Fludarabine accord

Package leaflet: Information for the user

Fludarabine Accord, 25 mg/ml, concentrate for solution for injection or infusion
Fludarabini phosphas
Please read all of this leaflet carefully before using 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, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet

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

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

Fludarabine Accord 25 mg/ml concentrate for solution for injection or infusion contains the active substance fludarabine phosphate, which inhibits the growth of new tumour cells. All cells in the body produce new cells by dividing. Fludarabine Accord, taken up by tumour cells, blocks their division.

In patients with a cancer of the white blood cells (e.g. chronic leukaemia), the body produces many abnormal white blood cells (lymphocytes), leading to swollen lymph nodes in various parts of the body. These abnormal blood cells are unable to perform the body's normal defence functions and may displace healthy blood cells. This may lead to infections, reduced numbers of red blood cells (anaemia), bruising, excessive bleeding (haemorrhage), and even organ failure.

Fludarabine Accord is used to treat chronic B-cell lymphocytic leukaemia (B-CLL) in patients whose bone marrow is still producing sufficient healthy blood cells.

The first course of treatment with fludarabine phosphate for chronic lymphocytic leukaemia should only be initiated in patients with advanced disease who have related symptoms or clear disease progression.

2. Important information before using Fludarabine Accord

When not to use Fludarabine Accord

• if the patient is allergic to fludarabine phosphate or any of the other ingredients of this medicine (listed in section 6);
• if the patient is breastfeeding;
• if the patient has severe kidney function impairment;
• if the patient has a low number of red blood cells due to a specific type of anaemia (uncontrolled haemolytic anaemia). The doctor will inform the patient if this condition is present. Inform the doctor if any of the above apply to the patient.

Warnings and precautions
When to talk to the doctor before using Fludarabine Accord

• If the patient has impaired bone marrow function or impaired function or suppression of the immune system, or has a history of severe infections.
• The doctor may decide not to use this medicine or may take appropriate precautions.
• If the patient feels unwell, has unusual bruising, excessive bleeding following injury, or increased susceptibility to infections.
• If during treatment the patient's urine becomes red or brownish in colour, or if skin changes such as rash or blisters occur.

These may be symptoms of reduced blood cell counts caused by the disease itself or by treatment. This condition may persist for up to a year, regardless of whether the patient has previously been treated with fludarabine or not. During fludarabine treatment, the patient's immune system may attack various parts of the body or its own red blood cells (so-called “autoimmune disorders”). This may be life-threatening. In the event of any of these conditions, the doctor will order discontinuation of the medicine and may initiate alternative treatment, e.g. transfusion of irradiated blood (see below) and administration of adrenocorticosteroids. During fludarabine treatment, the patient will undergo regular blood tests and remain under close medical supervision.

• If unusual neurological symptoms occur, such as vision disturbances, headache, disorientation, or seizures.

The long-term effect of fludarabine on the central nervous system is not known. However, patients have tolerated the recommended dose of the drug for up to 26 treatment cycles. When Fludarabine Accord is administered at the recommended doses, following or concurrently with other medicines, the following adverse reactions have been reported: neurological disorders including headache, nausea, vomiting, seizures, visual disturbances (including loss of vision), changes in mental status (cognitive disturbances, confusion, disturbances of consciousness), and occasionally neuromuscular disorders such as limb muscle weakness (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or posterior reversible leukoencephalopathy syndrome - RPLS).
In patients receiving doses four times higher than the recommended dose, loss of vision, coma, and even death have been reported. Some of these symptoms occurred with a delay, approximately 60 days or more after completion of treatment. In some patients receiving Fludarabine Accord at doses higher than recommended, leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL), and posterior reversible leukoencephalopathy syndrome (RPLS) have also been reported. The same symptoms as described above may occur.
Leukoencephalopathy, acute toxic leukoencephalopathy, and posterior reversible leukoencephalopathy syndrome may be irreversible, life-threatening, or fatal.
If LE, ATL, or RPLS is suspected, Fludarabine Accord should be discontinued pending further investigations. If LE, ATL, or RPLS is confirmed, the doctor will permanently discontinue Fludarabine Accord.

• If the patient experiences flank pain, blood in the urine, or reduced urine output.

In severe disease, the body may be unable to eliminate all substances released from cells destroyed by fludarabine. This is known as tumour lysis syndrome and may lead to kidney failure and heart disturbances within the first week of treatment. The doctor will be aware of this risk and may administer additional medicines to prevent such complications.

• If a bone marrow biopsy is required and the patient is (or has been) treated with fludarabine.
• If the patient requires a blood transfusion and is currently receiving (or has previously received) fludarabine.

If a blood transfusion is necessary, the doctor will ensure that the patient receives irradiated blood. Severe complications, including death, have occurred following transfusion of non-irradiated blood.

