CYTARABINE - GENERIC DRUG - PACKAGE LEAFLET - LEAFLETS

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Cytarabine - Generic drug - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Cytarabine

Cytarabine Accord 100 mg / ml solution for injection or infusion

Why is Cytarabine used - Generic drug? What is it for?

Injectable Cytarabine is used in adults and children. The active ingredient is cytarabine.
Cytarabine belongs to a group of medicines known to be cytotoxic; these medicines are used to treat acute leukemia (cancer of the blood, where too many white blood cells are present in the blood). Cytarabine interferes with the growth of cancer cells, which are eventually destroyed.
Induction of remission is an intensive treatment to put leukemia into remission. When it works, the balance of cells in the blood becomes more normal, which improves your health. This period of relatively healthy health is called "remission".
Maintenance therapy is a lighter treatment to make remission last as long as possible. Rather low doses of cytarabine are used to keep leukemia under control and avoid relapse.

Contraindications When Cytarabine should not be used - Generic drug

You must not receive Injectable Cytarabine

If you are allergic (hypersensitive) to citara bine or any of the ingredients of Cytarabine Injectable.
If your blood cell count is very low due to other causes than cancer or a doctor's decision.
If you feel increased difficulty in coordinating your body after radiation treatment with other anti-cancer drugs such as methotrexate.

Precautions for use What you need to know before taking Cytarabine - Generic drug

Talk to your doctor, pharmacist or nurse before taking Cytarabine Injectable.

Take special care with the administration of Injectable Cytarabine:

If your bone marrow is in poor condition, therapy should be started under close medical supervision.
If you have liver problems.
Cytarabine markedly reduces the production of blood cells in the bone marrow. This reduction may increase the chance that you are prone to infection or bleeding. Your blood cell count may continue to drop for up to a week after stopping treatment. Your doctor will have regular blood tests and examine your bone marrow if necessary.
Serious and sometimes life-threatening side effects can occur in the central nervous system, intestines or lungs
Your liver and kidney functions will need to be monitored during cytarabine therapy. If your liver is not functioning well before treatment, you will only be given cytarabine with the utmost care.
Levels of uric acid (which demonstrate the destruction of cancer cells) in the blood (hyperuricaemia) may be high during treatment. Your doctor will tell you if you need to take any medicines to control this effect.
Administration of live or attenuated vaccines is not recommended during treatment with cytarabine. If required, consult your doctor. The use of killed or inactivated vaccines may not have the desired effect due to suppression of the immune system while on cytarabine treatment.
Do not forget to tell your doctor if you have had radiotherapy.

Interactions Which drugs or foods can modify the effect of Cytarabine - Generic drug

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Medicines given containing 5-fluorocytosine (a medicine used to treat infections caused by fungi).
Taking medicines containing digitoxin or beta-acetyl digoxin, which are used to treat certain heart disorders.
Taking gentamicin (an antibiotic used to treat bacterial infections).
Medicines given containing cyclophosphamide, vincristine and prednisone which are used in cancer treatment programs.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

Pregnancy

Avoid becoming pregnant while you or your partner are receiving cytarabine treatment. If you are sexually active, whether male or female, you are advised to use effective contraception to prevent pregnancy during treatment. Cytarabine can cause birth defects, so it is important that you tell your doctor if you think you are pregnant. Men and women should use effective contraceptive methods during treatment and for up to 6 months after treatment.

Feeding time

You must stop breastfeeding before starting cytarabine treatment because this medicine may be harmful to breastfed babies.

Fertility

Cytarabine can lead to interruption of the menstrual cycle in women and lead to amenorrhea and can suppress sperm production in male patients. Males being treated with cytarabine must use reliable contraception.

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

Driving and using machines

Citara bine does not affect the ability to drive or use machines. However, cancer treatment can usually affect some patients' ability to drive or operate machinery. If you are affected, you should not drive or use machines.

Dosage and method of use How to use Cytarabine - Generic drug: Posology

Method and routes of administration

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

The recommended dose is

Based on your condition, your doctor will decide the dose of cytarabine, whether you will receive induction or maintenance therapy and the surface area of your body. Your body weight and height will be used to calculate your surface area. corporeal.

You will need to have regular checkups, including blood tests, during your treatment. Your doctor will tell you how often these checks will be done. The doctor will carry out regular checks:

Blood, to check for low numbers of blood cells that may need treatment. • The liver, again using blood tests, to check that cytarabin does not adversely affect the functioning of the liver.
Of the kidneys, again using blood tests, to check that cytarabine does not adversely affect the functioning of the kidneys.
Blood uric acid levels. Cytarabine can increase blood uric acid levels. Another medicine can be given if uric acid levels are too high.
If you are on dialysis your doctor may vary the time you take the medicine because dialysis can decrease the effectiveness of the medicine.

Overdose What to do if you have taken an overdose of Cytarabine - Generic drug

High doses can worsen side effects, such as mouth ulcers, or can decrease the number of white blood cells and platelets (these help blood to clot) in the blood. In this case, he will likely need antibiotics or blood transfusions. Oral ulcers can be treated to make them less bothersome as they heal.

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

Side Effects What are the side effects of Cytarabine - Generic drug

Like all medicines, Cytarabine Injectable can cause side effects, although not everybody gets them.

