Cytosar NovaMedica Lyophilisate solution for injection 1000mg vials, 1pc

Composition

1 bottle contains: Active ingredient:  cytarabine-1000 mg; excipients:  missing items. The composition of the attached solvent: benzyl alcohol 9 mg, water for injection q. s. up to 1 ml

Pharmacological action

Pharmacotherapeutic group: antitumor agent, antimetabolite.

ATX code: L01 BC 01

Pharmacological properties

Pharmacodynamics .

Cytarabine belongs to the group of antimetabolites of pyrimidine metabolism and is an S-phase-specific drug. Inhibits the synthesis of DNA in the cell. Antileukemic activity is obtained by phosphorylation to 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 are known for the development of cytarabine resistance: inhibition of membrane transport, deficiency

of phosphorylating enzymes, increased activity of inactivating enzymes, reduced affinity of DNA polymerase, or an increased pool of deoxy-CTPs. The cytotoxic effect is achieved by creating constant high intracellular concentrations of Ara-CTF.

After intravenous use, cytarabine is rapidly and almost completely converted to inactive uracil, a metabolite of Ara-Y, by cytidine deaminase in the liver and in other tissues. The half-life in the initial phase is 10 minutes, in the final phase-approximately 1-3 hours. Since deaminase activity in the central nervous system is minimal, cytarabine elimination from the cerebrospinal fluid is slow, and its half-life is 2-11 hours.

With continuous intravenous infusions of cytarabine in normal doses (100-200 mg/m2 of body surface area), concentrations of 0.04-0.6 mmol/l are achieved. With subcutaneous (subcutaneous) use, the maximum plasma concentration is reached within 20-60 minutes. Then a two-phase decrease in concentration occurs. A small part of cytarabine undergoes phosphorylation under the action of kinases at the intracellular level, resulting in the formation of the active metabolite Ara-CTF. Binding to plasma proteins is 15%.

Cytarabine penetrates the blood-brain barrier. After continuous infusion, a concentration of 10-40% of the plasma concentration is achieved in the cerebrospinal fluid. After use 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.

Indications

Contraindications

Side effects

Adverse reactions caused by cytarabine depend on the dosage, method of use, and duration of therapy. From the hematopoietic system:  leukopenia, thrombocytopenia, anemia, megaloblastosis, reticulocytopenia. The decrease in the number of white blood cells is biphasic, with the first maximum decrease being achieved by day 7-9. This is followed by a short rise with a maximum of 12 days. With the second and deeper decrease, the minimum number of white blood cells is noted in 15-24 days. In the next 10 days, the number of white blood cells increases rapidly. A decrease in the number of platelets becomes noticeable by day 5, the minimum occurs between 12-15 days. In the next 10 days, there is a rapid increase in the number of platelets to the initial level. The severity of these reactions depends on the dose and use schedule. From the gastrointestinal tract:  nausea, vomiting, loss of appetite, abdominal pain, diarrhea, inflammation or ulceration of the gastrointestinal mucosa (mouth and rectum, less often-esophagus). Nausea and vomiting most often occur after rapid intravenous use. When using high doses (2-3 g/m2), ulceration of the gastrointestinal tract can be severe, it is possible to develop necrotic colitis, necrosis of the small intestine, cystic pneumatosis of the intestine, leading to peritonitis. From the liver and pancreas:  impaired liver function, jaundice. With high-dose therapy-impaired liver function with hyperbilirubinemia, sepsis and liver abscess. Isolated cases of pancreatitis have also been reported with high-dose cytarabine therapy in combination with other medications. Nervous system disorders:  neuritis, neurotoxicity, headache, dizziness, CNS disorders are mainly observed during high-dose therapy, while disorders of the brain and cerebellum functions (nystagmus, dysarthria, ataxia, confusion), including personality changes, drowsiness, coma, are mainly detected. CNS disorders are usually reversible. Cases of peripheral motor and sensory neuropathy and late progressive ascending paralysis have also been reported. In some cases, nausea, vomiting, dizziness and fever were observed after intrathecal use of the drug. These complaints may also be caused by a lumbar puncture. Cumulative neurotoxicity may also occur, especially at short intervals between doses. Isolated cases of necrotizing leukoencephalopathy, paraplegia, and blindness following intrathecal cytarabine use have been reported. From the side of the senses:  conjunctivitis (photophobia, burning eyes, severe lacrimation), keratitis. When treated with high doses, reversible ulcerative keratitis and hemorrhagic conjunctivitis may occur. From the cardiovascular and respiratory systems:  cardiomyopathy (including fatal, when using cytarabine in high doses in combination with cyclophosphamide), pericarditis, sore throat, shortness of breath, pneumonia, diffuse interstitial pneumonitis (average doses – 1 g/m2), progressive respiratory distress syndrome, leading to pulmonary edema and cardiomegaly with a possible fatal outcome (high doses of cytarabine). From the side of the kidneys and urinary tract:  impaired renal function, urinary retention, hyperuricemia, or urate nephropathy. From the side of the skin and skin appendages:  pruritus, rash (maculopapular and urticular), the appearance of pigmented spots on the skin, ulceration of the skin, alopecia. There are rare reports of severe skin rashes leading to desquamation. Local reactions:  inflammation of subcutaneous adipose tissue at the injection site. Infectious complications:  viral, bacterial, fungal, parasitic or saprophytic infections of any localization (including sepsis), usually mild or moderate in severity, but can be severe and sometimes fatal (their development is due to a decrease in immunity). Cytarabine syndrome:  fever, muscle pain, bone pain, sometimes chest pain, maculopapular rash, conjunctivitis, malaise. These symptoms usually appear 6-12 hours after the drug is administered. Glucocorticosteroids have been shown to be effective in treating or preventing the development of this syndrome. Other services:  fever, thrombophlebitis, allergic reactions (including anaphylaxis, urticaria, edema). When using cytarabine from other manufacturers, there are separate reports of the following side effects: individual cases of development of the syndrome of inadequate production of antidiuretic hormone, rhabdomyolysis, hepatic vein thrombosis (Budd-Chiari syndrome), bleeding, visual disturbances, transient arrhythmia (when using the drug Cytosar, there are currently no reports of the above side effects).

Interaction

Do not mix in the same syringe or dropper with other drugs: pharmacologically incompatible with heparin, insulin, methotrexate,5-fluorouracil, oxacillin, benzylpenicillin, methylprednisolone. Combined use with other antitumor myelosuppressive drugs or radiation therapy increases the cytotoxic and immunosuppressive activity of these drugs. When using polychemotherapy with the inclusion of cytarabine, a reversible decrease in the steady-state plasma concentration of digoxin was noted (due to a decrease in absorption – a violation of absorption due to toxic effects on the intestinal mucosa), as well as a decrease in renal excretion of glycoside. An alternative for such patients can be considered the use of digitoxin, the equilibrium plasma concentration of which does not change.In vitro studies of the interaction between gentamicin and cytarabine revealed the existence of antagonism, which may reduce the sensitivity of K. pneumoniae strains to gentamicin. It is possible to reduce the effectiveness of fluorocytosine with simultaneous use. Immunosuppressants (azathioprine, chlorambucil, glucocorticosteroids, cyclophosphamide, cyclosporine, mercaptopurine, tacrolimus) increase the risk of infectious complications. Killed viral vaccines – due to the suppression of normal cytarabine defense mechanisms, antibody formation may decrease. Live viral vaccines-due to the suppression of normal defense mechanisms by cytarabine, it is possible to potentiate viral replication, increase side effects, and reduce the formation of antibodies.

How to take, course of use and dosage

The scheme and method of application vary when using different chemotherapy regimens. In each individual case, you should refer to the specialized literature. Cytosar can be administered intravenously by jet or drip, subcutaneously (usually used only during therapy aimed at maintaining remission), and also intrathecally. The average daily dose is 100-200 mg / m2. Elderly patients or with reduced hematopoietic reserves – 50-70 mg/m2. Induction of remission in acute leukemia: in combination with other antitumor drugs – 100 mg/m2/day as a continuous intravenous infusion for 7 days or 100 mg/m2 IV every 12 hours for 7 consecutive days. In total,4-7 treatment courses are conducted. Intervals between courses – at least 14 days. High-dose therapy: high-dose therapy in the treatment of leukemias with a poor prognosis, as well as refractory leukemias and relapses, is carried out using Cytosar at a dose of 2-3 g/m2 of body surface area in the form of an intravenous infusion lasting 1-3 hours, with a 12-hour interval, for 2-6 days as monotherapy or in combination with other antitumor drugs. Intrathecal therapy: in acute leukemia, the dose of Cytosar is 5-75 mg / m2. The frequency of use can vary from once a day for 4 days to once every 4 days. Most often, cytarabine is prescribed 30 mg/m2 of body surface area every 4 days until the parameters normalize, followed by another additional use. However, the dosage and intervals between use of doses depend on the clinical situation. In patients with renal and hepatic insufficiency, there is no need to reduce the dose of the drug, if the usual doses are used. If high-dose therapy is used, then the increased risk of CNS complications should be taken into account when choosing the dose. Preparation of the solution: lyophilizate is diluted with the attached solvent, water for injection,0.9% sodium chloride solution or 5% dextrose solution, both with and without preservative. The cytarabine concentration should not exceed 100 mg / ml. The solvent for intrathecal use and high-dose therapy should not contain preservatives (benzyl alcohol), in this case, a 0.9% sodium chloride solution is usually used. Do not use the supplied solvent for intrathecal use (contains benzyl alcohol)!After dissolving the drug in a solvent containing a preservative, store the solution at room temperature for no more than 48 hours. After dissolving in a preservative-free solvent, use as soon as possible. Note: The neck of the solvent ampoule is pre-incised at the point of constriction. A colored dot on the ampoule head helps you orient the ampoule correctly. Take the ampoule in your hands and turn its point towards you. If you lightly press your thumb on this point, the ampoule will easily open.

Overdose

Chronic overdose can lead to severe bone marrow depression, which can be accompanied by massive bleeding, the development of life-threatening infections, and the manifestation of neurotoxic effects. Since there are no effective antidotes for cytarabine, each use of the drug should be carried out very carefully. If an overdose occurs, it is necessary to carry out auxiliary measures (blood transfusion, antibiotic therapy). In case of severe overdose that occurred during intrathecal use, repeated lumbar punctures should be performed to ensure rapid drainage of the cerebrospinal fluid, and neurosurgical intervention with ventriculolumbal perfusion is possible. Cytarabine can be eliminated by hemodialysis. However, there is no information on the effectiveness of hemodialysis for cytarabine overdose.

Special instructions

When handling the drug and when using it, you should follow the recommendations developed for the safe handling of cytostatics. Induction and consolidation therapy with Cytosar in acute leukemia should be performed only in a hospital setting, under the supervision of experienced oncologists and with careful monitoring. It is necessary to regularly monitor the picture of peripheral blood (daily with induction therapy), the function of bone marrow, liver and kidneys, as well as the level of uric acid in serum. If the platelet count is below 50,000 or the polymorphonuclear granulocyte count is below 1,000 / mm3, therapy should be suspended or modified. The number of formed elements in the peripheral blood may continue to fall after discontinuation of the drug and reach a minimum level after 12-24 days. If there are indications, you can resume therapy if there are clear signs of hematopoiesis restoration based on the results of a bone marrow study. When conducting high-dose therapy, do not use solutions containing benzyl alcohol as a solvent (benzyl alcohol is contained in the attached solvent!). The fatal syndrome of “shortness of breath” in premature newborns may be associated with the presence of benzyl alcohol. The solvent for intrathecal use and high-dose therapy should not contain preservatives (benzyl alcohol), usually 0.9% sodium chloride solution is used. When conducting high-dose therapy, CNS and lung function should be constantly monitored. With high-dose therapy and impaired liver or kidney function, the likelihood of CNS toxicity may increase. In patients with impaired liver or kidney function, the drug should be used with caution and possibly at a reduced dose. Patients receiving high doses of Cytosar should be monitored for the possibility of developing neuropathy, since changes in the dose or treatment regimen may be necessary to prevent the occurrence of irreversible neurological disorders. When symptoms of toxic effects on the central nervous system appear, a special risk assessment should be made; the same actions are necessary for the first symptoms of allergies. Like other antitumor drugs, Cytosar can lead to the development of hyperuricemia due to the rapid breakdown of tumor cells. It is recommended to prevent hyperuricemia in patients with a high content of blast cells or with large tumor masses (for example, in non-Hodgkin’s lymphomas). Vaccination of patients undergoing Cytosar therapy should be carried out with extreme caution, after a thorough assessment of the hematological status and with the consent of the doctor conducting 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 during hemodialysis. Therefore, patients undergoing dialysis should not be given Cytosar immediately before and during dialysis. Women and men should use reliable methods of contraception during treatment and for 6 months after treatment. Avoid contact of the drug with the skin and mucous membranes, especially it is necessary to protect the eyes. Data on the effect of Cytosar therapy on the ability to drive a vehicle and work with mechanisms are not available, however, since nausea and vomiting may occur during this therapy, this may indirectly affect the ability to drive a car and work with mechanisms. Therefore, you should carefully consider the individual action of the drug in the above situations.

Storage conditions

At a temperature not exceeding 25° C. List B. Keep out of reach of children.

Shelf

life is 5 years. Do not use after the expiration date indicated on the package.

Active ingredient

Cytarabine

Conditions of release from pharmacies

By prescription

Dosage form

lyophilizate for solution preparation