Cytarabine
Cytarabine: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Use in the elderly
- 14. Drug interactions
- 15. Analogs
- 16. Terms and conditions of storage
- 17. Terms of dispensing from pharmacies
- 18. Reviews
- 19. Price in pharmacies
Latin name: Cytarabine
ATX code: L01BC01
Active ingredient: cytarabine (Cytarabine)
Manufacturer: RUE "Belmedpreparaty" (Republic of Belarus)
Description and photo update: 2020-16-04
Cytarabine is a drug of antitumor and cytostatic action; structural antagonist of pyrimidine metabolites, inhibiting their inclusion in DNA (deoxyribonucleic acid) and RNA (ribonucleic acid).
Release form and composition
The drug is produced in the form of a lyophilizate for the preparation of a solution for injection, which is a porous white mass, compacted into a tablet (100 mg each in colorless glass ampoules; in a cardboard box 5 ampoules, an ampoule scarifier and instructions for using Cytarabin).
Composition for 1 ampoule:
- active substance: cytarabine - 100 mg;
- auxiliary components: low molecular weight povidone (polyvinylpyrrolidone) K-17.
Pharmacological properties
Pharmacodynamics
Cytarabine is an antimetabolite of pyrimidine metabolism. It is an S-phase-specific drug that inhibits DNA synthesis in tumor (leukemic) cells. The drug acquires antileukemic properties after phosphorylation in Ara-CTP (arabinosyl cytosine triphosphate), which competitively inhibits DNA polymerase. According to some reports, inhibition of DNA synthesis also occurs due to the incorporation of cytarabine into DNA and RNA. The drug has an immunosuppressive effect.
Cytarabine resistance can develop in the following cases:
- deficiency of phosphorylating enzymes;
- increased pool of deoxy-CTF (deoxycytidine triphosphate) or decreased affinity of DNA polymerase;
- inhibition of membrane transport;
- increased activity of inactivating enzymes.
The cytotoxic effect is achieved through the creation of constant high concentrations of Ara-CTP inside the cells.
Pharmacokinetics
After intravenous administration of the drug, the metabolism of cytarabine is rapid and almost complete. Under the action of cytidine deaminase, an inactive uracil metabolite (Ara-U) is formed in the liver and other tissues. In the initial phase, the half-life is 10 minutes, and in the final phase it is about 1-3 hours. Since the activity of deaminase in the central nervous system (central nervous system) is minimal, the drug is slowly excreted from the cerebrospinal fluid, the half-life is 2-11 hours.
When s / c (subcutaneous) administration, the maximum plasma concentration is reached after 20-60 minutes, and then a two-phase decrease in concentration is observed. With continuous intravenous (intravenous) infusion at the usual dose (100-200 mg per m2 of body surface), the concentration of Cytarabin in the blood plasma is 0.04-0.6 μmol / L.
At the intracellular level, a small amount of Cytarabin is phosphorylated by kinases to form an active metabolite, Ara-CTF.
About 15% of the drug binds to plasma proteins. Cytarabine crosses the BBB (blood-brain barrier). After continuous intravenous infusion, its level in the cerebrospinal fluid is 10 to 40% of the plasma concentration. After administration of the drug in normal or high doses, only 4-10% is excreted by the kidneys in the form of unchanged cytarabine. From 70 to 96% of the administered dose in the first 24 hours is found in urine in the form of an inactive uracil metabolite.
Indications for use
Cytarabine is used as monotherapy or in combination with other antineoplastic agents. Combined therapy usually achieves better results. Drug-induced remissions are short-lived and do not require further maintenance treatment.
The use of Cytarabin is recommended in the following cases:
- the final stage of development of chronic myeloid leukemia;
- acute neuroleukemia in adults and children (endolumbar use);
- acute lymphoblastic or acute non-lymphoblastic leukemia in adults and children (self-supportive therapy, as part of a combined supportive treatment, to induce remission);
- non-Hodgkin's lymphoma in adults and children (in combination therapy).
