Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

The safety of this drug for use in infants is not established.
ARA-cell® 5 g must not be administered intrathecally and should not be administered undiluted (hypertonic solution!).

Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre- existing drug-induced bone marrow suppression.
For induction and consolidation in acute leukaemia, treatment with ARA-cell® should be performed only on an inpatient basis under the supervision of experienced oncologists and requires careful monitoring. Regular blood count monitoring is required, as well as monitoring of liver and kidney function and serum uric acid levels. In patients with high blast counts or extensive tumour masses (non-Hodgkin’s lymphomas), preventive treatment against hyperuricaemia is recommended. Supportive therapeutic measures should be available.

Anaphylaxis
Treatment with cytarabine may be associated with anaphylactic reactions. One case of anaphylactic shock with acute cardiopulmonary failure and the need for resuscitation has been reported in the literature. This event occurred immediately after IV administration of cytarabine.

Tumour lysis syndrome
Like other cytostatic drugs, cytarabine may produce secondary hyperuricaemia following rapid lysis of neoplastic cells. Therefore, uric acid levels in the blood should be monitored at regular intervals, taking appropriate action if necessary.

Liver and kidney function
In patients with pre-existing impairment of liver or kidney function, the risk of CNS toxicity may increase, especially at higher dosages. These patients should be given cytarabine only with caution, adjusting the dosage as necessary. Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine.

High-dose therapy
High-dose therapy with 2-3 g/m² cytarabine may be associated with serious, sometimes fatal CNS, gastrointestinal and pulmonary toxicity. The following reactions may occur: reversible corneal toxicity and haemorrhagic conjunctivitis; usually reversible cerebral and cerebellar dysfunction including personality changes, somnolence, convulsions and coma, affected alertness, dysarthria, ataxia, tremor, nystagmus, headache, confusion, dizziness, etc. appear in 8-37% of treated patients. Peripheral motor and sensory neuropathies have also been reported with high dose therapy. The incidence in elderly (>55 years) may be even higher. Other predisposing factors are impaired liver and renal function, previous CNS treatment (e.g., radiotherapy) and alcohol abuse. CNS disturbances are in the most cases reversible.
The risk of CNS toxicity increases if the cytarabine treatment - given as high dose i.v.- combined with another CNS toxic treatment such as radiation therapy or high dose.
Corneal and conjuctival toxicity: Reversible lesion of corneal and haemorrhagic conjunctivitis have been described. These phenomena can be prevented or decreased by installation of corticosteroid eye drops.
 severe gastrointestinal ulcerations including Intestinal perforation, pneumatosis cystoides intestinalis, which may lead to peritonitis, sepsis and liver abscess, intestinal necrosis with ileus, necrotising colitis, liver damage with hyperbilirubinaemia, hepatomegaly, Budd- Chiari-syndrome (hepatic venous thrombosis) and pancreatitis.
The pulmonary toxicity includes the following reactions in particular: pulmonary oedema and acute respiratory distress syndrome (ARDS). The reaction is probably caused by an alveolar capillary injury. It is difficult to make an assessment of frequencies (stated as 10- 26% in different publications), since the patients usually have been in relapse where other factors may contribute to this reaction.

In high-dose treatments, ongoing monitoring of CNS and lung function should be performed by doctors with proven experience of this treatment. To avoid ophthalmological complications, regular rinsing of the eyes is required in high-dose therapy.

Patients may very rarely experience severe exanthema with desquamation, alopecia.
Viral, bacterial, fungal, parasitic, or saprophytic infections, in any location in the body. May be associated with the use of Cytarabine alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity.

Following administration of high-dose cytarabine in combination with daunorubicin and asparaginase, adult patients with acute myeloid leukaemia rarely experienced peripheral motor and sensory neuropathies. Close monitoring and dose adjustment as necessary are recommended to prevent irreversible neurological injury.

Experimental high-dose therapy with cytarabine and cyclophosphamide for preparation for bone-marrow transplantation has been associated with cases of cardiomyopathy, some with a fatal outcome.
In high-dose treatment, profound Pancytopenia seen which may last 15-25 days along with more severe bone marrow aplasia than that observed at conventional doses.


In the event of severe gastrointestinal reactions, antiemetic measures and supportive therapeutic measures are indicated.

Due to the marked suppression of bone marrow function, patients receiving induction therapy or consolidation therapy should be placed in sterile isolation.

During therapy with ARA-cell®, no vaccinations with live pathogens should be given.

As with treatment with other antitumour agents, there is a risk of bleeding complications and dangerous infections during treatment with ARA-cell®, due to bone marrow suppression.

Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.
Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defences, and haemorrhage secondary to thrombocytopenia).

Suspend or modify therapy when drug induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear count under 1,000 per cubic mm.
Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped, and reach lowest values after drug free intervals of five to seven days. If indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until 'normal' peripheral blood values are attained may escape from control.

If signs of CNS toxicity occur, or if there are any signs of allergy development, a special risk assessment is recommended.
The risk of CNS side effects is higher in patients who have previously had CNS treatment as chemotherapy intrathecally or radiation therapy.

Cytarabine is a teratogenic and mutagenic substance.

Cytarabine 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.

Contact with the skin and mucous membranes (especially in the eye area) should be avoided.

Extravasation of cytarabine during intravenous administration must be avoided because of the risk of severe local tissue injury. Administration must be stopped immediately if there are any signs of extravasation.

When intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours afterwards. This problem tends to be less severe when the drug is infused.

Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency have been reported.

Combination therapy
The use of cytarabine in combination with other products may be associated with abdominal tenderness (peritonitis) and guaiac test positive colitis, with concurrent neutropenia and thrombocytopenia. Patients have responded to drug therapy.

Delayed progressive ascending paralysis resulting in death has been reported in children with acute myeloid leukaemia following concurrent intrathecal and intravenous administration of cytarabine in combination with other products.

Patients treated with cytarabine in combination with other products may develop acute pancreatitis.

Excipients:
ARA-cell® 5 g contains 11.15 mmol (256.5 mg) sodium per vial with 50 ml concentrate, equivalent to 12.83% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effects on Driving

4.7 Effects on ability to drive and use machines

Due to its undesirable effects, (vomiting, dizziness, eye complaints), cytarabine may influence the ability to drive and use machines. patients receiving chemotherapy may have an impaired ability to drive or operate machinery and should be warned of the possibility and advised to avoid such tasks if so affected.