Consumer medicine information

FLUDARABINE EBEWE

Fludarabine phosphate

BRAND INFORMATION

Brand name

Fludarabine Ebewe

Active ingredient

Fludarabine phosphate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using FLUDARABINE EBEWE.

SUMMARY CMI

FLUDARABINE EBEWE®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Fludarabine Ebewe?

Fludarabine Ebewe contains the active ingredient Fludarabine phosphate. Fludarabine Ebewe is used to treat a form of leukaemia known as B-cell chronic lymphocytic leukaemia (B-CLL). This is a cancer of a type of white blood cells called lymphocytes. For more information, see Section 1. Why am I using Fludarabine Ebewe? in the full CMI.

2. What should I know before I use Fludarabine Ebewe?

Do not use if you have ever had an allergic reaction to Fludarabine phosphate or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Fludarabine Ebewe? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fludarabine Ebewe and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Fludarabine Ebewe?

  • Fludarabine Ebewe must only be given by a doctor or nurse. Fludarabine Ebewe is injected into a vein (often in the arm) once each day for 5 consecutive days. This 5 day course is then repeated once every 28 days.
  • Fludarabine Ebewe should only be administered intravenously. More instructions can be found in Section 4. How do I use Fludarabine Ebewe? in the full CMI.

5. What should I know while using Fludarabine Ebewe?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are being given Fludarabine Ebewe.
  • Call your doctor straight away if you notice anything new or unusual on your skin, suggestive of skin cancer.
Things you should not do
  • Do not take any additional medicines without the advice of your doctor or pharmacist.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Fludarabine Ebewe affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Fludarabine Ebewe will be stored appropriately at the pharmacy or on the ward.
  • The injection is kept in a refrigerator where the temperature stays between 2°C and 8°C.

For more information, see Section 5. What should I know while using Fludarabine Ebewe? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with this medicine. It is important to be aware of them so that you can ident ify any symptoms if they occur (see the full CMI for more details). The most common and serious side effects are infections, symptoms of anaemia, bruising, loss of appetite, weight loss, numbness or weakness in the arms and legs, cough, nausea, vomiting, diarrhoea, sore mouth or gums, mouth ulcers, skin rash, fever, tiredness, chills, weakness and/or generally feeling unwell, swelling due to excessive fluid retention, severe bruising, more bleeding than usual after injury, infections, symptoms of pneumonia, visual disturbances, sudden signs of allergy, red to brownish urine, rash or any blisters on your skin, vomiting blood or material that looks like coffee grounds, bleeding from your anus or in stools or bloody diarrhoea, seizures, unconsciousness, vision changes, symptoms of heart disease such as shortness of breath, and swelling of the feet or legs due to fluid build-up, abnormal heartbeat, difficulty breathing, severe cough, sharp chest pains, signs of tumour lysis syndrome, signs of Stevens-John syndrome, signs of toxic epidermal necrolysis, neurological disorders, bleeding in the lungs, pain when passing urine. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

FLUDARABINE EBEWE®

Active ingredient(s): Fludarabine phosphate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Fludarabine Ebewe. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Fludarabine Ebewe.

Where to find information in this leaflet:

1. Why am I using Fludarabine Ebewe?
2. What should I know before I use Fludarabine Ebewe?
3. What if I am taking other medicines?
4. How do I use Fludarabine Ebewe?
5. What should I know while using Fludarabine Ebewe?
6. Are there any side effects?
7. Product details

1. Why am I using Fludarabine Ebewe?

Fludarabine Ebewe contains the active ingredient Fludarabine phosphate. Fludarabine Ebewe is an anti-cancer drug approved to treat a form of leukaemia known as B-cell chronic lymphocytic leukaemia (B-CLL). This is a cancer of a type of white blood cells called lymphocytes.

Patients with B-CLL have too many abnormal white blood cells (lymphocytes) and lymph nodes start to grow in various parts of the body. The abnormal white blood cells cannot carry out their normal disease fighting functions, and may push aside healthy blood cells. This can result in infections, a decreased number of red blood cells (anaemia), bruising and/ or bleeding.

Fludarabine Ebewe is used to stop the growth of new cancer cells. All cells of the body produce new cells like themselves by dividing. To do this, the cells' genetic material (DNA) must be copied and reproduced.

Fludarabine Ebewe is taken up by the cancer cells and hinders the production of new DNA.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

There is not enough information to recommend the use of this medicine for children.

2. What should I know before I use Fludarabine Ebewe?

Warnings

Do not use Fludarabine Ebewe if:

  • you are allergic to Fludarabine phosphate, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • You are pregnant
  • You are breast-feeding
  • Your red blood cell count is low because of a type of anaemia (haemolytic anaemia)
  • You have severe kidney problems

Check with your doctor if you:

  • have allergies to any other medicines, foods, preservatives or dyes
  • have or have had any of the following medical conditions:
    - low protein in the blood (hypoalbuminaemia).
    Your doctor will have told you if you have this
    - you feel very unwell, have unusual bruising, more bleeding than usual after injury, or if you seem to be catching a lot of infections
    - poor kidney function
    - enlarged liver or spleen, reduced liver function
    - skin cancer. If you have or have had skin cancer it may worsen or flare up again while you take Fludarabine Ebewe or afterwards
  • take any medicines for any other condition
  • Are over 75 years of age. Your doctor will administer Fludarabine Ebewe to you with caution and monitor your closely
  • Are below 18 years of age. It is not recommended to give this medicine to a child under the age of 18 years.
  • Are pregnant or plan to become a parent. Men and women who may still be fertile must use a reliable form of contraception during treatment and for at least 6 months after stopping Fludarabine Ebewe therapy. It is not known whether Fludarabine Ebewe decreases your fertility. Your doctor can discuss with you the risks and benefits involved.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant.

