Pharmacotherapeutic group: antitumor drug, antimetabolite.
ATC code: L01BC01
Citarabine belongs to the group of pyrimidine metabolites and is an S-phase-specific drug. It inhibits DNA synthesis in the cell. The drug acquires antileukemic activity as a result of phosphorylation into arabinosyl cytosine triphosphate (Ara-CTP), which competitively inhibits DNA polymerase. In addition, there is evidence that DNA synthesis is also inhibited by the incorporation of cytarabine into DNA and RNA.Several mechanisms for the development of resistance to cytarabine are known: inhibition of membrane transport, deficiency of
phosphorylation enzymes, increased activity of inactivating enzymes, reduced affinity for DNA polymerase or increased pool of deoxy-CTF. Cytotoxic action is achieved by creating constant high intracellular concentrations of Ara-CTF.
After intravenous administration, cytarabine is rapidly and almost completely converted to the inactive uracil metabolite Ara-U under the action of cytidine deaminase in the liver and other tissues. The half-life in the initial phase is 10 minutes, in the final phase – about 1-3 hours. Since deaminase activity in the CNS is minimal, excretion of cytarabine from cerebrospinal fluid is slow, with a half-life of 2-11 hours.
Continuous intravenous infusions of cytarabine at normal doses (100-200 mg/m2 body surface) achieve concentrations equal to 0.04-0.6 μmol/L. When administered subcutaneously (p/k), maximum plasma concentrations are reached within 20-60 minutes. Then there is a biphasic decrease in concentration. A small part of cytarabine undergoes phosphorylation under the influence of kinases at the intracellular level, as a result of which the active metabolite Ara-CTP is formed. The binding to plasma proteins is 15%.
Citarabine penetrates the blood-brain barrier. After continuous infusion, a concentration equal to 10-40% of the plasma concentration is reached in the cerebrospinal fluid. After administration of normal or high doses, only 4-10% of the administered dose is excreted unchanged by the kidneys. In the first 24 hours, 71-96% of the administered drug is detected in the urine in the form of Ara-U.
High-dose cytarabine therapy:
1 bottle contains:
active ingredient: cytarabine – 500 mg;
Composition of the attached solvent: benzyl alcohol 9 mg, water for injections q.s. up to 1 ml.
How to take, the dosage
The regimen and method of administration vary with different chemotherapy regimens.
In each individual case, the specific literature should be consulted.
Cytosar can be administered intravenously by jet or drip, subcutaneously (usually used only during therapy to maintain remission), as well as intrathecally.
The average daily dose is 100-200 mg/m2. In patients of elderly age or with decreased hematopoiesis reserves – 50-70 mg/m2.
Induction of remission in acute leukemia: in combination with other antitumor drugs – 100 mg/m2/day in the form of continuous intravenous infusion within 7 days or 100 mg/m2 in infusion every 12 hours for 7 consecutive days. Generally, 4-7 treatment courses are carried out.
The intervals between the courses are at least 14 days.
High-dose therapy: high-dose therapy in treatment of leukemia with poor prognosis, as well as of refractory leukemia and relapses is conducted with Cytozar in dose of 2-3 g/m2 of body surface in form of intravenous infusion lasting 1-3 hours, with 12-hour intervals, during 2-6 days as monotherapy or in combination with other anti-tumor drugs.
Intrathecal therapy: In acute leukemia the dose of Cytosar is 5-75 mg/m2. The frequency of administration can vary from once a day for 4 days to once every 4 days.
Most commonly, cytarabine is administered at 30 mg/m2 of body surface every 4 days until normalization, followed by another additional administration. However, the dosage and intervals between doses depend on the clinical situation.
In renal and hepatic insufficiency there is no need to reduce the dose of the drug if the usual doses are used. If therapy with high doses is administered the increased risk of CNS complications should be taken into consideration while choosing the dose.
Preparation of solution: lyophilisate is diluted with included solvent, water for injection, 0.9% sodium chloride solution or 5% dextrose solution with or without preservative. The concentration of cytarabine should not exceed 100 mg/ml.
The solvent for intrathecal application and high-dose therapy should not contain preservatives (benzyl alcohol), in which case 0.9% sodium chloride solution is usually used. Do not use the included solvent for intrathecal administration (contains benzyl alcohol)!
After dissolving the drug in the solvent containing the preservative, store the solution at room temperature for not more than 48 hours. After dissolving in a solvent containing no preservative, use as soon as possible.
Note: The neck of the ampoule with the solvent is pre-cut at the point of contraction. The colored dot on the head of the ampoule helps to orient the ampoule correctly. Take the ampoule in your hand and turn it with the dot facing you. If you press this point lightly with your thumb, the ampoule will open easily.
