Cytarabine Injection Solution 100 mg/ml

Cytarabine may be used alone or in combination with other antineoplastic agents. It is indicated alone or in combination for induction of remission and/or maintenance in patients with acute myeloid leukaemia, acute non-lymphoblastic leukaemias, acute lymphoblastic leukaemias, acute lymphocytic leukaemia, erythroleukaemia, blast crises of chronic myeloid leukaemia, diffuse histiocytic lymphomas (non-Hodgkin's lymphomas of high malignancy), meningeal leukaemia and meningeal neoplasms. Clinicians should refer to the current literature on combination therapy before initiating treatment.

Posology

Cytarabine 100 mg/ml Injection can be diluted with Water for Injections BP, Glucose Intravenous Infusion BP or Sodium Chloride Intravenous Infusion BP. Prepared infusions, in the recommended diluents, should be used immediately. Alternatively, the diluted infusion fluids may be stored at 2-8°C, protected from light, but portions remaining unused after 24 hours must be discarded.

Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion.

Remission Induction: Adults

Continuous dosing: The usual dose in leukaemia is 2 mg/kg by rapid intravenous injection daily for ten days. If after ten days neither therapeutic response nor toxicity has been observed, the dose may be increased to 4 mg/kg until a therapeutic response or toxicity is evident. Daily blood counts should be taken. Almost all patients can be carried to toxicity with these doses.

Alternatively, 0.5 to 1 mg/kg may be infused daily in 1-24 hours for ten days, and then at a rate of 2 mg/kg/day until toxicity is observed. Continue to toxicity or until remission occurs. Results from one-hour infusions have been satisfactory in the majority of patients.

Intermittent dosing: Cytarabine may be given as intermittent intravenous doses of 3-5 mg/kg daily, for five consecutive days. This course of treatment can be repeated after an interval of 2 to 9 days and repeated until the therapeutic response or toxicity is exhibited.

Evidence of bone marrow improvement has been reported to occur 7-64 days after the beginning of therapy.

In general, if a patient shows neither remission nor toxicity after a trial period, then cautiously administered higher doses can be administered. Generally patients tolerate higher doses given by rapid intravenous injection rather than slow infusion.

As a single agent for induction of remissions in patients with acute leukaemia, cytarabine has been given in doses of 200 mg/m² by continuous intravenous infusion for five days at approximately 2 week intervals.

Maintenance therapy: To maintain remission, doses of 1 mg/kg may be given intravenously or subcutaneously, once or twice weekly.

Leukaemic meningitis: Therapy for established meningitis employs a wide variety of dose regimens but a recommended total daily dose not exceeding 100 mg, alternating with methotrexate is recommended.

Myelosuppression, anaemia and thrombocytopenia occur almost to all patients given daily infusions or injections. Myelosuppression is biphasic and nadirs at 7-9 and 15-24 days. Evidence of bone marrow improvement may be expected 7-64 (mean 28) days after the beginning of treatment.

Paediatric population: Children appear to tolerate higher doses of cytarabine than adults, and where the range of doses is given, children should receive the higher dose.

Elderly: No data is available to suggest that a change in dose is necessary in the elderly. However, the elderly patient is more susceptible to toxic reactions and therefore particular attention should be paid to drug induced leukopenia, thrombocytopenia and anaemia.

Method of administration

Cytarabine 100 mg/ml Injection is a ready to use solution and is suitable for intravenous and subcutaneous use. Cytarabine 100 mg/ml Injection should not be administered by the intrathecal route due to the slight hypertonicity of this formulation (see section 4.8).

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Anaemia, leukopenia and thrombocytopenia of non-malignant aetiology (e.g. bone marrow aplasia), unless the benefits outweigh the risk.

Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionising radiation.

During pregnancy, cytarabine should only be administrated on strict indication, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus.

General

Only physicians experienced in cancer chemotherapy should use cytarabine.

