Alexan

Leaflet accompanying the packaging: information for the user

Alexan, 20 mg/ml, solution for injection

Cytarabine

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor, nurse or pharmacist.
• If the patient experiences any side effects, including those not listed in this leaflet, they should inform their doctor, nurse or pharmacist. See section 4.

Table of contents of the leaflet:

• 1. What Alexan is and what it is used for
• 2. Important information before using Alexan
• 3. How to use Alexan
• 4. Possible side effects
• 5. How to store Alexan
• 6. Contents of the packaging and other information

1. What Alexan is and what it is used for

Alexan is used to treat cancer. It can be used alone or in combination with other anticancer medicines for initial and maintenance treatment of:

• acute myeloid leukemia,
• acute lymphoblastic leukemia,
• leukemic infiltrations in the central nervous system,
• malignant non-Hodgkin's lymphoma.

High doses of Alexan are used in the treatment of:

• refractory non-Hodgkin's lymphoma,
• refractory acute myeloid leukemia,
• refractory acute lymphoblastic leukemia,
• blast crisis in chronic myeloid leukemia.

2. Important information before using Alexan

When not to use Alexan

• if the patient is hypersensitive (allergic) to cytarabine or any of the other ingredients of this medicine (listed in section 6);
• in patients with bone marrow depression not related to malignant disease (with symptoms such as anemia, decreased white blood cell count - leukopenia, decreased platelet count - thrombocytopenia), unless the doctor decides that the treatment is essential for the patient;
• in pregnant women, unless there are compelling reasons and the doctor believes that the benefits to the mother outweigh the potential risk to the fetus.

Warnings and precautions

Alexan is administered with caution only under the supervision of personnel specializing in oncology, equipped with tools for regular monitoring of treatment efficacy during and after administration of the medicine.
Before using Alexan, the patient should discuss it with their doctor if they:

• have liver or kidney function disorders; this will help the doctor decide whether Alexan is a suitable medicine for the patient;
• have received or are going to receive any vaccinations, including live attenuated vaccines
• are receiving cytarabine intravenously together with methotrexate administered intrathecally, as in such cases, children and young adults have experienced headache, paralysis, coma, and symptoms resembling stroke;
• have acute and/or severe infections;
• have a diagnosed peptic ulcer disease;
• have recently undergone surgery

During treatment, the doctor will order blood tests, kidney and liver function tests, and uric acid levels in the blood.
The toxic effect of high doses of cytarabine
Alexan administered in high doses may cause more severe side effects than when administered in lower doses. See section 4 "Possible side effects".

Children and adolescents

The safety of using the medicine in infants has not been established.

Alexan and other medicines

The patient should inform their doctor, nurse or pharmacist about all medicines they are currently taking or have recently taken, as well as any medicines they plan to take, including those available without a prescription. Alexan is often used in combination with other medicines.
Concomitant use of Alexan with other medicines that cause cell breakdown or bone marrow suppression, or with radiation therapy, may sometimes weaken their effect. The doctor may decide to change their dosage.
The patient should inform their doctor about the use of such medicines as:

• medicines containing 5-fluorocytosine (a medicine used to treat fungal infections);
• medicines containing cardiac glycosides (medicines used to treat certain heart diseases);
• gentamicin (an antibiotic used to treat bacterial infections);
• medicines containing cyclophosphamide, vincristine, and prednisone (medicines used in cancer treatment regimens);
• cytarabine administered intravenously together with methotrexate administered intrathecally (due to the occurrence of headache, paralysis, coma, and symptoms resembling stroke in children and young adults after administration of these medicines).

Pregnancy, breastfeeding, and fertility

If the patient is pregnant or breastfeeding, thinks they may be pregnant, or plans to have a child, they should consult their doctor or pharmacist before using this medicine.
Pregnancy
Alexan may cause serious birth defects in the child. The medicine should not be used during pregnancy, unless there are compelling reasons and the doctor believes that the benefits to the mother outweigh the potential risk to the fetus.
Men and women of childbearing age should use effective contraceptive methods during therapy and for six months after its completion.
Breastfeeding
It is not known whether cytarabine passes into breast milk. Alexan, like many other medicines, may pass into breast milk and may cause serious side effects in infants.
Therefore, breastfeeding should be discontinued before starting treatment.