Do not mix in one syringe or dropper with other drugs: pharmaceutically incompatible with heparin, insulin, methotrexate, 5-fluorouracil, oxacillin, benzylpenicillin, methylprednisolone.
Concomitant use with other anti-tumor myelosuppressive drugs or radiation therapy increases cytotoxic and immunosuppressive activity of these drugs.
A reversible decrease in equilibrium plasma concentration of digoxin (due to reduced absorption – impaired absorption due to toxic effects on the intestinal mucosa), as well as reduced renal excretion of the glycoside was noted when using polychemotherapy with cytarabine inclusion. The use of digitoxin, whose equilibrium plasma concentration does not change, may be considered an alternative for such patients.
In vitro studies of interaction between gentamicin and cytarabine revealed the existence of antagonism due to which sensitivity of K. pneumoniae strains to gentamicin can decrease.
Possible decrease of fluorocytosine effectiveness in concomitant use.
Immunosuppressants (azathioprine, chlorambucil, glucocorticosteroids, cyclophosphamide, cyclosporine, mercaptopurine, tacrolimus) increase the risk of infectious complications.
Killed virus vaccines – due to suppression of normal defense mechanisms by cytarabine a decrease of antibody formation is possible.
Live virus vaccines – due to the suppression of normal defense mechanisms by cytarabine, viral replication may potentiate, increased side effects, reduced antibody formation.
When handling and using the drug it is necessary to follow the recommendations developed on the procedure of safe handling of cytostatics.
Induction and consolidation therapy with Cytosar for acute leukemia should be carried out only in hospital conditions, under the supervision of experienced oncologists and ensuring close monitoring. Peripheral blood counts (daily during induction therapy), bone marrow, liver and kidney function, as well as serum uric acid levels should be monitored regularly. If platelets fall below 50,000 or polymorphonuclear granulocytes fall below 1,000/mm3, therapy should be suspended or modified. The number of cells in peripheral blood may continue to decrease after discontinuation of the drug and reach a minimum level after 12-24 days.
If indicated, therapy may be resumed when there are clear signs of hematopoiesis recovery based on the results of bone marrow examination.
In high-dose therapy, solutions containing benzyl alcohol must not be used as a solvent (benzyl alcohol is contained in the solvent provided!).
Fatal “difficulty breathing” syndrome in premature infants may be associated with the presence of benzyl alcohol. The solvent for intrathecal application and high-dose therapy should not contain preservatives (benzyl alcohol), usually 0.9% sodium chloride solution is used.
During high-dose therapy, continuous monitoring of CNS and lung function should be performed.
In high-dose therapy and liver or renal function disorders, the possibility of CNS toxicity may increase. Patients with impaired hepatic or renal function should use the drug with caution and possibly at a reduced dose.
Patients receiving high-dose Cytosar should be monitored for the possibility of neuropathy, as doses or therapy regimen changes may be necessary to prevent irreversible neurological impairment. A specific risk assessment should be performed if symptoms of CNS toxicity appear; the same action is necessary if the first symptoms of allergy appear.
Like other antitumor drugs, Cytozar may lead to the development of hyperuricemia due to rapid decay of tumor cells. Prevention of hyperuricaemia is recommended in patients with a high blast cell count or with large tumor masses (e.g., in non-Hodgkin’s lymphoma).
Vaccination of patients receiving Cytozar therapy should be performed with extreme caution, after careful evaluation of hematologic status and with the consent of the doctor administering the cytarabine therapy. The interval between the end of immunosuppressive therapy and vaccination depends on the type of immunosuppressant, the underlying disease and other factors and varies from 3 months to 1 year.
Cytarabine is eliminated from the body by hemodialysis. Therefore, patients on dialysis should not administer Cytosar immediately before and during dialysis.
Women and men during treatment and within 6 months after treatment should use reliable methods of contraception.
The drug should not be allowed to contact with skin and mucous membranes, especially eyes should be protected.
There is no data on the effect of Cytosar therapy on the ability to drive a vehicle and operate mechanisms, but since during this therapy nausea and vomiting may occur, it may indirectly affect the ability to drive vehicles and operate mechanisms. Therefore, the individual action of the drug in the above situations should be carefully considered.
With caution: hepatic and/or renal insufficiency (due to increased risk of neurotoxicity, especially during high-dose therapy), drug-induced suppression of hematopoiesis, bone marrow infiltration by tumor cells, acute infectious diseases of viral (including varicella, chicken pox and lepox).varicella, shingles), fungal or bacterial diseases (risk of severe complications and generalization), diseases with increased risk of hyperuricemia (gout or urate nephrolithiasis).
Side effects caused by cytarabine depend on the dosage, method of administration and duration of therapy.
