Alexan

Package leaflet: Information for the user

Alexan, 20 mg/ml, solution for injection
Cytarabine
Please read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, nurse, or pharmacist.
• If you get any side effects, talk to your doctor, nurse, or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the leaflet:

1. What Alexan is and what it is used for
2. What you need to know before you are given Alexan
3. How Alexan is given
4. Possible side effects
5. How to store Alexan
6. Contents of the pack and other information

1. What Alexan is and what it is used for

Alexan is used in the treatment of cancerous diseases. It may be used alone or in combination with other anticancer medicines in initial and maintenance therapy for:

• acute myeloid leukaemias,
• acute lymphoblastic leukaemias,
• leukaemic involvement of the central nervous system,
• malignant non-Hodgkin's lymphomas.

High-dose Alexan is used in the treatment of:

• treatment-resistant non-Hodgkin's lymphomas,
• treatment-resistant acute myeloid leukaemias,
• treatment-resistant acute lymphoblastic leukaemias,
• blast crisis in chronic myeloid leukaemia.

2. Important information before using Alexan

When not to use Alexan

• if the patient is allergic (hypersensitive) to cytarabine or to any of the other components of this medicine (listed in section 6);
• in patients in whom the doctor has diagnosed bone marrow suppression unrelated to tumour disease (with symptoms such as anaemia, reduced number of white blood cells – leukopenia, reduced number of platelets – thrombocytopenia), unless the doctor decides that treatment is essential for the patient;
• in pregnant women, unless there are strict medical indications and, in the doctor's opinion, the benefits to the mother from using the medicine outweigh the potential risks to the foetus.

Warnings and precautions
Alexan should only be administered cautiously and under the supervision of personnel specialised in oncology, equipped with tools for regular monitoring of treatment efficacy during and after administration of the medicine.
Before using Alexan, discuss with your doctor if the patient:

• has impaired liver or kidney function; this will help the doctor decide whether Alexan is the appropriate medicine for the patient;
• has received or is due to receive any vaccination, including live attenuated vaccines;
• is receiving cytarabine concurrently with intrathecal methotrexate, as in such cases headache, paralysis, coma and stroke-like symptoms have occurred in children and young adults;
• has acute and/or severe infection;
• has diagnosed gastrointestinal ulcer disease;
• has recently undergone surgery.

During treatment, the doctor will order regular blood tests, kidney and liver function tests, and blood uric acid levels.
Toxic effects of high-dose cytarabine
Alexan administered in high doses may cause more severe adverse reactions than when given in lower doses. See section 4 "Possible side effects".
Children and adolescents
The safety of Alexan in infants has not been established.
Alexan with other medicines
Tell your doctor, nurse or pharmacist about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take, including those available without a prescription. Alexan is often used together with other medicines.
Concurrent use of Alexan with other medicines causing tumour cell breakdown or bone marrow suppression, or with radiotherapy, may sometimes reduce their effectiveness. The doctor may decide to adjust their dosage.
Tell your doctor if the patient is taking any of the following medicines:

• medicines containing 5-fluorocytosine (a medicine used to treat fungal infections);
• medicines containing cardiac glycosides (medicines used to treat certain heart conditions);
• 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 intrathecal methotrexate (due to occurrence of headache, paralysis, coma and stroke-like symptoms in children and young adults after administration of these medicines).

Pregnancy, breastfeeding and fertility
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.
Pregnancy
Alexan may cause serious developmental abnormalities in the child. The medicine should not be used during pregnancy unless there are strict medical indications and, in the doctor's opinion, the benefits to the mother outweigh the potential risks to the foetus.
Men and women of reproductive age should use effective contraceptive methods during therapy and for 6 months after completion of treatment in women and 3 months in men.
Breastfeeding
It is not known whether cytarabine passes into breast milk. Like many other medicines, Alexan may pass into the breast milk of nursing mothers and may cause serious adverse reactions in infants. If the patient is breastfeeding, she should contact her doctor, who will decide whether she should continue breastfeeding, discontinue breastfeeding during Alexan treatment and for at least one week after completion of treatment, or discontinue/withhold cytarabine administration.
Driving and operating machinery
Alexan does not affect psychomotor performance; however, chemotherapy may impair the ability to drive or operate machinery. If the patient feels unwell and experiences adverse reactions (such as vomiting, dizziness or visual disturbances), he or she should not drive or operate machinery.
Alexan contains sodium
The medicine contains 14.35 mg of sodium (the main component of table salt) per vial. This corresponds to 0.7% of the maximum recommended daily sodium intake in the adult diet.
The medicine may be diluted in 0.9% sodium chloride solution. The sodium content originating from the diluent should be taken into account when calculating the total sodium content in the prepared diluted medicine. For precise information on the sodium content in the diluent used to dilute the medicine, refer to the patient leaflet of the diluent used.