You must not become pregnant during treatment with Fludarabine Ebewe because animal studies and very limited experience in humans have shown a possible risk of abnormalities in the unborn baby as well as early pregnancy loss or premature delivery. If pregnancy occurs during your treatment, you must immediately inform your doctor. It may affect your developing baby if you take it during pregnancy.

You must not breastfeed while you are treated with Fludarabine Ebewe.

It is possible that your baby may be affected if you breastfeed.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Fertility in males and females

  • Females: you must use an effective method of contraception during and for 6 months after end of treatment, because Fludarabine Ebewe may be harmful for the unborn baby.
  • Males: you are advised not to father a child during and after end of treatment and to seek advice on conservation of sperm prior to treatment because Fludarabine Ebewe may alter male fertility.
  • Individual genetic counselling is required for male and female patient before start of Fludarabine Ebewe treatment.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Fludarabine Ebewe and affect how it works. These include:

  • Pentostatin (deoxycoformycin) also used to treat B-CLL. Taking these two drugs together can lead to severe lung problems.
  • Cytarabine (Ara-C) used to treat chronic lymphatic leukaemia
  • Dipyridamole, used to prevent excessive blood clotting, or other similar drugs
  • Live viral vaccines. It is recommended that patients do not receive live viral vaccines during and after treatment with Fludarabine Ebewe.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Fludarabine Ebewe.

4. How do I use Fludarabine Ebewe?

How much is given

  • The dosage of Fludarabine Ebewe that is correct for you will be exactly worked out by your specialist.
  • Because of the complexity of CLL and the possible side effects of Fludarabine Ebewe, it should only be prescribed by specialist doctors with experience with similar medications.
  • If you have any concerns about the dosage you receive, ask your doctor.

How is Fludarabine Ebewe given

  • Fludarabine Ebewe must only be given by a doctor or nurse.
  • Fludarabine Ebewe is injected into a vein (often in the arm) once each day for 5 consecutive days. This 5 day course is then repeated once every 28 days.

If you are given too much Fludarabine Ebewe

Your doctor will decide what dose of Fludarabine Ebewe you need, and this will be administered in the clinic or hospital under close supervision from nursing and medical staff.

The dose is determined by your weight and height. The risk of overdose in these circumstances is low. In the event of overdose occurring, your doctor will stop the therapy and decide on the necessary treatment. If you think that you have been given too much Fludarabine Ebewe, you may need urgent medical attention. Overdose can cause delayed blindness, coma and even death.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Fludarabine Ebewe?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Fludarabine Ebewe.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

Females: you must not become pregnant during treatment with Fludarabine Ebewe and must use an effective method of contraception during and for 6 months after end of treatment, because Fludarabine Ebewe may be harmful for the unborn baby. If pregnancy occurs during your treatment, you must immediately inform your doctor.

Males: you are advised not to father a child during and after end of treatment and to seek advice on conservation of sperm prior to treatment because Fludarabine Ebewe may alter male fertility.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

If you need a blood transfusion, tell your doctor.

Your doctor will ensure that you receive blood that has been treated by irradiation. There have been severe complications and even death, from transfusion of non-irradiated blood.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects. Check with your doctor before receiving any vaccinations.

Live vaccinations should be avoided during and after treatment with Fludarabine Ebewe.

Call your doctor straight away if you:

  • Notice anything new or unusual on your skin, suggestive of skin cancer
  • If you have or have had skin cancer it may worsen or flare up again while you take Fludarabine Ebewe or afterwards. You may develop skin cancer during or after Fludarabine Ebewe therapy as it reduces your body's defence mechanisms.

Remind any doctor, dentist or pharmacist you visit that you are using Fludarabine Ebewe.

Things you should not do

  • Fludarabine Ebewe must not be administered if you are pregnant unless clearly indicated by your doctor
  • Do not use Fludarabine Ebewe to treat any other complaints unless your doctor tells you to
  • Do not give this medicine to anyone else, even if they have the same condition as you
  • Do not take any additional medicines without the advice of your doctor or pharmacist
  • If you stop getting it administered suddenly, your condition may worsen.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Fludarabine Ebewe affects you.

