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INFORMATION FOR MEDICAL STAFF

Cytarabine

20mg/ml and lOOmg/ml Solution for infusion or injection

1.    TRADE NAME OF THE MEDICINAL PRODUCT

Cytarabine 20mg/ml Cytarabine 100mg/ml

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 20mg of cytarabine.

1 ml of solution contains 10Omg of cytarabine.

For a 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 conseguent 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 Contra-indications

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. Cytarabine is contraindicated in those patients who are hypersensitive to Cytarabine or to any of the excipients listed in section 6.1.

4.4 Special warnings and special precautions for use

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

Warnings: Cytarabine is a potent bone marrow suppressant; the severity depends on the dose of the drug and 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 freguently after blasts have disappeared from the peripheral blood.

The main toxic effect of cytarabine is bone marrow suppression with leukopenia, thrombocytopenia and anemia. Less serious toxicity includes nausea, vomiting, diarrhoea and abdominal pain, oral ulceration, and hepatic dysfunction.

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 reguired resuscitation has been reported. This occurred immediately after the intravenous administration of Cytarabine (see section 4.8). Severe and at times fatal CNS, Gl 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 gastrointestinal 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. Freguent 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 subseguent 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 guickly, patients are freguently 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 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.

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/lncreased 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 Medicaments and Other Forms of Interaction

5-Lluorocytosine should not be administered with Cytarabine as the therapeutic efficacy of 5-Lluorocytosine 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 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 fetus and the advisability of preganancy 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.

Nursing Mothers

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 breastfeeding.

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

Most freguent 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, leucopenia, 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: Pneumonia, sepsis, cellulitis at injection site, liver abscess

-    Immune system disorders: Anaphylaxis, allergic oedema

-    Metabolism and nutrition disorders: Anorexia

-    Nervous system disorders: Neural toxicity, neuritis, dizziness, headache

-    Eye disorders: Conjunctivitis (may occur with rash)

-    Cardiac disorders: Pericarditis

-    Vascular disorders: Thrombophlebitis

-    Respiratory, thoracic and mediastinal disorders: Shortness of breath, sore throat

-    Gastrointestinal disorders: Pancreatitis, esophageal ulceration, abdominal pain, diarrhoea, esophagitis, nausea/vomiting, oral and anal inflammation or ulceration

-    Hepatobiliary disorders: Hepatic dysfunction, jaundice

-    Skin and subcutaneous tissue disorders: Skin ulceration, alopecia, freckling, rash, pruritus, urticaria

-    Renal and urinary disorders: Renal dysfunction, urinary retention

-    General disorders and administration site conditions: Chest pain, fever, injection site reaction (pain and inflammation at subcutaneous injection sites)

High Dose Therapy (see section 44)

-    Infections and infestations: Sepsis, liver abscess

-    Nervous system disorders: Coma, cerebral and cerebellar dysfunction including personality changes, somnolence, and convulsion; peripheral motor and sensory neuropathies.

-    Eye disorders: Corneal toxicity, conjunctivitis

-    Cardiac disorders: Cardiomyopathy with subseguent death

-    Respiratory, thoracic and mediastinal disorders: Adult respiratory distress syndrome, pulmonary oedema

-    Gastrointestinal disorders: Gastrointestinal necrosis, necrotizing colitis, gastrointestinal ulceration (including pneumatosis cystoides intestinalis leading to peritonitis)

-    Hepatobiliary disorders: Liver damage with increased hyperbilirubinemia

-    Skin and subcutaneous tissue disorders: Skin rash leading to desguamation, alopecia

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PATIENT INFORMATION LEAFLET

Read all of this leaflet carefully before you start taking this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, ask your doctor or pharmacist.

•    This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

•    If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1.    What Cytarabine is and what it is used for

2.    Before you are given Cytarabine

3.    How Cytarabine is given to you

4.    Possible side effects

5.    How to store Cytarabine

6.    Further information

1. What Cytarabine is and what it is used for

•    Cytarabine is used in adults and children. The active ingredient is cytarabine.

•    Cytarabine is one of a group of the medicines known as cytotoxics, these medicines are used in the treatment of acute leukaemias (cancer of blood where you have too many white blood cells). Cytarabine interferes with the growth

of cancer cells, which are eventually destroyed.

•    Cytarabine is also used for the induction and maintenance of remission of leukaemia.

•    Remission induction is an intensive treatment to force leukaemia into retreat. When it works, the balance of cells in your blood becomes more normal and your health improves. This relatively healthy spell is called a remission.

•    Maintenance therapy is a milder treatment to make your remission last as long as possible. Quite low doses of Cytarabine are used to keep the leukaemia under control and stop it flaring up again.

You should consult your doctor if you are

unsure why you have been given Cytarabine.

2. Before you are given Cytarabine

Do not use Cytarabine if you:

•    are allergic (hypersensitive) to cytarabine, or any of the other ingredients of Cytarabine 20mg/ml and 10Omg/ml Solution for Injection.

•    are already taking medicines that have caused you to have a low blood count caused by suppression of your bone marrow.