The undesirable effects of cytarabine are dose dependent. The digestive system is the most commonly affected, but blood is also affected.

Tell your doctor or nurse immediately who will monitor you during this time if you suffer from the following symptoms after taking this medicine:

An allergic reaction, such as "sudden shortness of breath, difficulty breathing, swelling of the eyelids, face or lips, rash or itching (particularly affecting the whole body).
Severe allergic reaction (anaphylaxis): rash including itchy red skin, swelling of the hands, feet, ankles, face, lips or throat (which can cause difficulty in swallowing or breathing), bronchospasm and feeling faint (a spontaneous loss of consciousness caused by insufficient blood supply to the brain). It can be fatal (uncommon).
Clinical signs of pulmonary edema / ARDS may develop, particularly in high dose therapy: acute, distressing breathing difficulties and water in the lungs (pulmonary edema) have been observed, especially at high doses (common).
He feels tired and sleepy.
Has flu-like symptoms, eg. increase in temperature or fever or chills.
Severe chest pain.
Severe pain in the abdomen.
Loss of vision, loss of sense of touch, mental disorder or loss of the ability to move normally (this medicine can cause side effects in the brain and eyes, which are usually reversible but can be very serious).
Her skin bruises more easily or bleeds more than normal if it hurts.

These are the symptoms of low blood cell numbers. Tell your doctor or nurse immediately if you have these symptoms. These are serious side effects. He probably needs urgent medical attention.

Common (affects 1 to 10 users in 100):

Fever
Insufficient number of white and red blood cells or platelets in the blood, which can increase the chance that you are prone to infection or bleeding
- a drop in white blood cells may be accompanied by chills and fever that immediately require medical evaluation;
- a drop in platelets may be accompanied by bleeding which requires immediate medical evaluation
Abnormal blood cells (megaloblastosis)
Loss of appetite
Difficulty swallowing
Belly pain (abdominal pain)
Nausea (feeling nauseous)
He retched
Diarrhea
Inflammation or ulceration of the mouth or anus
Reversible effects on the skin, such as redness (erythema), blistering, rash, hives, inflammation of the blood vessels (vasculitis), hair loss
Reversible effects on the liver, such as an increase in enzyme levels
Reversible effects on the eyes, such as sore eyes with bleeding (haemorrhagic conjunctivitis) with impaired vision, sensitivity to light (photophobia), watery or burning eyes and inflammation of the cornea (keratitis)
Reduced state of consciousness (at high doses)
Difficulty speaking (in high doses)
Abnormal eye movements (high dose nystagmus)
Inflammation of the vein at the injection site
Abnormally high blood uric acid levels (hyperuricaemia)

Uncommon (affects 1 to 10 users in 1,000):

Sore throat
Headache
Severe allergic reactions (anaphylaxis), which cause, for example, difficulty in breathing or dizziness
Blood poisoning (sepsis)
Inflammation and ulcers of the esophagus
Severe intestinal inflammation (necrotizing colitis)
Intestinal cysts
Skin ulceration
Itching • Inflammation at the injection site • Brown / black patches on the skin (lentigo) • Yellowish skin and eyeballs (jaundice) • Pulmonary infection (pneumonia) • Breathing difficulties • Paralysis of the legs and lower body may occur when citara bine is given into the space surrounding the spinal cord • Muscle and joint pain • Inflammation of the lining surrounding the heart (pericarditis) • Impaired kidney function • Inability to urinate (urinary retention) • Chest pain • Burning pain in the palms of the hands and soles of the feet

Very rare (affects less than 1 user in 10,000):

Salivary gland inflammation • Irregular heartbeat (arrhythmias)

Not known (frequency cannot be estimated from the available data):

Damage to nerve tissue (neural toxicity) and inflammation of one or more nerves (neuritis) • Inflammation of the pancreas (pancreatitis) • Sore eyes (conjunctivitis)

Other side effects:

Cytarabine syndrome can occur 6-12 hours after starting treatment. Symptoms include:

Fever
Bone and muscle pain
Occasional chest pain
Rash
Sore eyes (conjunctivitis)
Nausea (feeling nauseous)

Your doctor may prescribe corticosteroids (anti-inflammatory medicines) to prevent or treat these symptoms. If they are effective, treatment with citara bine can be continued.

Reactions observed with higher dose therapy

Central nervous system:

The following symptoms, which are usually reversible, may develop in up to one third of patients after treatment with high doses of cytarabine:

Personality changes
Impaired lucidity
Difficulty speaking
Problems with coordination
Tremor
Abnormal eye movements (nystagmus)
Headache
Peripheral motor and sensory neuropathies (damage to the nerves of the peripheral nervous system)
Confusion
Drowsiness
Dizziness
Coma
Convulsions

These side effects can occur more often:

in elderly patients (> 55 years of age)
in patients with impaired liver and kidney functions
after previous treatment for brain and spinal cord cancer, such as radiation therapy or injection of cytostatics
with alcohol abuse

The risk of nerve damage increases if cytarabine treatment:

it is given in high doses or at short intervals
it is combined with other treatments that are toxic to the nervous system (such as radiation therapy or methotrexate)

Digestive system:

Particularly in the treatment with high doses of cytarabine, more severe reactions may arise in addition to the common symptoms. Perforation, tissue death (necrosis) and obstruction of the intestine and inflammation of the inner lining of the abdomen have been reported. Abscesses in the liver, liver enlargement, blockage of liver veins and inflammation of the pancreas have been observed after high dose therapy.

