This information is intended for use by health professionals

1. Name of the medicinal product

Cytarabine 20mg/ml solution for infusion or injection

2. Qualitative and quantitative composition

1 ml of solution contains 20mg of cytarabine

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Solution for infusion or injection.

4. Clinical particulars
4.1 Therapeutic indications

Cytotoxic. For induction of remission in acute myeloid leukaemia in adults and for other acute leukaemias of adults and children.

4.2 Posology and method of administration

By intravenous infusion or injection, or subcutaneous injection.

Dosage recommendations may be converted from those in terms of bodyweight to those related to surface area by means of nomograms, as presented in Documenta Geigy.

1) Remission induction:

a) Continuous treatment:

i) Rapid injection - 2 mg/kg/day is a judicious starting dose. Administer for 10 days. Obtain daily blood counts. If no antileukaemic effect is noted and there is no apparent toxicity, increase to 4 mg/kg/day and maintain until therapeutic response or toxicity is evident. Almost all patients can be carried to toxicity with these doses.

ii) 0.5 - 1.0 mg/kg/day may be given in an infusion of up to 24 hours duration. Results from one-hour infusions have been satisfactory in the majority of patients. After 10 days this initial daily dose may be increased to 2 mg/kg/day subject to toxicity. Continue to toxicity or until remission occurs.

b) Intermittent treatment:

3 - 5 mg/kg/day are administered intravenously on each of five consecutive days. After a two to nine-day rest period, a further course is given. Continue until response or toxicity occurs.

The first evidence of marrow improvement has been reported to occur 7 - 64 days (mean 28 days) after the beginning of therapy.

In general, if a patient shows neither toxicity nor remission after a fair trial, the cautious administration of higher doses is warranted. As a rule, patients have been seen to tolerate higher doses when given by rapid intravenous injection as compared with slow infusion. This difference is due to the rapid metabolism of cytarabine and the consequent short duration of action of the high dose.

2) Maintenance therapy: Remissions which have been induced by cytarabine, or by other drugs, may be maintained by intravenous or subcutaneous injection of 1 mg/kg once or twice weekly.

Paediatric population: Children appear to tolerate higher doses than adults and, where dose ranges are quoted, the children should receive the higher dose and the adults the lower.

Elderly Patients: There is no information to suggest that a change in dosage is warranted in the elderly. Nevertheless, the elderly patient does not tolerate drug toxicity as well as the younger patient, and particular attention should thus be given to drug induced leukopenia, thrombocytopenia, and anaemia, with appropriate initiation of supportive therapy when indicated.

4.3 Contraindications

Therapy with cytarabine should not be considered in patients with pre-existing drug-induced bone marrow suppression, unless the clinician feels that such management offers the most hopeful alternative for the patient. Cytarabine should not be used in the management of non-malignant disease, except for immunosuppression.

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

4.4 Special warnings and precautions for use

General: Only physicians experienced in cancer chemotherapy should use cytarabine.

Warnings:

Haematologic Effects: Cytarabine is a potent bone marrow suppressant; the severity depends on the dose of the drug and the schedule of administration. 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.

The main toxic effect of cytarabine is bone marrow suppression with leukopenia, thrombocytopenia, anaemia, megaloblastosis and reduced reticulocytes. Less serious toxicity includes nausea, vomiting, diarrhoea and abdominal pain, oral ulceration, and hepatic dysfunction (see section 4.8).

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.

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). Anaphylactic reactions have occurred with cytarabine treatment. Anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of Cytarabine (see section 4.8).

High Dose Schedules: 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 high dose (2-3 g/m2) schedules with Cytarabine. These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; somnolence; convulsion; severe gastro-intestinal ulceration, including pneumatosis cystoides intestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema (see section 4.8).

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

Precautions: Patients receiving Cytarabine must be monitored closely. Frequent platelet and leucocyte counts are mandatory. Suspend or modify therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte count under 1,000 per cubic mm. 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. If 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.

Peripheral motor and sensory neuropathies after consolidation with high doses of cytarabine, daunorubicin, and asparaginase have occurred in adult patients with acute non lymphocytic leukemia. Patients treated with high doses of cytarabine should be observed for neuropathy since dose schedule alterations may be needed to avoid irreversible neurologic disorders.

Severe and sometimes fatal pulmonary toxicity, sudden respiratory distress syndrome and pulmonary oedema have occurred following experimental high dose schedules with cytarabine therapy.

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

When intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours afterwards. This problem tends to be less severe when the drug is 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 nonoperative medical management. Delayed progressive ascending paralysis resulting in death has been reported in children with AML following intrathecal and intravenous cytarabine at conventional doses in combination with other drugs.