High-dose cytarabine therapy is prescribed for the following diseases and conditions:
- relapses of acute leukemia;
- overt leukemia after transformation of pre-leukemia;
- blast crisis in patients with chronic myeloid leukemia;
- non-Hodgkin lymphomas that are resistant to therapy;
- secondary leukemias after prior radiation therapy and / or chemotherapy;
- acute lymphoblastic and / or non-lymphoblastic leukemia resistant to therapy, as well as variants of the disease with a poor prognosis;
- acute non-lymphoblastic leukemia in persons under the age of 60 (with the aim of consolidating remission).
Contraindications
Absolute contraindications to the use of Cytarabin are pregnancy, lactation and hypersensitivity to the main or auxiliary components of the drug.
Cytarabine is used with caution in patients with the following diseases and conditions:
- renal and / or hepatic impairment;
- oppression of hematopoiesis in the bone marrow;
- infiltration of bone marrow with tumor cells;
- diseases with an increased risk of developing hyperuricemia (for example, urate nephrolithiasis, gout);
- acute infectious diseases of bacterial, fungal or viral origin (including shingles and chicken pox);
- chemotherapy or radiation therapy (including a history of instructions);
- elderly age over 60 years (with high-dose therapy).
Cytarabine, instructions for use: method and dosage
A solution prepared from a lyophilisate of Cytarabine is administered intrathecally (endolumbar), subcutaneously, intravenously, by stream or infusion. The drug is used as monotherapy with usual doses, as part of a combination treatment, or in high-dose chemotherapy programs. Cytarabine dose, duration of therapy and frequency of administration depend on the type of program used.
Immediately before administration, the drug is dissolved in water for injection or isotonic sodium chloride solution. For subcutaneous and endolumbar administration, 100 mg of the lyophilisate is dissolved in 1 ml of the solvent, for intravenous administration - in 400 ml of the solvent.
Usually the average daily dose of Cytarabine is 100-200 mg / m 2. In elderly patients and people with reduced reserves of hematopoiesis, the daily dose is reduced to 50–70 mg / m 2.
For remission induction in acute leukemia Cytarabine used in / in combination with other anticancer drugs at a dose of 100 mg / m 2 per day as a continuous / in infusion or in / at the same dose, but every 12 h. The course of treatment is 7 days, and a total of 4 to 7 courses are required at intervals of at least 14 days. The maintenance dose is 1–1.5 mg / kg s / c 1–2 times a week.
For patients with acute leukemia or acute lymphoma resistant to cytarabine, the drug is prescribed in high doses by intravenous drip (duration of infusion is 1-3 hours). Single dose - 2.3 g / m 2, the multiplicity of applications - 2 times a day (every 12 hours), the duration of the treatment - 2-6 days.
Intrathecal (endolumbar) administration is used for neuroleukemia. A single dose for adults is 5–75 mg / m 2. The frequency of administration varies from 1 time per day for 4 days to 1 time per day, once every 4 days, which depends on the severity and type of neurological symptoms, as well as the effectiveness of previous treatment. Most often intrathecal cytarabine is administered to children and adults at a dose of 30 mg / m 2 every 4 days until cerebrospinal fluid until the indicators are not normalized. After that, another additional dose is administered.