Fludarabine Ebewe may cause fatigue, weakness, visual disturbances, confusion, agitation and whist rare seizures in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Fludarabine Ebewe will be stored appropriately at the pharmacy or on the ward. The injection is kept in a refrigerator where the temperature stays between 2°C and 8°C.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

This medicine helps most people with B-cell chronic lymphocytic leukaemia (B-CLL), but it may have unwanted side effects.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Infections with symptoms of:
  • Fever
  • Severe chills
  • Sore throat
  • Mouth ulcers
Symptoms of anaemia such as:
  • Tiredness
  • Headaches
  • Being short of breath when exercising
  • Dizziness
  • Looking pale
Other:
  • Some bruising
  • Loss of appetite leading to weight loss
  • Numbness or weakness in the arms and legs
  • Cough
  • Nausea, vomiting, diarrhoea
  • Sore mouth or gums
  • Weakness and/or generally feeling unwell
  • Swelling due to excessive fluid retention
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Bleeding related
  • Severe bruising
  • More bleeding than usual after injury
  • Vomiting blood or material that looks like coffee grounds, bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea
Infection related
  • You seem to be catching a lot of infections
  • Symptoms of pneumonia such as fever, chills, shortness of breath, cough and phlegm that may be blood stained
Eyes related
  • Visual disturbances
  • Sudden dimming or loss of vision
Allergy related
  • Sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
Skin related
  • Anything new or unusual on your skin such as mole, freckle or sore; a spot, mole or freckle that has changed in colour, shape or size
  • Red to brownish urine, rash or any blisters on your skin
  • Signs of Stevens-John syndrome, such as skin and/or mucous membrane reaction with redness, inflammation, blistering and erosion
  • Signs of toxic epidermal necrolysis which starts with painful red areas, then large blisters and ends with peeling of layers of skin. This is accompanied by fever and chills, aching muscles and generally feeling unwell
Head or neurology related
  • Seizures, unconsciousness
  • Neurological disorders manifested by headache, feeling sick (nausea) and vomiting, seizures, visual disturbances including vision loss, changes in mental status (thinking abnormal, confusion, altered consciousness), and occasionally neuromuscular disorders manifested by muscle weakness in your limbs (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy or posterior reversible leukoencephalopathy syndrome (RPLS))
Heart related
  • Symptoms of heart disease such as shortness of breath, and swelling of the feet or legs due to fluid build-up
  • Abnormal heartbeat (irregular, fast or slow)
Lungs related
  • Difficulty breathing, shortness of breath, severe cough, sharp chest pains
  • Bleeding in the lungs
Others
  • Signs of tumour lysis syndrome such as pain in one side of the body under the rib cage, little or no urine, drowsiness, nausea, vomiting, breathlessness, irregular heart beat, loss of memory, loss of consciousness
  • Inflammation of the bladder, which can cause pain when passing urine, and can lead to blood in the urine (haemorrhagic cystitis)
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Keep all doctor's appointments so your progress can be checked.

Some side effects (for example, blood disorders) can only be found when your doctor does tests on a regular basis.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Fludarabine Ebewe contains

Active ingredient
(main ingredient)		Fludarabine phosphate (50mg in 2mL)
Other ingredients
(inactive ingredients)
  • dibasic sodium phosphate dihydrate
  • nitrogen
  • sodium hydroxide
  • water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Fludarabine Ebewe looks like

Fludarabine Ebewe – clear, colourless to almost colourless solution, in a clear glass vial. Pack size of 1, 5 and 10 vials (Aust R 135540).

Who distributes Fludarabine Ebewe

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Tel: 1800 726 369

This leaflet was prepared in March 2023.

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Fludarabine Ebewe

Active ingredient

Fludarabine phosphate

Schedule

S4

 

1 Name of Medicine

Fludarabine phosphate.

2 Qualitative and Quantitative Composition

Fludarabine phosphate is a white or almost white, hygroscopic crystalline powder, slightly soluble in water, freely soluble in dimethylformamide, and very slightly soluble in anhydrous ethanol.
Fludarabine Ebewe is a sterile, clear, colourless solution containing 50 mg fludarabine phosphate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fludarabine Ebewe 50 mg/2 mL injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Fludarabine Ebewe is indicated for the treatment of B-cell chronic lymphocytic leukaemia.

4.2 Dose and Method of Administration

Dosage.

Adults.

The recommended dose is 25 mg/m2 body surface given daily for 5 consecutive days every 28 days by the intravenous route. Each vial contains 25 mg fludarabine phosphate per mL (50 mg in 2 mL).
The required dose (calculated on the basis of the patient's body surface) is drawn up into a syringe. For intravenous bolus injection, this dose is further diluted into 10 mL of physiological saline. Alternatively, the required dose drawn up in a syringe may be diluted into 100 mL physiological saline and infused over approximately 30 minutes.
The duration of treatment depends on the treatment success and the tolerability of the drug. Fludarabine Ebewe should be administered up to achievement of best response (complete or partial remission, usually 6 cycles) and then the drug should be discontinued.

Toxicity.

Dosage may be decreased or delayed based on evidence of haematological and non-haematological toxicity. Physicians should consider delaying or discontinuing the drug if toxicity occurs.

Retreatment options after initial Fludarabine Ebewe treatment.

Patients who primarily respond to Fludarabine Ebewe have a good chance of responding again to Fludarabine Ebewe monotherapy. A crossover from initial treatment with Fludarabine Ebewe to chlorambucil for nonresponders to Fludarabine Ebewe should be avoided. In a clinical trial, 46 subjects who failed initial fludarabine therapy were treated with chlorambucil 40 mg/m2 every 28 days. Only one subject (2%) achieved a partial response.

