Cytarabine Injection

CYTARABINE INJECTION

Faulding

Antileukemic

Action And Clinical Pharmacology: Cytarabine is converted intracellularly to the nucleotide, cytarabine triphosphate. Although the exact mechanism(s) of action of cytarabine has not been fully elucidated, cytarabine triphosphate appears to inhibit DNA polymerase by competing with the physiologic substrate, deoxycytidine triphosphate, resulting in the inhibition of DNA synthesis. Although limited, incorporation of cytarabine triphosphate into DNA and RNA may also contribute to the cytotoxic effects of the drug.

Cytarabine is a potent immunosuppressant which can suppress humoral and/or cellular immune responses; however, the drug does not decrease pre-existing antibody titres and has no effect on established delayed hypersensitivity reactions.

Cytarabine is ineffective orally; less than 20% of a dose is absorbed from the gastrointestinal tract. Constant i.v. infusions of cytarabine produce relatively constant plasma concentrations of the drug in 8 to 24 hours. Following s.c. administration of cytarabine, peak plasma levels of the drug are attained about 20 to 60 minutes after injection and fall below steady-state infusion levels after about 100 minutes.

Cytarabine is rapidly and widely distributed into tissues. After rapid i.v. injection of cytarabine, approximately 13% of the drug is bound to plasma proteins. Cytarabine crosses the blood-brain barrier to a limited extent. During a continuous i.v. or s.c. infusion, cytarabine concentrations in the cerebrospinal fluid (CSF) are higher than those attained after rapid i.v. injection and are about 40 to 60% of plasma concentrations. Most of an intrathecal dose of cytarabine diffuses into the systemic circulation but is rapidly metabolized and usually only low plasma concentrations of unchanged drug occur. The drug apparently crosses the placenta. It is not known if cytarabine or its metabolites are excreted in breast milk.

Cytarabine disappears rapidly from the plasma following i.v. injection. I.V doses of cytarabine exhibit biphasic elimination with an initial half-life of approximately 10 minutes in which a major fraction of a dose is hepatically metabolized by cytidine deaminase to inactive 1-beta-D-arabinofuranosyluracil (uracil arabinoside). The terminal elimination half-life is about 1 to 3 hours. Reportedly cytarabine undergoes triphasic elimination in some patients. After intrathecal injection, cytarabine concentrations in the CSF decline with a half-life of about 2 hours.

Cytarabine and its metabolite, uracil arabinoside, are excreted in urine. After rapid i.v., s.c. or intrathecal injection or continuous i.v. infusion, about 70 to 80% of the dose is excreted in urine within 24 hours. Approximately 90% of the urinary drug excretion occurs as the metabolite and about 10% as unchanged cytarabine.

Indications And Clinical Uses: Primarily for induction and maintenance of remission in acute leukemia in both adults and children. It has found use in the treatment of acute myelocytic leukemia (AML), chronic myelocytic leukemia (blast phase), acute lymphocytic leukemia (ALL) and erythroleukemia. It may be used alone or in combination with other antineoplastic agents, superior results being obtained with combination therapy. Cytarabine is often used with daunorubicin, doxorubicin, thioguanine or vincristine.

Good results have been obtained from a combination drug program (LSA2-L2), which included cytarabine, in children with nonHodgkin’s lymphoma.

Response has been obtained with intrathecal administration of cytarabine in the treatment of meningeal leukemia and other meningeal neoplasms (e.g., lymphoma), as well in children with lymphocytic leukemia with CNS involvement. Intrathecal cytarabine may be useful in patients whose CNS disease does not respond to intrathecal methotrexate or in patients with methotrexate-related neurotoxicity. Focal leukemic involvement of the CNS may not respond to intrathecal cytarabine or intrathecal methotrexate, and may be better treated with radiation therapy.

Cytarabine in high doses (2 to 3 g/m, given as an i.v. infusion over 1 to 3 hours every 12 hours for 2 to 6 days, with or without additional cancer chemotherapeutic agents, has been shown to be effective in the therapy of poor-risk leukemia, refractory leukemia and relapsed acute leukemia.

Unless followed by maintenance therapy, remissions induced by cytarabine have been brief.

Contra-Indications: Patients with known hypersensitivity to the drug.

Manufacturers’ Warnings In Clinical States: Caution: Cytarabine is a potent drug and should only be used by physicians experienced with cancer chemotherapy (see Precautions). Hematologic, hepatic and renal evaluations must be performed at regular intervals.

