Package Insert: Information for the User

Citarabina Accord 100 mg/ml Injectable Solution and for Infusion

Read the entire package insert carefully before starting to use the medication

• Keep this package insert, as you may need to refer to it again.
• If you have any questions, consult your doctor or pharmacist.
• This medication has been prescribed for you and should not be given to others, even if they have the same symptoms, as it may harm them.
• If you consider any of the adverse effects you are experiencing to be severe or if you notice any adverse effect not mentioned in this package insert, inform your doctor or pharmacist.

Citarabina Accord is used in children and adults. The active ingredient is citarabina.

Citarabina is part of a group of medicines called cytotoxics; these medicines are used in the treatment of acute leukaemias (blood cancer characterised by an excess of leucocytes). Citarabina interferes with the growth of neoplastic cells, which are eventually destroyed.

Citarabina is also used to induce and maintain remission of acute leukaemia.

Remission induction is an intensive treatment that aims to force a reduction in leukaemia. When it works, the balance of blood cells normalises and their health improves. This period of relative health is called remission.

Maintenance treatment is a less intensive treatment whose aim is to make remission last as long as possible. Low doses of citarabina are used to keep leukaemia under control and prevent it from worsening.

No use Citarabina Accord

• If you are allergic to the active ingredient or any of the other components of this medication.
• If you are already taking medications that have caused a reduction in blood cell counts due to bone marrow suppression (the tissue that has the ability to generate blood cells).

Warnings and precautions

Consult your doctor or pharmacist before starting to use Citarabina Accord.

• If your bone marrow is affected, treatment should be initiated under close medical supervision.
• If you have liver problems.
• Citarabina significantly reduces blood cell production in the bone marrow. This can increase the risk of infections or bleeding. Blood cell counts may continue to decrease up to a week after stopping treatment. Your doctor will perform periodic blood tests and examine your bone marrow if necessary.
• Severe and potentially life-threatening adverse effects may occur in the central nervous system, intestines, or lungs.
• During treatment with citarabina, your liver and kidney functions should be monitored. If your liver and/or kidneys do not function properly before treatment, citarabina can only be administered with maximum caution.
• Your blood levels of uric acid (which shows that cancer cells have been destroyed) may be high during treatment. Your doctor will tell you if you need to take any medication to control it.

Use of Citarabina Accord with other medications

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication, as well as in the following cases:

• If you receive medications containing 5-fluorocytosine (a medication used to treat fungal infections).
• If you take medications containing digitoxin or beta-acetildigoxin, which are used to treat certain heart conditions.
• If you take gentamicin (an antibiotic to treat bacterial infections).
• If you receive medications containing cyclophosphamide, vincristine, and prednisone, which are used in cancer treatment programs.
• If you are administered citarabina intravenously in combination with methotrexate intrathecally.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medication.

Pregnancy

You should not become pregnant while you or your partner are being treated with citarabina. If you are sexually active, you are recommended to use effective contraceptive methods to avoid pregnancy during treatment, regardless of your sex. Citarabina can cause congenital anomalies, so it is essential to inform your doctor if you think you are pregnant. Both men and women should use effective contraceptive methods during treatment and for 6 months after.

Contraception in fertile women

Women should always use effective contraceptive methods (contraception) to avoid pregnancy during treatment and for 6 months after the last dose. Consult your doctor about the contraceptive methods that are suitable for you and your partner.

Contraception in men

Male patients with female partners in fertile age should always use highly effective contraceptive methods to prevent pregnancy during treatment and for 3 months after the last dose.

Breastfeeding

You should stop breastfeeding during treatment with citarabina and for at least a week after the last dose or stop treatment, as this medication may be harmful to infants.

Fertility

Due to the potential risk of infertility after treatment, you should consider preserving semen before starting treatment with citarabina.

Driving and operating machinery

Cancer treatment in general may affect some patients' ability to drive or operate machinery. If you are affected, you should not drive or operate machinery.

Form and Route of Administration

Citarabina will be administered through infusion in a vein (through "drip") or through injection in the hospital, under the supervision of specialists. Your doctor will decide the dose to administer and the number of treatment days you will receive based on your condition.

Dosing Schedule

Your doctor will determine the citarabina dose based on your condition, and according to your weight or body surface area and whether you are receiving induction or maintenance treatment. Your body surface area will be calculated based on your weight and height.

During treatment, you will require frequent examinations, which will include blood tests. Your doctor will tell you how often you need to do this, and will be responsible for performing regular tests of:

• Blood, to check if you have low blood cell counts that require treatment.
• Liver (also through blood tests) to check that citarabina is not negatively affecting your liver function.
• Kidneys (also through blood tests) to check that citarabina is not negatively affecting your kidney function.
• Uric acid levels in blood: citarabina could increase uric acid levels in the blood. If your uric acid levels are too high, another medication may be administered.

If You Use More Citarabina Accord Than You Should

High doses can exacerbate adverse effects, such as mouth ulcers, or reduce the count of white blood cells and platelets (which contribute to blood clotting) in the blood. In this case, you may need antibiotics or blood transfusions. Mouth ulcers can be treated to reduce discomfort during the healing process.

If you have any doubts about the use of this product, consult your doctor or pharmacist.

Like all medicines, Citarabina Accord may cause side effects, although not everyone will experience them.

The side effects of citarabine depend on the dose. The digestive tract is usually the most affected organ, as well as the blood.

Frequent side effects (may affect more than 1 in 10 patients) include:

• Infections, generalized infection, pneumonia.
• Reduction in the number of red blood cells, white blood cells, and/or platelets in the blood.
• Depression of the bone marrow, i.e., alteration of its immune system with loss of ability to fight infections or diseases.
• Alteration of the normal function of the brain and cerebellum*, feeling of sleepiness*.
• Corneal disorder of the eye*.
• Accumulation of fluid in the lungs*, difficulty breathing*.
• Nausea, vomiting, diarrhea, inflammation or ulcers in the mouth or anus, abdominal pain.
• Liver dysfunction.
• Rash, hair loss.
• Fever, citarabine syndrome (consists of muscle pain, bone pain, and sometimes chest pain, fever, conjunctivitis, rash, and discomfort, which usually appears 6-12 hours after administration and is treated with corticosteroids).
• Changes in the appearance of bone marrow cells and blood cells.

Frequent side effects (may affect up to 1 in 10 patients) include:

• Colitis necrosante*, i.e., inflammation of a portion of the intestine with death of intestinal cells.
• Ulcers on the skin, desquamation*.

Side effects of unknown frequency (cannot be estimated from available data) include:

• Severe allergic reaction.
• Inflammation at the injection site.
• Localized pus formation in the liver*.
• Allergic fluid retention.
• Loss of appetite.
• Change in personality*.
• Toxicity to the nervous system, inflammation of nerves, headache, dizziness, coma*, alterations in peripheral nervous system motor and sensory function* (when administered intrathecally), in children, a rare inflammatory disorder may occur that causes damage to the nerve covering material (leucoencephalopathy necrosante), paralysis of the legs and lower body (paraplegia), ascending progressive paralysis, progressive toxicity, convulsions.
• Conjunctivitis (infection in a part of the eye that may be accompanied by rash), conjunctivitis with hemorrhage*, blindness (when administered intrathecally).
• Pericarditis, i.e., inflammation of the tissue covering the heart, bradycardia sinusal, i.e., slower than usual heart rate.
• Cardiomyopathy*, i.e., heart disease, cardiomegaly*, i.e., increased heart size.
• Thrombophlebitis, i.e., obstruction and inflammation of the blood vessel at the injection site.
• Throat pain, shortness of breath, inflammation of a part of the lung tissue*.
• Esophageal ulcer, esophageal inflammation, gastrointestinal ulcer*, presence of cysts in the intestinal wall*, peritonitis*, death of intestinal cells*, pancreatitis.
• Yellowish discoloration of the skin, liver damage*, increased bilirubin levels*.
• Urticaria, skin rash, itching.
• Urinary retention, kidney dysfunction.
• Chest pain.
• Reaction at the injection site.
• Hand and foot palm rash.

*Due only to high doses of citarabine

Reporting of side effects:

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish System of Pharmacovigilance of Medicines for Human Use: https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep out of reach and sight of children.

Do not store above 25°C.

Store the vial in the outer packaging to protect it from light.

Do not refrigerate.

Do not use this medication after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

The medication must be used immediately after opening the vial.

Do not use the solution if it is not clear, colorless, and free of particles.

The disposal of unused medication and all materials that have been in contact with it will be carried out in accordance with local regulations.

Composition of Citarabina Accord

The active ingredient is citarabine. Each milliliter of solution contains 100 mg of citarabine.

Each 1 mL vial contains 100 mg of citarabine.

Each 5 mL vial contains 500 mg of citarabine.

Each 10 mL vial contains 1 g of citarabine.

Each 20 mL vial contains 2 g of citarabine.

Each 40 mL vial contains 4 g of citarabine.

Each 50 mL vial contains 5 g of citarabine.

The other components are macrogol 400, trometamol, and water for injection preparations.

Appearance of the product and contents of the package

Clear and colorless solution, free of visible particles.

Package sizes:

1 vial of 1 mL, 5 vials of 1 mL

1 vial of 5 mL, 5 vials of 5 mL

1 vial of 10 mL

1 vial of 20 mL

1 vial of 40 mL

1 vial of 50 mL

Only some package sizes may be marketed.

Marketing Authorization Holder

Accord Healthcare, S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est. 6th floor

08039 Barcelona

Spain

Responsible for manufacturing

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,95-200 Pabianice,

Poland

Last review date of this leaflet:April 2023.

The detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.es/.

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Information intended exclusively for medical professionals or healthcare personnel

Dosage and administration

By intravenous injection or infusion, or subcutaneous injection.

Citarabine should not be administered intrathecally.

When citarabine is administered intravenously at high doses, solvents containing benzyl alcohol should not be used.

In the recommended dosages, body weight-based values can be converted to surface area-based values using nomograms.

1. Induction of remission:

a) Continuous treatment:

1. Fast injection: 2 mg/kg/day is a prudent initial dose. Administer for 10 days. Obtain daily hemograms. If no effect on leukemia is observed and no apparent toxicity exists, increase the dose to 4 mg/kg/day and maintain until a therapeutic response or toxicity is observed. Almost all patients experience toxicity at these doses.
2. May be administered 0.5-1.0 mg/kg/day in perfusion of up to 24 hours' duration. Results of one-hour perfusions have been satisfactory in most patients. After 10 days, this initial daily dose may be increased to 2 mg/kg/day, depending on toxicity. Continue until toxicity is observed or until remission is produced.

b) Intermittent treatment:

Administer 3-5 mg/kg/day intravenously over five consecutive days. After a two- to nine-day rest period, an additional course is administered. Continue until a response is observed or until toxicity is observed.

Initial signs of medullary improvement have been observed between 7 and 64 days (mean 28 days) after starting treatment.

Generally, if a patient does not show toxicity or remission after adequate attempts, administration of higher doses with caution is justified. As a general rule, it has been observed that patients tolerate higher doses when receiving a rapid intravenous injection than when receiving a slow infusion. This difference is due to the rapid metabolism of citarabine and the consequent short duration of action of the high dose.

2. Maintenance treatment:

Remissions induced by citarabine or other drugs may be maintained by intravenous or subcutaneous injection of 1 mg/kg once or twice a week.

Secondary or refractory acute myeloid leukemia:Citarabine, alone or in combination with other chemotherapeutic agents, has been used at doses of 2-3 g/m2 in perfusion of 1-3 hours, every 12 hours for 6 days.