3. How to use Alexan

Alexan may only be administered by medical personnel – do not administer it yourself.
The medicine may be given intravenously, subcutaneously, or intrathecally.
The duration of treatment and the daily dose of the medicine are determined by the treating physician.
The duration of treatment depends on the patient's condition. The physician will monitor the body's response to treatment, the patient's health status, and the duration of therapy.
Information intended for healthcare professionals is provided at the end of the leaflet.
Use of a higher than recommended dose of Alexan
In case of overdose or the occurrence of pronounced adverse reactions, contact the physician immediately. The physician will immediately discontinue administration of the medicine. Management depends on symptoms: blood transfusion or administration of antibiotics to prevent infections may be necessary.
The physician may decide to use hemodialysis to remove cytarabine from the body.
Missed dose of Alexan
Contact the treating physician as soon as possible to schedule a new dose administration time.
If you have any further doubts regarding the administration of this medicine, consult your physician or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Adverse reactions to Alexan are dose-dependent – the higher the dose, the greater the likelihood of their occurrence. The most common are gastrointestinal symptoms and disturbances in bone marrow function (myelosuppression), and consequently, blood disorders.
If any of the following severe adverse reactions occur, seek medical advice immediately:

• severe allergic reaction (anaphylaxis), frequency unknown, with symptoms such as: sudden itchy rash (urticaria), swelling of hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in breathing), feeling of fainting
• flu-like symptoms, e.g. fever and chills, as they may indicate an infection which could become serious (may occur in more than 1 in 10 people)
• feeling of fatigue and drowsiness, easier than usual bruising or bleeding following injury. These are symptoms of insufficient production or reduced numbers of red blood cells, white blood cells or platelets (may occur in less than 1 in 10 people).

If any of the adverse reactions listed below occur, consult your 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 occasionally chest pain
• rash
• eye pain

These are symptoms of so-called cytarabine syndrome, which is treatable. Your doctor may recommend corticosteroids to prevent and treat these symptoms. If corticosteroids prove effective, treatment with Alexan may continue.
Other possible adverse reactions
Very common adverse reactions (may affect more than 1 in 10 people)

• lung inflammation
• liver damage
• decreased number of reticulocytes
• rash

Common adverse reactions (may affect less than 1 in 10 people)

• decreased appetite
• high levels of uric acid in the blood, caused by the breakdown of tumour cells, which may lead to gout
• conjunctivitis with light sensitivity, burning sensation, visual disturbances, excessive tearing, pain and redness (reversible hemorrhagic conjunctivitis, keratitis)
• indigestion and abdominal pain
• loss of appetite, nausea, vomiting
• diarrhea
• inflammation or ulceration of the mucous membranes of the mouth or anus
• rash, itching, redness of the skin, formation of large blisters (bullous dermatitis), red spots on the skin
• inflammation of blood vessels
• hair loss (usually reversible)
• kidney function disorders, difficulty in passing urine
• fever
• inflammation of the vein at the injection site with formation of blood clots

Uncommon adverse reactions (may affect less than 1 in 100 people)

• petechiae
• pericarditis
• shortness of breath, sore throat
• inflammation or ulceration of the esophagus
• presence of gas-filled bubbles located in the intestinal wall (pneumatosis intestinalis)
• severe inflammation of the large intestine (necrotizing colitis)
• peritonitis
• lentigo-like changes (presence of flat, brown spots on the skin)
• skin ulceration and inflammation
• itching
• burning pain in palms and soles
• muscle and joint pain

Very rare adverse reactions (may affect less than 1 in 10,000 people)

• heart rhythm disturbances
• nodules and blisters on palms and soles (neutrophilic eccrine hidradenitis)
• pancreatitis

Adverse reactions occurring with unknown frequency (frequency cannot be estimated from the available data)

• infection at the injection site
• liver abscess
• headache or dizziness
• tingling
• nerve inflammation
• jaundice (yellowing of the skin and whites of the eyes)
• decreased heart rate
• hand-foot syndrome (also known as palmar-plantar erythrodysesthesia)
• redness, pain or swelling of the ears, which may occur during or shortly after cytarabine treatment (known as "Ara-C ears")
• inflammation of sweat glands, sometimes causing tender, red skin lesions (known as neutrophilic pustular hidradenitis).

