Citosar

Leaflet attached to the packaging: information for the user

CYTOSAR, 20 mg/ml, solution for injection/infusion
Cytarabine

Please read carefully the contents of the leaflet before using the medicine, as it contains important information for the patient.

• Please keep this leaflet, so that you can read it again if you need to.
• If you have any doubts, you should consult a doctor, pharmacist, or nurse.
• If the patient experiences any side effects, including any side effects not listed in this leaflet, they should inform their doctor or pharmacist. See section 4.

Table of contents of the leaflet

• 1. What is Cytosar and what is it used for
• 2. Important information before using Cytosar
• 3. How to use Cytosar
• 4. Possible side effects
• 5. How to store Cytosar
• 6. Contents of the pack and other information

1. What is Cytosar and what is it used for

Cytosar belongs to a group of anticancer medicines. The medicine should only be used by doctors with experience in cancer chemotherapy and only when the benefits of treatment with cytarabine outweigh the risks.
Cytosar is used to treat acute myeloid leukemia in adults and children. It is also indicated for the treatment of acute lymphoblastic leukemia and chronic myeloid leukemia. It can be used as monotherapy (as the only medicine) or in combination with other anticancer medicines.
The best results are achieved after combined therapy.
Cytosar in monotherapy or in combination with sodium hydrocortisone acetate and methotrexate administered intrathecally can be used to treat leukemia with central nervous system involvement.
Cytosar in high doses, administered as an intravenous infusion in combination with other anticancer medicines or as monotherapy, is effective in the treatment of poorly prognostic leukemia, refractory leukemia, and in relapses (recurrences) of acute leukemia.
Cytosar is rarely effective in the treatment of patients with solid tumors.

2. Important information before using Cytosar

When not to use Cytosar

• it must not be used with diluents containing benzyl alcohol for the preparation of the medicine in the case of high-dose intravenous therapy, intrathecal administration, or administration to infants and children up to 3 years of age.

Warnings and precautions

Before starting treatment with Cytosar, the patient should discuss it with their doctor, pharmacist, or nurse.

• In patients with previously detected drug-induced bone marrow suppression. Cytosar strongly inhibits bone marrow function, causing leukopenia (decreased white blood cell count), thrombocytopenia (decreased platelet count), and anemia. There is a risk of potentially fatal infections associated with granulocytopenia (decreased granulocyte count), a risk of impaired immune function, and bleeding due to thrombocytopenia. The doctor will consider discontinuing the medicine or adjusting the dose if the patient's peripheral blood count shows less than 50,000 platelets/mm or 1000 granulocytes/mm. Re-administration of the medicine is possible after bone marrow recovery and an increase in platelet and granulocyte count.

Cytosar may cause hyperuricemia (increased uric acid levels in the blood) as a consequence of rapid lysis (breakdown) of cancer cells. The doctor should monitor the patient's uric acid levels and, if necessary, take appropriate pharmacological measures.
Patients receiving Cytosar should have periodic checks of bone marrow, liver, and kidney function.
Patients taking Cytosar should not be vaccinated with live vaccines. They may receive killed or inactivated vaccines, but their effectiveness may be reduced.
Administration of live or live attenuated vaccines to patients with impaired immunity due to chemotherapy (including Cytosar) may lead to severe infections, even death.

Cytosar and other medicines

Before using a new medicine with Cytosar, the patient should inform their doctor. They should tell their doctor about all medicines they are currently taking or have recently taken, as well as any medicines they plan to take.
Cytosar may affect digoxin levels in the blood.
A lack of rapid improvement in the condition of patients infected with Klebsiella pneumoniaeand treated with Cytosar and gentamicin has been observed. A change in antibacterial treatment is recommended.
Cytosar may reduce the effectiveness of fluorocytosine.
Cytosar administered intravenously in combination with methotrexate administered intrathecally may increase the risk of severe neurological side effects.

Pregnancy and breastfeeding

Pregnancy
If the patient is pregnant or breastfeeding, thinks they may be pregnant, or plans to have a child, they should consult their doctor or pharmacist before using this medicine.
In case of pregnancy, the patient should contact their doctor.
Women who are pregnant or of childbearing potential may only take Cytosar after careful consideration of the potential benefits and risks to the mother and fetus.
Use of Cytosar in the first trimester of pregnancy may cause fetal malformations. The risk of fetal damage is much lower if treatment starts in the second or third trimester of pregnancy.
Contraception in women of childbearing potential
Women should always use effective contraception to prevent pregnancy during treatment and for 6 months after the last dose. They should discuss suitable contraception methods with their doctor.
Contraception in men
Men with partners of childbearing potential should always use highly effective contraception during treatment and for 3 months after the last dose.
Breastfeeding
There is insufficient data on the excretion of Cytosar into human milk.
Due to the risk of severe side effects in infants breastfed by mothers taking Cytosar, the doctor will consider either discontinuing breastfeeding for the duration of treatment with Cytosar and for at least one week after the last dose or discontinuing the medicine, taking into account the benefit of treatment for the mother.

Driving and using machines

The effect of Cytosar on the ability to drive and use machines has not been studied.
Cytosar may affect the ability to drive and use machines due to possible side effects (e.g., central nervous system disorders, dizziness).

Cytosar contains sodium

Cytosar 100 mg/5 ml (20 mg/ml) solution for injection/infusion contains 13.25 mg of sodium (the main component of common salt) in each 5 ml vial. This corresponds to 0.7% of the maximum recommended daily intake of sodium for adults.
Cytosar 500 mg/25 ml (20 mg/ml) solution for injection/infusion contains 66.25 mg of sodium (the main component of common salt) in each 25 ml vial. This corresponds to 3.31% of the maximum recommended daily intake of sodium in the diet for adults.
When preparing the medicine for administration, the sodium content from the diluent, i.e., sodium chloride solution, should also be taken into account.

3. How to use Cytosar

The doctor will determine the dose of the medicine that is most suitable for the patient. The scheme and method of administration depend on the treatment scheme used. Cytosar can be administered as an intravenous infusion, intravenous injection, subcutaneously, or intrathecally.

Using a higher dose of Cytosar than recommended

Cytosar will be used in a hospital setting by doctors with experience in cancer chemotherapy, so using a higher dose than recommended is unlikely.

Discontinuing Cytosar

The decision to discontinue treatment is made by the doctor. If there are any further doubts about the use of this medicine, the patient should consult their doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common (may affect more than 1 in 10 people):

• Sepsis (generalized infection), pneumonia, infection.
• Bone marrow suppression, thrombocytopenia (decreased platelet count), anemia, megaloblastic anemia (a condition characterized by lower than normal hemoglobin values and a decreased number of enlarged red blood cells), leukopenia (decreased white blood cell count), decreased reticulocyte count (immature red blood cells).
• Mouth ulcers, oral mucositis, anal ulcers, proctitis, diarrhea, vomiting, nausea, abdominal pain.
• Liver function disorders.
• Hair loss, rash.
• Cytarabine syndrome (fever, muscle pain, bone pain, sometimes chest pain, maculopapular rash, conjunctivitis, and malaise occurring usually 6 to 12 hours after administration of the medicine).
• Fever.
• Abnormal bone marrow biopsy and blood test results.
• Central nervous system disorders and cerebellar disorders*, drowsiness*.
• Corneal disorders*.
• Acute respiratory distress syndrome (a condition characterized by respiratory failure)*, pulmonary edema*.

Common (may affect up to 1 in 10 people):

• Skin ulcers.
• Necrotizing enterocolitis*.
• Exfoliative dermatitis*.

Frequency not known (cannot be estimated from the available data):

• Subcutaneous tissue inflammation at the injection site.
• Anaphylactic reaction (a severe allergic reaction), allergic edema.
• Decreased appetite.
• Neurotoxicity, neuropathy, dizziness, headache.
• Conjunctivitis.
• Pericarditis, bradycardia (decreased heart rate), atrial bradycardia.
• Thrombophlebitis.
• Dyspnea, sore throat.
• Pancreatitis, esophagitis, esophageal ulcers.
• Jaundice.
• Painful erythema and blistering on hands and soles (palmar-plantar erythrodysesthesia syndrome), urticaria, pruritus, petechiae.
• Kidney function disorders, urinary retention.
• Chest pain, pain and inflammation at the subcutaneous injection site.
• Hepatic abscess*.
• Personality changes*.
• Coma*, seizures*, peripheral motor neuropathy*, peripheral sensory neuropathy*.
• Cardiomyopathy* (a heart condition).
• Gastric or intestinal necrosis*, gastric or intestinal ulcers*, intestinal obstruction*, peritonitis*.
• Liver damage*, hyperbilirubinemia* (increased bilirubin levels in the blood).