Blood system: leukopenia, thrombocytopenia, anemia, megaloblastosis, reticulocytopenia. The decrease in the number of leukocytes is biphasic, with the first maximum decrease reached by day 7-9. This is followed by a short rise with a maximum on day 12. With a second and deeper decrease, the minimum leukocyte count is noted on days 15-24. In the next 10 days, the leukocyte count increases rapidly. The decrease in the platelet count becomes noticeable by day 5, with a minimum occurring between days 12-15. In the next 10 days, there is a rapid increase in the platelet count to the baseline level. The severity of these reactions depends on the dose and route of administration.
Gastrointestinal tract: nausea, vomiting, loss of appetite, abdominal pain, diarrhea, inflammation or ulceration of the gastrointestinal mucosa (oral cavity and rectum, less frequently the esophagus). Nausea and vomiting most often occur following rapid intravenous administration. When using high doses (2-3 g/m2) gastrointestinal ulcers may be severe; necrotic colitis, small intestine necrosis, cystic pneumatosis of intestine leading to peritonitis may develop.
Liver and pancreas: liver dysfunction, jaundice. In high-dose therapy – hepatic dysfunction with hyperbilirubinemia, sepsis and liver abscess.
Individual cases of pancreatitis have also been reported during high-dose therapy with cytarabine in combination with other drugs.
Nervous system disorders: neuritis, neurotoxicity, headache, dizziness
CNS disorders are generally observed during high-dose therapy, with brain and cerebellar disorders (nystagmus, dysarthria, ataxia, confusion), including personality changes, somnolence and coma being the most common. CNS disturbances are usually reversible.
Cases of peripheral motor and sensory neuropathy and late progressive ascending paralysis have also been reported. Nausea, vomiting, dizziness, and fever have been reported in isolated cases after intrathecal administration of the drug. These complaints may also be due to lumbar puncture. Cumulative neurotoxicity may also occur, especially with short intervals between doses.
Individual cases of necrotizing leukoencephalopathy as well as paraplegia and blindness after intrathecal administration of cytarabine have been described.
Senses: conjunctivitis (photophobia, burning of the eyes, marked lacrimation), keratitis. Reversible ulcerative keratitis and hemorrhagic conjunctivitis may occur when treated with high doses.
Cardiovascular and respiratory system: cardiomyopathy (including fatal, when using cytarabine in high doses in combination with cyclophosphamide), pericarditis, sore throat, dyspnea, pneumonia, diffuse interstitial pneumonitis (average doses – 1 g/m2), progressive respiratory distress syndrome leading to pulmonary edema and cardiomegaly with possible death (high doses of cytarabine).
Renal and urinary tract: renal dysfunction, urinary retention, hyperuricemia or urate nephropathy.
Skin and skin appendages: itching, rash (patchy-papular and urtic), occurrence of pigment spots on skin, skin ulceration, alopecia. There are rare reports of severe skin rash leading to desquamation.
Local reactions: inflammation of subcutaneous fatty tissue at the injection site.
Infectious complications: viral, bacterial, fungal, parasitic or saprophytic infections of any localization (including Sepsis), usually mild to moderate severity, but can be severe and sometimes fatal (their development is due to decreased immunity).
Cytarabine syndrome: fever, muscle pain, bone pain, sometimes chest pain, patchy-papular rash, conjunctivitis, malaise. These symptoms usually appear 6-12 hours after drug administration. Glucocorticosteroids have been found to be effective in treating or preventing the development of this syndrome.
Other: fever, thrombophlebitis, allergic reactions (including anaphylaxis, urticaria, edema).
When using cytarabine of other manufacturers there are separate reports of the following side effects: individual cases of inadequate antidiuretic hormone production syndrome, rhabdomyolysis, hepatic vein thrombosis (Budd-Chiari syndrome), bleeding, visual disturbances, transient arrhythmia (when using the drug Cytozar there are no reports of the above side effects at the moment).
Chronic overdose may lead to severe bone marrow depression, which may be accompanied by massive bleeding, development of life-threatening infections, and manifestation of neurotoxic effects. Since there are no effective antidotes for cytarabine, each administration of the drug should be done very carefully. If an overdose occurs, auxiliary measures (hemotransfusion, antibiotic therapy) should be carried out.
In severe overdose that occurred during intrathecal administration, repeated lumbar punctures should be performed to ensure rapid drainage of cerebrospinal fluid; neurosurgical intervention with ventriculolumbar perfusion is possible.
Citarabine can be excreted by hemodialysis. However, there is no information on the effectiveness of hemodialysis for cytarabine overdose.
5 years. Do not use after the expiration date stated on the package.
|Conditions of storage|
At the temperature not more than 25 ° C. List B. Keep out of reach of children.
Actavis Italia S.p.A., Italy
Actavis Italia S.p.A.
Buy Cytosar NovaMedica, lyophilizate 500 mg with delivery to USA, UK, Europe and over 120 other countries.