Cytarabine is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under the supervision of physicians experienced with cytotoxic agents.

Cytarabine is a potent myelosuppressive agent capable of producing severe leukopenia, thrombocytopenia and anemia with striking megaloblastic changes. Therapy should be begun with caution in patients with pre-existing drug-induced bone marrow suppression. Treatment of severe hematologic toxicity may consist of supportive therapy, antibiotics for complicating infections resulting from granulocytopenia and other impaired body defences, and blood product transfusions in case of hemorrhage secondary to thrombocytopenia, the consequences of bone marrow suppression.

Some high dosage (2 to 3 g/m protocols have incurred severe, sometimes fatal CNS, gastrointestinal and pulmonary toxicities. These have included paraplegia, disseminated necrotizing leukoencephalopathy, blindness, reversible corneal toxicity and hemorrhagic conjunctivitis which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction including personality changes, somnolence and coma, usually reversible, mucosal alterations and lesions in the gastrointestinal tract with frequent infections complicated by peritonitis, liver abscesses, pneumatosis cystoides intestinalis and sepsis; liver damage with increased hyperbilirubinemia; bowel necrosis; necrotizing colitis and pulmonary edema. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with high dose therapy than with standard treatment programs (see Adverse Effects).

Pregnancy: Cytarabine is known to be teratogenic in some animal species. The drug should not be used in women who are pregnant (particularly during the first trimester) or who may become pregnant unless the possible benefits outweigh the potential risks.

One infant with upper and lower limb defects and one infant with obvious extremity and ear deformities were delivered by women who had received therapy with cytarabine during the first trimester.

When cytarabine therapy is initiated during the second or third trimester, there is still a considerable risk to the fetus, but it is reduced. A few women have received cytarabine with other antineoplastic drugs during the second and third trimesters (20th to 28th week of gestation) and have delivered apparently normal infants. However, in another report where cytarabine was given together with thioguanine to 4 mothers, beginning at 11, 20, 25 and 26 weeks’ gestation, trisomy C was found in a 24-week fetus following a therapeutic abortion, while no abnormalities were detected in the other 3 cases.

Although normal infants have been delivered to patients treated in all 3 trimesters of pregnancy, follow-up of such infants would be advisable.

Precautions: Patients receiving cytarabine must be closely monitored. Leukocyte and platelet counts should be performed frequently during therapy (see Dosage). Periodic determinations of renal and hepatic functions are recommended in patients on cytarabine therapy. Patients who receive myelosuppressive drugs experience an increased frequency of infections as well as possible hemorrhagic complications. Because these complications are potentially fatal, the patient should be told to notify the physician if fever, sore throat, or unusual bleeding or bruising occurs.

Since cytarabine appears to be metabolized to some extent in the liver, the drug should be used cautiously and at a reduced dosage in patients with poor or impaired liver function.

Cytarabine, like other cytotoxic drugs, may induce hyperuricemia secondary to rapid lysis of neoplastic cells. The patient’s plasma uric acid level should be monitored and appropriate supportive and pharmacologic measurements should be available. Hyperuricemia may be minimized or prevented by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.

Nausea and vomiting may occur in patients receiving cytarabine and normally occur more frequently and more severely following rapid i.v. injection of large doses than following i.v. infusion of the drug.

Intrathecal administration of cytarabine rarely causes systemic effects; however the hematologic status of the patient must still be monitored. Dosage adjustments of concurrently administered antineoplastic agents may be necessary. The most frequent adverse effects of intrathecal cytarabine are nausea, vomiting, fever, and transient headaches; these effects generally are mild and self-limiting.

Neurotoxicity following intrathecal injection of cytarabine has been associated with diluents containing preservatives. If high dose therapy is given, do not use a diluent containing preservative.

Thrombophlebitis has occurred at the site of i.v. drug injection or infusion in some patients. Pain and inflammation at s.c. injection sites are rare. S.C. injection sites should be rotated around the areas of body fat: the abdomen, thighs and flank region. The drug is locally well tolerated in most instances.

Higher total doses are tolerated better when administered by rapid i.v. injection as compared to slow infusion. This may be due to the rapid inactivation of the drug and the brief exposure of susceptible normal and neoplastic cells to significant drug levels after rapid injection.

Clinical experience to date indicates that success with cytarabine therapy depends more on adeptness in modifying day-to-day dosage to obtain maximum leukemic cell kill with tolerable toxicity, than on the fundamental treatment protocol selected at the start of therapy. Toxicity necessitating dosage modification almost always occurs.

