Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Cytarabine should only be used with caution in specialised oncological institutions with facilities for regular monitoring of clinical, biochemical and haematological parameters before, during, and after administration. The usual precautions must be followed when handling the vials (safety glasses, gloves, mouth and nose protection, exhaust ventilation if possible). Particular care must be taken to ensure that facilities are available to monitor the effect on the patient and take appropriate measures if necessary.

Haematological effects
Cytarabine has a potent myelosuppressive effect. The treatment should be initiated carefully in patients with a history of medication-induced bone marrow suppression.
Patients who receive this medicinal product must be closely monitored. Furthermore, at the beginning of the treatment, the leukocyte and platelet counts should be determined daily. In general, the platelet and leukocyte counts should be determined as frequently as possible and regularly monitored after the end of therapy. This also applies to intrathecal use.
If a drug-induced bone marrow suppression has resulted in a platelet count <50,000 or polymorphonuclear count <1,000/mm3, the therapy should be discontinued or modified. The number of formed elements in peripheral blood can further decrease following administration of the medicinal product has ceased, and reaches nadir after 5−7 medication-free days. If indicated, the therapy should be re-started if obvious signs of bone marrow recovery are seen (in consecutive bone marrow tests). For patients in whom the medicinal product is not administered until the “normal” peripheral blood values are achieved, monitoring is not required.

Regular bone marrow tests should be performed once peripheral blood shows no more blasts.

Facilities should be available to treat the possibly fatal complications of bone marrow suppression (infections due to granulocytopenia and other affected defence mechanisms, secondary haemorrhaging due to thrombocytopenia).

Tumour lysis syndrome
Like other cytostatics, cytarabine can cause hyperuricaemia due to rapid lysis of neoplastic cells.
The physician should monitor the uric acid levels in the blood and be prepared to use supportive and pharmacological measures that may be required to control the complications that arise.
In patients with high blast counts or extensive tumour masses (non-Hodgkin’s lymphoma), hyperuricaemia prophylaxis is recommended. Facilities for supportive measures should be available.

Hepatic and renal impairment are considered to be predisposing factors for the increased CNS toxicity of cytarabine.

Anaphylactic reactions occurred during cytarabine therapy. One case of anaphylaxis was reported, which lead to acute cardiopulmonary arrest, requiring resuscitation. This occurred immediately following intravenous administration of cytarabine (see section 4.8).

High-dose therapy
The risk of CNS undesirable effects is higher for patients who were previously treated for a CNS disorder with intrathecal chemotherapy or radiation therapy.

In patients with acute non-lymphatic leukaemia, peripheral motor and sensory neuropathy occurred following consolidation with high-dose cytarabine, daunorubicin and asparaginase therapy. Patients treated with high cytarabine doses should be investigated for neuropathy, as dose adjustments may be required to prevent irreversible neurological damage.

Following some experimental high-dose regimens (2–3 g/m2) with cytarabine, severe and occasionally fatal toxicity of the central nervous system, the gastrointestinal tract and the lungs (unlike with conventional therapy regimens with cytarabine) have been reported. These reactions included reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; somnolence; seizures; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis, which led to peritonitis; septicaemia and hepatic abscess; adult respiratory distress syndrome (ARDS) and pulmonary oedema (see section 4.8).

Cytarabine has been shown to be mutagenic and carcinogenic in animals. The possibility of a similar effect should be considered in the long-term management of the patient.

If the intravenous dose is administered quickly, patients are often nauseous, with vomiting occurring for several hours after administration. This problem is less pronounced if the medicinal product is infused.

Conventional dose regimen
In patients who were treated with conventional cytarabine doses in combination with other medicinal products, abdominal tenderness (peritonitis) and guaiac-positive colitis with neutropenia and thrombocytopenia were reported. These patients responded to non-surgical medical treatment.

In children with AML, delayed progressive, ascending and fatal paralysis was reported following intrathecal and intravenous administration of conventional cytarabine doses in combination with other drugs.

