Rx Prescription information
(Information for Experts)
Name of the medicinal product:CYTARABINE-BELMED
Appearance:Clear, colorless solution.
Composition per ampoule:
Active substance – cytarabine 100 mg
Excipients – sodium chloride, water for injection.
Pharmaceutical form: Solution for injection.
Pharmaceutical group: Anti-tumor preparations. Anti-metabolic agents. Pyrimidine analogues.
ATC Code: L01BC01.
Cytarabine has anti-tumor, immunity suppressing effects. It is referred to the group of anti-metabolic agents for the pyrimidine metabolism and is active against leukemia. The Cytarabine anti-leukemia action is caused by the myeloblasts, lymphoblasts, and lymphocytes proliferation hindering.
Cytarabine (ARA-C) is metabolised in vivo to ARA-CTP phosphorylated compound. This competitively inhibits DNA polymerase and may also inhibit certain acid kinase enzymes. Primarily the drug acts as a false nucleoside and competes for enzymes involved in the conversion of cytidine nucleotide to deoxycytidine nucleotide and also incorporation into the DNA.
Cytarabine has no effect on non proliferating cells nor on proliferating cells unless in the S phase. It is a cell cycle specific antineoplastic drug.
Cytarbine is rapidly metabolised and is orally ineffective. Less than 20% of a dose administered orally is absorbed in the gastrointestinal tract.
In the event of continuous intravenous administration, virtually constant plasma levels are achieved.
After subcutaneous administration of cytarabine, peak plasma levels are achieved approximately 20 to 60 minutes after injection which are significantly lower than after intravenous administration.
Cytarabine serum levels can vary considerably from patient to patient for an identical dose. Some studies have shown that these variations could be linked to the clinical response: high serum levels guarantee the best chance of haematological remissions.
Cytarabine has a distribution volume of 0.7 l/kg. Cytarabine should be intrathecally administered as prophylaxis and in the treatment of CNS leukaemia, because intravenously administered cytarabine only crosses the blood-brain barrier in limited quantities. Intrathecal administration of cytarabine results in extremely low plasma levels.
It penetrates badly through the hematoencephalic barrier after a single intravenous infusion whereas a continuous infusion provides its concentration in the cerebrospinal fluid equal to 40% – 50% of the blood level.
Cytarabine is converted rapidly by deoxycitidine kinase and other nucleotidases into its active form (cytarabine-5' triphosphate) by phosphorylation in leukaemic blast cells and in healthy bone marrow. Metabolism into the inactive compound uracilarabinoside (1-beta-D-arabinofuranosyluracil) by means of cytidinedeaminase activity takes place primarily in the liver, and to a lesser extent in the other tissues and blood.
It is assumed that the balance between kinase and deaminase levels can form an important factor in the determination of whether the cell is sensitive or resistant to cytarabine.
Binding to plasma protein is low (13.3%) with concentrations of 0.005 – 1 mg/l
The percentage of bound drug was independent of the concentration within the limits indicated.
After a rapid intravenous infusion of cytarabine, biphasic elimination from the blood takes place. There is an initial distribution phase with a half life of 1-3 hours.
After 24 hours, appoximately 80% of the administered cytarabine is found in the urine, 90% of which is excreted as inactivated metabolite and 10% as unchanged cytarabine.
Due to the low cytarabinedeaminase activity in the cerebrospinal fluid, cytarabine has an elimination half life in the CNS of 3 - 3.5 hours.
+ Lymphoblast and myeloblast leukemia
+ Chronic myeloleukemia
+ Erythroleukemia, lymphogranulomatosis
+ Non-Hodgkin’s lymphoma
+ Syndrome of bone marrow dysplasia.
The Cytarabine high-dose therapy is applied within the induction and consolidation programs under primary acute lymphoblast and myeloblast leukemia; under secondary leukemia developed either after the preceding cytostatic and/or beam therapy or as a result of the MDS transformation; under primarily resistant forms of acute leukemia; under resistant relapses of acute leukemia; under a blast crisis of chronic myeloleukemia; under resistant forms of highly malignant Hodgkin’s and non-Hodgkin’s lymphomas.
Clinicians should refer to the current literature on combination therapy before initiating treatment.
Mode of administration and dosage:
Cytarabine20 mg/ml Injection is a ready to use solution and is suitable for intravenous, subcutaneous or intrathecal use.
Cytarabine 20 mg/ml Injection can be diluted with Sterilised Water for Injection, Glucose Intravenous Infusion or Sodium Chloride Intravenous Infusion (based on: for intravenous administration – 100 mg of cytarabine in 400 ml of solvent). Prepared infusions, in the recommended diluents should be used immediately. Alternatively,the diluted infusion fluids may be stored at 2-80C, protected from light, but portions remaining unused after 24 hours must be discarded.
Cytarabine is injected intravenously in the dose 100 mg/m2 per 24 hours: in form of two drop infusions for 3 hours with a 10-hour interval or continuously for 24 hours.