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 is bone marrow suppression with leukopenia, thrombocytopenia and anaemia. Less serious toxicity includes nausea, vomiting, diarrhoea and abdominal pain, oral ulceration, and hepatic dysfunction.

Haematologic effects

Cytarabine is a potent bone marrow suppressant, the severity depends on the dose of the drug and administration. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving the drug should be kept under close medical supervision. Leucocyte and platelet counts should be performed frequently and daily during induction. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood. Therapy should be suspended or modified when drug-induced bone marrow depression results in a platelet count of less than 50,000 or a polymorphnuclear count of under 1000 per mm³. Counts of formed elements in the peripheral blood may continue to fall after the therapy has been discontinued and may reach lowest values after drug-free intervals of 12 to 24 days. Therapy may be restarted when the bone marrow appears to be recovering on successive bone marrow studies. Therapy should not wait until the normal blood values are obtained to be re-initiated. If treatment is not resumed before blood values return to normal, the disease can get out of control.

Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defences, and haemorrhage secondary to thrombocytopenia).

Immune system

Anaphylactic reactions have occurred with cytarabine treatment. One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitation has been reported. This occurred immediately after intravenous cytarabine was administered.

High dose schedules

Severe and at times fatal central nervous system (CNS), gastrointestinal (GI) and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine) has been reported following high dose (2-3 g/m²) schedules of cytarabine. Reversible adverse reactions include corneal toxicity, haemorrhagic conjunctivitis (which may be prevented or reduced by prophylactic corticosteroid eye drops), and cerebral or cerebellar dysfunction (including personality changes and somnolence), which are usually reversible.

Other adverse reactions reported include convulsions and coma, severe gastrointestinal ulceration (including pneumatosis cystoides intestinalis which may progress to peritonitis), sepsis, liver abscess, pulmonary oedema, hepatic injury (including hyperbilirubinaemia), bowel necrosis, and necrotising colitis.

Severe and sometimes fatal pulmonary toxicity, acute respiratory distress syndrome, and pulmonary oedema have occurred following high dose schedules with cytarabine therapy. A syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukaemia.

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

Peripheral motor and sensory neuropathies after consolidation with high doses of cytarabine, daunorubicin, and asparaginase have occurred in adult patients with acute non lymphocytic leukaemia.

Patients treated with high doses of cytarabine should be observed for neuropathy since dose adjustments may be needed to avoid irreversible neurologic disorders.

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 of cytarabine.

When large intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours afterwards. The problem tends to be less severe when infused.

Conventional dose schedules

Abdominal tenderness (peritonitis) and guaiac positive colitis, with concurrent neutropenia and thrombocytopenia, have been reported in patients treated with conventional doses of cytarabine in combination with other drugs. Patients have responded to non-operative medical management.

Delayed progressive ascending paralysis resulting in death has been reported in children with AML following intravenous cytarabine at conventional doses in combination with other drugs.

Concurrent radiotherapy/chemotherapy

The risk of CNS toxicity increases if high dose cytarabine is given in combination with another CNS toxic treatment such as radiation therapy or in patients who have previously had CNS treatment as chemotherapy intrathecally.

Neurological

Rarely, neurological effects such as severe spinal cord toxicity even leading to necrotising encephalopathy, quadriplegia and paralysis and blindness have been reported with cytosine arabinoside and have been predominantly associated with intrathecal administration. Isolated cases have also been reported with high intravenous doses during combination chemotherapeutic regimens (see section 4.8).

Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given intravenous cytarabine in combination with intrathecal methotrexate.

Cytarabine has been shown to be mutagenic and carcinogenic in animals. The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

Tumour lysis syndrome

Cytarabine should only be used under the constant supervision by physicians experienced in therapy with cytotoxic agents. Hyperuricaemia secondary to rapid lysis of neoplastic cells may occur in patients receiving cytarabine; serum uric acid concentrations should be monitored. The physician should be prepared to use such supportive and pharmacological measures as may be necessary to control this problem.

Hepatic and/or renal impairment

Periodic determinations of renal and hepatic functions and bone marrow should also be performed, and the drug should be used with caution in patients with impaired hepatic function.

