Cytarabine (Solution, Lyophilisate) Instructions for Use

ATC Code

L01BC01 (Cytarabine)

Active Substance

Cytarabine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agents; antimetabolites; pyrimidine analogues

Pharmacological Action

An antitumor agent from the group of antimetabolites-pyrimidine analogues. Cytarabine inhibits DNA synthesis in the cell, predominantly in the S-phase of the cell cycle. Cytarabine acquires 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 T_1/2 of the initial phase is 1.4-7.5 min, and of the terminal phase is approximately 10-200 min, averaging 120 min. Due to the low activity of deaminase 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. With SC or IM administration, the C_max of cytarabine in plasma is reached in 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 leukemic 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 maintenance therapy); prevention and treatment of neuroleukemia (intrathecal administration as monotherapy; in combination with other antitumor 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 radiation therapy; 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 intravenously (bolus or infusion), subcutaneously, intramuscularly, or intrathecally.

Establish the regimen individually based on indication, disease stage, hematological status, and the specific antitumor protocol.

For induction therapy in acute leukemias, use 100-200 mg/m² daily as a continuous 24-hour intravenous infusion for 5-10 days.

Alternatively, administer 100-200 mg/m² intravenously every 12 hours for 5-10 days.

For subcutaneous or intramuscular administration, use the same daily dose as a single injection.

For maintenance therapy, use 10-30 mg/m² subcutaneously once daily for 5 days, repeating cycles every 4 weeks.

Alternatively, administer 1-1.5 mg/kg intravenously once or twice weekly.

For intrathecal administration to treat or prevent neuroleukemia, use 5-75 mg/m² once every 4 days until cerebrospinal fluid normalization.

The typical intrathecal dose is 30 mg/m², not to exceed 70 mg.

For high-dose therapy in refractory disease or consolidation, use 1-3 g/m² intravenously over 1-3 hours every 12 hours for 2-6 days.

Repeat high-dose cycles at 2-4 week intervals depending on hematological recovery.

Adjust dose based on hematological toxicity; delay administration if neutrophil count is below 1,000/µL or platelet count is below 50,000/µL.

Reduce dose by 30-50% for patients with impaired hepatic or renal function.

Monitor complete blood counts, liver and kidney function, and serum uric acid levels before and during therapy.

Ensure adequate hydration and administer prophylactic allopurinol to prevent tumor lysis syndrome.

Adverse Reactions

Infectious diseases 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 can last 15-25 days with more pronounced bone marrow aplasia than with the use of 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, shortness of breath. 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 pneumatosis cystoides, 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 – liver function disorders; 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 is possible, 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 side effects, 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 developing 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 thorough assessment of the benefit/risk ratio.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding. If it is necessary to use during lactation, 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 side effects, 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 side effects, 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 thorough 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 antitumor chemotherapeutic drugs, and only in a hospital setting. Cytarabine can be used both as monotherapy and in combination with other antitumor 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 include impaired renal and/or liver function, liver abscesses, CNS damage 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 number of leukocytes decreases, reaching minimum values on days 7-9, then briefly increases until day 12, after which it decreases again more significantly with a minimum on days 15-24. Over the next 10 days, the number of leukocytes rapidly increases to the initial level. The number of platelets decreases significantly on the 5th day 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 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 mechanisms

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 antitumor drugs or radiation therapy enhances the cytotoxic as well as immunosuppressive activity of these drugs. In patients receiving chemotherapy including vincristine, prednisolone, 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 with simultaneous use with cytarabine.

With simultaneous use of immunosuppressants (azathioprine, chlorambucil, corticosteroids, cyclophosphamide, cyclosporine, mercaptopurine, tacrolimus), the risk of developing infectious complications increases.

With simultaneous use of killed viral vaccines, due to the suppression of normal defense mechanisms by cytarabine, a decrease in antibody formation is possible.

With simultaneous use of live viral vaccines, due to the suppression of normal defense mechanisms by cytarabine, potentiation of virus replication, increased side effects, and decreased antibody formation are possible.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°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.