Consumer medicine information

Fludara Oral

Fludarabine phosphate

BRAND INFORMATION

Brand name

Fludara Oral

Active ingredient

Fludarabine phosphate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fludara Oral.

SUMMARY CMI

FLUDARA ORAL®

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 Fludara Oral?

Fludara Oral contains the active ingredient Fludarabine phosphate. Fludara Oral 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 Fludara Oral? in the full CMI.

2. What should I know before I use Fludara Oral?

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 Fludara Oral? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fludara Oral 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 Fludara Oral?

  • Swallow the tablets whole with a full glass of water. Do not chew or break the tablets.
  • The exact number of tablets you should take is calculated by your doctor. The usual dose is between 3 to 10 tablets a day.

More instructions can be found in Section 4. How do I use Fludara Oral? in the full CMI.

5. What should I know while using Fludara Oral?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Fludara Oral
  • 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 Fludara Oral to treat any other complaints unless your doctor tells you to
  • Do not stop taking your medicine or change the dosage without checking with your doctor
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Fludara Oral affects you
Drinking alcohol
  • Tell your doctor if you drink alcohol
Looking after your medicine
  • Keep your tablets in the pack until it is time to take them.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using Fludara Oral? 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 identify 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

FLUDARA ORAL®

Active ingredient(s): Fludarabine phosphate


Consumer Medicine Information (CMI)

This leaflet provides important information about using Fludara Oral. 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 Fludara Oral.

Where to find information in this leaflet:

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

1. Why am I using Fludara Oral?

Fludara Oral contains the active ingredient Fludarabine phosphate. Fludara Oral 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.

Fludara Oral 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.

Fludara Oral 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 Fludara Oral?

Warnings

Do not use Fludara Oral 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 Fludara Oral or afterwards
  • Take any medicines for any other condition
  • Are over 75 years of age. Your doctor will administer Fludara Oral 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 Fludara Oral therapy. It is not known whether Fludara Oral 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 Fludara Oral 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 Fludara Oral.

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 Fludara Oral 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 Fludara Oral may alter male fertility.
  • Individual genetic counselling is required for male and female patients before start of Fludara Oral 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 Fludara Oral 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 Fludara Oral.

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

4. How do I use Fludara Oral?

How much to take / use

  • The recommended dose is 40mg per square metre of body surface area, once a day. The exact number of tablets you should take is calculated by your doctor. The usual dose is between 3 to 10 tablets once a day.
  • Follow the instructions provided and use Fludara Oral until your doctor tells you to stop.

When to take / use Fludara Oral

  • Swallow the tablets whole with a full glass of water. Do not chew or break the tablets
  • Fludara Oral can be taken either on an empty stomach or together with food
  • Take the tablets the same time every day
  • Take the dose worked out by your doctor once a day for 5 consecutive days
  • The 5-day-course of treatment will be repeated every 28 days until your doctor has decided that the best effect has been achieved (usually after 6 courses). Your doctor may adjust the dose and number of treatment days
  • Attend all of your doctor's appointments so that your progress can be checked
  • You will have blood tests after every treatment course. Your individual dose will be carefully adjusted according to the number of your blood cells and your response to the therapy
  • Continue taking your medicine for as long as your doctor tells you
  • This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel better

If you forget to use Fludara Oral

Fludara Oral should be used regularly at the same time each day. If you miss your dose at the usual time, or vomit after tablet taking, talk to your doctor as soon as possible.

Do not take a double dose to make up for the dose you missed.

  • This may increase the chance of you getting an unwanted side effect
  • If you have trouble remembering to take your medicine, ask your pharmacist for some hints

If you use too much Fludara Oral

If you think that you have used too much Fludara Oral, 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 in Australia or 0800 764 766 in New Zealand), 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 Fludara Oral?

Things you should do

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

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 Fludara Oral and must use an effective method of contraception during and for 6 months after end of treatment, because Fludara Oral 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 Fludara Oral 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 Fludara Oral.