Acute lymphoblastic leukemia:Citarabine is administered in combination with other antineoplastic agents as part of complex treatments for the induction and consolidation of remission of acute lymphoblastic leukemia. Consult existing treatment protocols for the dose and route of administration of citarabine in monotherapy or in combination with other antineoplastic agents.

High doses:

Citarabine is administered as monotherapy or in combination with other cytostatics, 2-3 g/m2, as intravenous perfusion, for 1-3 hours every 12 hours for 2-6 days. The total dose of the treatment should not exceed 36 g/m2.

High-dose therapies in patients over 60 years of age should only be administered after a thorough benefit-risk evaluation.

Pediatric population:

Children appear to tolerate higher doses than adults. When specifying dose intervals, the higher dose should be administered to children and the lower dose to adults.

The safety of this medicine for use in infants has not been determined.

Patients with hepatic and/or renal insufficiency

Apparently, a significant fraction of the administered dose is metabolized at the hepatic level and a small fraction at the renal level. In patients with hepatic and/or renal dysfunction, the drug should be used with caution and at reduced doses.

Older patients:

No data suggest that the dosage should be adjusted in older patients. However, older patients do not tolerate drug toxicity as well as younger patients, and special attention should be paid to drug-induced leukopenia, thrombocytopenia, and anemia, initiating appropriate complementary treatment when indicated.

Incompatibilities

Incompatible with: heparin, insulin, methotrexate, 5-fluorouracil, nafcillin, oxacillin, penicillin G, and methylprednisolone succinate.

This medicine should not be mixed with other drugs except those mentioned in the "Instructions for use and handling" section.

Instructions for use and handling

The disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.

Once opened, the contents of each vial must be used immediately and should not be stored.

Commonly used perfusion liquids with citarabine include water for injection, 0.9% sodium chloride solution, and 5% dextrose solution. Compatibility should be checked before mixing with any other substance.

Perfusion liquids containing citarabine should be used immediately.

Protective measures

• Due to the toxic nature of the compound, the following protective recommendations should be followed:
• Pregnant women will avoid handling this medicine
• Personnel handling citarabine should wear protective clothing: protective glasses, gowns, gloves, and disposable masks
• Reconstitution should be performed in a designated area (preferably under a laminar flow system). The working surface should be protected with absorbent, plasticized, and disposable paper
• All materials used for reconstitution, administration, or cleaning, including gloves, should be disposed of in high-risk waste bags for destruction by high-temperature incineration
• If a spill occurs, restrict access to the affected area and wear appropriate protective gear, including gloves and safety glasses. Limit the spill's spread and clean the area with absorbent material or paper. Spills can also be cleaned with 5% sodium hypochlorite solution. The spill area should be washed with an abundance of water. Dispose of contaminated materials in a leak-proof bag for cytotoxic waste and incinerate at 1100°C.
• All cleaning materials should be disposed of as indicated above
• In the event of accidental contact with the skin or eyes, wash immediately with plenty of water, soap and water, or bicarbonate solution, and seek medical attention
• Wash hands thoroughly after removing gloves.

Disposal

(See section 5). For disposal, the medicine and materials that have come into contact with it should be placed in a high-risk waste bag (for cytotoxics) and incinerated at 1100°C.

Shelf life

2 years.

The physical-chemical stability during use after dilution with sodium chloride injection (0.9% w/v) and dextrose injection (5% w/v) indicates that after dilution with the recommended intravenous liquids, the reconstituted solution remains stable for 24 hours at a temperature below 25°C and for 72 hours at 2°C-8°C. From a microbiological standpoint, the reconstituted solution should be used immediately. If not used immediately, storage conditions and times for possible use are the responsibility of the user and should not exceed 24 hours at a temperature of 2-8°C, unless the dilution was performed in validated and controlled aseptic conditions.

Storage

Do not store at a temperature above 25°C.

Store the vial in the outer packaging to protect it from light.

Do not refrigerate.