Cytosar

Patient Information Leaflet

CYTOSAR, 20 mg/ml, solution for injection/infusion
Cytarabine
Please read all of this leaflet carefully before using this medicine, as it contains
important information for you.

• Keep this leaflet, so that you can read it again if necessary.
• If you have any further questions, please consult your doctor, pharmacist or nurse.
• 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 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 drugs. 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 leukemia in adults and children. It is also indicated for the treatment of acute lymphoblastic leukemia and chronic myeloid leukemia. It may be used as monotherapy (as a single drug) or in combination with other anticancer agents.
The best results are achieved with combination therapy.
Cytosar, administered alone or in combination with hydrocortisone sodium succinate and methotrexate by intrathecal route, may be used in the treatment of leukemia involving the meninges.
High-dose Cytosar administered by intravenous infusion, either alone or in combination with other anticancer drugs, is effective in the treatment of poor-prognosis leukemia, treatment-resistant leukemia, and relapses of acute leukemia.
Cytosar is rarely effective in treating patients with solid tumors.

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).
• benzyl alcohol-containing diluents must not be used for the preparation of the medicine in the case of high-dose intravenous therapy, intrathecal administration, or administration to 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 detected drug-induced bone marrow suppression. Cytosar 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 associated with granulocytopenia (reduction in the number of neutrophil granulocytes – a type of white blood cell), impaired immune defense, and bleeding due to thrombocytopenia. The doctor will consider discontinuing treatment or adjusting the dose if the patient’s peripheral blood shows fewer 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 (e.g., seizures), gastrointestinal, lung damage (adult respiratory distress syndrome, pulmonary edema), and symptoms of cardiomegaly (enlargement of the heart).

• In patients treated with high doses of Cytosar, because severe eye damage and risk of neuropathy (peripheral nerve disease) have been observed. Changes in the treatment regimen may be necessary to avoid irreversible neurological disorders.

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

• In patients with acute non-lymphocytic 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 and 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 the possibility of peritonitis, colitis with accompanying neutropenia and thrombocytopenia.

• In children with acute myeloid leukemia, following intrathecal and intravenous administration of standard doses of cytarabine 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 drug should be used, if possible, at reduced doses.

• During treatment with Cytosar together with other drugs due to the risk of acute pancreatitis.

• During intrathecal administration of Cytosar due to the risk of systemic toxic effects. Careful monitoring of hematopoietic function by the physician is recommended. Dose adjustment may be necessary.

• In patients receiving Cytosar both intrathecally and intravenously within several days, because of an increased risk of spinal cord damage. In life-threatening situations, the decision to administer the drug both intrathecally and intravenously simultaneously should be based solely on the attending physician’s assessment.

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

Cytosar may cause hyperuricemia (increased blood uric acid levels) as a consequence of rapid lysis (breakdown) of tumor cells. The doctor should monitor the patient’s blood uric acid levels and, if necessary, apply appropriate pharmacological measures.
Patients receiving Cytosar should undergo periodic 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 effectiveness may be reduced.
Administration of live or live attenuated vaccines to patients with immunosuppression due to chemotherapy (including Cytosar) may lead to severe infections or even death.

Cytosar and other medicines
Before using any new medicine together with Cytosar, inform your doctor. Tell your doctor about all medicines currently used or recently used, as well as any medicines the patient plans to take.
Cytosar may affect digoxin plasma concentrations.
Lack of rapid improvement has been observed in patients infected with Klebsiella pneumoniae who are receiving Cytosar and being treated with gentamicin. A change in antibacterial therapy is recommended.
Cytosar may reduce the efficacy 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 have a child, she should consult her doctor or pharmacist before using this medicine.
If pregnancy occurs, contact your doctor immediately.
Pregnant women or women of childbearing age 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 begins in the second or third trimester of pregnancy.

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 suitable 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 Cytosar into human milk.
Due to the risk of serious adverse effects in infants breastfed by mothers receiving Cytosar, the doctor will consider the decision to discontinue breastfeeding during treatment with Cytosar and for at least one week after the last dose, or to discontinue 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 and operate machinery has not been studied.
Cytosar may affect the ability to drive and operate machinery due to possible adverse effects (e.g., brain function disorders, dizziness).

Cytosar contains sodium
Cytosar 100 mg/5 ml (20 mg/ml) solution for injection/infusion contains 13.25 mg of sodium (main component of table salt) in each 5 ml vial. This corresponds to 0.7% of the maximum recommended daily sodium intake for adults.
Cytosar 500 mg/25 ml (20 mg/ml) solution for injection/infusion contains 66.25 mg of sodium (main component of table salt) in each 25 ml vial. This corresponds to 3.31% of the maximum recommended daily dietary sodium intake for adults.
When calculating total sodium content in the prepared medication, the sodium content from the diluent (e.g., sodium chloride solution) must also be taken into account.

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, subcutaneously, or intrathecally.
Use of a higher than recommended dose of Cytosar
Cytosar will be used in a hospital setting by physicians experienced in the field of cancer chemotherapy, therefore the use of a higher than recommended dose is unlikely.
Discontinuation of Cytosar treatment
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 (systemic infection), pneumonia, infection.
• Bone marrow suppression, thrombocytopenia (reduced number of blood platelets), anaemia, megaloblastic anaemia (a syndrome of symptoms resulting from haemoglobin levels below normal and a 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), 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 cerebellum*, somnolence*.
• Corneal disorders*.
• Acute respiratory distress syndrome (lung disease)*, pulmonary oedema*.