Remission induction therapy in acute leukemia is usually administered in a short course without adjustment or discontinuation based upon peripheral blood counts. However, depending on the physician’s judgment, modifications may be made based on hematologic response. Consider discontinuing the drug if the patient has less than 50 000 platelets or 1 000 polymorphonuclear granulocytes/mmin the peripheral blood. These guidelines may be modified depending on signs of toxicity in other systems and on the rapidity of fall in formed blood elements. Restart the drug when there are signs of marrow recovery and the above platelet and granulocyte levels have been attained. Warning: Withholding therapy until the patient’s blood values are normal may result in escape of the patient’s disease from control by cytarabine.

Drug Interactions: The gastrointestinal absorption of oral digoxin tablets has been found to be substantially reduced in patients receiving combination chemotherapy regimens containing cytarabine, possibly as a result of temporary damage to intestinal mucosa caused by cytotoxic agents.

An in vitro study indicated that cytarabine may antagonize the activity of gentamicin against K. pneumoniae. Patients receiving cytarabine and aminoglycoside therapy for the treatment of infections caused by K. pneumoniae should be closely monitored. If therapeutic response is not achieved, re-evaluation of the antibiotic therapy may be necessary.

Limited data suggest that cytarabine may antagonize the antifungal activity of flucytosine, possibly by competitive inhibition of the anti-infective uptake by fungi.

Adverse Reactions: The major adverse effect of cytarabine is hematologic toxicity. Myelosuppression is normally manifested by megaloblastosis, leukopenia, anemia, reticulocytopenia and thrombocytopenia. Leukopenia follows mainly from granulocyte depression; lymphocytes are minimally affected. The severity of these adverse effects is dependent on the dose of the drug and schedule of administration. The incidence and severity of hematologic toxicity is minimal after a single i.v. dose of cytarabine, but myelosuppression occurs in almost all patients with daily i.v. injections or continuous i.v. infusions of the drug.

Following 5-day constant i.v. infusions or rapid i.v. injections of cytarabine 50 to 600 mg/m the white blood cell count follows a biphasic course, regardless of initial white blood cell count, dosage level or schedule. Two distinct nadirs are observed. Initial leukocyte fall occurs within 24 hours of administration, reaching the first nadir at 7 to 9 days. A brief recovery period peaking at about 12 days is again followed by a sharp leukocyte fall to the second nadir (which is greater than the first) occurring between days 15 to 24. Then there is a rapid rise to above baseline levels in the following 10 days. The platelet count starts to fall 5 days after starting cytarabine therapy, reaching the nadir at 12 to 15 days, after which, a rapid rise to above baseline levels occurs in the following 10 days.

Nausea and vomiting may occur in patients on cytarabine therapy, and usually occur more frequently and severely following rapid i.v. administration as opposed to continuous infusion of the drug. Other adverse effects of the gastrointestinal tract include anorexia, diarrhea, oral and anal inflammation or ulceration. Abdominal pain, esophagitis, sore throat, esophageal ulceration and gastrointestinal hemorrhage occur less frequently. In one study, cytarabine induced severe intestinal toxicity when used in several sequential chemotherapeutic protocols. The mucosal alterations induced were characterized by surface and glandular epithelial atypia, immaturity and necrosis. These were associated with diarrhea, ileus, abdominal pain, hematemesis and melena, severe hypokalemia, hypocalcemia, a protein-losing enteropathy, transient weight gains and intestinal infections.

Hepatic dysfunction, characterized by jaundice, elevations in serum bilirubin, transaminases and alkaline phosphates have occurred in patients receiving cytarabine alone or with other antineoplastic agents, but a causal relationship has not been definitely established.

Meningism, paresthesia, paraplegia, spastic paraparesis, and seizures have been reported rarely with the intrathecal administration of cytarabine. Blindness occurred in 2 patients with all during remission, who had received systemic combination therapy, prophylactic CNS radiation as well as intrathecal cytarabine. Necrotizing leukoencephalopathy occurred in 5 children who had received triple intrathecal therapy consisting of cytarabine, methotrexate and hydrocortisone, and CNS irradiation.

Other reported adverse effects of cytarabine include fever, rash, conjunctivitis (may occur with rash), alopecia, freckling, skin ulceration, urinary retention, renal dysfunction, chest pain, dizziness, somnolence, neuritis or neural toxicity and reactions at the site of injection such as pain, inflammation, thrombophlebitis or cellulitis.

