英文药名: Cytarabine Injection

中文药名: 阿糖胞苷注射剂

药品介绍

【适用症】
注射用盐酸阿糖胞苷适用于急性白血病的诱导缓解期及维持巩固期。对急性非淋巴细胞性白血病效果较好，对慢性粒细胞白血病的急变期，恶性淋巴瘤。

【注意事项】
1、使用注射用盐酸阿糖胞苷时可引起血清丙氨酸氨基转移酶ALT（SGPT）、血及尿中尿酸量的增高；
2、下列情况应慎用：骨髓抑制、白细胞及血小板显著减低者、肝肾功能不全、有胆道疾患者、有痛风病史、尿酸盐肾结石病史、近期接受过细胞毒药物或放射治疗。
3、用药期间应定期检查：周围血象、血细胞和血小板计数、骨髓涂片以及肝肾功能。

【用法用量】
1、成人常用量
（1）诱导缓解：静脉注射或滴注一次按体重2mg/kg（或1～3mg/kg），一日1次，连用10～14日，如无明显不良反应，剂量可增大至一次按体重4～6 mg/kg，。
（2）维持：完全缓解后改用维持治疗量，一次按体重1mg/kg，一日1～2次，皮下注射，连用7～10日。
2、中剂量阿糖胞苷
中剂量是指阿糖胞苷的剂量为一次按体表面积0.5～1.0g/m2的方案，一般需静滴1～3小时，一日2次，以2～6日为一疗程；大剂量阿糖胞苷的剂量为按体表面积为1～3g/m2的方案，静滴及疗程同中剂量方案。
由于阿糖胞苷的不良反应随剂量增大而加重，有时反而限制了其疗效，故现多偏向用中剂量方案。中或大剂量阿糖胞苷主要用于治疗难治性或复发性急性白血病，亦可用于急性白血病的缓解后，延长其缓解期。由于不良反应较多，故疗程中必须由有丰富经验的医生指导，并要有充分及时的支持疗法保证方可进行。
3、小剂量阿糖胞苷
剂量为一次按体表面积10mg/m2，皮下注射，一日2次，以14～21日为一疗程，如不缓解而患者情况容许，可于2～3周重复一疗程。本方案主要用于治疗原始细胞增多或骨髓增生异常综合征患者，亦可治疗低增生性急性白血病、老年性急性淋巴细胞白血病等。
4、鞘内注射
阿糖胞苷为鞘内注射防治脑膜白血病的第二线药物，剂量为一次25～75mg，联用地塞米松5mg，用2ml 0.9％氯化钠注射液溶解，鞘内注射，每周1～2次，至脑脊液正常。如为预防性则每4～8周一次。
使用注射用盐酸阿糖胞苷时，应适当增加患者液体的摄入量，使尿液保持碱性，必要时同用别嘌醇以防止血清尿酸增高及尿酸性肾病的形成；
快速静脉注射虽引起较严重的恶心、呕吐反应，但对骨髓的抑制较轻，患者亦更能耐受较大剂量的阿糖胞苷。

【禁忌症】孕妇及哺乳期妇女忌用。

【孕妇、哺乳期妇女用药注意事项】孕妇及哺乳期妇女最好不用。

【老年人用药注意事项】由于老年人对化疗药物的耐受性差，用药需减量并注意根据体征等及时调整药量。

【不良反应】
1、造血系统：主要是骨髓抑制，白细胞及血小板减少，严重者可发生再生障碍性贫血或巨幼细胞性贫血；
2、白血病、淋巴瘤患者治疗初期可发生高尿酸血症，严重者可发生尿酸性肾病；
3、较少见的有口腔炎、食管炎、肝功能异常、发热反应及血栓性静脉炎。
阿糖胞苷综合征多出现于用药后6～12小时，有骨痛或肌痛、咽痛、发热、全身不适、皮疹、眼睛发红等表现。

【药物相互作用】
四氢尿苷可抑制脱氨酶，延长阿糖胞苷血浆半衰期，提高血中浓度，起增效作用。注射用盐酸阿糖胞苷可使细胞部分同步化，继续应用柔红霉素、阿霉素、环磷酰胺及亚硝脲类药物可以增效。注射用盐酸阿糖胞苷不应与5－Fμ并用。

【药理】
注射用盐酸阿糖胞苷为主要作用于细胞S增殖期的嘧啶类抗代谢药物，通过抑制细胞DNA的合成，干扰细胞的增殖。阿糖胞苷进入人体后经激酶磷酸化后转为阿糖胞苷三磷酸及阿糖胞苷二磷酸，前者能强有力地抑制DNA聚合酶的合成，后者能抑制二磷酸胞苷转变为二磷酸脱氧胞苷，从而抑制细胞DNA聚合及合成。注射用盐酸阿糖胞苷为细胞周期特异性药物，对处于S增殖期细胞的作用最为敏感，对抑制RNA及蛋白质合成的作用较弱。

【药物代谢动力学】
可静脉、皮下、肌内或鞘内注射而吸收。静脉注射后能广泛分布于体液、组织及细胞内，静脉滴注后约有中等量的药物可透过血脑屏障，其浓度约为血浆中浓度的40％。注射用盐酸阿糖胞苷在肝、肾等组织内代谢，在血及组织中很容易被胞嘧啶脱氨酶迅速脱氨而形成无活性的尿嘧啶阿拉伯糖苷。在脑脊液内，由于脱氨酶含量较低，故其脱氨作用较缓慢。静脉给药时，T1/2α为10～15分钟。T1/2β2～2.5小时；鞘内给药时，T1/2可延至11小时。在24小时内约10％以阿糖胞苷，70%～90％以尿嘧啶阿糖胞苷为主的无活性物质形式从肾脏排泄。

【用药过量】
采用中剂量或大剂量的阿糖胞苷治疗时，部分患者可能发生严重的胃肠道及神经系统不良反应，如胃肠道溃疡、胃肠囊样积气、坏死性结肠炎、周围神经病变、大脑或小脑功能障碍如性格改变、肌张力减退、癫痫、嗜睡、昏迷、定向力障碍、眼球震颤、语音失调、步态不稳；其他尚可发生出血性结膜炎、皮疹、脱发、脱皮、严重心肌病、肺脓疡毒血症等。
如出现上述各项严重的不良反应，应立即停用阿糖胞苷，并即采用各种有效措施治疗，给患者肾上腺皮质激素可能减轻中剂量或大剂量阿糖胞苷的不良反应。

规格：

1000mg*100ml
   
100mg*10 ml 

CYTARABINE injection, solution
（Hospira Worldwide, Inc.）
Rx only
PHARMACY BULK PACKAGE - NOT FOR DIRECT INFUSION

WARNING 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 toxic effects of this drug in considering the advisability of therapy with Cytarabine Injection. Before making this judgement or beginning treatment, the physician should be familiar with the following text.

DESCRIPTION

Cytarabine Injection, an antineoplastic, is a sterile isotonic solution for intravenous and subcutaneous use, which contains no preservative and is available in 20 mg/mL (1000 mg/50 mL) Pharmacy Bulk Package.

A Pharmacy Bulk Package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion.

Each mL contains 20 mg Cytarabine, USP and the following inactive ingredients: sodium chloride 0.68% and Water for Injection q.s. When necessary, the pH is adjusted with hydrochloric acid and/or sodium hydroxide to a target pH of 7.4. Each vial contains approximately 5.82 mEq sodium.

Cytarabine is chemically 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone. The structural formula is:

Cytarabine is an odorless, white to off-white, crystalline powder which is freely soluble in water and slightly soluble in alcohol and in chloroform.

CLINICAL PHARMACOLOGY

Cell Culture Studies: Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported. Extensive chromosomal damage, including chromatoid breaks, have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported. Deoxycytidine prevents or delays (but does not reverse) the cytotoxic activity.

Cellular Resistance and Sensitivity: Cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate, an effective inhibitor of DNA polymerase; it is inactivated by a pyrimidine nucleoside deaminase which converts it to the nontoxic uracil derivative. It appears that the balance of kinase and deaminase levels may be an important factor in determining sensitivity or resistance of the cell to cytarabine.

Human Pharmacology: 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. However, in one patient in whom cerebrospinal levels were examined after 2 hours of constant intravenous infusion, levels approached 40 percent of the steady state plasma level. With intrathecal administration, levels of cytarabine in the cerebrospinal fluid declined with a first order half-life of about 2 hours. Because cerebrospinal fluid levels of deaminase are low, little conversion to ara-U was observed.

Immunosuppressive Action: Cytarabine is capable of obliterating immune responses in man during administration with little or no accompanying toxicity. Suppression of antibody responses to E. coli-VI antigen and tetanus toxoid have been demonstrated. This suppression was obtained during both primary and secondary antibody responses.

Cytarabine also suppressed the development of cell-mediated responses such as delayed hypersensitivity skin reaction to dinitrochlorobenzene. However, it had no effect on already established delayed hypersensitivity reactions.

Following 5-day courses of intensive therapy with cytarabine, the immune response was suppressed, as indicated by the following parameters: macrophage ingress into skin windows; circulating antibody response following primary antigenic stimulation; lymphocyte blastogenesis with phytohemagglutinin. A few days after termination of therapy there was a rapid return to normal.

INDICATIONS AND USAGE

Cytarabine in combination with other approved anticancer drugs is indicated for remission induction in acute non-lymphocytic leukemia of adults and children. It has also been found useful in the treatment of acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal administration of cytarabine is indicated in the prophylaxis and treatment of meningeal leukemia.