Elderly patients and those lacking hematopoietic reserves are administered the preparation in smaller doses – 50 – 75 mg/m2 per 24 hours.
A course dose is 500 – 1000 mg. Intervals between the courses are 7 – 14 days.
The Cytarabine high-dose therapy can be performed by 3 g/m2 infusions for 75 minutes every 12 hours for 1 – 6 days.
Cytarabine is injected subcutaneously in the day dose 20 mg/m2 2 – 3 times a day every day for 3 – 10 days (no longer).
The drug is administered intrathecally as a prophylactic agent every 3 days for 2 weeks the dose being 20 mg/m2.
For determining the drug individual tolerance, the single dose may be increased step-by-step from 3 mg/m2 to 20 mg/m2.
Totally 4 – 7 therapeutic courses are carried out; intervals between the courses are 10 – 14 days or more.
The Cytarabine therapy course may be repeated after the haematopoeisis has been restored.
The Cytarabine high-dose therapy should be performed by physicians and specially trained medical staff having experience of chemotherapy for oncohematological diseases at special hospitals (units).
When a combined chemotherapy is carried out the Cytarabine doses are cut.
Cytarabine may be administered alone or combined with other cytostatic preparations (Thioguanin, Doxorubicin, Daunorubicin, etc.) and Prednisolone.
Children appear to tolerate higher doses of cytarabine than adults, and where the range of doses is given, children should receive the higher dose.
Cytarabine is contraindicated in patients with known hypersensitivity to the drug. Therapy with cytarabine should not be considered in patients with pre-existing drug-induced bone marrow suppression, unless in the opinion of the physician the potential benefits outweigh the hazards. Cytarabine should not be used in the management of non-malignant disease, except for immunosuppression.
Cytarabine is contraindicated in patients with acute infectious diseases.
Cytarabine should not be used in pregnant or breast feeding women (the breast feeding should be stopped for the therapy period).
Treating with Cytarabine is carried out under the peripheral (every day or every other day) and bone marrow (before every therapeutic course and after the same) leukocytes numbers control. When the platelets number is less than 50,000/mm3 and/or the polymorph granulocytes number less than 1000/mm3 treatment is stopped.
Cytarabine is administered cautiously in patients their bone marrow infiltrated by tumor cells.
Cytarabine administration is not recommended for patients with varicella (including the survived one recently or after a contact with a sick person), herpes zoster.
The liver functional state should be controlled at least once a week, the kidneys excretory function should be controlled before the beginning of the therapeutic course by Cytarabine and after it has been completed.
When the Cytarabine high-dose therapeutic programs are carried out the blood count and biochemical values should be monitored daily. The patients having hyperleucocytosis or a large tumor (for lymphoma) initially should be controlled the blood uric acid levels.
It has been determined in experimental studies that Cytarabine has teratogenic, embryotoxic, and mutagenic effects.
For preventing hyperuricemia, allopurinol and ingestion of sufficient amounts of liquids are recommended.
In 24 hours after the Cytarabine administration, the leucocytes number reduces, achieves the minimal values by day 7 – 9, then increases for a short time up to day 12 reducing again achieving the minimum on day 15 – 24. The leucocytes number increases quickly for the next 10 days achieving the initial value. The platelets number reduces significantly on day 5 after the Cytarabine administration the level being lowest on day 12 – 15 and achieving the initial value within the next 10 days.
Measures of precaution:
Cytarabine is a potent bone marrow suppressant. Patients receiving the drug should be kept under close medical supervision. Leucocyte and platelet counts should be performed frequently and daily during induction. One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitiation has been reported. This occurred immediately after intravenous cytarabine was administered.
Severe and at times fatal central nervous system (CNS), gastrointestinal (GI) and pulmonary toxicity (different from that seen with conventional therapy regimens of dosage schedules). These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; severe gastrointestinal ulceration including pneumatosiscysteroidesintestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema.
Central Nervous System: Rarely, neurological effects such as quadriplegia and paralysis have been reported with cytosine arabinoside and have been predominantly associated with intrathecal administration. Isolated cases have also been reported with high intravenous doses during combination chemotherapeutic regimens.
Cytarabine has been shown to be mutagenic and carcinogenic in animals.
Cytarabine should only be used under the constant supervision by physicians experienced in therapy with cytotoxic agents. Hyperuricaemia secondary to lysis of neoplastic cells may occur in patients receiving cytarabine; serum uric acid concentrations should be monitored.
Periodic determinations of renal and hepatic functions and bone marrow should also be performed and the drug should be used with caution in patients with impaired hepatic function.
However, dosage reduction does not appear to be necessary in patients with impaired renal function. The human liver apparently detoxifies a substantial fraction of the administered dose. The drug should be used with caution and at a reduced dose when liver function is poor. Frequent platelet and leucocyte counts are manditory. Therapy should be suspended or modified when drug-induced bone marrow depression results in a platelet count of less than 50,000 or a polymorphonuclear count of under 1000 per mm3. Counts may continue to fall after the therapy has been discontinued and may reach lowest values after five to seven days. Therapy may be restarted when the bone marrow appears to be recovering on successive bone marrow studies. Therapy should not wait until the normal blood values are obtained to be re-initiated.
