Cytosar

Patient Information Leaflet

CYTOSAR, 500 mg, powder and solvent 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. This medicine may harm other people, 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.

Contents of the leaflet

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. This medicine must 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 leukemia in adults and children. It is also indicated in the treatment of acute lymphoblastic leukemia and chronic myeloid leukemia. 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 in combination with other anticancer medicines or as monotherapy, is effective in the treatment of poor-prognosis leukemia, treatment-resistant leukemia, and relapses of acute leukemia.
It is rarely effective in the treatment of patients with solid tumors.

2. Information before using the medicine

When not to use the medicine

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

When preparing high-dose intravenous therapy, solvents containing benzyl alcohol must not be used.

Warnings and precautions

• In patients with previously diagnosed 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 number of platelets) and anemia. There is a risk of potentially fatal infections related to granulocytopenia (reduced number of neutrophil granulocytes – 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 shows less than 50,000 platelets/mm³ or 1,000 granulocytes/mm³. Re-administration of the medicine may be considered after bone marrow recovery and increased platelet and granulocyte counts.

• In patients receiving high doses of the medicine (2–3 g/m² BSA) due to the occurrence of severe and sometimes fatal central nervous system toxicity (including seizures), gastrointestinal, and pulmonary toxicity (adult respiratory distress syndrome, pulmonary edema), as well as cardiomegaly (enlargement of the heart).

• In patients treated with high doses of the medicine, due to observed severe eye damage and 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, due to reported cases of fatal cardiomegaly.

• In patients with acute non-lymphocytic leukemia receiving high-dose cytarabine, daunorubicin, and asparaginase concomitantly, due to observed motor and sensory peripheral neuropathies.

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

• In patients receiving standard doses of the medicine together with other drugs, due to the possible occurrence of peritonitis, colitis associated with neutropenia and thrombocytopenia.

• In children with acute myeloid leukemia, after intrathecal and intravenous administration of standard doses of the medicine together with other drugs, 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 reduced doses.

• During concomitant use of the medicine with other drugs due to the possible occurrence of acute pancreatitis.

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

• Cases of severe neurological adverse reactions, including headache, paralysis, coma, and stroke-like episodes, have been reported in patients receiving the medicine intravenously together with intrathecally administered methotrexate.

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

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

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

Other medicines

Before using any new medicine together with this medicine, inform your doctor. Tell your doctor about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take.

The medicine may affect digoxin plasma concentrations.

Lack of rapid clinical 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 effectiveness of fluorocytosine.

Intravenous administration of the medicine together with intrathecal 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 become pregnant, she should consult her doctor or pharmacist before using this medicine. If pregnancy occurs, contact the doctor immediately.

Pregnant women or women of childbearing potential may receive the medicine only after careful consideration of the benefit-risk ratio for both 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.

Cytosar 500 mg powder and solvent for solution for injection contains benzyl alcohol – a preservative that may cross the placenta (see section 2 “The medicine contains benzyl alcohol and sodium”).

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 you and your 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 breastfed infants, the physician will consider either discontinuing breastfeeding during treatment with the medicine 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 the medicine on the ability to drive and operate machinery has not been studied. The medicine may affect the ability to drive and operate machinery due to possible adverse effects (e.g., central nervous system disorders, dizziness).

The medicine contains benzyl alcohol and sodium

Cytosar 500 mg powder and solvent for solution for injection contains 9 mg of benzyl alcohol in each 1 ml of solvent, equivalent to 9 mg/ml benzyl alcohol. Benzyl alcohol may cause allergic reactions. Administration to young children is associated with the risk of serious adverse effects, including respiratory distress (so-called "gasping syndrome").

Do not administer to newborns (up to 4 weeks of age) without medical advice.

Do not administer to young children (under 3 years of age) for longer than one week without medical advice or pharmacist consultation.

Patients with liver or kidney disease, and pregnant or breastfeeding women should consult their doctor or pharmacist before using the medicine, as large amounts of benzyl alcohol may accumulate in their bodies and cause adverse effects (such as metabolic acidosis).

When the medicine is administered in high doses, solvents containing benzyl alcohol must not be used. The medicine should be reconstituted with preservative-free 0.9% sodium chloride solution.

The medicine contains less than 1 mmol (23 mg) of sodium per vial, meaning the medicine is considered "sodium-free".

