Cytarine

Cytarabine.

Each mL contains Cytarabine 100 mg.
Cytarabine is a cell cycle-phase specific antimetabolite category of antineoplastics. It is an analogue of the nucleoside cytosine and essentially imitates this natural substance.
Cytarabine is chemically 1-β-D-arabinofuranosylcytosine having molecular formula of C₉H₁₃N₃O₅ and molecular weight of 243.22.

Pharmacology: Mechanism of action: Cytarabine being an antimetabolite it interferes with the synthesis of DNA. The inhibition of the conversion of cytidine to deoxycytidine is the presumed primary site of action. Cytarabine may also be incorporated into DNA and RNA as in vitro chromosome breaks have been associated with the drug and the clinical effects are limited to tissues with a high rate of cellular proliferation. Alternatively, cytarabine may have a differentiating role rather than an antimitotic effect as the mechanism of action. Cytarabine reportedly also has immunosuppressive activity. Cytarabine is cell cycle phase-specific for the S-phase, cytarabine may also block progression from the G1-phase to the S-phase.
Pharmacokinetics: Cytarabine is rapidly metabolized and is not effective orally; less than 20 percent of the orally administered dose is absorbed from the gastrointestinal tract.
Following rapid intravenous injection of cytarabine labeled with tritium, the disappearance from plasma is biphasic. There is an initial distributive phase with a half-life of about 10 minutes, followed by a second elimination phase with a half-life of about 1 to 3 hours. After the distributive phase, more than 80 percent of plasma radioactivity can be accounted for by the inactive metabolite 1-β-D-arabinofuranosyluracil (ara-U). Within 24 hours about 80 percent of the administered radioactivity can be recovered in the urine, approximately 90 percent of which is excreted as ara-U.
Relatively constant plasma levels can be achieved by continuous intravenous infusion. After subcutaneous or intramuscular administration of cytarabine labeled with tritium, peak-plasma levels of radioactivity are achieved about 20 to 60 minutes after injection and are considerably lower than those after intravenous administration.
Cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels after single intravenous injection.

CYTARINE (Cytarabine) is indicated primarily for induction and maintenance of remission in acute myelocytic leukaemia of both adults and children. It has also been found to be useful in the treatment of other leukaemias such as acute lymphoblastic leukaemia or acute lymphocytic leukaemia, chronic myelocytic leukaemia (blastphase) and erythroleukaemia. CYTARINE (Cytarabine) may be used alone or in combination with other antineoplastic agents, the best results are often obtained with combination therapy. Children with non-Hodgkin's lymphoma have benefited from a combination drug program (LSA₂L₂) that includes cytarabine. Remissions induced by CYTARINE (Cytarabine) not followed by maintenance treatment have been brief. Maintenance therapy has extended these and provided useful and comfortable remissions with relatively little toxicity.

RECOMMENDED DOSE AND MODE OF ADMINISTRATION: Cytarabine 100 mg/ml injection is a ready to use injection and can be administered by intravenous and subcutaneous routes.
Cytarabine 100 mg/ml Injection should not be administered by the intrathecal route.
Remission Induction: Adult: Continuous Dosing: The usual dose in leukaemia, is 2 mg/kg by rapid intravenous injection daily for ten days. If after ten days neither therapeutic response nor toxicity has been observed, the dose may be increased to 4 mg/kg until a therapeutic response or toxicity is evident. Daily blood counts should be taken. Almost all patients can be carried to toxicity with these doses.
Alternatively, 0.5 to 1 mg/kg may be infused daily in 1-24 hours for ten days, and then at a rate of 2 mg/kg/day until toxicity is observed. Continue to toxicity or until remission occurs. Results from one-hour infusions have been satisfactory in the majority of patients.
For the induction of remission in acute leukaemias many dosage regimens have been used: 100 mg/m² twice daily by rapid intravenous injection, or 100 mg/m² daily by continuous intravenous infusion, both for 7 days, are used in combination regimens for acute myeloid leukaemia.
Intermittent dosing: Cytarabine may be given as intermittent intravenous doses of 3-5 mg/kg daily, for five consecutive days. This course of treatment can be repeated after an interval of 2 to 9 days and repeated until the therapeutic response or toxicity is exhibited.
Evidence of bone marrow improvement has been reported to occur 7-64 days after the beginning of therapy. In general, if a patient shows neither remission nor toxicity after a trial period, then cautiously administered higher doses can be administered. Generally patients tolerate higher doses given by rapid intravenous injection rather than slow infusion.
As a single agent for induction of remission in patients with acute leukaemia, cytarabine has been given in doses of 200 mg/m² by a continuous intravenous infusion for five days at approximately two week intervals.
Dilutions of CYTARINE (Cytarabine) should be made in Glucose 5% or Sodium Chloride 0.9% Intravenous Infusions to concentrations as low as 0.1 mg/mL. In order to reduce any microbiological hazard it is recommended that dilution should be effected immediately prior to use and infusion commenced as soon as practicable after preparation of the admixture. Infusion should be completed within 24 hours of preparation and any residue discarded. Any storage should be between 2-8°C, protected from light.
Maintenance therapy: To remission, doses of 1 mg/kg may be given intravenously or subcutaneously, once or twice weekly.
Children: Children appear to tolerate higher doses of cytarabine than adults, and where the range of doses is given, children should receive the higher dose.
Elderly: No data is available to suggest that a change in dose is necessary in the elderly. However, the elderly patient is more susceptible to toxic reactions and therefore particular attention should be paid to drug induced leucopenia, thrombocytopenia and anaemia.

