Cytarabine

(BAN, USAN, rINN)
Cytarabine Chemical formula
Synonyms: Arabinosylcytosine; Ara-C; Citarabin; Citarabina; Citarabinas; Cytarabin; Cytarabina; Cytarabinum; Cytosine Arabinoside; NSC63878 (cytarabine hydrochloride); Sitarabin; Sytarabiini; U19920; U-19920A (cytarabine hydrochloride); WR-28453. 1pyrimidin-2(1H)-one.
Cyrillic synonym: Цитарабин.

💊 Chemical information

Chemical formula: C9H13N3O5 = 243.2.
CAS — 147-94-4 (cytarabine); 69-74-9 (cytarabine hydrochloride).
ATC — L01BC01.
ATC Vet — QL01BC01.

Pharmacopoeias.

In Eur., Int., Jpn, and US. Chin. includes the hydrochloride.

Ph. Eur. 6.2

(Cytarabine). A white or almost white, crystalline powder. Freely soluble in water; very slightly soluble in alcohol and in dichloromethane. Store in airtight containers. Protect from light.

USP 31

(Cytarabine). An odourless, white to off-white, crystalline powder. Freely soluble in water; slightly soluble in alcohol and in chloroform. Protect from light.

Incompatibility.

Although cytarabine has been stated in the literature to be incompatible with solutions of fluorouracil 1,2 and methotrexate 2 some studies have reported it to be stable for some hours when mixed with the latter. 3 1. McRae MP, King JC. Compatibility of antineoplastic, antibiotic and corticosteroid drugs in intravenous admixtures. Am J Hosp Pharm 1976; 33: 1010–13. 2. D’Arcy PF. Reactions and interactions in handling anticancer drugs. Drug Intell Clin Pharm 1983; 17: 532–8. 3. Cheung Y-W, et al. Stability of cytarabine, methotrexate sodium, and hydrocortisone sodium succinate admixtures. Am J Hosp Pharm 1984; 41: 1802–6.

💊 Adverse Effects, Treatment, and Precautions

The major dose-limiting adverse effect of cytarabine is bone-marrow depression, manifest as leucopenia (particularly granulocytopenia), thrombocytopenia, and anaemia, sometimes with striking megaloblastic changes. Myelosuppression appears to be more evident after continuous infusions. Leucopenia is biphasic, with a nadir at 7 to 9 days after a dose and another, more severe, at 15 to 24 days. The nadir of the platelet count occurs at about 12 to 15 days. Recovery generally occurs in a further 10 days. Gastrointestinal disturbances may occur: nausea and vomiting may be more severe when doses are given rapidly (but other adverse effects are reported to be worse when the drug is given by infusion). Other adverse effects reported include hepatic dysfunction, renal dysfunction, neurotoxicity, bleeding complications, rashes, oral and anal ulceration, gastrointestinal haemorrhage, oesophagitis, and conjunctivitis. A syndrome of bone and muscle pain, fever, malaise, conjunctivitis, and rash, sometimes described as flu-like, has been reported 6 to 12 hours after cytarabine doses, and may be treated or prevented with corticosteroids. Anaphylactoid reactions and pancreatitis have occurred rarely. There may be local pain, cellulitis, and thrombophlebitis at the site of injection. Intrathecal use of the liposomal cytarabine formulation commonly causes chemical arachnoiditis manifesting as neck stiffness or pain, nausea, vomiting, headache, and fever. Dexamethasone should be used prophylactically to reduce the incidence and severity of this complication. Other rare adverse effects include encephalopathy, and focal seizures. Intrathecal use of conventional cytarabine formulations has rarely been associated with severe spinal cord toxicity, necrotising encephalopathy, blindness, and other neurotoxicities. If given intrathecally, preservative-free diluents must be used. High-dose therapy has been associated with particularly severe gastrointestinal and CNS effects, including severe ulceration of the gastrointestinal tract, pneumatosis cystoides leading to peritonitis, necrotising colitis and bowel necrosis, peripheral neuropathy, and cerebral and cerebellar dysfunction, with personality changes, somnolence, and coma. There may also be corneal toxicity leading to punctate keratitis and haemorrhagic conjunctivitis, sepsis, liver abscess, severe skin rash leading to desquamation, alopecia, and cardiac disorders including pericarditis and fatal cardiomyopathy. Pulmonary oedema, sometimes fatal, has occurred. Cytarabine is teratogenic in animals (but see Pregnancy, below). In addition to frequent white blood cell and platelet counts, blood-uric acid should be monitored because of the risk of hyperuricaemia secondary to lysis of neoplastic cells, and renal and hepatic function should be periodically assessed. Cytarabine should be given with care to patients with impaired liver function; dosage reduction may be necessary.
The principal toxicity of standard dosage regimens is myelosuppression but bleeding complications and gastrointestinal toxicity are also major problems at standard doses. With the high-dose regimens neurological toxicity may be dose-limiting: severe and sometimes irreversible symptoms have been seen in some 6 to 10% of patients receiving a cumulative dose of 36 g/m2. Ocular toxicity may occur in up to 80% of patients at the highest doses. Since cytarabine toxicity is largely dose-related, low-dose cytarabine is generally well tolerated, even in elderly patients (who are more susceptible): its only significant toxicity is myelosuppression.
1. Stentoft J. The toxicity of cytarabine. Drug Safety 1990; 5: 7–27.