• If the patient notices any skin changes, both during and after treatment.
• If the patient has or has had skin cancer, worsening or recurrence may occur during or after fludarabine therapy. Skin cancer may also develop during or after fludarabine treatment.

Other considerations during treatment with Fludarabine Accord:

• Men and women of reproductive age must use effective contraception during treatment and for at least 6 months after treatment ends. It cannot be excluded that Fludarabine Accord may have harmful effects on the foetus. The doctor will assess the benefit-risk balance for the patient and will prescribe fludarabine during pregnancy only if absolutely necessary.
• Breastfeeding must not be initiated or continued during treatment with Fludarabine Accord.
• If vaccination is required, consult the doctor, as live vaccines should be avoided during and after fludarabine treatment.
• If the patient has kidney impairment or is over 65 years of age, regular blood tests and/or laboratory tests will be performed to monitor kidney function. In case of severe kidney impairment, this medicine must not be administered at all (see sections 2 and 3).

Children and adolescents:
The efficacy and safety of fludarabine phosphate in children under 18 years of age have not been established; therefore, use of this medicine in children is not recommended.
Elderly patients:
Patients over 65 years of age will undergo regular tests to assess kidney function (see also section 3: “How to use Fludarabine Accord”).
Patients over 75 years of age will be monitored particularly closely.

Fludarabine Accord and other medicines
Inform the doctor or pharmacist about all medicines currently used, recently used, or planned for use, including over-the-counter medicines. It is especially important to inform the doctor about the use of the following medicines:

• Pentostatin (deoxycoformycin), also used in the treatment of B-cell chronic lymphocytic leukaemia. Concurrent use of these two medicines may lead to severe lung disease;
• Dipyridamole, a medicine that reduces blood clotting, or other medicines with similar effects. These may reduce the effectiveness of fludarabine;
• Cytarabine (Ara-C), used in the treatment of chronic lymphocytic leukaemia. Concurrent use of fludarabine with cytarabine may increase the concentration of the active form of fludarabine in leukaemia cells. However, no changes in overall blood concentration or elimination from blood have been observed.

Pregnancy, breastfeeding, and effects on fertility
Pregnancy
Fludarabine Accord must not be used during pregnancy, as animal studies and limited human experience have shown a possible risk of developmental abnormalities in the foetus, as well as miscarriage and premature delivery.

• If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult the doctor before using this medicine.

The doctor will assess the benefit to the patient against the risk to the foetus and will prescribe this medicine during pregnancy only if absolutely necessary.
Breastfeeding
Breastfeeding must not be initiated or continued during treatment with Fludarabine Accord, as this medicine may affect the child's growth and development.
Fertility
Fertile men and women must use effective contraception during treatment and for at least 6 months after treatment ends.

Driving and operating machinery
Some patients treated with Fludarabine Accord may experience fatigue, weakness, visual disturbances, confusion, agitation, or seizures. Patients should not drive or operate machinery until they are certain that this medicine does not affect them in such a way.

Important information about certain ingredients of Fludarabine Accord
This medicine contains less than 1 mmol sodium per dose, i.e. essentially "sodium-free".

3. How to take Fludarabine Accord

This medicine should always be taken exactly as recommended by your doctor or pharmacist. If in doubt,
you should consult your doctor.
Fludarabine must be administered under the supervision of a qualified doctor experienced in managing
anti-cancer therapy.

• Information on the preparation of solution dilutions, see section 6 "Contents of the pack and other information".

What dose of Fludarabine Accord should be given:
The dose of Fludarabine Accord depends on the patient's body surface area. This is measured in square
metres (m²) and is calculated by the doctor based on the patient's height and body weight.
The recommended dose is 25 mg of fludarabine phosphate per m² of body surface area.

How to administer Fludarabine Accord:
Fludarabine Accord is given as a solution, either as an injection or, more commonly, as an intravenous
infusion.
An intravenous infusion means that the medicine is delivered directly into a vein as a drip. Each infusion
lasts approximately 30 minutes.
Your doctor will ensure that Fludarabine Accord is not administered extravascularly. However, in cases
of accidental extravascular administration, no serious local adverse effects have been reported.

How long to administer Fludarabine Accord:
The recommended dose is given once daily for 5 consecutive days.
This 5-day treatment cycle will be repeated every 28 days until your doctor decides that the best possible
treatment outcome has been achieved (usually after 6 treatment cycles).
The duration of treatment depends on its effectiveness and the patient's tolerance. If adverse reactions
occur, the next cycle may be delayed.
During treatment, the patient will have regular blood tests. The individual dose of the medicine will be
carefully adjusted** depending on blood cell counts and the patient's response to treatment.
If adverse reactions occur, the dose may be reduced.