There is no specific antidote for cytarabine overdose. Cessation of therapy followed by management of ensuing bone marrow depression including whole blood or platelet transfusion and antibiotics as required.
Twelve doses of 4.5 g/m² by intravenous infusion over 1 hour every 12 hours induce irreversible and fatal CNS toxicity.
Cytarabine may be removed by haemodialysis.
Single doses as high as 3 g/m² have been administered by rapid intravenous infusion without apparent toxicity.

Cytarabine Injection is contraindicated in those patients who are hypersensitive to cytarabine or to any of the excipients.
Anaemia, leucopenia and thrombocytopenia of non-malignant aetiology (e.g. bone marrow aplasia), unless the benefits outweigh the risk.
Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation.
During pregnancy, cytarabine should only be administrated on strict indication, where the benefits of the drug to the mother should be weighed against possible hazards to the fetus.

Only physicians experienced in cancer chemotherapy should use Cytarabine Injection. For induction therapy patients should be treated in a facility with laboratory and supportive resources sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The main toxic effect of cytarabine injection is bone marrow suppression with leukopenia, thrombocytopenia and anemia. Less serious toxicity includes nausea, vomiting, diarrhea and abdominal pain, oral ulceration and hepatic dysfunction.
The physician must judge possible benefit to the patient against known side effects of this drug in considering the advisability of therapy with Cytarabine Injection. Before making this judgment or beginning treatment the physician should be familiar with the following text.

Cytarabine Injection should not be administered by the intrathecal route. Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving the drug should be kept under close medical supervision. Leucocyte and platelet counts should be performed frequently and daily during induction. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.
Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses and haemorrhage secondary to thrombocytopenia).
One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitation has been reported. This occurred immediately after intravenous cytarabine was administered.
Severe and at times fatal central nervous system (CNS), gastrointestinal (GI) and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine) has been reported following some experimental cytarabine dose schedules. These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; somnolence; convulsion; severe gastrointestinal ulceration including pneumatosis cysteroides intestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema.
The risk of CNS toxicity increases if high dose cytarabine is given in combination with another CNS toxic treatment such as radiation therapy or in patients who have previously had CNS treatment as chemotherapy intrathecally. Rarely, neurological effects such as severe spinal cord toxicity even leading to necrotising encephalopathy, quadriplegia and paralysis and blindness have been reported with cytosine arabinoside and have been predominantly associated with intrathecal administration. Isolated cases have also been reported with high intravenous doses during combination chemotherapeutic regimens.
Delayed progressive ascending paralysis resulting in death has been reported in children with AML following intravenous cytarabine at conventional doses in combination with other drugs.
Cytarabine has been shown to be mutagenic and carcinogenic in animals. The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.
Cytarabine should be administered only under constant supervision by physicians experienced in therapy with cytotoxic agents.  Hyperuricaemia secondary to rapid lysis of neoplastic cells may occur in patients receiving cytarabine; serum uric acid concentrations should be monitored. The physician should be prepared to use such supportive and pharmacological measures as may be necessary to control this problem. Periodic determinations of renal and hepatic functions and bone marrow should also be performed, and the drug should be used with caution in patients with impaired hepatic function. However, dosage reduction does not appear to be necessary in patients with impaired renal function. The human liver apparently detoxifies a substantial fraction of the administered dose. The drug should be used with caution and at a reduced dose when liver function is poor. Frequent platelet and leucocyte counts are mandatory.
Therapy should be suspended or modified when drug-induced bone marrow depression results in a platelet count of less than 50,000 or a polymorphonuclear count of under 1000 per mm³. Counts may continue to fall after the therapy has been discontinued and may reach lowest values after five to seven days. Therapy may be restarted when the bone marrow appears to be recovering on successive bone marrow studies. Therapy should not wait until the normal blood values are obtained to be re-initiated. If treatment is not resumed before blood values return to normal, the disease can get out of control.
When intravenous doses are given quickly, patients may become nauseated and may vomit for several hours afterwards. The problem tends to be less severe when infused. Abdominal tenderness (peritonitis) and guaiac positive colitis, with concurrent neutropenia and thrombocytopenia, have been reported in patients treated with conventional doses of cytarabine in combination with other drugs. Patients have responded to nonoperative medical management. Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency has been reported.
Immunosuppressant effects/Increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cytarabine, result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving cytarabine. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
High dose therapy: Peripheral motor and sensory neuropathies after consolidation with high doses of cytarabine, daunorubicin, and asparaginase have occurred in adult patients with acute non-lymphocytic leukemia. Patients treated with high doses of cytarabine should be observed for neuropathy since dose adjustments may be needed to avoid irreversible neurologic disorders. Severe and sometimes fatal pulmonary toxicity, adult respiratory distress syndrome, and pulmonary edema have occurred following high dose schedules with cytarabine therapy. Cases of cardiomyopathy with subsequent death have been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation.
The safety of the drug has not been established in infants.
Patients receiving chemotherapy may have an impaired ability to drive or operate machinery and should be warned of the possibility and advised to avoid such tasks if so affected.
Carcinogenesis, Mutagenesis, Impairment of fertility: Extensive chromosomal damage, including chromatoid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported.
Fertility studies to assess the reproductive toxicity of cytarabine have not been conducted. Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking cytarabine therapy, especially in combination with alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Given that cytarabine has a mutagenic potential which could induce chromosomal damage in the human spermatozoa, males undergoing cytarabine treatment and their partner should be advised to use a reliable contraceptive method.

