Cytosar

Package leaflet: Information for the user

CYTOSAR, 1 g, powder for solution for injection
Cytarabine
Please read all of this leaflet carefully before using this medicine, as it contains
important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm someone else, even if their symptoms are the same.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Leaflet contents

1. What Cytosar is and what it is used for
2. What you need to know before you use 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 Cytosar is and what it is used for

Cytosar belongs to a group of anticancer medicines. It should be used only by doctors experienced in cancer chemotherapy, and only when the benefits of treatment with cytarabine outweigh the risks.
Cytosar is used in the treatment of acute myeloid leukaemia in adults and children. It is also indicated in the treatment of acute lymphoblastic leukaemia and chronic myeloid leukaemia. It may be used as monotherapy (as a single agent) or in combination with other anticancer medicines. The best results are achieved with combination therapy.
High-dose Cytosar administered by intravenous infusion, either alone or in combination with other anticancer agents, is effective in the treatment of poor-prognosis leukaemia, treatment-resistant leukaemia, and relapsed acute leukaemia.
It is rarely effective in the treatment of patients with solid tumours.

2. Information before using the medicine

When not to use the medicine

• if the patient is allergic to cytarabine or any of the other components of this medicine (listed in section 6).

When treating with high doses administered intravenously or administering the medicine to infants and children under 3 years of age, solvents containing benzyl alcohol must not be used for preparation of the medicine.

Warnings and precautions

• In patients with previously detected drug-induced bone marrow suppression. The medicine strongly suppresses bone marrow function, causing leukopenia (reduced number of white blood cells in peripheral blood), thrombocytopenia (reduced platelet count), and anemia. There is a risk of potentially fatal infections associated with granulocytopenia (reduced number of neutrophils – a type of white blood cell), impaired immune defense, and bleeding due to thrombocytopenia. The physician may consider discontinuing treatment or adjusting the dose if the patient's peripheral blood platelet count is less than 50,000/mm³ or granulocyte count is less than 1,000/mm³. Re-administration of the medicine may be possible after bone marrow recovery and an increase in platelet and granulocyte counts.

• In patients receiving high doses of the medicine (2–3 g/m² body surface area) due to the occurrence of severe and sometimes fatal damage to the central nervous system (manifesting, among others, as seizures), gastrointestinal tract, lungs (adult respiratory distress syndrome, pulmonary edema), and symptoms of cardiomegaly (enlargement of the heart).

• In patients treated with high doses of the medicine, because severe eye damage has been observed, as well as risk of neuropathy. Changes in the treatment regimen may be necessary to avoid irreversible neurological disorders.

• In patients receiving high-dose cytarabine in combination with cyclophosphamide, because cases of fatal cardiomegaly have been reported.

• In patients with acute non-lymphocytic leukemia receiving concomitant high-dose cytarabine, daunorubicin, and asparaginase, because peripheral motor and sensory neuropathies have been observed.

• During administration of rapid intravenous injections of high doses of the medicine, because nausea and vomiting frequently occur, which may persist for several hours. These symptoms are usually less pronounced when the medicine is administered as an infusion.

• In patients receiving standard doses of the medicine concomitantly with other medicines due to the possibility of peritonitis-like symptoms, colitis associated with neutropenia and thrombocytopenia.

• In children with acute myeloid leukemia, following intrathecal and intravenous administration of standard doses of the medicine together with other medicines, delayed progressive ascending paralysis leading to death has been observed.

• In patients with impaired liver or kidney function, in whom the medicine should be used, if possible, at a reduced dose.

• During concomitant use of the medicine with other medicines due to the risk of acute pancreatitis.

• In patients receiving the medicine both intrathecally and intravenously within several days, because there is an increased risk of spinal cord damage. In life-threatening situations, the decision to administer the medicine intrathecally and intravenously simultaneously should be made solely at the discretion of the treating physician.

• In patients receiving the medicine intravenously while methotrexate is administered intrathecally, severe neurological adverse reactions have been reported, including headache, paralysis, coma, and stroke-like episodes.

The medicine may cause hyperuricemia (increased blood uric acid levels) as a consequence of rapid lysis (breakdown) of tumor cells. The physician should monitor uric acid levels in the patient's blood and, if necessary, apply appropriate pharmacological measures.

Patients receiving the medicine should undergo regular monitoring of bone marrow, liver, and kidney function.

Patients taking the medicine should not be vaccinated with live vaccines. They may receive inactivated or killed vaccines, although their effectiveness may be reduced. Administration of live or live attenuated vaccines to patients with immunosuppression due to chemotherapy (including this medicine) may lead to severe infections or even death.

Other medicines

Before using any new medicine together with this medicine, inform your doctor.

Tell your doctor about all medicines currently taken or recently taken, as well as any medicines the patient plans to take.

The medicine may affect digoxin plasma concentrations.

