Cytarabine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYTARABINE (CYTARABINE)

Composition:

Active substance: cytarabine;

1 ml of solution contains 100 mg of cytarabine;

Excipients: macrogol 400, TRIS buffer, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01BC01.

Pharmacological properties.

Pharmacodynamics.

Cytarabine, a pyrimidine nucleoside analogue, is an antineoplastic agent that inhibits deoxyribonucleic acid (DNA) synthesis. It also has antiviral and immunosuppressive properties.

Mechanism of cytotoxicity in vitro: the primary action of cytarabine is the inhibition of deoxycytidine synthesis, although inhibition of cytidine kinases and incorporation of the compound into nucleic acids may also contribute to the cytostatic and cytotoxic effects of the drug on cells.

Pharmacokinetics.

Cytarabine is deaminated to arabino­furanosyluracil in the liver and kidneys. After intravenous administration, only 5.8% of the administered dose is excreted unchanged in the urine within 12–24 hours. 90% of the dose is excreted as deaminated drug.

Cytarabine is rapidly metabolized, primarily in the liver, as well as in the kidneys. After single high intravenous doses, drug levels in the blood decline to unmeasurable levels within 15 minutes in most patients. In some patients, circulating drug levels were undetectable as early as 5 minutes after injection.

Clinical characteristics.

Indications.

Achievement and maintenance of remission in acute non-lymphoblastic leukemias in adults and children. Treatment of other types of leukemia, such as acute lymphoblastic leukemia and chronic myeloid leukemia (blast crisis).

Cytarabine may be used as monotherapy or in combination with other antineoplastic agents; better results are usually achieved with combination therapy. Remissions induced by Cytarabine are short-lived without further maintenance therapy.

Treatment of high-risk leukemia, refractory leukemia, and relapsed acute leukemia, regardless of concomitant use of high-dose cytotoxic chemotherapeutic agents.

In combination therapy (LSA2L2) for the treatment of non-Hodgkin's lymphomas in children.

Cytarabine-containing preparations have been experimentally used in the treatment of various solid tumors. Overall, a positive response to treatment has been observed in a small number of patients with solid tumors.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Drug-induced bone marrow suppression (only after careful assessment of risk versus expected benefit).
• During pregnancy, the drug should be administered only after evaluation of risks and expected benefits (see section "Use during pregnancy or breastfeeding").
• Breastfeeding must be discontinued during treatment with the drug (see section "Use during pregnancy or breastfeeding").

Special safety precautions.

When handling the drug, standard procedures for handling cytotoxic agents must be followed. Cytarabine has teratogenic and mutagenic effects in humans. Measures must be taken to prevent contact of cytarabine solutions with skin and mucous membranes. If the drug does come into contact with the skin, the affected area should be immediately rinsed with large amounts of water, followed by washing with soap and water or sodium bicarbonate solution, and medical advice should be sought. If cytarabine solutions enter the eyes, they should be immediately flushed with water and ophthalmological medical assistance should be sought.

Pregnant healthcare workers should not handle the drug.

Personnel handling cytarabine must wear protective clothing (goggles, medical gowns, disposable gloves, and masks). A designated area (preferably with laminar airflow) should be used for solution preparation. Work surfaces should be protected with absorbent paper with a plastic backing, intended for single use.

Unused drug residues and all instruments and materials used in preparing the infusion solution and administering the drug must be disposed of according to approved procedures for cytotoxic waste disposal.

Spilled or splashed drug should be inactivated with a 5% sodium hypochlorite solution or another buffer solution with pH 7–8 (e.g., phosphate-buffered solution). All materials used during cleanup must be disposed of as described above.

Interaction with other medicinal products and other forms of interaction.

Combination therapy with cytarabine and other oncolytic agents, myelosuppressive drugs, or radiation therapy may enhance the cytotoxic and immunosuppressive effects of these agents. Dose adjustments may be necessary in such cases.