Side effects
- digestive system: often - loss of appetite, abdominal pain, difficulty swallowing, vomiting, nausea, ulceration or inflammation of the oral mucosa or anal area, anorexia, diarrhea; infrequently - ulceration of the esophageal mucosa, esophagitis, liver dysfunction, jaundice, hyperbilirubinemia, necrotizing colitis, cystic pneumatosis of the intestine, leading to inflammation of the peritoneum; rarely - necrosis of the small intestine, bleeding, acute pancreatitis (especially if treatment was preceded by the appointment of L-asparaginase), liver abscess, peritonitis;
- respiratory system: infrequently - chest pain, diffuse interstitial pneumonitis, pneumonia; rarely - feeling short of breath, pulmonary edema, severe shortness of breath;
- cardiovascular system: very often - arrhythmia; infrequently - cardiomyopathy, pericarditis;
- central nervous system: often (usually when large doses are prescribed) - dysfunction of the cerebellum, paresthesia of the skin of the face and toes; infrequently - headache, weakness, memory impairment, dizziness, impaired consciousness, drowsiness, neuritis, convulsions, peripheral sensorimotor neuropathy, late progressive ascending paralysis, coma;
- sensory organs: often - visual impairment, photophobia, lacrimation, burning eyes, keratitis (including ulcerative, arising from high-dose therapy);
- hematopoietic system: often - a decrease in the number of leukocytes and platelets, megaloblastosis, anemia; rarely - a decrease in the content of reticulocytes; infrequently - immunosuppression;
- urinary system: infrequently - hyperuricemia, urinary retention, urate nephropathy (due to the rapid destruction of cells);
- musculoskeletal system: infrequently - pain in muscles and joints;
- skin and subcutaneous fat: often - skin pigmentation, vasculitis, pathological hair loss, bullous dermatitis, reversible skin cover disorders; infrequently - itchy skin, freckles, ulceration, cellulite at the injection site, burning pain in the soles of the feet and palms; very rarely - erythroderma, tuberous abscess;
- allergic reactions: often - nettle rash, itching; infrequently - fever, skin rash; rarely - allergic edema, anaphylactoid reactions; very rarely - peeling of the skin;
- local reactions: often - burning sensation at the injection site; infrequently - thrombophlebitis, phlegmon;
- after endolumbar (intrathecal) administration: leukoencephalopathy, loss of vision, paralysis of the lower or upper extremities, neurotoxic effect;
- cytarabine syndrome: chest pain, febrile syndrome, muscle and bone pain, conjunctivitis, hepatic vein thrombosis, maculopapular rash, rhabdomyolysis, inappropriate antidiuretic hormone secretion, infections.
Overdose
With intravenous drip of Cytarabin at a dose of 4.5 g / m 2 every 12 hours for 12 days, irreversible damage to the central nervous system occurs, incompatible with life.
In chronic overdose, massive bleeding may develop due to severe bone marrow suppression, the appearance of dangerous infections and the occurrence of neurotoxicity.
In case of intoxication with cytarabine, additional measures may be required - blood transfusion, antibiotic therapy. In case of severe overdose due to intrathecal administration, repeated lumbar punctures should be performed to ensure rapid drainage of cerebrospinal fluid. The need for neurosurgical intervention with ventriculolumbar perfusion is not excluded.
There is no specific antidote.
special instructions
During treatment with Cytarabine, it is important to control the number of leukocytes in the peripheral blood daily or every other day. In the bone marrow, the level of leukocytes is determined before and after each therapeutic course.
It is necessary to discontinue treatment if the platelet count falls below 50,000 per mm 3 and / or the number of polymorphonuclear granulocytes falls below 1000 per mm 3.
All patients receiving Cytarabin require regular monitoring of renal and liver function. The functional state of the liver is determined at least once a week, and the function of the kidneys is determined before the start of treatment and after the end of the course.
In patients receiving high-dose therapy, general and biochemical blood tests should be performed daily. With a large tumor mass (with lymphomas) or in persons with hyperleukocytosis, it is necessary to control the level of uric acid in the blood. In order to prevent hyperuricemia, it is recommended to take sufficient fluids and prescribe allopurinol.
It has been established that Cytarabin has embryotoxic, mutagenic and teratogenic effects.
24 hours after the administration of the drug, the number of leukocytes decreases, reaching the minimum values on days 7-9. Then there is a short-term increase in the number of leukocytes (from 9 to 12 days), and after that their level decreases again and reaches a minimum value on 15-24 days. Over the next 10 days, the white blood cell count rapidly rises to the starting level. The platelet count decreases significantly on day 5, reaching a minimum value on day 12-15, and then returns to its initial level within 10 days.
The picture of the bone marrow should be monitored after the disappearance of immature cells from the peripheral blood. The total number of formed elements may continue to decrease after the abolition of Cytarabin and reach the lowest values after 12-24 days. Treatment is resumed in the presence of indications and the appearance of distinct symptoms of bone marrow recovery, without waiting for the normalization of peripheral blood parameters.
IV infusion is recommended for a long time, especially in the case of large doses. This can reduce the likelihood of nausea and vomiting. When conducting high-dose cytarabine programs, it is not recommended to use solvents containing benzyl alcohol.
Since Cytarabine is a toxic agent, special safety measures must be observed when working with it:
- Personnel should be trained in drug handling, lyophilisate dilution and solution administration.
- It is forbidden to work with the drug for pregnant women.
- The personnel are obliged to use personal protective equipment, namely, medical gowns, glasses, disposable masks and gloves.
- The solution is prepared in a specially designated area, preferably with a unidirectional air flow.
- The work surface is protected with disposable absorbent paper on a plastic base.
- Materials used in the dilution of the lyophilisate, the introduction of the solution and the cleaning of the premises, including gloves, are disposed of in accordance with the current sanitary requirements.
- In case of accidental contact of the drug on the skin or eyes, the affected area should be washed immediately with plenty of running water, soap and water or sodium bicarbonate solution, and then consult a doctor.
- The spilled solution is washed off with a buffer solution with a pH of 7-8, for example, phosphate buffer.
Influence on the ability to drive vehicles and complex mechanisms
During the period of treatment, one should not work with potentially dangerous and complex mechanisms and drive vehicles.
Application during pregnancy and lactation
Cytarabine is contraindicated in pregnant and lactating women, since experimental studies have revealed its teratogenicity, embryotoxicity and mutagenicity.
Pediatric use
There is no reliable data on the safety of using the drug in children.
Dosing regimens for Cytarabin for children are similar to those for adults. There have been reports of the development of delayed progressive ascending paralysis after intrathecal use of the drug in standard doses as part of the complex treatment of children with acute myelocytic leukemia, leading to death.
With impaired renal function
In patients with impaired renal function, Cytarabine is used with caution.
For violations of liver function
Cytarabine is prescribed with caution to patients with impaired liver function.
Use in the elderly
Elderly patients tolerate toxic side reactions worse, which requires increased monitoring of their condition due to the likely development of anemia, leukopenia, thrombocytopenia. Supportive treatment is prescribed if necessary.
High-dose therapy in patients over 60 years of age is prescribed after a careful assessment of the ratio of potential risks and expected benefits.
Drug interactions
Radiation therapy and other anticancer drugs, when used together with cytarabine, can mutually enhance toxicity and immunosuppressive effects.
The likelihood of infectious complications increases with the simultaneous use of immunosuppressants (cyclosporine, tacrolimus, chlorambucil, cyclophosphamide, azathioprine, mercaptopurine and glucocorticosteroids).
Cytarabine reduces the equilibrium concentration of digoxin and reduces its excretion by the kidneys.
During the treatment period, any vaccination using vaccines with viruses is ineffective. Vaccination with a vaccine with killed viruses is ineffective due to a decrease in the formation of antibodies, since the defense mechanisms are weakened. Vaccination with a live virus vaccine increases the risk of adverse reactions because not enough antibodies are produced.
Antagonism was found between Cytarabin and gentamicin, which can lead to a decrease in the sensitivity of pathogenic Klebsiella pneumoniae strains to gentamicin.
Pharmaceutically, the drug is incompatible with insulin, fluorouracil, oxacillin, methylprednisolone, heparin, methotrexate, benzylpenicillin and nafcillin.
Cytarabine is chemically stable in 0.2–0.9% sodium chloride solution and 5% dextrose solution (in the amount of 2.6 g and 8 g per 250 ml). At a concentration of 2 mg / ml, it is stable in 5% dextrose solution, 0.9% sodium chloride solution and in the presence of potassium chloride (50 mEq / 500 ml). At concentrations of 1 mg / ml and 0.2 mg / ml, Cytarabine is chemically stable in 5% dextrose solution, 0.24% sodium chloride solution and sodium bicarbonate solution (50 mEq / l).
Analogs
Analogues of Cytarabin are Aleksan, Cytosar NovaMedica, Cytarabin-LENS, Cytostadin.
Terms and conditions of storage
Store in a dry place at a temperature not exceeding 25 ° C. Keep out of the reach of children.
The shelf life is 3 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Cytarabin
Despite the fact that there are very few reviews about Cytarabine, it is important to consider that the drug, like other antineoplastic agents, is vital for patients with cancer.
Its main disadvantage is a large number of side effects, especially immunosuppressive action (suppression of immunity). It should also be noted the rather high cost of course treatment.
Price for Cytarabine in pharmacies
The price of Cytarabine 100 mg is from 1200 rubles. for a package of 5 vials of lyophilisate for the preparation of solution for injection.
Anna Kozlova Medical journalist About the author
Education: Rostov State Medical University, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