Pregnancy: Category D.
Cytarabine is teratogenic in some animal species. Its should not be used in pregnant women (especially during the first trimester) or in those who may become pregnant, unless the possible benefits outweigh the potential risks. Women who are, or who may become, pregnant during treatment with cytarabine should be informed of the risks. Men and women have to use effective contraception during and up to 6 months after treatment.
Lactation: It is not known whether cytarabine or its metabolite is distributed into breast milk, and it should not be used in mothers who are breastfeeding.

The following adverse events have been reported in association with cytarabine therapy.
Frequencies are defined using the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Undesirable effects from cytarabine are dose-dependent. Most common are gastrointestinal undesirable effects. Cytarabine is toxic to the bone marrow, and cause haematological undesirable effects.
Infection and infestations: Uncommon: Sepsis (immunosuppression).
Blood and lymphatic system disorders: Common: Anaemia, megaloblastosis, leucopenia, thrombocytopenia.
Not known: Reticulocytopenia.
These appear to be more evident after high doses and continuous infusions; the severity depends on the dose of the drug and schedule of administration.
Gastrointestinal disorders: Common: Dysphagia, abdominal pain, nausea, vomiting, diarrhea, oral/anal inflammation or ulceration.
Uncommon: Oesophagitis, oesophageal ulceration, pneumatosis cystoides intestinalis, necrotising colitis, peritonitis.
Not known: Gastrointestinal haemorrhage, pancreatitis.
Nausea and vomiting occur and are generally more frequent following rapid intravenous infusion than with continuous IV infusion of the drug.
Skin and subcutaneous tissue disorders: Common: Reversible undesirable effects to the skin, such as erythema, bullous dermatitis, urticarial, vasculitis, alopecia.
Uncommon: skin ulceration, pruritus, burning pain of palms and soles.
Very rare: Neutrophilic eccrine hidradenitis.
Not known: Rash, freckling, skin bleeding.
Renal and urinary disorders: Common: Renal impairment, urinary retention.
Not known: Renal dysfunction.
General disorders and administration site conditions: Common: Fever, thrombophlebitis at the site of injection.
Uncommon: Cellulitis at the injection site.
Not known: Chest pain, irritation or sepsis at the injection site, mucosal bleeding.
Cardiac disorders: Uncommon: Pericarditis.
Very rare: Arrhythmia.
Hepatobiliary disorders: Common: Reversible effects on the liver with increased enzyme levels.
Not known: Hepatic dysfunction and jaundice.
Metabolism and nutrition disorders: Common: Anorexia, hyperuricaemia.
Nervous system disorders: Common: At high doses cerebellar or cerebral influence with deterioration of the level of consciousness, dysarthria, nystagmus.
Uncommon: Headache, peripheral neuropathy, paraplegia at intrathecal administration.
Not known: Dizziness, neuritis or neural toxicity and pain, neurotoxicity rash.
Eye disorders: Common: Reversible haemorrhagic conjunctivitis (photophobia, burning, visual disturbance, increased lacrimation), keratitis.
Not known: Conjunctivitis.
Respiratory, thoracic and mediastinal disorders: Uncommon: Pneumonia, dyspnea, sore throat.
Musculoskeletal and connective tissue disorders: Uncommon: Myalgia, joint pain.
A Cytarabine Syndrome (immunoallergic effect) is characterized by fever, myalgia, bone pain, occasionally chest pain, exanthema, maculopapular rash, conjunctivitis, nausea and malaise. It usually occurs 6-12 hours after administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are serious enough to warrant treatment, corticosteroids should be contemplated. If treatment is effective, therapy with cytarabine may be continued.
Adverse effects due to high dose cytarabine treatment, other than those seen with conventional doses include: Blood and lymphatic system disorders: Hematological toxicity has been seen as profound pancytopenia which may last 15-25 days along with more severe bone marrow aplasia than that observed at conventional doses.