Driving and using machines

Alexan does not affect psychomotor performance, but chemotherapy can impair the ability to drive vehicles and operate machines. If the patient feels unwell and experiences side effects (such as nausea, dizziness, or vision disturbances), they should not drive vehicles or operate machines.

Alexan contains sodium

The medicine contains 14.35 mg of sodium (the main component of common salt) per vial. This corresponds to 0.7% of the maximum recommended daily intake of sodium in the diet for adults.
The medicine can be diluted in a 0.9% NaCl solution. The sodium content from the diluent should be taken into account when calculating the total sodium content in the prepared dilution of the medicine. To obtain accurate information about the sodium content in the solution used to dilute the medicine, the patient should consult the patient information leaflet for the diluent used.

3. How to use Alexan

Alexan can only be administered by medical personnel - it must not be used by the patient themselves.
The medicine can be administered intravenously, subcutaneously, and intrathecally.
The duration of treatment and the daily dose of the medicine are determined by the attending physician.
The duration of treatment depends on the patient's condition. The doctor will monitor the body's response to treatment, the patient's health, and the duration of therapy.
Information intended for healthcare professionals is provided at the end of the leaflet.

Using a higher dose of Alexan than recommended

In case of overdose or severe side effects, the patient should immediately inform their doctor. The doctor will immediately stop administering the medicine. The course of action depends on the symptoms: blood transfusion or antibiotic administration may be necessary to prevent infections.
The doctor may decide to use hemodialysis to remove cytarabine from the body.

Missing a dose of Alexan

The patient should consult their attending physician as soon as possible to determine a new administration schedule.
In case of any further doubts related to the administration of this medicine, the patient should consult their doctor or pharmacist.

4. Possible side effects

Like all medicines, Alexan can cause side effects, although not everybody gets them.
The side effects of Alexan are dose-dependent - the higher the dose, the higher the likelihood of their occurrence. The most common side effects include gastrointestinal symptoms and bone marrow suppression (myelosuppression) and, consequently, blood count disorders.

In case of the following severe side effects, the patient should immediately consult their doctor:

• severe allergic reaction (anaphylaxis), occurring with an unknown frequency, with symptoms such as: sudden itching rash (hives), swelling of hands, feet, ankles, face, lips, mouth, or throat (which may cause breathing difficulties), feeling of fainting

symptoms resembling flu, such as fever and chills, as they may indicate an infection that can become severe (may occur in more than 1 in 10 people)

• fatigue and lethargy, easier bruising or bleeding due to decreased production or reduced number of red blood cells, white blood cells, or platelets (may occur in less than 1 in 10 people).

In case of the following side effects, the patient should consult their doctor or nurse as soon as possible:

Sometimes the following symptoms may occur together, usually 6 to 12 hours after administration of Alexan:

• malaise with high fever
• bone pain, muscle pain, and occasional chest pain
• rash
• eye pain

These are symptoms of the so-called cytarabine syndrome, which can be treated. The doctor may recommend taking corticosteroids to prevent and treat these symptoms. If corticosteroids are effective, the use of Alexan can be continued.

Other possible side effects

Very common side effects (may occur in more than 1 in 10 people)

• pneumonia
• liver damage
• decreased reticulocyte count
• rash

Common side effects (may occur in less than 1 in 10 people)

• decreased appetite
• high uric acid levels in the blood, caused by the breakdown of cancer cells, which may lead to gout
• conjunctivitis with sensitivity to light, feeling of burning, vision disturbances, excessive tearing, pain, and redness (reversible hemorrhagic conjunctivitis, keratitis)
• nausea and abdominal pain
• loss of appetite, nausea, vomiting
• diarrhea
• inflammation or ulceration of the mucous membrane of the mouth or anus
• rash, itching, redness of the skin, formation of large blisters (bullous dermatitis), red spots on the skin
• vasculitis
• hair loss (usually reversible)
• kidney function disorders, difficulty urinating
• fever
• phlebitis at the injection site with blood clot formation

Uncommon side effects (may occur in less than 1 in 100 people)

• hives
• pericarditis
• shortness of breath, sore throat
• esophageal inflammation or ulceration
• presence of gas-filled blisters in the intestinal wall (pneumatosis cystoides intestinalis)
• severe colitis (necrotizing colitis)
• peritonitis
• lentigo (presence of flat, brown spots on the skin)
• skin ulceration and inflammation
• itching
• burning pain in the palms and soles
• muscle and joint pain

Rare side effects (may occur in less than 1 in 100 people)

• heart rhythm disorders
• presence of nodules and blisters on the palms and soles (neutrophilic eccrine hidradenitis)
• pancreatitis

Side effects with unknown frequency (frequency cannot be estimated from available data)

• infection at the injection site
• liver abscess
• headache or dizziness
• tingling
• neuritis
• jaundice (yellowing of the skin and eyes)
• decreased heart rate
• palmoplantar erythrodysesthesia syndrome.

