Consumer medicine information

FLUDARABINE EBEWE

Fludarabine phosphate

BRAND INFORMATION

Brand name

Fludarabine Ebewe

Active ingredient

Fludarabine phosphate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet provides a summary of some of the important things you need to know about this medicine. It does not contain all available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you receiving Fludarabine Ebewe against the benefits they expect it will have for you. Only your doctor is able to weigh up all the relevant facts and you should consult him/her about all aspects of this medication as it relates to you.

If you have any concerns about receiving Fludarabine Ebewe, ask your doctor.

Keep this leaflet. You may need to read it again.

It is important to remember that Fludarabine Ebewe is a PRESCRIPTION ONLY MEDICINE.

Fludarabine Ebewe will only be given to you by specially trained personnel in a hospital environment.

What Fludarabine Ebewe is used for

Fludarabine Ebewe is used to treat a form of leukaemia known as chronic lymphocytic leukaemia, or CLL. All cells in the body produce new cells like themselves by dividing. For this purpose, the cells genetic material (DNA) must be copied and reproduced. Fludarabine Ebewe works by hindering the production of new DNA. Therefore, when Fludarabine Ebewe is taken up by the cancer cells it stops the growth of new cancer cells. It has been discovered that Fludarabine Ebewe works especially well against some cancers of the white blood cells.

Fludarabine Ebewe may have been prescribed for another reason. Ask your doctor if you have any questions about why Fludarabine Ebewe has been prescribed for you.

Before you are given Fludarabine Ebewe

This medicine should not be given to you if:

  • You are pregnant or intend to become pregnant.
    This medicine is not recommended during pregnancy.
  • You are breast-feeding or plan to breast feed.
    This medicine is not recommended while you are breast-feeding.
  • Your kidney function is severely reduced
  • The number of red blood cells is reduced due to a breaking down of these cells (haemolytic anaemia)
  • You have an allergic or unusual reaction previously to fludarabine phosphate or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include rashes, itching and redness of the skin and swelling of the tongue or face.

The effects of Fludarabine Ebewe have not been studied in children.

If your liver does not work properly, you have a poor state of health or if you are over 75 years old, Fludarabine Ebewe will be given with caution.

If you are not sure whether any of these apply to you, check with your doctor or pharmacist.

Things to be careful of:

Be careful driving or operating machinery until you know how Fludarabine Ebewe affects you.

Fludarabine Ebewe may reduce your ability to drive or use machines, since tiredness, weakness and visual disturbances have been observed. Patients experiencing such adverse effects should avoid driving and using machines.

Before you are given Fludarabine Ebewe, tell your doctor if:

You have or have had any other medical conditions, especially the following:

  • Kidney problems
  • Anaemia
  • You are taking other medicines.

Fludarabine Ebewe should not be used together with the leukaemia drug pentostatin.

If it is found that your kidneys do not work properly you may be given this medicine at a reduced dose.

The effectiveness of Fludarabine Ebewe may be reduced by medications containing dipyridamole and similar substances.

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

Men, and women who may still be fertile, must use a reliable form of contraception during and for at least 6 months after stopping treatment.

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

Some medicines may interfere with Fludarabine Ebewe and some may cause unwanted side effects if taken while you are on Fludarabine Ebewe treatment.

This is especially true if you are on any other medicines with similar side effects as Fludarabine Ebewe. In some cases, two different medicines may be used together by your doctor even if an interaction might occur. In these cases, your doctor may change your dose

If you are in doubt, check with your doctor.

How Fludarabine Ebewe is given

How it is given

Fludarabine Ebewe must only be given by a doctor or nurse.

Fludarabine Ebewe is injected into a vein (often in the arm) once each day for 5 consecutive days. This 5 day course is then repeated once every 28 days.

How much is given

The dosage of Fludarabine Ebewe that is correct for you will be exactly worked out by your specialist.

Because of the complexity of CLL and the possible side effects of Fludarabine Ebewe, it should only be prescribed by specialist doctors with experience with similar medications.

If you have any concerns about the dosage you receive, ask your doctor.

In Case of Overdose

Your doctor will decide what dose of Fludarabine Ebewe you need, and this will be administered in the clinic or hospital under close supervision from nursing and medical staff. The dose is determined by your weight and height. The risk of overdose in these circumstances is low. In the event of overdose occurring, your doctor will stop the therapy and decide on the necessary treatment.

While you are being given Fludarabine Ebewe

Things you MUST do:

  • Be sure to keep all of your doctors appointments so that your progress can be checked.
  • If you become pregnant while under Fludarabine Ebewe treatment, tell your doctor immediately

Things you MUST NOT do:

  • Take any additional medicines without the advice of your doctor or pharmacist.

Side Effects

Tell your doctor as soon as possible if you do not feel well while you are being given Fludarabine Ebewe.

Any medicine may cause some unwanted side effects, including Fludarabine Ebewe. Sometimes they are serious, most of the time they are not. Side effects can sometimes be prevented or minimised by blood and urine tests as well as taking into account your overall physical condition.

Ask your doctor to answer any questions that you may have.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor immediately if you notice any of the following:

The following are uncommon or rare effects. You may need urgent medical attention.