However, dosage reduction does not appear to be necessary in patients with impaired renal function. The human liver apparently detoxifies a substantial fraction of the administered dose of cytarabine. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose treatment with cytarabine. The drug should be used with caution and at a reduced dose when liver or kidney function is poor.

Haematology/transfusions

Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency has been reported.

Pancreatitis

Acute pancreatitis has been reported to occur in patients being treated with cytarabine in combination with other drugs.

Immunosuppressant effects/Increased susceptibility to infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cytarabine, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving cytarabine. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Paediatric population

The safety of the drug has not been established in infants.

Excipient information

Cytarabine 100 mg/ml Injection contains less than 1 mmol sodium (23 mg) in each vial, that is to say essentially 'sodium-free'.

Cardiac glycosides

GI absorption of oral digoxin tablets may be substantially reduced in patients receiving combination chemotherapy regimens (including regimens containing cytarabine), possibly as a result of temporary damage to intestinal mucosa caused by the cytotoxic agents. Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyl digoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine or procarbazine. Limited data suggest that the extent of GI absorption of digitoxin is not substantially affected by concomitant administration of combination chemotherapy regimens known to decrease absorption of digoxin. 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 utilisation of digitoxin for such patients may be considered as an alternative.

Gentamicin

One in vitro study indicates that cytarabine may antagonise the activity of gentamicin against Klebsiella pneumoniae. In patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, a lack of a prompt therapeutic response may indicate the need for re-evaluation of antibacterial therapy.

5-Fluorocytosine

5-Fluorocytosine should not be administered with cytarabine as the therapeutic efficacy of 5-Fluorocytosine has been shown to be abolished during such therapy.

Immunosuppressive agents

Due to the immunosuppressive action of cytarabine, viral, bacterial, fungal, parasitic, or saprophytic infections, in any location in the body, may be associated with the use of cytarabine alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity. These infections may be mild, but can be severe and at times fatal.

Methotrexate

Intravenous cytarabine given concomitantly with intrathecal methotrexate may increase the risk of severe neurological adverse reactions such as headache, paralysis, coma and stroke like episodes (see section 4.4).

Women of childbearing potential/Contraception in males and females

Due to the potential for genotoxicity, female patients of reproductive potential should be advised to use highly effective contraception during treatment and for 6 months after the last dose of cytarabine.

Due to the potential for genotoxicity, male patients with female partners of reproductive potential should be advised to use highly effective contraception during treatment and for 3 months after the last dose of cytarabine.

Pregnancy

There are limited data on the use of cytarabine in pregnant women. Cytarabine is teratogenic in some animal species. It should not be used in pregnant women (especially during the first trimester) or in those who may become pregnant, unless the possible benefits outweigh the potential risks. Women who are, or who may become, pregnant during treatment with cytarabine should be informed of the risks.

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 should be apprised of the potential risk to the foetus. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable.

Breast-feeding

It is not known if cytarabine or its metabolite is distributed into breast 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 for the duration of cytarabine therapy and for at least 1 week after the last dose of cytarabine or to discontinue the drug, taking into account the importance of the drug to the mother.

Fertility

Fertility studies to assess the reproductive toxicity of cytarabine have not been conducted. Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking cytarabine therapy, especially in combination with alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Cytarabine has a mutagenic potential which could induce chromosomal damage in the human spermatozoa.

Cytarabine has no or negligible influence on the ability to drive and use machines.

Nevertheless, patients receiving chemotherapy may have an impaired ability to drive or operate machinery and should be warned of the possibility and advised to avoid such tasks if so affected.

Undesirable effects from cytarabine are dose-dependent. Most common are gastrointestinal undesirable effects.

Blood and lymphatic system disorders

Cytarabine is toxic to the bone marrow, and causes undesirable haematological effects. Because cytarabine is a bone marrow suppressant, anaemia, leukopenia, thrombocytopenia, megaloblastosis and reduced reticulocytes can be expected as a result of its administration. These appear to be more evident after high doses and continuous infusions; 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 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.

