Cytarabine and Daunorubicin

Daunorubicin/cytarabine combination should only be used in patients with severe hepatic impairment if the benefits outweigh the risks.

Concurrent use of cardiotoxic agents may increase the risk of cardiotoxicity. Use of daunorubicin/cytarabine in patients who have previously received doxorubicin increases the risk of cardiotoxicity. Do not administer daunorubicin/cytarabine in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored.

Treatment with daunorubicin/cytarabine should be discontinued in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk.

There are no data on the use of daunorubicin/cytarabine in pregnant women. Based on results from animal studies and its mechanism of action, daunorubicin/cytarabine 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/cytarabine, 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/cytarabine is excreted in human milk. Because of the potential for serious adverse reactions in breast-feeding children from daunorubicin/cytarabine, mothers should be advised not to breast-feed during daunorubicin/cytarabine therapy.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should avoid becoming pregnant while receiving daunorubicin/cytarabine. Women of childbearing potential should use effective contraception while they or their male partner undergo treatment. Women of childbearing potential should not receive treatment until pregnancy is excluded.

Women of childbearing potential should undergo pregnancy testing before initiation of daunorubicin/cytarabine. Men with sexual partners of reproductive potential and women should use effective contraception during treatment and for 6 months following the last dose of daunorubicin/cytarabine.

Fertility

Based on findings in animals, male fertility may be compromised by treatment with daunorubicin/cytarabine.

Daunorubicin/cytarabine has minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported with the use of daunorubicin/cytarabine. Therefore, caution is recommended when driving or operating machines.

Summary of the safety profile

The most frequently occurring adverse reactions (ADRs) were hypersensitivity including rash (66.9%), febrile neutropenia (63.5%), oedema (52.3%), diarrhoea/colitis (49.9%), mucositis (49.9%), fatigue (46.4%), musculoskeletal pain (44.5%), abdominal pain (36.3%), decreased appetite (33.9%), cough (33.9%), headache (32.3%), chills (31.2%), arrhythmia (30.4%), pyrexia (29.6%), sleep disorders (25.1%), and hypotension (23.7%).

The most serious and frequently occurring ADRs were infection (58.7%), cardiotoxicity (18.7%) and haemorrhage (13.1%).

Tabulated list of adverse reactions

ADRs have been included under the appropriate category in the table below according to the highest frequency observed in any of the main clinical studies.

Frequencies are defined as: Very Common (≥1/10); common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. For classification of ADRs which occur at Grades 3-5, a comprehensive listing is available from the NCI at NCI CTCAE. Toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4), with specific parameters according to the organ system involved. Death (Grade 5) is used for some of the criteria to denote a fatality.

ADRs reported in clinical studies in patients treated with daunorubicin/cytarabine (n=375):

^a Arrhythmia group terms includes atrial fibrillation, bradycardia, and the most commonly reported arrhythmia was tachycardia

Description of selected adverse reactions

Infections

Due to the neutropenia experienced with daunorubicin/cytarabine, infections of various types were very common ADRs. Pneumonia, sepsis and bacteriaemia were the most frequently seen serious infection ADRs in the clinical studies population. The incidence of infection events was 78.1%; the incidence of non-serious events of infections was 73.1%, the incidence of serious events of infections was 28.5%; the incidence of infections which led to discontinuation is 0.5%. The incidence of fatal infections was 6.9%. The fatal infections experienced were sepsis and pneumonia.

Haemorrhage

Due to the thrombocytopenia experienced with daunorubicin/cytarabine a variety of haemorrhagic events were seen in clinical studies. The most common haemorrhagic event was epistaxis, and the majority of these were considered not serious (29.1%). The incidence of haemorrhage events is 69.1%; the incidence of non-serious events of haemorrhage was 67.2%; the incidence of serious events of haemorrhage is 5.6%; the incidence of haemorrhage which led to discontinuation is 0. The incidence of fatal haemorrhage was 2.1%. Serious or fatal haemorrhagic events, including fatal central nervous system (CNS) haemorrhages, associated with severe thrombocytopenia were seen in patients treated with daunorubicin/cytarabine.

Cardiotoxicity

Cardiotoxicities were seen in daunorubicin/cytarabine clinical studies. The most frequently reported serious ADRs were decreased ejection fraction and congestive cardiac failure. Cardiotoxicity is a known risk of anthracycline treatment. The incidence of all cardiotoxicity events was 72.0%; the incidence of non-serious events of cardiotoxicity was 68.5%; the incidence of serious events of cardiotoxicity was 9.1%; the incidence of cardiotoxicity which led to discontinuation is 0.5%. Incidence of fatal cardiotoxicity events is 0.5%. Cardiac arrest was reported as a fatal event; the patient experienced thrombocytopenia and neutropenia which contributed to cardiac arrest.

Hypersensitivity

Hypersensitivity reactions were very common ADRs in daunorubicin/cytarabine clinical studies. The most frequently reported hypersensitivity ADRs were rash and the majority of these were not serious (38.9%). The incidence of all hypersensitivity events was 66.9%; the incidence of non-serious events of hypersensitivity was 66.4%, of which 38.9% were rash; the incidence of serious events of hypersensitivity is 1.1%; the frequency of hypersensitivity which led to discontinuation is 0. The frequency of fatal hypersensitivity events was 0.

Paediatric population

The safety profile of daunorubicin/cytarabine in 38 paediatric patients with relapsed AML in study AAML1421 appeared to be in general similar to that observed in the approved indication in adults with newly treated AML treated with daunorubicin/cytarabine. However, adverse events in study AAML 1421 observed in paediatric patients that were different from or more severe than those seen in adults (acknowledging limitations of cross study comparisons) included rash maculo-papular (47.4%), electrocardiogram QT prolongation (28.9%), the early onset of cardiotoxicity (defined as >10% decrease LVEF to final LVEF <50% LVEF; 21.0%), severe hypokalaemia (13.2%), hyperglycaemia (7.9%) and ALT increased (7.9%). Hypertension was observed in 18.2% of these paediatric patients.

No paediatric long-term safety data beyond the study duration (26 months) are available. There is, thus, no paediatric safety data to address the long-term cardiotoxicity of daunorubicin/cytarabine, including long-term cardiotoxicity when used at doses above the maximum life-time cumulative anthracycline dose. There are no data on the effects of daunorubicin/cytarabine treatment on growth and maturation.