  • If you experience any difficulty in breathing or have a cough tell your doctor immediately. An allergic reaction in the lungs, symptoms of which are difficulties in breathing and coughing, is a rare effect.
  • Unusual bruising
  • Excessive bleeding after injury
  • Signs of infection (e.g. fever, chills, feeling unwell, pain)
  • Fatigue, weakness,
  • Nausea, and vomiting
  • Difficulty moving, speaking or seeing
  • Agitation
  • Confusion
  • Pain in your side
  • Blood in your urine
  • Diarrhoea
  • Dark, tarry stools or stools containing blood
  • Severe blisters, or bleeding in the lips, eyes, nose, mouth or genitals.

When used in patients with acute leukemia at doses four times greater than the recommended dose for CLL, a third of patients experienced severe central nervous system effects including blindness, coma and death.

In rare cases heart failure, irregular heart beat and skin cancer have been reported in patients treated with Fludarabine Ebewe.

The following are the more common side effects of Fludarabine Ebewe and are usually mild.

Tell your doctor if you notice any of the following and they worry you.

  • Generally feeling unwell
  • Nausea and vomiting. This medicine can cause nausea and vomiting. If symptoms are severe or persistent you should contact your doctor or clinic.
  • Tiredness.
  • Loss of appetite.
  • Weakness
  • Numb or weak arms or legs
  • Swelling in your hands feet or ankles
  • Problems with your eyesight
  • Inflammation of the lining of the mouth
  • Skin rashes

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor. Some side effects may only be seen by your doctor.

Storage

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

Product Description

What it looks like

Fludarabine Ebewe is a clear, colourless to almost colourless solution, in a clear glass vial.

Fludarabine Ebewe can be identified by an Australian Register Number, which is found on the packaging:
AUST R 135540

Fludarabine Ebewe 50mg in 2mL glass vial (packs of 1 vial, 5 vials, and 10 vials).

Ingredients

Fludarabine Ebewe contains fludarabine phosphate 25mg/mL, dibasic sodium phosphate dihydrate, sodium hydroxide, in water for injections.

Manufacturer

Fludarabine Ebewe is made by:

EBEWE Pharma
Ges.m.b.H. Nfg. KG
A-4866 Unterach
Austria

Sponsor

Fludarabine Ebewe is distributed in Australia by:

Sandoz Pty Ltd
54 Waterloo Road
Macquarie Park NSW 2113
Australia
Telephone: 1800 726 369

This leaflet was prepared in November 2016

Published by MIMS April 2017

BRAND INFORMATION

Brand name

Fludarabine Ebewe

Active ingredient

Fludarabine phosphate

Schedule

S4

 

1 Name of Medicine

Fludarabine phosphate.

2 Qualitative and Quantitative Composition

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

3 Pharmaceutical Form

Fludarabine Ebewe 50 mg/2 mL injection.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Dosage.

Adults.

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

Toxicity.

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

Retreatment options after initial Fludarabine Ebewe treatment.

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

Method of administration.

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

Instructions for use.

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

Handling and disposal.

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

Dosage adjustment.

Renal impairment.

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

State of health impairment.

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

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Neurotoxicity.

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

Myelosuppression.

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

Disease progression.

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

Transfusion of blood products.

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

Skin cancer lesions.

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

Tumour lysis syndrome.

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

Autoimmune phenomena.

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

Impaired state of health.

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

Vaccination.

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

Use in hepatic impairment.

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

Use in renal impairment.

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

Use in the elderly.

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

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

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

Haematopoietic system.

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

Metabolic.

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

Nervous system.

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

Pulmonary system.

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

Gastrointestinal system.

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

Hepatobiliary disorders.

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

Cardiovascular.

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

Genitourinary system.

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

Skin.

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

Special senses.

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

Body as a whole.

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

Postmarketing experience.

Postmarketing experience with unknown frequency.

Nervous system disorders.

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

Vascular disorders.

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

Reporting suspected adverse effects.

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

4.9 Overdose

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Fludarabine phosphate is a fluorinated nucleotide analogue of the antiviral agent vidarabine, (9-β-D-arabinofuranosyladenine) that is relatively resistant to deamination by adenosine deaminase.
Pharmacotherapeutic group: Antineoplastic agents, purine analogues.
ATC code: 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 fludarabine phosphate in first line chronic lymphocytic leukaemia.
Intravenous fludarabine 25 mg/m2 on days 1-5 of a 28 day cycle significantly delayed disease progression compared with comparators in the first line treatment of B-cell CLL in three randomised controlled trials (Table 1, Table 2, Table 3). A difference in survival was not shown due to insufficient follow up and confounding as a result of cross-overs. There was a median 7 and maximum 21 treatment cycles.
Fludarabine tablets were assessed in an uncontrolled trial in 81 patients for first line treatment of B-cell CLL. The dose was 40 mg/m2 on days 1-5 of each 28 day treatment cycle for a mean of 6 cycles. Fewer patients in this trial had Rai stage III/IV disease (22%) than in the intravenous fludarabine trials (35-50%). The median time to disease progression had not been reached at the time of the analysis, but exceeded 38 months, which is comparable or better than the result in the intravenous trials. The NCI complete response rate was 12% and overall response rate 80%. In a subgroup analysis, patients with Rai stage III or IV disease had a response rate of 61%, which is comparable to that observed in this subgroup in the IV studies. There were no data on survival.

5.2 Pharmacokinetic Properties

Absorption.

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

Distribution.

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

Metabolism.

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

Excretion.

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

Impaired renal function.

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

Note.

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

Cellular pharmacokinetics of fludarabine triphosphate.

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

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

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

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

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

6.5 Nature and Contents of Container

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

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

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

CAS number.

75607-67-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes