Cytarabine

Cytarabine is a pyrimidine-analogue antimetabolite. It is cytotoxic to proliferating cells and acts mainly on cells that are making DNA (S phase); DrugBank adds that under some conditions it also blocks the passage of cells from the G1 phase into S phase.

Mechanism of Action

• Activation: inside the cell, deoxycytidine kinase and other nucleotide kinases convert cytarabine to cytarabine triphosphate (ara-CTP), the active metabolite.
• DNA synthesis: ara-CTP competes with the natural substrate, deoxycytidine 5’-triphosphate, for DNA polymerase and inhibits DNA synthesis in the S phase. It also slows elongation of the DNA chain and may inhibit reverse transcriptase. The SmPC notes that the mechanism is not completely understood.
• DNA damage: according to DrugBank, ara-CTP damages DNA in several ways: it inhibits alpha-DNA polymerase, impairs repair through beta-DNA polymerase and is built into DNA, which is probably the most important route. A limited incorporation into RNA has also been reported.
• Cell-cycle specificity: cytotoxicity is highly specific for the S phase.
• Inactivation: cytidine deaminase converts cytarabine to the inactive uracil arabinoside (ara-U), and a pyrimidine nucleoside deaminase inactivates ara-CTP to the uracil derivative.

Pharmacokinetics

• Absorption: less than 20% of an oral dose is absorbed from the gut, so cytarabine is not effective by mouth. After subcutaneous or intramuscular injection, peak plasma levels come after 20–60 minutes and are considerably lower than after intravenous dosing. An intravenous infusion gives relatively constant plasma levels within 8–24 hours.
• Distribution: rapid and wide, into tissues and fluids including liver, plasma and peripheral granulocytes. About 13% is bound to plasma proteins after a rapid intravenous dose. It crosses the blood–brain barrier to a limited extent; cerebrospinal fluid levels after intravenous infusion or subcutaneous dosing are about 40–60% of plasma levels. Most of an intrathecal dose diffuses into the circulation but is quickly metabolised. It appears to cross the placenta; whether it or ara-U passes into breast milk is not known.
• Metabolism: rapid and extensive, mainly in the liver but also in the kidney, gut mucosa, granulocytes and other tissues. Cytidine deaminase forms the inactive ara-U; after the initial distribution phase more than 80% of the drug in plasma is ara-U. Little is converted in the cerebrospinal fluid, which has low cytidine deaminase levels.
• Elimination: after a rapid intravenous injection, plasma levels fall in two phases, with half-lives of about 10 minutes (initial) and 1–3 hours (terminal); in some patients elimination has three phases. After intrathecal dosing, cerebrospinal fluid levels fall with a half-life of about 2 hours. About 70–80% of the dose is excreted in urine within 24 hours, roughly 90% of it as ara-U and 10% unchanged.
• Special populations: the liver is the main site of inactivation of cytarabine and of ara-U, which is excreted in urine; build-up of ara-U in the central nervous system may cause acute cerebellar toxicity.

Cytarabine is authorised nationally. The indications below are those of the two Spanish SmPCs for Citarabina Pfizer (powder and solvent, and 20 mg/mL solution), which word them identically.

• Acute myeloid leukaemia (AML): induction and maintenance of remission in adults and children.
• Other leukaemias: also shown to be useful in other acute leukaemias and in chronic myeloid leukaemia (blast phase).
• Meningeal leukaemia: prophylaxis and treatment, given intrathecally, alone or in combination with other medicines.
• Cytarabine can be used alone or in combination with other antineoplastic agents; combination therapy generally gives better results.

• Hypersensitivity to cytarabine or to any of the excipients.
• Pre-existing drug-induced bone-marrow suppression, unless the physician judges that this treatment offers the patient the most promising option.

Cytarabine is a potent bone-marrow suppressor, so anaemia, leucopenia and thrombocytopenia are the main reactions, together with megaloblastosis and a fall in reticulocytes; their severity depends on the dose and schedule. Infections, mouth and gut ulceration, nausea and vomiting, hair loss, rash and the cytarabine syndrome are also very common. The groups below cover conventional and high-dose therapy.