Take special care with Cytarabine:

•    Tell your doctor if your liver is not working properly. This will help your doctor decide if Cytarabine is suitable for you.

•    If you have had or are due to have any vaccination including a live or live-attenuated vaccination.

Taking other medicines

Tell your doctor or pharmacist if you are:

•    given medicines containing 5-Fluorocytosine (a medicine used to treat fungal infections).

•    taking medicines containing digitoxin or beta-acetyldigoxin which are used to treat certain heart conditions.

•    taking Gentamicin (an antibiotic used to treat bacterial infections).

•    given medicines containing cyclophosphamide, vincristine and prednisone which are used in cancer treatment programmes.

•    taking or have recently taken any other medicines, even those not prescribed.

Pregnancy

Avoid becoming pregnant while you or your partner is being treated with Cytarabine. If you are sexually active, you are advised to use effective birth control to prevent pregnancy during treatment, whether you are male or female. Cytarabine may cause birth defects, so it is important to tell your doctor if you think you are pregnant.

Breast-feeding

You should stop breast-feeding before starting treatment with Cytarabine because this medicine may be harmful to infants being breast-fed.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machinery

If feeling unwell following treatment with Cytarabine you should avoid driving or using machinery.

Ask your doctor or pharmacist for advice before taking any medicine.

3. How Cytarabine is given to you

Cytarabine will be given to you by infusion into a vein (through a ‘drip’) or by injection under the direction of specialists in hospital. Your doctor will decide what dose to give and the number of days’ treatment you will receive depending on your condition.

The dose of Cytarabine will be decided by your doctor based on your condition being treated for, whether you are in induction or maintenance therapy and your body surface area. Your body weight and height will be used to calculate your body surface area.

Regular Check-ups

During treatment you will need regular checks including blood tests. Your doctor will tell you how often this should be done. He/she will be making regular checks of:

•    Your blood - to check for low blood cell counts that may need treatment.

•    Your liver - again using blood tests - to check that Cytarabine is not affecting the way it functions in a harmful way.

•    Your kidneys - again using blood tests - to check that Cytarabine is not affecting the way it functions in a harmful way.

•    Blood uric acid levels - Cytarabine may increase uric acid levels in the blood. Another medicine may be given if your uric acid levels are too high.

If you receive high doses of Cytarabine:

High doses can worsen side effects like sores in the mouth or may decrease the number of white blood cells and platelets (these help the blood to clot) in the blood. Should this happen, you may need antibiotics or blood transfusions. Mouth ulcers can be treated to make them less uncomfortable as they heal.

4. Possible side effects

Like all cytotoxic medicines, Cytarabine causes side effects, although these can vary from patient to patient.

Tell your doctor or nursing staff who will be monitoring you during this time immediately, if you suffer from the following symptoms after taking this medicine:

•    An allergic reaction such as sudden wheeziness, difficulty in breathing, swelling of eyelids, face or lips, rash or itching (especially affecting the whole body).

•    You are feeling tired and lethargic.

•    You have flu like symptoms e.g. raised temperature or fever and chills.

•    You bruise more easily or bleed more than usual if you hurt yourself. These are the symptoms of low numbers of blood cells. Tell your doctor or nursing staff immediately if you experience these symptoms.

Other side effects that may occur are:

If any of these side effects gets serious

please tell your doctor or nursing staff

immediately.

•    Reactions at Injection site:

inflammation to your veins (caused by a blood clot).

•    Effects on your nervous system:

Headaches or feeling dizzy, feeling of pins and needles, shaking and fits, drowsiness, experience problems in walking, speech problems, involuntary muscular movement, changes in your personality, tiredness, weakness, fainting.

•    Effects on your skin and hair:

Hair loss is common and may be quite severe. Hair normally re-grows when your treatment course ends. A rash or ulceration on your skin, peeling of the skin, itching or increased freckles. You may get an infection, including infection or inflammation at the site of your injection.

•    Effects on your stomach, intestines: Feeling sick, being sick, diarrhoea, loss of appetite, abdominal pain.

•    Effects on your mouth, gullet and anus: Inflammation of the gullet, causing heartburn may make you feel sick, and the appearance of sores in the mouth, lips, or on the anus (back passage).

•    Effects on your pancreas: Pancreatitis (pain in the upper abdomen) often accompanied by feeling sick or vomiting. Tell your doctor if this happens to you.

•    Effects on your liver: Liver damage (seen as yellowing of the skin and whites of the eye).

•    Effects on your kidneys, bladder and urine: Difficulty or pain when passing urine. Blood in your urine and impaired kidney function.

•    Effects on your hands, face and body:

Feeling hot and feverish, conjunctivitis, and pain and numbness in joints, fingers, toes or face, swelling of the abdomen, legs, ankles and feet.

•    Effects on respiratory system and chest: Shortness of breath, pneumonia, short or stabbing chest pain, build up of fluid in the lungs, sore throat.

•    Effects on your muscles and bone: muscle pain, bone pain.

•    Effects on your heart and circulation: fast heart beat, pericarditis (inflammation of the covering of the heart).

•    Effects on your eyes and vision: eye infection, irritation, pain and blurred vision, visual loss.

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