5-Fluorocytosine should not be administered concurrently with cytarabine, as this may abolish the therapeutic efficacy of 5-fluorocytosine. This may be due to potential competitive inhibition of its accumulation.

Digoxin: In patients receiving beta-acetyldigoxin and chemotherapy regimens including cyclophosphamide, vincristine, and prednisone, reversible decreases in plasma digoxin steady-state concentrations and renal glycoside excretion have been observed, regardless of whether cytarabine or procarbazine was administered. No changes in digotoxin steady-state concentrations have been observed. Therefore, plasma digoxin concentrations should be monitored in patients receiving such combination chemotherapy regimens. Digotoxin may be considered as an alternative treatment option in such patients.

Gentamicin: In vitro studies of the interaction between gentamicin and cytarabine have demonstrated antagonism against sensitive strains of K. pneumoniae. This suggests that in patients receiving cytarabine and gentamicin for K. pneumoniae-induced infections, lack of rapid therapeutic response may necessitate reevaluation of antibacterial therapy. When cytarabine is used in combination with other cytotoxic agents, their toxic effects, particularly on the hematopoietic system, are enhanced.

Concomitant use of flucytosine and cytarabine reduces the efficacy of flucytosine treatment.

Methotrexate: Intravenous administration of cytarabine in combination with intrathecal administration of methotrexate may increase the risk of serious neurological adverse reactions, such as headache, paralysis, coma, and stroke-like episodes.

Administration of live vaccines to patients with chemotherapy-induced immunosuppression, including due to cytarabine, may lead to severe or fatal infections. Vaccination with live vaccines is contraindicated during cytarabine therapy. Inactivated vaccines may be used, but their efficacy may be reduced.

Special precautions for use.

During the induction phase of remission, patients should be treated in medical facilities equipped with appropriate laboratory and resuscitation equipment sufficient to monitor drug tolerability and to provide patient protection and support during the drug's toxic effects. The main toxic effect of Cytarabine is bone marrow suppression leading to the development of leukopenia, thrombocytopenia, and anemia. Less severe toxic manifestations include nausea, vomiting, diarrhea, abdominal pain, oral ulceration, and impaired liver function.

Before prescribing Cytarabine, the potential benefit for the patient should be weighed against the risk of developing toxic effects. Prior to conducting a benefit-risk assessment or initiating therapy, the physician must review the recommendations provided below.

Anaphylactic reactions

Anaphylactic reactions have been observed during treatment with cytarabine (see section "Adverse reactions"). An anaphylactic reaction occurred immediately after intravenous administration of the drug, resulting in circulatory and respiratory disturbances requiring resuscitation measures.

Disorders of the blood and lymphatic systems

Cytarabine is potentially harmful to the bone marrow. The extent of this adverse effect depends on the dosage and administration regimen. When drug-induced bone marrow suppression is expected, treatment should be initiated cautiously, following evaluation of potential risks and expected benefits. Therapy must be administered under close medical supervision. Daily monitoring of leukocyte and platelet counts in the blood is required at the beginning of treatment. After disappearance of blast cells from peripheral blood, continuous monitoring of bone marrow is recommended, as suppression of its activity may lead to severe, sometimes fatal, consequences (infectious complications due to granulocytopenia and other immune system disorders, secondary hemorrhages due to thrombocytopenia).

Patients receiving Cytarabine require careful monitoring. Frequent determination of leukocyte and platelet counts is recommended. If drug-induced bone marrow suppression leads to a decrease in leukocyte count below 50,000/mm³ and polymorphonuclear granulocytes below 1,000/mm³, treatment interruption or modification should be considered. After discontinuation of therapy, blood cell counts may continue to decline for 5–7 days, reaching the lowest level on days 12–24 after stopping the drug. Treatment may be resumed only after clear signs of bone marrow recovery are observed (confirmed by repeated bone marrow examinations). The medical facility must be equipped to manage potentially life-threatening complications of bone marrow suppression.