Effects on the nervous system.

Although paraplegia has been reported with intrathecal cytarabine1 and peripheral neuropathy has occurred in a patient who had received only conventional intravenous doses,2 the majority of cases of neurotoxicity associated with cytarabine appear to be in patients given high-dose regimens.3-7 Although some cases have manifested as demyelinating peripheral neuropathy,3,4 including a syndrome of painful legs and involuntary movements in the toes which showed some response to carbamazepine,3 most studies have reported in particular a syndrome of cerebellar toxicity,5-8 with symptoms such as dysarthria, nystagmus, and ataxia. Toxicity appears to be dose-related: in one series5 CNS toxicity occurred in none of 12 patients given total doses of up to 24 g/m2 of cytarabine, 3 of 19 receiving 36 g/m2, and 1 of 12 given 48 g/m2, none of which were lifethreatening or irreversible, whereas 4 of 6 given 54 g/m2 (as 4.5 g/m2 every 12 hours for 12 doses) developed neurotoxicity, which was fatal in one and irreversible in another. However, persistent, severe cerebellar toxicity has also been reported in a patient who had received a total dose of only 36 g/m2 (as 3 g/m2every 12 hours).8 There is some evidence6 that patients aged over 50, and those who have recently received conventional-dose cytarabine7 may be at increased risk. Intracranial hypertension (pseudotumor cerebri) has occurred rarely.9
1. Saleh MN, et al. Intrathecal cytosine arabinoside-induced acute, rapidly reversible paralysis. Am J Med 1989; 86: 729–30
2. Russell JA, Powles RL. Neuropathy due to cytosine arabinoside. BMJ 1974; 4: 652–3
3. Malapert D, Degos JD. Jambes douloureuses et orteils instables: neuropathie induite par la cytarabine. Rev Neurol (Paris) 1989; 145: 869–71
4. Openshaw H, et al. Acute polyneuropathy after high dose cytosine arabinoside in patients with leukemia. Cancer 1996; 78: 1899–1905
5. Lazarus HM, et al. Central nervous system toxicity of high-dose systemic cytosine arabinoside. Cancer 1981; 48: 2577–82
6. Graves T, Hooks MA. Drug-induced toxicities associated with high-dose cytosine arabinoside infusions. Pharmacotherapy 1989; 9: 23–8
7. Barnett MJ, et al. Neurotoxicity of high-dose cytosine arabinoside. Prog Exp Tumor Res 1985; 29: 177–82
8. Dworkin LA, et al. Cerebellar toxicity following high-dose cytosine arabinoside. J Clin Oncol 1985; 3: 613–16
9. Fort JA, Smith LD. Pseudotumor cerebri secondary to intermediate-dose cytarabine HCl. Ann Pharmacother 1999; 33: 576–8.

Effects on the skin.