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 Fludara Oral or afterwards. You may also develop skin cancer during or after Fludara Oral therapy as it reduces your body's defence mechanisms.

Remind any doctor, dentist or pharmacist you visit that you are using Fludara Oral.

Things you should not do

  • Fludara Oral must not be administered if you are pregnant unless clearly indicated by your doctor
  • Do not breastfeed while you are being treated with Fludara Oral
  • Do not take Fludara Oral to treat any other complaints unless your doctor tells you to
  • Do not give your medicine to anyone else, even if they have the same condition as you
  • Do not stop taking your medicine or change the dosage without checking with your doctor
  • If you stop taking it suddenly, your condition may worsen

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Fludara Oral affects you.

Fludara Oral 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

  • Keep your tablets in the pack until it is time to take them
  • If you take the tablets out of the pack they may not keep well
  • Keep your tablets in a cool dry place where the temperature stays below 25°C
  • Heat and dampness can destroy some medicines

Follow the instructions in the carton on how to take care of your medicine properly.

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.

A locked cupboard at least one-and-a-half metres about the ground is a good place to store medicines.

When to discard your medicine

If your doctor tells you to stop taking this medicine, ask your pharmacist what to do with any medicine that is left over.

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
  • Mouth ulcers
  • Skin rash
  • Fever
  • Tiredness
  • Chills
  • 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
  • Severe bruising
  • More bleeding than usual after injury
  • You seem to be catching a lot of infections
  • 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
  • Symptoms of pneumonia such as fever, chills, shortness of breath, cough and phlegm that may be blood stained
  • Visual disturbances
  • 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
  • Red to brownish urine, rash or any blisters on your skin
  • Vomiting blood or material that looks like coffee grounds, bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea
  • Seizures, unconsciousness
  • Sudden dimming or loss of vision
  • 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)
  • Difficulty breathing, shortness of breath, severe cough, sharp chest pains
  • 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
  • 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
  • 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))
  • Bleeding in the lungs
  • 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 in Australia or https://nzphvc.otago.ac.nz/reporting. 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 Fludara Oral contains

Active ingredient
(main ingredient)
Fludarabine phosphate
Other ingredients
(inactive ingredients)
Microcrystalline cellulose
Sugars as lactose
Colloidal anhydrous silica
Croscarmellose sodium
Magnesium stearate
Hypromellose
Purified talc
Titanium dioxide
Iron oxide red CI 77491
Iron oxide yellow CI 77492
Potential allergensNot Applicable

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

What Fludara Oral looks like

Fludara Oral film-coated tablets are salmon coloured oval shaped with “LN” indented in a regular hexagon on one side. The tablets are packaged in Al/Al blister packs of 15 and 20 tablets (each blister foil contains 5 tablets) (Aust R 81998).

Who distributes Fludara Oral

In Australia this product is distributed by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
North Ryde
NSW 2113
Toll Free Number (medical information): 1800 818 806
Email: [email protected]

In New Zealand this product is distributed by:

Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics
PO Box 62027
Sylvia Park Auckland 1644
Freecall: 0800 283 684
Email: [email protected]

This leaflet was prepared in January 2023

fludara-oral-ccdsv27-cmiv6-03jan23

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Fludara Oral

Active ingredient

Fludarabine phosphate

Schedule

S4

 

1 Name of Medicine

Fludarabine phosphate.

2 Qualitative and Quantitative Composition

Fludara Oral contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, (9-β-D-arabinofuranosyladenine) that is relatively resistant to deamination by adenosine deaminase.
Each Fludara Oral tablet contains 10 mg of fludarabine phosphate.

Excipients with known effect.

Sugars as lactose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablets (salmon coloured oval shaped tablets with "LN" indented in a regular hexagon on one side).

4 Clinical Particulars

4.1 Therapeutic Indications

Fludara Oral is indicated for the treatment of B-cell chronic lymphocytic leukaemia.

4.2 Dose and Method of Administration

Adults.