* side effects occurring after high-dose treatment with Cytosar, other than after standard doses.

Reporting side effects

If side effects occur, including any side effects not listed in this leaflet, the patient should inform their doctor or pharmacist, or nurse. Side effects can be reported directly to the Department of Drug Safety Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder or its representative.
Reporting side effects will help to gather more information on the safety of the medicine.

5. How to store Cytosar

The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label, box, or blister after:
Expiry date (EXP). The expiry date refers to the last day of the month stated.
Store below 25°C. Do not freeze.
Store in the original packaging to protect from light.
Storage conditions for the medicine after dilution, see section "Information intended for healthcare professionals only. Shelf life of the medicine after dilution".

6. Contents of the pack and other information

What Cytosar contains:

• The active substance of the medicine is cytarabine. One ml of the solution contains 20 mg of cytarabine. One 5 ml vial contains 100 mg of cytarabine. One 25 ml vial contains 500 mg of cytarabine.
• The other ingredients are: sodium chloride, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), water for injections.

What Cytosar looks like and contents of the pack

A clear, colorless or slightly yellowish aqueous solution, free from visible particles, in a polypropylene vial with a chlorobutyl rubber stopper coated with teflon, with an aluminum seal and a purple, non-transparent, flip-off plastic cap, in a cardboard box.
The pack contains 1 vial of 5 ml or 1 vial of 25 ml, or 25 vials of 25 ml.
Not all pack sizes may be marketed.

Marketing authorization holder

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Brussels
Belgium

Manufacturer

Pfizer Service Company BV
Hoge Wei 10
1930 Zaventem
Belgium

To obtain more detailed information about this medicine, please contact the representative of the marketing authorization holder:

Pfizer Polska Sp. z o.o.
phone: 22 335 61 00
Date of last revision of the leaflet:12/2022
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Information intended for healthcare professionals only

Cytosar may only be used by doctors with experience in cancer chemotherapy.
For intrathecal administration, the product should be diluted with a preservative-free 0.9% sodium chloride injection solution.
For intravenous administration, the product should be diluted with a preservative-free 0.9% sodium chloride injection solution or 5% glucose solution or water for injections.
High doses of the product are better tolerated by patients when administered as a rapid intravenous injection rather than a slow intravenous infusion.
pH 7.4.
Osmolality from 250 to 350 mOsm/kg.

Dosage and administration

Intravenous administration
Standard doses
At the start of treatment (induction of remission) of acute non-lymphocytic leukemia, the dose of Cytosar used in combination with other anticancer medicines is usually 100 mg/m² per day as a continuous intravenous infusion (days 1 to 7) or 100 mg/m² intravenously every 12 hours (days 1 to 7).
High doses
From 2 g/m² to 3 g/m², administered as an intravenous infusion lasting from 1 to 3 hours, given every 12 hours for 2-6 days in combination with other anticancer medicines or as monotherapy. In the case of high-dose therapy, diluents containing benzyl alcohol should not be used; only preservative-free diluents should be used.
Subcutaneous administration
Usually, 20-100 mg/m² is administered, depending on the indication and the treatment scheme used.
Dosage of Cytosar in acute lymphatic leukemia and non-Hodgkin's lymphoma in children should be in accordance with current guidelines.
Intrathecal administration in leukemia with central nervous system involvement
When preparing Cytosar for intrathecal administration, diluents containing benzyl alcohol should not be used; a preservative-free 0.9% sodium chloride injection solution should be used. The product should be administered immediately after preparation.
Cytosar has been administered intrathecally in leukemia at doses ranging from 5 mg/m² to 75 mg/m². The frequency of administration ranged from one dose per day for 4 days to one dose every 4 days. The most commonly used dose was 30 mg/m² every 4 days until the cerebrospinal fluid parameters normalized, followed by one additional course of treatment. The dosage scheme usually depends on the type and severity of central nervous system symptoms and the response to previous treatment.
Cytosar has been administered intrathecally with sodium hydrocortisone acetate and methotrexate, both in the prophylaxis of newly diagnosed acute lymphoblastic leukemia in children and in the treatment of leukemia with central nervous system involvement. Prophylactic treatment with these three medicines prevented central nervous system involvement and ensured a similar frequency of complete remissions and survival rate as in patients who received cranial irradiation and intrathecal methotrexate as initial prophylaxis. The dose of cytarabine was 30 mg/m², sodium hydrocortisone acetate 15 mg/m², and methotrexate 15 mg/m² (the total, maximum single dose was 15 mg/m² of methotrexate). Before starting treatment with this scheme, the doctor should familiarize themselves with it; however, in children and adolescents, methotrexate dosing should be based on age rather than body surface area.
Prophylactic treatment with the three medicines can be used after successful initial treatment of leukemia with central nervous system involvement. Before starting therapy with this scheme, the doctor should familiarize themselves with current guidelines.
Cytarabine administered intrathecally may cause general toxic symptoms, and careful monitoring of the hematopoietic system is necessary. Modification of the antileukemic treatment may be necessary. Severe toxic effects are rare. When cytarabine is administered both intrathecally and intravenously at intervals of a few days, there is an increased risk of its toxic effect on the bone marrow; however, in cases of severe, life-threatening disease, the simultaneous use of cytarabine intravenously and intrathecally is left to the discretion of the treating physician.
In the case of leukemic infiltrates in the central nervous system, intrathecal administration of the medicine may be ineffective. Cranial irradiation is more beneficial in this case.
For intrathecal administration, the maximum volume of the solution is 10 ml. Before intrathecal administration of the required dose, an equivalent amount of cerebrospinal fluid (usually 7-10 ml) must be removed to minimize any change in cerebrospinal fluid volume.

