CERUBIDIN Powder for concentrate for solution for infusion Ref.[51399] Active ingredients: Daunorubicin

Special warnings

Daunorubicin should only be administered under the direction of a specialist having the facilities for regular monitoring of clinical, biochemical and haematological effects during and after administration.

Urine, sweat or tear may be coloured in red due to daunorubicin composition. This will last a few days and then return to normal.

Daunorubicin has been shown to be carcinogenic in animals. The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

Precautions for use

Caution is indicated when daunorubicin hydrochloride is used concomitantly with phenytoin due to drug-drug interaction potentially affecting both daunorubicin hydrochloride and phenytoin plasma exposure which can lead to seizure (see section 4.5).

Haematopoietic system

Daunorubicin produces bone marrow depression. Daunorubicin should be administered with caution when the neutrophil count is <1,500/mm³. Febrile neutropenia has been reported when daunorubicin is given in combination with other antineoplastic treatments.

Monitoring of blood counts prior to and during daunorubicin treatment is recommended, and hematological abnormalities should be treated promptly (see sections 4.2 and 4.8).

Secondary malignancies

Secondary malignancies (including leukaemia) have been reported when daunorubicin was given in combination with other antineoplastic treatments known to be associated with secondary malignancies (see section 4.8). Secondary malignancies may occur during daunorubicin-containing therapy, or several months or years after the end of therapy. Patients should be monitored for secondary malignancies.

Cardiotoxicity

Extreme caution should be exercised when using the product in patients with cardiac disorders or in the elderly. Cardiotoxicity if it occurs is likely to be heralded by either a persistent tachycardia, shortness of breath, swelling of feet and lower limbs or by minor changes in the electrocardiogram and for this reason an electrocardiographic examination should be made at regular intervals during the treatment.

Cardiotoxicity usually appears within 1 to 6 months after initiation of the therapy. It may develop suddenly and not be detected by routine ECG. It may be irreversible and fatal but responds to treatment if detected early.

The risk may be decreased through regular monitoring of left ventricular ejection fraction (LVEF) during the course of treatment. Initiation of cardio-protective drugs might be considered to limit the risk of cardiomyopathy, while treatment should be discontinued upon the first sign of cardiomyopathy. A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patient with risk factors for increased cardiotoxicity. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). ECG changes may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity.

The risk of congestive heart failure increases significantly when the total cumulative dosage exceeds 600 mg/m² body surface area in adults, 300 mg/m² in children over 2 years or 10mg/kg bodyweight in children under 2 years. Cardiotoxicity may be more frequent in children and the elderly. The dosage should be modified if previous or concomitant cardiotoxic drug therapy is used.

Hepatic and renal function

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.

Infections

Infections should be treated before the start of daunorubicin therapy. If during daunorubicin treatment a patient becomes febrile (regardless of the neutrophil count), treatment with broad spectrum antibiotics should be initiated.

Gastrointestinal disorders

Cases of colitis, entercolitis and neutropenic entercolitis (typhlitis) have been reported in patients treatment with daunorubicin. Treatment discontinuation and prompt appropriate medical management are recommended.

Immunosuppressive effects/Increased sensitivity to infections

The administration of live or live attenuated vaccines to patients whose immune system has been compromised by chemotherapeutic drugs, including daunorubicin, can lead to severe or fatal infections. Patients who receive daunorubicin should not be vaccinated with live vaccines such as yellow fever vaccine. Dead or inactivated vaccines may be administered. Such vaccines may, however, be less effective.

Nervous system disorders

Posterior reversible encephalopathy syndrome (PRES) also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Cases of PRES have been reported with daunorubicin used in combination chemotherapy. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. In patients with PRES, the discontinuation of daunorubicin treatment should be considered (See section 4.8).

Care should be taken to avoid extravasation during intravenous administration. Using catheters or implanted ports reduces the risk of extravasation. All steps should be taking to avoid tissuing and bandages should not be used. Facial flushing or erythematous streaking along the vein indicates too rapid infusion. If tissue necrosis is suspected, the infusion should be stopped immediately and resumed in another vein. Where extravasation has occurred, an attempt should be made to aspirate the fluid back through the needle. The affected area may be injected with hydrocortisone. Sodium bicarbonate (5 ml of 8.4%) may also be injected in the hope that through pH changes the drug will hydrolyse. The opinion of a plastic surgeon should be sought as skin grafting may be required.

Application of ice packs may help decrease local discomfort and also prevent extension. Liberal application of corticosteroid cream and dressing the area with sterile gauze should then be carried out.

Each patient should be given a clinical and bacteriological examination to determine whether infection is present; any infection should be adequately eliminated before treatment with Daunorubicin which might depress the bone marrow to the point where anti-infective agents would no longer be effective. If facilities are available, patients should be treated in a germ-free environment or, where it is not possible, reverse barrier nursing and aseptic precautions should be employed. Anti-infective therapy should be employed in the presence of suspected or confirmed infection and during a phase of aplasia. It should be continued for some time after the marrow has regenerated. Care should also be used in patients at risk of infection. Personnel handling this product should wear protective clothing and be trained in good handling techniques.

Immunosuppressive agents: 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 (see section 4.4).

Yellow fever vaccine with daunorubicin hydrochloride is not recommended due to the risk of fatal systemic vaccine disease.

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.

Pregnancy

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 (see section 5.3).

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.

Breast-feeding

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 (see section 4.3).

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 (see section 4.4). 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.

Table 1. 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.

3. See section 4.4 Special warnings and precautions for use.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, website: www.hpra.ie.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

The reconstituted product is incompatible with heparin sodium injection and dexamethasone sodium phosphate injection.