Hepatic and/or renal function

The liver appears to neutralize a significant portion of the administered dose of cytarabine. In particular, central nervous system (CNS) toxic reactions following high-dose cytarabine therapy are more likely in patients with renal or hepatic impairment. Patients with renal or hepatic insufficiency should receive the drug with caution and possibly at reduced doses.

Neurological adverse reactions

Severe neurological adverse reactions, ranging from headache to paralysis, coma, and stroke-like episodes, have been observed in patients receiving intravenous cytarabine in combination with intrathecal methotrexate, primarily in young individuals and adolescents.

Tumor lysis syndrome (TLS)

As with other cytotoxic agents, administration of Cytarabine may lead to tumor lysis syndrome caused by rapid destruction of tumor cells. Secondary hyperuricemia associated with this syndrome may result in acute renal failure. In addition to other laboratory tests and clinical evaluations, serum uric acid levels should be monitored regularly. Appropriate supportive therapy should be provided when necessary.

High-dose Cytarabine therapy

Severe, sometimes fatal, toxic reactions involving the central nervous system (CNS), gastrointestinal tract, and lungs—distinct from those observed with standard-dose Cytarabine—have been reported following high-dose cytarabine therapy (2–3 g/m²). These include reversible corneal damage and hemorrhagic conjunctivitis, which can be prevented or minimized by prophylactic use of corticosteroid-containing eye drops; mostly reversible central nervous system and cerebellar dysfunction, including personality changes, somnolence, and coma; severe gastrointestinal tract ulceration, including intestinal pneumatosis cystoides leading to peritonitis; sepsis and hepatic abscess; pulmonary edema, hepatic injury with hyperbilirubinemia; intestinal necrosis, and necrotic colitis. Peripheral motor and sensory neuropathy developed in two adult patients with acute non-lymphocytic leukemia after consolidation therapy with high-dose Cytarabine, daunorubicin, and asparaginase. Patients receiving high-dose Cytarabine therapy should be examined for symptoms of neuropathy, as dose regimen adjustments may be required to prevent irreversible neurological damage.

Immunosuppression/vaccination/increased susceptibility to infections

Administration of live or attenuated live vaccines to patients whose immune system is suppressed due to chemotherapy, including cytarabine, may result in serious or fatal infections. Patients receiving Cytarabine should avoid live vaccines. Inactivated or killed vaccines may be administered, but the immune response to such vaccines may be diminished.

Viral, bacterial, fungal, parasitic, or saprophytic infections at any site may occur during treatment with Cytarabine as monotherapy or in combination with other immunosuppressive agents at doses that suppress cellular or humoral immunity. These infections may be mild but can also be severe and even fatal.

Nausea, vomiting

Nausea or vomiting may occur within several hours after rapid intravenous administration of the drug. These reactions can be avoided by administering the drug via infusion.

Pancreatitis

Acute pancreatitis has been observed in patients treated with Cytarabine in combination with other medicinal products.

Carcinogenesis

Carcinogenicity of Cytarabine has been demonstrated in animal studies. Such an effect cannot be excluded with long-term use of cytarabine in humans.

Use during pregnancy or breastfeeding

Pregnancy

Studies on the use of the drug in pregnant women have not been conducted. Cytarabine is a teratogenic substance in certain animal species. This drug should be administered to pregnant women or women who may become pregnant only when the potential benefit to the woman outweighs the potential risk to the fetus. Women of reproductive age should avoid pregnancy during treatment with cytarabine by using appropriate contraceptive methods.

Healthy children have been born to women who received cytarabine during pregnancy (as monotherapy or in combination with other drugs). Some infants were premature or had low birth weight. Follow-up of some children from 6 weeks to 7 years after drug exposure revealed no abnormalities. One infant died at 80 days from gastroenteritis.

