both phenytoin and fosphenytoin increase hepatic metabolism.

Extreme caution should be exercised when using daunorubicin in patients with cardiac disorders or in the elderly.

There are no data on the use of daunorubicin in pregnant women. Based on results from animal studies and its mechanism of action, daunorubicin should not be used during pregnancy, unless the clinical condition of the woman requires treatment and justifies the potential risk to the foetus.

If the medicinal product is used during pregnancy, or if the patient becomes pregnant while receiving daunorubicin, the woman should be informed of the potential hazard to the foetus. In any case, cardiologic examination and a blood count are recommended in foetuses and newborns born to mothers who received treatment during pregnancy.

It is not known whether daunorubicin is excreted in human milk. Because of the potential for serious adverse reactions in breast-feeding children, breastfeeding is contraindicated during treatment with daunorubicin.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while on daunorubicin and should be informed of the potential hazard to the foetus. Women of childbearing potential should undergo pregnancy testing before initiation of daunorubicin. Men with sexual partners of reproductive potential should use effective contraception during treatment and for 14 weeks following the last dose of daunorubicin. Women should use effective contraception during treatment and for 6 months following the last dose of daunorubicin.

No studies on the effects on the ability to drive and use machines have been performed. However, confusion, seizures and visual disturbances have been observed in patients treated with daunorubicin combination therapy. Moreover, daunorubicin hydrochloride causes episodes of nausea and vomiting, which in some cases may affect the ability to drive or use machines. Therefore, patients should be warned of the possible impact of the side effects on their ability to drive or use machines, and be advised not to drive or use machines if they experience these side effects during treatment.

Adverse reactions associated with daunorubicin obtained from clinical studies and post-marketing surveillance are listed in the table below. Adverse reactions are listed by system organ class and can occur in the following frequencies: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions:

1. Including severe infections (including septic shock, sepsis/septicaemia and pneumonia) which can sometimes be fatal.

2. Secondary malignancies, including acute myeloid leukaemia, have been reported in association with daunorubicin when used in combination with other antineoplastic treatments known to be associated with secondary malignancies.

4. Fatal outcome has been reported.

5. Such as sinus tachycardia, premature ventricular contractions, heart block

6. Urine may be coloured red for several days after administration.

7. Immediate local pain/burning sensation, severe cellulitis, painful ulceration.

8. Such as nonspecific ST-T wave changes, low voltage QRS complex, T waves.

Local Adverse reactions

Two kinds of local adverse reactions are reported:

• Extravasation with risk of tissue necrosis: the infusion must be stopped, a maximum of infiltrated product aspirated and a cold dressing applied. A corticosteroid may possibly be injected or dimethyl sulfoxide applied topically. Daily surveillance is required. Indwelling i.v catheters and Portacath devices reduce the risk of extravasation.
• Recall of skin reaction due to prior radiotherapy, consisting of pain and erthyema which may last several days.

Cardiotoxicity

Acute toxicity:

• Onset within 48 hours
• ECG modification may occur: arrhythmias, in particular prolonged QT interval usually with no clinical signs. In the event of arrhythmia, treatment can be continued but any associated electrolyte imbalance (hypokalemia, hyponatremia, etc.) must be corrected.
• Early onset of acute myopericarditis is rare.
• Cardiomyopathy which may progress to congestive heart failure; this potentially fatal condition requires specialized care.
• Chronic toxicity is correlated to the total cumulative dose administered.

Prevention

Cardiotoxicity may be prevented by:

• Clinical monitoring
• Regular monitoring of cardiac function by evaluating ventricular performance using echocardiography or radionuclide scanning. These tests should be performed before the first administration and repeated regularly. Treatment should be discontinued if any significant change occurs.
• Some cardioprotective drugs can limit risks of toxicity.

Blood and lymphatic system disorders

Very common: Bone marrow failure.

Bone marrow depression (very common): in every patient bone marrow function will be depressed by treatment with daunorubicin and in a variable proportion of cases, severe aplasia will develop. Risk of sepsis, severe opportunistic infections may occur with bone marrow depression.

Frequency not known: febrile neutropenia, including with fatal outcomes, has been reported.

Leucopenia is usually more significant than thrombocytopenia. The nadir for leucopenia usually occurs between 10-14 days and recovery occurs gradually over the next 1-2 weeks. Bone marrow depression must be anticipated in every case by eliminating infection before the treatment, by isolating the patient from infection during the treatment and by means of supportive therapy. This includes the continuous administration of anti-infective agents, the administration of platelet-rich plasma or fresh whole blood transfusion and, under some circumstances, the transfusion of white cell concentrates.