The undesirable effects on the digestive system are minor if citara bine is administered by infusion.

Lungs:

Acute distressing breathing difficulties and water in the lungs (pulmonary edema) have been observed, particularly at high doses.

Others:

Heart muscle disease (cardiomyopathy)
Abnormal breakdown of muscle cells (rhabdomyolysis)
Blood infection (sepsis)
Corneal toxicity
Viral, bacterial infections, etc.
Loss of semen and menstruation

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

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system: www.agenziafarmaco.it By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep out of the sight and reach of children.

Do not store above 25 ° C.

Do not refrigerate or freeze.

Do not use Cytarabine Injectable after the expiry date which is stated on the vial or carton (mm / yy).

The expiry date refers to the last day of that month.

Stability in use:

Chemical-physical stability in use has been demonstrated in sodium chloride solution for injection (0.9% w / v) and dextrose solution for injection (5% w / v) for up to 24 hours at a temperature below 25 °. C and up to 72 hours at a temperature of 2 to 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 been performed under controlled and validated aseptic conditions.

Do not use Cytarabine Injectable if you notice that the solution is not clear, colorless and free from particles.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other information

What Cytarabine Injectable contains

Injectable Cytarabine contains the active substance cytarabine.

1 ml contains 100 mg of cytarabine.

Each 1 ml vial contains 100 mg of cytarabine.
Each 5 ml vial contains 500 mg of cytarabine.
Each 10 ml vial contains 1 g of cytarabine.
Each 20 ml vial contains 2 g of cytarabine.
Each 40 ml vial contains 4 g of cytarabine.
Each 50 ml vial contains 5 g of cytarabine.

The other ingredients are macrogol 400, trometamol and water for injections.

What Cytarabine Injectable looks like and contents of the pack

Cytarabine Injectable is a clear and colorless solution for injection or infusion.

1 ml

The solution for injection is contained in a 2 ml Type I clear glass vial closed with a 13 mm gray rubber stopper and a 13 mm clear blue or azure blue aluminum flip-off seal.

5 ml

The solution for injection is contained in a 5 ml clear Type I tubular glass vial closed with a 20 mm gray rubber stopper and a 20 mm transparent blue or blue-azure aluminum flip-off seal.

10 ml

The solution for injection is contained in a 10 ml Type I clear tubular glass vial closed with a 20 mm gray rubber stopper and a 20 mm clear blue or blue-azure aluminum flip-off seal.

20 ml

The solution for injection is contained in a 20 ml Type I clear glass vial closed with a 20 mm gray rubber stopper and a 20 mm blue-blue aluminum flip-off seal.

40 ml

The solution for injection is contained in a 50 ml type I clear glass vial closed with a 20 mm gray rubber stopper and a 20 mm blue-blue aluminum flip-off seal.

50 ml

The solution for injection is contained in a 50 ml type I clear glass vial closed with a 20 mm gray rubber stopper and a 20 mm violet aluminum flip-off seal.

Packaging:

1 vial of 1 ml, 5 vials of 1 ml
1 vial of 5 ml, 5 vials of 5 ml
1 vial of 10 ml. 1 vial of 20 ml
1 vial of 40 ml
1 vial of 50 ml

Not all pack sizes may be marketed.

The following information is intended for medical or healthcare professionals only

Posology and method of administration

By intravenous infusion or injection, or subcutaneous injection.

Cytarabine 100 mg / ml should not be administered intrathecally.

Dosage recommendations can be converted from those in terms of body weight (mg / kg) to those relating to body surface area (mg / m2) by means of nomograms.

Induction of remission:

a) Continuous treatment:

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

ii) 0.5-1.0 mg / kg / day can be administered as an "infusion lasting up to 24 hours. The results of one" hour infusions have been satisfactory in most patients. After 10 days, this initial daily dose can be increased to 2 mg / kg / day depending on toxicity. Continue until toxicity or until remission occurs.

b) Intermittent treatment:

i) 3-5 mg / kg / day are administered intravenously on each of five consecutive days. After a 2-9 day rest period, an additional course is given. Continue until response or toxicity appears.

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

In general, if a patient experiences neither toxicity nor remission after an adequate trial period, cautious administration of higher doses is warranted. Normally, patients have been shown to tolerate higher doses when administered by rapid intravenous injection rather than slow infusion. This difference is due to the rapid metabolism of cytarabine and the resulting short duration of action of the high dose.

ii) Cytarabine 100-200 mg / m2 / 24 hours has been used as a continuous infusion for 5-7 days alone or in combination with other cytostatic agents including, for example, an "anthracycline. Additional courses can be administered at 2 intervals. -4 weeks, until remission or intolerable toxicity is achieved.

Maintenance therapy:

i) Remissions, which have been induced by cytarabine or other medicinal products, can be maintained by intravenous or subcutaneous injection of 1 mg / kg once or twice weekly.

ii) Cytarabine was also administered in doses of 100-200 mg / m2, as a continuous infusion for 5 days at monthly intervals as monotherapy or in combination with other cytostatics.

