Consumer medicine information

Fludarabine JUNO

Fludarabine phosphate

BRAND INFORMATION

Brand name

Fludarabine JUNO

Active ingredient

Fludarabine phosphate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fludarabine JUNO.

SUMMARY CMI

FLUDARABINE JUNO

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 Juno?

Fludarabine Juno contains the active ingredient fludarabine phosphate. Fludarabine Juno 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 Juno? in the full CMI.

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

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 Juno? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fludarabine Juno 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 Juno?

  • Fludarabine Juno must only be given by a doctor or nurse. Fludarabine Juno 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 Juno should only be administered intravenously. More instructions can be found in Section 4. How do I use Fludarabine Juno? in the full CMI.

5. What should I know while using Fludarabine Juno?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Fludarabine Juno.
  • 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 Juno affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Fludarabine Juno will be stored appropriately at the pharmacy or on the ward.

For more information, see Section 5. What should I know while using Fludarabine Juno? 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

FLUDARABINE JUNO

Active ingredient(s): Fludarabine phosphate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Fludarabine Juno. 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 Juno.

Where to find information in this leaflet:

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

1. Why am I using Fludarabine Juno?

Fludarabine Juno contains the active ingredient fludarabine phosphate. Fludarabine Juno is s an anticancer 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 Juno 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 Juno 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 Juno?

Warnings

Do not use Fludarabine Juno 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 Juno or afterwards
  • take any medicines for any other condition
  • Are over 75 years of age. Your doctor will administer Fludarabine Juno to you with caution and monitor you 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 Juno therapy. It is not known whether Fludarabine Juno 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 Juno 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 Juno.

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 Juno 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 Juno may alter male fertility.
  • Individual genetic counselling is required for male and female patient before start of Fludarabine Juno 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 Juno and affect how it works. These include:

  • Pentostatin (deoxycoformycin) also used to treat BCLL. 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 Juno.

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 Juno.

4. How do I use Fludarabine Juno?

How much is given

  • The dosage of Fludarabine Juno 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 Juno, 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 Juno given

  • Fludarabine Juno must only be given by a doctor or nurse.
  • Fludarabine Juno 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 use too much Fludarabine Juno

If you think that you have used too much Fludarabine Juno, 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 Juno?

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 Juno.

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

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

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

Things you should not do

  • Fludarabine Juno must not be administered if you are pregnant unless clearly indicated by your doctor
  • Do not use Fludarabine Juno 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 Juno affects you.

Fludarabine Juno 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 Juno will be stored appropriately at the pharmacy or on the ward. The injection is kept at 25°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
[Grouping 2 as per effect on body]:
  • Tiredness
  • Headaches
  • Being short of breath when exercising
  • Dizziness
  • Looking pale
[Grouping 2 as per effect on body]:
  • 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.

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 Juno contains

Active ingredient
(main ingredient)		Fludarabine phosphate
Other ingredients
(inactive ingredients)		Mannitol
Sodium hydroxide

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

What Fludarabine Juno looks like

Fludarabine Juno is a white or almost white powder in a pack size of 1 vial (Aust R 147831).

Who distributes Fludarabine Juno

Juno Pharmaceuticals Pty Ltd
15-17 Chapel Street, Cremorne VIC 3121

This leaflet was prepared in May 2024.

Published by MIMS July 2024

BRAND INFORMATION

Brand name

Fludarabine JUNO

Active ingredient

Fludarabine phosphate

Schedule

S4

 

1 Name of Medicine

Fludarabine phosphate.

2 Qualitative and Quantitative Composition

Each vial contains 50 mg of fludarabine phosphate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White or almost white powder for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of B-cell chronic lymphocytic leukaemia.

4.2 Dose and Method of Administration

Formulation for intravenous use.

Fludarabine JUNO should be administered under the supervision of a qualified doctor experienced in the use of antineoplastic therapy.
It is strongly recommended that Fludarabine JUNO should only be administered intravenously. Paravenous administration must be avoided.

Adults.

