Fludarabine Teva

Package leaflet: Information for the user

Fludarabine Teva concentrate for solution for injection or infusion

fludarabine phosphate
Please read all of this leaflet carefully before you start 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.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

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

1. What Fludarabine Teva is and what it is used for
Fludarabine Teva is a cytotoxic (anti-tumour) medicine: a drug that inhibits the growth of tumour cells.
Fludarabine Teva is used to treat B-cell chronic lymphocytic leukaemia (B-CLL) in patients who have sufficient production of healthy blood cells. Initial treatment with fludarabine phosphate for chronic lymphocytic leukaemia should only be started in patients with advanced-stage disease who have disease-related symptoms or evidence of disease progression.
CLL is a cancer affecting white blood cells (called lymphocytes).
If you have been diagnosed with CLL, it means you have an excessive production of lymphocytes. These cells do not function properly or are too immature to fight disease, which is the normal role of white blood cells. When present in excessive numbers, these abnormal cells replace healthy blood cells in the bone marrow (the tissue where most new blood cells are formed). They also replace healthy blood cells in the bloodstream and organs. The lack of sufficient normal blood cells can lead to infections, anaemia, bruising, bleeding, and even organ failure.

2. What you need to know before using Fludarabine Teva

Do not use Fludarabine Teva:

• if you are allergic to fludarabine phosphate or to any of the other ingredients of this medicine (listed in section 6).
• if you have severely reduced renal function. Based on your renal function, your doctor will decide whether Fludarabine Teva 25 mg/ml can be used or not.
• if you have a particular type of anaemia (decompensated haemolytic anaemia; this condition involves a deficiency in red blood cells). Your doctor will have informed you if this applies to you.
• if you are breastfeeding (see also section “Pregnancy, breastfeeding and fertility”).

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using Fludarabine Teva:

• If your bone marrow is not functioning properly, or if your immune system is impaired or not working well, or if you have suffered from severe infections ► Your doctor may decide not to administer this medicine or may take certain precautions.
• If you feel very unwell, notice unusual bruising or excessive bleeding after a cut, or have the impression that you are developing frequent infections ► Inform your doctor if any of these occur before treatment.
• If, during treatment, you notice that your urine becomes red to brownish in colour, or if you develop skin rashes or blisters on the skin ► Inform your doctor immediately. These could be signs of a reduced number of blood cells, which may be caused by the disease or by the therapy. This condition may last up to one year, regardless of previous fludarabine use. During treatment with Fludarabine Teva, your immune system may also attack various parts of the body or red blood cells (these are called "autoimmune disorders"). These conditions can be life-threatening. If this occurs, your doctor will stop treatment and may initiate further treatments, such as irradiated blood transfusion (described below) and administration of adrenocorticosteroids. You will undergo regular blood tests and careful monitoring during treatment with Fludarabine Teva.
• If you notice any unusual neurological symptoms, such as vision problems ► Inform your doctor. The long-term effects of Fludarabine Teva on the nervous system are not fully known. However, patients treated with the recommended dose for up to 26 treatment cycles have tolerated it well. In patients treated with doses four times higher than the recommended dose, blindness, coma and death have occurred. Some of these symptoms appeared late, approximately 60 days or more after treatment discontinuation.
• If you experience flank pain or notice blood in your urine or produce a reduced amount of urine ► Inform your doctor immediately. If the disease is very severe, your body may be unable to eliminate all waste products from cells destroyed by Fludarabine Teva. This phenomenon is known as tumour lysis syndrome and may lead to kidney failure and heart problems starting within the first week of treatment. Your doctor is aware of these risks and may administer other medications to help prevent them.
• If you are scheduled to undergo stem cell collection and are currently taking Fludarabine Teva (or have taken it previously) ► Inform your doctor.
• If you require a blood transfusion and are currently taking Fludarabine Teva (or have taken it previously) ► Inform your doctor. If a blood transfusion is needed, your doctor will ensure that you receive only irradiated blood. Transfusions with non-irradiated blood have led to serious complications, including death.
• If you notice any skin changes while taking this medicine or after completing treatment ► Inform your doctor.
• If you have or have had skin cancer, it may worsen or recur during or after treatment with Fludarabine Teva. You may develop skin cancer during or

after treatment with Fludarabine Teva.
Other considerations during treatment with Fludarabine Teva:

• Men and women of childbearing age must use effective contraceptive methods during treatment and for at least 6 months after treatment ends. Fludarabine Teva may be harmful to the foetus. Your doctor will carefully evaluate the benefits of treatment against the potential risks to the foetus and will only administer Fludarabine Teva during pregnancy if strictly necessary.
• If you are breastfeeding or considering starting to breastfeed, you must not start or continue breastfeeding during treatment with Fludarabine Teva.
• If you need vaccination, discuss it with your doctor, as live vaccines must be avoided during and after treatment with Fludarabine Teva.
• If you have kidney problems or are over 65 years old, you will need regular blood tests and/or laboratory examinations to monitor kidney function. If your kidney problems are severe, this medicine will not be administered (see also "Do not use Fludarabine Teva" and section 3 "How to use Fludarabine Teva").
• If you have liver problems, your doctor must administer this medicine with caution.
• If you are over 75 years old, Fludarabine Teva will be administered with caution.