At high doses cytarabine is administered 2-3 g / m2 under close medical supervision, as monotherapy or in combination with other cytostatics, as an intravenous infusion, for 1-3 hours every 12 hours for 2-6 days (total of 12 doses per cycle. ). A total treatment dose of 36 g / m2 should not be exceeded.

Pediatric patients:

Safety in infants has not been established.

Patients with hepatic and renal impairment:

Patients with impaired hepatic or renal function: the dosage should be reduced.

Elderly patients:

No information is available to suggest that a change in posology is warranted in the elderly. Nevertheless, like the younger patient, the elderly patient does not tolerate drug toxicity. High dose therapy in patients over 60 years of age should only be given after a "careful risk-benefit assessment."

Incompatibility

Incompatibility with: carbenicillin sodium, cephalothin sodium, gentamicin sulfate, sodium heparin, hydrocortisone sodium succinate, regular insulin, methotrexate, 5-fluorouracil, nafcillin sodium, oxacillin sodium, penicillin sodium succinate (benzylpenicillin), sodium methyl-prednisolone and prednisolone.

Instructions for use / handling

For single use only.

If the solution appears discolored or contains visible particles, it should be discarded.

Once opened, the contents of each vial should be used immediately. Discard the unused product.

Commonly used infusion fluids for cytarabine (see section 6.3) are water for injections, 0.9% w / v saline or 5% w / v dextrose. Injectable cytarabine must not be mixed with other medicinal products except those mentioned in section 6.6.

Guidelines on the handling of cytotoxics

Administration:

It should be administered by, or under the direct supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.

Preparation:

Chemotherapeutic agents should be prepared for administration only by professionals trained in the safe use of the preparation.
Operations such as dilution and transfer to the syringe should only be performed in the appropriate area.
Personnel performing these procedures must be adequately protected with gowns, gloves and goggles.
Pregnant staff are advised not to manipulate chemotherapy drugs.

Disposal and contamination:

Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.

To destroy, place in a high risk (for cytotoxic) waste disposal bag / container and incinerate at 1100oC.

In the event of dispersion, restrict access to the affected area and wear appropriate protective equipment, including gloves and safety glasses. Limit spread and clean area with paper / absorbent material.

The dispersions can also be treated with 5% sodium hypochlorite. The area of the dispersion must be cleaned with copious amounts of water. Place contaminated material in an airtight bag / container for cytotoxic disposal and incinerate at 1100 ° C.

Period of validity

2 years

Stability in use:

Physico-chemical stability in use has been demonstrated in sodium chloride (0.9% w / v) and dextrose (5% w / v) solution for injection for 24 hours below 25 ° C and for up to 72 hours. at a temperature from 2 to 8 ° C. From a microbiological point of view, the medicinal 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 exceed 24 hours at 2 to 8 ° C, unless dilution has taken place in conditions aseptic controlled and validated.

storage

Do not store above 25 ° C.

Do not refrigerate or freeze.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information on Cytarabine - Generic drug can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

CITARABIAN ACCORD 100 MG / ML SOLUTION FOR INJECTION OR FOR INFUSION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml contains 100 mg of cytarabine.

Each 1 ml vial contains 100 mg of cytarabine.

Each 5 ml vial contains 500 mg of cytarabine.

Each 10 ml vial contains 1 g of cytarabine.

Each 20 ml vial contains 2 g of cytarabine.

Each 40 ml vial contains 4 g of cytarabine

Each 50 ml vial contains 5 g of cytarabine

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Solution for injection or infusion.

The product is a clear, colorless solution practically free of particles.

pH: 7.0-9.5

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

To induce remission in acute myeloid leukemia in adults and for other forms of acute leukemia in adults and children.

04.2 Posology and method of administration

Dosage

Treatment with cytarabine should be initiated by, or should be in consultation with, a physician with special experience in cytostatics treatment. Only general recommendations can be given as acute leukemia is almost exclusively treated with combinations of cytostatics.

Dosage recommendations can be made according to body weight (mg / kg) or according to body surface area (BSA, mg / m2).

Dosage recommendations can be converted from those in terms of body weight to those relating to the body surface area by means of nomograms.

1. Induction of remission:

The induction dosage of therapy and the treatment schedule vary depending on the regimen used.

a) Continuous treatment:

The following dosage regimens have been used for continuous treatment in inducing remission.

i) Rapid injection - a starting dose of 2 mg / kg / day is adequate. Administer for 10 days. Perform blood counts daily. If no antileukaemic effect is observed and no toxicity is evident, increase the dose to 4 mg / kg / day and maintain until therapeutic response or toxicity is evident. For almost all patients these doses can be toxic.

ii) 0.5-1.0 mg / kg / day can be administered as an infusion lasting up to 24 hours. The results of the one-hour infusions have been satisfactory for most patients. After 10 days, this starting daily dose can be increased to 2 mg / kg / day depending on toxicity. Continue until toxicity or until remission occurs.

b) Intermittent treatment:

The following dose regimens have been used for intermittent remission inducing treatment.

i) 3-5 mg / kg / day are administered intravenously on each of the five consecutive days. After a 2-9 day rest period, an additional course is given. Continue until response or toxicity appears.