Two cases of congenital malformations have been reported, particularly when the fetus was exposed to systemic cytarabine therapy during the first trimester of pregnancy. These malformations included defects of the distal parts of upper and lower limbs and deformities of limbs and ears.

Cases of pancytopenia, leukopenia, anemia, thrombocytopenia, electrolyte disturbances, transient eosinophilia, elevated IgM levels, hyperpyrexia, sepsis, and fatal outcomes during the neonatal period have been reported in infants exposed to cytarabine in utero. Some of these infants were premature.

Therapeutic abortions were performed in five women undergoing cytarabine therapy. Four fetuses were generally normal, but one had splenomegaly and another had trisomy X in chorionic tissue.

Due to the potential risk of abnormalities during cytotoxic therapy, especially during the first trimester, the potential risk to the fetus and the advisability of continuing pregnancy should be evaluated in patients who are pregnant or may become pregnant during cytarabine treatment. The risk is lower if therapy is initiated during the second or third trimester. Although healthy children have been born to women who received cytarabine throughout all three trimesters, these children require ongoing medical follow-up.

Breastfeeding

It is unknown whether the drug is excreted in breast milk. Since many drugs are excreted in breast milk and due to the potential risk of adverse reactions caused by cytarabine, breastfeeding should be discontinued or drug treatment stopped, taking into account the benefit of therapy for the mother.

Impairment of fertility

Men should use contraceptive methods to prevent conception during treatment and for at least 6 months after treatment. Patients should be informed before starting therapy about the possibility of sperm cryopreservation, as there is a risk of irreversible infertility following treatment with Cytarabine.

Ability to affect reaction speed when driving or operating machinery

Cytarabine does not affect the ability to drive vehicles or operate machinery. However, discomfort, dizziness, or nausea may occur during treatment with cytarabine (see section "Adverse reactions"). In such cases, driving vehicles or operating machinery is not recommended.

Administration and Dosage

Treatment with Cytarabine should be conducted under the supervision of an experienced oncologist or hematologist in a specialized inpatient setting with appropriate laboratory and resuscitation support.

Cytarabine may be used as monotherapy, but it is more commonly administered in combination with other cytotoxic agents.

Prepare the infusion solution by diluting the drug with 0.9% sodium chloride solution or 5% glucose solution.

Patients may tolerate higher doses of cytarabine when administered via rapid intravenous infusion compared to slow infusion. This phenomenon is related to the rapid inactivation of the drug and brief exposure to high concentrations of cytarabine following rapid intravenous administration. With both administration methods, normal and neoplastic cells respond similarly, and no clear clinical advantage of rapid versus slow intravenous infusion has been demonstrated to date.

Dosages and treatment regimens should be selected based on diagnosis and the patient's clinical condition.

Cytarabine may be administered via intravenous infusion or injection, as well as subcutaneously. The standard dose for subcutaneous administration is 20–100 mg/m² body surface area, depending on the indication and dosing regimen.

Leukemia Remission Induction

Continuous administration

The recommended dose for bolus injection is 2 mg/kg body weight daily for 10 days. Daily blood counts should be monitored. If no therapeutic effect is observed and no signs of toxicity appear, the dose may be increased to 4 mg/kg body weight daily. This dose may be continued until a therapeutic response or signs of toxicity occur. When using the above doses, toxic symptoms are observed in nearly all patients.

A dose of 0.5–1.0 mg/kg body weight daily may be administered via infusion over no more than 24 hours. A satisfactory response is usually observed within the first hour of infusion in most patients. After 10 days, the dose may be increased up to a maximum of 2 mg/kg body weight daily and continued until signs of toxicity appear or remission is achieved.

Intermittent therapy

Cytarabine should be administered intravenously for 5 consecutive days at doses of 3–5 mg/kg body weight daily. Treatment should be repeated after a break lasting 2 to 9 days. This regimen should continue until signs of toxicity appear or remission is achieved.