One patient suffered anaphylaxis with acute cardiopulmonary arrest which required resuscitation, immediately following i.v. administration of the drug.

A cytarabine syndrome, characterized by fever, myalgia, bone pain, malaise, maculopapular rash, conjunctivitis and occasionally chest pain, has been reported. It normally occurs 6 to 12 hours after administration of the drug; corticosteroids have been shown to be of benefit in the treatment and prevention of the syndrome. If treatment of the symptoms of the syndrome is required, administration of corticosteroids should be considered as well as continuation of cytarabine therapy.

Severe and sometimes fatal CNS, gastrointestinal and pulmonary toxicity, which differs from that seen with usual dosages, has been associated with high-dose cytarabine regimens (2 to 3 g/mgiven every 12 hours for 12 doses) for refractory or secondary acute leukemia.

Adverse effects of high-dose therapy have included somnolence; cerebral and cerebellar dysfunction which is generally reversible; conjunctivitis and reversible corneal toxicity (keratitis) consisting of ocular pain, tearing, foreign-body sensation, photophobia and blurred vision; pulmonary edema and severe gastrointestinal ulceration including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess, liver damage with increased hyperbilirubinemia; pericarditis with tamponade. Rarely severe rash leading to desquamation has occurred. Complete alopecia occurs more frequently with high-dose regimens than with usual dosage regimens of the drug.

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomyopathy with subsequent death, has been reported in patients receiving high-dose cytarabine in combination with cyclophosphamide in preparation for bone marrow transplantation.

Peripheral motor and sensory neuropathies also have occurred occasionally in patients receiving high-dose cytarabine therapy. Diffuse interstitial pneumonitis, possibly related to cytarabine therapy, has been reported occasionally in patients receiving relatively high doses (e.g., 1 g/m of cytarabine alone or in combination with other antineoplastic agents.

Pancreatitis has also occurred.

Symptoms And Treatment Of Overdose: Symptoms: Serious myelosuppression may follow chronic overdosage with cytarabine. Nausea and vomiting, severe hemorrhage into the gastrointestinal tract and generalized infection may act as additional warnings of overdosage.

Treatment: Cytarabine should be discontinued and supportive therapy instituted. Platelet transfusions should be given for hemorrhage. Patients should be closely monitored for intercurrent infection. Any infection requires rapid and rigorous treatment with appropriate antibiotic therapy.

Doses exceeding recommended dosage schedules have been used clinically and have been tolerated. The major toxicities with the use of 3 g/mi.v. infusion over 1 hour every 12 hours for 12 doses and 3 g/mcontinuous infusion for 4 days, other than reversible bone marrow suppression has been reversible corneal, cerebral and cerebellar dysfunction. Doses of 4.5 g/mi.v. infused over 1 hour every 12 hours for 12 doses has caused an unacceptable increase in irreversible toxicity and death.

Dosage And Administration: See Special Instructions for Handling Cytotoxic Drugs.

Cytarabine is administered primarily by the i.v. route, by push or by i.v. infusion. Relatively constant plasma levels can be achieved by continuous i.v. infusion. Cytarabine may also be administered s.c. It may be administered intrathecally when unpreserved (see Preparation for Use).

Dosage of cytarabine must be based on the clinical and hematological response and tolerance of the patient so as to obtain optimum therapeutic results with minimum adverse effects. The most effective dosage schedule and method of administration are yet to be established, but it appears that success with cytarabine is dependent more on adeptness in modifying day-to-day dosage to obtain maximum leukemic cell kill with tolerable toxicity than on the basic treatment schedule chosen at the outset of therapy.

Cytarabine used in combination with other cytotoxic drugs, may require dose reduction. Clinicians should consult published protocols for the dosage of cytarabine and other chemotherapeutic agents, and the method as well as the sequence of administration.

Warning on Use of Diluents Containing Preservatives: Preserved diluents are not generally recommended for dilution of cytarabine of Faulding (Canada) Inc. In any case, preserved diluents must not be used for intrathecal administration, and solutions containing benzyl alcohol should not be used for neonates. Because of the potential toxicity of large amounts of benzyl alcohol, diluents containing benzyl alcohol must not be used to dilute cytarabine if high dose regimens are employed.

