Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use

General: Only physicians experienced in cancer chemotherapy should use cytarabine.
Warnings:
Haematologic Effects: Cytarabine is a potent bone marrow suppressant; the severity depends on the dose of the drug and the schedule of administration. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leucocyte and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.

The main toxic effect of cytarabine is bone marrow suppression with leukopenia, thrombocytopenia, anaemia, megaloblastosis and reduced reticulocytes. Less serious toxicity includes nausea, vomiting, diarrhoea and abdominal pain, oral ulceration, and hepatic dysfunction (see section 4.8).

Following 5-day constant infusions or acute injections of 50 mg/m2 to 600 mg/m2, white cell depression follows a biphasic course. Regardless of initial count, dosage level, or schedule, there is an initial fall starting the first 24 hours with a nadir at days 7-9. This is followed by a brief rise which peaks around the twelfth day. A second and deeper fall reaches nadir at days 15-24. Then there is rapid rise to above baseline in the next 10 days. Platelet depression is noticeable at 5 days with a peak depression occurring between days 12-15. Thereupon, a rapid rise to above baseline occurs in the next 10 days.

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). Anaphylactic reactions have occurred with cytarabine treatment. Anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of Cytarabine (see section 4.8).

High Dose Schedules: Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of Cytarabine) has been reported following some experimental high dose (2-3 g/m2) schedules with Cytarabine. These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; somnolence; convulsion; severe gastro-intestinal ulceration, including pneumatosis cystoides 
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intestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema (see section 4.8).

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.

Precautions: Patients receiving Cytarabine must be monitored closely. Frequent platelet and leucocyte counts are mandatory. Suspend or modify therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte 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 12 to 24 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.

Peripheral motor and sensory neuropathies after consolidation with high doses of cytarabine, daunorubicin, and asparaginase have occurred in adult patients with acutenon lymphocytic leukemia. Patients treated with high doses of cytarabine should be observed for neuropathy since dose schedule alterations may be needed to avoid irreversible neurologic disorders.

Severe and sometimes fatal pulmonary toxicity, sudden respiratory distress syndrome and pulmonary oedema have occurred following experimental high dose schedules with cytarabine therapy.

Cases of cardiomyopathy with subsequent death have been reported following experimental high dose cytarabine and cyclophosphamide therapy when used for bone marrow transplant preparation. This may be schedule dependent.

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.

Conventional Dose Schedules: Abdominal tenderness (peritonitis) and guaiac positive colitis, with concurrent neutropenia and thrombocytopenia, have been reported in patients treated with conventional doses of cytarabine in combination with other drugs. Patients have responded to nonoperative medical management. Delayed progressive ascending paralysis resulting in death has been reported in children with AML following intrathecal and intravenous cytarabine at conventional doses in combination with other drugs.

Hepatic and/or Renal Function: The human liver apparently detoxifies a substantial fraction of an administered dose of cytarabine. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose treatment with cytarabine. Use the drug with caution and at reduced dose in patients whose liver function is poor.

Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine.

Neurological: Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given intravenous cytarabine in combination with intrathecal methotrexate.

The safety of this drug for use in infants is not established.

Tumour Lysis Syndrome: Like other cytotoxic drugs, cytarabine may induce hyperuricaemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood 2020-0061980                                Page 3 of 10
uric acid level and be prepared to use such supportive and pharmacological measures as may be necessary to control this problem.

Pancreatitis: Cases of pancreatitis have been observed with the induction of cytarabine.

Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cytarabine, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving cytarabine. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Excipient information
This medicinal product contains less than 1 mmol (23 mg) sodium in each vial, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Cytarabine has no effect on intellectual function or psychomotor performance. Nevertheless, 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.