A syndrome of pain and erythema of the palms and soles, progressing to bullae and desquamation, has been seen in patients receiving intermediate- or high-dose cytarabine.1-3 The syndrome is similar to the palmar-plantar erythrodysesthesia syndrome reported in patients receiving chemotherapy not including cytarabine,4 although some considered the two forms of toxicity distinct.5 Cutaneous small vessel necrotising vasculitis has been reported after high-dose therapy with cytarabine.6
1. Baer MR, et al. Palmar-plantar erythrodysesthesia and cytarabine. Ann Intern Med 1985; 102: 556
2. Peters WG, Willemze R. Palmar-plantar skin changes and cytarabine. Ann Intern Med 1985; 103: 805
3. Calista D, Landi C. Cytarabine-induced acral erythema: a localized form of toxic epidermal necrolysis? J Eur Acad Dermatol Ve ne re ol 1998; 10: 274–5
4. Lokich JJ, Moore C. Chemotherapy-associated palmar-plantar erythrodysesthesia syndrome. Ann Intern Med 1984; 101: 798–800
5. Vogelzang NJ, Ratain MJ. Cancer chemotherapy and skin changes. Ann Intern Med 1985; 103: 303–4
6. Ahmed I, et al. Cytosine arabinoside-induced vasculitis. Mayo Clin Proc 1998; 73: 239–42.

Pregnancy.

Although there has been a report of limb and ear deformities in the infant of a woman given cytarabine at the estimated time of conception and 4 to 8 weeks later,1 no congenital abnormalities were noted in 17 infants, 5 therapeutic abortions, and one still-birth (after pre-eclamptic toxaemia) resulting from over 20 known cases in which cytarabine was given during pregnancy.2
1. Wagner VM, et al. Congenital abnormalities in baby born to cytarabine treated mother. Lancet 1980; ii: 98–9
2. Morgenstern G. Cytarabine in pregnancy. Lancet 1980; ii: 259.

💊 Interactions

For a general outline of antineoplastic drug interactions.

Antifungals.

Antineoplastics.

Acute pancreatitis has been reported in patients given cytarabine who had previously received asparaginase therapy.1 Subclinical damage to the pancreas by asparaginase may have rendered it susceptible to cytarabine. For a report of hepatic dysfunction in patients who had received cytarabine and daunorubicin see under Daunorubicin Hydrochloride. Giving cytarabine after fludarabine is reported to result in a fivefold increase in intracellular cytarabine concentrations in leukaemic cells,2 producing improved clinical response rates.
1. Altman AJ, et al. Acute pancreatitis in association with cytosine arabinoside therapy. Cancer 1982; 49: 1384–6
2. Avramis VI, et al. Pharmacokinetic and pharmacodynamic studies of fludarabine and cytosine arabinoside administered as loading boluses followed by continuous infusions after a phase I/II study in pediatric patients with relapsed leukemias. Clin Cancer Res 1998; 4: 45–52.

💊 Pharmacokinetics

Cytarabine is not effective orally due to rapid deamination in the gastrointestinal tract; less than 20% of an oral dose is absorbed. After intravenous injection it disappears rapidly from the plasma with an initial half-life of about 10 minutes; the terminal elimination half-life ranges from 1 to 3 hours. It is converted by phosphorylation to an active form, which is rapidly deaminated, mainly in the liver and the kidneys, to inactive 1β-Darabinofuranosyluracil (uracil arabinoside, ara-U). The majority of an intravenous dose is excreted in the urine within 24 hours, mostly as the inactive metabolite with about 10% as unchanged cytarabine. There is only moderate diffusion of cytarabine across the blood-brain barrier after intravenous injection, but, because of low deaminase activity in the CSF, concentrations achieved after continuous intravenous infusion or intrathecal injection are maintained for longer in the CSF than are those in plasma, with a terminal elimination half-life of 3.5 hours. After intrathecal doses of the liposomal formulation, a terminal elimination half-life of 100 to 263 hours was seen. Cytarabine also crosses the placenta.
1. Slevin ML, et al. The pharmacokinetics of subcutaneous cytosine arabinoside in patients with acute myelogenous leukaemia. Br J Clin Pharmacol 1981; 12: 507–10
2. DeAngelis LM, et al. Pharmacokinetics of ara-C and ara-U in plasma and CSF after high-dose administration of cytosine arabinoside. Cancer Chemother Pharmacol 1992; 29: 173–7
3. Hamada A, et al. Clinical pharmacokinetics of cytarabine formulations. Clin Pharmacokinet 2002; 41: 705–18.