Lack of rapid improvement has been observed in patients infected with Klebsiella pneumoniae who are receiving cytarabine and being treated concomitantly with gentamicin. A change in antibacterial therapy is recommended.

The medicine may reduce the efficacy of flucytosine.

The intravenous administration of the medicine together with intrathecal administration of methotrexate may increase the risk of severe neurological adverse reactions.

Pregnancy and breastfeeding

Pregnancy

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult a doctor or pharmacist before using this medicine.

In case of becoming pregnant, contact your doctor immediately.

Women who are pregnant or of childbearing age may receive the medicine only after careful consideration of the potential benefits versus risks to the mother and fetus.

Use of the medicine during the first trimester of pregnancy may cause fetal developmental abnormalities. The risk of fetal damage is considerably lower if treatment is initiated during the second or third trimester of pregnancy.

Benzyl alcohol contained in certain solvents may cross the placenta.

Contraception in women of childbearing potential

Women should always use an effective method of contraception (birth control) to prevent pregnancy during treatment and for 6 months after the last dose. Discuss with your doctor which contraceptive methods are appropriate for the patient and her partner.

Contraception in men

Men with partners of childbearing potential should always use highly effective contraceptive methods during treatment and for 3 months after the last dose.

Breastfeeding

There are insufficient data on the passage of the medicine into human milk. Due to the risk of serious adverse effects in infants breastfed by mothers receiving the medicine, the physician will consider the decision to discontinue breastfeeding during treatment with the medicine and for at least one week after the last dose, or to discontinue the medicine, taking into account the benefit of treatment for the mother.

Driving and operating machinery

The effect of the medicine on the ability to drive vehicles and operate machinery has not been studied.

The medicine may affect the ability to drive vehicles and operate machinery due to possible adverse effects (e.g., brain function disorders, dizziness).

Benzyl alcohol

The use of benzyl alcohol is associated with severe adverse effects, including "gasping syndrome" (respiratory distress syndrome in infants) and cases of death in children. Although the amounts of benzyl alcohol delivered with standard therapeutic doses of the medicine are significantly lower than those reported in connection with "gasping syndrome," the minimal amount of benzyl alcohol at which toxic effects may occur is unknown. The risk of toxic effects of benzyl alcohol depends on the administered dose and the liver's ability to eliminate toxins. Premature infants and newborns with low birth weight are at higher risk of toxic effects.

Benzyl alcohol may cause toxic effects and allergic reactions in infants and children under 3 years of age. If the medicine is administered in high doses, solvents containing benzyl alcohol must not be used. The medicine may be dissolved in preservative-free 0.9% sodium chloride solution.

3. How to use the medicine

The doctor will determine the dose of the medicine most suitable for the individual patient. The regimen and method of administration depend on the treatment schedule used. The medicine may be administered as an intravenous infusion, intravenous injection, or subcutaneously.
Use of a higher than recommended dose of the medicine
The medicine will be used in hospital conditions by doctors experienced in the field of cancer chemotherapy, therefore use of a higher than recommended dose is unlikely.
Interrupting treatment with the medicine
The decision to interrupt treatment is made by the doctor. If you have any further questions regarding the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.

Very common (may affect more than 1 in 10 people):
Sepsis (systemic infection), pneumonia, infection.
Bone marrow suppression, thrombocytopenia (reduced number of platelets), anemia, megaloblastic anemia (syndrome of symptoms resulting from hemoglobin values below normal and reduced number of enlarged red blood cells), leukopenia (reduced number of white blood cells), decreased reticulocyte count (immature forms of red blood cells).
Mucositis (inflammation of the mucous membrane of the oral cavity), ulceration of the oral mucosa, ulceration of the anal mucosa, proctitis (inflammation of the anal mucosa), diarrhea, vomiting, nausea, abdominal pain.
Liver function abnormalities.
Alopecia (hair loss), rash.
Cytarabine syndrome (fever, muscle pain, bone pain, sometimes chest pain, maculopapular rash, conjunctivitis, and malaise, most commonly occurring 6 to 12 hours after administration of the medicine).
Fever.
Abnormal results of bone marrow biopsy and blood smear.
Central nervous system and cerebellar dysfunction*, somnolence*.
Corneal disorders*.
Acute respiratory distress syndrome (lung disease)*, pulmonary edema*.

Common (may affect up to 1 in 10 people):
Skin ulceration.
Necrotizing enteritis*.
Skin desquamation*.

