Cytosar

Package leaflet: Information for the user

CYTOSAR, 100 mg/ml, solution for injection/infusion
Cytarabinum
Please read all of this leaflet carefully before using this medicine because it contains
important information for you.

• Keep this leaflet as you may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you experience any side effects, including any not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Contents of the leaflet

1. What Cytosar is and what it is 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 Cytosar is and what it is used for

Cytosar belongs to a group of anticancer medicines. This medicine may be administered only by physicians 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 medicines, is effective in the treatment of poor-prognosis leukaemia, treatment-resistant leukaemia, and relapses of acute leukaemia.
Cytosar is rarely effective in the treatment of patients with solid tumours.

2. Important information before using Cytosar

When not to use Cytosar

• if the patient is allergic to cytarabine or any of the other ingredients of this medicine (listed in section 6);
• diluents containing benzyl alcohol must not be used to prepare the medicine when high-dose therapy is administered intravenously or in infants and children under 3 years of age.

Warnings and precautions
Before starting treatment with Cytosar, discuss this with your doctor, pharmacist, or nurse.

• In patients with previously diagnosed drug-induced bone marrow suppression. Cytosar 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 neutrophil granulocytes – a type of white blood cell), impaired immune defense, and bleeding due to thrombocytopenia. The doctor will consider interrupting 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 drug may be possible after bone marrow recovery and an increase in platelet and granulocyte counts.

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

• In patients treated with high doses of Cytosar, because severe ocular damage has been observed, as well as risk of neuropathy (peripheral nerve disease). Dose modifications or changes in treatment regimen may be necessary to avoid irreversible neurological disorders.

• In patients receiving high doses of Cytosar in combination with cyclophosphamide, because cases of fatal cardiomegaly have been reported.

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

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

• In patients receiving standard doses of Cytosar together with other drugs, due to possible occurrence of peritonitis, colitis accompanied by neutropenia and thrombocytopenia.

• In children with acute myeloid leukemia, following intrathecal and intravenous administration of standard doses of cytarabine in combination with other drugs, delayed progressive ascending paralysis resulting in death has been observed.

• In patients with impaired liver or kidney function, for whom the drug should be used, if possible, at reduced doses.

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

• In patients receiving intravenous Cytosar together with intrathecal methotrexate, severe neurological adverse reactions have been reported, including headache, paralysis, coma, and stroke-like episodes.

Cytosar may cause hyperuricemia (increased serum uric acid levels) as a consequence of rapid lysis (breakdown) of tumor cells. The doctor should monitor the patient's serum uric acid levels and, if necessary, initiate appropriate pharmacological measures.
Patients receiving Cytosar should undergo regular monitoring of bone marrow, liver, and kidney function.
Patients receiving Cytosar 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 patients with immunosuppression due to chemotherapy (including Cytosar) may lead to severe infections and even death.

Cytosar with other medicines
Before using any new medicine together with Cytosar, inform your doctor. Tell your doctor about all medicines currently being taken or recently used, as well as any medicines the patient plans to take.
Cytosar may affect serum digoxin levels.
Lack of rapid improvement has been observed in patients infected with Klebsiella pneumoniae who are receiving Cytosar and being treated concomitantly with gentamicin. A change in antibacterial therapy is recommended.
Cytosar may reduce the effectiveness of flucytosine.
Intravenous administration of Cytosar 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 during treatment, contact the doctor immediately.
Pregnant women or women of childbearing potential may receive Cytosar only after careful consideration of the potential benefits versus risks to the mother and fetus.
Use of Cytosar 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.

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 excretion of Cytosar into human milk.
Due to the risk of serious adverse effects in infants breastfed by mothers receiving Cytosar, the doctor will consider either discontinuing breastfeeding during treatment with Cytosar and for at least one week after the last dose, or discontinuing the drug, taking into account the benefit of treatment for the mother.

Driving and operating machinery
The effect of Cytosar on the ability to drive or operate machinery has not been studied.
Cytosar may affect the ability to drive and operate machinery due to possible adverse effects (e.g., central nervous system disorders, dizziness).

Cytosar contains sodium
The medicine contains less than 1 mmol (23 mg) of sodium per 1 ml vial, meaning the medicine is considered "sodium-free".
In the prepared solution for administration, the total sodium content should also include sodium from the diluent, e.g., sodium chloride solution.

3. How to use Cytosar

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. Cytosar may be administered
by intravenous infusion, intravenous injection, or subcutaneously.
Use of a higher than recommended dose of Cytosar
Cytosar will be used in hospital settings by physicians experienced in cancer chemotherapy,
therefore the use of a higher than recommended dose is unlikely.
Discontinuation of Cytosar treatment
The decision to discontinue 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 will experience them.