Very common (≥1/10): infections (septicaemia, pneumonia, infection, which may be mild but can become severe or fatal); blood and lymphatic system (bone-marrow failure, thrombocytopenia, anaemia, megaloblastic anaemia, leucopenia, decreased reticulocyte count); gastrointestinal (stomatitis, mouth ulceration, anal ulcer, anal inflammation, diarrhoea, vomiting, nausea, abdominal pain); liver (abnormal liver function); skin (alopecia, rash); musculoskeletal (cytarabine syndrome); general (pyrexia); investigations (abnormal bone-marrow biopsy, abnormal blood smear).

Common (≥1/100 to <1/10): skin ulcer.

Not known: cellulitis at the injection site; anaphylactic reaction, allergic oedema; decreased appetite; neurotoxicity, neuritis, dizziness, headache; conjunctivitis (which can come with rash and be haemorrhagic at high doses); pericarditis, sinus bradycardia; thrombophlebitis; dyspnoea, oropharyngeal pain; pancreatitis, oesophageal ulcer, oesophagitis; jaundice; palmar-plantar erythrodysaesthesia syndrome, urticaria, pruritus, freckling; renal impairment, urinary retention; chest pain, injection-site reaction (pain and swelling under the skin).

With high doses, very common (≥1/10): cerebral disorder, cerebellar disorder, somnolence; corneal disorder; acute respiratory distress syndrome, pulmonary oedema.

With high doses, common (≥1/100 to <1/10): necrotising colitis; skin exfoliation.

With high doses, not known: liver abscess; personality change (reported with cerebral and cerebellar dysfunction); coma, convulsion, peripheral motor and sensory neuropathy; cardiomyopathy (with later death in reported cases); gastrointestinal necrosis, gastrointestinal ulcer, pneumatosis intestinalis, peritonitis; liver damage, hyperbilirubinaemia.

After a 5-day course of 50–600 mg/m², white cells in the marrow fall in two phases: a first fall to a low point on days 7–9, a brief rise around day 12, then a second, deeper fall to a low point on days 15–24, followed by a rapid return to baseline within about 10 days. The cytarabine syndrome (fever, muscle pain, bone and joint pain, occasional chest pain, maculopapular rash, conjunctivitis and malaise) starts about 6–12 hours after a dose; corticosteroids can be used for prevention and treatment, and if the patient responds, cytarabine can be continued. At experimental intermediate doses (1 g/m²), diffuse interstitial pneumonitis without an evident cause, possibly related to cytarabine, has been reported.

• Digoxin: in patients on beta-acetyldigoxin with regimens containing cyclophosphamide, vincristine and prednisone, with or without cytarabine or procarbazine, digoxin steady-state plasma levels fell reversibly and its renal excretion decreased. Digitoxin levels did not appear to change. Digoxin levels should be monitored with similar regimens; digitoxin may be an alternative.
• Gentamicin: in vitro, cytarabine could antagonise gentamicin against Klebsiella pneumoniae. If a patient on cytarabine treated with gentamicin for such an infection does not respond promptly, the antibiotic therapy should be reassessed.
• Flucytosine: in one patient, cytarabine possibly inhibited the efficacy of flucytosine, perhaps through competitive inhibition of its uptake.
• Intrathecal methotrexate: intravenous cytarabine together with intrathecal methotrexate may raise the risk of serious neurological reactions such as headache, paralysis, coma and stroke-like episodes.
• Live vaccines: not to be given during treatment (see Special Instructions).
• Other chemotherapy: caution is advised when cytarabine is combined with cardiac glycosides, other chemotherapeutic agents and anti-infectives such as gentamicin and flucytosine.

Cytarabine must be given by staff experienced in cytostatic chemotherapy, and the SmPC states that treatment is to be carried out exclusively in hospital. It can be given as an intravenous bolus injection or infusion, subcutaneously or intrathecally; it is not active by mouth. High total doses are better tolerated as a bolus than as a slow infusion, although no clear difference has been shown. For high-dose intravenous or intrathecal use, diluents containing benzyl alcohol must not be used. Doses are a guide only: they are set from the patient’s tolerance and clinical and haematological response, following current treatment protocols.