Side effects that may occur as a result of high-dose Alexan treatment, other than those noted with standard dosing:

• significant decrease in red blood cell, white blood cell, and platelet count, which may persist for 15 to 25 days
• personality changes, decreased alertness, speech disorders, loss of motor control, tremors, involuntary eye movements, headache, confusion, drowsiness, dizziness, coma, seizures; these disorders are usually reversible and occur mainly in elderly patients, patients with kidney or liver function disorders, patients who consume large amounts of alcohol, and patients who have undergone previous treatment affecting brain function (e.g., radiation)
• conjunctivitis, also with sensitivity to light, feeling of burning, and vision disturbances; the doctor may recommend preventive use of eye drops containing corticosteroids
• perforation in the stomach and intestines, nausea, vomiting
• liver abscess, blood clots in the liver, and pancreatitis
• acute respiratory distress syndrome progressing to pulmonary edema
• rhabdomyolysis (breakdown of striated muscle)
• worsening of heart function due to myocarditis
• lack of sperm production
• amenorrhea

Side effects reported after intrathecal administration:

• bone marrow suppression, nausea, vomiting
• nerve tissue damage
• paralysis of arms or legs
• vision loss

Reporting side effects

If the patient experiences any side effects, including those not listed in the leaflet, they should inform their doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49 21 301/fax: +48 22 49 21 309/website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder.
Reporting side effects will help gather more information on the safety of the medicine.

5. How to store Alexan

The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after EXP.
The expiry date refers to the last day of the month stated.
Do not use this medicine if signs of spoilage are visible, such as a change in the color of the solution.
Store in a temperature below 25°C.
Medicines should not be disposed of via wastewater or household waste. The patient should ask their pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the packaging and other information

What Alexan contains

The active substance of the medicine is cytarabine. 1 ml of the solution for injection contains 20 mg of cytarabine.
A 5 ml vial contains 100 mg of cytarabine.
The other ingredients are: sodium chloride, sodium lactate, lactic acid, water for injection.

What Alexan looks like and what the packaging contains

Alexan is a clear and colorless solution.
The packaging contains 1 or 10 vials of 100 mg cytarabine in 5 ml solution for injection.

Marketing authorization holder and manufacturer

EBEWE Pharma Ges.m.b.H. Nfg. KG
Mondseestrasse 11
A-4866 Unterach, Austria

Manufacturer

Fareva Unterach GmbH
Mondseestraße 11
4866 Unterach, Austria

For more detailed information, please contact:

Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warszawa
tel. 22 209 70 00

Date of last revision of the leaflet: 06/2021

Information intended exclusively for healthcare professionals

Information on dosing

• Remission induction treatment The usual dose in remission induction treatment is 100 to 200 mg of cytarabine/m2 per day, usually in continuous intravenous infusion or rapid infusion for 5 to 10 days.

The duration of treatment depends on the results of clinical and morphological examinations (bone marrow examinations). Treatment may last up to 7 days, followed by a 7-9 day break, until remission is achieved in the bone marrow; subsequent therapy cycles (often limited in number) may last until remission is achieved or until toxic effects occur. Alternatively, treatment can be continued until bone marrow hypoplasia occurs, which should be considered a tolerance threshold.
Before repeating therapy cycles (often limited in number), a treatment break of 14 days should be ensured, and preferably until the bone marrow picture normalizes.

• Maintenance remission treatment The maintenance dose is usually 70 to 200 mg of cytarabine/m2 per day in rapid intravenous or subcutaneous injection, administered for 5 days, every 4 weeks or once a week.
• Treatment of non-Hodgkin's lymphoma

Adult treatment
These cases are usually treated with combination chemotherapy according to schemes, and e.g., in the PROMACE-CYTABOM scheme, cytarabine is administered at a dose of 300 mg/m2 per day

• on the 8th day of the treatment cycle.