Method of administration.

Fludarabine Ebewe should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.
It is strongly recommended that Fludarabine Ebewe should only be administered intravenously. Paravenous administration must be avoided.
Product is for single use in one patient only. Discard any residue.

Instructions for use.

Each mL of Fludarabine Ebewe injection contains 25 mg of fludarabine phosphate, with sodium phosphate (dibasic dihydrate) and sodium hydroxide in water for injections. The pH range for the product is 7.2 to 7.8.
In clinical studies, the product has been diluted in 100 mL or 125 mL of 5% dextrose injection or 0.9% sodium chloride injection. The product may also be diluted with 5% glucose injection.
To reduce microbiological hazard, use as soon as practicable after preparation of infusion solutions. If storage is necessary, hold at 2-8°C for not more than 24 hours after preparation. Administration should be completed within 24 hours of preparation of the infusion and any residue discarded according to the guidelines for the disposal of cytotoxic drugs (see Handling and disposal, below). Any solutions, which are discoloured, hazy or contain visible particulate matter, should not be used.

Handling and disposal.

Fludarabine Ebewe should not be handled by pregnant staff.
Caution should be exercised in the handling and preparation of the Fludarabine Ebewe solution. The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution comes into contact with the skin or mucous membranes, the area should be washed thoroughly with soap and water. In the event of contact with the eyes, rinse them thoroughly with copious amounts of water. Exposure by inhalation should be avoided. (For instruction for disposal, see Section 6.6 Special Precautions for Disposal.)

Dosage adjustment.

Renal impairment.

Dosage reduction is required in renally impaired patients. See Section 5.2 Pharmacokinetic Properties, Impaired renal function; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment.

State of health impairment.

A number of clinical settings may predispose to increased toxicity from Fludarabine Ebewe. These include advanced age, renal insufficiency and bone marrow impairment - see Section 4.4 Special Warnings and Precautions for Use, Impaired state of health. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

4.3 Contraindications

Fludarabine Ebewe is contraindicated in those patients who are hypersensitive to this drug or its components, in renally impaired patients with creatinine clearance < 30 mL/min and in patients with haemolytic anaemia.
Fludarabine Ebewe is contraindicated during pregnancy and lactation.

4.4 Special Warnings and Precautions for Use

Neurotoxicity.

When used at high doses in dose-ranging studies in patients with acute leukaemia, fludarabine phosphate was associated with severe neurologic effects, including blindness, coma and death. This severe central nervous system toxicity occurred in 36% of patients treated intravenously with doses approximately four times greater (96 mg/m2/day for 5-7 days) than the dose recommended for treatment of CLL. In patients treated at doses in the range of the dose recommended for CLL, severe central nervous system toxicity occurred rarely (coma, seizures and agitation) or uncommonly (confusion). Patients should be closely observed for signs of neurologic side effects.
In postmarketing experience, neurotoxicity has been reported to occur earlier or later than in clinical trials.
The effect of chronic administration of fludarabine phosphate on the central nervous system is unknown. However, patients tolerated the recommended dose, in some studies for relatively long treatment times, whereby up to 26 courses of therapy were administered.
Patients should be closely observed for signs of neurologic effects.
Administration of fludarabine phosphate can be associated with leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL) or reversible posterior leukoencephalopathy syndrome (RPLS).
These may occur:
at the recommended dose;
when fludarabine phosphate is given following, or in combination with, medications known to be associated with LE, ATL or RPLS;
when fludarabine phosphate is given to patients with other risk factors such as previous exposure to cranial or total body irradiation, Hematopoietic Cell Transplantation, Graft versus Host Disease, renal impairment, or hepatic encephalopathy;
at doses higher than the recommended dose.
LE, ATL or RPLS symptoms may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, altered sensorium, and focal neurological deficits. Additional effects may include optic neuritis, and papillitis, confusion, somnolence, agitation, paraparesis/ quadriparesis, muscle spasticity and incontinence. LE/ ATL/ RPLS may be irreversible, life threatening, or fatal.
Whenever LE, ATL or RPLS is suspected, fludarabine treatment should be stopped. Patients should be monitored and should undergo brain imaging, preferably utilizing MRI. If the diagnosis is confirmed, fludarabine therapy should be permanently discontinued. Treating physicians should diagnose and monitor the patient with appropriate techniques (ideally brain imaging, MRI etc).

Myelosuppression.

Severe bone marrow suppression, notably anaemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a Phase I study in solid tumour patients, the median time to nadir counts was 13 days (range, 3-25 days) for granulocytes and 16 days (range, 2-32) for platelets. Most patients had haematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of fludarabine phosphate requires careful haematological monitoring.
Fludarabine Ebewe is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of haematologic and non-haematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of anaemia, neutropenia and thrombocytopenia. In such cases, as a general rule, the dose of myelosuppressive agents should be reduced or the dosage interval extended.
Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to 1 year. These episodes have occurred both in previously treated or untreated patients.
As with other cytotoxics, caution should be exercised with fludarabine phosphate, when further haematopoietic stem cell sampling is considered.