Signs of bone marrow recovery may be expected between 7 and 64 days (average 28 days). The standard dose may be gradually increased if no signs of toxicity occur or if remission is observed under the standard dosing regimen.

The drug is most commonly administered via continuous intravenous infusion or rapid intravenous infusions.

The duration and frequency of treatment cycles should be determined based on the patient's clinical status and bone marrow function parameters.

Consolidation/maintenance dosing

Remission achieved with cytarabine and/or other agents may be maintained by administering 1–2 weekly intravenous or subcutaneous doses of Cytarabine at 1 mg/kg body weight.

Non-Hodgkin’s Lymphoma Therapy

Adult treatment. Various polychemotherapy regimens may be used.

Pediatric treatment. Various treatment regimens for non-Hodgkin’s lymphoma in children should be applied depending on disease stage and histological tumor type (e.g., BFM protocol). Detailed information on this topic can be found in relevant medical literature.

High-Dose Therapy

In high-dose therapy, Cytarabine is usually administered at 2–3 g/m² body surface area via intravenous infusions lasting 1–3 hours, every 12 hours, for 1–6 days.

High-dose chemotherapy must be administered with extreme caution and only by medical personnel experienced in such treatment.

The total tolerable dose may be higher when patients receive the drug via rapid intravenous injections rather than slow infusions. This phenomenon is related to the rapid inactivation of the drug and the brief exposure of sensitive normal and tumor cells to high concentrations after rapid administration. Normal and tumor cells respond similarly to these different administration methods, and thus no clear clinical advantage of any particular method has been demonstrated.

Patients with Hepatic or Renal Impairment

Cytarabine should be used with caution in patients with impaired liver or kidney function, possibly at reduced doses. Central nervous system (CNS) toxic reactions following high-dose cytarabine therapy are more likely in patients with renal and/or hepatic impairment.

Geriatric Patients

Elderly patients tolerate toxic side effects less well; therefore, enhanced monitoring of elderly patients is required due to the potential development of leukopenia, thrombocytopenia, and anemia. Supportive treatment should be initiated if necessary. High-dose therapy in patients over 60 years of age should only be considered after careful benefit-risk assessment.

Children

There are no definitive data on the safety of Cytarabine use in children under 2 years of age. Dosing regimens in children are similar to those used in adults. Delayed progressive ascending paralysis leading to fatal outcomes has been reported in children with acute myeloid leukemia following standard-dose intravenous cytarabine in combination with other agents.

Overdose

There is no specific antidote for cytarabine overdose. An unacceptable acceleration of irreversible neurotoxic effects and a fatal case were reported after administration of 12 infusions of 4.5 g/m² body surface area, each lasting 1 hour and given every 12 hours. In case of overdose, treatment with Cytarabine should be discontinued, and supportive therapy should be initiated, including management of bone marrow suppression (complete blood and platelet transfusions, antibiotics).

Adverse Reactions

Frequency is defined as: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1,000 to <1/100), rare (from ≥1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

Adverse effects associated with cytarabine therapy are dose-dependent. The most frequently observed adverse effects are hematopoietic suppression and gastrointestinal disturbances.

Expected Adverse Reactions

Blood and Lymphatic System Disorders

Since cytarabine has a toxic effect on the bone marrow, changes in bone marrow and peripheral blood cells may occur. Treatment with cytarabine may lead to anemia, leukopenia, thrombocytopenia, megaloblastosis, and decreased reticulocyte count. The severity of these reactions depends on the dose and administration regimen. Changes in bone marrow and peripheral blood cells are possible.

Following 5-day continuous infusions or single injections at doses of 50–600 mg/m² body surface area, leukocyte reduction has a biphasic pattern. Regardless of the initial leukocyte count, dose, or treatment regimen, an initial decrease occurs within the first 24 hours, with the lowest levels reached on days 7–9. This is followed by a transient increase peaking on day 12. A second, deeper decline follows, with the nadir occurring on days 15–24. Over the subsequent 10 days, leukocyte counts rapidly rise above baseline levels. Thrombocytopenia begins on day 5, reaches maximum severity on days 12–15, and is followed by a rapid increase in platelet count above baseline levels over the next 10 days.