Hepatic and/or Renal Function: The human liver apparently detoxifies a substantial fraction of an 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. Use the drug with caution and at reduced dose in patients whose liver function is poor.

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

Neurological: 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.

The safety of this drug for use in infants is not established.

Tumour Lysis Syndrome: Like other cytotoxic drugs, cytarabine may induce hyperuricaemia 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 pharmacological measures as may be necessary to control this problem.

Pancreatitis: Cases of pancreatitis have been observed with the induction of cytarabine.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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

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 utilisation 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. 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.

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).

4.6 Fertility, pregnancy and lactation

Pregnancy

Cytarabine is known to be teratogenic in some animal species. The use of cytarabine in women who are or who may become pregnant should be undertaken only after due consideration of the potential benefits and hazards.

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 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.

Breast-feeding

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.

This product should not normally be administered to patients who are pregnant or to mothers who are breast-feeding.

4.7 Effects on ability to drive and use machines

Cytarabine has no effect on intellectual function or psychomotor performance. 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.

4.8 Undesirable effects

Summary of the safety profile (see also section 4.4)

Most frequent adverse reactions include nausea, vomiting, diarrhoea, fever, rash, anorexia, oral and anal inflammation or ulceration, and hepatic dysfunction.

Blood and lymphatic system disorders:

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

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:

A Cytarabine syndrome has been described. It is characterised 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 serious enough to warrant treatment, corticosteroids should be contemplated as well as continuation of therapy with cytarabine.

The reported adverse reactions are listed below by MedDRA System Organ Class and by frequency. Frequencies are defined as: Very common (>10%), Common (>1%, ≤10%), Uncommon (>0.1%, ≤1%), Rare (>0.01%, ≤0.1%), and Frequency not known (cannot be estimated from available data).

Adverse Reactions Table

Infections and Infestations:

Very common

Sepsis, pneumonia, infectiona

Frequency not known

Injection site cellulitis, liver abscess

Blood and Lymphatic System Disorders:

Very common

Bone marrow failure, thrombocytopenia, anaemia, anaemia megaloblastic, leukopenia, reticulocyte count decreased

Immune System Disorders:

Frequency not known

Anaphylactic reaction, allergic oedema

Metabolism and Nutrition Disorders:

Frequency not known

Decreased appetite

Nervous System Disorders:

Frequency not known

Neurotoxicity, neuritis, dizziness, headache

Eye Disorders:

Frequency not known

Conjunctivitisb

Cardiac Disorders:

Frequency not known

Pericarditis, sinus bradycardia

Vascular Disorders:

Frequency not known

Thrombophlebitis

Respiratory, Thoracic and Mediastinal Disorders:

Frequency not known

Dyspnoea, oropharyngeal pain

Gastrointestinal Disorders:

Very common

Stomatitis, mouth ulceration, anal ulcer, anal inflammation, diarrhoea, vomiting, nausea, abdominal pain

Frequency not known

Pancreatitis, oesophageal ulcer, oesophagitis

Hepatobiliary Disorders:

Very common

Hepatic function abnormal

Frequency not known

Jaundice

Skin and Subcutaneous Tissue Disorders:

Very common

Alopecia, rash

Common

Skin ulcer

Frequency not known

Palmar-plantar erythrodysaesthesia syndrome, urticaria, pruritus, ephelides

Musculoskeletal, Connective Tissue and Bone Disorders:

Very common

Cytarabine syndrome

Renal and Urinary Disorders:

Frequency not known

Renal impairment, urinary retention

General Disorders and Administration Site Conditions:

Very common

Pyrexia

Frequency not known

Chest pain, injection site reactionc

Investigations:

Very common

Biopsy bone marrow abnormal, blood smear test abnormal

amay be mild, but can be severe and at times fatal

bmay occur with rash and may be hemorrhagic with high dose therapy

cpain and inflammation at subcutaneous injection site

Adverse reactions reported in association with high dose therapy (see section 4.4) are included in the following table:

Adverse Reactions Table (High Dose Therapy)

Infections and Infestations:

Frequency not known

Liver abscess, sepsis

Psychiatric Disorders:

Frequency not known

Personality changea

Nervous System Disorders:

Very common

Cerebral disorder, cerebellar disorder, somnolence

Frequency not known

Coma, convulsion, peripheral motor neuropathy, peripheral sensory neuropathy

Eye Disorders:

Very common

Corneal disorder

Cardiac Disorders:

Frequency not known

Cardiomyopathyb , sinus bradycardia

Respiratory, Thoracic and Mediastinal Disorders:

Very common

Acute respiratory distress syndrome, pulmonary oedema

Gastrointestinal Disorders:

Common

Necrotising colitis

Frequency not known

Gastrointestinal necrosis, gastrointestinal ulcer, pneumatosis intestinalis, peritonitis

Hepatobiliary Disorders:

Frequency not known

Liver injury, hyperbilirubinaemia

Skin and Subcutaneous Tissue Disorders:

Common

Skin exfoliation,

apersonality change was reported in association with cerebral and cerebellar dysfunction.

bwith subsequent death

Other adverse reactions

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 (1g/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 leukemia; fatal outcome has been reported.

Intrathecal use

Cytarabine is not recommended for intrathecal use; however, the following side-effects have been reported with such use. Expected systemic reactions: bone marrow depression, nausea, vomiting. Occasionally, severe spinal cord toxicity even leading to quadriplegia and paralysis, necrotising encephalopathy, with or without convulsion, blindness and other isolated neurotoxicities have been reported.

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

Cessation of therapy, followed by management of ensuing bone marrow depression including whole blood or platelet transfusion and antibiotics as required.

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pyrimidine analogues, ATC Code: L01BC01

Cytarabine, a pyrimidine nucleoside analogue, is an antineoplastic agent which inhibits the synthesis of deoxyribonucleic acid. It also has antiviral and immunosuppressant properties. Detailed studies on the mechanism of cytotoxicity in vitro suggests that the primary action of Cytarabine is inhibition of deoxycytidine synthesis, although inhibition of cytidylic kinases and incorporation of the compound into nucleic acids may also play a role in its cytostatic and cytocidal actions.

5.2 Pharmacokinetic properties

Cytarabine is deaminated to arabinofuranosyl uracil in the liver and kidneys. After intravenous administration to humans, only 5.8% of the administered doses is excreted unaltered in urine within 12-24 hours, 90% of the dose is excreted as the deaminated product. Cytarabine appears to be metabolised rapidly, primarily by the liver and perhaps by the kidney. After single high intravenous doses, blood levels fall to unmeasurable levels within 15 minutes in most patients. Some patients have indemonstrable circulating drug as early as 5 minutes after injection.

5.3 Preclinical safety data

Cytarabine is embryotoxic and teratogenic when administered to rodents during the period of organogenesis at clinically relevant doses. It is reported that cytarabine causes developmental toxicity, including damage to the developing brain, when administered during the peri- and postnatal period. No formal fertility studies have been reported however sperm head abnormalities were observed following cytarabine treatment in mice.

Cytarabine is mutagenic and clastogenic and produced malignant transformation of rodent cells in vitro.

6. Pharmaceutical particulars
6.1 List of excipients

Hydrochloric Acid

Sodium Hydroxide

Nitrogen

Water for injections

Sodium Chloride

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

18 months

6.4 Special precautions for storage

Store at 15°C - 25°C. Keep container in outer carton.

Cytarabine should not be stored at refrigerated temperatures (2-8°C).

6.5 Nature and contents of container

Polypropylene vials, closed with either a West S63/1704 Grey EPDM rubber stopper or a West 4110/40 Grey FluroTec® Plus-faced rubber stopper, and sealed with an aluminium crimp with a plastic flip-off top.

Cytarabine is supplied as vials containing 20mg/ml cytarabine in 5 ml (100mg) in packs of 5, or 25ml (500mg) as single vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Once opened, the contents of each vial must be used immediately and not stored. Discard any unused portion.

Water for injections, 0.9% saline or 5% dextrose are commonly used infusion fluids for Cytarabine. Compatibility must be assured before mixing with any other substance.

Infusion fluids containing Cytarabine should be used immediately.

Disposal and Spills: To destroy, place in a high risk (for cytotoxics) waste disposal bag and incinerate at 1100°C. If spills occur, restrict access to the affected area and adequate protection including gloves and safety spectacles should be worn. Limit the spread and clean the area with absorbent paper/material. Spills may also be treated with 5% sodium hypochlorite. The spill area should be cleaned with copious amounts of water. Place the contaminated material in a leak proof disposal bag for cytotoxics and incinerate at 1100°C.

7. Marketing authorisation holder

Pfizer Limited

Ramsgate Road

Sandwich, Kent

CT13 9NJ

UK

8. Marketing authorisation number(s)

Cytarabine 20mg/ml PL 00057/0954

9. Date of first authorisation/renewal of the authorisation

03 June 1999

10. Date of revision of the text

11/2017

Ref: CC 12_0