Infections and infestations

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.

Musculoskeletal and connective tissue disorders

Cytarabine syndrome (immunoallergic effect) is characterised by fever, myalgia, bone pain, occasionally chest pain, exanthema, maculopapular rash, conjunctivitis, nausea and malaise. It usually occurs 6-12 hours after administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are serious enough to warrant treatment, corticosteroids should be contemplated. If treatment is effective, therapy with cytarabine may be continued.

The following adverse events have been reported in association with cytarabine therapy. Frequencies are defined using the following convention:

Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data)

Adverse Reactions Table (Conventional and High Dose Therapy)

^a may be mild, but can be severe and at times fatal

^b may occur with rash and may be haemorrhagic with high dose therapy

^c nausea and vomiting occur and are generally more frequent following rapid intravenous administration than with continuous intravenous infusion of the drug

^d pain and inflammation at subcutaneous injection site

Adverse effects due to high dose cytarabine treatment, other than those seen with conventional doses include:

Blood and lymphatic system disorders

Haematological toxicity has been seen as profound pancytopenia which may last 15-25 days along with more severe bone marrow aplasia than that observed at conventional doses.

Nervous system disorders

After treatment with high doses of cytarabine, symptoms of cerebral or cerebellar influence like personality changes, affected alertness, dysarthria, ataxia, tremor, nystagmus, headache, confusion, somnolence, dizziness, coma, convulsions, etc. appear in 8-37 % of treated patients. The incidence in elderly (>55 years) may be even higher. Other predisposing factors are impaired liver and renal function, previous CNS treatment (e.g., radiotherapy) and alcohol abuse. CNS disturbances are in the most cases reversible.

The risk of CNS toxicity increases if the cytarabine treatment, given as high dose IV, is combined with another CNS toxic treatment such as radiation therapy or high dose of a cytotoxic agent.

Eye disorders

Reversible corneal lesion and haemorrhagic conjunctivitis have been described. These phenomena can be prevented or decreased by installation of corticosteroid eye drops.

Gastrointestinal disorders

Especially in treatment with high doses of cytarabine, more severe reactions may appear in addition to common symptoms. Intestinal perforation or necrosis with ileus and peritonitis have been reported. Pancreatitis has also been observed after high-dose therapy.

Hepatobiliary disorders

Liver abscesses, hepatomegaly, Budd-Chiari-syndrome (hepatic venous thrombosis), and hyperbilirubinaemia have been observed after high-dose therapy.

Respiratory, thoracic and mediastinal disorders

Clinical signs as present in pulmonary oedema/ARDS may develop, particularly in high-dose therapy. The reaction is probably caused by an alveolar capillary injury. It is difficult to make an assessment of frequencies (stated as 10-26 % in different publications), since the patients usually have been in relapse where other factors may contribute to this reaction.

Reproductive system and breast disorders

Amenorrhoea and azoospermia.

Other adverse reactions

Following cytarabine therapy, cardiomyopathy and rhabdomyolysis have been reported.

The gastrointestinal undesirable effects are reduced if cytarabine is administered as infusion.

Local glucocorticoids are recommended as prophylaxis of haemorrhagic conjunctivitis.

One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitation has been reported (see section 4.4).

A diffuse interstitial pneumonitis without clear cause that may have been related to cytarabine was reported in patients treated with experimental intermediate doses of cytarabine (1 g/m²) with and without other chemotherapeutic agents (meta-AMSA, daunorubicin, VP-16).

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and a radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukaemia; fatal outcome has been reported.

Adverse Reactions Table (High Dose Therapy)

^a personality change was reported in association with cerebral and cerebellar dysfunction.

^b with subsequent death

Adverse effects due to high dose cytarabine treatment, other than those seen with conventional doses include:

Blood and lymphatic system disorders

Haematological toxicity, which may include bone marrow aplasia, may be more severe and more prolonged than that observed with conventional doses.