Dosing Guidance

• AML induction, single agent: 200 mg/m² per 24 hours as a continuous infusion for 5 days, repeating the cycle about every 2 weeks.
• AML induction, combination chemotherapy: 100–200 mg/m² per 24 hours as a bolus or infusion for 5–10 days.
• Maintenance: started after induction or once remission is reached, usually alone. Doses vary between patients; for example a single dose of 1 or 1.5 mg/kg per day subcutaneously at intervals of 1–4 weeks, or 70–200 mg/m² daily as a bolus or infusion for 2–5 days at monthly intervals.
• Secondary or refractory acute leukaemia: 2–3 g/m² as a 1–3 hour infusion every 12 hours for 6 days has been used, alone or with other chemotherapy.
• Acute lymphoid leukaemia and chronic myeloid leukaemia: used with other antineoplastic agents as part of complex regimens; the SmPC refers to current protocols for the dose and route.
• Meningeal leukaemia (intrathecal): 5–75 mg/m², once daily for 4 days or once every 4 days. The dose most often used is 30 mg/m² every 4 days until the cerebrospinal fluid is normal, followed by one more course. The schedule depends on the type and severity of central nervous system involvement and on the response to earlier therapy. Cytarabine has also been given intrathecally with hydrocortisone and methotrexate to prevent meningeal leukaemia in children newly diagnosed with acute lymphoid leukaemia, and to treat it.

Dose Adjustments for Blood Counts

• Treatment is stopped or modified if bone-marrow depression brings polymorphonuclear leucocytes below 1,000/mm³ or platelets below 50,000/mm³.
• Counts may keep falling after stopping, reaching their lowest between days 12 and 24. If indicated, treatment is restarted when repeated bone-marrow studies clearly show recovery. Loss of disease control can occur in patients who are not given the medicine again until normal peripheral blood counts are restored.

Special Populations

• Children: doses are similar to those in adults. Safety in infants has not been established.
• Hepatic or renal impairment: use with caution, considering a lower dose, because the liver is the main site of inactivation of cytarabine and ara-U, which is excreted in urine. There is not enough clinical data for clear dose recommendations.
• Elderly: advanced age is a risk factor for neurological toxicity, including cerebellar toxicity; use with caution in patients over 60.

Preparation and In-Use Stability

• Powder and solvent: reconstituted with the supplied water for injections (preservative-free 0.9% sodium chloride is also common practice) and used at once. The reconstituted solution keeps for 48 hours and must not be kept above 30 °C.
• 20 mg/mL solution: stable after dilution to 0.1–1.0 mg/mL in water for injections, 5% glucose or 0.9% sodium chloride in PVC infusion bags for up to 4 days (see Shelf Life). The SmPC gives further in-use storage conditions.

Hospital Use and Blood Monitoring

• Treatment is carried out exclusively in hospital with close monitoring. Cytarabine is a potent bone-marrow depressant, so it is started with caution in patients with pre-existing drug-induced marrow depression.
• White cell and platelet counts are done daily during induction, and marrow examinations are repeated often once blast cells have cleared from the blood. Measures to treat complications of marrow depression, such as infections from granulocytopenia and bleeding from thrombocytopenia, must be available. Liver, kidney and marrow function are tested periodically.

Anaphylaxis

Anaphylactic reactions have occurred, including one case of anaphylaxis that caused acute cardiorespiratory arrest and needed resuscitation immediately after intravenous administration.