Frequency not known (cannot be estimated from available data):
Subcutaneous tissue inflammation at injection site.
Anaphylactic reaction (sudden allergic reaction), allergic edema.
Decreased appetite.
Toxic nerve damage, neuritis, dizziness, headache.
Conjunctivitis.
Pericarditis, sinus bradycardia (reduced heart rate).
Thrombophlebitis.
Dyspnea (shortness of breath), sore throat.
Pancreatitis, esophageal ulceration, esophagitis.
Jaundice.
Painful redness and blistering of hands and soles (hand-foot syndrome, erythrodysaesthesia palmoplantaris), urticaria, pruritus (itching), petechiae.
Renal dysfunction, urinary retention.
Chest pain, pain and inflammation at subcutaneous injection site.
Liver abscess*.
Personality changes*.
Coma*, seizures*, peripheral motor neuropathy*, peripheral sensory neuropathy*.
Cardiomyopathy* (heart disease).
Necrosis of stomach or intestines*, gastric or intestinal ulcer*, intestinal emphysema*, peritonitis*.
Liver damage*, hyperbilirubinemia* (increased concentration of bilirubin in blood).

*Adverse reactions occurring after high-dose therapy, not observed with standard doses.

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions, 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

Adverse reactions may also be reported to the marketing authorization holder or its representative.
Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store the medicine

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and (or) the carton after:
EXP. The expiry date refers to the last day of the stated month.
Store below 25ºC.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What the medicinal product contains

• The active substance is cytarabine. Each vial contains 1 g of cytarabine.
• Other ingredients: hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment).

What the medicine looks like and contents of the pack
White, crystalline powder.
The pack contains 1 vial made of colourless glass, closed with a bromobutyl stopper and an aluminium seal, placed in a cardboard box.

Marketing Authorisation Holder
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

Manufacturer
Actavis Italy S.p.A.
Viale Pasteur 10
20014 Nerviano (Milan)
Italy

For further information, please contact the Marketing Authorisation Holder:
Pfizer Polska Sp. z o.o.
tel: 22 335 61 00

Information intended exclusively for healthcare professionals

Complete drug information is contained in the Summary of Product Characteristics.

Dosage and administration

The drug is inactive when administered orally. The drug may be given by intravenous infusion, intravenous injection, or subcutaneously. When preparing the product for administration in high doses or for use in infants and children under 3 years of age, solvents containing benzyl alcohol must not be used. For reconstitution, preservative-free 0.9% sodium chloride injection solution should be used. The product should be administered immediately after preparation.

High doses of the drug are better tolerated by patients when administered as a rapid intravenous injection rather than as a slow intravenous infusion.

Intravenous administration

Standard doses
At the beginning of treatment (induction of remission) of acute non-lymphocytic leukemia, the dose of the drug, used concomitantly with other antineoplastic agents, is usually 100 mg/m²/day administered 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 by intravenous infusion lasting 1 to 3 hours, given every 12 hours for 2–6 days, either concomitantly with other antineoplastic agents or as monotherapy.

Subcutaneous administration
Typically, 20–100 mg/m² is administered depending on the indication and treatment regimen used.

Dosing of the drug in acute lymphoblastic leukemia and non-Hodgkin’s lymphoma in children should follow current guidelines.

Children and adolescents
Drug dosing is similar to that recommended for adults. Current recommendations for dosing in children and adolescents should be verified in the latest treatment guidelines.

Pharmaceutical incompatibilities
The drug is physically incompatible with heparin, insulin, 5-fluorouracil, sodium succinate of methylprednisolone, and penicillins such as oxacillin and penicillin G.

Pharmaceutical compatibility
Cytarabine remains pharmaceutically compatible with the following products at specified concentrations in 5% aqueous glucose solution for 8 hours: cytarabine 0.8 mg/ml and cephalothin (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.

Special precautions during storage

Stability and compatibility after reconstitution
Chemical and physical stability studies of the drug have shown that cytarabine remains stable for 7 days at temperatures below 25°C in glass bottles and plastic infusion bags in a solution at a concentration of 0.5 mg/ml when combined with the following solvents:

• Water for injections,
• 5% glucose solution for injections,
• 0.9% sodium chloride solution for injections.

Cytarabine also remains stable for 7 days at temperatures below 25°C, at 20°C and 4°C, in glass bottles and plastic infusion bags in a solution at a concentration of 8–32 mg/ml when combined with the following solvents:
5% glucose solution for injections,

• 5% glucose in 0.2% sodium chloride solution for injections,
• 0.9% sodium chloride solution for injections.

Cytarabine remains stable for up to 8 days at temperatures below 25°C at a concentration of 2 mg/ml in the presence of KCl at a concentration of 50 mEq/500 ml when combined with the following solvents:

• 5% glucose solution for injections,
• 0.9% sodium chloride solution for injections.

Cytarabine also remains stable at temperatures below 25°C or at temperatures from 8°C at concentrations of 0.2–1.0 mg/ml in the presence of sodium bicarbonate at 50 mEq/l in 5% glucose solution or 5% glucose in 0.2% sodium chloride solution for 7 days in glass bottles or infusion bags.

Cytarabine injections and prepared infusion solutions do not contain antimicrobial agents. Therefore, it is recommended that further dilutions be prepared immediately before use and that infusion be started as soon as possible after solution preparation. The infusion should be completed within 24 hours of solution preparation, and any remaining solution should be discarded.