Rx Prescription information
(Information for Experts)
Name of the medicinal product: CYTARABINE-BELMED
Lyophilized powder injection, 1000 mg.
Porous white mass in form of tablet.
Composition per vial:
Active substance – cytarabine 1000 mg
Excipients – Low-molecular polyvinyl pyrrolidone medical grade Mr 12600 ± 2700 (povidone)
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.
When Cytarabine is phosphorylized – the process most active in the tumor (leukemic) cells – an active metabolite is formed suppressing the DNA-polymerase thus damaging the DNA synthesis.
Cytarbine is rapidly metabolised and is orally ineffective. Less then 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 cytidine deaminase 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 cytarabine deaminase 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.
Mode of administration and dosage
When the drug is to be administered intermittently by drops the vial content is dissolved by 100 – 250 ml of isotonic (0.9%) solution of sodium chloride or of water for injections or of 5% solution of dextrose in isotonic (0.9%) solution of sodium chloride or of water for injections or in Ringer’s solution just before the administration. The infusion duration is 30 minutes to 2 hours. The Cytarabine high-dose therapy duration should not exceed 2 hours.
When the drug is to be infused for a long time the vial content is dissolved by 500 – 1000 ml of isotonic (0.9%) solution of sodium chloride or of water for injections or of 5% solution of dextrose in isotonic (0.9%) solution of sodium chloride or of water for injections or in Ringer’s solution just before the administration. The Cytarabine concentration and the infusion rate are determined individually.
When the drug is to be injected subcutaneously or intrathecally 0.5 or 1.0 g of Cytarabine is dissolved in 10 ml of isotonic (0.9%) solution of sodium chloride or of water for injections just before the administration the preparation final concentration being 50 mg/ml or 100 mg/ml respectively. (Attention! No solvent containing benzyl alcohol can be injected intrathecally).
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 (not 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.
- Bone marrow aplasia,
- Severe changes of the liver and kidneys functions,
- Acute infectious diseases,
- Pregnancy and breast feeding (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
The patients should not drive and practice potentially dangerous activities needing more attention and quicker psychomotor reactions during the period of treatment.
When the drug gets on skin accidently the skin should be washed under running water with soap
Interaction with other drugs and other forms of interaction
The absorption of digoxin may be reduced if digoxin is combined with chemotheraputics (including cytarabine). This is probably dependent on temporary damage to the mucosa. The plasma levels of digoxin must therefore be monitored.
When administered in combination with other anti-tumor drugs and with beam 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.
Cytarabine is incompatible pharmaceutically with Heparin, Insulin, Methotrexate, Fluoriouracil, Nafticillin, Oxacillin, Benzylpenicillin, Methylprednisolone.
- Suppression of the bone marrow function, leucopenia, thrombocytopenia, megaloblast anemia, thrombophlebitis
- GIT hemorrhages
- Stomatitis, esophagitis, nausea, vomiting, diarrhea
- CNS activity changes
- Liver function impairment
- Pulmonary edema, diffuse interstitial pneumonitis,
- Headache after intrathecal injections.
- Itching, loss of hair
- “Cytarabine syndrome” – fever, myalgia, bone and breastbone pains, maculopapular eruptions, conjunctivitis, anxiety.
In case of the Cytarabine high-dose therapy – myelosuppression: thrombocytopenia, leucopenia, anemia; megaloblastosis; immunity suppression, fever, alopecia, allergic reactions, nausea, vomiting, diarrhea, stomatitis, abdominal pains, dysorexia, liver function impairment, myalgia, thrombophlebitis. As a rule, the symptoms disappear when the therapeutic course has been completed.
When Cytarabine high doses are administered a more profound and prolonged myelosuppression can develop than in case of standard doses administration (the average duration of agranulocytosis and thrombocytopenia can be 28 – 30 days). Side effects caused by the drug increased concentration in the lachrymal fluid (eye burning, lacrymation, photophobia, complaints of vision worsening) may be prevented or diminished by prophylaxis with a local corticosteroid eye drop. Cerebral and cerebellar dysfunction including personality changes and sleepiness are possible. The ophthalmological and neurological symptoms resolve in several days after the Cytarabine therapy has been completed. In 6 – 12 hours after the Cytarabine administration, the “Cytarabine syndrome” can develop.
When it is necessary because of an evident side effect development glucocorticoids are prescribed to be taken in average therapeutic doses during the Cytarabine therapy course.
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.
Store at temperature below 30°C.
Keep out of reach of children.
Do not use the drug with expired period of validity indicated on the package.
1000 mg vial in pack No. 1.
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