If the patient has kidney disease or is over 65 years of age, the patient will undergo regular tests to
assess kidney function. If the kidneys are not functioning properly, the patient may receive a lower dose
of this medicine. This medicine should not be used if the patient has severe kidney dysfunction (see section 2).

What to do in case of accidental spillage of Fludarabine Accord solution:
If the Fludarabine Accord solution comes into contact with the skin or the mucous membranes of the nose
or mouth, wash the affected areas thoroughly with soap and water. If the solution gets into the eyes, rinse
them thoroughly with plenty of water. Avoid inhaling vapours emanating from the solution.

Use of a higher than recommended dose of Fludarabine Accord
If a patient has received too high a dose of the medicine, the doctor will discontinue treatment and provide
symptomatic treatment. High doses may lead to severe reduction in blood cell counts.
Overdose of intravenously administered Fludarabine Accord has led to delayed blindness, coma, and even
death.

Missed dose of Fludarabine Accord
Your doctor will schedule the times for administering the medicine. If you think a dose has been missed,
contact your doctor as soon as possible.
Do not take a double dose to make up for a missed dose.

Stopping treatment with Fludarabine Accord
If severe adverse reactions occur, the doctor will decide to discontinue treatment.
If you have any further questions about the use of this medicine, consult your doctor.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone will experience them.
If you have any doubts regarding the adverse reactions described below, please consult your doctor for clarification.
Some adverse reactions may be life-threatening.

• If the patient experiences difficulty breathing, cough, or chest pain with or without fever. These may be symptoms of a lung infection.
• If the patient notices unusual bruising, excessive bleeding after injury, or increased susceptibility to infections. These symptoms may be caused by a reduced number of blood cells. This may lead to an increased risk of (severe) infections caused by microorganisms that usually do not cause disease in healthy individuals (opportunistic infections), including late reactivation of viruses, e.g. shingles.
• If the patient experiences pain in the side, notices blood in the urine, or a reduced amount of urine produced. These may be signs of tumour lysis syndrome (see section 2).
• If the patient notices skin and/or mucous membrane changes such as redness, inflammation, blisters, and tissue damage. These may be symptoms of a severe allergic reaction (Lyell's syndrome, Stevens-Johnson syndrome).
• If the patient experiences palpitations (noticeable abnormal heartbeat) or chest pain. These may be symptoms of heart disorders. Seek immediate medical attention if any of the above adverse reactions occur.

The following adverse reactions are listed according to their frequency of occurrence. Rare adverse reactions (occurring in less than 1 in 1,000 patients) have been reported mainly after the medicine was placed on the market.
Very common (occurring in more than 1 in 10 patients):

• infections (including severe infections);
• infections due to suppression of the immune system function (opportunistic infections);
• lung infections (pneumonia), with symptoms such as difficulty breathing and/or cough with or without fever;
• decreased platelet count (thrombocytopenia), which may be associated with bruising and bleeding;
• reduced white blood cell count (neutropenia);
• reduced red blood cell count (anaemia);
• cough;
• vomiting, diarrhoea, nausea;
• fever;
• fatigue;
• weakness.

Common (occurring in less than 1 in 10 patients):

• other blood cancers (myelodysplastic syndrome, acute myeloid leukaemia). Most patients who developed these conditions had previously or concurrently been treated with other anticancer medicines (alkylating agents, topoisomerase inhibitors) or radiotherapy;
• reduced bone marrow cell count (myelosuppression);
• severe loss of appetite leading to weight loss (anorexia);
• numbness or weakness in limbs (peripheral neuropathy);
• vision disorders;
• inflammation of the mouth lining;
• skin rash;
• swelling due to excessive fluid retention;
• inflammation of the mucous membrane in the gastrointestinal tract from the mouth to the anus (mucositis);
• chills;
• general malaise.

Uncommon (occurring in less than 1 in 100 patients):

• autoimmune diseases (see section 2 "Warnings and precautions");
• tumour lysis syndrome (see section 2 "Warnings and precautions");
• feeling disoriented;
• lung damage; scarring of the lungs (pulmonary fibrosis), lung inflammation, shortness of breath;
• bleeding into the abdominal cavity or intestines;
• abnormal liver or pancreatic enzyme activity.

Rare (occurring in less than 1 in 1,000 patients):

• lymphatic system disorders due to viral infection (lymphoproliferative disease associated with EBV infection);
• coma;
• seizures;
• restlessness;
• loss of vision;
• inflammation or damage to the optic nerve, optic neuropathy;
• heart failure;
• irregular heartbeat (arrhythmia);
• skin cancer;
• skin and/or mucous membrane changes such as redness, inflammation, blisters, and tissue damage (Lyell's syndrome, Stevens-Johnson syndrome).