Disease progression.

Disease progression and transformation (e.g. Richter's syndrome) have been commonly reported in CLL patients.

Transfusion of blood products.

Transfusion-associated graft-versus-host disease has been observed after transfusion of nonirradiated blood in fludarabine phosphate treated patients. Fatal outcome as a consequence of this disease has been reported with a high frequency. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received treatment with Fludarabine Ebewe should receive irradiated blood only.

Skin cancer lesions.

The worsening or flare up of pre-existing skin cancer lesions as well as new onset of skin cancer has been reported in patients during or after fludarabine phosphate therapy.

Tumour lysis syndrome.

Tumour lysis syndrome associated with fludarabine phosphate treatment has been reported in CLL patients with large tumour burdens. Since Fludarabine Ebewe can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.

Autoimmune phenomena.

Irrespective of any previous history of autoimmune processes or Coombs test status, life threatening and sometimes fatal autoimmune phenomena (e.g. autoimmune haemolytic anaemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans' syndrome) have been reported to occur during or after treatment with fludarabine phosphate. The majority of patients experiencing haemolytic anaemia developed a recurrence in the haemolytic process after rechallenge with fludarabine phosphate.
Patients undergoing treatment with Fludarabine Ebewe should be closely monitored for signs of autoimmune haemolytic anaemia (decline in haemoglobin linked with haemolysis and positive Coombs test). Discontinuation of therapy with Fludarabine Ebewe is recommended in case of haemolysis. Blood transfusion (irradiated) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia.

Impaired state of health.

Patients who have advanced stage disease, hypoalbuminaemia, reduced platelet count or haemoglobin levels, white cell count above 50 x 109/L, significant hepatic or spleen enlargement, extensive prior therapy or poor performance status are at risk of serious and sometimes fatal toxicity during the first 6 months of treatment.
Fludarabine treatment may be associated with a spectrum of infections different from those seen with neutropenia from standard chemotherapy drugs. Prophylactic treatment should be considered in patients at increased risk of developing opportunistic infections, which include, but are not limited to, pneumocystis, fungi and herpes virus infections.
The dose of 25 mg/m2/day for 5 days by intravenous infusion may be greater than needed in some patients, especially those at risk and consideration should be given to using a lower dose in such patients.

Vaccination.

During and after treatment with Fludarabine Ebewe, vaccination with live vaccines should be avoided.

Use in hepatic impairment.

No data are available concerning the use of fludarabine phosphate in patients with hepatic impairment. In this group of patients, Fludarabine Ebewe should be used with caution, and administered if the potential benefit outweighs any potential risk.

Use in renal impairment.

There are limited data in dosing of patients with renal insufficiency. Careful monitoring for haematological toxicity is required and possible dose reductions of Fludarabine Ebewe in patients with renal impairment and patients with depressed white cell count and platelet counts or patients with infection or bleeding, may be required.
The total body clearance of 2-fluoro-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced renal function demonstrated an increased total body exposure (AUC of 2F-ara-A). Limited clinical data are available in patients with impairment of renal function (creatinine clearance below 70 mL/min). Fludarabine Ebewe must be administered cautiously in patients with renal insufficiency. Therefore, if renal impairment is clinically suspected, or in patients over the age of 70 years, creatinine clearance should be measured. If creatinine clearance is between 30 and 70 mL/min, the dose should be reduced in proportion to the reduced creatinine clearance and close haematological monitoring should be used to assess toxicity. Fludarabine Ebewe treatment is contraindicated, if creatinine clearance is < 30 mL/min.

Use in the elderly.

Since there are limited data for the use of fludarabine phosphate in elderly persons (> 75 years), caution should be exercised with the administration of Fludarabine Ebewe in these patients. In patients aged 65 years or older, creatinine clearance should be measured before start of treatment.

Paediatric use.

