CITARABINE ACCORD 100 mg/ml INJECTABLE SOLUTION AND PERFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Citarabine Accord 100 mg/ml Solution for Injection and Infusion

Read all of this leaflet carefully before you start using this medicine

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

Contents of the pack:

1. What Citarabine Accord is and what it is used for
2. What you need to know before you use Citarabine Accord
3. How to use Citarabine Accord
4. Possible side effects
5. Storage of Citarabine Accord
6. Contents of the pack and other information

1. What Citarabine Accord is and what it is used for

Citarabine Accord is used in children and adults. The active substance is cytarabine.

Cytarabine belongs to a group of medicines called cytotoxics; these medicines are used in the treatment of acute leukemias (blood cancer characterized by an excess of white blood cells). Cytarabine interferes with the growth of neoplastic cells, which are eventually destroyed.

Cytarabine is also used to induce and maintain remission of acute leukemia.

Remission induction is an intensive treatment aimed at forcing a reduction in leukemia. When it works, the balance of blood cells normalizes and your health improves. This period of relative health is called remission.

Maintenance treatment is a less intensive treatment aimed at making remission last as long as possible. Quite low doses of cytarabine are used to keep leukemia under control and prevent it from recurring.

2. What you need to know before you use Citarabine Accord

Do not use Citarabine Accord

• If you are allergic to the active substance or to any of the other ingredients of this medicine.
• If you are already taking medicines 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 treatment with Citarabine Accord.

• If your bone marrow is affected, treatment should be started under close medical supervision.
• If you have liver problems.
• Cytarabine markedly reduces the production of blood cells in the bone marrow. This can increase the predisposition to infections or bleeding. Blood cell counts may continue to decrease until one week after treatment is stopped. Your doctor will perform regular blood tests and examine your bone marrow if necessary.
• Severe and sometimes potentially fatal side effects can occur in the central nervous system, intestines, or lungs.
• During treatment with cytarabine, your liver and kidney function should be monitored. If your liver and/or kidney are not functioning properly before treatment, cytarabine can only be administered with maximum caution.
• Uric acid levels (which demonstrate that neoplastic cells have been destroyed) in your blood (hyperuricemia) may be high during treatment. Your doctor will tell you if you need to take any medication to control it.

Using Citarabine Accord with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, as well as in the following cases:

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

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy

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

Contraception in women of childbearing age

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 of childbearing age should always use highly effective contraceptive methods to prevent pregnancy during treatment and for 3 months after the last dose.

Breastfeeding

Breastfeeding should be discontinued during treatment with cytarabine and for at least one week after the last dose or treatment should be discontinued, as this medicine could be harmful to breastfed babies.

Fertility

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

Driving and using machines

Cancer treatment in general can affect some patients' ability to drive or use machines. If you are affected, you should not drive or use machines.

3. How to use Citarabine Accord

Form and administration routes

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

Posology

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

During treatment, you will require frequent examinations, including blood tests. Your doctor will tell you how often you need to do this, and will perform regular checks on:

• Blood, to check if you have low blood cell counts that require treatment.
• Liver (also through blood tests) to check that cytarabine does not negatively affect its function.
• Kidneys (also through blood tests) to check that cytarabine does not negatively affect their function.
• Uric acid levels in the blood: cytarabine could increase uric acid levels in the blood. If your uric acid levels are too high, you may be given another medicine.

If you use more Citarabine Accord than you should

High doses can worsen side effects, such as mouth ulcers, or may reduce white blood cell and platelet counts in the blood. In such cases, 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.

4. Possible side effects

Like all medicines, Citarabine Accord can cause side effects, although not everybody gets them.

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

Very common 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.
• Bone marrow depression, i.e., alteration of your immune system with loss of the ability to fight infections or diseases.
• Alteration of normal brain and cerebellum function*, feeling of sleepiness*.
• Disorder of the cornea of the eye*.
• Fluid accumulation in the lungs*, difficulty breathing*.
• Nausea, vomiting, diarrhea, inflammation or ulcers in the mouth or anus, abdominal pain.
• Alteration of liver function.
• Rash, hair loss.
• Fever, cytarabine syndrome (consisting 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 and blood cells.

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

• Inflammation of a portion of the intestine with cell death (necrotizing colitis)*.
• Ulcers on the skin, peeling*.

Uncommon side effects(may affect up to 1 in 100 patients) include:

• Severe allergic reaction.
• Inflammation at the injection site.
• Localized pus formation in the liver*.
• Fluid retention due to an allergic reaction.
• Loss of appetite.
• Change in personality*.
• Toxicity to the nervous system, nerve inflammation, headache, dizziness, coma*, alterations in motor and sensory function of the peripheral nervous system* (when administered intrathecally), in children, a rare inflammatory disorder that causes damage to the material covering the nerves (leukoencephalopathy) may appear, paralysis of the legs and lower body (paraplegia), progressive ascending paralysis, progressive toxicity, seizures.
• Conjunctivitis (infection in an area of the eye that may be accompanied by a rash), conjunctivitis with bleeding*, blindness (when administered intrathecally).
• Inflammation of the tissue covering the heart (pericarditis), slower than normal heart rate (sinus bradycardia).
• Heart disease (cardiomyopathy)*, increased heart size (cardiomegaly)*.
• Obstruction and inflammation of the blood vessel where the injection is performed (thrombophlebitis).
• Sore throat, shortness of breath, inflammation of a part of the lung tissue*.
• Ulcer in the esophagus, inflammation in the esophagus, gastrointestinal ulcer*, presence of cysts in the intestinal wall*, peritonitis*, death of intestinal cells*, pancreatitis (inflammation of the pancreas).
• Yellowish color of the skin, liver damage*, increased bilirubin levels*.
• Hives, skin spots, itching.
• Urine retention, kidney disorder.
• Chest pain.
• Reaction at the injection site.
• Skin rash on the palms of the hands and soles of the feet.