Adverse reactions that may occur with high-dose Alexan treatment, other than those observed with standard dosing:

• significant reduction in red and white blood cells and platelets, which may persist for 15 to 25 days
• personality changes, decreased alertness, articulation disorders, loss of motor control, tremor, involuntary eye movements, headache, confusion, drowsiness, dizziness, coma, seizures; these disorders are mostly reversible and occur predominantly in elderly patients, patients with kidney or liver dysfunction, patients consuming large amounts of alcohol, and patients previously treated with therapies affecting brain function (e.g. radiotherapy)
• conjunctivitis, including light sensitivity, stabbing sensation and visual disturbances; your doctor may recommend prophylactic use of eye drops containing glucocorticosteroids
• perforation of the stomach and intestines, nausea, vomiting
• liver abscess, blood clots in the liver and pancreatitis
• syndrome of acute progressive respiratory disorders leading to pulmonary edema
• breakdown of striated muscle (rhabdomyolysis)
• worsening of heart function due to myocarditis
• absence of sperm production
• absence of menstruation

Adverse reactions reported after intrathecal administration:

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

Reporting of adverse reactions
If any adverse reactions occur, including any 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
tel.: +48 22 4921 301/fax: +48 22 4921 309/website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Alexan

Keep the medicine out of the 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 specified month.
Do not use this medicine if signs of deterioration are observed, such as a change in the colour of the solution.
Store below 25°C.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Alexan contains
The active substance is cytarabine. 1 ml of injection solution contains 20 mg of cytarabine.
The 5 ml vial contains 100 mg of cytarabine.
The other components are: sodium chloride, sodium lactate, lactic acid, water for injections.
What Alexan looks like and contents of the pack
Alexan is a clear and colourless solution.
The pack contains 1 or 10 vials with 100 mg cytarabine in 5 ml of injection solution.
Marketing Authorisation 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 further information, please contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warszawa
tel. 22 209 70 00

Information intended exclusively for healthcare professionals

Dosing information

• Induction therapy
  The usual dose for induction therapy is 100 to 200 mg of cytarabine/m²/day, administered in most cases as a continuous intravenous infusion or as a rapid infusion over 5 to 10 days.

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

• Maintenance therapy
  The usual maintenance dose is 70 to 200 mg of cytarabine/m²/day administered as a rapid intravenous or subcutaneous injection for 5 days, every 4 weeks or once weekly.

• Treatment of non-Hodgkin's lymphoma

Adult treatment
These cases are usually treated with combination chemotherapy regimens, e.g., in the PROMACE-CYTABOM regimen, cytarabine at a dose of 300 mg/m²/day is administered
on day 8 of the treatment cycle.

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

• High-dose therapy
  During high-dose therapy, only diluents without preservatives should be used.

In high-dose therapy, 1 to 3 g cytarabine/m² is usually administered as an intravenous infusion lasting 1 to 3 hours, given every 12 hours for 4 to 6 days.

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

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

Information on storage after first opening and after dilution

• Opened vial
  The solution should be withdrawn from the vial immediately before use. From a microbiological standpoint, the product should be used immediately. Otherwise, the responsibility for storage conditions and duration of the remaining solution in the vial lies with the user. The remaining solution in the vial after first withdrawal should not be stored for longer than 24 hours at a temperature of 2°C to 8°C, unless the withdrawal was performed under controlled, validated aseptic conditions. In such cases, the solution remains physico-chemically stable for up to 28 days when stored in the refrigerator or at room temperature, with or without exposure to light.

• Diluted injection solution
  From a microbiological standpoint, the product should be used immediately. Otherwise, the responsibility for storage conditions and duration of the prepared solution lies with the user. Prepared solutions should not be stored for longer than 24 hours at a temperature of 2°C to 8°C, unless dilution was performed under controlled, validated aseptic conditions. Physical and chemical stability has been demonstrated for up to 28 days for a solution at a concentration of 0.1 mg/ml diluted with 0.9% NaCl, stored in the refrigerator or at room temperature, with or without exposure to light.

Instructions for preparation of the drug for administration
Before administration, Alexan should be diluted with 0.9% sodium chloride solution or 5% glucose solution.
Compatibility of Alexan with 0.9% sodium chloride solution and 5% glucose solution has been studied at concentrations of 0.2–3.2 mg/ml in PVC infusion bags, polyethylene infusion vials, and perfusion syringes.
If cytarabine comes into contact with the skin, the affected area should be thoroughly rinsed with water and then washed carefully with soap and water. If the solution gets into the eyes, the eyes should be thoroughly rinsed with a large amount of water, and an ophthalmologist should be contacted immediately.
Pregnant women should not handle this drug.

Instructions for disposal of drug residues
Vials and materials used during infusion, including protective gloves, should be disposed of according to the regulations applicable to cytotoxic drugs.
In case of spillage or leakage, the solution can be neutralized with a 5% sodium hypochlorite solution. All materials used for this purpose should then be disposed of as mentioned above.

Instructions for managing extravasation

1. Immediately stop administration of the drug.
2. Replace the infusion line or syringe with a single-use 5 ml syringe and slowly aspirate the extravasated drug.
   WARNING! Do not press on the extravasation site.
3. Withdraw the needle while continuously aspirating fluid from the extravasation site.
4. Inform the physician.

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