The safety and effectiveness of fludarabine phosphate in children has not been established. Therefore, treatment with fludarabine phosphate in children and adolescents is not recommended.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukaemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludarabine Ebewe in combination with pentostatin is not recommended.
A pharmacokinetic drug interaction was observed in AML patients during combination therapy with fludarabine phosphate and Ara-C. Clinical studies and in vitro experiments with cancer cell lines demonstrated elevated intracellular Ara-CTP levels in combination with fludarabine phosphate treatment.
The therapeutic efficacy of fludarabine phosphate may be reduced by dipyridamole and other inhibitors of adenosine uptake.
In clinical investigation, pharmacokinetic parameters after peroral administration were not significantly affected by concomitant food intake.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Due to the genotoxic risk of fludarabine phosphate females of childbearing potential must be apprised of the potential hazard to the foetus.
Females of childbearing potential must take effective contraceptive measures during and at least for 6 months after cessation of therapy. Male patients must use effective methods of contraception and be advised to not father a child while receiving fludarabine, and following completion of treatment. Prior to fludarabine treatment, patients must seek advice on fertility preservation options. After fludarabine treatment, patients planning pregnancy are advised to seek genetic counselling.
Studies in mice, rats and dogs have demonstrated dose-related adverse effects on the male reproductive system. Observations consisted of a decrease in mean testicular weights in dogs and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats and dogs. These results indicate that fludarabine phosphate may adversely affect male fertility, but this has not been directly investigated in studies of reproductive function. No information is available from animal studies on potential effects on female fertility. The possible adverse effects on fertility in humans have not been adequately evaluated.
(Category D)
Fludarabine is contraindicated in pregnancy (see Section 4.3 Contraindications). Fludarabine Ebewe should not be used during pregnancy. There are very limited data of Fludarabine Ebewe use in pregnant women in the first trimester.
One case of fludarabine phosphate use during early pregnancy leading to skeletal and cardiac malformation in the newborn has been reported. Early pregnancy loss has been reported in fludarabine phosphate monotherapy as well as in combination therapy. Premature delivery has been reported.
Fludarabine phosphate has been shown to be genotoxic. Fludarabine phosphate has also been shown to be embryotoxic, foetotoxic and teratogenic in animal studies. Preclinical data in rats demonstrated a transfer of fludarabine phosphate and/or metabolites through the foetoplacental barrier. In view of the small exposure margin between teratogenic doses in animals and the human therapeutic dose as well as in analogy to other antimetabolites, which are assumed to interfere with the process of differentiation, the therapeutic use of fludarabine phosphate is associated with a relevant risk of teratogenic effects in humans.
Fludarabine may cause foetal harm when administered to pregnant females. Therefore, fludarabine must not be used during pregnancy.
Females of childbearing potential receiving fludarabine should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.
Due to the genotoxic risk of fludarabine phosphate, females of childbearing potential or fertile males must take contraceptive measures during and at least for 6 months after cessation of therapy. If the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazard to the foetus.
 It is not known whether this drug is excreted in human milk. However, there is evidence from preclinical data that fludarabine phosphate and/or metabolites transfer from maternal blood to milk. Because of the potential for serious adverse reactions in nursing infants from Fludarabine Ebewe, breastfeeding should be discontinued for the duration of Fludarabine Ebewe therapy.
Breastfeeding should not be initiated during Fludarabine Ebewe therapy.

4.7 Effects on Ability to Drive and Use Machines

The effect of treatment with fludarabine phosphate on the patient's ability to drive or operate machinery has not been evaluated. However, fludarabine phosphate treatment may reduce the ability to drive or use machines, since fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed. Patients experiencing such adverse effects should avoid driving and using machines.

4.8 Adverse Effects (Undesirable Effects)

Based on the experience with the intravenous use of fludarabine phosphate, the most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anaemia), fever, chills and infection including pneumonia, cough, fever, fatigue, weakness, nausea, vomiting and diarrhoea. Other commonly reported events include chills, oedema, mucositis, malaise, anorexia, peripheral neuropathy, visual disturbances, stomatitis, skin rashes. Serious opportunistic infections have occurred in CLL patients treated with fludarabine phosphate. Fatalities as a consequence of serious adverse events have been reported.
The most frequently reported adverse events and those reactions which are more clearly related to the drug are arranged below according to body system.
Their frequencies (common > 1%, uncommon > 0.1% and < 1%) are based on clinical trial data regardless of the causal relationship with fludarabine phosphate. The rare events (< 0.1%) were mainly identified from postmarketing experience.

Haematopoietic system.

Haematologic events (neutropenia, thrombocytopenia, and anaemia) have been reported in the majority of CLL patients treated with fludarabine phosphate. Myelosuppression may be severe and cumulative. The prolonged effect of fludarabine phosphate on the decrease in the number of T-lymphocytes may lead to increased risk for opportunistic infections, including those due to latent viral reactivation, e.g. herpes zoster, Epstein-Barr virus (EBV) or progressive multifocal leukoencephalopathy. Evolution of EBV-infection/reactivation into EBV associated lymphoproliferative disorder has been observed in immunocompromised patients.
Commonly, the occurrence of myelodysplastic syndrome (MDS) and acute myeloid leukaemia has been described in patients treated with fludarabine phosphate. The majority of these patients also received prior, concomitant or subsequent treatment with alkylating agents, topisomerase inhibitors or irradiation. Monotherapy with fludarabine phosphate has not been associated with an increased risk for the development of MDS.
Clinically significant autoimmune phenomena (including autoimmune haemolytic anaemia, Evans syndrome, thrombocytopenic purpura, acquired haemophilia, pemphigus) are uncommon in patients receiving fludarabine phosphate.

Metabolic.

Tumour lysis syndrome has been reported uncommonly in CLL patients treated with fludarabine phosphate. This complication may include hyperuricaemia, hyperphosphataemia, hypocalcaemia, metabolic acidosis, hyperkalaemia, haematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and haematuria.
Changes of hepatic and pancreatic enzymes are uncommon.
Oedema has been commonly reported.

Nervous system.

Peripheral neuropathy has been commonly observed. Confusion is uncommon. Coma, agitation and seizures occur rarely.

Pulmonary system.

Pneumonia commonly occurs in association with fludarabine phosphate treatment. Pulmonary hypersensitivity reactions to fludarabine phosphate (pulmonary infiltrates/pneumonitis/fibrosis) associated with dyspnoea and cough are uncommon.

Gastrointestinal system.

Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhoea, mucositis and stomatitis are common events. Gastrointestinal bleeding, mainly related to thrombocytopenia and pancreatic enzymes abnormal has been uncommonly reported in patients treated with fludarabine phosphate.

Hepatobiliary disorders.

Hepatic enzyme abnormal are uncommon in patients treated with fludarabine phosphate.

Cardiovascular.

In rare cases, heart failure and arrhythmia have been reported in patients treated with fludarabine phosphate.

Genitourinary system.

Rare cases of haemorrhagic cystitis have been reported in patients treated with fludarabine phosphate.

Skin.

Skin rashes have been commonly reported in patients treated with fludarabine phosphate.
In rare cases a toxic epidermal necrolysis (Lyell's disease), Stevens-Johnson syndrome or skin cancer may develop.

Special senses.

Visual disturbances are commonly reported events in patients treated with fludarabine phosphate. In rare cases optic neuritis, optic neuropathy and blindness have occurred.

Body as a whole.

Fever, chills, infection, malaise, weakness and fatigue have been commonly reported.

Postmarketing experience.

Postmarketing experience with unknown frequency.

Nervous system disorders.

Leukoencephalopathy (see Section 4.4 Special Warnings and Precautions for Use).
Acute toxic leukoencephalopathy (see Section 4.4 Special Warnings and Precautions for Use).
Reversible posterior leukoencephalopathy syndrome (RPLS) (see Section 4.4 Special Warnings and Precautions for Use).

Vascular disorders.

Haemorrhage (including cerebral haemorrhage, pulmonary haemorrhage, haemorrhagic cystitis).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

High doses of fludarabine phosphate have been associated with leukoencephalopathy, acute toxic leukoencephalopathy, reversible posterior leukoencephalopathy syndrome (RPLS). Symptoms may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, altered sensorium, and focal neurological deficits. Additional effects may include optic neuritis, and papillitis, confusion, somnolence, agitation, paraparesis/ quadriparesis, muscle spasticity, incontinence, irreversible central nervous system toxicity characterised by delayed blindness, coma, and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for fludarabine phosphate overdosage. Treatment consists of drug discontinuation and supportive therapy.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia) and 0800 POISON or 0800 764766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Fludarabine phosphate is a fluorinated nucleotide analogue of the antiviral agent vidarabine, (9-β-D-arabinofuranosyladenine) that is relatively resistant to deamination by adenosine deaminase.
Pharmacotherapeutic group: Antineoplastic agents, purine analogues.
ATC code: L01BB05.

Mechanism of action.

Fludarabine phosphate is rapidly dephosphorylated to fludarabine (2F-ara-A) which is taken up by cells and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, fludarabine triphosphate (2F-ara-ATP). This metabolite has been shown to inhibit ribonucleotide reductase, DNA polymerase α, δ and ε, DNA primase and DNA ligase thereby inhibiting DNA synthesis. Furthermore, partial inhibition of RNA polymerase II and consequent reduction in protein synthesis occurs.
Whilst some aspects of the mechanism of action of fludarabine triphosphate are as yet unclear, it is assumed that effects on DNA, RNA and protein synthesis all contribute to inhibition of cell growth with inhibition of DNA synthesis being the dominant factor. In addition, in vitro studies have shown that exposure of chronic lymphocytic leukaemia (CLL) lymphocytes to fludarabine (2F-ara-A) triggers extensive DNA fragmentation and cell death characteristic of apoptosis. Fludarabine phosphate has also been shown to trigger these changes in normal (nonmalignant) lymphoid cells.

Clinical trials.

The following information refers to the use of fludarabine phosphate in first line chronic lymphocytic leukaemia.
Intravenous fludarabine 25 mg/m2 on days 1-5 of a 28 day cycle significantly delayed disease progression compared with comparators in the first line treatment of B-cell CLL in three randomised controlled trials (Table 1, Table 2, Table 3). A difference in survival was not shown due to insufficient follow up and confounding as a result of cross-overs. There was a median 7 and maximum 21 treatment cycles.
Fludarabine tablets were assessed in an uncontrolled trial in 81 patients for first line treatment of B-cell CLL. The dose was 40 mg/m2 on days 1-5 of each 28 day treatment cycle for a mean of 6 cycles. Fewer patients in this trial had Rai stage III/IV disease (22%) than in the intravenous fludarabine trials (35-50%). The median time to disease progression had not been reached at the time of the analysis, but exceeded 38 months, which is comparable or better than the result in the intravenous trials. The NCI complete response rate was 12% and overall response rate 80%. In a subgroup analysis, patients with Rai stage III or IV disease had a response rate of 61%, which is comparable to that observed in this subgroup in the IV studies. There were no data on survival.

5.2 Pharmacokinetic Properties

Absorption.

After single dose infusion of 25 mg fludarabine phosphate per m2 to CLL patients for 30 minutes, fludarabine (2F-ara-A) reached mean maximum concentrations in the plasma of 3.5-3.7 microM at the end of the infusion. Corresponding fludarabine (2F-ara-A) levels after the fifth dose showed a moderate accumulation with mean maximum levels of 4.4-4.8 microM at the end of infusion. During a 5 day treatment schedule, fludarabine (2F-ara-A) plasma trough levels increased by a factor of about 2. An accumulation of fludarabine (2F-ara-A) over several treatment cycles can be excluded. Postmaximum levels decayed in three disposition phases with an initial half life of approximately 5 minutes, an intermediate half life of 1-2 hours and a terminal half life of approximately 20 hours.