Child treatment
The use of cytarabine in non-Hodgkin's lymphoma in children depends on the stage of the disease and its histological type. Cytarabine is used in various treatment protocols and at different doses. Below are the dosages in selected combination therapies that are currently considered effective. Detailed information can be found in the relevant medical literature.
150 mg of cytarabine/m2, administered in a 1-hour intravenous infusion every 12 hours on the 4th and 5th days of therapy, called "part A" or "part AA" (a total of 4 intravenous infusions); in combination with other cytotoxic medicines (BMF protocols for stage II and III or stage IV B-cell lymphoma).
75 mg of cytarabine/m2 on days 31-34, 38-41, 45-48, and 52-55 of induction therapy; in combination with other cytotoxic medicines (BMF protocol for non-B-cell lymphoma in stage I and II).

• High-dose treatment During high-dose treatment, only preservative-free diluents should be used.

High-dose treatment usually involves 1 to 3 g of cytarabine/m2 in an intravenous infusion lasting from 1 to 3 hours, administered every 12 hours for 4 to 6 days.

• Treatment of leukemias localized in the central nervous system (CNS)

Intrathecal treatment
The usual dose of cytarabine is 5 to 30 mg/m2 every 2 to 7 days.
The frequency of administration and dosing vary depending on the treatment method used.
Most often, 30 mg/m2 is administered every 4 days until the cerebrospinal fluid no longer contains an increased number of malignant cells.
If the solution for injection for intrathecal administration needs to be diluted, only 0.9% sodium chloride solution without preservatives should be used.

Information on storage of the medicine after first opening and after dilution

• Opened vial The solution should be drawn from the vial immediately before use. From a microbiological point of view, the product should be used immediately. Otherwise, the user is responsible for the storage conditions and storage time of the remaining solution in the vial. The remaining solution in the vial should not be stored for more than 24 hours at a temperature between 2°C and 8°C, unless the withdrawal was done under controlled, verified aseptic conditions. In this case, the solution remains physically and chemically stable for 28 days when stored in a refrigerator or at room temperature, with or without light access.
• Diluted solution for injection From a microbiological point of view, the product should be used immediately. Otherwise, the user is responsible for the storage conditions and storage time of the prepared solution. The prepared solutions should not be stored for more than 24 hours at a temperature between 2°C and 8°C, unless the dilution was done under controlled, verified aseptic conditions. Physical and chemical stability has been demonstrated for 28 days for a solution with a concentration of 0.1 mg/ml diluted with 0.9% NaCl, stored in a refrigerator or at room temperature, with or without light access.

Instructions for preparing the medicine for use

Before administration, Alexan should be diluted with 0.9% sodium chloride solution or 5% glucose solution.
The compatibility of Alexan with 0.9% sodium chloride solution and 5% glucose solution has been tested at concentrations of 0.2-3.2 mg/ml in infusion bags made of PVC, polyethylene infusion vials, and perfusion syringes.
If cytarabine comes into contact with the skin, the area should be rinsed thoroughly with water and then washed with soap and water. If the solution gets into the eyes, they should be rinsed thoroughly with a large amount of water, and an ophthalmologist should be consulted immediately.
Pregnant women should not come into contact with this medicine.

Instructions for disposal of the medicine

Bottles and materials used during infusion, including protective gloves, should be disposed of in accordance with the rules for cytotoxic medicines.
In case of spillage or leakage of the solution, it can be neutralized with a 5% sodium hypochlorite solution. All materials used for this purpose should then be disposed of as described above.

Instructions for action in case of extravasation

• 1. Immediately stop administering the medicine.
• 2. Replace the infusion line or syringe with the administered medicine with a single-use syringe with a capacity of 5 ml and slowly aspirate the extravasated medicine. NOTE! Do not press the area of extravasation.
• 3. Withdraw the needle while continuously aspirating the fluid from the area of extravasation.
• 4. Inform the doctor.

Pharmaceutical incompatibilities

Alexan shows physical incompatibility with heparin, insulin, methotrexate, 5-fluorouracil, nafcillin, oxacillin, benzylpenicillin, and sodium salt of methylprednisolone succinate.