💊 Uses and Administration

Cytarabine, a pyrimidine nucleoside analogue, is an antimetabolite antineoplastic that inhibits the synthesis of deoxyribonucleic acid. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. Cytarabine is one of the mainstays of the treatment of acute myeloid leukaemias, together with an anthracycline,, and is used for the prophylaxis of meningeal leukaemia, as well as in regimens for consolidation, in patients with acute lymphoblastic leukaemia. It has also been investigated in the blast crisis of chronic myeloid leukaemia and the myelodysplasias (see also Low-dose Therapy, under Administration, below). It may be used in salvage regimens for Hodgkin’s disease, as part of the complex regimens sometimes employed in aggressive intermediate- and high-grade non-Hodgkin’s lymphomas, and for meningeal lymphoma. Cytarabine is usually given intravenously. Higher doses can be tolerated when given by rapid injection rather than slow infusion, because of the rapid clearance of cytarabine, but there is little evidence of clinical advantage either way. Cytarabine may be given intrathecally for leukaemic or lymphomatous meningitis. For the induction of remission in adults and children with acute leukaemias many dosage regimens have been used: 100 mg/m 2 twice daily by rapid intravenous injection, or 100 mg/m 2 daily by continuous intravenous infusion, have often been employed. These doses are generally given for 5 to 10 days, depending on therapeutic response and toxicity. Children reportedly tolerate high doses better than adults. For maintenance 1 to 1.5 mg/kg once or twice weekly has been given intravenously or subcutaneously; other regimens have been used. In the treatment of refractory disease high-dose regimens have been used, with cytarabine given in doses of up to 3 g/m 2 every 12 hours for up to 6 days. These doses should be given by intravenous infusion over at least 1 hour. In leukaemic meningitis cytarabine has been given intrathecally, often in a dose of 10 to 30 mg/m 2 every 2 to 4 days; it has also been used prophylactically. A liposomal formulation is available in some countries for intrathecal use, and permits less frequent dosing because of its longer duration of action: the recommended dose for lymphomatous meningitis is 50 mg intrathecally every 2 weeks for 5 doses then every 4 weeks for 5 doses. White cell and platelet counts should be determined regularly during treatment with cytarabine and therapy should be stopped immediately if the count falls rapidly or to low values. Cytarabine ocfosfate is an orally active prodrug of cytarabine under investigation in chronic myeloid leukaemia.

Administration.

INTRATHECAL. Intrathecal doses of the liposomal formulation of cytarabine result in prolonged drug exposure when compared with intrathecal doses of the conventional formulation (see Pharmacokinetics, above). In a randomised study,1 the liposomal formulation given once every 2 weeks produced a higher response rate and improved Karnofsky score compared with the conventional formulation given twice a week in patients with lymphomatous meningitis secondary to lymphoma. The use of liposomal formulations intrathecally to treat leukaemic or lymphomatous meningitis has been reviewed.2,3
1. Glantz MJ, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999; 17: 3110–16
2. Rueda Domínguez A, et al. Liposomal cytarabine (DepoCyte) for the treatment of neoplastic meningitis. Clin Transl Oncol 2005; 7: 232–8
3. Benesch M, Urban C. Liposomal cytarabine for leukemic and lymphomatous meningitis: recent developments. Expert Opin Pharmacother 2008; 9: 301–9.
LOW-DOSE THERAPY. Because of initial suggestions that low doses of cytarabine might induce differentiation and maturation of leukaemic cells, low-dose therapy has been tried in patients with myelodysplastic syndrome and acute myeloid leukaemia. Although complete remission may occur in about 20% of patients with myelodysplastic syndromes a similar proportion succumb to treatment-related mortality, and remissions do not appear to be particularly long-lasting. Bone-marrow suppression may be marked even at these doses.1 Lowdose subcutaneous cytarabine (20 mg twice daily for 10 days, at intervals of 4 to 6 weeks) was found to be superior to hydroxycarbamide (with or without all-trans retinoic acid) in elderly patients with acute myeloid leukaemia. Although the authors considered the prognosis for these patients to still be unsatisfactory, they suggested that therapy with low-dose cytarabine could represent a baseline against which other promising treatments might be compared.2
1. Aul C, Gattermann N. The role of low-dose chemotherapy in myelodysplastic syndrome. Leuk Res 1992; 16: 207–15
2. Burnett AK, et al. The National Cancer Research Institute Haematological Oncology Study Group Adult Leukemia Working Party. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007; 109: 1114–24.