Frequency not known (cannot be estimated from available data):

• bladder inflammation, which may cause pain during urination and presence of blood in the urine (haemorrhagic cystitis);
• bleeding into brain tissue (intracerebral haemorrhage);
• bleeding in the lungs (pulmonary haemorrhage).

Neurological disorders manifesting as headache, nausea, vomiting, seizures, visual disturbances including loss of vision, mental status changes (cognitive disorders, confusion, altered consciousness), and occasionally neuromuscular disorders such as muscle weakness in the limbs (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome (RPLS)).
Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, 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
Reporting adverse reactions helps to provide more information on the safety of this medicine.

5. How to store Fludarabine Accord
Keep the medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the vial/fial and outer carton after: EXP.
The expiry date refers to the last day of the stated month.

Storage conditions for the product (unopened vials):
Store in a refrigerator (2-8°C).
Do not freeze.

Storage conditions for the product after dilution:
Chemical and physical stability of solutions diluted to concentrations of 0.2 mg/ml and 6 mg/ml in 0.9% NaCl and 5% glucose has been demonstrated for 7 days at 2-8°C and 5 days at 20-25°C in non-PVC infusion bags and glass bottles.
From a microbiological standpoint, this medicinal product should be used immediately. If not used immediately, the user is responsible for storage conditions and duration, which should not exceed 24 hours at 2°C to 8°C, provided dilution was performed under controlled and validated aseptic conditions.

Information intended exclusively for medical personnel or healthcare professionals—see section 6. Contents of the pack and other information.
Do not use the solution if signs of deterioration are visible.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Fludarabine Accord contains
The active substance is fludarabine phosphate. 1 ml of concentrate contains 25 mg of fludarabine phosphate.
The other ingredients are: mannitol, disodium phosphate dihydrate, water for injections.
Fludarabine Accord is supplied in 2 ml glass vials.
What Fludarabine Accord looks like and contents of the pack
Fludarabine Accord is a sterile, clear, colourless or slightly brownish-yellow solution in a vial made of colourless glass.
Fludarabine Accord is available in three pack sizes: 1, 5 or 10 vials per pack.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warszawa
Tel: +48 22 577 28 00
Manufacturer/Importer
Accord Healthcare Polska Sp. z o.o.
ul. Lutomierska 50
95-200 Pabianice
Accord Healthcare single member S.A.
64th Km National Road Athens, Lamia
Schimatari, 32009
Greece
This medicinal product is authorised in the European Economic Area and the United Kingdom (Northern Ireland) under the following names:

Information intended exclusively for medical personnel or healthcare professionals:

Fludarabine Accord, as a cytotoxic medicinal product, must be prepared by trained personnel in a designated area. Handling of the medicinal product should comply with local guidelines for cytotoxic medicinal products.
The product is intended for intravenous use only.
Pharmaceutical incompatibilities
Due to lack of compatibility studies, the medicinal product must not be mixed with other medicinal products.
Dilution
The required dose (calculated based on the patient's body surface area) is drawn into a syringe.
For direct intravenous injection (bolus), this dose is subsequently diluted in 10 mL of 0.9% (9 mg/mL) sodium chloride injection solution. Alternatively, for infusion, the required dose may be diluted in 100 mL of 0.9% (9 mg/mL) sodium chloride solution and administered over approximately 30 minutes.
In clinical studies, the product was diluted in 100 mL or 125 mL of either 5% dextrose solution or 0.9% sodium chloride (9 mg/mL).
Storage
Shelf life (unopened vials): 2 years
Chemical and physical stability of solutions at concentrations of 0.2 mg/mL and 6 mg/mL has been demonstrated after dilution in 0.9% NaCl and 5% glucose for 7 days at 2–8°C and for 5 days at 20–25°C in non-PVC infusion bags and glass bottles.
From a microbiological standpoint, this medicinal product should be used immediately. If not used immediately, the user is responsible for storage duration and conditions, which under aseptically controlled and validated conditions should not exceed 24 hours at 2°C to 8°C.
Visual inspection prior to use
The diluted solution is clear, colorless or slightly brownish-yellow.
It should be inspected visually before use.
Only clear, colorless or slightly brownish-yellow solutions, free from visible particulate matter, should be used. Do not use the product if the container is damaged.
Handling and disposal of waste
Pregnant women should not handle fludarabine phosphate.
Handling of the medicinal product should comply with local guidelines for cytotoxic medicinal products.
Caution should be exercised when handling fludarabine solutions. Use of latex gloves and protective goggles is recommended to avoid exposure in case of vial breakage or accidental spillage. If accidental contact with skin or mucous membranes occurs, the affected area should be thoroughly washed with soap and water. In case of eye contact, eyes should be rinsed thoroughly with copious amounts of water. Inhalation should be avoided.
The medicinal product is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local regulations.