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

In general, if a patient experiences neither toxicity nor remission after an adequate trial period, it is warranted to administer higher doses with caution. Normally, patients have been shown to tolerate higher doses when administered by rapid intravenous injection compared to slow infusion. This difference is due to the rapid metabolism of cytarabine and the resulting short duration of action of the high dose.

2. Maintenance therapy:

The maintenance dosage and schedule vary depending on the regimen used.

The following dosage regimens have been used for continuous treatment in inducing remission.

i) Remissions, which have been induced by cytarabine or other medicinal products, can be maintained by intravenous or subcutaneous injection of 1 mg / kg once or twice weekly.

ii) Cytarabine was also administered in doses of 100-200 mg / m2, as a continuous infusion for 5 days at monthly intervals as monotherapy or in combination with other cytostatics.

High dosages :

Cytarabine is administered at 2-3 g / m2 under close medical supervision, as monotherapy or in combination with other cytostatics, as an intravenous infusion, for 1-3 hours every 12 hours for 2-6 days (total of 12 doses per cycle). A total treatment dose of 36 g / m2 should not be exceeded. The frequency of treatment cycles depends on the response to treatment and on haematological and non-haematological toxicity. Also refer to precautions for treatment discontinuation requirements.

Pediatric patients :

Safety in infants has not been established.

Patients with hepatic and renal impairment :

Patients with impaired hepatic or renal function: the dosage should be reduced.

Cytarabine can be dialyzed. Therefore cytarabine should not be administered immediately before or after dialysis.

Elderly patients :

High dose therapy in patients over 60 years of age should only be given after a careful risk-benefit assessment.

Method of administration :

For instructions on dilution of the medicinal product before administration, see section 6.6.

Injectable cytarabine is intended for intravenous infusion or injection or subcutaneous injection.

Subcutaneous injection is generally well tolerated, and may be recommended when used in maintenance therapy.

Cytarabine 100 mg / ml should not be administered intrathecally.

04.3 Contraindications

Hypersensitivity to cytarabine or to any of the excipients of injectable cytarabine.

Anemia, leukopenia and thrombocytopenia of non-malignant etiology (e.g. bone marrow aplasia), unless the physician deems this therapy to be the best alternative for the patient.

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

04.4 Special warnings and appropriate precautions for use

Pediatric patients

The safety of this medicine has not been established in infants.

Warnings:

Cytarabine is a potent myelosuppressant. Therapy should be initiated with caution in patients with pre-existing drug-induced bone marrow depression. Patients treated with this medicinal product should be kept under close medical surveillance and, during induction therapy, white blood cell and platelet counts should be performed daily. Bone marrow tests should be performed frequently after the blast forms have disappeared. from peripheral blood.

All appropriate measures must be available for the management of complications, including fatal ones, of bone marrow suppression (infections resulting from granulocytopenia and compromise of other defense systems of the body, and secondary bleeding due to thrombocytopenia).

Anaphylactic reactions have been reported following treatment with cytarabine. One case of anaphylaxis leading to acute cardiopulmonary arrest and requiring resuscitation of the patient has been reported. This event occurred soon after intravenous administration of cytarabine.

Cytarabine administered according to experimental dosage regimens has caused severe and sometimes fatal toxicity of the CNS, gastrointestinal tract and lungs (different from that seen with conventional cytarabine regimens). These reactions include: reversible corneal toxicity, brain and brain dysfunction. cerebellar usually reversible, somnolence, convulsions, severe gastrointestinal ulceration including intestinal cystoid pneumatosis resulting in peritonitis, sepsis and liver abscesses and pulmonary edema.

Cytarabine has been shown to be carcinogenic in animals. The possibility of a similar effect should be taken into consideration when planning the patient's long-term treatment.

Precautions:

Patients receiving cytarabine should be kept under close medical surveillance. Platelet and white blood cell counts should be done frequently. Therapy should be discontinued or modified when drug-induced bone marrow depression results in a platelet count below 50,000 mm3 or a platelet count below 50,000 mm3. polymorphonuclear leukocytes below 1,000 mm3. Peripheral blood formation counts may continue to drop after drug withdrawal, and reach their lowest values after drug-free intervals of five to seven days. If indicated, treatment can be resumed when precise signs of bone marrow recovery appear (in subsequent bone marrow examinations). Disease control may be lost for those patients who have been discontinued with the drug until "normal" peripheral blood values are not achieved.

Peripheral motor and sensory neuropathy has been reported after consolidation with high doses of cytarabine, daunorubicin and asparaginase in adult patients with acute non-lymphocytic leukemia. Patients treated with high doses of cytarabine should be observed for neuropathy, since Changes in the dosage schedule may be necessary to avoid the onset of irreversible neurological disorders.

Severe and in some cases fatal pulmonary toxicity, adult respiratory distress syndrome and pulmonary edema have been reported following high dose cytarabine administration.

Following rapid intravenous administration, patients are frequently affected by nausea and vomiting which may last up to several hours. This problem is usually less when the medicine is given by infusion.