CONTRAINDICATIONS

Cytarabine Injection is contraindicated in those patients who are hypersensitive to the drug.

WARNINGS

(See boxed WARNING)

Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leucocyte and platelet counts performed daily. 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 hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine.

Severe and at times fatal CNS, 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, 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; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia; bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard cytarabine treatment programs. If experimental high dose therapy is used, do not use a diluent containing benzyl alcohol.

Cases of cardiomyopathy with subsequent death has been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation.

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. The outcome of this syndrome can be fatal.

Two patients with childhood acute myelogenous leukemia who received intrathecal and intravenous cytarabine at conventional doses (in addition to a number of other concomitantly administered drugs) developed delayed progressive ascending paralysis resulting in death in one of the two patients.

Use in Pregnancy (Category D): Cytarabine Injection can cause fetal harm when administered to a pregnant woman. Cytarabine causes abnormal cerebellar development in the neonatal hamster and is teratogenic to the rat fetus. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

1.  General Precautions:

Patients receiving Cytarabine Injection must be monitored closely. Frequent platelet and leukocyte counts and bone marrow examinations are mandatory. Consider suspending or modifying therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte count under 1000/mm3. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until “normal” peripheral blood values are attained may escape from control.

When large intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours postinjection. This problem tends to be less severe when the drug is infused.

The human liver apparently detoxifies a substantial fraction of an administered dose. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor.

Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving Cytarabine Injection.

Like other cytotoxic drugs, Cytarabine Injection may induce hyperuricemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient’s blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem.

Acute pancreatitis has been reported to occur in a patient receiving cytarabine by continuous infusion and in patients being treated with cytarabine who have had prior treatment with L-asparaginase.

2.  Information for patient:

Not applicable.

3.  Laboratory tests:

See General Precautions.

4.  Drug Interactions:

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 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. This study suggests that in patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for reevaluation of antibacterial therapy.

Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine. This may be due to potential competitive inhibition of its uptake.

5.  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.

6.  Pregnancy:

Pregnancy Category D. See WARNINGS. A review of the literature has shown 32 reported cases where cytarabine was given during pregnancy, either alone or in combination with other cytotoxic agents.

Eighteen normal infants were delivered. Four of these had first trimester exposure. Five infants were premature or of low birth weight. Twelve of the 18 normal infants were followed up at ages ranging from six weeks to seven years, and showed no abnormalities. One apparently normal infant died at 90 days of gastroenteritis.

Two cases of congenital abnormalities have been reported, one with upper and lower distal limb defects, and the other with extremity and ear deformities. Both of these cases had first trimester exposure.

There were seven infants with various problems in the neonatal period, including pancytopenia; transient depression of the WBC, hematocrit or platelets; electrolyte abnormalities; transient eosinophilia; and one case of increased IgM levels and hyperpyrexia possibly due to sepsis. Six of the seven infants were also premature. The child with pancytopenia died at 21 days of sepsis.

Therapeutic abortions were done in five cases. Four fetuses were grossly normal, but one had an enlarged spleen and another showed Trisomy C chromosome abnormality in the chorionic tissue.

Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or who may become pregnant while on Cytarabine Injection should be apprised of the potential risk to the fetus and the advisability of pregnancy continuation. There is a definite, but considerably reduced risk if therapy is initiated during the second or third trimester. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable.

7.  Labor and delivery:

Not applicable.

8.  Nursing mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cytarabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

9.  Pediatric use:

See INDICATIONS AND USAGE.

ADVERSE REACTIONS

Expected Reactions: Because cytarabine is a bone marrow suppressant, anemia, leukopenia, thrombocytopenia, megaloblastosis and reduced reticulocytes can be expected as a result of administration with cytarabine. The severity of these reactions are dose and schedule dependent. Cellular changes in the morphology of bone marrow and peripheral smears can be expected.

Following 5-day constant infusions or acute injections of 50 mg/m2 to 600 mg/m2, white cell depression follows a biphasic course. Regardless of initial count, dosage level, or schedule, there is an initial fall starting the first 24 hours with a nadir at days 7-9. This is followed by a brief rise which peaks around the twelfth day. A second and deeper fall reaches nadir at days 15-24. Then there is a rapid rise to above baseline in the next 10 days. Platelet depression is noticeable at 5 days with a peak depression occurring between days 12-15. Thereupon, a rapid rise to above baseline occurs in the next 10 days.

Infectious Complications: Infection: 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.

The Cytarabine (Ara-C) Syndrome: A cytarabine syndrome has been described by Castleberry. It is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6-12 hours following drug administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are deemed treatable, corticosteroids should be contemplated as well as continuation of therapy with Cytarabine Injection.