Infections and Infestations

Viral, bacterial, fungal, parasitic, or saprophytic infections at any site may occur during treatment with cytarabine as monotherapy or in combination with other immunosuppressive agents at immunosuppressive doses, which negatively affect cellular or humoral immunity. These infections may be mild but can become severe and occasionally fatal.

Cytarabine Syndrome

This syndrome is characterized by fever, myalgia, bone pain, rarely chest pain, maculopapular rash, conjunctivitis, and general malaise. It usually occurs 6–12 hours after administration of the drug. Corticosteroids have been shown to be effective in both treatment and prevention of this syndrome. If symptoms are responsive to treatment, corticosteroids should be administered and cytarabine therapy should not be discontinued.

Standard Dosing Regimen

When cytarabine is administered according to standard dosing regimens in combination with other agents, patients have reported abdominal pain (peritonitis) and colitis with positive occult blood test, accompanied by neutropenia and thrombocytopenia. Patients responded to conservative medical treatment.

In children with acute myeloid leukemia, delayed progressive ascending paralysis leading to fatal outcomes has been reported after intravenous administration of cytarabine at standard doses in combination with other drugs.

Infections and Infestations

Very common: sepsis, pneumonia, infection
Frequency not known: cellulitis at injection site, liver abscess

Benign, Malignant and Unspecified Tumors (including cysts and polyps)

Uncommon: lentigo

Blood and Lymphatic System Disorders

Very common: bone marrow suppression, anemia, megaloblastosis, leukopenia, granulocytopenia, thrombocytopenia, reticulocytopenia, hemorrhage, bone marrow hypoplasia

Immune System Disorders

Allergic edema, anaphylaxis (one case of immediate cardiopulmonary shock after intravenous administration of cytarabine requiring resuscitation measures was reported)

Metabolism and Nutrition Disorders

Common: anorexia, hyperuricemia
Frequency not known: decreased appetite

Cardiac Disorders

Frequency not known: pericarditis, sinus bradycardia

Vascular Disorders

Frequency not known: thrombophlebitis
Very rare: arrhythmia

Nervous System Disorders

Frequency not known: neurotoxicity, neuritis, dizziness, headache

With high-dose therapy – dysfunction of the cerebrum and cerebellum, manifesting as confusion, dysarthria, nystagmus, peripheral neuropathy, neurotoxicity

Eye Disorders

Frequency not known: reversible hemorrhagic conjunctivitis (with symptoms such as photophobia, burning or pain in the eyes, visual disturbances, excessive tearing; may be accompanied by rash), keratitis

To prevent the development of hemorrhagic conjunctivitis, topical glucocorticosteroids are recommended.

Respiratory, Thoracic and Mediastinal Disorders

Uncommon: pneumonia, dyspnea, interstitial pneumonitis, acute respiratory distress syndrome progressing to pulmonary edema
Frequency not known: respiratory distress, sore throat

Gastrointestinal Disorders

Very common: stomatitis, mucosal inflammation or ulceration in the oral cavity and anus, diarrhea, nausea, vomiting, abdominal pain
Common: mucositis, anorexia, dysphagia
Uncommon: intestinal pneumatosis, necrotizing colitis, gastrointestinal perforation, nausea, peritonitis
Frequency not known: pancreatitis, esophageal ulceration, esophagitis

Renal and Urinary Disorders

Frequency not known: renal dysfunction, renal failure, urinary retention

Skin and Subcutaneous Tissue Disorders

Very common: alopecia, rash
Common: skin ulcers, erythema, bullous dermatitis, vasculitis
Very rare: neutrophilic eccrine hidradenitis
Uncommon: skin pigmentation, panniculitis at injection site, burning and pain in palms and soles
Frequency not known: palmar-plantar syndrome, urticaria, pruritus, stretch marks