Common (may occur in not more than 1 in 10 people):

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

Frequency unknown (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 hands and soles of feet (hand-foot syndrome, palmar-plantar erythrodysesthesia), 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 ulcer*, intestinal emphysema*, peritonitis*.
• Liver damage*, hyperbilirubinemia* (increased concentration of bilirubin in blood).

* Adverse reactions occurring after high-dose therapy, other than those following 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 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
Adverse reactions may also be reported to the marketing authorisation holder or its representative.

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

5. How to store Cytosar

Keep this medicine out of 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 after dilution, see section "Information intended solely for healthcare professionals. Shelf life after dilution".

6. Contents of the package and other information

What Cytosar contains:

• The active substance is cytarabine. One ml of 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, colourless or slightly yellow aqueous solution, free from visible particles, in a
polypropylene vial with a chlorobutyl rubber stopper coated with Teflon*, an aluminium seal and a plastic, opaque, purple flip-off cap, packed 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 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 more detailed information about this medicine, please contact:
Pfizer Polska Sp. z o.o.
tel: 22 335 61 00

Information intended exclusively for medical professionals

The medicinal product Cytosar may be administered only by physicians experienced in cancer chemotherapy.
When administering intrathecally, the medicinal product should be diluted with preservative-free 0.9% sodium chloride injection solution.
When administering intravenously, the medicinal product should be diluted with preservative-free 0.9% sodium chloride solution, 5% glucose solution, or water for injections.
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 between 250 and 350 mOsm/kg.

Dosage and method of administration
Intravenous administration
Standard doses
At the beginning of treatment (induction of remission) of acute non-lymphocytic leukemia, the dose of Cytosar used concomitantly with other antineoplastic agents is usually 100 mg/m²/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 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 doses, 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.

Intrathecal administration in leukemia with meningeal involvement
When preparing the medicinal product Cytosar for intrathecal administration, diluents containing benzyl alcohol must not be used; only preservative-free 0.9% sodium chloride injection solution should be used. The medicinal product should be administered immediately after preparation.

Cytosar has been administered intrathecally in acute leukemia at doses ranging from 5 mg/m² to 75 mg/m². The frequency of administration varied from once daily for 4 days to once every 4 days. The most commonly used dose was 30 mg/m² every 4 days until normalization of cerebrospinal fluid test results, followed by one additional course of treatment. The dosing regimen generally depends on the type and severity of central nervous system symptoms and the response to prior treatment.

Cytosar has been administered intrathecally together with hydrocortisone sodium succinate and methotrexate, both for prophylaxis in newly diagnosed acute lymphoblastic leukemia in children and for treatment of leukemia with meningeal involvement. Prophylactic treatment with these three drugs prevented central nervous system (CNS) disease involvement and provided similar overall remission rates and survival levels compared to patients who received CNS irradiation and intrathecal methotrexate as initial prophylaxis. The dose of cytarabine was 30 mg/m², hydrocortisone sodium succinate 15 mg/m², and methotrexate 15 mg/m² (total maximum single dose of 15 mg/m² methotrexate). Before initiating treatment, the physician should be familiar with this regimen; however, in children and adolescents, methotrexate dosing should be based on age rather than body surface area.

Prophylactic treatment with the three-drug regimen may be used after successful initial treatment of leukemia with meningeal involvement. Before initiating therapy according to this regimen, the physician should consult current guidelines.

Intrathecally administered cytarabine may cause systemic toxic effects, requiring careful monitoring of the hematopoietic system. Modification of anti-leukemic treatment may be necessary. Severe toxic effects are rare. When cytarabine is administered both intrathecally and intravenously within a few days of each other, there is an increased risk of toxic effects on the bone marrow; however, in cases of severe, life-threatening disease, concomitant intravenous and intrathecal administration of cytarabine may be considered at the discretion of the treating physician.

In cases of focal leukemic infiltrates in the central nervous system, intrathecal administration of the drug may be ineffective. In such cases, radiotherapy is preferred.

For intrathecal administration, the maximum volume of the solution is 10 ml. Prior to intrathecal administration of the required dose, an equivalent volume of cerebrospinal fluid (usually 7–10 ml) must be removed to minimize any change in cerebrospinal fluid volume.

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

When preparing the medicinal product Cytosar for administration in 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 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 25°C/60% relative humidity with exposure to light, and at 2°C–8°C/environmental humidity without exposure to light.

From a microbiological standpoint, the medicinal product should be used immediately. If the medicinal 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 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 handling 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 of the medicinal product, 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 solution, followed by water;
• All materials used for decontamination should be disposed of as described above;
• Any unused remnants of the medicinal product should be disposed of as described above;
• In case of contact of the medicinal product with the skin, the area should be thoroughly washed with soap and water or sodium carbonate solution. A brush should not be used to avoid abrading the epidermis;
• In case of contact of the medicinal product with the eye, the eyelid should be held open and the eye irrigated with large amounts of water for at least 15 minutes. Medical evaluation should then be sought;
• Hands should always be washed after removing gloves.