Cerubidin 20mg Powder for Solution for Injection

Section 4.4

Posterior reversible encephalopathy syndrome (PRES):

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.

Section 4.8

Infections and Infestations

Very common:  serious infections (including sepsis, septic shock and pneumonia), which sometimes can be fatal.

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 should be administered with caution when the neutrophil count is <1,500/mm3. Daunorubicin dose reduction should be considered in case of severe neutropenia.

The number of infusions required varies widely from patient to patient and must be determined in each case according to response and tolerance.

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.

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).

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.

PRES, a neurologic disorder, has been reported in patients receiving daunorubicin combination chemotherapy. PRES may present with headache, visual disturbances, altered mental status, confusion, status epilepticus, seizures, nausea and vomiting, usually associated with hypertension. The diagnosis of PRES requires confirmation by brain Magnetic Resonance Imaging (MRI). Discontinuation of daunorubicin therapy is recommended in patients developing PRES. Symptoms, including uncontrolled hypertension, should be treated promptly. Clinical symptoms and MRI changes usually improve within a few weeks after treatment discontinuation. Following resolution of PRES, daunorubicin treatment may be resumed at the discretion of the prescriber. Cases of neurologic sequelae and fatal outcomes have been reported (see section 4.8).

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

Care should be taken to avoid extravasation during intravenous administration. 

4.7       Effects on ability to drive and use machines

Not applicable

. 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). 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.

4.8       Undesirable effects

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. 

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Frequency not known:  secondary malignancies, including leukaemia has have been reported in association with daunorubicin when used in combination with other antineoplastics.treatments known to be associated with secondary malignancies.

Metabolism and nutrition disorders

Frequency not known:  Tumour lysis syndrome.

Nervous system disorders

Frequency not known: Posterior Reversible Encepahlopathy Syndrome (PRES, also known as Reversible Posterior Leukoencephalopathy Syndrome, RPLS), including with fatal outcomes, has been reported.

Other less serious adverse reactions that have been reported (in order of reducing frequency) are: stomatitis, alopecia, phlebitis, fever, anaemia, nausea, vomiting, mucositis, diarrhoea and rash.

Gastrointestinal disorders:

Unknown: colitis.

Blood and lymphatic system disorders:

Very common:  Bone marrow failure.

Approved changes to affect the following sections of the SPC

Section 6.3: Shelf life

Section 6.4: Special Precautions for storage

Section 6.6: Instructions for use/handling