Children
The safety of this medicine in children has not been established.
Other medicines and Fludarabine Teva
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
It is particularly important that you inform your doctor about the following medicines:

• Pentostatin (deoxycoformycin), also used in the treatment of chronic B-cell lymphocytic leukaemia (B-CLL). Concomitant use of these two medicines may cause serious lung problems;
• Dipyridamole, used to prevent excessive blood clotting, or other similar substances that may reduce the effectiveness of Fludarabine Teva;
• Cytarabine (Ara-C), used in the treatment of chronic lymphocytic leukaemia. If Fludarabine Teva is administered together with cytarabine, the concentrations of the active form of Fludarabine Teva in leukaemic cells may increase. However, overall blood concentrations and elimination from the blood were not significantly altered.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.
Fludarabine Teva must not be administered during pregnancy, as animal studies and limited human experience have shown a potential risk of fetal developmental abnormalities. Women of childbearing age must avoid pregnancy. However, if pregnancy occurs, you must inform your doctor immediately (see also “Other considerations during treatment with Fludarabine Teva”).
Men and women of childbearing age must use adequate contraceptive measures during treatment and for at least 6 months after treatment ends.
It is not known whether fludarabine is excreted in human breast milk. However, in animal studies, fludarabine has been detected in breast milk. Therefore, breastfeeding must be discontinued during treatment with this medicine.
Driving and using machines
Fludarabine Teva may reduce your ability to drive or operate machinery, as fatigue, weakness, visual disturbances, confusion, agitation and seizures have been reported.
Fludarabine Teva contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. it is essentially “sodium-free”.

3. How to use Fludarabine Teva

Follow your doctor's instructions carefully when using Fludarabine Teva. Your doctor will decide when you should take Fludarabine Teva and for how long. Fludarabine Teva must be administered under the supervision of a qualified and experienced physician in the use of anticancer drugs.
For instructions on dilution, handling, and disposal, see “The following information is intended exclusively for physicians or healthcare professionals” at the end of this leaflet.
The amount of Fludarabine Teva administered (the dose) depends on body surface area.
Technically, body surface area is measured in square meters (m²), but in practice it is calculated based on your height and weight.
General guidelines
The recommended dose is 25 mg per m² of body surface area per day, administered by injection or infusion for 5 consecutive days. This cycle, consisting of five days of treatment, should be repeated every 28 days until your doctor determines that the maximum possible benefit has been achieved.
Generally, this occurs after 6 cycles, i.e. after approximately 6 months. If side effects become problematic, the dose may be reduced or the next treatment cycle delayed.
If you have kidney problems, you must be given a reduced dose, and you will need to have regular blood tests.

What to do in case of overdose with Fludarabine Teva
There is no specific antidote for overdose with Fludarabine Teva. If you have been given an excessive amount of Fludarabine Teva, your doctor will stop the treatment and treat any symptoms.
High doses of Fludarabine Teva have been associated with irreversible side effects on the central nervous system, characterized by delayed blindness, coma, and death.
Administration of high doses is also associated with severe reduction in the number of certain types of blood cells (severe thrombocytopenia, i.e. decreased platelet count accompanied by bruising and bleeding, and neutropenia, i.e. decreased white blood cell count with increased risk of infection) due to reduced bone marrow activity (myelosuppression).

If you forget to take Fludarabine Teva
It is your doctor's responsibility to determine when this medicine should be administered to you. If you think you have missed a dose, you must contact your doctor as soon as possible.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you are unsure about the adverse reactions listed below, please ask your doctor for an explanation.
Some side effects may be life-threatening.

• If you have difficulty breathing, cough, or feel chest pain, with or without fever. These could be signs of a lung infection.
• If you notice unusual bruising or more severe bleeding than usual after a cut, or if you feel you are getting many infections. These symptoms may be caused by a decrease in blood cells. This condition may also lead to an increased risk of (serious) infections caused by organisms that normally do not cause disease in healthy people (opportunistic infections), for example, late reactivation of a virus such as herpes zoster.
• If you feel pain in your side, notice blood in your urine, or produce less urine than usual. These could be signs of tumour lysis syndrome (see section 2, "Warnings and precautions").
• If you notice skin and/or mucosal reactions with redness, inflammation, blistering, and tissue damage. These could be signs of a severe allergic reaction (Lyell syndrome, Stevens-Johnson syndrome).
• If you feel palpitations (sudden awareness of your heartbeat) or chest pain. These could be signs of heart problems.

► Contact your doctor immediately if you experience any of these effects.
The possible side effects listed below are classified according to frequency. Rare side effects (which may affect up to 1 in 1,000 people) have mainly been identified from post-marketing experience.