When intravenous doses are given quickly, patients may become nauseated and may vomit for several hours afterwards. The problem tends to be less severe when infused.
When given intrathecally, as with any other intrathecal drug, care must be taken with radiotherapy given either during or after treatment; it is well recognised that this can exacerbate the toxicity of radiotherapy.
The safety of the drug has not been established in infants.
When the drug gets on skin accidently the skin should be washed under running water with soap
Use in Pregnancy:
Cytarabine is teratogenic in some animal species. It should not be used in pregnant women (especially during the first trimester) or in those who may become pregnant, unless the possible benefits outweigh the potential risks. Women who are, or become, pregnant during treatment with cytarabine should be informed of the risks.
Use in Lactation:
Cytarabine should not be used in breast feeding women (the breast feeding should be at least stopped for the therapy period).
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.
Interaction with other drugs and other forms of interaction:
GI absorption of oral digoxin tablets may be substantially reduced in patients receiving combination chemotherapy regimens (including regimens containing cytarabine), possibly as a result of temporary damage to intestinal mucosa caused by the cytotoxic agents. Limited data suggest that the extent of GI absorption of digitoxin is not substantially affected by concomitant administration of combination chemotherapy regimens known to decrease absorption of digoxin.
One in vitro study indicates that cytarabine may antagonise the activity of gentamicin against Klebsiella pneumoniae. Limited data may suggest that cytarabine may antagonise the anti-infective activity of flucytosine, possibly by competitive inhibition of the anti-infective uptake by fungi.
Solutions of cytarabine have been reported to be incompatible with various drugs, i.e. carbenicillin sodium, cephalothin sodium, fluorouracil, gentamicin sulphate, heparin sodium, hydrocortisone sodium succinate, insulin-regular, methotrexate, methylprednisolone sodium succinate, nafacillin sodium, oxacillin sodium, penicillin G sodium. However, the incompatibility depends on several factors (e.g. concentrations of the drug, specific diluents used, resulting pH, temperature). Specialised references should be consulted for specific compatibility information.
When administered in combination with other anti-tumor drugs and with radiation therapy a reciprocal aggravation of toxicity and immunosuppressive effects are possible.
Immunity suppressing preparations (Azatioprim, Chlorambucol, GCS, Cyclophosphamide, Cyclosporine, Mercaptopurin, Tacrolimus) increase the risk of infectious complications development.
Vaccinations using killed viruses (the antibodies generation is reduced because of the protective mechanisms reduction) and with live vaccines (the side effects number increase, the anti-bodies generation reduction) are inefficient.
The major adverse effect of cytarabine is the haematological toxicity. Myelosuppression is manifested by megaloblastosis, reticulocytopenia, thrombocytopenia and anaemia.
These appear to be more evident after high doses and continuous infusions; the severity depends on the dose of the drug and schedule of administration.
Nausea and vomiting occur and are generally more frequent following rapid intravenous administration than with continuous intravenous infusion of the drug.
Diarrhoea, anorexia, oral and anal inflammation or ulceration and less frequently abdominal pain, sore throat, oesphagitis, oesophageal ulceration and gastrointestinal haemorrhage may also occur.
Other reported adverse effects of cytarabine include fever, rash, alopecia, skin ulceration, conjunctivitis, chest pain, urinary retention, dizziness, neuritis or neural toxicity and pain, cellulitis or thrombophlebitis at the site of injection. Cytarabine has also been associated with renal dysfunction, hepatic dysfunction and jaundice in some patients. It has also been associated with sepsis, irritation or sepsis at the injection site, neuritis or neurotoxicity rash, freckling, skin and mucosal bleeding, chest pain, joint pain and reduction in reticulocytes.
A cytarabine reaction is characterised by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6-12 hours after administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are serious enough to warrant treatment, corticosteroids should be contemplated as well as continuation of cytarabine therapy.
Intravenous infusion by drops of 4.5 g/m2 every 12 hours for 12 days results in the CNS irreversible impairment incompatible with life. Therapy: symptomatic, effective antidote is unavailable.
Cessation of therapy followed by management of ensuing bone marrow depression including whole blood or platelet transfusion and antibiotics as required.
Storage conditions: Store at temperature below 30°C. Freezing is unacceptable. Keep out of reach of children.
Shelf life: 2 years. Do not use the drug with expired period of validity indicated on the package.
5 ml ampoules in pack No. 5.
Read carefully before using. If you need further information, please contact your physician.
This preparation is used only on prescription.
Manufacturer : Republican Unitary Production Enterprise “Belmedpreparaty”
Address : 30, Fabritsius St.,220007, Minsk, Republic of Belarus