Abdominal pain (peritonitis) and guaiac test positive colitis, with associated neutropenia and thrombocytopenia, have been reported in patients treated with conventional doses of cytarabine in combination with other medicinal products. Patients responded to nonsurgical medical intervention.

Delayed progressive ascending paralysis, which resulted in death, in children with AML following intrathecal and intravenous administration of conventional doses of cytarabine in combination with other medicinal products has been reported.

Patients with pre-existing hepatic impairment

Both hepatic and renal function should be monitored during cytarabine therapy. In patients with pre-existing hepatic insufficiency, cytarabine should only be administered with extreme caution.

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

Like other cytotoxic drugs, cytarabine can induce hyperuricaemia secondary to rapid lysis of cancer cells. Physicians should monitor the patient's blood uric acid levels and be prepared to initiate supportive and pharmacological measures that may be needed to control this problem.

Vaccines / Immunosuppressive Effects / Increased Sensitivity to Infections.

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

High doses

The risk of CNS side effects is higher in patients who have already had CNS treatment such as intrathecal chemotherapy or radiotherapy.

Concomitant transfusion of granulocytes should be avoided as severe respiratory failure has been reported.

Cases of cardiomyopathy with subsequent death have been reported following experimental therapy with high doses of cytarabine in combination with cyclophosphamide when used in preparation for bone marrow transplantation.

04.5 Interactions with other medicinal products and other forms of interaction

5-fluorocytosine

5-fluorocytosine should not be administered with cytarabine, because the therapeutic efficacy of 5-fluorocytosine has been shown to be abolished during this therapy.

Digoxin

Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion have been observed in patients receiving beta-acetyldigoxin with chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine or procarbazine. Plasma concentrations of digoxin at steady state did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar chemotherapy regimens. Use of digitoxin in these patients may be considered as an alternative.

Gentamicin

An interaction study in vitro between gentamicin and cytarabine demonstrated cytarabine-related antagonism in the susceptibility of K. pneumoniae strains. In cytarabine-treated patients receiving gentamicin for a "K. pneumoniae infection," the absence of a prompt therapeutic response may indicate the need for re-evaluation of antibacterial therapy.

Use of cytarabine alone or in combination with other immunosuppressive agents

Due to the immunosuppressive action of injectable cytarabine, viral, bacterial, fungal, parasitic or saprophytic infections anywhere in the body may be associated with the use of cytarabine alone or in combination with other immunosuppressive agents following immunosuppressive doses that they affect cellular or humoral immunity. These infections can be mild, but they can be serious and sometimes fatal.

04.6 Pregnancy and breastfeeding

Pregnancy

Cytarabine is known to have teratogenic action in some animal species. The use of citara bine in women who are pregnant, or who may become pregnant, should only be undertaken after consideration of the potential benefits and risks. Women should use effective birth control methods during treatment and for up to 6 months after treatment. treatment.

Feeding time

This medicine should not normally be given to patients who are pregnant or to mothers who are breastfeeding.

Fertility

Fertility studies to evaluate the reproductive toxicity of cytarabine have not been conducted. Inhibition of the gonads, resulting in amenorrhea or azoospermia, may occur in patients taking cytarabine, especially in combination with alkylating agents. In general, these effects appear to be related to dose and duration of therapy and may be irreversible (see section 4.8. Since cytarabine has a mutagenic potential that can cause chromosomal damage in human spermatozoa, males undergoing cytarabine treatment and their partners should be advised to use reliable contraception during treatment and for up to six months after treatment. .

04.7 Effects on ability to drive and use machines

Cytarabine does not affect the ability to drive and use machines. However, the ability to drive or use machines may be impaired in patients receiving chemotherapy; patients should therefore be warned and advised to avoid carrying out such activities if this occurs.

04.8 Undesirable effects

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,

Uncommon (≥1 / 1,000 to

Rare (≥1 / 10,000,

Very rare (

Not known (frequency cannot be estimated from the available data)

The undesirable effects caused by cytarabine are dose-dependent. The most common are gastrointestinal side effects. Cytarabine is toxic to the bone marrow and causes haematological side effects.

Infections and infestations:

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

Not known: Pneumonia, liver abscess

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Uncommon: Lentigo

Disorders of the blood and lymphatic system:

common: Anemia, megaloblastosis, leukopenia, thrombocytopenia.

Not known: Reticulocytopenia.

The severity of these reactions is dependent on the dose and dosage regimen. Changes in the morphology of bone marrow cells and peripheral smears may occur.

Immune system disorders:

Uncommon: Anaphylaxis.

Not known: Allergic edema.

Metabolism and nutrition disorders:

common: Anorexia, hyperuricemia.

Nervous system disorders:

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

Uncommon: Headache, peripheral neuropathy

Not known: Neurotoxicity, neuritis, dizziness

Eye disorders:

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

Not known: Conjunctivitis (may be associated with rash).

Cardiac disorders:

Uncommon: Pericarditis.

Very rare: Arrhythmia.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Pneumonia, dyspnoea, sore throat.

Gastrointestinal disorders:

common: Dysphagia, abdominal pain, nausea, vomiting, diarrhea, oral / anal inflammation or ulceration.

Uncommon: Esophagitis, esophageal ulceration, intestinal cystoid pneumatosis, necrotizing colitis, peritonitis.

Not known: Pancreatitis.

Hepatobiliary disorders:

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

Uncommon: Jaundice.

Not known: Hepatic dysfunction.

Skin and subcutaneous tissue disorders:

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

Uncommon: Skin ulceration, itching, burning pain in the palms of the hands and soles of the feet.

Very rare: Neutrophilic eccrine hydradenite.

Not known: Ephelides, skin rash.

Musculoskeletal and connective tissue disorders:

Uncommon: Myalgia, arthralgia.

Renal and urinary disorders:

common: Renal impairment, urinary retention.

General disorders and administration site conditions:

common: Fever, thrombophlebitis at the injection site.

Uncommon: Chest pain.

Cytarabine Syndrome (Ara-C) (Immunoallergic effect):

Fever, myalgia, bone pain, occasionally chest pain, rash, conjunctivitis, and nausea may occur 6 to 12 hours after initiation of therapy. Corticosteroid administration may be considered as prophylaxis and therapy. If corticosteroids are effective, continued administration may be made. cytarabine therapy.

Undesirable effects due to treatment with high doses of cytarabine, in addition to those seen with conventional doses include:

Hematological toxicity:

Seen as profound pancytopenia which can last 15-25 days with more severe bone marrow aplasia than is seen at conventional doses.

Infections and infestations: Sepsis, liver abscess.

Nervous system disorders:

Following high-dose cytarabine treatment, symptoms of cerebral or cerebellar dysfunction, such as personality changes, impaired lucidity, dysarthria, ataxia, tremor, nystagmus, headache, confusion, somnolence, occur in 8-37% of treated patients, dizziness, coma, convulsions, etc. Peripheral motor and sensory neuropathies have also been reported following high dose therapy. The incidence in the elderly (> 55 years) may be higher. Other predisposing factors are impaired liver and kidney function, previous CNS treatment (eg radiotherapy) and alcohol abuse. In most cases, CNS changes are reversible.

The risk of CNS toxicity increases if cytarabine treatment - given at high doses by the intravenous route - is associated with another CNS toxic treatment, such as radiotherapy or at high doses.

Corneal and conjunctival toxicity:

Corneal lesions and haemorrhagic conjunctivitis have been described. These phenomena can be prevented or reduced by instilling corticosteroids in eye drops.

Skin and subcutaneous tissue disorders: skin rash inducing peeling, alopecia.

Viral, bacterial, fungal, parasitic or saprophytic infections, at any body location, may be associated with the use of cytarabine alone or in combination with other immunosuppressive agents, following administration of doses affecting cellular or humoral immunity. These infections can be mild, but they can also be severe.

A cytarabine syndrome has been described. It is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6-12 hours after drug administration. Corticosteroid administration has been found to be effective in treating or preventing this syndrome. If symptoms of the syndrome are severe enough to require treatment, both the use of corticosteroids and continuation of cytarabine therapy should be envisaged.

Gastrointestinal disorders:

Particularly in the treatment with high doses of cytarabine, in addition to the common symptoms, more severe reactions may occur. 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 following high-dose therapy.

Respiratory, thoracic and mediastinal disorders:

Clinical signs similar to those present in pulmonary edema / ARDS may develop, especially in high dose therapy. The reaction is probably caused by an alveolar capillary lesion. It is difficult to estimate the frequency (indicated as 10-26% in several publications), because patients typically have a relapse, where other factors can contribute to this reaction.

Others:

After cytarabine therapy, cardiomyopathy and rhabdomyolysis have been reported. One case of anaphylaxis leading to cardiopulmonary arrest requiring resuscitation was reported. This event occurred soon after intravenous administration of cytarabine.

Gastrointestinal side effects are reduced if cytarabine is administered as an infusion. The use of local glucocorticoids as prophylaxis of haemorrhagic conjunctivitis is recommended.

Amenorrhea and azoospermia (see section 4.6)

Intrathecal use of cytarabine is not recommended; however, the following undesirable effects have been reported with this type of use. Expected systemic reactions: myelosuppression, nausea, vomiting. Occasionally, severe myelotoxicity has been reported even resulting in quadriplegia and paralysis, encephalopathy necrotizing, blindness and other isolated neurotoxicities.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions that occur after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the reporting system at: http://www.agenziafarmaco.gov.it/it/ responsibles.

04.9 Overdose

No specific antidote. Advice for management in the event of an overdose include: discontinuing therapy, then treating the resulting myelosuppression including whole blood or platelet transfusions and, if required, antibiotics. A dose of 4.5 g / m2 by intravenous infusion administered over one hour every 12 hours for 12 times induces irreversible and fatal central nervous system toxicity.

Cytarabine can be eliminated by hemodialysis.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pyrimidine analogue

ATC Code: L01BC01

Cytarabine, a nucleotide analogue of pyrimidine, is an antineoplastic agent, which inhibits the synthesis of deoxyribonucleic acid, particularly in the S phase of the cell cycle. It also possesses antiviral and immunosuppressive properties. Detailed studies on the mechanism of cytotoxicity. in vitro suggest that the primary action of cytarabine is the inhibition of the synthesis of deoxycytidine through its active metabolite triphosphate, arabinofuranosyl cytosine triphosphate ARA-CTP, although the inhibition of cytidyl kinases and incorporation of the compound into nucleic acids also probably plays a role. role in its cytostatic and cytocidal actions.