Serious Toxicity with High and Experimental Doses

• Some experimental high-dose regimens caused severe, sometimes fatal toxicity of the central nervous system, gastrointestinal tract and lungs that differs from conventional regimens: reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; somnolence; convulsions; severe gastrointestinal ulcers including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; and pulmonary oedema.
• Peripheral sensory and motor neuropathies followed high-dose consolidation with cytarabine, daunorubicin and asparaginase in adults with acute non-lymphocytic leukaemia. Patients on high doses should be monitored for neuropathy, because the schedule may need changing to avoid irreversible neurological disorders.
• After high doses, severe and sometimes fatal lung toxicity, adult respiratory distress syndrome and pulmonary oedema have been seen. Cardiomyopathy with later death was reported with experimental high-dose cytarabine plus cyclophosphamide before bone-marrow transplantation.
• Serious neurological reactions, from headache to paralysis, coma and stroke-like episodes, were reported mostly in young people and adolescents given intravenous cytarabine with intrathecal methotrexate.
• Nausea and vomiting lasting hours can follow rapid high-dose intravenous injections and are milder with infusion. Abdominal tenderness (peritonitis) and colitis with blood in the stool, with neutropenia and thrombocytopenia, occurred with conventional doses in combination regimens and responded to non-surgical treatment. Thrombophlebitis has occurred at injection and infusion sites and at the subcutaneous injection site.

Tumour Lysis Syndrome

Cytarabine can cause hyperuricaemia from the rapid breakdown of tumour cells. Blood uric acid, potassium, calcium phosphate and creatinine should be checked after the first treatment. Hydration, alkalinisation of the urine and allopurinol prophylaxis can keep complications to a minimum.

Infections and Vaccines

Cytarabine suppresses immunity and increases susceptibility to infection. Live or attenuated virus vaccines must not be given to patients on cytarabine, as they can cause serious or fatal infections in immunocompromised patients; killed or inactivated vaccines may be given, although the response may be reduced.

Benzyl Alcohol

Intravenous benzyl alcohol preservative has been linked to a serious, sometimes fatal reaction in paediatric patients including neonates (central nervous system depression, metabolic acidosis, gasping respiration, cardiovascular failure and blood abnormalities). Premature and low-birth-weight infants are most at risk. For high-dose or intrathecal cytarabine, diluents containing benzyl alcohol must not be used; preservative-free 0.9% sodium chloride can be used for reconstitution.

Pregnancy, Breastfeeding and Fertility

• Contraception: because of its genotoxic potential, women of childbearing potential should use highly effective contraception during treatment and for at least 6 months after the last dose. Men with female partners of childbearing potential should do so during treatment and for at least 3 months after the last dose.
• Pregnancy: there are no studies in pregnant women, and cytarabine was teratogenic in some animal species. It is considered in pregnant women or women of childbearing potential only if the potential benefit justifies the risk to the foetus. Malformations can occur because of its cytotoxic effect; the risk is lower with exposure in the second and third trimesters. Patients should be told of the risk to the foetus.
• Breastfeeding: it is not known whether cytarabine passes into breast milk. Treatment or breastfeeding should be stopped during therapy and for at least one week after the last dose.
• Fertility: cytarabine may be genotoxic; the SmPC gives further advice.

Sodium

One mL of the 20 mg/mL solution contains 2.67 mg of sodium. The SmPC of the powder states that it contains less than 1 mmol (23 mg) of sodium per dose unit, that is, it is essentially sodium-free.

Effect on Driving

No reports explicitly link cytarabine to the ability to drive or use machines. Patients having chemotherapy may have a reduced ability to drive and use machinery; they should be warned and should avoid these tasks in that case.

• Powder and solvent (100 mg and 500 mg): no special storage conditions. The vials and solvent ampoules are Type I glass.
• 20 mg/mL solution: store between 15 and 25 °C, with the vial kept in the outer carton to protect it from light.
• Cytarabine is not a cold-chain product. For storage after reconstitution or dilution, see Shelf Life.

• Powder and solvent: 5 years. After reconstitution with the water ampoule: 48 hours; the reconstituted solution must not be kept above 30 °C.
• 20 mg/mL solution: 18 months. Diluted to 0.1–1.0 mg/mL in water for injections, 5% glucose or 0.9% sodium chloride in PVC infusion bags, it is chemically and physically stable for up to 4 days at 25 °C and 60% relative humidity under ambient light, and at 2–8 °C protected from light. From a microbiological point of view the diluted medicine should be used immediately; the SmPC gives further in-use storage conditions.

Prescription only (Rx), for use by staff experienced in cytostatic chemotherapy. Cytarabine is given by intravenous, subcutaneous or intrathecal injection in hospital, so it is supplied to the hospital or clinic that administers it.