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Document: leaflet MAH GENERIC_PL 00057-0954 change

• leaflet MAH GENERIC_PL 00032-0197
• leaflet MAH GENERIC_PL 00057-0954
• leaflet MAH GENERIC_PL 04569-1536
• leaflet MAH GENERIC_PL 04569-1538

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Cytarabine

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

The following information is intended for medical or healthcare professionals

1.    NAME OF THE MEDICINAL PRODUCT

Cytarabine 20mg/ml solution for infusion or injection Cytarabine 100mg/ml solution for infusion or injection

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 20mg of cytarabine.

1 ml of solution contains 10Omg 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 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.

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 freguently 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 reguired 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,

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 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. 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.

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 strokelike 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/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 medicinal

products 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 Kpneumoniae 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 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, 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 freguency. Frequencies are defined as: Very common (>10%), Common (>1%, <10%), Uncommon (>0.1%, <1 %),

Rare (>0.01%, <0.1%), and Freguency not known (cannot be estimated from available data).

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Read all of this leaflet carefully before

you start taking this medicine because

it contains important information for

you.

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

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

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

•    If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Cytarabine is and what it is used for

2.    What you need to know before you are given Cytarabine

3.    How Cytarabine is given to you

4.    Possible side effects

5.    How to store Cytarabine

6.    Contents of the pack and other information

1. What Cytarabine is and what it is used for

•    Cytarabine is used in adults and children.

•    This medicine contains cytarabine, which 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, if

you do not feel better or if you feel worse.

2. What you need to know before you are given Cytarabine

Do not use Cytarabine:

•    If you are allergic (hypersensitive) to cytarabine, or any of the other ingredients of this medicine (listed in section 6).

•    If you are already taking medicines that have caused you to have a low blood count caused by suppression of your bone marrow. Your doctor might not give this medicine if you have a non-malignant disease, except for immunosuppression.

Warnings and precautions

Tell your doctor if:

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

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

•    you are given Cytarabine in combination with methotrexate administered through your spine, because cases of headache, paralysis, coma and stroke-like symptoms have been reported in children and young adults given intravenous Cytarabine in combination with intrathecal methotrexate.

Other medicines and Cytarabine

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, have recently taken or might take any other medicines, even those not prescribed.

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before you are given this medicine because Cytarabine may cause birth defects. 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.

Breast-feeding

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

Driving and using machines

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

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

•    your kidneys - 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.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all cytotoxic medicines, this medicine causes side effects, although not everybody gets them.

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.

Very common: may affect more than 1 in 10 people

•    Pneumonia, infection (which can become serious and lead to organ failure),

•    Insufficient production or decrease in numbers of red blood cells, white blood cells or platelets.

•    Inflammation or appearance of sores in the mouth, lips, or on the anus (back passage), feeling sick, being sick, diarrhoea, abdominal pain

•    Liver damage

•    Hair loss is common and may be quite severe. Hair normally re-grows when your treatment course ends. Skin rash

•    Cytarabine syndrome, sometimes the following side effects can happen together 6 to12 hours after receiving Cytarabine. Feeling generally unwell with a high temperature, pain in bone, muscle and sometimes the chest, blistery rash, sore eyes. This is called “Cytarabine Syndrome” and can be treated.

•    Feeling hot and feverish

•    Abnormal bone marrow results from a biopsy, or blood results from a smear test

Common: may affect up to 1 in 10 people

•    Ulceration on your skin

Not known: frequency cannot be estimated from the available data

•    You may get an infection, including infection or inflammation at the site of your injection

•    Loss of appetite

•    Headaches or feeling dizzy, feeling of pins and needles, shaking and fits, drowsiness

•    Conjunctivitis

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