Fludara Oral tablets should be prescribed by a qualified physician experienced in the use of antineoplastic therapy.
The recommended dose is 40 mg fludarabine phosphate/m2 body surface given daily for 5 consecutive days every 28 days by the oral route. Fludara Oral tablets can be taken either on an empty stomach or together with food. The tablets are to be swallowed whole with water, and must not be chewed or broken.
The duration of treatment depends on the treatment success and the tolerability of the drug. Fludara Oral 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 nonhaematological toxicity. Physicians should consider delaying or discontinuing the drug if toxicity occurs.

Impaired state of health.

A number of clinical settings may predispose to increased toxicity from Fludara Oral. These include advanced age, renal insufficiency and bone marrow impairment (see Section 4.4, Use in specialised groups). Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

Impaired renal function.

Dosage reduction is required in renally impaired patients. See Section 4.4, Use in specialised groups; Section 5.2, Special populations of this document.

Retreatment options after initial Fludara Oral treatment.

Patients who primarily respond to Fludara Oral have a good chance of responding again to Fludara Oral monotherapy. A crossover from initial treatment with Fludara Oral to chlorambucil for nonresponders to Fludara Oral 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Renal impairment with creatinine clearance < 30 mL/min.
Hemolytic anemia.
Fludara Oral 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, Fludara Oral was associated with severe neurologic effects, including blindness, coma and death. Symptoms appeared from 21 to 60 days from last dose. 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.
Similar severe central nervous system toxicity has also been observed in patients treated at doses recommended for CLL. Confusion occurred uncommonly and coma, seizures and agitation rarely (see Section 4.8 Adverse Effects (Undesirable Effects)).
In postmarketing experience, neurotoxicity has also been reported to occur with a latency ranging from 7 to 225 days after the last dose of Fludara Oral.
The effect of chronic administration of Fludara Oral on the central nervous system is unknown. However, patients tolerated the recommended dose in some studies for relatively long treatment times (for up to 26 courses of therapy). Patients should be closely observed for signs of neurologic side effects.
Administration of Fludara Oral can be associated with leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL) or reversible posterior leukoencephalopathy syndrome (RPLS).
These may occur:
at the recommended dose when Fludara Oral is given following, or in combination with, medications known to be associated with LE, ATL or RPLS, when Fludara Oral 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 Fludara Oral. 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.
Fludara Oral is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of haematologic and nonhaematologic 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.

Disease progression.

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

Tumour lysis syndrome.

Tumour lysis syndrome associated with Fludara Oral treatment has been reported in CLL patients with large tumour burdens. Since Fludara Oral 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 Fludara Oral. The majority of patients experiencing haemolytic anaemia developed a recurrence in the haemolytic process after rechallenge with Fludara Oral.
Patients undergoing treatment with Fludara Oral should be closely monitored for signs of haemolysis. Discontinuation of therapy with Fludara Oral is recommended in case of haemolysis. Blood transfusion (irradiated) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia.

Use in specialised groups.

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.

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 Fludara Oral 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). Fludara Oral must be administered cautiously in patients with renal insufficiency. In patients with moderate impairment of renal function (creatinine clearance 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. Fludara Oral treatment is contraindicated if creatinine clearance is < 30 mL/min.

Use in hepatic impairment.

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

Use in the elderly.

Since there are limited data for the use of Fludara Oral in elderly persons (> 75 years), caution should be exercised with the administration of Fludara Oral in these patients.

Pediatric use.

Fludara Oral is not recommended for the use in children below age 18 due to a lack of data on safety and efficacy.

Effects on laboratory tests.

No data available.

Vaccination.