Distribution.

An interstudy comparison of fludarabine (2F-ara-A) pharmacokinetics resulted in a mean total plasma clearance (CL) of 79 mL/min/m2 (2.2 mL/min/kg) and a mean volume of distribution (Vss) of 83 L/m2 (2.4 L/kg). Data showed a high interindividual variability. After i.v. and peroral administration of fludarabine phosphate tablets in doses of 50-90 mg, the plasma concentration of fludarabine phosphate and the area under the plasma concentration time curve increased linearly with the dose. Additionally, after i.v. administration half lives, plasma clearance and volumes of distribution remained constant independent of the dose indicating a dose linear behaviour.
In vitro investigations with human plasma proteins revealed no pronounced tendency of fludarabine (2F-ara-A) protein binding.

Metabolism.

Fludarabine phosphate (2F-ara-AMP) is a water soluble prodrug of fludarabine (2F-ara-A), which is rapidly and quantitatively dephosphorylated in humans to the nucleoside fludarabine.

Excretion.

Fludarabine (2F-ara-A) elimination is largely by renal excretion. 40-60% of the administered i.v. dose was excreted in the urine. Mass balance studies in laboratory animals with 3H-2F-ara-AMP showed a complete recovery of radiolabelled substances in the urine.

Impaired renal function.

Individuals with impaired renal function exhibited a reduced total body clearance, indicating the need for a dose reduction. Three groups of CLL/non-Hodgkin's lymphoma patients with differing creatinine clearance, > 70 (n = 10), 30 - 70 (n = 9), < 30 (n = 2) mL/min, were compared. After a single dose of 25 mg fludarabine by 30 minute IV infusion, AUC increased 16% in the second group and 116% in the third group relative to the first group. Multiple adjusted IV doses were then given over 5 days. The first group received 25 mg/m2/day, the second 20 mg/m2/day and the third 15 mg/m2/day. AUC was equivalent in the first and second groups, but increased 41% in the third group.

Note.

Fludarabine is not recommended for patients in the third group (see Section 4.3 Contraindications).
There was a statistically significant inverse correlation between fludarabine AUC and creatinine clearance.

Cellular pharmacokinetics of fludarabine triphosphate.

Fludarabine (2F-ara-A) is actively transported into leukaemic cells, whereupon it is rephosphorylated to the monophosphate and subsequently to the di- and triphosphate. The triphosphate 2F-ara-ATP, is the major intracellular metabolite and the only metabolite known to have cytotoxic activity. Maximum 2F-ara-ATP levels in leukemic lymphocytes of CLL patients were observed at a median of 4 hours and exhibited a considerable variation with a median peak concentration of approximately 20 microM. 2F-ara-ATP levels in leukemic cells were always considerably higher than maximum 2F-ara-A levels in the plasma indicating an accumulation at the target sites. In-vitro incubation of leukemic lymphocytes showed a linear relationship between extracellular 2F-ara-A exposure (product of 2F-ara-A concentration and duration of incubation) and intracellular 2F-ara-ATP enrichment. 2F-ara-ATP elimination from target cells showed median half life values of 15 and 23 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Fludarabine phosphate has been shown not to cause gene mutations in bacterial and mammalian cells in vitro. Chromosomal aberrations were observed in an in vitro assay using Chinese hamster ovary (CHO) cells under metabolically activated conditions. Fludarabine phosphate has also been shown to be clastogenic in the in vivo mouse micronucleus test. In addition, fludarabine phosphate was shown to cause increased sister chromatid exchanges using an in vitro sister chromatid exchange (SCE) assay under both metabolically activated and nonactivated conditions.

Carcinogenicity.

No animal carcinogenicity studies with fludarabine phosphate have been conducted. However, positive findings in carcinogenicity studies with other cytotoxic drugs and the positive genotoxicity findings with fludarabine phosphate suggest that it has carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium phosphate - dibasic dihydrate, and sodium hydroxide in water for injections.

6.2 Incompatibilities

The formulation for intravenous use must not be mixed with other drugs.
For information on interactions with other medicines and other forms of interactions, see Section 4.5.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze).

6.5 Nature and Contents of Container

Fludarabine Ebewe 50 mg/2 mL injection - glass vial. Pack of 1 vial and of 5 vials.
Vial stopper is not made with natural rubber latex.

6.6 Special Precautions for Disposal

Procedures for proper handling and disposal should be observed. Consideration should be given to handling and disposal according to guidelines used for cytotoxic drugs. Any spillage or waste material may be disposed of by incineration.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The chemical name of fludarabine phosphate is 2-Fluoro-9(5-O-phosphono-β-D-arabinofuranosyl)-9H-purin-6-amine. Its molecular formula is C10H13FN5O7 (Molecular weight: 365.2) and its chemical structure is:

CAS number.

75607-67-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes