Cytosar^® NovaMedica (Lyophilisate, Powder) Instructions for Use

ATC Code

L01BC01 (Cytarabine)

Active Substance

Cytarabine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

An antineoplastic agent from the group of pyrimidine analog antimetabolites. Cytarabine inhibits DNA synthesis in the cell, predominantly in the S-phase of the cell cycle. Cytarabine acquires its antileukemic activity as a result of phosphorylation into arabinosyl cytosine triphosphate (Ara-CTP), which competitively inhibits DNA polymerase.

DNA synthesis is also inhibited due to the incorporation of cytarabine into DNA. The cytostatic effect is dose-dependent.

Several mechanisms for the development of resistance to cytarabine are known: inhibition of membrane transport, deficiency of phosphorylating enzymes, increased activity of inactivating enzymes, and reduced affinity of DNA polymerase. Maintaining a high intracellular concentration of Ara-CTP is crucial for the development of the cytotoxic effect.

Pharmacokinetics

After IV administration, Cytarabine is rapidly and almost completely converted into the inactive uracil metabolite Ara-U under the action of cytidine deaminase in the liver and other tissues. The initial phase T_1/2 is 1.4-7.5 min, and the terminal phase is approximately 10-200 min, averaging 120 min. Due to the low deaminase activity in the CNS, the elimination of cytarabine from the cerebrospinal fluid is slow, with a T_1/2 of 2-11 hours.

During continuous IV infusion of cytarabine at conventional doses (100-200 mg/m² body surface area), concentrations of 0.04-0.6 µmol/L are achieved. After SC or IM administration, the C_max of cytarabine in plasma is reached within 20-60 minutes, and these levels are significantly lower than with IV administration. The C_max of cytarabine in blood plasma at the same dose varies greatly among different patients. This is followed by a biphasic decrease in concentration.

The V_d is 0.7 L/kg. Cytarabine penetrates the blood-brain barrier. After continuous infusion, the concentration in the cerebrospinal fluid reaches 10-40% of the concentration in blood plasma. Plasma protein binding is 2-20%.

Upon entering the body, Cytarabine is rapidly converted into the active metabolite Ara-CTP in leukemia and normal bone marrow cells as a result of phosphorylation under the action of nucleotidases. The formation of the inactive metabolite Ara-U under the action of cytidine deaminase occurs mainly in the liver and, to a lesser extent, in other tissues and blood.

The elimination of cytarabine from plasma is biphasic. Within 24 hours, about 80% of the cytarabine dose is detected in the urine, of which 71-96% is in the form of the inactive metabolite and 4-10% is unchanged Cytarabine.

Indications

Acute non-lymphoblastic and/or lymphoblastic leukemia (induction of remission, as well as for maintenance therapy); prevention and treatment of neuroleukemia (intrathecal administration as monotherapy; in combination with other antineoplastic drugs); non-Hodgkin’s lymphomas; blast crises in chronic myeloid leukemia.

High-dose cytarabine therapy therapy-refractory non-Hodgkin’s lymphomas; therapy-refractory acute non-lymphoblastic and/or lymphoblastic leukemia, as well as variants with an unfavorable prognosis; relapses of acute leukemias; secondary leukemias after prior chemotherapy and/or radiotherapy; manifest leukemia after transformation of preleukemias; acute non-lymphoblastic leukemia in patients under 60 years of age (for consolidation of remission); blast crises in chronic myeloid leukemia.

ICD codes

Dosage Regimen

Administer Cytosar^® intravenously (as a bolus injection or continuous infusion), subcutaneously, intramuscularly, or intrathecally.

Establish the regimen individually based on the disease indication, treatment phase, and the patient’s hematological status.

For induction therapy in acute leukemia, use 100-200 mg/m²/day as a continuous 24-hour IV infusion for 5-10 days. Repeat the course after a 9-14 day interval if necessary.

For maintenance therapy, administer 10-30 mg/m² subcutaneously once daily for 5 days, repeating every 4 weeks. Alternatively, use 100-200 mg/m² as a single IV infusion every 5-7 days.

For high-dose therapy in refractory disease or consolidation, use 1-3 g/m² as a 1-3 hour IV infusion every 12 hours for 2-6 days. Closely monitor for severe myelosuppression and neurotoxicity.

For intrathecal administration to treat or prevent neuroleukemia, use 5-75 mg/m² per dose. The frequency is typically every 4 days until cerebrospinal fluid normalization, not exceeding one intrathecal administration per day.

Adjust dosage for patients with impaired hepatic or renal function and for those over 60 years of age. Do not use high doses in these populations without a careful benefit-risk assessment.

Monitor complete blood counts, liver and kidney function, and serum uric acid levels before and during therapy. Provide prophylactic anti-hyperuricemic therapy (e.g., allopurinol) and ensure adequate hydration, especially with high tumor burden.

Adverse Reactions

Infections very common – sepsis, pneumonia, viral, bacterial, fungal, parasitic, or saprophytic infections of any location; frequency unknown – inflammation of the subcutaneous tissue at the injection site, liver abscess.

From the hematopoietic system very common – myelosuppression, reticulocytopenia; common – thrombocytopenia, anemia, megaloblastic anemia, leukopenia; possible – changes in cell morphology in smears from bone marrow aspirate and peripheral blood. With high-dose therapy, severe pancytopenia is possible, which may last 15-25 days with more pronounced bone marrow aplasia than with conventional doses.

From the immune system frequency unknown – anaphylactic reactions.

From metabolism common – anorexia, hyperuricemia due to tumor cell lysis.

From the nervous system frequency unknown – neurotoxicity, neuritis, dizziness, headache. During high-dose therapy, personality changes, decreased concentration, dysarthria, ataxia, tremor, nystagmus, headache, confusion, drowsiness, dizziness, coma, and convulsions have been observed.

From the organ of vision common – reversible hemorrhagic conjunctivitis (photophobia, burning in the eyes, increased lacrimation, visual disturbances), keratitis.

From the cardiovascular system: uncommon – pericarditis; very rare – cardiac arrhythmias; frequency unknown – sinus bradycardia.

From the respiratory system: uncommon – sore throat, dyspnea. During high-dose therapy, pulmonary edema/acute respiratory distress syndrome has been observed.

From the digestive system common – dysphagia, abdominal pain, nausea, vomiting, diarrhea, inflammation or ulceration of the oral mucosa and/or anal canal walls; uncommon – esophagitis, esophageal ulcers, necrotic colitis, intestinal cystic pneumatosis, peritonitis; very rare – pancreatitis. During high-dose therapy, cases of intestinal perforation, necrosis of a section of the intestine with the development of intestinal obstruction and peritonitis have been noted.

From the liver and biliary tract: very common – impaired liver function; frequency unknown – jaundice. After high-dose chemotherapy with cytarabine, liver abscesses, Budd-Chiari syndrome (hepatic vein thrombosis) have been observed.

From the skin and subcutaneous tissues: very common – rash; common – reversible erythema, bullous dermatitis, urticaria, vasculitis, alopecia; uncommon – lentigo, skin ulceration, skin itching, burning pain in the palms and soles of the feet; very rare – neutrophilic eccrine hidradenitis; frequency unknown – palmar-plantar erythrodysesthesia syndrome.

From the musculoskeletal system: uncommon – myalgia, arthralgia.

From the urinary system: common – impaired renal function, urinary retention.

Other common – thrombophlebitis at the injection site, fever; cytarabine syndrome, including bone or muscle pain, chest pain, elevated temperature, general weakness, fever, skin rash (occurs 6-12 hours after administration). With intrathecal administration, bone marrow suppression, nausea, and vomiting are possible. Sometimes, the development of severe spinal cord toxicity may occur, which can lead to quadriplegia and muscle paralysis, necrotizing encephalopathy, blindness, and other isolated manifestations of neurotoxicity.

Contraindications

Hypersensitivity to cytarabine; anemia, leukopenia, thrombocytopenia of non-oncological etiology (including bone marrow aplasia), except in cases where use is necessary for vital indications; pregnancy, breastfeeding period.

With caution

In patients with hepatic and/or renal insufficiency (due to an increased risk of adverse reactions, especially during high-dose therapy), with drug-induced suppression of hematopoiesis, with bone marrow infiltration by tumor cells, with acute infectious diseases of viral (including chickenpox, herpes zoster), fungal, or bacterial nature (risk of severe complications and generalization of the process), diseases in which there is an increased risk of hyperuricemia (gout or urate nephrolithiasis). When treating with cytarabine, as with the use of other immunosuppressive agents, vaccination with live vaccines should be avoided. In patients over 60 years of age, the use of high doses of cytarabine is possible after a careful assessment of the benefit/risk ratio.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding. If use during lactation is necessary, the issue of discontinuing breastfeeding should be decided.

In experimental studies, the teratogenic and embryotoxic effects of cytarabine have been established.

Use in Hepatic Impairment

Should be used with caution in patients with hepatic insufficiency, due to an increased risk of adverse reactions, especially during high-dose therapy.

Use in Renal Impairment

Should be used with caution in patients with renal insufficiency, due to an increased risk of adverse reactions, especially during high-dose therapy.

It is not recommended to use Cytarabine immediately before and immediately after a dialysis session.

Geriatric Use

Should be used with caution in elderly patients. In patients over 60 years of age, the use of high doses of cytarabine is possible after a careful assessment of the benefit/risk ratio.

Special Precautions

The use of cytarabine should be carried out under the supervision of a qualified physician experienced in working with anticancer chemotherapeutic drugs and only in a hospital setting. Cytarabine can be used both as monotherapy and in combination with other antineoplastic drugs. In the case of combination therapy, the cumulative myelosuppressive effect of all drugs included in the regimen should be taken into account.

Cytarabine should be used with caution in patients with suppression of the hematopoietic system, impaired renal and/or liver function, with bone marrow infiltration by tumor cells, as well as in patients who have previously received cytotoxic drugs or radiation therapy.

During cytarabine therapy, peripheral blood counts, liver and kidney function, plasma uric acid levels, bone marrow function, CNS, and lungs should be monitored.

Predisposing factors for the development of neurotoxicity during cytarabine treatment are impaired renal and/or liver function, liver abscesses, CNS involvement from previous treatment (e.g., after radiation therapy), ethanol abuse, as well as combination with other CNS-toxic treatments. CNS disorders are reversible in most cases. Isolated cases of severe toxic effects on the spinal cord have been described, leading to the development of quadriplegia and paralysis, necrotic encephalopathy, blindness, and other isolated manifestations of neurotoxicity.

Within 24 hours after administration, the leukocyte count decreases, reaches minimum values on days 7-9, then briefly increases until day 12, after which it decreases more significantly with a minimum on days 15-24. Over the next 10 days, the leukocyte count rapidly increases to the initial level. The platelet count decreases significantly on day 5 after cytarabine administration, the lowest level is reached on days 12-15, reaching the initial level over the next 10 days.

The administration of corticosteroids can prevent or reduce the manifestations of the cytarabine syndrome.

During treatment, especially in the presence of a large number of blast cells or a large tumor mass (lymphomas), mandatory drug prophylaxis of hyperuricemia should be carried out and the intake of allopurinol and sufficient fluids should be ensured.

In experimental studies, the mutagenic effect of cytarabine has been established.

Men and women of childbearing potential should use reliable methods of contraception during treatment and for 6 months after the end of cytarabine therapy.

Effect on ability to drive vehicles and operate machinery

During the treatment period, patients should avoid driving vehicles and other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

Concomitant use with other myelosuppressive antineoplastic drugs or radiation therapy enhances the cytotoxic as well as immunosuppressive activity of these drugs. In patients receiving chemotherapy including vincristine, prednisone, and cyclophosphamide with cytarabine or procarbazine, the equilibrium concentration of digoxin in plasma is reversibly reduced (impaired absorption due to toxic effects on the intestinal mucosa), and the renal excretion of the glycoside is also reduced.

In vitro studies of the interaction between gentamicin and cytarabine revealed the existence of antagonism, which may lead to a decrease in the sensitivity of Klebsiella pneumoniae strains to gentamicin.

A decrease in the effectiveness of flucytosine is possible when used concomitantly with cytarabine.

When used concomitantly with immunosuppressants (azathioprine, chlorambucil, corticosteroids, cyclophosphamide, cyclosporine, mercaptopurine, tacrolimus), the risk of infectious complications increases.

When used concomitantly with killed viral vaccines, due to the suppression of normal defense mechanisms by cytarabine, antibody formation may be reduced.

When used concomitantly with live viral vaccines, due to the suppression of normal defense mechanisms by cytarabine, potentiation of virus replication, increased adverse reactions, and reduced antibody formation are possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.