The recommended dose is 25 mg/m2 body surface, given daily for five consecutive days every 28 days by the intravenous route. Each vial is to be made up with water for injections 2 mL. Each mL of the resulting solution will contain fludarabine phosphate 25 mg.
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 in physiological saline 10 mL. Alternatively, the required dose drawn up in a syringe may be diluted in physiological saline 100 mL and infused over approximately 30 minutes.
The duration of treatment depends on the treatment success and the tolerability of the drug. Fludarabine JUNO should be administered up to achievement of best response (complete or partial remission, usually six cycles) and then the drug should be discontinued.

Toxicity.

Dosage may be decreased or delayed based on evidence of haematological and non-haematological toxicity. Doctors 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 Fludarabine JUNO. These include advanced age, renal insufficiency and bone marrow impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in specialised groups, Impaired state of health). 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 5.2 Pharmacokinetic Properties, Impaired renal function; Section 4.4 Special Warnings and Precautions for Use, Use in specialised groups.

Retreatment options after initial fludarabine phosphate treatment.

Patients who primarily respond to Fludarabine JUNO have a good chance of responding again to fludarabine phosphate monotherapy. A crossover from initial treatment with Fludarabine JUNO to chlorambucil for nonresponders to fludarabine phosphate 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.

Instructions for use/ handling of the intravenous dose form.

Fludarabine JUNO should be prepared for parenteral use by aseptically adding sterile water for injections. When reconstituted with sterile water for injections 2 mL, the solid cake should fully dissolve in 15 seconds or less. Each mL of the resulting solution will contain fludarabine phosphate 25 mg, mannitol 25 mg and sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2 to 8.2. In clinical studies the product has been diluted in 100 mL or 125 mL of glucose 5% injection or sodium chloride 0.9%.
Physiochemical stability of Fludarabine JUNO has been demonstrated for a maximum storage period and storage temperature for the reconstituted solution of 7 days, at 2°C-8°C or 8 hours at room temperature (25°C). However, to reduce microbiological hazard, dilute the reconstituted solution as soon as practicable after reconstitution and administer the diluted solution as soon as practicable after dilution. If storage is necessary, hold at 2°-8°C for a total time of not more than 24 hours after reconstitution or at room temperature (25°C) for a total time of not more than 6 hours.
Fludarabine JUNO should not be handled by pregnant staff.
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.
Caution should be exercised in the handling and preparation of the Fludarabine JUNO 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.

Incompatibilities.

The formulation for intravenous use must not be mixed with other drugs.

4.3 Contraindications

Fludarabine phosphate 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 phosphate 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 neurological effects including blindness, coma and death. This severe central nervous system (CNS) toxicity occurred in 36% of patients treated intravenously with doses approximately four times greater (96 mg/m2/day for five to seven days) than the dose recommended for treatment of CLL. In patients treated at doses in the range of the dose recommended for CLL, severe CNS toxicity occurred rarely (coma, seizures and agitation) or uncommonly (confusion).
In postmarketing experience, neurotoxicity has also been reported to occur, with a latency ranging from 7 to 225 days after the last dose of fludarabine phosphate.
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 to 25 days) for granulocytes and 16 days (range 2 to 32) for platelets. Most patients had haematological 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 phosphate is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of haematological and nonhaematological 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 two months to one 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 associated graft versus host disease.

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 patients who require blood transfusion and who are undergoing, or who have received, treatment with fludarabine phosphate 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 phosphate 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 phosphate 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 phosphate is recommended in case of haemolysis. Blood transfusion (irradiated) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia.

Vaccination.

During and after treatment with fludarabine phosphate vaccination with live vaccines should be avoided.

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 six 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 five 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 hepatic impairment.

No data are available concerning the use of fludarabine phosphate in patients with hepatic impairment. In this group of patients, fludarabine phosphate 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 phosphate 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/minute). 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/minute, the dose should be reduced in proportion to the reduced creatinine clearance and close haematological monitoring should be used to assess toxicity. Fludarabine phosphate treatment is contraindicated if creatinine clearance is < 30 mL/minute.

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 phosphate 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 have not been established. Therefore, treatment with fludarabine phosphate in children and adolescents is not recommended.

Effects on laboratory tests.

Fludarabine phosphate 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.

4.5 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 phosphate 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 (cytarabine). 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 child-bearing 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)
Category D - Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Fludarabine is contraindicated in pregnancy (see Section 4.3 Contraindications). Fludarabine JUNO should not be used during pregnancy. There are very limited data of Fludarabine JUNO 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 embryotoxic and/or teratogenic in animal studies. Preclinical data in rats demonstrated a transfer of fludarabine phosphate and/or metabolites through the foeto-placental 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 males must take contraceptive measures during and at least for six 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 breastfed infants from fludarabine phosphate, breastfeeding should be discontinued for the duration of fludarabine phosphate therapy.
Breastfeeding should not be initiated during fludrarabine phosphate 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 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, malaise, anorexia, nausea, peripheral neuropathy, visual disturbances, diarrhoea, stomatitis, skin rashes and mucositis. Serious opportunistic infections have occurred in CLL patients treated with fludarabine phosphate. 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 fludarabine phosphate. 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 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.

4.9 Overdose

Symptoms and signs.

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.

Treatment.

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 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 alpha, delta and epsilon, DNA primase and DNA ligase, thereby inhibiting DNA synthesis. Furthermore, partial inhibition of RNA polymerase II and consequent reduction in protein synthesis occurs.
While 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 to 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 to 5 of each 28 day treatment cycle for a mean of six cycles. Fewer patients in this trial had Rai stage III/IV disease (22%) than in the intravenous fludarabine trials (35 to 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

The pharmacokinetics of fludarabine (2F-ara-A) have 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 haemopoiesis 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 fludarabine phosphate 25 mg/m2 to CLL patients for 30 minutes, fludarabine (2F-ara-A) reached mean maximum concentrations in the plasma of 3.5 to 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 to 4.8 microM at the end of infusion. During a five 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 five minutes, an intermediate half-life of one to two hours and a terminal half-life of approximately 20 hours.
An interstudy comparison of fludarabine (2F-ara-A) pharmacokinetics resulted in a mean total plasma clearance (CL) of 79 mL/minute/m2 (2.2 mL/minute/kg) and a mean volume of distribution (Vss) of 83 L/m2 (2.4 L/kg). Data showed a high interindividual variability. After intravenous and peroral administration of fludarabine phosphate tablets in doses of 50 to 90 mg, the plasma concentration of fludarabine phosphate and the area under the plasma concentration time curve increased linearly with the dose. Additionally, after intravenous 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 to 30% of corresponding intravenous levels at the end of infusion and occurred one to two hours post dose. The mean systemic fludarabine (2F-ara-A) availability was in the range of 50 to 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 to 60% of the administered intravenous 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 to 70 (n = 9), < 30 (n = 2) mL/minute, were compared. After a single dose of fludarabine 25 mg by 30 minute intravenous infusion, AUC increased 16% in the second group and 116% in the third group relative to the first group. Multiple adjusted intravenous doses were then given over five 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 diphosphate 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 leukaemic lymphocytes of CLL patients were observed at a median of four hours and exhibited a considerable variation with a median peak concentration of approximately 20 microM. 2F-ara-ATP levels in leukaemic 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 leukaemic 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 fludarabine phosphate has carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

This product also contains mannitol and sodium hydroxide.

6.2 Incompatibilities

The formulation for intravenous use must not be mixed with other drugs.

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

Unopened product: Store below 25°C. This product is for single use in one patient only. Discard any residue.

6.5 Nature and Contents of Container

Sterile, Type I glass vial with a grey bromobutyl rubber stopper with a metallic aluminium cap with a polypropylene disk.

Pack size.

1 vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Fludarabine phosphate is a fluorinated nucleotide analogue of the antiviral agent vidarabine (9-beta-d-arabinofuranosyladenine) that is relatively resistant to deamination by adenosine deaminase. When reconstituted as instructed, the pH range of the final solution is 7.2 to 8.2 (target 7.7).
Fludarabine phosphate is a white or almost white, hygroscopic, crystalline powder. It is slightly soluble in water; very slightly soluble in dehydrated alcohol; freely soluble in dimethylformamide.
Chemical name: 9-β-D-arabinofuranosyl -2-fluoroadenine 5'-(dihydrogen phosphate). Molecular formula: C10H13FN5O7P. MW: 365.2.

Chemical structure.


CAS number.

75607-67-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only Medicine.

Summary Table of Changes