• Due solely to high doses of cytarabine

Reporting of side effects:

If you experience any side effects, talk to your doctor or pharmacist, even if it is possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Citarabine Accord

Keep out of the reach and sight of children.

Do not store above 25°C.

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

Do not refrigerate.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date is the last day of the month stated.

The medicine should be used immediately after opening the vial.

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

Disposal of unused medicine and all materials that have come into contact with it should be done in accordance with local regulations.

6. Additional Information

Composition of Citarabina Accord

The active ingredient is cytarabine. Each ml of solution contains 100 mg of cytarabine

Each 1 ml vial contains 100 mg of cytarabine.

Each 5 ml vial contains 500 mg of cytarabine.

Each 10 ml vial contains 1g of cytarabine.

Each 20 ml vial contains 2 g of cytarabine.

Each 40 ml vial contains 4 g of cytarabine.

Each 50 ml vial contains 5 g of cytarabine.

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

Appearance of the Product and Packaging Content

Transparent 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. 6ª planta

08039 Barcelona

Spain

Manufacturer

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,95-200 Pabianice,

Poland

Date of the Last Review of this Prospectus:April 2023.

Detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.es/.

-----------------------------------------------------------------------------------------------------------------

Information Intended Exclusively for Doctors or Healthcare Professionals

Dosage and Administration

By injection or intravenous perfusion, or subcutaneous injection.

Cytarabine should not be administered by the intrathecal route.

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

In the dosage recommendations, values based on body weight can be converted to values based on body surface area using nomograms.

1. Induction of remission:

• Continuous treatment:
  1. Rapid injection: 2 mg/kg/day is a prudent initial dose. Administer for 10 days. Obtain daily hemograms. If no effect against 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 present toxicity with these doses.
  2. 0.5-1.0 mg/kg/day can be administered in perfusions of up to 24 hours in duration. The 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 or remission is observed.

• Intermittent treatment:

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

The first signs of bone marrow improvement have been observed between 7 and 64 days (average of 28 days) after the start of treatment.

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

1. Maintenance treatment:

Remissions induced by cytarabine or other medications can be maintained by intravenous or subcutaneous injection of 1 mg/kg one or two times a week.

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

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

High doses:

Cytarabine 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 meticulous benefit-risk evaluation.

Pediatric population:

Children seem to tolerate higher doses than adults. When dose ranges are specified, the higher dose should be administered to children and the lower dose to adults.

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

Patients with hepatic and/or renal impairment

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 alterations of hepatic and/or renal function, the drug should be used with caution and at reduced doses.

Elderly patients:

There are no data to suggest that the dosage should be adjusted in elderly patients. However, elderly patients do not tolerate drug toxicity as well as young patients, and special attention should be paid to leukopenia, thrombocytopenia, and anemia due to medications, initiating appropriate complementary treatment when indicated.

Incompatibilities

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

This medication should not be mixed with others except those mentioned in the "Instructions for use and handling" section.

Instructions for use and handling

The disposal of unused medication 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 should be used immediately and not stored.

The infusion liquids commonly used with cytarabine include injectable water, 0.9% saline solution, and 5% dextrose. Compatibility should be checked before mixing with any other substance.

Infusion liquids containing cytarabine should be used immediately.

Protection measures

• Due to the toxic nature of the compound, the following protection recommendations should be followed:
• Pregnant women should avoid handling this medication
• Personnel handling cytarabine should wear protective clothing: safety glasses, gowns, gloves, and masks
• Reconstitution should be carried out in a designated area (preferably under a laminar flow system). The work surface should be protected with absorbent, plasticized, and disposable paper
• All material used for reconstitution, administration, or cleaning, including gloves, should be disposed of in high-risk material bags for destruction by high-temperature incineration
• If a spill occurs, restrict access to the affected area and wear adequate protection, including gloves and safety glasses. Limit the spread and clean the area with absorbent material or paper. Spills can also be cleaned with 5% sodium hypochlorite. The spill area should be washed with a large amount of water. Place the contaminated material in a sealed bag for cytotoxic waste and incinerate at 1100°C.
• All cleaning materials should be disposed of as indicated above
• In case of accidental contact with skin or eyes, wash immediately with plenty of water, with soap and water, or with a sodium bicarbonate solution, and seek medical attention
• Always wash hands after removing gloves.

Elimination

(See section 5). For elimination, the medication 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% p/v) and dextrose injection (5% p/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 point of view, the reconstituted solution should be used immediately. If not used immediately, the storage conditions and times for possible use are the responsibility of the user and should not exceed 24 hours at a temperature between 2 and 8°C, unless the dilution has been carried out in validated and controlled aseptic conditions.

Storage

Do not store at a temperature above 25°C.

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

Do not refrigerate.