Leukoencephalopathy.

There are anecdotal reports1-3 of marked improvement in patients with progressive multifocal leukoencephalopathy secondary to AIDS or chemotherapy-induced immunosuppression who were given intravenous or intrathecal cytarabine. However, a randomised multicentre study4 indicated that cytarabine was ineffective and had no role in this condition. Others5 have suggested that even intrathecal dosage may not provide adequate delivery of cytarabine to target cells, and that delivering the drug directly into the brain under pressure might be an alternative. Cytarabine has also been used with cidofovir.6
1. O’Riordan T, et al. Progressive multifocal leukoencephalopathyremission with cytarabine. J Infect 1990; 20: 51–4
2. Portegies P, et al. Response to cytarabine in progressive multifocal leucoencephalopathy in AIDS. Lancet 1991; 337: 680–1
3. Nicoli F, et al. Efficacy of cytarabine in progressive multifocal leucoencephalopathy in AIDS. Lancet 1992; 339: 306
4. Hall CD, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med 1998; 338: 1345–51
5. Levy RM, et al. Convection-enhanced intraparenchymal delivery (CEID) of cytosine arabinoside (AraC) for the treatment of HIV-related progressive multifocal leukoencephalopathy (PML). J Neurovirol 2001; 7: 382–5
6. Terrier B, et al. Leucoencéphalite multifocale progressive en dehors du sida: efficacité de l’association cytarabine-cidofovir. Rev Med Interne 2007; 28: 488–91.

💊 Preparations

BP 2008: Cytarabine Injection; USP 31: Cytarabine for Injection.

Proprietary Preparations

Arg.: Aracytin†; Citagenin; Austria: Alexan; ARA-cell; Belg.: Cyta-Cell; Cytosar; DepoCyte; Braz.: Aracytin; Citab†; Citarax; Darbin; Serotabir†; Tabine†; Canad.: Cytosar; DepoCyt†; Chile: Alexan; Aracytin; Laracit; Cz.: Alcysten†; Alexan; Cytosar; DepoCyte; Denm.: Arabine; Cytosar†; DepoCyte; Fin.: Arabine; DepoCyte; Fr.: Aracytine; DepoCyte; Ger.: Alexan; ARA-cell; DepoCyte; Udicil; Gr.: Aracytin; Citabion; Hong Kong: Alexan; Cytosar; Hung.: Alexan; Cytosar; India: Biobin; Cytarine; Indon.: CytosarU; Irl.: Cytosar†; Israel: Alexan; Cytosar; Ital.: Aracytin; DepoCyte; Erpalfa; Jpn: Cylocide; Starasid; Malaysia: Cytosar-U; Mex.: Alexan†; Cytosar; Ifarab; Laracit; Medsara; Novumtrax; Neth.: Alexan; Cytosar; DepoCyte; Norw.: Cytosar†; DepoCyte; Philipp.: Cytosar-U; Leucyt; Tabine; Pol.: Alexan; Cytosar; DepoCyte; Port.: Alexan†; ARA-cell; Citaloxan; Cytosar; Depocyte; Rus.: Alexan (Алексан); Cytosar (Цитозар); S.Afr.: Alexan; Cytosar; Singapore: Alexan†; Cytosar†; Spain: DepoCyte; Swed.: Arabine; Cytosar†; DepoCyte; Switz.: Cytosar; Thai.: Alexan†; Cytarine; Cytosar; Turk.: Alexan; ARA-cell; Cytonal; UK: DepoCyte; USA: Cytosar-U†; DepoCyt; Venez.: Cytosar.
Published December 15, 2018.