Hepatic and renal function:

Hepatic and renal function should be monitored during a cytarabine therapy. Special caution is required in cases of mild hepatic and renal impairment.
Periodic tests of bone marrow, hepatic and renal function should be performed on patients receiving cytarabine.

As cytarabine is predominantly metabolized in the liver, the substance may have a stronger effect in hepatic damage. An increased effect is also seen in renal impairment. In cases of renal and/or hepatic impairment, the dose should be reduced accordingly while monitoring the blood levels.
Especially patients with impaired hepatic and/or renal function have an increased risk of CNS toxicity after a treatment with high dose cytarabine. Hepatic and renal function and uric acid levels should be regularly monitored. In patients with pre-existing hepatic dysfunction, cytarabine should be used with care, at a reduced dose, and only after a strict risk-benefit analysis.

Following experimental high-dose cytarabine therapies in combination with cyclophosphamide as preparation for a bone marrow transplant, cases of cardiomyopathy and resulting deaths were reported.

Large fluid intake is indicated.

High-dose cytarabine treatment should only be given to patients aged over 60 after especially careful risk-benefit analysis.

Contraceptive measures
Cytarabine can have mutagenic effects. Men should therefore not father children during treatment and for up to six months after end of treatment. Furthermore, they should be informed before treatment about the possibility of sperm preservation, as cytarabine therapy may cause irreversible infertility.

If patients wish to have children after completing therapy, genetic counselling is strongly recommended.

Severe gastrointestinal undesirable effects require anti-emetic and other supportive measures.

Treatments with high doses require regular monitoring of CNS and lung function by a physician experienced in this type of treatment.

In order to prevent ophthalmological complication, the eyes should be rinsed regularly during high- dose treatment.

In cases of severe bone marrow suppression, the patients should be transferred to a sterile isolation room.

Immunosuppressive effects/increased susceptibility to infections
In patients with immunosuppression due to chemotherapeutic drugs like cytarabine, the administration of live vaccines can lead to severe or life-threatening infections.
During cytarabine therapy, no vaccinations with live vaccines should be performed. Dead vaccines or inactivated vaccines can be administered, however the response to these vaccines may be reduced.


Like other tumour-inhibiting substances, cytarabine treatment bears the risk of bleeding complications and severe infections due to bone marrow suppression. During high-dose therapy, CNS disorders, gastrointestinal disorders, hepatic dysfunction, skin reactions and eye disorders may occur.

If signs of CNS toxicity appear, or an allergy, a thorough risk-benefit evaluation should be performed.

Contact with skin and mucosa, especially in the area around the eyes, should be avoided.
Cytarabine is a teratogenic and mutagenic substance.

The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role in breaking down 5-FU. Nucleoside analogues, e.g. brivudine and sorivudine, may increase the plasma concentration of 5-FU and other fluoropyrimidines, thereby causing a marked increase in toxicity.

Furthermore, at least 4 weeks must pass between treatment with Alexan and brivudine, sorivudine, and analogues.

If applicable, determination of DPD enzyme activity is indicated prior to the treatment with Alexan. In case of an inadvertent administration of brivudine to patients receiving Alexan, effective measures should be taken to reduce the fluorouracil toxicity. Immediate hospitalisation is recommended. All measures should be initiated to prevent systemic infections and dehydration.

Patients receiving phenytoin together with Alexan should be regularly investigated for elevated phenytoin plasma levels.

Pancreatitis
Cases of pancreatitis have been observed after cytarabine use.

Neurology
Cases of severe neurological undesirable effects, ranging from headache to paralysis, coma, and stroke-like episodes, were observed mainly in children and adolescents receiving intravenous cytarabine in combination with intrathecal methotrexate.

Paediatric population
Safety in infants was not proven.

Alexan contains sodium:
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially ‘sodium-free’.

Effects on Driving

4.7   Effects on ability to drive and use machines

Cytarabine has no effect on the ability to drive or use machines. However, in patients receiving chemotherapy the ability to drive or use machines may be impaired due to undesirable effects.
Patients should therefore be informed and instructed not to perform such activities if possible.