During and after treatment with Fludara Oral vaccination with live vaccines should be avoided.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In a clinical investigation using Fludara Oral 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 Fludara Oral 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 Fludara Oral treatment.
Dipyridamole and other inhibitors of adenosine uptake may reduce the therapeutic efficacy of Fludara Oral.
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 Fludara Oral, and following completion of treatment. Prior to Fludara Oral treatment, patients must seek advice on fertility preservation options. After Fludara Oral 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)
Fludara Oral should not be used during pregnancy. There are very limited data of Fludara Oral 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 Fludara Oral 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, fetotoxic and teratogenic in animal studies. Preclinical data in rats demonstrated a transfer of fludarabine phosphate and/or metabolites through the fetoplacental 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 Fludara Oral is associated with a relevant risk of teratogenic effects in humans.
Fludara Oral may cause foetal harm when administered to pregnant females. Therefore, Fludara Oral must not be used during pregnancy.
Females of childbearing potential receiving Fludara Oral 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 fludarabine phosphate 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 adverse reactions in nursing infants from Fludara Oral, breastfeeding must be discontinued for the duration of Fludara Oral therapy.
Breastfeeding should not be initiated during Fludara Oral treatment.

4.7 Effects on Ability to Drive and Use Machines

Fludara Oral 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 Fludara Oral, the most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anaemia), infection including pneumonia, cough, fever, fatigue, weakness, nausea, vomiting and diarrhoea.
Other commonly reported events include chills, oedema, malaise, anorexia, peripheral neuropathy, visual disturbances, stomatitis, skin rashes, and mucositis. Serious opportunistic infections have occurred in CLL patients treated with Fludara Oral. Fatalities as a consequence of serious adverse events have been reported.
Table 1 reports adverse events by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data regardless of the causal relationship with Fludara Oral. The rare adverse reactions were mainly identified from post marketing experience.

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 hemorrhage, pulmonary haemorrhage, haemorrhagic cystitis).

Reporting suspected adverse reactions.

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 www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

High doses of Fludara Oral 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 Fludara Oral overdosage. Treatment consists of drug discontinuation and supportive therapy.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) or the National Poisons Centre on 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, purine analogues. ATC code: L01B B05.

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 Fludara Oral in 1st 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 (see Tables 2 to 4). A difference in survival was not shown due to insufficient follow-up and confounding as a result of crossovers. 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.

The pharmacokinetics of fludarabine (2F-ara-A) has been studied after intravenous administration by rapid bolus injection, short-term infusion and following continuous infusion as well as after peroral dosing of fludarabine phosphate (2F-ara-AMP).
No clear correlation was found between fludarabine pharmacokinetics and treatment efficacy in cancer patients. However, occurrence of neutropenia and haematocrit changes indicated that the cytotoxicity of fludarabine phosphate depresses haematopoiesis in a dose dependent manner.

Distribution.

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.
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.

Metabolism.

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.
After peroral fludarabine phosphate (2F-ara-AMP) doses, maximum fludarabine (2F-ara-A) plasma levels reached approximately 20-30% of corresponding i.v. levels at the end of infusion and occurred 1-2 hours postdose. The mean systemic fludarabine (2F-ara-A) availability was in the range of 50-65% following single and repeated doses and was similar after ingestion of a solution or immediate release tablet formulation.
After peroral dosing of fludarabine phosphate (2F-ara-AMP) with concomitant food intake a slight increase (< 10%) of systemic availability (AUC), a slight decrease of maximum plasma levels (Cmax) of fludarabine (2F-ara-A) and a delayed time of occurrence of Cmax was observed. Terminal half-lives were unaffected. In vitro investigations with human plasma proteins revealed no pronounced tendency of fludarabine (2F-ara-A) protein binding.

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.

Special populations.

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.

Renal impairment.

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.

5.3 Preclinical Safety Data

Carcinogenicity.

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

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.

Fertility.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica, croscarmellose sodium, magnesium stearate, hypromellose, purified talc, titanium dioxide, iron oxide red, iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 below 25°C

6.5 Nature and Contents of Container

Al/Al blister packs of 15 and 20 tablets (each blister foil contains 5 tablets).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Molecular Formula: C10H13FN5O7P.
Molecular Weight: 365.2.
Chemical Name: 9-β-D-arabinofuranosyl-2-fluoroadenine 5'-(dihydrogen phosphate).

CAS number.

21679-14-1.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes