INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
P&U CYTARABINE CSV

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

P&U CYTARABINE CSV

P & U CYTARABINE CSV 100 mg/5 mL INJECTION
P & U CYTARABINE CSV 500 mg/25 mL INJECTION
P & U CYTARABINE CSV 1 000 mg/10 mL INJECTION
P & U CYTARABINE CSV 2 000 mg/20 mL INJECTION

COMPOSITION:
P & U CYTARABINE CSV 100 mg/5 mL Injection: Each 1 mL contains 20 mg Cytarabine.
P & U CYTARABINE CSV 500 mg/25 mL Injection: Each 1 mL contains 20 mg Cytarabine.
P & U CYTARABINE CSV 1 000 mg/10 mL Injection: Each 1 mL contains 100 mg Cytarabine.
P & U CYTARABINE CSV 2 000 mg/20 mL Injection: Each 1 mL contains 100 mg Cytarabine.

PHARMACOLOGICAL CLASSIFICATION:
A 26 Cytostatic agents

PHARMACOLOGICAL ACTION:
CYTARABINE (Cytosine Arabinoside) is an analogue of 2'-deoxycytidine.
CYTARABINE must be "activated" by conversion to the 5'-monophosphate nucleotide (AraCMP), in this case catalysed by deoxycytidine kinase. AraCMP can then react with appropriate nucleotide kinases to form the diphosphate and triphosphate nucleotides (AraCDP and AraCTP). Accumulation of AraCTP causes potent inhibition of DNA synthesis in many cells.
Studies now indicate that inhibition of DNA synthesis by mammalian cells occurs at AraCTP concentrations 1/100 or less than those required for inhibition of DNA polymerise. There is a significant relationship between inhibition of DNA synthesis and the total amount of AraC incorporated into DNA. AraC inhibits B-DNA polymerise, an enzyme involved in DNA repair.
AraC is a potent inducer of tumour cell differentiation. Inhibition of DNA synthesis by AraC without concomitant inhibition of protein and RNA synthesis can result in marked increases in cellular volume and in cellular death.

INDICATIONS:
CYTARABINE is indicated for induction and maintenance of remission in acute myelocytic leukaemia of adults and children. It is also indicated for the treatment of acute lymphocytic leukaemia, and chronic myelocytic leukaemia (blast phase). CYTARABINE may be used alone or in combination with other antineoplastic agents. It is more effective when used in combination with other agents. It is also used in combination therapy for non-Hodgkin's lymphomas and intrathecally for prophylaxis or treatment of meningeal leukaemia.

CONTRA-INDICATIONS:
CYTARABINE is contra-indicated in patients with depressed bone marrow. Hypersensitivity to CYTARABINE. CYTARABINE is teratogenic in animals, therefore it should be avoided during pregnancy.

WARNINGS:
Only physicians experienced in cancer chemotherapy should use CYTARABINE. For induction therapy patients should be treated in a facility with laboratory and supportive resources sufficient to monitor medicine tolerance and protect and maintain a patient compromised by toxicity of the agent. The main toxic effect of CYTARABINE is bone marrow suppression with leucopenia, thrombocytopenia and anaemia. The possible benefit of the medicine must be judged against the known toxic effects of the medicine in considering the advisability of therapy with CYTARABINE.
CYTARABINE is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing medicine-induced bone marrow suppression. Patients receiving this medicine must be under close medical supervision and during induction therapy should have leucocyte and platelet counts performed daily.
Facilities should be available for management of complications, possibly fatal, of bone marrow suppression. Anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of CYTARABINE. Seizures and other manifestations may occur after intrathecal administration. Breast-feeding is not recommended because of risk of serious side effects.
Fatal cardiomyopathy has been reported following high dose CYTARABINE. This may be dosage dependant.
A potentially fatal syndrome of sudden respiratory distress progressing to pulmonary edema and cardiomegaly has been reported with high dose therapy.

DOSAGE AND DIRECTIONS FOR USE:
The physician should in all cases be familiar with the current literature before choosing a specific dosage.
Dosage for induction or remission of acute myelocytic leukaemia is 100 to 200 mg/m² by rapid body surface or 2 mg - 6 mg/kg body mass intravenous infusion daily over 1 to 24 hours or intravenous injection for 5 to 7 days or until bone-marrow hypoplasia occurs.
Courses may be repeated after 7 to 14 days or once a degree of bone marrow recovery has occurred.
Maintenance therapy with intravenous, intramuscular or subcutaneous injections of 1 to 1,5 mg/kg weekly or every other week can be used.
In the treatment of refractory disease high dose regimens have been employed, with CYTARABINE given in doses of up to 3 g per m² by continuous intravenous infusion every 12 hours for 6 days.
In prophylactic use for leukaemic meningitis CYTARABINE has been given intrathecally, often in a dose of 10 to 30 mg per m² bodysurface every 2 to 4 days.
P&U CYTARABINE 100 mg/mL injection should not be administered by the intrathecal route due to the slight hypertonicity of this formulation.
In general, children seem to tolerate higher doses than adults.
CYTARABINE may be used continuously with 5% dextrose, 0,9% sodium chloride, sodium bicarbonate equivalent to 50 mEq/l in dextrose 5 % in water, or dextrose 5% in 0,2% sodium chloride.
Heparin, insulin, methotrexate, 5-fluorouracil, penicillins (such as oxacillin and Pen-G), and Solu-Medrol is incompatible with CYTARABINE and should not be mixed in the same container.
Discard any unused portion.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The major adverse effect of CYTARABINE is bone marrow depression, manifested as leucopenia, particularly granulocytopenia, thrombocytopenia, and anaemia, sometimes with striking megaloblastic changes and reduced reticulocytes. The severity of these reactions is dose and schedule dependent. Cellular changes in the morphology of bone marrow and peripheral smears can be expected. Following 5-day constant infusions or acute injections white cell depression follows a biphasic course. Regardless of initial count, dosage level or schedule there is an initial fall starting within the first 24 hours with a nadir between 7 to 9 days. This is followed by a brief rise, which peaks around the twelfth day. A second and deeper fall reaches nadir between days 15 to 24. Then there is rapid rise to above baseline in the next 10 days.
Platelet depression is noticeable after 5 days with a peak depression occurring between days 12 to 15. Recovery generally occurs in the next ten days.
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. These infections may be mild, but can be severe and at times fatal.
Incidence of side effects is higher with continuous intravenous administration than with rapid intravenous injection.
The most frequent adverse reactions are anorexia, nausea and vomiting which may be more severe when doses are given rapidly, hepatic dysfunction, fever and rash. Thrombophlebitis has occurred at the site of injection or infusion.
Less frequent adverse reactions are sepsis, cellulitis at injection site with subcutaneous injection, skin ulceration, urinary retention, renal dysfunction, neuritis, neurotoxicity (particularly via the intrathecal route), sore throat, oesophageal ulceration, oesophagitis, chest pain, headache, urticaria, pneumonia, abdominal pain, freckling, jaundice, conjunctivitis (may occur with rash), dizziness, alopecia, anaphylaxis (see WARNINGS), allergic edema, pruritus and shortness of breath. A CYTARABINE syndrome characterized by bone and muscle pain, fever, malaise, occasionally chest pain, conjunctivitis and maculopapular rash, sometimes described as "flu-like", has been reported. It usually occurs 6 - 12 hours following CYTARABINE administration. It may be prevented or treated with corticosteroid therapy.
High-dose therapy has been associated with particularly severe gastro-intestinal and pulmonary toxicity and central nervous system effects (different from that of conventional high dose 2-3 g/m²). These reactions include severe ulceration of the gastro-intestinal tract, pneumatosis cystoides intestinalis leading to peritonitis, necrotising colitis and bowel necrosis, peripheral neuropathy, and cerebral and cerebellar dysfunction, with personality changes, somnolence, and coma ( usually reversible). There may also be reversible corneal toxicity and haemorrhagic conjunctivitis (which can be prevented or reduced with prophylactic local corticosteroid eye drops), sepsis, liver abscess, severe skin rash leading to desquamation, and complete alopecia. Pulmonary edema and cardiomegaly and cardiomyopathy, sometimes fatal, have occurred (See also WARNINGS).
Acute pancreatitis has been reported in patients treated with CYTARABINE in combination with other products and in patients previously treated with asparaginase.
CYTARABINE may induce hyperuricemia secondary to rapid lysis of neoplastic cells. This can lead to elevated serum uric acid levels and supportive and pharmacological measures might be necessary to control this problem.
Anti-emetic therapy should be given to reduce, and if possible prevent, nausea and vomiting, since once experienced, it may become a conditioned response, and may not respond to anti-emetics.
Patients receiving the agent should be kept under close medical supervision. Leucocyte and platelet counts should be performed frequently and daily during induction. Consider suspending or modifying therapy when medicine-induced marrow depression has resulted in platelet counts under 50 000 or leucocyte counts under 1 000/ mm³. Counts of formed elements in the peripheral blood may continue to fall after the medicine is stopped and reach lowest values after medicine-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear. These levels may be lower than normal to avoid patient escape from control.
Patients with renal or hepatic function impairment (where there is a risk of reduced detoxification of CYTARABINE) may have a higher likelihood of central nervous system toxicity after high dose CYTARABINE and should be used with caution in these patients.
Of particular importance is the management of bone marrow depression. Active measures may be necessary to combat infection and bleeding.
Intrathecal use may result in systemic toxicity and careful monitoring of the hemopoietic system is indicated. Modification of the anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in patients treated with CYTARABINE, methotrexate and hydrocortisone, as well as central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in patients who had combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal CYTARABINE.
Interactions
Cardiac glycosides:
Reversible decreases in steady state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without CYTARABINE or procarbazine. Steady state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens.
Anti-infective agents:
CYTARABINE may antagonise the activity of gentamicin against Klebsiella pneumoniae.
Limited data suggest that CYTARABINE may antagonise the activity of fluorocytosine, possibly by competitive inhibition of the anti-effective uptake by fungi.
Combination therapy:
Hepatic dysfunction was associated with the combined use of CYTARABINE and daunorubicin.
Veno-occlusive disease was associated with combined thioguanine and CYTARABINE therapy.
Allopurinol, colchicine, probenecid or sulfinpyrazone may interact with CYTARABINE.
Blood dyscrasia-causing medication (increase in leucopenia and/or thrombocytopenic effects), bone marrow depressants or radiotherapy (additive bone marrow depression), cyclophosphamide (increased cardiomyopathy), methotrexate (synergistic cytotoxic effect), killed vaccines (decreased response), live vaccines (replication of virus may be potentiated, increased side effects and decreased antibody response).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See SIDE-EFFECTS AND SPECIAL PRECAUTIONS.
Cessation of therapy followed by management of ensuing bone-marrow depression including whole blood platelet transfusion and antibiotics as required.
Treatment is symptomatic and supportive.

IDENTIFICATION:
A clear, colourless solution free from visible particles.

PRESENTATION:

P & U CYTARABINE CSV 100 mg/5 mL:	Packs of 5 x 5 mL single dose vials
P & U CYTARABINE CSV 1 000 mg/10 mL:	Single dose Vials
P & U CYTARABINE CSV 500 mg/25 mL:	Single dose Vials
P & U CYTARABINE CSV 2 000 mg/20 mL:	Single dose Vials

STORAGE INSTRUCTIONS:
Store between 15 - 25°C. Protect from light. If a precipitate has formed as a result of exposure to low temperatures, redissolve by warming to 55°C with adequate shaking. Allow to cool prior to use.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBERS:
P & U CYTARABINE CSV 100 mg/5 mL (INJECTION): 29/26/0499
P & U CYTARABINE CSV 500 mg/25 mL (INJECTION): 30/26/0308
P & U CYTARABINE CSV 1 000 mg/10 mL (INJECTION): 29/26/0500
P & U CYTARABINE CSV 2 000 mg/20 mL (INJECTION): 30/26/0309

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Limited
Alphen West G
George Street
MIDRAND
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
December 1995
New addition to this site: February 2005
Source: Pharmaceutical Industry
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