Suggested I.V. Dosage Regimens: Induction: The usual dosage of cytarabine as a single agent for induction of remissions in patients with acute leukemia is 200 mg/mdaily administered by continuous i.v. infusion for 5 days (120 hours; total dose 1 000 mg/m at approximately 2-week intervals. Remission induction therapy in acute leukemia is usually administered in a short course without adjustment or discontinuation based upon peripheral blood counts. However, depending on the physician’s judgment, modifications may be made based on hematologic response. Consider discontinuing the drug if the patient has less than 50 000 platelets or 1 000 polymorphonuclear granulocytes/mmin the peripheral blood. These guidelines may be modified depending on signs of toxicity in other systems and on the rapidity of fall in formed blood elements. Restart the drug when there are signs of marrow recovery and the above platelet and granulocyte levels have been attained. Warning: Withholding therapy until the patient’s blood values are normal may result in escape of the patient’s disease from control by cytarabine.

Some dosage regimens reported in the literature are described briefly below:

Combination Chemotherapy: Before instituting a program of combination chemotherapy, the physician should be familiar with the literature, adverse reactions, precautions, contraindications and warnings applicable to all the drugs involved in the program.

Cytarabine-Doxorubicin: Cytarabine 100 mg/mday, continuous i.v. infusion (days 1 to 10); doxorubicin 30 mg/mday, i.v. infusion of 30 minutes (days 1 to 3). Additional (complete or modified) courses as necessary at 2- to 4-week intervals if leukemia is persistent.

Cytarabine-Thioguanine-Daunorubicin: Cytarabine 100 mg/mday i.v. infusion over 30 minutes every 12 hours (days 1 to 7); thioguanine 100 mg/morally every 12 hours (days 1 to 7); daunorubicin 60 mg/mday i.v. infusion (days 5 to 7). Additional (complete or modified) courses as necessary at 2- to 4-week intervals if leukemia is persistent.

Cytarabine-Doxorubicin-Vincristine-Prednisone: Cytarabine 100 mg/mday continuous i.v. infusion (days 1 to 7); doxorubicin 30 mg/mday i.v. infusion (days 1 to 3); vincristine 1.5 mg/mday i.v. infusion (days 1, 5); prednisone 40 mg/mday i.v. infusion every 12 hours (days 1 to 5). Additional (complete or modified) courses as necessary at 2- to 4-week intervals if leukemia is persistent.

Cytarabine-Daunorubicin-Thioguanine-Prednisone-Vincristine: Cytarabine 100 mg/mday i.v. every 12 hours (days 1 to 7); daunorubicin 70 mg/mday i.v. infusion (days 1 to 3); thioguanine 100 mg/morally every 12 hours (days 1 to 7); prednisone 40 mg/mday orally (days 1 to 7); vincristine 1 mg/mday i.v. infusion (days 1 to 7). Additional (complete or modified) courses as necessary at 2- to 4-week intervals if leukemia is persistent.

Cytarabine-Daunorubicin: Cytarabine 100 mg/mday continuous i.v. infusion (days 1 to 7); daunorubicin 45 mg/mday i.v. push (days 1 to 3). Additional (complete or modified) courses as necessary at 2- to 4-week intervals if leukemia is persistent.

High Dose Chemotherapy: Before instituting a program of high dose and/or combination chemotherapy, the physician should be familiar with the literature, adverse reactions, precautions, contraindications and warnings applicable to high dose regimens of cytarabine and for all the drugs involved in the program.

Cytarabine: 2 mg/minfused over 3 hours every 12 hours´12 doses (days 1 to 6). 3 g/minfused over 1 hour every 12 hours´12 doses (days 1 to 6). 3 g/minfused over 75 minutes every 12 hours´12 doses (days 1 to 6).

Cytarabine-Doxorubicin: Cytarabine 3 g/minfused over 2 hours every 12 hours´12 doses (days 1 to 6); doxorubicin 30 mg/mi.v. on days 6 and 7.

Cytarabine-Asparaginase: Cytarabine 3 g/minfused over 3 hours at 0 hours, 12 hours, 24 hours and 36 hours. At 42 hours, 6 000 units/mof asparaginase i.m. (days 1 and 2). Repeat the same schedules days 8 and 9.

Maintenance: Appropriate maintenance therapy may be initiated following induction of a complete remission. Maintenance programs are modifications of induction programs and, in general, use similar schedules of drug therapy as were used during induction. Most programs have a greater time spacing between courses of therapy during remission maintenance.

Acute Myelocytic Leukemia (AML): Adults as described above.

Children: Childhood AML usually responds better than adult AML given similar regimens. Where the adult dosage is stated in terms of body weight or surface area, the children’s dosage may be calculated on the same basis. When specified amounts of a drug are indicated for the adult dosage, these should be adjusted for children on the basis of such factors as age, body weight or body surface area.