• Very common (may affect more than 1 in 10 people):
  • infections (some severe);
  • infections due to weakened immune system (opportunistic infections);
  • lung infection (pneumonia) with possible symptoms such as difficulty breathing and/or cough, with or without fever;
  • reduced platelet count (thrombocytopenia) with risk of bleeding and bruising;
  • reduced white blood cell count (neutropenia);
  • reduced red blood cell count (anemia);
  • cough;
  • vomiting, diarrhoea, nausea;
  • fever;
  • fatigue (tiredness);
  • weakness.
• Common (may affect up to 1 in 10 people):
  • other blood cancers (myelodysplastic syndrome, acute myeloid leukaemia. Most patients affected by these diseases had previously, concurrently, or subsequently been treated with other cancer medicines [alkylating agents, topoisomerase inhibitors] or radiotherapy);
  • bone marrow suppression (myelosuppression);
  • severe loss of appetite leading to weight loss (anorexia);
  • numbness or weakness in limbs (peripheral neuropathy);
  • visual disturbances;
  • inflammation inside the mouth (stomatitis);
• skin rash;
• swelling due to excessive fluid retention (oedema);
• inflammation of the mucous membranes from mouth to anus (mucositis);
• chills;
• feeling generally unwell.
  • Uncommon (may affect up to 1 in 100 people):
• autoimmune disorders (see section 2, "Warnings and precautions");
• tumour lysis syndrome (see section 2, "Warnings and precautions");
• confusion;
• pulmonary toxicity; development of lung lesions (pulmonary fibrosis), lung inflammation (pneumonitis), shortness of breath (dyspnoea);
• bleeding from the stomach or intestine;
• abnormal levels of liver or pancreatic enzymes.
  • Rare (may affect up to 1 in 1,000 people):
• lymphatic system disorders due to viral infection (EBV-associated lymphoproliferative disorder);
• coma;
• seizures;
• agitation;
• blindness;
• inflammation or damage to the optic nerve (optic neuritis; optic neuropathy);
• heart failure;
• irregular heartbeat (arrhythmia);
• skin tumour;
• skin and/or mucosal reactions with redness, inflammation, blistering, and tissue damage (Lyell syndrome, Stevens-Johnson syndrome);
  • Not known (frequency cannot be estimated from the available data):
• inflammation of the bladder, which may cause pain during urination and blood in the urine (haemorrhagic cystitis);
• bleeding in the lungs (pulmonary haemorrhage);
• bleeding in brain tissue (cerebral haemorrhage).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system at: http://www.agenziafarmaco.gov.it/it/responsabili.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Fludarabine Teva

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the pack and vial after "EXP.". The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Fludarabina Teva contains

• The active substance is fludarabine phosphate. 1 ml of concentrate contains 25 mg of fludarabine phosphate. Each 2 ml vial contains 50 mg of fludarabine phosphate.
• The other components are mannitol (E421), sodium hydroxide (E524, for pH adjustment) and water for injections.

Description of the appearance of Fludarabina Teva and package contents
Fludarabina Teva is a clear, colourless or slightly yellowish-brown solution, essentially free from particles, contained in a transparent glass vial with a rubber stopper, aluminium seal and plastic tamper-evident cap. Each package contains one vial.
Marketing Authorization Holder
Teva Italia S.r.l. - Piazzale Luigi Cadorna, 4 - 20123 Milan, Italy
Manufacturer
Pharmachemie B.V. - Swensweg 5 - PO Box 552 - 2003 RN Haarlem (The Netherlands)
Teva Operations Poland Sp. z o.o. - ul. Mogilska 80 - 31-546 Kraków (Poland)

The following information is intended exclusively for physicians or healthcare professionals:
Instructions for dilution, handling and disposal
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those specifically mentioned below.
Dilution
The required dose (calculated according to the patient's body surface area) should be withdrawn with a syringe.
For intravenous bolus injection, this dose must be further diluted in 10 ml of 0.9% sodium chloride solution. Alternatively, if administered by infusion, the required dose may be diluted in 100 ml of 0.9% sodium chloride solution and infused over approximately 30 minutes.
Clinical studies have been conducted using fludarabine diluted in 100 ml or 125 ml of 5% dextrose injection solution or 0.9% sodium chloride solution.
Inspection prior to use
Only clear, colourless solutions free from particles should be used. This product must not be used if the packaging is damaged.
Storage after dilution
The chemical and physical in-use stability of the prepared solution for injection or infusion is:

From a microbiological standpoint, the product should be used immediately. If not used immediately, the user is responsible for the storage times and conditions of the solution prior to use, which generally should not exceed 24 hours at 2 °C - 8 °C, unless the dilution was carried out under controlled and validated aseptic conditions.

Handling and disposal
Fludarabine must not be handled by personnel who are pregnant.
Proper handling and disposal procedures must be observed, in accordance with local regulations for cytotoxic medicinal products.
Caution is recommended when handling fludarabine solution. The use of latex gloves and protective eyewear is advised to prevent direct contact in case of vial breakage or accidental splashing. In case of contact with skin or mucous membranes, wash thoroughly with water and soap. If the solution comes into contact with the eyes, rinse them thoroughly with water. Inhalation must be avoided.
This medicinal product is for single use only. Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations applicable to cytotoxic agents.