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

• Septicaemia (systemic infection), pneumonia, infection.
• Bone marrow suppression, thrombocytopenia (reduced number of blood platelets), anaemia, megaloblastic anaemia (syndrome characterized by lower than normal haemoglobin levels 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 mouth), ulceration of the oral mucosa, ulceration of the anal mucosa, proctitis (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 results of bone marrow biopsy and blood smear.
• Disorders of brain and cerebellar function*, somnolence*.
• Corneal disorders*.
• Acute respiratory distress syndrome (lung disease)*, pulmonary oedema*.

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 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 ulcer, oesophagitis.
• Jaundice.
• Painful redness and blistering of the palms and soles (hand-foot syndrome), urticaria, pruritus, pigmentation.
• Renal function impairment, 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 ulcer*, intestinal emphysema*, peritonitis*.
• Liver damage*, hyperbilirubinemia* (increased concentration of bilirubin in blood).

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

Reporting of adverse reactions

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

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

5. How to store Cytosar

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label, carton after:
Expiry date (EXP). The expiry date refers to the last day of the stated month.
Store below 25°C. Do not freeze.
Store in the original packaging to protect from light.
For storage conditions of the medicine after reconstitution, see section "Information intended solely for healthcare professionals. Shelf life after reconstitution".

6. Contents of the pack and other information

What Cytosar contains:

• The active substance is cytarabine. One ml of solution contains 100 mg of cytarabine. One 10 ml vial contains 1000 mg of cytarabine. One 20 ml vial contains 2000 mg of cytarabine.
• The other ingredients are: hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), water for injections.

What Cytosar looks like and contents of the pack
A clear, colourless or slightly yellow aqueous solution, free from visible particles, in a
polypropylene vial with a chlorobutyl rubber stopper coated with Teflon, sealed with an
aluminium cap and a plastic, opaque, purple flip-off cap, packed in a cardboard box.
The pack contains 1 vial of 10 ml or 5 vials of 10 ml, or 1 vial of 20 ml, or 10 vials of 20 ml.
Not all pack sizes may be marketed.

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

Manufacturer
Pfizer Service Company BV
Hoge Wei 10
1930 Zaventem
Belgium

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

Information intended exclusively for healthcare professionals

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

Dosage and method of administration
Intravenous administration
Standard doses
At the beginning of treatment (induction of remission) for acute non-lymphocytic leukemia, the dose of Cytosar medicinal product, used concomitantly with other antineoplastic agents, is usually 100 mg/m² daily 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 as an 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, diluents containing benzyl alcohol must not be used; only preservative-free diluents should be used.

Subcutaneous administration
The usual dose is 20–100 mg/m², depending on the indication and treatment regimen used.

Dosing of the medicinal product Cytosar in acute lymphocytic leukemia and non-Hodgkin’s lymphoma in children should follow current guidelines.

Children and adolescents
Dosing of the medicinal product Cytosar is similar to that recommended in adults. Current recommendations for dosing in children and adolescents should be verified in the latest treatment standards.

When preparing the medicinal product Cytosar for administration to infants and children under 3 years of age, diluents containing benzyl alcohol must not be used; preservative-free diluents should be used. The medicinal product should be administered immediately after preparation.

Cytosar is inactive when administered orally. The route of administration depends on the treatment regimen used.

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.

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

Shelf-life of the medicinal product after dilution
The cytarabine injection solution is physically and chemically stable at concentrations from 0.1 mg/ml to 1 mg/ml after dilution with:

• 0.9% sodium chloride solution,
• 5% glucose solution,
• water for injections,
  for up to 4 days at either 25°C/60% relative humidity with exposure to light or at 2°C–8°C/environmental humidity in the absence of light.

From a microbiological standpoint, the medicinal product should be used immediately. If the product is not used promptly, 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 dilution was performed under controlled and validated aseptic conditions.

Protective measures
Due to the toxicity of the substance, the following precautions are recommended:

• Personnel should be trained in the proper techniques for dilution and handling of the medicinal product;
• Pregnant women should not be allowed to handle this medicinal product;
• Individuals in contact with cytarabine should wear protective clothing: goggles, gowns, disposable gloves, and masks;
• Dilution of the medicinal product should be performed in a designated area (preferably equipped with a laminar airflow system); the work surface should be protected with disposable absorbent paper with a plastic backing;
• All materials used for dilution, administration, or cleaning, including gloves, should be placed in tightly sealed high-risk waste bags and then incinerated at 1100°C;
• Spilled or leaking medicinal product should be washed off with 5% sodium hypochlorite, followed by water;
• All materials used for decontamination should be disposed of as described above;
• Any unused remnants of the medicinal product should be discarded as described above;
• In case of contact with the skin, the affected area should be thoroughly washed with soap and water or sodium carbonate solution. A brush should not be used to avoid abrading the epidermis;
• If the medicinal product gets into the eye, the eyelid should be held open and the eye irrigated with copious amounts of water for at least 15 minutes. A medical examination should then be performed;
• Hands should always be washed after removing gloves.