Acute Lymphocytic Leukemia: In general, dosage schedules are similar to those used in acute myelocytic leukemia.

NonHodgkin’s Lymphoma in Children: Cytarabine has been used as part of a multi-drug program (LSA2-L2) to treat NonHodgkin’s lymphoma in children.

Suggested S.C. Use: S.C. administration of cytarabine has been generally used for maintenance therapy after remission (also see Suggested I.V. Regimens above). A single dose of 1 or 1.5 mg/kg s.c. at intervals of 1 to 4 weeks has been used for maintenance therapy.

S.C. administration of low-dose cytarabine has also been used to treat elderly patients (³60 years of age), who had underlying disease sufficiently serious to prevent more aggressive therapy. Doses of 10 to 20 mg s.c. have been given by bolus or infusion at 12-hour intervals over periods from 3 to 6 weeks. Cytoreduction usually occurs slowly with these dosage regimens, which are generally well tolerated.

Intrathecal Use: Warning: Do not use preserved diluents for intrathecal administration. See Preparation for use.

Meningeal Leukemia: In the treatment and maintenance therapy of meningeal leukemia and other meningeal neoplasms, cytarabine has been given by intrathecal injection in doses of 5 to 75 mg/mor 30 to 100 mg once every 2 to 7 days to once daily for 4 or 5 days. The dosage schedule is usually determined by the type and severity of CNS manifestations and the patient’s response to prior therapy. A frequently used intrathecal cytarabine dosage has been 30 mg/monce every 4 days until CSF findings are normal, followed by 1 additional dose. If systemic toxicity occurs with intrathecal cytarabine, modification of other therapy may be necessary.

Renal and Hepatic Impairment: Dosage reduction does not appear to be necessary in cases of renal impairment. Dosage reduction may not be necessary in patients with hepatic impairment; however, these patients should be carefully monitored.

Preparation for Use: S.C. and I.V. Injection: Cytarabine injection is suitable for s.c. or i.v. injection.

I.V. Infusion: Cytarabine injection may be further diluted to 0.1 mg/mL with any of the solutions for i.v. infusion listed: Water for Injection USP, 5% Dextrose Injection USP, 0.9% Sodium Chloride USP and Lactated Ringer’s Injection USP.

Intrathecal Injection: Diluents containing preservatives should not be used for intrathecal administration. Diluents for intrathecal injection are usually physiologic or isotonic solutions. Cytarabine is usually administered as a 5 mg/mL concentration in 5 to 15 mL of solution, after an equivalent volume of CSF is removed.

Stability of Solutions: Cytarabine injection is supplied in single dose vials. The solution must be used once punctured within 24 hours and the unused portion discarded.

Further diluted solutions should be used within 24 hours from the time of the initial puncture or within 72 hours when refrigerated. Injectable solutions should be inspected visually for particulate matter and discoloration prior to administration.

Further diluted unpreserved solutions for intrathecal injection must be used immediately, since bacterially contaminated intrathecal solutions could pose very grave risks.

Cytarabine injection when admixed with 0.9% Sodium Chloride Injection to a concentration of 32.5 mg/mL of cytarabine, is chemically stable for a period of 6 days at room temperature, protected from light.

Incompatibilities: Cytarabine is known to be incompatible with solutions of heparin, insulin, methotrexate, 5-fluorouracil, nafcillin, oxacillin, penicillin G, hydrocortisone and methylprednisolone.

Special Instructions for Handling Cytotoxic Drugs: The following are precautionary measures recommended in the handling and preparation of cytotoxic agents such as cytarabine:

1. The procedure should be carried out in a vertical laminar flow hood (Biological Safety Cabinet – Class II).

2. PVC gloves, safety glasses, disposable gowns and masks should be worn by personnel.

3. All vials, syringes, needles and other materials which have come in contact with cytarabine should be segregated and destroyed by incineration (sealed containers may explode). If incineration is unavailable, neutralization using 5% sodium hypochlorite or 5% sodium thiosulfate should be carried out instead.

4. Biannual hematologic examinations should be performed on personnel regularly involved in the handling and preparation of cytarabine.

Availability And Storage: Each mL of solution contains: cytarabine 100 mg. Single dose vials of 1, 5, 10 or 20 mL (100 mg, 500 mg, 1 g or 2 g). Intact vials should be stored at controlled room temperatures not exceeding 25°C.

CYTARABINE INJECTION Faulding Antileukemic

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