• 7-10 ml) must be removed to minimize any change in cerebrospinal fluid volume.

Children and adolescents
The dosage of Cytosar is similar to that recommended for adults. Current recommendations for dosing in children and adolescents should be consulted in the latest treatment standards.
When preparing Cytosar for administration in infants and children up to 3 years of age, diluents containing benzyl alcohol should not be used; preservative-free diluents should be used. The product should be administered immediately after preparation.
Cytosar is inactive when administered orally. The method of administration depends on the treatment scheme used.

Pharmaceutical compatibility

Cytarabine is pharmaceutically compatible with the following products at the specified concentrations in a 5% aqueous glucose solution for 8 hours: cytarabine 0.8 mg/ml and cefalotin (sodium) 1.0 mg/ml; cytarabine 0.4 mg/ml and prednisolone (sodium phosphate) 0.2 mg/ml; cytarabine 16 mg/ml and vincristine (sulfate) 4 µg/ml. Cytarabine is also physically compatible with methotrexate.

Pharmaceutical incompatibility

Cytosar is physically incompatible with heparin, insulin, 5-fluorouracil, and methylprednisolone sodium succinate, as well as with penicillins such as oxacillin and penicillin G.

Shelf life of the medicine after dilution

The cytarabine injection solution is physically and chemically stable at concentrations from 0.1 mg/ml to 1 mg/ml after dilution:

• 0.9% sodium chloride solution,
• 5% glucose solution,
• water for injections for up to 4 days at both 25°C/60% relative humidity with access to light and 2°C - 8°C/ambient humidity without access to light.

From a microbiological point of view, the product should be used immediately. If the product is not used immediately, the user is responsible for the storage time and conditions after preparation. This time should not exceed 24 hours at a temperature of 2°C to 8°C, unless the dilution of the product was carried out under controlled and validated aseptic conditions.
Precautions
Due to the toxicity of the substance, the following precautions are recommended:

• personnel should be trained in the proper technique of dilution and handling of the product;
• women who are pregnant should not be allowed to work with this product;
• persons in contact with cytarabine should wear protective clothing: goggles, gowns, single-use gloves, and masks;
• dilution of the product should be carried out in a designated area (preferably equipped with a laminar airflow system); the work surface should be protected with single-use absorbent paper with a plastic bottom layer;
• all materials used for dilution, administration of the product, or cleaning should be placed in tightly sealed bags for high-risk waste and then incinerated at 1100°C;
• spilled or leaked product should be washed with 5% sodium hypochlorite solution and then with water;
• all materials used to clean up the spill should be disposed of as described above;
• any unused remains of the product should be disposed of as described above;
• in case of contact of the product with the skin, the area should be carefully washed with soap and water or a sodium carbonate solution. However, a brush should not be used to avoid skin abrasion;
• in case of the product getting into the eye, the eyelid should be pulled back and the eye flushed with a large amount of water for at least 15 minutes. The patient should then undergo a medical examination;
• after removing gloves, hands should always be washed.