Most Frequent Adverse Reactions: Anorexia, hepatic dysfunction, nausea, fever, vomiting, rash, diarrhea, thrombophlebitis, oral and anal inflammation or ulceration, bleeding (all sites). Nausea and vomiting are most frequent following rapid intravenous injection.

Less Frequent Adverse Reactions: Sepsis, abdominal pain, pneumonia, freckling, cellulitis at injection site, jaundice, skin ulceration, conjunctivitis (may occur with rash), urinary retention, dizziness, renal dysfunction, alopecia, neuritis, anaphylaxis (see WARNINGS), neural toxicity, allergic edema, sore throat, pruritus, esophageal ulceration, shortness of breath, esophagitis, urticaria, chest pain, pericarditis, headache, bowel necrosis, pancreatitis.

Experimental Doses: Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine) has been reported following some experimental dose schedules of Cytarabine. These reactions include 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; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia; bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard cytarabine treatment programs. If experimental high dose therapy is used, do not use a diluent containing benzyl alcohol.

Cases of cardiomyopathy with subsequent death has been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation. This cardiac toxicity may be schedule dependent.

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. The outcome of this syndrome can be fatal.

Two patients with adult acute non-lymphocytic leukemia developed peripheral motor and sensory neuropathies after consolidation with high-dose cytarabine, daunorubicin, and asparaginase. Patients treated with high-dose cytarabine should be observed for neuropathy since dose schedule alterations may be needed to avoid irreversible neurologic disorders.

Ten patients treated with experimental intermediate doses of cytarabine (1 g/m2) with and without other chemotherapeutic agents (meta-AMSA, daunorubicin, etoposide) at various dose regimens developed a diffuse interstitial pneumonitis without clear cause that may have been related to the cytarabine.

Two cases of pancreatitis have been reported following experimental doses of cytarabine and numerous other drugs. Cytarabine could have been the causative agent.

OVERDOSAGE

There is no antidote for cytarabine overdosage. Doses of 4.5 g/m2 by intravenous infusion over 1 hour every 12 hours for 12 doses has caused an unacceptable increase in irreversible CNS toxicity and death.

Single doses as high as 3 g/m2 have been administered by rapid intravenous infusion without apparent toxicity.

DOSAGE AND ADMINISTRATION

Cytarabine Injection (non-preserved) can be administered by intravenous injection or infusion, subcutaneously, or intrathecally. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for IV infusion only. Intrathecal use of cytarabine requires the use of single-dose, unpreserved solutions only.

Cytarabine Injection is not active orally. The schedule and method of administration varies with the program of therapy to be used. While Cytarabine Injection may be given by intravenous infusion or injection, or subcutaneously or intrathecally, THE PURPOSE OF THE PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF INTRAVENOUS INFUSIONS. Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated.

Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion. This phenomenon is related to the drug’s rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either.

In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/m2 IV every 12 hours (Days 1-7).

The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

Intrathecal Use in Meningeal Leukemia: Cytarabine has been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

If used intrathecally, do not use a solution containing benzyl alcohol. This pharmacy bulk package is not intended to be used for the preparation of intrathecal doses.

Cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic system is indicated. Modification of other anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine.

When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician.

Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine and may better be treated with radiotherapy.

Chemical Stability of Infusion Solutions: Chemical stability studies were performed by a stability indicating HPLC assay on Cytarabine Injection in infusion solutions. These studies showed that when Cytarabine Injection was diluted with Water for Injection, 5% Dextrose Injection or Sodium Chloride Injection, in both glass and plastic infusion bags, 97-100% of the cytarabine was present after 8 days storage at room temperature.

This chemical stability information in no way indicates that it would be acceptable practice to infuse a cytarabine admixture well after the preparation time. Good professional practice suggests that administration of an admixture should be as soon after preparation as feasible.

Parenteral drugs should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Handling and Disposal: Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Direction for Dispensing From Pharmacy Bulk Package: The 50 mL Pharmacy Bulk Package is for use in the Pharmacy Admixtures Service only. The vials should be inserted into the plastic handling device provided, suspended as a unit in the laminar flow hood.

A single entry through the vial closure should be made with a sterile dispensing set or transfer device. Transfer individual doses to appropriate intravenous infusion solutions. Use of a syringe with needle is not recommended. Multiple entries will increase the potential of microbial and particulate contamination.

The above process should be carried out under a laminar flow hood using aseptic technique. Care should be exercised to protect personnel from aerosolized drug (see DOSAGE AND ADMINISTRATION, REFERENCES). Discard any unused portion within 4 hours after initial closure entry.

HOW SUPPLIED

Cytarabine Injection, PHARMACY BULK PACKAGE. Sterile, Isotonic Solution. Preservative Free. NDC No. 61703-303-46.

Cytarabine Injection 20 mg/mL (1000 mg) in a 50 mL flip-top vial (green cap), packaged individually. Store product at controlled room temperature, 15° - 30°C (59° - 86°F).