Nervous system disorders

Symptoms of cerebral and cerebellar disturbance, which may include headache and dizziness, can occur following treatment with high doses of cytarabine. Neurological toxicity may occur more frequently in patients aged >55 years. Other predisposing factors include impaired hepatic and renal function, previous CNS treatment (e.g. radiotherapy) and alcohol abuse. CNS disturbances are in most cases reversible.

The risk of CNS toxicity increases if high-dose IV cytarabine is combined with another CNS-toxic treatment such as radiation therapy or a high dose of a cytotoxic agent.

Eye disorders

Haemorrhagic conjunctivitis has been described; local corticosteroid eye drops are recommended as prophylaxis.

Gastrointestinal disorders

Especially during high-dose cytarabine treatment, more severe gastrointestinal reactions may occur in addition to common symptoms. Intestinal perforation with ileus and pancreatitis have also been observed after high-dose therapy.

The gastrointestinal undesirable effects are reduced if cytarabine is administered as infusion.

Hepatobiliary disorders

Liver abscesses have been observed after high-dose therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no specific antidote for cytarabine overdose. Cessation of therapy followed by management of ensuing bone marrow depression including whole blood or platelet transfusion and antibiotics as required.

Twelve doses of 4.5 g/m² by IV infusion over one hour every 12 hours induces irreversible and fatal CNS toxicity.

Cytarabine may be removed by haemodialysis.

Pharmacotherapeutic group: Pyrimidine analogues, ATC code: L01BC01

Mechanism of action

Cytarabine (ARA-C) is metabolised in vivo to ARA-CTP phosphorylated compound. This competitively inhibits DNA polymerase and may also inhibit certain acid kinase enzymes. Primarily the drug acts as a false nucleoside and competes for enzymes involved in the conversion of cytidine nucleotide to deoxycytidine nucleotide and also incorporation into the DNA.

Cytarabine has no effect on non-proliferating cells nor on proliferating cells unless in the S phase. It is a cell cycle specific antineoplastic drug.

Absorption

Oral administration is ineffective due to rapid deamination in the gut. Cytidine deaminase is concentrated in the liver and intravenous doses show biphasic elimination with half-lives of approximately 10 minutes and 1-3 hours.

Distribution

Cerebrospinal fluid levels of 50% of plasma levels are achieved with intravenous infusion. Intrathecal dosing results in slower elimination (T_1/2 2-11 hours).

Cytarabine is rapidly and widely distributed into tissues, crosses the blood brain barrier and also the placenta.

Elimination

After 24 hours 80% of a dose has been eliminated either as the inactive metabolite or as the unchanged cytarabine, mostly in urine but some in bile.

There is no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Water for Injections

Hydrochloric Acid (for pH adjustment)

Sodium Hydroxide (for pH adjustment)

Solutions of cytarabine have been reported to be incompatible with various drugs, i.e. carbenicillin sodium, cephalothin sodium, fluorouracil, gentamicin sulphate, heparin sodium, hydrocortisone sodium succinate, insulin-regular, methylprednisolone sodium succinate, nafacillin sodium, oxacillin sodium, penicillin G sodium. However, the incompatibility depends on several factors (e.g. concentrations of the drug, specific diluents used, resulting pH, temperature). Specialised references should be consulted for specific compatibility information.

Before use: 18 months

In use: Chemical and physical in-use stability has been demonstrated for 7 days at room temperature.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not store above 25°C.

Do not refrigerate or freeze.

Keep vial in the outer carton, in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Clear Type I glass vial with rubber stopper.

Clear Type I glass Onco-Tain^® vial with rubber stopper.

Clear Type I glass Onco-Vial^® with rubber stopper.

Pack sizes of 1, 5, 10 and 20 vials.

Not all presentations and pack sizes may be marketed.

Prior to use, vials of Cytarabine 100 mg/ml Injection must be warmed to 55°C, for 30 minutes, with adequate shaking, and allowed to cool to room temperature.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.