High dose regimens of cytarabine can overcome the resistance of leukemia cells that no longer respond to conventional doses. Several mechanisms appear to be involved in this resistance:

Increase in the amount of substrate

Increase in the intracellular group of ARA-CTP, since c "is a positive correlation between the cellular retention of ARA-CTP and the percentage of S-phase cells.

05.2 Pharmacokinetic properties

Cytarabine is deaminated to arabinofuranosiluracil in the liver and kidneys. After intravenous administration in humans, only 5.8% of the administered doses are excreted unchanged in the urine within 12-24 hours, while 90% of the dose is excreted as the deaminated inactive product, uracil arabinofuranosil (ARA-U). Cytarabine is rapidly metabolised, primarily by the liver and possibly the kidney. After administration of single high doses intravenously, plasma levels drop to undetectable levels within 15 minutes in most patients. In some patients there is demonstrable circulating drug as early as 5 minutes after injection. The half-life of the drug is 10 minutes.

High-dose cytarabine achieves peak plasma levels 200 times higher than those seen with the conventional dosing regimen. The peak of the inactive metabolite ARA-U, with the high-dose regimen, was observed after only 15 minutes. Renal clearance is slower with high-dose cytarabine than with conventional-dose cytarabine. Levels achieved in cerebrospinal fluid (CSF) after intravenous infusion of high doses of 1-3 g / m2 of cytarabine are approximately 100-300 nanograms / ml.

The peak plasma levels achieved are approximately 20-60 minutes after subcutaneous application. At comparable doses, they are significantly lower than the plasma levels achieved after intravenous administration.

05.3 Preclinical safety data

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

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Macrogol 400

Trometamol (to adjust the pH)

Water for injections

06.2 Incompatibility

However, incompatibility depends on several factors (eg drug concentrations, specific diluents used, resulting pH, temperature). Specific references should be consulted for specific compatibility information.

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

06.3 Period of validity

2 years

Stability in use:

Physico-chemical stability in use has been demonstrated in sodium chloride (0.9% w / v) and dextrose (5% w / v) solution for injection for up to 24 hours at temperatures below 25 ° C and up to 72 hours at a temperature of 2 to 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 to 8 ° C, unless dilution has taken place in conditions aseptic controlled and validated.

06.4 Special precautions for storage

Do not store above 25 ° C.

Do not refrigerate or freeze.

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

06.5 Nature of the immediate packaging and contents of the package

For 1 ml,

The solution for injection is contained in a 2 ml Type I clear glass vial, closed with a 13 mm gray rubber stopper and a 13 mm clear blue or azure blue aluminum flip-off seal.

For 5 ml,

The solution for injection is contained in a 5 ml Type I clear tubular glass vial, closed with a 20 mm gray rubber stopper and a 20 mm transparent blue or blue-azure aluminum flip-off seal.

For 10 ml,

The solution for injection is contained in a 10 ml Type I clear tubular glass vial, closed with a 20 mm gray rubber stopper and a 20 mm clear blue or blue-blue aluminum flip-off seal.

For 20 ml,

The solution for injection is contained in a 20 ml Type I clear glass vial closed with a 20 mm gray rubber stopper and a 20 mm blue-blue aluminum flip-off seal.

For 40 ml,

The solution for injection is contained in a 50 ml Type I clear glass vial, closed with a 20 mm gray rubber stopper and a 20 mm blue-blue aluminum flip-off seal.

For 50 ml,

The solution for injection is contained in a 50 ml Type I clear glass vial, closed with a 20 mm gray rubber stopper and a 20 mm violet aluminum flip-off seal.

Pack sizes

1 vial of 1 ml, 5 vials of 1 ml

1 vial of 5 ml, 5 vials of 5 ml

1 vial of 10 ml

1 vial of 20 ml

1 vial of 40 ml

1 vial of 50 ml

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

For single use only.

If the solution appears discolored or contains visible particles, it should be discarded.

Once opened, the contents of each vial should be used immediately. Discard the unused product.

Guidelines on the handling of cytotoxics

Administration:

It should be administered by, or under the direct supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.

Preparation:

• Chemotherapeutic agents should be prepared for administration only by professionals trained in the safe use of the preparation.

• Operations such as dilution and transfer to the syringe should only be performed in the appropriate area.

• Personnel performing these procedures must be adequately protected with gowns, gloves and goggles.

• Pregnant staff are advised not to handle chemotherapy drugs.

Disposal and contamination:

The product or any unused waste material should be disposed of in accordance with local regulations.

To destroy, place in a high risk (for cytotoxic) waste disposal bag / container and incinerate at 1100oC.

In the event of dispersion, restrict access to the affected area and wear appropriate protective equipment, including gloves and safety glasses. Limit spread and clean the area with paper / absorbent material. Dispersions can also be treated with 5% sodium hypochlorite. Dispersion area should be cleaned with copious amounts of water. Place contaminated material in a bag. / watertight container for disposing of cytotoxics and incinerating at 1100 ° C.