Cytarabine 100 mg / ml Solution for Injection or Infusion

1. Name Of The Medicinal Product

Cytarabine 100 mg/ml Solution for Injection or Infusion

2. Qualitative And Quantitative Composition

1 ml contains 100 mg Cytarabine.

Each 1 ml vial contains 100 mg of Cytarabine.

Each 5 ml vial contains 500 mg of Cytarabine.

Each 10 ml vial contains 1000 mg of Cytarabine.

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection or infusion. The product is a clear, colourless solution, which is practically free from particles.

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.

Cytarabine should not be administered by the intrathecal route.

Dosage recommendations may be converted from those in terms of bodyweight to those related to surface area by means of nomograms.

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.

Children:

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 leucopenia, thrombocytopenia, and anaemia, with appropriate initiation of supportive therapy when indicated.

4.3 Contraindications

Hypersensitivity to the Cytarabine or to any of the excipients of cytarabine injection.

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.

4.4 Special Warnings And Precautions For Use

Warnings:

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 defences, and haemorrhage secondary to thrombocytopenia). Anaphylactic reactions have occurred with cytarabine treatment. 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; 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.

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 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 five to seven 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 leukaemia. 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, adult respiratory distress syndrome and pulmonary oedema have occurred following high dose schedules with cytarabine therapy.

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.

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.

The human liver apparently detoxifies a substantial fraction of an administered dose. 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.

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

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.

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.

4.6 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. Men and women have to use effective contraception during and up to 6 months after treatment.

Lactation

This product should not normally be administered to patients who are pregnant or to mothers who are breastfeeding.

4.7 Effects On Ability To Drive And Use Machines

Cytarabine has no 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.

4.8 Undesirable Effects

The following adverse events have been reported in association with cytarabine therapy:

Frequencies are defined using the following convention: Very common (

Undesirable effects from cytarabine are dose-dependent. Most common are gastrointestinal undesirable effects. Cytarabine is toxic to the bone marrow, and causes haematological undesirable effects.

Cardiac disorders:

Uncommon: Pericarditis

Very rare: Arrhythmia.

Blood and lymphatic system disorders:

Common: Anaemia, megaloblastosis, leucopenia, thrombocytopenia.

Nervous system disorders:

Common: At high doses cerebellar or cerebral influence with deterioration of the level of consciousness, dysarthria, nystagmus.

Uncommon: headache.

Eye disorders:

Common: Reversible haemorrhagic conjunctivitis (photophobia, burning, visual disturbance, increased lacrimation), keratitis.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Pneumonia, dyspnea, sore throat.

Gastrointestinal disorders:

Common: Dysphagia, abdominal pain, nausea, vomiting, diarrhoea, oral / anal inflammation or ulceration.

Uncommon: Esophagitis, esophageal ulceration, pneumatosis cystoides intestinalis, necrotising colitis.

Renal and urinary disorders:

Uncommon: Renal impairment, urinary retention

Skin and subcutaneous tissue disorders:

Common: Reversible undesirable effects to the skin, such as erythema, bullous dermatitis, urticaria, vasculitis, alopecia.

Uncommon: Skin ulceration, pruritus, burning pain of palms and soles.

Very rare: Neutrophilic eccrine hidradenitis.

Musculoskeletal and connective tissue disorders:

Uncommon: Myalgia, arthralgia.

Metabolism and nutrition disorders:

Common: Anorexia, hyperuricaemia.

Infections and infestations:

Uncommon: Sepsis (immunosuppression), cellulitis at injection site.

Neoplasm benign, malignant and unspecified (Incl. cysts and polyps)

Uncommon: Lentigo.

General disorders and administration site conditions

Common: Fever, thrombophlebitis at the injection site.

Uncommon: Chest pain.

Immune system disorders

Uncommon: Anaphylaxis.

Hepatobiliary disorders

Common: Reversible effects on the liver with increased enzyme levels.

Uncommon: Jaundice.

Cytarabine (Ara-C) Syndrome:

Fever, myalgia, bone pain, occasional chest pain, exanthema, conjuctivitis and nausea may occur 6-12 h after start of therapy. Corticosteroids may be considered as prophylaxis and therapy. If they are effective, therapy with cytarabine may be continued.

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 i.v.- combined with another CNS toxic treatment such as radiation therapy or high dose.

Gastrointestinal disorders:

Especially in treatment with high doses of cytarabine, more severe reactions may appear in addition to common symptoms (see table). Intestinal perforation or necrosis with ileus and peritonitis have been reported.

Liver abscesses, hepatomegaly, Budd-Chiari-syndrome (hepatic venous thrombosis) and pancreatitis 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.

Others:

Following cytarabine therapy, cardiomyopathy and rhabdomyolysis have been reported. One case of anaphylaxis that resulted in cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine.

The gastro-intestinal undesirable effects are reduced if cytarabine is administered as infusion. Local glucocorticoides are recommended as prophylaxis of haemorrhagic conjunctivitis.

4.9 Overdose

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

Cytarabine may be removed by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Pyrimidine analogue

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 in demonstrable circulating drug as early as 5 minutes after injection.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Macrogol 400

Trometamol

Water for Injections

6.2 Incompatibilities

Incompatibilities with: Heparin, insulin, Methotrexate, 5-fluorouracil, nafcillin, oxacillin, penicillin G, methyl-prednisolone succinate.

This medicinal product must not be mixed with other medicinal products excepts those mentioned in section 6.6

6.3 Shelf Life

2 years

In use stability: Chemical and physical in-use stability has been demonstrated in sodium chloride injection (0.9 % w/v) and dextrose injection (5% w/v) for up to 24 hours at temperature below 25° C and for up to 72 hours at 2-8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use 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.

6.4 Special Precautions For Storage

Do not store above 25° C. Keep the vial in the outer carton in order to protect from light. Do not refrigerate.

6.5 Nature And Contents Of Container

For 1 ml, Solution for injection is filled in 2 ml Type - I clear glass vial closed with 13 mm grey rubber stopper and 13 mm aluminium flip-off transparent blue seal.

For 5 ml, Solution for injection is filled in 5 ml Type - I clear tubular glass vial closed with 20 mm grey rubber stopper and 20 mm aluminium flip-off transparent blue seal.

For 10 ml, Solution for injection is filled in 10 ml Type - I clear tubular glass vial closed with 20 mm grey rubber stopper and 20 mm aluminium flip-off transparent blue seal.

Pack sizes:

1 × 1 ml vial,

5× 1 ml vial

1 × 5 ml vial,

5× 5 ml vial

1 × 10 ml vial

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

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

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

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: 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

Accord Healthcare Limited Sage House, 319

Pinner Road, North Harrow, Middlesex, HA1

4HF, United Kingdom

8. Marketing Authorisation Number(S)

PL 20075/0121

9. Date Of First Authorisation/Renewal Of The Authorisation

15-Dec-2009

10. Date Of Revision Of The Text

01-Dec-2010