Nervous system disorders: After treatment with high doses of cytarabine, symptoms of cerebral or cerebellar influence like personality changes, affected alertness, dysarthria, ataxia, tremor, nystagmus, headache, confusion, somnolence, dizziness, coma, convulsions, etc. The incidence in elderly (>55 years) may be even higher. Other predisposing factors are impaired liver and renal function, previous CNS treatment (e.g., radiotherapy) and alcohol abuse. CNS disturbances are in the most cases reversible.
The risk of CNS toxicity increases if the cytarabine treatment - given as high dose i.v.- is combined with another CNS toxic treatment such as radiation therapy or high dose of a cytotoxic agent.
Eye disorders: Reversible corneal lesion and haemorrhagic conjunctivitis have been described. These phenomena can be prevented or decreased by installation of corticosteroid eye drops.
Gastrointestinal disorders: Especially in treatment with high doses of cytarabine, more severe reactions may appear in addition to common symptoms. Intestinal perforation or necrosis with ileus and peritonitis have been reported. Pancreatitis has also been observed after high-dose therapy.
Hepatobiliary disorders: Liver abscesses, hepatomegaly and Budd-Chiari-syndrome (hepatic venous thrombosis) have been observed after high-dose therapy.
Respiratory, thoracic and mediastinal disorders: Clinical signs as present in pulmonary oedema/ARDS may develop, particularly in high-dose therapy.
Reproductive system and breast disorders: Amenorrhoea and azoospermia.
Others: Following cytarabine therapy, cardiomyopathy and rhabdomyolysis have been reported. The gastrointestinal undesirable effects are reduced if cytarabine is administered as infusion. Local glucocorticoids are recommended as prophylaxis of haemorrhagic conjunctivitis.

Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine injection or procarbazine. Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative.
An in vitro interaction study between gentamicin and cytarabine showed a cytarabine related antagonism for the susceptibility of K. pneumoniae strains.
Clinical evidence showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine injection. This may be due to potential competitive inhibition of its uptake.
Due to the immunosuppressive action of cytarabine viral, bacterial, fungal, parasitic, or saprophytic infections, in any location in the body may be associated with the use of cytarabine alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity. These infections may be mild but can be severe and at times fatal.

Handling and Disposal: Procedures for proper handling and disposal of anti-cancer drugs should be considered. Only persons conversant with standard practices of handling and disposal of anticancer agents should handle cytarabine. Unused portion and all materials that have been utilized for dilution and administration should be disposed of according to standard procedures of anticancer drugs.
Solutions of cytarabine have been reported to be incompatible with various drugs, i.e. fluorouracil, gentamicin sulphate, heparin sodium, hydrocortisone sodium succinate, insulin-regular, methylprednisolone sodium succinate, nafacillin sodium, oxacillin sodium, penicillin G sodium. However, the incompatibility depends on several factors (e.g. concentrations of the drug, specific diluents used, resulting pH, temperature). Specialised references should be consulted for specific compatibility information.
Parenteral drugs should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution and container permit.
Special Precautions for Handling: If crystallization is observed as a result of exposure to low temperatures, redissolve the crystals by warming up to 55°C for no longer than 30 minutes and shake until the crystals are dissolved. Allow to cool prior to use.

Store at a temperature below 25°C. Protect from light.

Cytotoxic Chemotherapy

L01BC01 - cytarabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

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