Musculoskeletal and Connective Tissue Disorders

Very common: cytarabine syndrome
Uncommon: myalgia, arthralgia, occasionally rhabdomyolysis

Hepatobiliary Disorders

Very common: elevated liver enzymes (reversible), hepatic dysfunction
Frequency not known: jaundice

General Disorders and Administration Site Conditions

Very common: fever
Common: hyperuricemia
Frequency not known: chest pain, injection site reactions

Investigations

Very common: abnormal bone marrow biopsy findings, abnormal blood test results

Adverse Reactions with High-Dose Cytarabine Distinct from Those Occurring with High-Dose Therapy

With high-dose regimens: sepsis, interstitial pneumonitis; concentration disturbances, dysarthria, ataxia, tremor, nystagmus, headache, confusion, dizziness, coma.

Hematologic Toxicity

Hematologic toxicity manifests as profound pancytopenia lasting 15–25 days, along with more severe bone marrow aplasia than with standard-dose regimens.

Infections and Infestations: frequency not known: liver abscess

Psychiatric Disorders: frequency not known: personality changes associated with cerebral and cerebellar dysfunction

Nervous System Disorders: very common: cerebral and cerebellar dysfunction, somnolence; frequency not known: coma, seizures, peripheral motor and sensory neuropathy

Adverse reactions may be more intense in elderly patients (>55 years of age).

Eye Disorders: very common: corneal damage, corneal toxicity, hemorrhagic conjunctivitis. These reactions can be prevented or reduced by using corticosteroid eye drops.

Cardiac Disorders: frequency not known: fatal cardiomyopathy, sinus bradycardia

Respiratory, Thoracic and Mediastinal Disorders: very common: acute respiratory distress syndrome, pulmonary edema

Gastrointestinal Disorders: common: necrotic colitis; frequency not known: gastrointestinal necrosis, gastrointestinal ulceration, intestinal pneumatosis, peritonitis, pancreatitis

Hepatobiliary Disorders: frequency not known: liver injury, hyperbilirubinemia, liver abscesses, liver damage with hyperbilirubinemia, Budd-Chiari syndrome (hepatic vein thrombosis)

Skin and Subcutaneous Tissue Disorders: common: skin rash with subsequent desquamation, alopecia

Other. Cardiomyopathy and rhabdomyolysis have been reported after cytarabine therapy. One case of anaphylaxis resulting in cardiac arrest requiring resuscitation measures was reported. This reaction occurred immediately after intravenous administration of cytarabine.

Amenorrhea and azoospermia are possible.

Cases of rapidly progressive respiratory distress syndrome progressing to pulmonary edema and radiologically detected cardiomegaly have been reported after experimental high-dose cytarabine therapy for leukemia relapse. A fatal case was documented.

Thrombophlebitis at the injection or infusion site has occurred in some patients. Some patients reported pain and inflammation at subcutaneous injection sites. However, in most cases, the drug is well tolerated.

In isolated cases, skin rash leading to desquamation has been reported. Complete alopecia is more common with high-dose therapy than with standard treatment regimens.

Shelf Life. 2 years.

Storage Conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities.

The infusion solution is prepared by diluting the drug with 0.9% sodium chloride solution or 5% glucose solution.

Cytarabine must not be mixed with other medicinal products.

Physical incompatibility of cytarabine has been observed with heparin, insulin, 5-fluorouracil, nafcillin, oxacillin, benzylpenicillin, and methylprednisolone sodium succinate.

Packaging. 1 ml or 10 ml solution in a vial; 1 vial per cardboard box.

Prescription Category. Prescription only.

Manufacturer.

Venus Remedies Limited.

Manufacturer's Address and Place of Business.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh 173205, India.