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 protocol used. The medicine may be administered by intravenous infusion, intravenous injection, or subcutaneously.
Use of a higher than recommended dose of the medicine
The medicine will be used in a hospital setting by physicians experienced in cancer chemotherapy, therefore administration of a higher than recommended dose is unlikely.
Discontinuation of the medicine
The decision to discontinue treatment will be made by the doctor. If you have any further doubts 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 occur in more than 1 in 10 people):

• Septicaemia (generalised infection), pneumonia, infection.
• Bone marrow suppression, thrombocytopenia (reduced number of blood platelets), anaemia, megaloblastic anaemia (a syndrome of symptoms resulting from haemoglobin levels and number of red blood cells lower than normal, with 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 mouth), oral mucosal ulceration, anal mucosal ulceration, inflammation of the anal mucosa, diarrhoea, 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, most commonly occurring 6 to 12 hours after administration of the drug).
• Fever.
• Abnormal bone marrow biopsy and blood smear results.
• Disorders of brain and cerebellar function*, somnolence*.
• Corneal disorders*.
• Acute respiratory distress syndrome (lung disease)*, pulmonary oedema*.

Common (may occur in no more than 1 in 10 people):

• Skin ulceration.
• Necrotising enteritis*.
• Skin desquamation*.

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

• Subcutaneous tissue inflammation at the injection site.
• Anaphylactic reaction (sudden allergic reaction), allergic oedema.
• Decreased appetite.
• Toxic nerve damage, neuritis, dizziness, headache.
• Conjunctivitis.
• Pericarditis, sinus bradycardia (reduced heart rate).
• Thrombophlebitis.
• Dyspnoea, sore throat.
• Pancreatitis, oesophageal ulceration, oesophagitis.
• Jaundice.
• Painful redness and blistering of the palms and soles (hand-foot syndrome), urticaria, pruritus, pigmentation.
• Renal dysfunction, urinary retention.
• Chest pain, pain and inflammation at the subcutaneous injection site.
• Liver abscess*.
• Personality change*.
• Coma*, seizures*, peripheral motor neuropathy*, peripheral sensory neuropathy*.
• Cardiomyopathy* (heart disease).
• Gastric or intestinal necrosis*, gastric or intestinal ulceration*, intestinal perforation*, peritonitis*.
• Liver damage*, hyperbilirubinemia* (increased concentration of bilirubin in the blood).

*Adverse reactions occurring after high-dose treatment, different from those observed after standard doses.

Reporting of adverse reactions

If any adverse reactions occur, including any adverse reactions not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Reactions of Medicinal Products at 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
Adverse reactions can also be reported to the marketing authorisation holder or its representative.

Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store the medicine

Keep the medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label and (or) outer packaging following:
EXP. The expiry date refers to the last day of the stated month.
Store below 25°C.
The prepared solution (using the solvent provided in the package) may be stored
for up to 4 days in a refrigerator (2°C - 8°C) or up to 24 hours at temperatures below 30°C.
Medicines must not be disposed of via wastewater or household waste. Ask your
pharmacist how to dispose of medicines no longer in use. This will help protect
the environment.

6. Contents of the pack and other information

What the medicine contains

• The active substance is cytarabine. Each vial contains 500 mg of cytarabine.
• The other components are: hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment).
• Solvent: water for injections, benzyl alcohol (see section 2 "The medicine contains benzyl alcohol and sodium").

What the medicine looks like and contents of the pack
A white crystalline powder and a clear solvent.
The pack contains 1 vial made of clear glass closed with a bromobutyl stopper and an aluminium cap, and 1 ampoule made of clear glass containing the solvent, in a cardboard box.

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

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

For further information, contact the marketing authorisation holder:
Pfizer Poland Sp. z o.o.
tel: 22 335 61 00

Information intended exclusively for medical 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.

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

Intravenous administration

Standard doses
At the beginning of treatment (induction of remission) of acute non-lymphocytic leukemia, the usual dose of the drug, used concomitantly with other antineoplastic agents, is typically 100 mg/m² body surface area 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 by intravenous infusion lasting 1 to 3 hours, given every 12 hours for 2–6 days, either in combination with other antineoplastic agents or as monotherapy. When administering high-dose therapy, solvents containing benzyl alcohol must not be used.

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

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

Children and adolescents
Dosing of the drug is similar to that recommended for adults. Current recommendations for dosing in children and adolescents should be verified in the most recent treatment guidelines.

For reconstitution of the product, preservative-free 0.9% sodium chloride solution for injection should be used. The product should be administered immediately after preparation.

Pharmaceutical incompatibilities
The drug is physically incompatible with heparin, insulin, 5-fluorouracil, and sodium succinate methylprednisolone, as well as 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 for 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 intravenous infusion bags in a solution at a concentration of 0.5 mg/ml when combined with the following diluents:

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

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

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

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 diluents:

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

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 intravenous 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 the infusion should 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.